selenocatalysis: the synthesis and application ......andrew brown, hannah byczkowski, nicholas...
TRANSCRIPT
Department of Chemistry Imperial College London South Kensington London SW7 2AZ June 2018
SELENOCATALYSIS: THE SYNTHESIS AND
APPLICATION OF CHIRAL ORGANIC
SELENIDES AND DISELENIDES
A Thesis Submitted by
ALEXANDER PHILIP NOEL BROWN
In partial fulfilment of the requirements for the degree of
Doctor of Philosophy
2
Declaration of Originality
I, Alexander Philip Noel Brown, certify that the research described in this manuscript was
carried out under the supervision of Dr. Christopher J. Cordier, Imperial College London,
and is my own unaided work unless otherwise stated and neither the whole nor any part has
been submitted before for a degree in any other institution.
Alexander Philip Noel Brown
6th June 2018, London
Copyright Declaration
The copyright of this thesis rests with the author and is made available under a Creative
Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to
copy, distribute or transmit the thesis on the condition that they attribute it, that they do not
use it for commercial purposes and that they do not alter, transform or build upon it. For any
reuse or redistribution, researchers must make clear to others the licence terms of this work.
3
Abstract
Organoselenium reagents have found varied applications throughout organic chemistry. Like
many transition metals selenium can occupy a variety of oxidation states, giving access to a
range of redox processes. It may also be bound covalently to organic frameworks that offer
the possibility of straightforward catalyst design and tuning for enantio- and
stereoselectivity. Hence selenium offers access to a unique niche of reactivity, however, the
use of organoselenium compounds as catalysts, or to perform enantioselective
transformations, is still an under-exploited area.
The work described herein presents investigations towards the syntheses of chiral organic
selenides and diselenides and their applications to enantioselective processes. Catalyst
design was centred around cyclic C2-symmetric organic frameworks such as binaphthalene I,
2,5-disubstituted tetrahydroselenophenes II, dihydroselenepines III and dihydroselenocines
IV.
The effectiveness of these reagents in a variety of catalytic processes was tested.
Transformations included oxidative processes such as allylic and propargylic C–H oxidation
to afford α,β-unsaturated alcohols; Lewis base catalysed halolactonisations; Corey-
Chaykovsky epoxidations; and conjugate reactions of alkenylselenonium(IV) species.
During the course of these investigations novel conditions for a palladium-catalysed cross-
coupling of aryl electrophiles and organic selenolates were developed enabling the facile
synthesis of asymmetric diaryl- and arylalkyl- selenides. The dealkylation of
arylalkylselenides was further investigated to enable an alternative route to diselenides.
SeSe
R
R
Se RRSeSe
I II III IV
4
Acknowledgements
I would first like to thank my supervisor and mentor, Dr. Chris Cordier for the amazing
opportunity to work in his group and on this project. He has been an endless source of
stimulating discussion and support, academically or otherwise.
Secondly, I would like to thank the members of the Cordier Group, past and present,
including, but not limited to, Dr. Li-Jie Cheng, Francis Adeleke, Kari Mosleh and Alex
Williams. Thank you all for making the lab a fun and motivational environment in which to
complete my research.
I am also grateful to the academic staff at Imperial who have helped me along the way: Alan
Spivey, Phil Parsons, Chris Braddock, Andrew White, Pete Haycock, Lisa Haigh, James
Bull and Rob Davies.
I’d like to give special mentions to my proof-readers: Josh “Riddle Master” Almond-
Thynne, Rob “Shots” Davidson and James “Filet-O-Fish” Rushworth for the constant
entertainment, lunches and hijinks over the years, making Imperial and London life even
more memorable. Thanks to the other members of the Chemistry Department that I have had
the pleasure of working with: Claire Weston, Christian Nielsen, Taniya Zaman, Dan Jones,
Lewis Allen, Tsz “Freeman” Ma, Sara Goldstein, Dan Elliot, Luiza Dos Reis Cruz, Hannah
Cook, Alex Lubin and Kate Montgomery.
Finally, I would like to thank my amazing family for their constant encouragement and
support throughout my PhD and everything prior that has enabled me to be where I am
today. Thank you Georges for being there every step of the way. Thanks also to my friends:
Andrew Brown, Hannah Byczkowski, Nicholas Cullinan, Jane Dando, Dan Frawley, Lucy
Holliday, Rebecca Huddart, Lydia Pithers, Jenna Saidi, Rosie Slowe, Tom Strong, Jess
Topley and all the others, whom I couldn’t fit in the last line of this page, for putting up with
my erratic schedule and incessant moaning.
5
“There are no facts, only interpretations.”
Friedrich Nietzsche
6
Abbreviations
[α]25D optical rotation
Å Angstrom (10-10 metres)
Ac acetyl
Acac acetylacetonate
Ac2O acetic anhydride
App. apparent
Aq. aqueous
Ar aryl
br broad
Bn benzyl
b.p. boiling point
Bu butyl
Bs benzenesulfonyl
BSA benzeneseleninic anhydride
Bz benzoyl
°C degrees Celsius
cat. catalytic
CBS Corey-Bakshi-Shibata
CI chemical ionisation
δ chemical shift
d doublet
dd doublet of doublet
7
ddd doublet of doublet of doublet
DIBALH diisopropylaluminium hydride
DIPEA N,N-diisopropylethylamine
DFT density functional theory
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
dr diastereomeric ratio
dt doublet of triplets
dq doublet of quartets
ee enantiomeric excess
EI electron ionisation
eq. equivalents
ES electrospray
Et ethyl
h hour
hept heptet
HMDS bis(trimethylsilyl)amine
HMPA hexamethylphosphoramide
Hz Hertz
i iso
IBX 2-iodoxybenzoic acid
IR infrared spectroscopy
J coupling constant
L litre
LDA lithium diisopropylamine
8
µ micro
m multiplet
m meta
M molar
mCPBA 3-chloroperbenzoic acid
Me methyl
min minute(s)
mL millilitre(s)
mmol millimole(s)
mol mole(s)
m.p. melting point
NBS N-bromosuccinimide
NCS N-chlorosuccinimide
NFSI N-fluorodibenzenesulfonimide
NIS N-iodosuccinimide
NMR nuclear magnetic radiation
Nu nucleophile
o ortho
p quintet
PG general protecting group
pH potential hydrogen
Ph phenyl
PMB para-methoxybenzyl
ppm parts per million
Pr propyl
9
p-TSA para-toluenesulfonic acid
py pyridine
q quadruplet
R general substituent
r.t. room temperature
RCM ring-closing metathesis
s singlet
t or tert tertiary
t triplet
TBAF tetrabutylammonium fluoride
TBHP tert-butyl hydroperoxide
TBS tert-butyldimethylsilyl
TEMPO 2,2,6,6-tetramethylpiperidine 1-oxyl
Tf trifluoromethanesulfonyl
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TMS trimethylsilyl
UV ultra-violet
10
Table of Contents
1.Generalintroduction....................................................................................................................17
1.1Enantioselectivecatalysis.......................................................................................................17
1.2Organoseleniumcatalysis.......................................................................................................18
1.2.1C–HOxidations.....................................................................................................................................................18
1.2.2Oxidativehalogenation......................................................................................................................................23
1.2.3Lewisbasicprocesses........................................................................................................................................28
1.2.4Enantioselectiveprocesses..............................................................................................................................30
1.3Privilegedchiralscaffolds......................................................................................................32
1.3.1Binaphthalene-basedstructures....................................................................................................................32
1.3.2Otherprivilegedstructures..............................................................................................................................34
1.4Initialaimsandobjectives......................................................................................................36
2.Synthesisofaryldiselenides.....................................................................................................39
2.1Overviewofmethods...............................................................................................................39
2.2Metallation..................................................................................................................................39
2.2.1Lithiation................................................................................................................................................................39
2.2.2Grignardreagents................................................................................................................................................41
2.3Diazotisation..............................................................................................................................41
2.4Nucleophilicsubstitution........................................................................................................42
2.5SelenoNewman-Kwartrearrangement..............................................................................43
2.6VANOL-derivedscaffold..........................................................................................................45
2.7Alternativechiraldiselenide.................................................................................................46
3.Allylicoxidationswithdiselenides..........................................................................................49
3.1Stoichiometricoxidation.........................................................................................................49
11
3.2Catalyticoxidation....................................................................................................................52
3.3OxidationwithVANOL-derivedscaffold.............................................................................53
3.4Allylicimidation........................................................................................................................56
3.5Summary.....................................................................................................................................57
4.Ar-XRSe-MCross-coupling.........................................................................................................59
4.1Introduction...............................................................................................................................59
4.1.1Aminationofarylhalides..................................................................................................................................60
4.1.2Carbon-sulfurbondformation........................................................................................................................62
4.2Mechanistichypothesis...........................................................................................................64
4.3Initialinvestigations................................................................................................................65
4.4Selanylstannanes......................................................................................................................67
4.4.1Synthesisofselanylstannanes.........................................................................................................................67
4.4.2Couplingofselenylstannaneswithpara-tolyl-Xspecies........................................................................67
4.4.3Optimisationofcross-couplingusingxantphos........................................................................................71
4.4.4Reactionofselenylstannaneswithmorehinderedortho-tolyl-Xspecies........................................72
4.4.5Expansionofthesubstratescope..................................................................................................................74
4.4.6Useofotherselanylstannanesincross-couplingreactions..................................................................76
4.4.7Removalofthealkylgroupfromarylalkylselenides..............................................................................77
4.4.8Binaphthylsubstratesincross-couplingswithselenylstannanes......................................................80
4.5Summary.....................................................................................................................................82
5.Cyclicalkylselenides....................................................................................................................84
5.1Overview......................................................................................................................................84
5.2Dinaphthodihydroselenepine..............................................................................................84
5.33,3’-Disubstituteddinaphthodihydroselenepines..........................................................85
5.3.1Overview................................................................................................................................................................85
12
5.3.2Synthesisof3,3’-diphenylanalogue..............................................................................................................86
5.3.33,5-xylylanalogue...............................................................................................................................................87
5.3.4Mesitylanalogue..................................................................................................................................................88
5.3.5Alternativesyntheticroutesto3,3’-binaphthyls......................................................................................89
5.4Spirobiindanes...........................................................................................................................91
5.4.1Overview................................................................................................................................................................91
5.4.2SynthesisofSPINOL...........................................................................................................................................92
5.4.3Spirobiindanodihydroselenocine(SPISe)...................................................................................................93
5.4.4TowardsSPINOL-deriveddiselenide............................................................................................................94
6.Oxidationswithcyclicalkylselenides...................................................................................97
6.1Allylicoxidation.........................................................................................................................97
6.2Propargylicoxidation..............................................................................................................98
6.2.1Initialinvestigationsintopropargylicoxidation......................................................................................98
6.2.2Substratescope....................................................................................................................................................99
6.3Mechanisticinsights...............................................................................................................100
6.4Summary...................................................................................................................................102
7.Tetrahydroselenophenes.........................................................................................................104
7.1Introduction.............................................................................................................................104
7.2CBSreduction...........................................................................................................................105
7.2.1Overview.............................................................................................................................................................105
7.2.22,5-diaryltetrahydroselenophenes............................................................................................................108
7.3Enzymaticresolution.............................................................................................................111
7.3.1Overview.............................................................................................................................................................111
7.3.22,5-Diphenyltetrahydroselenophene........................................................................................................112
7.3.32,5-dialkyltetrahydroselenophenes...........................................................................................................114
7.4Epoxidedimerisation.............................................................................................................115
13
7.4.1Overview.............................................................................................................................................................115
7.4.22,5-dialkyltetrahydroselenophenes..........................................................................................................117
7.5Summary...................................................................................................................................118
8.Lewisbasecatalysedcyclisations........................................................................................120
8.1Halocyclisation........................................................................................................................120
8.1.1Background........................................................................................................................................................120
8.1.2Configurationalstability................................................................................................................................121
8.1.3IntroductiontoLewisbasecatalysedhalocyclisations.......................................................................123
8.1.4RecentadvancesinLewisbasecatalysedhalocyclisations................................................................125
8.2Bromolactonisation................................................................................................................129
8.2.1Carboxylicacids................................................................................................................................................129
8.2.2Alternativecarboxylicacidderivatives....................................................................................................132
8.3Thiolactonisation....................................................................................................................134
8.4Summary...................................................................................................................................135
9.Selenoniumylides.......................................................................................................................137
9.1Corey-Chaykovskyreaction.................................................................................................137
9.1.1Overview.............................................................................................................................................................137
9.1.2ExamplesofenantioselectiveCorey-Chaykovskyepoxidations.......................................................139
9.2Investigationsintoseleniumcatalysedepoxidations...................................................142
9.2.1EpoxidationswithBnBrandBenzaldehyde............................................................................................142
9.2.2EpoxidationswithBnBrandFormaldehyde...........................................................................................146
9.2.3Epoxidationswithallylicbromides............................................................................................................147
9.2.4Epoxidationswithpropargylicbromides.................................................................................................147
9.3Summary...................................................................................................................................150
10.Selenium(IV)salts....................................................................................................................153
14
10.1Background............................................................................................................................153
10.1.1Alkenylsulfoniumsalts................................................................................................................................153
10.1.2Alkenylselenoniumsalts.............................................................................................................................156
10.2Preparationofalkenylselenoniumsalts.......................................................................158
10.2.1Iodine(III)reagents.......................................................................................................................................158
10.2.2Alkylation–elimination................................................................................................................................159
10.2.3Frompre-oxidisedseleniumspecies.......................................................................................................160
10.3Attemptedapplicationsofselenoniumsalts.................................................................161
10.4Conclusionsandfuturework............................................................................................162
11.ConclusionsandFutureWork.............................................................................................164
11.1Allylicandpropargylicoxidations...................................................................................164
11.1.1Diselenides.......................................................................................................................................................164
11.1.2Dialkylselenides............................................................................................................................................164
11.2Palladium-catalysedcouplingsofselenidesandarylelectrophiles......................165
11.3Synthesisofcyclicselenides..............................................................................................167
11.3.1DihydroselenepinesandDihydroselenocines......................................................................................167
11.3.2Tetrahydroselenophenes............................................................................................................................167
11.4Lewis-basecatalysedhalofunctionalisations...............................................................168
11.4.1Bromolactonisation.......................................................................................................................................168
11.5Reactionsofseleniumylides.............................................................................................169
11.5.1Corey-Chaykovskyreaction........................................................................................................................169
11.6Summaryandoutlook.........................................................................................................171
12.Experimental.............................................................................................................................173
4.1GeneralMethods.....................................................................................................................173
12.1Generalprocedures.............................................................................................................175
15
12.2ProceduresandCompoundCharacterisation..............................................................187
13.Appendices..................................................................................................................................258
13.1Alternativeligandstrailedinthecross-couplingofselenylstannesandaryl
electrophiles...................................................................................................................................258
13.2OthersubstratestrailedinCorey-Chaykovskyreactions.........................................260
13.2.1Bromidemodifications.................................................................................................................................260
13.2.2Aldehydemodifications...............................................................................................................................261
13.2.3Towardscyclopropanation.........................................................................................................................262
13.3Crystallographicinformation............................................................................................263
16
CHAPTER ONE
General introduction
17
1. General introduction
Since the early 1990s, enantioselective catalysis has become a rapidly expanding and highly
cited area in organic chemistry (Figure 1). It has long been known that chirality plays a
significant role in the biological activity of pharmaceutical and agrichemical compounds; in
2006 over 50% of drugs on the market were chiral with almost 90% of these produced as
single enantiomers.1 The demand for enantiopure, bioactive molecules fuels the need to
develop novel, efficient processes for enantioselective bond formation and publications on
the topic of enantioselective catalysis currently gain approximately 50,000 citations per year,
a number that is steadily rising (Figure 1).
Figure 1. Number of citations of enantioselective catalysis (Web of Science).
In 2001, the field gained recognition with the Nobel Prize for Chemistry with prizes awarded
to Knowles, Noyori and Sharpless for the development of several transition-metal catalysed
processes involving chiral ligands.2–4 Since then, the field has still been dominated by metal-
0
5000
10000
15000
20000
25000
30000
35000
40000
45000
50000
1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016
Num
ber o
f cita
tions
Year
Titles involving organocatalysisAll other enantioselective catalysis
18
catalysed processes.5 However, as a result of increased demand for optically active
molecules for industrial applications, methods involving the use of chiral organic catalysts
containing main group non-metallic elements, coined organocatalysis, have emerged and
now make up approximately one third of publications annually (Figure 1).6 Compared to
metal-catalysed processes, which often require inert conditions, have poor functional group
tolerance and can suffer from catalyst poisoning, organocatalytic methods benefit from
excellent chemoselectivity and mild reaction conditions as well as intuitive catalyst design
for tuning of reactivity and stereoselectivity.7,8
1.2.1 C–H Oxidations
Among the main group elements, selenium occupies a unique area of reactivity and
organoselenium compounds have found a wide range of applications throughout organic
synthesis.9 Organoselenium compounds are not only able to react as strong nucleophiles but
also have access to redox processes. Se(II) is readily oxidised to Se(IV) which shares
characteristics with other hypervalent ten-electron oxidants such as I(III) and Xe(II) species.
These group 7 and 8 species have proven synthetic utility in a variety of oxidative processes,
however, to achieve enantioselectivity they are often used as stoichiometric reagents with a
chiral co-catalyst rather than the reactive centre being incorporated covalently into a chiral
scaffold.10 Nevertheless, several chiral hypervalent iodine reagents have been developed and
employed in enantioselective transformations, however, catalyst turn-over often remains a
challenge.11,12 A recent example that has overcome this issue is asymmetric and syn-
diastereoselective fluorolactonisation to afford 4-fluoroisochromanones 2, catalysed by
chiral iodine reagent 3, reported by Jacobsen and co-workers (Scheme 1).13
19
Scheme 1. Jacobsen’s enantioselective fluorolactonisation.
One of the oldest and most practically applied reactions involving a selenium reagent is the
oxidation of unsaturated compounds with selenium dioxide (SeO2) which was first studied
by Riley in the α-oxidation of carbonyls and later expanded to allylic C–H oxidations.14,15
The accepted mechanism for the allylic oxidation of alkenes was proposed by Sharpless and
later corroborated in computational and kinetic studies by Singleton. (Scheme 2).16–18
Scheme 2. Mechanism for the allylic oxidation of alkenes, SeO2 represented as shown for clarity.
Ene reaction of alkene 4 with selenium dioxide affords the intermediate allylic seleninic acid
5, which undergoes a [2,3]-sigmatropic rearrangement to form 6. Solvolysis or pyrolysis
liberates the reduced Se(II) species (e.g. EtOSeOH in ethanol) and the free allylic alcohol 7.
It is necessary to note that SeO2 is polymeric and the representation in the mechanistic
hypothesis is purely for clarity. Additionally, the [2,3]-sigmatropic shift of 5 proceeds via a
5-membered envelope-like transition state and thus for acyclic substrates the (E)-alkene is
formed preferentially. Sharpless and co-workers subsequently developed a catalytic variant
of the reaction, employing sub-stoichiometric quantities of selenium dioxide and TBHP as a
co-oxidant (Scheme 3).19
Scheme 3. Catalytic allylic oxidation with SeO2.
OMe
O 3 (10 mol%)mCPBA (1.2 eq.)
pyr•9H2O (2.8 eq.)
CH2Cl2, –50 °C24 h
O
O
F1 2 86%
(95% ee)
IO OBnO2C CO2Bn
Bn Bn
3
R
H
SeO
OSe
HO
Oenereaction [2,3]
R
solvolysis R
4 5 6 7
R
OSeOH OH
TBHP (3.6 eq.)SeO2 (2 mol%)
salicylic acid (10 mol%)CH2Cl2
OH O
9 54% 10 5%8
20
Salicylic acid was incorporated as a co-catalyst in order to increase the rates of the ene
reaction and reoxidation of Se(II) species.20,21 An issue often encountered using this
methodology is the over-oxidation of the alcohol product 9 to the respective carbonyl
compound 10. This could be a result of a second allylic oxidation or alternatively direct
oxidation of the alcohol.22
Barton has demonstrated the substitution of SeO2 with arylseleninic acids and anhydrides in
this transformation (Scheme 4). 2-Pyridine seleninic anhydride (12) (PSA) was more
effective than benzeneseleninic anhydride (11) (BSA), probably due to greater eneophilicity
caused by stronger polarisation of the Se–O bond in the more electron deficient compound.23
Scheme 4. Arylseleninic anhydrides.
The mechanism for allylic oxidations by these organoselenium reagents was predicted to be
analogous to that with SeO2. Seleninic anhydrides 14 are prepared from the corresponding
diselenides 13 and an oxidant, for example ozone, and are used as stoichiometric reagents
for allylic oxidations. Alternatively, the diselenides can be used catalytically with a co-
oxidant that does not react directly with alkenes such as iodoxybenzene (PhIO2). However,
catalytic reactions often require the use of super-stoichiometric oxidants, high temperatures
and long reactions times, exacerbating the issue of over oxidation. Hence, recent advances in
this methodology have focused on generating α,β-unsaturated carbonyl products 16 (Scheme
5).24
N SeO
ONSe
OSe
O
OSeO
11 12
RSe
SeR [O]
a) Arylseleninic anhydrides:
b) Arylseleninic anhydride synthesis:
R = aryl[O] = TBHP, O3 etc.
13 14R
SeO
SeR
O O
21
Scheme 5. Allylic oxidation with perfluoroalkyl seleninic acid 17.
Oxidation of diselenides 13 with H2O2 affords perseleninic acids 18 that perform Baeyer–
Villiger oxidation of aldehydes and ketones (Scheme 6a).25 Several groups have developed
catalysts for this process, for example, Sheldon and co-workers employed the electron
deficient aryldiselenide 23 (Scheme 6b).26–28 The same group also used this catalyst in
epoxidations of alkenes (Scheme 6c).29
Scheme 6. Oxidations with perseleninic acids.
Similarly to allylic oxidations using Se(IV) reagents, Sharpless and co-workers have also
demonstrated an allylic amidation with selenodiimide 27 (Scheme 7).30 The selenium
reagent 27 was generated from elemental selenium and chloramine-T (26) and used
stoichiometrically during the amidations of 28.
17 (0.1 equiv.)PhIO2 (3 equiv.)PhCF3, reflux
O
16 64%F17C8
SeOH
O
15 17
RSe
O
OH2O2 R
OR'
OH R
O
O HO
OR'
R'
20a (R ≠ H) 20b (R = H)13 18
a) Oxidation of carbonyls with perseleninic acids:
b) Catalytic Baeyer-Villiger oxidation with perseleninic acids:
c) Catalytic epoxidation of olefins with perseleninic acids:
O
O
O
22 95%21
F3C
CF3
Se2
23
H2O2 (2 eq.)23 (1 mol%)
CF3CH2OH
25 99%24
H2O2 (2 eq.)23 (0.25 mol%)
NaOAc (0.2 mol%)CF3CH2OH
O
or1/2 (RSe)2
(19)
22
Scheme 7. Allylic amidation with a selenium reagent 27.
Since the original publication this methodology has not been developed further and, to our
knowledge, a comparable selenium-catalysed process to allylic N-tosylsulfonamides has not
been reported. However, a similar sulfur-based reagent 31 has been used in an
enantioselective allylic amidation with catalytic palladium and a chiral ligand in a two-step
procedure (Scheme 8).31 The allyl sulfonium intermediate 32 was isolated and palladium was
used to catalyse the [2,3]-sigmatropic shift. Therefore it is unlikely such a process could be
adapted for selenium as the related Se-intermediates undergo spontaneous rearrangement.
Scheme 8. Enantioselective allylic amidation with a sulfodiimide 31.
Finally, Breder has recently developed a selenium catalysed method for the synthesis of
allylic sulfonimides which will be discussed in more detail later (see Section 3.4), however,
an electron-withdrawing group was required and allylic products were formed with
transposition of the double bond.32
NNa
TsClSe +
CH2Cl2, 24 hNTs
SeNTs
NHTs
29 74%
a) Formation of selenodiimide 27:
2726
27CH2Cl2
b) Allylic amidation with 27:
28
BsN=S=NBs (31) SBsN NHBs
30 32
Pd(TFA)2 (10 mol%)
O
N N
O
PhPh33 (12 mol%)
34 87%(94% ee)
NR2
23
1.2.2 Oxidative halogenation
Sharpless and co-workers first reported the organoselenium-catalysed oxidative halogenation
of olefins to form allylic chlorides in 1979 (Scheme 9).33 The reaction was catalysed by
phenylselanyl chloride (39) (PhSeCl) which could be prepared and used as an isolated
reagent or generated in situ from diphenyldiselenide (36) and NCS.
Scheme 9. Selenium-catalysed synthesis of allylic chlorides.
The method was applicable to a variety of non-activated olefins, however, Sharpless
encountered side reactions resulting in alkenyl chlorides and anti-dichlorination products. To
overcome this, Tunge and co-workers investigated the same process on substrates 38 that are
electronically biased to undergo transposition of the double bond during the chlorination
process (Scheme 10).34 Radical inhibitors did not affect the reaction and so the mechanistic
hypothesis proposed PhSeCl 39 as the active catalyst that adds across the double bond of the
alkene 38 (Scheme 10b). If regioisomers are formed at this stage, Tunge proposed that
interconversion between the two isomers would outpace elimination from ß-chloride
intermediate 42. Elimination from γ-chloride intermediate 41 affords the allylic chloride
product 40 and succinimide (omitted), regenerating the catalyst.
35
NCS (1.1 mmol)(PhSe)2 36 (3 mol%)pyridine (10 mol%)
CH2Cl2Cl
37 87%
24
Scheme 10. Selenium-catalysed chlorination of electronically-biased alkenes.
More recently, Zhao has developed a fluorination of similarly electronically-biased
substrates 44 catalysed by dibenzyldiselenide 45 (Scheme 11).35 The external oxidant and
source of fluoride was N-fluoro-2,4,6-trimethylpyridinium triflate (46) (TMFP-OTf). The
role of TEMPO (47) was unclear but preliminary studies have suggested that it inhibits
unproductive decomposition of the diselenide 45 precatalyst.
Scheme 11. Catalytic fluorination of alkenes to form allylic fluorides
Tunge and co-workers have also investigated the α-halogenation of carbonyls (Scheme
12).36 For example, cyclohexanone 49 was brominated or chlorinated using catalytic PhSeBr
and PhSeCl respectively (Scheme 12a).
R EWG
NCS (1.1 mmol)PhSeCl 39 (10 mol%)
CH3CN
R EWG
Cl38 40
a) Selenium-catalysed chlorination of alkenes:
b) Proposed mechanism:
PhSeCl
R EWG
Cl
SePh
39
41R EWG
Cl
Se
43
PhClNO O
R EWG
38
H
R EWG
Cl40
NCS
R EWG
SePh
Cl
42
R
R'
EWG
(BnSe)2 45 (10 mol%)TMFP-OTf 46 (2 eq.)TEMPO 47 (0.5 eq.)
(CH2Cl)2, r.t.
R'
R EWG
F
NFTfO
46
NO
47R = alkyl, arylR' = H, MeEWG = CO2R, C(O)NR2, CN, SO2R, PO(OEt)2
44 48
25
Scheme 12. Selenium-catalysed α-halogenation.
The mechanistic hypothesis proposed by the group began with the generation of
dichloroselenium(IV) species 51 (Scheme 12b). Deprotonation of substrate 49 followed by
electrophilic halogenation of enolate 53 affords the desired product 50-Cl, regenerating
PhSeCl in the process 39. In the majority of cases, only monochlorinated products were
obtained. In support of an electrophilic halogenation pathway as opposed to electrophilic
selenation, α-selenylated compounds 54 and 56 were prepared and found not to react to form
NXS (1.1 mmol)PhSeX (5 mol%)
O
49
O
5086% (X = Br)61% (X = Cl)
X
MeCN
a) Selenium-catalysed α-halogenation:
b) Proposed mechanism:
PhSeCl39
NCS
Se ClClNO O
Ph
OSe
ClPh
Cl
53 51
O
50-Cl
Cl
HN
O
O52
O
49
c) Selenated compounds synthesised in mechanistic investigations:
O O
OEtSePh
O O
OEtSeCl2Ph
54
56
NCS
slow
slow
O O
OEtCl
55
55
O O
OEtCl
26
chloride 55 over a timescale competitive with that of the catalysed process (Scheme 12c).
The Se(IV) intermediate 51, formed by the reaction of PhSeCl 39 with NCS, was implicated
in this case as the electrophilic chlorination agent whereas for the previous allylic
chlorination (Scheme 10), this species was identified as an off-cycle resting-state.
More recently, Denmark and co-workers reported the first syn-selective dichlorination of
alkenes with a main-group catalyst (Scheme 13).37
Scheme 13. Selenium-catalysed syn-dichlorination of alkenes.
The mechanistic hypothesis begins with oxidation of the diselenide precatalyst 36 by
fluoropyridinium oxidant 59 with the fluoride ions presumably captured by Me3SiCl
(Scheme 13b). The resulting neutral Se(IV) species 62, which was indicated as the active
OBn OBn
Cl
Cl
(PhSe)2 36 (5 mol%)BnEt3NCl 58 (3 eq.)
[PyF]+[BF4]– 59 (1.3 eq.)
Me3SiCl (2 eq.)lutidine N-oxide 60 (1 eq.)
MeCN, r.t. 61 71%(99:1 dr)
57
a) Selenium-catalysed chlorination of alkenes:
b) Proposed mechanism: 1/2 (PhSe)2 363 [PyF]+[BF4]– 59
3 Me3SiCl
3 Py + 3 Me3SiF
[PhSeCl2]+
PhSeCl3 – Cl
RR
Se
RR
Cl ClPh
RR
Se
ClCl
Cl PhCl
Cl
PhSeCl + Cl
Py + Me3SiF
[PyF]+[BF4]– + Me3SiCl
RR
Cl
Cl
62
63
65
64
66
67
39
59
27
catalyst by computation studies, then undergoes addition to the alkene 64, possibly through
initial loss of chloride to the cationic [PhSeCl2]+ 63.38 The three-membered seleniranium
species 65 is then opened through nucleophilic attack by a chloride anion to afford the anti-
1,2-chloro(dichlorophenyl)selenium species 66. Invertive Sɴ2 displacement of the selenium
leaving group by another chloride anion furnishes the syn-dichloride product 67. The leaving
group collapses in the process to PhSeCl 39 and a chloride anion. Finally, 39 is re-oxidised
to 62 by 59 and Me3SiCl. Without (PhSe)2 (36) only slow background anti-dichlorination
was observed. As of yet the role of lutidine N-oxide (60) has not been identified and it is not
included in the catalytic cycle. However, omission of the oxidant 59 from the reaction
mixture gave no reaction, indicating that the N-oxide 60 is not involved in the oxidation of
36 to 62. In fact, the reaction will proceed without 60 with no detriment to the
diastereoselectivity but a reduction in rate. Me3SiCl was found to be essential to the reaction
and is assumed to act as a fluoride trap, preventing degradation of the catalyst by fluoride
ions. The silyl chloride’s potential to act as the lone source of chloride was not tested in any
control experiments.
Denmark’s process was broadly applicable to a range of cyclic and acyclic 1,2-dialkyl
olefins. 1,1-disubstituted were unsuitable substrates and trisubstituted alkenes did not yield
any syn-dichlorination products. Secondary allylic alcohols and their derivatives were also
problematic often resulting in complicated mixtures of products or exclusively anti-
dichlorination. Aryl-substituted alkenes gave mixtures of syn- and anti-products and
substrates with pendant nucleophiles also gave complex mixtures. Anti-dichlorination
predominated for 8-membered rings, electron-poor alkenes and compounds with multiple
substituents at the allylic position.
28
1.2.3 Lewis basic processes
As well as oxidative processes, the availability of Se(II) lone pairs in organoselenium
compounds allow these species to act as nucleophilic Lewis basic catalysts.39 An example of
this reactivity was demonstrated by Yeung and co-workers in the chloroamidation of olefins
catalysed by diphenylselenide (68) (Ph2Se) (Scheme 14).40 The procedure was exemplified
on a range of cyclohexenes and styrenes.
Scheme 14. Selenium-catalysed chloroamidation of olefins.
The proposed mechanism proceeds with activation of the chlorine atom of NCS by Ph2Se 68
to form adduct 70 that adds to the alkene 71 to form a chloronium ion 72, stabilised by the
selenide (Scheme 15). Acetonitrile attacks 72, opening the ring to afford anti-species 73
which is subsequently hydrolysed by water followed by tautomerisation to the product 74.
Despite the high concentration of water, no chlorohydrin products were observed. It was also
possible to replace acetonitrile with benzonitrile or propionitrile to afford benzoyl and
propionyl amides respectively.
Scheme 15. Mechanistic hypothesis for selenium-catalysed chloroamidation.
NCS (2 eq.)Ph2Se 68 (20 mol%)
MeCN/H2O (3:2)
Cl
NHAc
24 69 65%
Ph2Se
Ph2Se Cl N
O
O
68
70
R
R
R
R
ClH
SePh2
72
MeCNR
R
Cl
NCMe
73
H2O
R
R
Cl
HN O
74
NCS
71
29
Another application of a diarylselenide catalyst 75 can be found in Zhao’s
trifluoromethylthiolyation (Scheme 16).41 This procedure exploits both the Lewis basic and
redox activities of organoselenium reagents and employs N-CF3S-saccharin 76 as the source
of the trifluoromethylthio group.
Scheme 16. Hydroxytrifluoromethylthiolation of alkenes.
The proposed mechanism invokes a dual catalytic cycle (Scheme 16b). MeNO2 and an
oxygen atmosphere were found to be essential to the reaction and studies of solutions of
selenide 75 in various solvents under oxygen indicated that these conditions were unique in
producing traces of selenoxide 78. Therefore, it was proposed that selenoxide 78 could
catalyse the formation of very low concentrations of triflic acid (TfOH) in the reaction
mixture. The SCF3-source 76 is then activated by TfOH, enabling formation of complex 79.
Addition of this species to starting material 80 generates thiiranium ion 81 that is attacked by
water to afford product 82 and TfOH. Several control experiments provided support for this
mechanism. For example, under N2 low yields were achieved unless TfOH (1 mol%) was
Ar2Se75
Ar = 4-MeOC6H4
Se SCF3
Ar
Ar79
Se
SCF3
ArAr
81
RR
ArSe
Ar
O
78
76 + H2O + O2 TfOH76
NS
O
OO
SCF3
R R80
O2
slow
76
OH2HO
RRSCF3
82
(4-MeOC6H4)2Se 75 (10 mol%)N-CF3S-saccharin 76 (1.3 eq.)
H2O (5 eq.), O2 (balloon)MeNO2
OHF3CS
8 77 88%
a) Selenide catalysed hydroxytrifluoromethylthiolation:
b) Proposed mechanism:
TfO
TfO
30
added, in which case yields were only marginally lower than reactions under O2. However,
addition of too much TfOH was detrimental to yield, highlighting the requirement for a very
low loading of acid. Furthermore, if selenoxide 78 was used under N2 as a precatalyst,
product was still formed due to traces of TfOH formed in the generation of active catalyst
75.
1.2.4 Enantioselective processes
Despite the broad reactivity profile of organoselenium reagents, enantioselective
applications of these species are rare. A recent example is Zhao and co-workers’
desymmetrisation to form trifluoromethylthiolated tetrahydronaphthalenes using chiral
selenide 84 (Scheme 17).42
Scheme 17. Enantioselective synthesis of trifluoromethylthiolated tetrahydronaphthalenes.
The procedure was applicable to a variety of alkyl and aryl substituted alkenes as well as
alkynes, which gave 1,2-dihydronaphthalenes. DFT calculations elucidated a potential key
transition state 87 demonstrating the bifunctional nature of the catalyst (Figure 2).
Figure 2. Key transition state in the synthesis of trifluoromethylthiolated tetrahydronaphthalenes.
PhPh
NHBz
Ph
83
selenide 84 (20 mol%)Bs2NSCF3 85 (1.5 eq.)
TMSOTf (1 eq.)CH2Cl2/(CH2Cl)2 (1:1)
–78 °C
Ph NHBz
SCF3Ph
86 99%(50:1 dr, 99% ee)
NHTf
Se OMe
84
NH Ph
SCF3
PhO
OS
OOCF3
H
NSe
O Me
SF3C
OO
87
31
Another recent example of an enantioselective process catalysed by an organoselenium
compound is the oxidative cyclization of ß,γ-unsaturated carboxylic acids 88 to 2-furanones
90 (Scheme 18).43
Scheme 18. Selenium-catalysed enantioselective oxidative cyclisation (anions omitted for clarity).
The mechanism proposed for this transformation involves oxidation of the selenium atom by
N-fluorodibenzenesulfonimide (NFSI) followed by loss of the para-methoxybenzyl (PMB)
protecting group. The resulting electrophilic species 91 undergoes addition to alkene
substrate 88 to afford seleniranium ion 92 that cyclises to selenyldihydrofuranone 93. This
species undergoes base-promoted E1cB elimination to release furan-2-one product 90 and
regenerate catalyst 91.
R COOH
selenide 89 (10 mol%)NFSI (1.1 eq.)
CaCO3 (3 eq.)toluene
OO
R
90(up to 97% ee)
88
OTBSPMBSeMeO
89R = alkyl, aryl
a) Selenide catalysed enantioselective oxidative cyclisation:
b) Proposed mechanism:1/2 R2Se 89
NFSI
OTBSSeMeO
91
R
88
Se
R COOH
Ar
OOOO
SeArH
R93 92
OO
R
90
E1cB
32
1.3.1 Binaphthalene-based structures
Over the course of the development of the field of enantioselective catalysis, several key
structures have been identified as having broad applicability across a number of
enantioselective processes, whether that be as ligands to metallic reactive centres or as
discrete organocatalysts.44 Of these, 1,1’-binaphthalene based catalysts and ligands are
probably the most well-known and widespread in use.
2,2'-Dihydroxy-1,1’-binaphthalene (94) (BINOL) and its derivatives have had great success
and demonstrated enantioselectivity in a wide range of processes (Figure 3). The molecule is
C2-symmetric with axial chirality derived from hindered rotation about the biaryl bond,
leading to atropisomerism. Under neutral conditions BINOL (94) is configurationally stable,
however it is prone to racemisation under both acidic and basic conditions.45 Related to
BINOL (94) is BINAP (95), which is an extremely common bidentate ligand in organic
synthesis with a wide variety of available analogues.46
Figure 3. BINOL 94 and selected derivatives.
BINOL (94) is commonly used as a ligand for metal-catalysed processes, for example,
titanium complexes have mediated highly enantioselective carbonyl-ene and aldol reactions
(Scheme 19).47,48
OHOH
94 96 97
OPO
NR2OPO
OHO
PPh3PPh3
95
33
Scheme 19. Reactions of BINOL-titanium complexes.
Phosphoramidite BINOL derivatives 96, are a class of monodentate ligands that have been
used in a wide variety of transition-metal catalysed reactions such as Cu-catalysed Michael
addition and Pd-catalysed allylation (Scheme 20).49,50 This class of catalyst has also been
used as an organocatalyst in asymmetric reductions with borane.51
Scheme 20. Applications of BINOL-derived phosphoramidites 96 to enantioselective catalysis.
Another class of BINOL-derived catalysts are Brønsted acids such as phosphoric acid 97.
These species are used as Brønsted acid catalysts throughout chemistry and a huge array of
Ph H
O
CO2Me Ph CO2Me
OH
99 98%(95% ee)
8 98
(R)-BINOL 94 (1 mol%)(i-PrO)2TiBr2 (1 mol%)
4 Å mol. sieveCH2Cl2, –30 °C
a) Enantioselective carbonyl-ene reaction:
b) Enantioselective vinylogous aldol reaction:
OTMS
OMeOMe
H
O
R101100
(R)-BINOL 94 (10 mol%)Ti(i-PrO)4 (10 mol%)
H2O (10 mol%)LiCl (10 mol%)
THF
OMe
OOMe
102(98–99% ee)
R
OH
Ph
Et
Ph
O
104 88%(90% ee)
96-(i-Pr) (3 mol%)Cu(OTf)2 (3 mol%)
Et2Zntoluene, –15 °C
a) Enantioselective Michael addition:
b) Palladium-catalysed allylation:96-Et (4 mol%)
[Pd(π-allyl)Cl]2 (2 mol%)
bis(trimethylsilyl)acetamideNaOAc, THF 107 99%
(90% ee)
Ph Ph
O
103
Ph Ph
OAc
106
MeO2C CO2Me
105
Ph Ph
MeO2C CO2Me
c) Chiral borane complex:
108
OP
O
NEt2
BH3
34
analogues are available with adjustable sterics through various substitutions on the
binaphthalene backbone as well as tuneable pKa through the use of different acidic groups.52
1.3.2 Other privileged structures
Following the development of BINOL, Wulff and co-workers designed and synthesised
vaulted biaryl species VANOL 109 and VAPOL 110 (Figure 4).53 Similarly to BINOL, these
structures both exhibit atropisomerism and were developed with the aim of increasing the
steric bulk at the active site of the ligand.
Figure 4. Structures of VANOL 109 and VAPOL 110 ligands.
Another chiral scaffold that has found many applications in organic synthesis is
spirobiindane, the simplest ligand of this type being SPINOL (111) (Figure 5). Like the
biaryl structures above, SPINOL (111) is also a C2-symmetric molecule possessing axial
chirality. However, unlike BINOL, the structure is extremely rigid, possessing a quaternary
centre and thus making racemisation an impossibility.
Figure 5. SPINOL 111 and selected derivatives.
A large number of derivatives of the SPINOL scaffold have been synthesised. The reactive
function groups in the 7,7’- positions are readily interchanged and substitution on the
PhOHOH
Ph
VANOL109
PhOHOH
Ph
VAPOL110
OH
OH
SPINOL111
PPh3
PPh3
SDP112
113
OI
IOAc
OAc
35
backbone has enabled tuning of the steric environment (for example, arylation at the 6,6’-
positions).44,54 Bis(phosphine) SDP (112) has been used as a chiral ligand in many
applications. Furthermore it regularly outclasses BINAP (95) in terms of enantioselectivity,
for example, in the asymmetric hydrogenation of α,ß-unsaturated carboxylic acids (Scheme
21).55
Scheme 21. Asymmetric hydrogenation with chiral bis(phosphine)/Ru complexes.
Finally, several spirobiindane based organocatalysts have also been developed, notably, 10-
electron I(III) oxidant (113) which was used in an enantioselective dearomatisation (Scheme
22).56 As above, the spiro catalyst performed the best out of those trialled, with the BINOL-
derived species achieving only 5% ee.
Scheme 22. Application of a spirobiindane-derived organocatalyst 113.
CO2HH2 (6 bar)
[Ru(OAc)2L] (0.5 mol%)
MeOH, r.t.CO2H
114 115with (S)-BINAP 95: 91% eewith (R)-SDP 112: 95% ee
OHCO2H (R)-113 (15 mol%)
mCPBA, AcOHCH2Cl2, 0 °C
OOH
O
116 117 68%(65% ee)
36
The initial aims of this project were the synthesis of chiral, cyclic selenium-containing
derivatives of the privileged chiral structures mentioned above (Figure 6). These scaffolds
were chosen as their syntheses and derivatisations are well documented. Focus would be
divided between diselenide (for example, 118) and selenide (for example, 120) catalysts.
Figure 6. Initial selenium-containing catalyst design.
Following the synthesis and resolution of these catalysts their applications to a variety of
selenium-catalysed processes would be investigated. For diselenides (i.e. 118 and 119),
investigations would begin with C–H oxidations adjacent to π-systems (Scheme 23a).
Scheme 23. Proposed enantioselective oxidation of α,ß-unsaturated C–H bonds.
SeSe
118 119 120
Se
R
R
R
R
Se
121
SeSe
R
R
R
L* Se O
pendant basic groupe.g. OSe(O)R, SeR, OR
chiralscaffold
R'
OH
R''133
R' R''
OSeR
LH
*
132R' R''
RL O
SeH
*
131
R' R''
RL
* OHSe
130
R'
H
R''129R
L* Se O
128Se
L
R*
134
[O]
enereaction
[2,3]
R'
HH
R'
Hor or
[O]Se-cat
122 123 124
R'
OHOH
R'
OHor or
125 126 127
b) Mechanistic hypothesis for allylic oxidation:
a) Enantioselective oxidations of α,ß-unsaturated C–H bonds:
37
The mechanism for this transformation is exemplified in our mechanistic hypothesis for
allylic oxidations of linear alkenes 129 which is based on the conclusions previously drawn
by Barton and Sharpless (Scheme 23b). A major challenge to this methodology is inhibiting
over-oxidation of the products to α,ß-unsaturated carbonyls (see Section 1.2.1). We also
recognise that there are mechanistic nuances between different substrate-classes that have an
influence on catalyst efficacy. For example, the stereochemistry of cyclic and propargylic
reactants can only be defined in the initial ene-reaction as there is only one option for the
[2,3]-sigmatropic shift whereas free rotation of aliphatic C–C bonds gives rise to a choice of
transition states.57
For selenide catalysts (i.e. 120 and 121), we trialled applications in the areas of Lewis basic
and nucleophilic catalysis. Following development of the first generation of the catalyst, we
focused on derivatisation of the scaffolds, for example, by modification of the R-groups in
the 3,3’-positions on the binaphthyl backbone to tune sterics and reactivity.
38
CHAPTER TWO
Synthesis of aryl diselenides
39
2. Synthesis of aryl diselenides
By exploiting privileged biaryl systems for the catalyst backbone, syntheses of the
precursors to the target catalysts are already well documented in the literature. Therefore, the
major challenge is the incorporation of selenium into the chiral frameworks. Initial efforts
were focussed on the synthesis of binaphthalene 135 due to the BINOL scaffold’s wide use
in catalysis and the commercial availability.44 Various methods for the synthesis of 135 are
exemplified below, focussing on the Ar-Se bond formation (Scheme 24). Of particular
interest were the routes from BINAM (137) and BINOL (94) as both of these starting
materials are commercially available as single enantiomers.
Scheme 24. Proposed routes to binaphthyl diselenide 135.
2.2.1 Lithiation
Initial studies involved the synthesis of a model catalyst 140, based upon a biphenyl scaffold
(Scheme 25). The compound was synthesised directly from biphenyl (138) via directed
ortho-metalation with n-BuLi and TMEDA, followed by a quench with elemental
SeSe
XX
XX
HOHO
NH2NH2
SɴAr(e.g. [Se2]2-)
metalation;Se(0) quench
diazotisation;RSe- quench
selenoNewman-Kwartrearrangement
X = Br, I
commercially availablestarting materials
136
135
136
94137
X = Br, I
40
selenium.58,59 The diselenide 140 was isolated following oxidative Se—Se bond formation in
air and the structure was confirmed by X-ray crystallography (Figure 7a, below).
Scheme 25. Lithiation-selenation of biphenyl 138.
When applied to the 1,1’-binaphthalene scaffold none of the desired product was observed.
However, a similar lithiation strategy via lithium-halogen exchange from 141 was employed
(Scheme 26).
Scheme 26. Lithium halogen exchange of binaphthyl-2,2’-dibromide 141.
In contrast to biphenyl 138, the only product isolated was dinaphthoselenophene 142. The
structure of compound 142 was confirmed by X-ray crystallography (Figure 7b).60
Figure 7. Crystal structures of a) biphenyl diselenide 140; b) dinaphthoselenophene 142 (50% probability
ellipsoids).
n-BuLi (2.1 eq.)TMEDA (2.1 eq.) Li
LiSeSe
Se (2 eq.)hexane, 60 °C 0 to 25 °C;
then air
140 (28%)138 139
n-BuLi (2.1 eq.)TMEDA (2.1 eq.)
Se (2 eq.)THF, 0 - 25 °C
hexane, 60 °C;BrBr
135 (0%)
SeSe
142 (18%)
Se
141
a) b)
140 142
41
2.2.2 Grignard reagents
A similar route to that discussed in the previous section is via a Grignard reagent, generated
in situ from magnesium metal insertion into Ar—X bonds.61 A Grignard can be quenched in
the same way as a lithiated intermediate with elemental selenium. The electron-rich
diselenide 144 was synthesised using this route (Scheme 27), however, as with the dilithio
species, when applied to binaphthyl dibromide 141, the selenophene 142 was the only
product observed.
Scheme 27. Grignard formation with selenium quench.
The mechanism for selenophene 142 formation is unclear but is probably facilitated by the
energetic stabilisation of aromatic character when forming the highly conjugated
selenophene as it was not observed with acyclic diselenides such as 144. It is possible that
the diselenide 135 is formed first followed by loss of selenium and concomitant ring
contraction. Alternatively the diselenide 135 could be oxidised by air under the mildly acidic
aqueous work up followed by loss of SeO2.62
Electrophilic diazonium salts, derived from aryl amines can be quenched with a selenium
nucleophile such as selenocyanate (-SeCN) to form Ar—Se bonds. Selenocyanates can be
hydrolysed or reduced to selenols or selenolates that readily oxidise to diselenides in air.63,64
This process was applied to biphenyl diamine 145, however, the bis(selenocyanate) 146 was
obtained in only 20% yield and a significant amount of selenophene 147 was isolated
(Scheme 28). Attempts to hydrolyse the selenocyanate 146 resulted in complex mixtures of
products, with further selenophene 147 formation observed. When applied to binaphthyl
diamine 137, only the selenophene 142 was isolated with no selenocyanate observed. Due to
2MeO
Br
MeO
SeMg; then SeTHF, reflux
143 144
42
the propensity of the binaphthyl scaffold to form the selenophene 142 following lithiation
this route was not pursued further (Scheme 26).65
Scheme 28. Arylselenocyanate formation via diazotisation
Similarly to the displacement of a diazo group, various selenium nucleophiles are known to
perform SɴAr with activated aryl halides.66–68 Sodium diselenide (Na2Se2) can be generated
by several methods, including the reduction of elemental selenium with NaBH4 in protic
solvent (Equation 1) or reduction by hydrazine in alkaline solutions (Equation 2).69
Sodium diselenide was generated from hydrazine (Equation 2) and reacted without being
isolated with electron-poor bis(3,5-trifluoromethyl)phenyl bromide (148) to afford the
corresponding diselenide 23 in 72% yield (Scheme 29).
Scheme 29. SɴAr of bromooarenes with Na2Se2.
While this method is suitable for electron-deficient aryl halides, with bromobenzene 149
only traces of diphenyldiselenide 36 were observed under these conditions despite some
NH2NH2
HCl, NaNO2H2O, 0 °C;
then KSeCNpH 6
SeCNSeCN
Se
146 (20%) 147 (22%)145
4Se 4NaOH+ 2Na2Se2 4H2ON2H4 N2+ + +DMFr.t. (2)
3Se 6EtOH+2NaBH4 2B(OEt)3+ + + (1)Na2Se2 H2Se 6H2+
F3C
CF3
Br
Na2Se2 (0.5 eq.)DMF, 120 °C
F3C
CF3
Se2
23 (72%)
16 h
148
Na2Se2 (0.5 eq.)DMF, 120 °C
Se2
36 (trace)
16 h
149
Br
43
examples of less electron-deficient aryl halides undergoing this type of SɴAr reaction with
this nucleophile.70
The Newman-Kwart rearrangement, first reported in 1966, is a method for converting
phenols into thiophenols via the thermal rearrangement of O- to S-aryl thiocarbamates.71,72
More recently, Pittelkow and co-workers have adapted the methodology for the
rearrangement of O- to Se-aryl selenocarbamates (Scheme 30).73 The group were then able
to cleave the Se-aryl selenocarbamates 152 using aqueous KOH to afford diselenides after
aerobic dimerization.
Scheme 30. Seleno Newman-Kwart rearrangement.
The experimentally-supported mechanism proceeds via an intramolecular nucleophilic
substitution and thus involves build-up of electron density on the aromatic ring (Scheme
31).74 This means that the reaction proceeds at lower temperatures for electron-deficient
arenes, for example when the R-group is an ester or nitro group. In support of this, for arenes
bearing electron-donating groups for example, para-methoxy, no reaction was noted even at
210 °C.
Scheme 31. Proposed mechanism for the seleno Newman-Kwart rearrangement.
OH
RCH2Cl2, reflux;
O
R
130 - 200 °Cneat or DMA
Cl-
Cl Cl
NMe2
NaHSe
Me2N Se
Se
R
Me2N O
150 151 152R = Me, EWG
O
Se NMe2
O
Se NMe2Se
O NMe2
R R R151 153 152
R = EWG => faster
44
This route was particularly attractive for the synthesis of binaphthyl diselenide 135 as it
would enable the commercial availability of enantiomerically pure BINOL (94) to be
exploited. In our hands, the published results for 4-nitrophenol were replicated closely,
achieving 84% yield for the rearrangement. However, it was noted that at the elevated
temperatures used, the purity of the starting materials had a dramatic effect on the yield with
trace impurities promoting decomposition into several undesirable by-products.
Unfortunately, this method was not directly applicable to 2,2’-biphenol (154) as the
synthesis of the bis(O-selenocarbamate) 155 was unsuccessful using the published
conditions (Scheme 32).
Scheme 32. Attempted synthesis of biphenyl SNK-precursor.
The only product in the attempted synthesis of 155 was the mono-substituted 156, possibly
formed via a bridged dioxepin iminium species 157. Several other attempts were made to
prepare 155 including performing two sequential reactions and employing preformed
selenocarbamoyl chloride 158, the preparation of which has been previously reported
(Scheme 33).75
Scheme 33. Preforming selenocarbamoyl chloride 158.
Rearrangement of the mono-substituted biphenol 156 was attempted in DMA at 160 °C,
however, the compound decomposed into a complex mixture of inseparable products and
OHOH CH2Cl2, reflux;
Cl-
Cl Cl
NMe2
NaHSeH2
(2 eq.) OO
OOH
NMe2
Se
Se
NMe2
NMe2
Se
155 (0%) 156 (55%)154 157
via:
O
ONMe2
Cl
Cl-
Cl Cl
NMe2 LiHSeTHF Cl NMe2
Sebiphenol 154
(0.5 eq.) OO
NMe2
Se
Se
NMe2
155 (0%)
158
45
none of the Se-aryl selenocarbamate was observed. It was hypothesised that this
decomposition could be accelerated by interference of the pendant hydroxyl group.
We also attempted to prepare the bis(O-binaphthyl selenocarbamate) 161 from the reaction
of biscarbamate 159 with Woollin’s reagent (160), a reagent for the conversion of carbonyls
to selenocarbonyls.76 No conversion of 159 was observed and it was noted that this reagent
was not effective for the formation of selenocarbamates (Scheme 34). With the knowledge
from these studies this route was not investigated further for the synthesis of binaphthyl
diselenide 135.
Scheme 34. Woollin’s reagent 160.
VANOL (Figure 8) is a C2-symmetric chiral biaryl ligand that has been applied successfully
in catalysis including asymmetric Diels-Alder and aziridination reactions.77–79 It was
proposed that the 3,3’-phenyl groups in the structure would help to overcome the issue of
selenophene formation in the synthesis of the diselenide as this structure would be highly
hindered and distorted.
Figure 8. VANOL 109.
OO NMe2
NMe2
O
O
OO NMe2
NMe2
Se
Se
PSeP
SeSeSe
160
159 161
PhPh
OHOH
VANOL109
46
Owing to the success of the lithiation procedure in the synthesis of the biphenyl diselenide
140, we set out to synthesise the VANOL dibromide analogue 164 via a double [4+2]
benzannulation (Scheme 35) with a view to performing a Li-Br exchange.80 The diyne 162
starting material was prepared by a Glaser coupling of phenyl acetylene and the yne-
aldehyde 163 prepared by a Sonogashira coupling of phenyl acetylene and 2-
bromobenzaldehyde. Using 2.5 equivalents of the aldehyde 163 relative to 162, the
dibromide 164 was isolated in 41% yield (lit. 45%).
Scheme 35. Double [4+2] benzannulation in the assembly of the VANOL scaffold.
Lithiation of the dibromide with n-BuLi followed by a quench with elemental selenium was
unsuccessful for this substrate, however, employing t-BuLi in its place afforded the
diselenide 165 in 39% yield (Scheme 36). 165 was resolved by preparative chiral HPLC as
there is not yet an asymmetric synthesis of dibromide 164.
Scheme 36. Formation of VanSe2 165 via Grignard formation.
As an alternative to axially chiral diselenides, we turned our attention to a catalyst containing
and auxiliary chiral group. Oxazoline-based diselenide 169 is known in the literature and has
O
H
PhPh
Ph
2CuBr2 (5 eq.)
(CH2Cl)2, 100 °CPhPh
BrBr
164 41%
162 163
PhPh
BrBr
PhPh
SeSe
i) t-BuLi (4.0 eq.), THF, –78 °C;ii) Se (2.2 eq.);iii) air
165 39%164
47
been employed as both a stoichiometric reagent and as a chiral ligand in enantioselective
synthesis.81,82 169 was synthesised by a slightly modified procedure in two steps from amino
alcohol, valinol 167 as the compound may be of some utility later (Scheme 37).
Scheme 37. Synthesis of oxazoline-based diselenide 169.
OHNH2Br
CN
O
N Br
O
N Setoluene, refluxZn(OTf)2
SeMg, Et2O;
42% (2 steps)
2166 167 168 169
48
CHAPTER THREE
Allylic oxidations with
diselenides
49
3. Allylic oxidations with diselenides
As mentioned previously (see Section 1.2.1), organic seleninic anhydrides can effect allylic
C–H oxidations to form allylic alcohols both stoichiometrically and catalytically when
combined with a stoichiometric co-oxidant. Biphenyl diselenide 140 was converted into the
seleninic anhydride 170 by oxidation with either TBHP or ozone (Scheme 38).
Scheme 38. Oxidation of biphenyl diselenide 140 with TBHP or ozone.
Solutions of the diselenide 140 are characteristically deep orange in colour whereas the
Se(IV) seleninic anhydride is colourless. The colour change allowed the endpoint of the
reaction to be accurately determined. With TBHP, the oxidation was slow with a colourless
solution being obtained after 72 hours. However, when ozone, generated from a stream of
dry air, was bubbled through a solution of 140 in CH2Cl2, the reaction was complete within
1.5 hours at 0 °C. The structure of 170 was confirmed by X-ray crystallography to be the
seleninic anhydride rather than the bis(seleninic acid) (Figure 9).
Figure 9. Crystal structure of seleninic anhydride 170 (50% probability ellipsoids).
SeSe
SeO
SeO
O
TBHP (10 eq.), r.t., 72 hor O3, 0 °C, 1.5 h
140 170 (99%)
170
50
The anhydride 170 (BiPhenSe2O3) was then used to perform an allylic oxidation of 1-nonene
171 (Table 1). The reaction produced mixtures of the allylic alcohol 172 and enone 173. The
reaction proceeded slowly, with some rate enhancement observed when the number of
equivalents of oxidant 170 was increased (Table 1, entries 2-3).
Table 1. Oxidation of non-1-ene (171) with stoichiometric seleninic anhydride (170).
Entry 170 / eq. Time / h Conversion (%) Yield (%)[a] 172:173
1 1 120 74 23 2.0:1 2 3 24 68 31 2.5:1 3 3 120 80 45 1.0:1
[a]Yield calculated using 1H NMR with mesitylene (0.33 eq.) as the internal standard.
In all cases the conversion of nonene was much higher than the yield achieved indicating
that side reactions were occurring. This could be via reaction of the substrate itself, or
consumption of the products, for example, the α-oxidation of the enone 173 in a reaction
similar to that described by Riley with SeO2.14 The high conversion could also be explained
by accounting for substrate that was bound to the oxidant 170, as intermediates in the
process of the reaction. While the by-products were not identified in the reaction mixture,
the rates of reaction were further investigated with a preliminary NMR study, taking one
spectrum every 15 minutes (Figure 10).
Figure 10. Oxidation of 1-nonene 171 with 1 eq. BiPhenSe2O3 170 in CDCl3 (0.02 M) at 50 °C using mesitylene as internal standard.
4 4 4OH OCHCl3, 50 °C
170
171 172 173
0
0.005
0.01
0.015
0.02
0.025
0 4 8 12 16 20 24 28 32 36 40 44 48
Concentration(/moldm
-3)
Time(/h)
[nonene]
[alcohol]
[ketone]
51
From this plot, it can be clearly seen that the rate of production of alcohol 172 is fast initially
but the concentration of alcohol reaches a plateau after approximately 10 hours where it then
begins to slowly decline as the amount of enone 173 in the reaction mixture begins to
steadily increase. Throughout the reaction, the mass balance of the three compounds also
declines and further investigation would be required to identify the cause of this as no
impurities were identified in the crude reaction mixture.
Following this investigation, the study was repeated but instead employing the electron-
deficient oxidant 174 as this should increase the rate of oxidation (Figure 11). As the
seleninic anhydride 174 is more electron deficient than the BiPhenSe2O3 170, it is thus more
electrophilic as the energy of the Se—O (π*) LUMO is lowered. As such, the rate of the ene
reaction would be expected to increase.
Figure 11. Oxidation of 1-nonene 171 with 1 eq. 174 in CDCl3 (0.02 M) at 50 °C using mesitylene as internal standard.
It should be noted that the data before approximately 19 hours is inaccurate due to an issue
with shimming of the sample, however, the general trends in concentrations of the reactant
and products can still be seen clearly. In this case, 174 was a considerably more powerful
oxidant and side-reactions appeared to be far more prevalent with only ~5% mass balance at
the end of the study. The starting material was consumed rapidly throughout the reaction
and, after the starting material was fully consumed the concentration of ketone can also be
0
0.0005
0.001
0.0015
0.002
0.0025
0.003
0.0035
0.004
0.0045
0.005
0
0.005
0.01
0.015
0.02
0 4 8 12 16 20 24 28 32 36 40 44
[products](/moldm
-3)
[nonene](/moldm
-3)
Time(/h)
[nonene][alcohol][ketone]
CF3
F3C SeO
OSeO
CF3
CF3
174
52
observed to decline, demonstrating that the products of the allylic oxidation are consumed by
side-reactions. Due to the low yield and high conversion, this reagent 174 was deemed too
reactive and unselective to further investigate.
To investigate the application of diselenides to catalytic allylic oxidation, a small survey of
stoichiometric oxidants was conducted (Table 2).
Table 2. Catalytic oxidation of non-1-ene 171 with biphenyl diselenide 140 and TBHP.
Entry Oxidant Yield of 172 (%)[a] 172:173
1 mCPBA 0 n/a 2 TBHP 48 5:1 3 PhIO2 0 n/a 4 IBX 0 n/a
[a]Yield calculated using 1H NMR with mesitylene (0.33 eq.) as the internal standard.
With mCPBA, iodoxybenzene (PhIO2) and 2-iodoxybenzoic acid (IBX), neither of the allylic
oxidation products were detected in the reaction mixture after 24 hours. However, with
TBHP (Table 2, entry 2) a yield of 48% was obtained with a 5:1 ratio of alcohol:enone.
When compared to the stoichiometric oxidations (see Section 3.1), the catalytic reaction is
considerably more selective for the allylic alcohol product. The reaction was repeated in
deuterated chloroform, taking a 1H NMR spectrum every 15 minutes and plotted the
concentration of reactant and products to gain further insight into the progression of the
reaction (Figure 12). As can be seen from the chart, at approximately 28 hours the reaction
rate of reactions decreases dramatically as reoxidation of the catalyst becomes rate-limiting
as the concentration of TBHP decreases. Any reaction after this point could be due to slow
disproportionation of lower oxidation state selenium species (for example, BiPhenSe2O) to
the active selenium(IV) oxidants.83
4 4 4OH OCHCl3, 50 °C24 h
140 (20 mol%)oxidant (1.0 eq.)
171 172 173
53
Figure 12. Oxidation of 1-nonene 171 with TBHP (1.0 eq.) and catalytic 140 (20 mol%) in CDCl3 (0.1 M) at 50 °C using mesitylene (0.33 eq.) as internal standard.
As opposed to the oxidations with stoichiometric BiPhenSe2O3 170, in this case the mass
balance is more favourable, with 89% of material accounted for as either starting material
171 or products 172 and 173. Interestingly, up until the point of TBHP consumption, the rate
for production of the alcohol appears to increase. We hypothesised that this could be due to a
number of reasons including: a long induction period for the catalyst; or increasing
concentrations of tert-butanol, produced in the reduction of TBHP, aiding the release of the
alcohol from the catalyst.84
Following the initial investigations into catalytic allylic oxidation, diselenide 165 (VanSe2)
was then employed as the catalyst under the conditions described above (Scheme 39).
Scheme 39. Catalytic oxidation of non-1-ene 171 with VanSe2 165.
0
0.02
0.04
0.06
0.08
0.1
0.12
0 5 10 15 20 25 30 35 40
Concentration(/moldm
-3)
Time(/h)
[nonene]
[alcohol]
[ketone]
4 4 4OH OCHCl3, 50 °C24 h
165 (20 mol%)TBHP (1.0 eq.)
171 172 70% 173 4%SeSePh
Ph
165
54
With racemic VanSe2 165, the selectivity for alcohol 172 versus enone 173 was improved
relative to BiPhenSe2 140. Furthermore, the reaction proceeded far quicker with 78%
conversion in 24 hours with only one equivalent of TBHP. With this result in hand a single
enantiomer of 165, isolated via preparative chiral HPLC, was employed for the reaction. For
nonene 171 (Scheme 40a), the alcohol product was benzoylated in order to furnish the
molecule with an appropriate chromophore for analysis with chiral HPLC. The reaction was
also performed on allylbenzene 176 which required no such modification for analysis
(Scheme 40b).
Scheme 40. Catalytic oxidations with enantiopure (s)-VanSe2 165 on a) non-1-ene 71; b) allyl benzene 176.
In neither case was any enantiomeric excess observed for the alcohol products. Upon further
study of the reaction mixture, it was noted that the NMR of the catalyst differed at the end of
the reaction. The catalyst was isolated post-reaction and submitted for X-ray crystallography
which confirmed the structure as the selenophene 179 (Figure 13). The dihedral angles
between adjacent constituents on the naphthalene ring were determined to be Cnaphthyl-C2-
C3-C1Ph = 20.87° and C1Ph-C3-C4-H4 = -17.88°, highlighting the amount of strain in the
structure as in unsubstituted naphthalene these angles are 0°. It was later discovered that the
diselenide 165 would slowly decompose to the selenophene 179 when stored as a solid,
further emphasising the tendency of this class of compounds to favour selenophene
formation.
4 4OHCHCl3, 50 °C24 h
(-)-165 (20 mol%)TBHP (1.0 eq.)
171 172 69%
BzClEt3N
CHCl34OBz
175 (0% ee)
OHCHCl3, 50 °C
24 h
(-)-165 (20 mol%)TBHP (1.0 eq.)
176 177 58%(0% ee)
O178 16%
a)
b)
55
Figure 13. a) Structure and b) Crystal structure of selenophene, VanSe 179 (50% probability ellipsoids).
To confirm whether this species was able to perform allylic oxidations, selenophene 179 was
synthesised directly from VanSe2 165 in 74% yield via bromination followed by treatment
with PhLi (Scheme 41).60
Scheme 41. Conversion of VanSe2 165 to VanSe 179.
The selenophene 179 was employed as the catalyst in the allylic oxidation of nonene 171,
however after 48 hours only very small quantities of oxidised products were obtained
compared to >70% in only 24 hours when VanSe2 165 was used (Scheme 42).
Scheme 42. Attempted catalytic oxidation of non-1-ene with selenophene 179.
a)
SePh
Ph
179
b)
2
3
4
SePh
Ph
179 74%
PhPh Se
Se
165
i) Br2, CH2Cl2, 0 °C
ii) PhLi, THF, -78 °C
4 4 4OH OCHCl3, 50 °C48 h
179 (20 mol%)TBHP (1.0 eq.)
171 172 5% 173 <1%
56
From this result, it was deduced that the active catalytic species when using VanSe2 165 was
in fact selenium dioxide that had been eliminated from the diselenide following its oxidation.
This hypothesis could also explain the increase in rate observed during the oxidation with
BiPhenSe2 140 if SeO2 were being released during the process of the reaction (Figure 12).
As mentioned previously, Breder and co-workers have recently described a selenium-
catalysed imidation of alkenes using N-fluorobenzenesulfonimide as both the stoichiometric
oxidant and source of nitrogen (Scheme 43).32
Scheme 43. Breder’s allylic imidation of alkenes.
As transposition of the double bond occurs, biased by the skip-conjugated substrate, this
process is not formally an allylic functionalisation. However, we hoped to apply our
catalysts to this transformation in order to develop an enantioselective process. Benzyl ester
182 was selected as a model substrate and repeated Breder’s reaction using BiPhenSe2 140
in place of diphenyl diselenide 36 (Scheme 44). With the cyclic diselenide 140, an isolated
yield of 78% was obtained (lit. 84% with 36).
Scheme 44. Allylic imidation with cyclic diselenide 140.
Unfortunately, with chiral catalysts (s)-VanSe2 165 and oxazoline 169 there was no reaction
of the substrate, even in refluxing THF. Preliminary attempts to expand the methodology to
synthesise other amines using other oxidants (Table 3, entries 4-5) or by interception with an
amine (Table 3, entries 2-3) were also unsuccessful and in each case none of the desired
EWG EWG
NFSI (1.0 eq.)(PhSe)2 36 (5 mol%)4 Å mol. sieve, THF
r.t.
N(SO2Ph)2
180 181
OBn
O
OBn
O
NFSI (0.97 eq.)140 (5 mol%)
4 Å mol. sieve, THFr.t., 16 h
N(SO2Ph)2
183 78%182
57
products were observed. Furthermore, the addition of amines into the reaction mixture with
NFSI resulted in no conversion of starting material, the reason for which is still unclear.
Table 3. Investigation into the versatility of Breder’s allylic imidation.
Entry Oxidant Additive (X eq.) Yield (%)
1 NFSI -- 78[a]
2 NFSI pyrrolidine (2.0 eq.) 0[b]
3 NFSI benzylamine (2.0 eq.) 0[c]
4 NCS -- 0[c]
5 26 -- 0[c]
[a]Isolated yield; [b]Starting material recovered by flash column chromatography; [c]No consumption of starting material by 1H NMR using 1,3,5-trimethoxybenzene as internal standard.
Allylic C–H oxidations have been successfully performed with stoichiometric cyclic
seleninic anhydride, BiPhenSe2O3 170. Using diselenides BiPhenSe2 140 and VanSe2 165 as
catalysts with a stoichiometric co-oxidant for the same transformation resulted in extrusion
of a selenium atom from the catalyst, forming the corresponding selenophenes, and apparent
acceleration in rate of oxidation of the substrate as the reaction progressed. This rate increase
is suspected to be caused by residual selenium dioxide (SeO2) that results from the
degradation of the catalysts. In order to overcome this, future work will focus on the
development of catalysts that do not benefit from a gain in aromaticity upon extrusion of a
selenium atom.
OBn
O
OBn
O
oxidant (1.0 eq.)140 (5 mol%)
additive (X eq.)4Å mol. sieve, THF
r.t., 16 h
NR2
182 183Na+
SO
O N- Cl
26
58
CHAPTER FOUR
Ar-X RSe-M Cross-coupling
59
4. Ar-X RSe-M Cross-coupling
In order to overcome the low yields and poor selectivity in the formation of diselenides via
the quenching of metalated species accessed from aryl-halides (see Section 2.2), we sought
to find an alternative method for the incorporation of selenium into the organic frameworks.
It was envisaged that this could be achieved by employing a transition metal mediated cross-
coupling. We proposed that a nucleophilic alkylselenium species of the type RSe-M could be
coupled to Ar-X (X = halide, triflate) using catalytic palladium and an appropriate ligand. It
could then be possible to remove the alkyl group via an oxidation-elimination pathway and
the resulting selenenic acid could then be converted to the diselenide via a reduction,
followed by oxidative Se-Se bond formation in air to form the desired diselenides without
unwanted selenide by-products (Scheme 45).
Scheme 45. Proposed route to diaryl diselenides exploiting a transition metal catalysed cross-coupling.
This route was particularly attractive as it could enable the use of triflates, derived simply
from readily-available phenols, including enantiopure BINOL-triflate that is synthesised in
one step from commercially available (R)- or (S)-BINOL (94).85 There has been little
precedent reported for the preparation of arylalkyl selenides in a transition-metal catalysed
process. For example, Krief and co-workers report the use of catalytic Pd(PPh3)4 in the
cross-coupling of n-hexyl-SeB(OR)3 (187), generated in situ from NaBH4 reduction of the
corresponding selenocyanoate 186, and iodobenzene to form hexylphenylselenide (188) in
76% yield (Scheme 46).86
X
X = Cl, Br, I, OTfR = alkyl
RSe-M
[cat] SeR'
H
oxidation;elimination;
Se2
reduction;air
184 185 36
60
Scheme 46. Krief’s palladium catalysed cross-coupling of selenoboronates and aryl iodides.
A similar transformation has been reported by Nishiyama and co-workers but instead
employing n-BuSeSn(n-Bu)3 as the nucleophilic component to form n-butylphenylselenide
in 79% yield.87 However, both publications use only iodobenzene and contain just a single
example for the formation of arylalkyl selenides, with the latter focusing on the synthesis of
unsymmetrical diarylselenides from ArX (X = I, Br, Cl) and PhSeSnBu3. In the few reported
cases of Ar-X RSe-M cross-couplings, the use of aryl bromides and oxygen-based leaving
groups (X = Br, OTf) is rare even for the formation of diarylselenides and hence the
electrophilic component is usually limited to aryl iodides. Therefore, we set out to expand
upon this methodology to include an array of more challenging substrates.
There are several issues that face such a transformation with the most prevalent being the
ability of selenium-containing compounds to act as ligands to transition metals which could
result in poisoning of the catalyst.88 A further issue is the high reactivity of RSeM species,
and their propensity to oxidise to diselenides in air.89 We aimed to overcome the former
issue by conducting a survey of ligands, initially focussing on palladium catalysts due to
their widespread use and versatility in cross-coupling reactions.90 While there are few
examples of Ar–X RSe–M cross-couplings, the use and development of specialised
phosphine ligands is commonplace throughout organic synthesis and such ligand series have
been applied to many varied transformations, providing an excellent platform from which to
base the initial investigations and a wide scope for optimisation.
4.1.1 Amination of aryl halides
Much of the early focus of research into palladium-catalysed cross-couplings was in the
formation of carbon-carbon bonds through methods such as those developed by Sonogashira
NaBH4 (1.25 eq.)
n-BuOH[n-hexylSeB(OR)3] Na
PhI, Pd(PPh3)4
110 °C(n-hexyl)SeCN
Se(n-hexyl)
188 (76%)186 187
61
(1975)91, Stille (1978)92 and Suzuki (1979)93, amongst others. It was not until later that
attention was given to the formation of carbon-heteroatom bonds. The first reports of a Pd-
catalysed coupling for the formation of amines 191 from aryl halides 190 was made by
Migita in 1983 employing a tributyltin amide 189 and P(o-tolyl)3 as the ligand (Scheme
47).94
Scheme 47. Cross-coupling of aryl halides with tributyltin amide.
However, methods for performing the reaction in the absence of a tin reagent were not
published until 1995 by the Buchwald95 and Hartwig96 groups, employing secondary amines
with an alkoxide or silazide base. The advancement of this chemistry to incorporate a wider
range of amine substrates lead to the use of bidentate phosphine ligands such as BINAP
(95)97 and DPPF (192),98 as well as investigations into hindered alkylphosphines such as P(t-
Bu)3 which enabled aminations to be performed at room temperature.99 During these
investigations Hartwig found that complexes of Q-Phos (193) were particularly effective in
the general amination of aryl chlorides with primary and secondary amines (Figure 14).100
Figure 14. Selected ligands used for the palladium-catalysed amination of aryl chlorides.
The increased efficiency of using sterically hindered and electron-rich phosphine ligands has
been generally attributed to the propensity of their metal complexes to exist as the active
mono-ligated species, stabilised by the steric bulk of the ligand.101 Furthermore, an electron-
rich ligand facilitates oxidative addition of the metal into the Ar-X bond. These hypotheses
Bu3Sn NEt2Br NEt2
Pd(P(o-tolyl)3)2Cl2 (1 mol%)
191 87%
toluene, 100 °C
189 190
Fe
P(t-Bu)2
PhPh
Ph
Ph Ph
Q-phos193
PPh2PPh2
BINAP95
Fe
PPh2
DPPF192
PPh2
62
led Hartwig and co-workers to further investigate the Josiphos (194) series of ligands (Figure
15) for this transformation based on earlier findings within the group.102
Figure 15. Josiphos ligands.
The Josiphos ligands are chiral ligands that were originally developed for applications in
enantioselective catalysis, such as hydrogenations and hydroborations.103 Although the
aforementioned C-N couplings do not generate chiral products, Hartwig postulated that the
Josiphos ligands possessed the correct electron-donating and steric properties to facilitate the
mono-coupling of primary amines. With Josiphos 195, the group were able to couple a large
variety of (hetero)aryl halides and triflates with a range of primary alkyl amines.104,105 The
couplings took place under catalyst loadings as low as 0.0005 mol%. The extremely high
turn-over numbers were attributed to the chelation of the ligand increasing the stability of the
catalyst towards ligand displacement as well as the pre-organisation of the phosphines on the
catalyst backbone to facilitate binding to the metal in a sterically-demanding environment.106
Due to the nucleophilicity of selenium, it was envisaged that these features would be
advantageous in the proposed cross-coupling.
4.1.2 Carbon-sulfur bond formation
The first Pd-catalysed coupling to form aryl alkyl sulfides 201 from aryl halides 184 was
reported by Migita in 1980.107 This process involved the use of Pd(PPh3)4 to catalyse the
reaction of aryl bromides and iodides with thiolates 199 generated in situ via the
deprotonation of thiols 198 with NaOt-Bu. A mechanistic hypothesis for the transformation
involves oxidative addition of the Pd(0) catalyst 196 into the aryl halide bond followed by
transmetallation of the thiolate 199 onto the palladium. A cis/trans isomerisation followed
FeCy2P
P(t-Bu)2
CyPF-t-Bu195
FeR2P
PR'2
Josiphos194
63
by reductive elimination of the product sulfide 201 regenerates Pd(0) for the next catalytic
cycle (Scheme 48).
Scheme 48. Proposed mechanism for the palladium-catalysed coupling of thiols with aryl halides.
Since Migita’s initial study, much of the development of the coupling of Ar–X with sulphur
nucleophiles has been performed by Hartwig and co-workers. Investigations into steric
effects of ligands indicated that the use of bidentate phosphines with large P-Pd-P bite angles
of up to 99.1° caused a rate increase on the reductive elimination of the sulfide from organo
Pd(II) thiolate complex 202 (Scheme 49).108 For transphos (208) the rate is reduced as the
methyl and thiolate must be cis- to one another for reductive elimination to occur.
Scheme 49. Effect of bite angle on the rates of reductive elimination of sulfides.
Following the application of the Josiphos ligand series to C-N bond forming couplings,
Hartwig investigated their use in the cross-coupling of thiolates and aryl halides. The CyPF-
t-Bu 195 catalyst was found to exhibit excellent reactivity in the couplings of a variety of
PdIILnXPdIILn
SR
SRPd0Ln
X
RSNaX Na RSHNaOt-BuX = Br, IR = alky, arylL = PPh3
196
184
199
197200
201
198
PdS(t-Bu)
Me PR2
R2PPd0LnMeS(t-Bu)
PPh2
PPh2PPh2
PPh2
Fe
DPPF192
PPh2
PPh2
PPh2
PPh2
DPPBz206
DPPE205
TRANSPHOS208
bite angle:
t1/2 complex:
Ligand:
85.8°
10 hr
--
9 hr
99.1°
0.5 hr
174.7°
2 hr
PPh2
PPh2
DPPP207
90.6°
5 hr
202 203 204
64
thiols and aryl chlorides. Again, high turn-over numbers were achieved, demonstrating the
stability of the catalyst with respect to poisoning by thiols and other sulfur species (Scheme
50).109
Scheme 50. Hartwig’s Pd/Josiphos catalysed cross-coupling of arylchlorides and thiols.
For the coupling of Ar–X 184 with Alk–SeM 213 species we propose a simplified
mechanistic overview with the role of palladium analogous to that found in other palladium-
mediated cross-coupling reactions such as the Sonogashira, Stille and Suzuki couplings
(Scheme 51).91–93
Scheme 51. Proposed, simplified mechanism for the cross-coupling of RSe-M and Ar-X.
Oxidative addition of the palladium(0) catalyst 211 into the Ar—X bond forms an aryl-
palladium(II) species 212. This insertion is followed by transmetallation of the alkyl
selenolate 213 and subsequent cis/trans isomerisation to form the arylpalladium(II)
selenolate 214. Reductive elimination releases the desired product 215 and regenerates the
free palladium(0) catalyst 211. Using evidence from the previous work of Hartwig it was
proposed that that bidentate, electron-rich phosphine ligands with rigid backbones and large
P–Pd–P bite angles would facilitate this mechanism.
Cl
RHSR'
[Pd] (0.01-3 mol%)CyPF-t-Bu 195 (0.01-3 mol%)
NaOt-BuDME or toluene
110 °CR
SR'
209 198 210
PdIILnXPdIILn
SeR
SeRPd0Ln
X
RSe-MMX
211
184
213
212214
215
65
Our initial attempts at optimising such a procedure began with 4-iodotoluene 216 and
lithium n-butylselenolate (217) (nBuSeLi), formed in situ via insertion of elemental selenium
in to n-butyl lithium. Using Pd(PPh3)4 as the catalyst, the aryl alkylselenide 218 product was
formed in good yield (Scheme 52).
Scheme 52. Palladium-catalysed coupling of 4-iodotoluene 216 and n-BuSeLi 217.
However, when aryl bromides and triflates were employed in place of iodide 216 a sharp
drop-off in yields was observed with only traces of product formation by GC and aryl
chlorides were completely unreactive under the conditions. It was apparent that
triphenylphosphine was not a particularly effective ligand for this reaction and it was
suspected that nucleophilic selenium species present in the reaction mixture could bind to the
palladium, reducing the availability of the catalyst and retarding the rate of reaction. These
factors would have a more apparent effect as the reactivity of the electrophilic Ar-X species
was decreased (I > Br/OTf >> Cl). Therefore, a small survey was conducted of electron-rich,
bidentate ligands that would a) bind more strongly to the palladium centre; b) increase
electron-density at palladium thus perturbing binding by selenium species. As the coupling
of aryl triflates was a far more valuable transformation to this work, 4-tolyl triflate 219 was
chosen as the model substrate (Table 4).
I
n-BuSeLi 217 (1.2 eq., 1 M in THF)
Pd(PPh3)4 (10 mol%)toluene (0.1 M), 110 °C
1 h
Se
218 68%216
66
Table 4. Survey of ligands for the Pd-catalysed coupling of n-BuSeLi 217 and aryl triflates.
Entry Ligand Conversion (%)[a] Yield (%)[a]
1 PPh3[b] 2 <1
2 192[c] 9 8 3 220[c] 3 1 4 221[c] 38 37 5 195[c] 22 22
All reactions conducted on a 0.1 mmol scale in Ar-X; [a]Measured by GC analysis with decane as internal standard; [b]Pd(PPh3)4 (10 mol%) used; [c]Pd(dba)2 and ligand were premixed for 30 minutes before addition of other reagents.
The survey indicated that bidentate bisphosphine ligands are more effective than PPh3 for
this transformation, with the Josiphos ligands, in particular PhPF-t-Bu (Table 4, entry 4),
proving the most effective of those trialled. However, even with increased reaction times the
yield did not improve. It was noted that an appreciable amount of starting material remained
in the reaction mixture and this was quantified by measuring the conversion. Thus, it was
concluded that poisoning of the catalyst was occurring after only 3-4 turnovers even in the
best case. To overcome this issue it was postulated that an alternative nucleophilic selenium
coupling partner may have a lesser effect on the catalyst.
FePh2P
P(t-Bu)2
221PhPF-t-Bu
P(p-tol)2P(p-tol)2
220T-BINAP
FeCy2P
P(t-Bu)2
195CyPF-t-Bu
Fe
192DPPF
PPh2
PPh2
OTf
n-BuSeLi 217 (1.2 eq., 1 M in THF)Ligand (10 mol%)
Pd(dba)2 (10 mol%)toluene (0.1 M), 110 °C
24 h
Se
Ligand =
218219
67
4.4.1 Synthesis of selanylstannanes
As mentioned previously, other groups had found success in the coupling of aryl halides
with arylselanyl stannanes to form diaryl selenides. We aimed to replicate the transformation
but employing analogous alkyl selenium nucleophiles. The easiest of these to access being
tri-n-butyl(butylselanyl)stannane (222) which could be generated by a straightforward route
from n-butyllithium (Scheme 53).
Scheme 53. In situ formation of alkylselanyl stannanes.
Attempts to isolate alkylselanylstannane 222 resulted in low purity and low yielding
mixtures, owing to the compound’s instability to moisture and oxygen. Instead, the reagent
was used without any purification. Stock solutions of the reagent were prepared on scales up
to 50 mmol, with equimolar quantities of n-BuLi, Se and BuSnCl3, and were stable for at
least 72 hours when kept in solution under inert atmosphere. It should be noted that these
solutions also contain one equivalent of lithium chloride as a by-product of the process. In
general, it was concluded that this would not be an issue as LiCl is a common additive to the
Stille cross-coupling and the majority could be removed by filtration prior to use in
reaction.110,111
4.4.2 Coupling of selenylstannanes with para-tolyl-X species
Utility of this reagent was demonstrated initially under conditions analogous to Nishiyama
and co-workers with 4-iodotoluene and catalytic Pd(PPh3)4, affording the product 218 in
75% yield (Table 5, entry 1).87 However, as with BuSeLi 217, a sharp drop-off in yield was
observed when the iodide was replaced with bromide or triflate using this catalyst system,
even when the loading was increased to 20 mol% (Table 5, entry 2).
Se
THF (1 M) SeLi SeSnBu3Bu3SnCl
n-BuLi
217 222
68
Table 5. Cross-coupling of n-BuSeSn(n-Bu)3 with aryl halides and triflates.
Entry X = Conversion (%)[a] Yield (%)[a]
1 I 82 75 2[b] Br 11 2 3 OTf <1 <1
All reactions conducted on a 0.1 mmol scale in Ar-X; [a]Measured by GC analysis with decane as internal standard; [b]20 mol% [Pd] used
Table 6. Survey of selected bidentate ligands.
Entry Ligand Conversion (%)[a] Yield (%)[a]
1 PPh3[b] <1 <1
2 192[c] 55 44 3 224[c] 66 60 4 221[c] 91 88
All reactions conducted on a 0.1 mmol scale in Ar-X; [a]Measured by GC analysis with decane as internal standard; [b]Pd(PPh3)4 (10 mol%) used; [c]Pd(dba)2 and ligand were premixed for 30 minutes before addition of other reagents.
With these results in hand, a preliminary survey of a selection of ligands was carried out
(Table 6). Pleasingly, the use of the selanylstannane nucleophilic component 222 resulted in
much higher yields and turnover numbers when compared to lithium selenolate 217
suggesting that selanylstannanes are less able to irreversibly bind to and deactivate the
catalyst. As with 217, a notable increase in yield and conversion was observed when
bidentate phosphines were employed in place of triphenylphosphine. The Josiphos ligand
221 was, once again, the most successful ligand under these conditions by some margin
X
222 (1 eq., 1 M in THF)Pd(PPh3)4 (10 mol%)
toluene (0.1 M), 110 °C18 h
Se
223 218
FePh2P
P(t-Bu)2
PhPF-t-Bu221
Fe
DPPF192
PPh2
PPh2
OTf
222 (1.0 eq., 1 M in THF)Ligand (10 mol%)
Pd(dba)2 (10 mol%)toluene (0.1 M), 110 °C
24 h
Se
Ligand =
OPPh2 PPh2
xantphos224
219 218
69
(Table 6, entry 4). In this survey, DPPF (207) produced a fair yield of 44% (Table 6, entry
2). Xantphos (224), a ligand with a wide bite angle of ~111°, performed slightly better than
DPPF under the conditions with a yield of 60% (Table 6, entry 3).112
Owing to the success with the Josiphos ligand, PhPF-t-Bu (221), a screen of other ligands in
the Josiphos series was conducted (Table 7). For these reactions, the catalyst loading was
lowered to 2 mol% in order to accentuate any differences between the ligands.
Table 7. Survey of Josiphos ligands.
Entry Ligand[a] Conversion (%)[b] Yield (%)[b]
1 PhPF-Cy (225) 41 38 2 t-BuPF-Ph (226) 55 52 3 (4-MeO-3,5-Me2C6H2)PF-t-Bu (227) 51 49 4 (3,5-(CF3)C6H3)PF-Cy (228) 17 16 5 PhPF-(3,5-Me2C6H3) (229) 35 33 6 PhPF-t-Bu (221) 54 50
All reactions conducted on a 0.1 mmol scale in Ar-X; [a]Pd(dba)2 and ligand were premixed for 30 minutes before addition of other reagents; [b]Measured by GC analysis with decane as internal standard.
At 2 mol% catalyst loading the yield for the original Josiphos ligand, PhPF-t-Bu (221) was
50% (Table 7, entry 6). Replacing the tert-butyl groups with cyclohexyl caused a decrease in
Ligand =
222 (1.0 eq.)Pd(dba)2 (2 mol%)Ligand (2 mol%)
toluene (0.1 M), 110 °C24 h
FePh2P
P(t-Bu)2
PhPF-t-Bu221
FePh2P
PCy2
PhPF-Cy225
Fe(t-Bu)2P
PPh2
t-BuPF-Ph226
FeP
P(t-Bu)2
(4-MeO-3,5-Me2C6H2)PF-t-Bu227
Ar
MeO
FeP
PCy2
(3,5-(CF3)2C6H3)PF-Cy228
Ar
CF3
F3CFe
Ph2PP
PhPF-(3,5-Me2C6H3)229
Ar
OTf Se219 218
70
yield (Table 7, entry 1) as observed earlier when using BuSeLi as the nucleophile. Reversing
the groups on each phosphine with t-BuPF-Ph (226) produced a comparable yield to the
original ligand (Table 7, entry 2). The use of the more electron rich (4-MeO-3,5-
Me2C6H2)PF-t-Bu (227) had little effect on the yield (Table 7, entry 3), however, the
electron deficient ligand, (3,5-(CF3)C6H3)PF-Cy (228), caused a marked decrease in yield to
only 16% (Table 7, entry 4). Finally, the use of a Josiphos ligand with aromatic groups on
both phosphines resulted in a more moderate yield of 33% (Table 7, entry 5). Thus,
investigations were continued with the original ligand, PhPF-t-Bu 221, as there was a
negligible difference between this and other best-performing ligands surveyed and 221 was
the most readily available.
Over the course of the investigations it was noted that the source of the palladium(0) could
have a substantial effect on the yield of the reaction with variances observed even when a
different batch of the same formulation of palladium-dba was used. While palladium(0)
sources such as Pd(dba)2 and Pd2(dba)3 are generally considered to have equivalent catalytic
activity,113 studies have shown that the purity of commercially available Pd2(dba)3 can be as
low as 60% and vary greatly from batch to batch.114 The chloroform adduct,
Pd2(dba)3·CHCl3, is proposed to be more stable in crystalline form than Pd2(dba)3 and thus
commercial sources are generally of higher purity. Using the chloroform adduct, the best
result so far under these conditions was achieved with a 5 mol% loading relative to
palladium, achieving 98% isolated yield on a 1 mmol scale (Scheme 54).
Scheme 54. Cross-coupling of 4-tolyltriflate with n-butylselanyl stannane.
222 (1.1 eq.)Pd2(dba)3·CHCl3 (2.5 mol%)
PhPF-t-Bu (5 mol%)toluene (0.1 M), 110 °C
21 h
OTf Se
218 98%219
71
4.4.3 Optimisation of cross-coupling using xantphos
Due to the high cost of the Josiphos ligands, it was desirable to optimise the reaction using a
more readily available and accessible ligand. Xantphos (224) was selected as the initial
candidate for optimisation owing to the previous results and its successful use with Pd2(dba)3
in a coupling of thiols with aryl halides and triflates reported previously.115
A preliminary survey of reaction solvent confirmed that toluene was the superior solvent out
of those trialled and hence toluene was used in all further reactions (Table 8).
Table 8. Solvent survey for the cross-coupling of selanyl stannanes and aryl triflates.
Entry Solvent Temperature / °C Conversion (%)[a] Yield (%)[a]
1 toluene 110 66 60 2 DMF 110 18 17 3 n-BuOH 110 6 6 4 DMSO 110 11 9 5 1,4-dioxane 110 3 <1 6 THF 80 6 3 7 MeCN 80 1 <1 8 (CH2Cl)2 80 6 3 9 DME 80 15 1
All reactions conducted on a 0.1 mmol scale in Ar-X; Pd(dba)2 and xantphos were premixed for 30 minutes before addition of other reagents; [a]Measured by GC analysis with decane as internal standard.
Reducing the reaction time showed that the reaction occurred quickly, with the majority of
the conversion occurring within the first three hours (Table 9, entries 1–3). However,
running the reactions for longer did not appear to be detrimental to the conversion or yield
(Table 9, entry 4). Increasing the number of equivalents of the nucleophilic component to
1.5x the triflate (Table 9, entry 5) gave excellent conversion of starting material and yield of
product. This could suggest that some of the selanylstannane is consumed in side reactions
but may also reflect the purity of the stock solution. Increasing the number of equivalents
further was detrimental to the yield (Table 9, entry 6). Unsurprisingly, decreasing the
222 (1.0 eq.)Pd(dba)2 (10 mol%)xantphos (10 mol%)solvent (0.1 M)
21 h
OTf Se
218219
72
temperature had a dramatic effect on the conversion with no reaction occurring at room
temperature (Table 9, entries 7–9).
Table 9. Cross-coupling of selanyl stannanes and aryl triflates at varied temperatures.
Entry X / eq. Temperature / °C Time / h Conversion (%)[a] Yield (%)[a]
1 1.0 110 3 58 56 2 1.0 110 6 63 59 3 1.0 110 9 66 61 4 1.0 110 21 66 60 5 1.5 110 21 >99 98 6 2.0 110 21 >99 76 7 1.0 80 21 17 11 8 1.0 60 21 3 2 9 1.0 25 21 <1 <1
All reactions conducted on a 0.1 mmol scale in Ar-X; Pd(dba)2 and xantphos were premixed for 30 minutes before addition of other reagents; [a]Measured by GC analysis with decane as internal standard.
4.4.4 Reaction of selenylstannanes with more hindered ortho-tolyl-X species
To further develop the utility of this procedure we sought to expand the scope to more
challenging substrates. 2-tolyl triflate (230) was chosen as an electronically equivalent but
sterically more hindered substrate. Preliminary results are shown below (Table 10). With one
equivalent of selanylstannane 222, xantphos (224) and PhPF-t-Bu (221) gave 22% and 50%
yields respectively (Table 10, entries 1-2). In comparison, with the less hindered 4-tolyl
triflate (219) substrate, the same conditions gave 60% and 88% (see Section 4.4.2, Table 6,
entries 3-4). Increasing the number of equivalents of selanylstannane 222 to 1.5x that of the
triflate resulted in a slight increase in yield (Table 10, entry 3) and it was found that with 1.2
equivalents the highest yield with the Pd(dba)2/xantphos system was achieved (Table 10,
entry 4).
222 (X eq.)Pd(dba)2 (10 mol%)xantphos (10 mol%)
toluene (0.1 M)OTf Se
218219
73
Table 10. Cross-coupling of 2-substituted aryl triflates.
Entry [Pd] Ligand[a] X / eq. Conversion (%)[b] Yield (%)[b]
1 Pd(dba)2 224 1.0 25 22 2 Pd(dba)2 221 1.0 55 50 3 Pd(dba)2 224 1.5 34 34 4 Pd(dba)2 224 1.2 43 43 5 Pd(OAc)2 224 1.5 23 21 6 [Pd(MeCN)Cl]2
[c] 224 1.5 13 11 7 [Pd(π-allyl)Cl]2
[c] 224 1.5 71 68 8 [Pd(π-cinnamyl)Cl]2
[c] 224 1.5 80 78
9 [Pd(π-cinnamyl)Cl]2[c] 221 1.5 87 87
10 [Pd(π-cinnamyl)Cl]2[c] 192 1.5 66 61
All reactions conducted on a 0.1 mmol scale in Ar-X; [a][Pd] and Ligand were premixed for 30 minutes before addition of other reagents; [b]Measured by GC analysis with decane as internal standard; [c]5 mol% of dimer.
Following this, alternative palladium sources were trialled. The proposed mechanistic cycle
(Scheme 51) requires a source of palladium(0). However, Pd(0) can be generated in situ by
the reduction of a Pd(II) pre-catalyst. This is known to occur via various reaction-specific
pathways, for example: 1) oxidation of a ligated phosphine by Pd(II); 2) the reductive
elimination of two equivalents of a nucleophilic coupling partner.116 It was proposed that
under the reaction conditions, transmetallation of two equivalents of selanylstannane to a
PdIILnX2 species, followed by reductive elimination of the corresponding diselenide, would
allow the generation of Pd(0) from a Pd(II) pre-catalyst. This would enable the use of a
variety of Pd(II) sources (for example Pd(OAc)2) which are known to be more stable and
have longer shelf-lives than the Pd(0) species used so far in the development of this
reaction.117 It was hoped that using a higher purity source of palladium would increase the
efficiency of the reaction by enabling more accurate ligand stoichiometry and decreasing the
amount of inactive palladium present at the start of the reaction. Although thus far the best
result was attained using 1.2 eq. of selanylstannane, for reactions conducted with Pd(II) pre-
222 (X eq.)[Pd] (10 mol%)
Ligand (10 mol%)toluene (0.1 M)
110 °C, 18 - 21 h
OTf Se
230 231
74
catalysts additional equivalents were included in the reactions mixture to account for that
lost in the generation of Pd(0). Using xantphos (224) as the ligand, no improvement in yield
was observed with Pd(OAc)2 or [Pd(MeCN)Cl]2 (Table 10, entries 5-6).
Palladium(II) π-allyl complexes are widely used in organic synthesis and readily available
commercially. This is due to their long shelf-life and high air stability as well as their rapid
activation to the corresponding monoligated Pd(0) species in the presence of nucleophiles.118
It has also been proposed that substitution on the allyl ligand, as found in the π-cinnamyl
catalyst, supresses the formation of inactive, stable µ-allyl Pd(I) complexes. With [Pd(π-
allyl)Cl]2 and [Pd(π-cinnamyl)Cl]2 the yield increased to 68% and 78% respectively (Table
10, entries 7-8). With PhPF-t-Bu (221) instead of xantphos (224), a further increase in yield
to 87% was achieved (Table 10, entry 9).
4.4.5 Expansion of the substrate scope
To demonstrate the versatility of this process the procedure was applied to a range of
substrates bearing different functionalities. Investigations focused on aryl bromides and
triflates, employing the [Pd(π-cinnamyl)Cl]2/xantphos catalyst system as xantphos is cheaper
and more readily available than the Josiphos ligands (Table 11).
Table 11 (vide infra). Scope for the cross-coupling of aryl halides and triflates with n-BuSeSn(n-Bu)3.
222 (1.5 eq.)[Pd(π-cinnamyl)Cl]2 (5 mol%)
xantphos (10 mol%)toluene (0.1 M)
110 °C, 18 h
ArX ArSe
232a-n 233a-n
75
Entry Starting material Product Yield (%)[a]
1 (232a)
97
2 (232b)
94
3 (232c)
98
4 (232d)
47
5 (232e)
78
6 (232f)
71
7 (232g)
59
8 (232h)
62
9 (232i)
98
10 (232j)
92
11 (232k)
96
12 (232l)
62 92[b]
All reactions conducted on a 1.0 mmol scale in Ar-X; [a]Isolated yields; [b]Yield obtained using PhPF-t-Bu.
Br SeBu
Br SeBu
BrO
HSeBu
O
H
OMe
Br
OMe
SeBu
MeO Br MeO SeBu
O2N
Br
O2N
SeBu
H2N Br H2N SeBu
Br SeBu
OTf SeBu
OTf SeBu
OTf SeBu
OTf
OTf
SeBu
SeBu
76
The procedure was applicable to a variety of electron rich and electron poor aryl bromides
and tolerant of several common functionalities including aldehydes (Table 11, entry 3,
232c), nitro groups (Table 11, entry 5, 232e) and amines (Table 11, entry 7, 232g).
Pleasingly the procedure responded well to scale with an increase in isolated yield observed
for the 2-tolyl substrate compared to the GC yield at 0.1 mmol (Table 11, entry 10). The
reaction was also successfully applied to naphthalenes (Table 11, entries 8 and 11, 232h and
232k) and in the disubstitution of biphenyl bis triflate 232l (Table 11, entry 12).
4.4.6 Use of other selanylstannanes in cross-coupling reactions
Following the successful expansion of the scope of the electrophilic component, focus was
turned to the nucleophilic selanylstannane component. n-BuSeSn(n-Bu)3 (222) was derived
from n-BuLi and thus other organometallics were explored to prepare alternative
selanylstannanes 236 that could be used in this reaction (Scheme 55). The resulting solutions
were then applied under the conditions developed previously.
Scheme 55. General preparation of selanyl stannanes.
With tri-n-butyl(methylselanyl)stannane (236-Me), derived from methyllithium,
selenoanisole 237 was isolated in excellent yield when Josiphos, PhPF-t-Bu, was employed
as the ligand (Scheme 56).
Scheme 56. Cross-coupling of 2-tolyl triflate with MeSeSnBu3.
Alternatively, starting with tert-butyllithium, the corresponding t-Bu- substituted compound
could be formed (Scheme 57).
Se
THF (1M)RSeLi
Bu3SnClRLi RSeSn(n-Bu)3
R = Me, t-Bu, Ph234 235 236
236-Me (1.2 eq.)[Pd(π-cinnamyl)Cl]2 (5 mol%)
PhPF-t-Bu (10 mol%)toluene (0.1 M)
110 °C, 18 h
OTf SeMe
237 95%230
77
Scheme 57. Cross-coupling of 2-tolyl triflate with t-BuSeSnBu3.
Finally, with phenyllithium, phenyltolylselenide 239 was synthesised in excellent yield
(Scheme 58).
Scheme 58. Cross-coupling of 2-tolyl triflate with PhSeSnBu3
4.4.7 Removal of the alkyl group from arylalkyl selenides
With three different alkyl groups available (Me-, n-Bu- and t-Bu-) we then focused on
developing conditions for their efficient removal to “de-protect” the selenium in order to
form the corresponding diaryl diselenides. As previously proposed, the n-butyl chain could
be removed via an oxidation-elimination pathway with the intermediate selenoxide 241
undergoing spontaneous elimination, as seen in the Greico elimination.119 The resulting
arylselenenic acid 242 could then be reduced to the selenol 243 which would undergo
oxidation in air to diselenide 36 (Scheme 59).
Scheme 59. Cleavage of Se-alkyl groups bearing ß-hydrogens via oxidation-elimination.
However, when this procedure was applied to 218 the yields were low and many by-products
were observed in the reaction mixture. Various oxidants were employed, for example H2O2,
236-(t-Bu) (1.2 eq.)[Pd(π-cinnamyl)Cl]2 (2.5 mol%)
xantphos (5 mol%)toluene (0.1 M)
110 °C, 18 h
OTf Se(t-Bu)
238 96%219
236-Ph (1.5 eq.)[Pd(π-cinnamyl)Cl]2 (5 mol%)
xantphos (10 mol%)toluene (0.1 M)
110 °C, 18 h
OTf SePh
239 91%230
240
Se+Et
H
Se2
SeEt
[O]
O- SeOH
SeH
[H]
air
241 242
24336
78
tert-butyl hydroperoxide (TBHP) and ozone, as well as several different reducing agents,
such as LiAlH4 and hydrazine. For this process, the best result was a 16% yield of diselenide
with TBHP and LiAlH4 (Scheme 60).
Scheme 60.
These results prompted investigation of alternative methods for the cleavage of selenium–
alkyl bonds. Demethylation of methyl-phenyl ethers is widely performed through various
methods in organic synthesis. A reliable method is the use of the lewis acidic BBr3, which
coordinates to the oxygen followed by nucleophilic substitution on the methyl carbon by
bromide to produce MeBr and, after workup, the demethylated alcohol.120 Unfortunately,
when applied to the methyl selenide 237, no reaction was observed (Scheme 61). Attempts
with HBr/AcOH at 110 °C were also unsuccessful.121
Scheme 61. Attempted demethylation of methyl selenide 237.
Sugai and co-workers have developed an alternative method for the demethylation of
anisoles employing a lithium metal and ethylene diamine (EDA).122 When applied to
selenoanisole 237, diselenide 245 was isolated in 48% yield under slightly modified
conditions (Scheme 62). It is worth noting that approximately 30% unreacted starting
material was recovered, suggesting that modification of the reaction conditions could result
in increased yields. However, preliminary studies with longer reaction times and increased
equivalents of lithium resulted in the observation of over-reduced products via Birch
reduction.
Se(n-Bu) i) TBHP (10 eq.), CH2Cl2ii) LiAlH4 (10 eq.), THF, refluxiii) air, CH2Cl2
Se
2
244 16%218
2SeMe
BBr3
CH2Cl2 Se237 245
79
Scheme 62. Demethylation of methylselenide 237 with lithium metal.
Various methods exist for the cleavage of t-butyl ethers and esters. Generally the use of a
strong Brønsted or Lewis acids result in facile and clean removal of the group via the
elimination of isobutylene.123 Thus, a selection of acids and conditions for the cleavage of
the t-butyl selenide 238 were trialled (Table 12).
Table 12. Conditions for the cleavage of t-butylselenide 238.
Entry Conditions[a] Yield (%)
1 TFA (3 eq.), CH2Cl2 (0.2 M), r.t., 24 h 0 2 Zn(OTf)2 (3 eq.), MeCN, 80 °C, 24 h 0 3 TFA (neat, 0.2 M), 80 °C, 22 h 70 4 MsOH (neat, 0.2 M), r.t., 24 h 0 5 MsOH (neat, 0.2 M), 80 °C, 2 h 76 6 MsOH (neat, 0.2 M), 80 °C, 24 h 0 7 MsOH (10 eq.), CHCl3 (0.2 M), reflux, 24 h 38
[a]All reactions were conducted under air.
Use of 3 equivalents of TFA at room temperature or Zn(OTf)2 at 80 °C resulted in only the
recovery of starting material 238 after 24 hours (Table 12, entries 1-2). However, neat TFA
at 80 °C overnight resulted in full conversion of the starting material with 70% yield of the
diselenide 244 (Table 12, entry 3). There was no product observed in neat methanesulfonic
acid (MsOH) at room temperature (Table 12, entry 4) but at 80 °C for 2 hours the product
was isolated in a 76% yield (Table 12, entry 5). Increasing the reaction time in hot MsOH
was detrimental to the yield demonstrating that the product is not stable under these
conditions (Table 12, entry 6). Finally, 10 equivalents of MsOH in refluxing chloroform
furnished the product in 38% yield after 24 hours but the rate of reaction was slow and
increasing the time had little effect on yield (Table 12, entry 7).
2SeMe Se
Li (3 eq.)EDA (3 eq.)
n-PrNH2 (0.5 M)0 °C
245 48%237
Se ConditionsSe
2238 244
80
4.4.8 Binaphthyl substrates in cross-couplings with selenylstannanes
With conditions for the cross-coupling and removal of the alkyl group in hand, we turned
our focus towards the synthesis of binaphthyl diselenide 135. BINOL (94) is commercially
available in both (R)- and (S)-enantiomers and was converted to the bis-triflate with Tf2O in
quantitative yield. The corresponding dibromide 141 was also commercially available but
only as the racemate. We did not attempt to synthesise enantiomerically enriched dibromide
141 as the conditions reported from either enantiopure BINOL or 2,2’-diamino-1,1’-
binaphthyl would likely result in racemisation as the dibromide 141 has been reported to
have a much lower barrier to racemisation compared to other 2,2’-disubstituted-1,1’-
binaphthalenes.124–126 With racemic 141 and using xantphos as the ligand, the desired, bis(n-
butylselenide) 246 was isolated in 83% yield (Scheme 63).
Scheme 63. Cross-coupling of 2,2’-dibromo-1,1’-binaphthyl (141) with n-BuSeSn(n-Bu)3.
With the racemic bis-substituted product 246 in hand, attempts were made to remove the
alkyl chains to synthesise the desired binaphthyl diselenide 135. Unfortunately, as in
previous attempts to synthesise this compound, following the dealkylation protocol resulted
in dinaphthoselenophene 142 as the sole product, presumably via intramolecular SɴAr
displacing an activated selenium, and hence this route was abandoned as a method to
synthesise this catalyst (Scheme 64).
Scheme 64. Cleavage of n-butylselenides in binaphthyl (246).
BrBr
222 (3 eq.)[Pd(π-cinnamyl)Cl]2 (5 mol%)
xantphos (10 mol%)toluene (0.1 M)
110 °C, 18 h
SeBuSeBu
246 83%141
SeBuSeBu
i) TBHP (10 eq.), CH2Cl2ii) LiAlH4 (10 eq.), THF, refluxiii) air, CH2Cl2
Se
142 18%246
81
However, with racemic BINOL triflate 247, an interesting observation was made that may
warrant further investigation in the future. When the cross-coupling using xantphos was
applied to the triflate 247, none of the desired product was observed in the reaction mixture.
When PhPF-t-Bu (221) was employed as the ligand the reaction only went to ~50%
conversion of starting material with the major product being the mono-substituted compound
248. Upon further investigation, the enantiomeric excess of the products was found to be
enhanced despite starting from racemic 247 and it was apparent that a kinetic resolution had
taken place. This was attributed to the use of a single enantiomer of Josiphos 221.
Furthermore, the catalyst appeared to be more selective for the minor enantiomer of the
monosubstituted compound 248 as the enantiomeric excess of the small amount of bis-
substituted compound 246 isolated was diminished compared to that of the mono 248
(Scheme 65).
Scheme 65. Kinetic resolution of binaphthyl triflate 247.
To confirm that the selectivity for the second cross-coupling was reversed, the
enantioenriched bis-substituted product 246 was subjected to heating in toluene for 24 h,
demonstrating the compound’s conformational stability under the reaction conditions
(Scheme 66).
OTfOTf
222 (3 eq.)[Pd(π-cinnamyl)Cl]2 (5 mol%)(R)-(SP)-PhPF-t-Bu (10 mol%)
toluene (0.1 M)110 °C, 24 h
OTfSeBu
248 42%(±)-247
SeBuSeBu
246 8%(43% ee)
OTfOTf
OTfSeBu
248 42%(97% ee)
247 44% (97% ee)
82
Scheme 66. Demonstration of conformational stability under heating of 246.
In summary, we have developed a versatile cross-coupling of aryl halides and triflates 249
with selanylstannanes to form arylalkylselenides 250 (Scheme 67). The protocol is tolerant
of various functional groups including aldehydes, nitro groups and unprotected anilines. The
procedure uses readily available and air stable Pd(II) sources and ligands. The nucleophilic
coupling partners, selanylstannanes, are produced in situ and used in the procedure with no
purification.
Scheme 67. General procedure for the cross-coupling of aryl halides and triflates with selanyl stannanes.
We have also investigated various methods for the cleavage of the Se-alkyl bonds to form
symmetrical diaryl diselenides.
SeBuSeBu
SeBuSeBu
toluene
110 °C, 24 h
246 (43% ee)246 (43% ee)
(n-Bu)3SnSeR' (1.5 eq.)[Pd(π-cinnamyl)Cl]2 (5 mol%)
xantphos or PhPF-t-Bu (10 mol%)toluene (0.1 M)
110 °C
XR
R = alkyl, aryl, -CHO, -OMe, -NO2, -NH2X = I, Br, OTfR' = Me, n-Bu, t-Bu, Ph
SeR'R249 250
83
CHAPTER FIVE
Cyclic alkyl selenides
84
5. Cyclic alkyl selenides
As well as oxidations with diselenides, we wished to explore the other potential applications
of chiral selenides to catalysis. Selenides are known to act as Lewis basic catalysts in
transformations such as halo-lactonisation/etherification and amino-cyclisations.127–129 There
are also examples of selenides behaving as nucleophiles in catalytic epoxidation and
chalcogeno-Baylis-Hillman reactions.130–132 To synthesise selenides, the most
straightforward route employs nucleophilic substitution of electrophilic species, for example
251, with a Se2- reagent, such as NaHSe, generated from the reduction of elemental
selenium, as exemplified in the synthesis of model achiral catalyst 252 (Scheme 68).67
Scheme 68. Dihydroselenepine 252 synthesis.
Catalyst design, in keeping with the themes of the project, was based on modification of
privileged chiral scaffolds. Initial focus was given to the binaphthyl structure 253 due to the
structure’s prevalence in catalysis (Figure 16). Compounds of this type have been applied as
chiral ligands for transition metals (A = phosphorus);133 employed as nucleophilic catalysts
(A = phosphorus);134 and used in electrophilic epoxidation reactions (A = nitrogen).135
Figure 16. Binaphthyl-based catalyst structures.
Br
Br
Se (1.0 eq.)NaBH4 (1.1 eq.)
EtOH Se
251 252
A
A = heteroatom253
85
Furthermore, the selenium variant 255 had been synthesised by Rayner and applied in the
oxidation of sulfides and kinetic resolution of ferrocenylphosphines.136,137 Rayner’s synthesis
was repeated, to afford binaphthyl selenepine 255 in 76% yield from commercially available
(R)-dibromide 254 (Scheme 69).
Scheme 69. Dihydroselenepine 255 synthesis.
5.3.1 Overview
The most prevalent modification to the binaphthalene scaffold is substitution at the 3,3’-
positions. Addition of steric hindrance at these positions often produces a marked increase in
enantioselectivity of the catalyst. For example, in Maruoka’s Brønsted acid catalysed
asymmetric Mannich reaction, a variety of binaphthyl dicarboxylic acids were trialled
(Scheme 70).138 With the unsubstituted acid (R = H) the products were synthesised with 0%
ee, however, with a bulky trisubstituted constituent (R = 2,6-Me2-4-t-Bu-C6H2) 258 they
attained 95% ee with no reduction in yield.
Scheme 70. Maruoka’s Brønsted acid catalysed Mannich reaction.
Other examples include use of 3,3’-disubstituted BINAP-type ligands in transition metal
catalysis,139–141 3,3’-diaryl BINOL phosphoric acid organocatalysts,142,143 and nucleophilic
phosphepine catalysts.144 Substitution at the 3,3’-positions is generally applied to transfer the
Br
Br
NaHSe (1.0 eq.)EtOH Se
254 255 76%
NBocCO2t-Bu
N2
catalyst 258NHBoc
N2
CO2t-BuCO2HCO2H
R
R
258256 257 259
86
chiral information of the catalyst to a remote subject without modifying the dihedral angle
which could negatively affect the properties of the ligand.46,145
5.3.2 Synthesis of 3,3’-diphenyl analogue
In order to access 3,3’-disubstituted binaphthalenes, a route developed by Maruoka and co-
workers was exploited.146 Commercially available (R)-BINOL (94) was converted into the
triflate 247 in quantitative yield with Tf2O (Scheme 71). A palladium-catalysed
methoxycarbonylation with CO under atmospheric pressure provided the diester 260 in 43%
yield, with a significant amount of monoester (30%) also isolated.147 Performing the reaction
in a Parr pressure vessel and increasing the pressure of carbon monoxide to 10 bar gave the
diester 260 in 78% yield after 72 hours.
Scheme 71. Methoxycarbonylation of BINOL (94).
The methyl diester 260 was converted into the iso-propyl diester by hydrolysis followed by
esterification via the acid chloride, generated with SOCl2, in 74% yield over the two steps
(Scheme 72). The diisopropyl ester 261 was then able to undergo ortho-directed bis-
metalation with magnesium bis(2,2,6,6-tetramethylpiperidinide) (Mg(TMP)2), followed by a
quench with bromine to yield the 3,3’-dibromobinaphthtalene 262. We envisaged shortening
the synthesis by performing the ortho-metalation directly on the methyl ester 260, in
divergence to Maruoka’s route. This route was trialled with several organometallic reagents
including t-BuLi, Mg(TMP)2 and n-BuLi/TMEDA. However, as alluded to by the literature,
this led to low yields and complex mixtures of inseparable products and hence we continued
to follow the published route.
OTfOTf
CO (10 bar)dppp (15 mol%)
Pd(OAc)2 (15 mol%)
DIPEA, MeOHDMSO, 80 °C
247 99%
CO2MeCO2Me
260 78%
OHOH
Tf2O (2.2 eq.)
pyridine (4.0 eq.)CH2Cl2
94
87
Scheme 72. 3,3’-dibromination of BINOL (94).
With dibromide 262 in hand, a variety of 3,3’-disubstituted binaphthyls could be accessed
via Suzuki coupling with the requisite aryl boronic acids. Diphenyl intermediate 263 was
synthesised in 83% yield with phenylboronic acid and catalytic Pd(OAc)2/PPh3 (Scheme 73).
263 was reduced to the diol with LiAlH4, followed by bromination with PBr3 to furnish
dibromide 264. The dibromide was only sparingly soluble in EtOH and so DMF was used as
a co-solvent in the cyclisation with NaHSe, which provided the dihydroselenepine 265 in
72% yield. The entire synthesis was completed 9 steps and 24% overall yield from (R)-
BINOL (94).
Scheme 73. Synthesis of 3,3’-diphenyldinaphthodihydroselenepine 265.
5.3.3 3,5-xylyl analogue
Following the successful synthesis of 265, we then attempted the Suzuki coupling of
dibromide 262 with 3,5-xylylboronic acid 266. Using the previous Pd(OAc)2/PPh3 catalyst
system, a yield of 71% was achieved. However, separation of the product 267 from the
i) KOH, H2O, MeOH Δ
ii) SOCl2 (neat), refluxiii) i-PrOH, pyridine
260 CO2i-PrCO2i-Pr
261 74%
CO2i-PrCO2i-Pr
262 82%
Mg(TMP)2 (4.0 eq.);
then Br2 (8.0 eq.)
Br
Br
Ph-B(OH)2 (2.4 eq.)Pd(OAc)2 (10 mol%)
PPh3 (30 mol%)K2CO3
DMF, 90 °C
262 CO2i-PrCO2i-Pr
263 83% 264 84%
i) LiAlH4, THF, reflux
ii) PBr3, THF, r.t.
Ph
Ph
Ph
Ph
Br
Br
265 72%
NaHSe (1.0 eq.)
EtOH, DMF
Ph
Ph
Se
88
starting material by flash column chromatography proved problematic as the compounds co-
eluted. Alternative reaction conditions for the Suzuki coupling were employed, under which
the yield increased to 76%, but, more significantly, all the starting material was consumed
enabling purification of 267 by flash column chromatography (Scheme 74).148 The
remaining three steps (vide supra) were completed in 37% yield to furnish the 3,3’-dixylyl
dihydroselenepine 268 in 13% overall yield from BINOL (94).
Scheme 74. Synthesis of 3,3’-dixylyl analogue 268.
5.3.4 Mesityl analogue
Further issues were encountered during the synthesis of the mesityl analogue. Initial attempts
at the Suzuki coupling were unsuccessful, with very low conversion of starting material and
similar problems to xylyl analogue 267 during the purification of the products. Following a
small survey of reaction conditions, it was found that the efficiency of the reaction could be
improved by employing the biaryl phosphine ligand, SPhos 269, affording the 3,3’-dimesityl
intermediate 270 in 87% yield (Scheme 75). Buchwald has previously noted the efficacy of
269 as a ligand in challenging Suzuki cross-coupling reactions and attributes this to the
ability of the ligand to stabilise active L1Pd species.149
Scheme 75. Suzuki cross-coupling with mesityl boronic acid.
Pd(PPh3)4 (10 mol%)
Ba(OH)2·H2ODME, H2O
90 °C
262 CO2i-PrCO2i-Pr
267 76% 268 37%
3 stepsSe
B(OH)2
266
mes-B(OH)2 (3 eq.)Pd(OAc)2 (5 mol%)
SPhos 269 (5 mol%)K3PO4
dioxane, 110 °C
CO2i-PrCO2i-Pr
270 87%
mes
mes
mes =
CO2i-PrCO2i-Pr
262
Br
Br
89
The reduction of 270 with LiAlH4 did not proceed as expected, with the reaction mixture
containing many different products. Diol 271 was only isolated in 38% yield and the
purification was problematic leading to impure product. It was found that, for this substrate
270, DIBAL-H was a far more effective reagent for the reduction, affording 271 in 92%
yield (Scheme 76). The final two steps proceeded as expected in 41% yield, furnishing 3,3’-
dimesityl dihydroselenepine 272 in 17% overall yield from BINOL (94).
Scheme 76. Dihydroselenepine 272 formation on 3,3’-mesityl analogue.
5.3.5 Alternative synthetic routes to 3,3’-binaphthyls
During the investigations, several alternative routes to this class of compounds were
explored to overcome problems encountered in the synthesis of mesityl product 272. In the
original route, the methyl ester product of the methoxycarbonylation requires conversion
into the diisopropyl ester in order to undertake directed ortho-metalation. This requires 3
additional steps and results in the loss of a quarter of material. To reduce the number of
steps, the carbonylation step can be replaced with an alternative C-C bond forming reaction.
Triflate 247 was instead coupled with cyanide to afford nitrile 273 (Scheme 77). When
subjected to the ortho-metalation/quench conditions used previously (Mg(TMP)2), 273 was
brominated in the 3,3’-positions in 50% yield. A Suzuki coupling with mesitylboronic acid
was then performed to afford 3,3’-diarylated binaphthyl 275. The nitrile groups could then
be hydrolysed with a mixture of aqueous sulfuric and acetic acids, or methanolysed (Pinner
reaction)150 with acidic methanol solutions to give the diacid or diester respectively. The
original route could then be intercepted at diol 271 via a reduction to complete the synthesis.
DIBAL-H (20 eq.)
CH2Cl2
mes
mes
OH
OH
2 steps
mes
mes
271 92%
270
272 41%
Se
90
Scheme 77. Alternative route to diol 271.
Also trialled was the installation of the mesityl group prior to addition of the carbon atom at
the 2,2’-positions. 3,3’-disubstituted BINOL derivatives have been synthesised via lithiation-
borylation of dimethyl BINOL (94) (Scheme 78).151,152 Boronic acid 277 is then coupled
with the appropriate aryl halide and demethylated with BBr3 to afford disubstituted BINOL
analogue 278.
Scheme 78. Early-stage 3,3’-disubstitution.
In this fashion, 3,3’-dimesityl BINOL triflate 279 was synthesised and subjected to the
methoxycarbonylation conditions employed earlier (Scheme 79). However, in this case, only
traces of diester 280 were observed in the reaction mixture with the vast majority of starting
material left unreacted. This was attributed to high steric hindrance caused by the bulky 3,3’-
substituents as well as poor solubility of the triflate 279.
CNCN
Mg(TMP)2 (4.0 eq.);
then Br2 (8.0 eq.)THF
273 86%
CNCN
274 50%
OTfOTf
Zn(CN)2 (3.0 eq.)Pd2dba3 (5 mol%)
DPPF 192 (10 mol%)
DMF, reflux
247
Br
Br
CNCN
275 79%
mes
mes
mes-B(OH)2 (3 eq.)Pd(OAc)2 (5 mol%)
SPhos 269 (5 mol%)K3PO4
dioxane, 110 °C
mes
mes
OH
OH
2 steps
271
OMeOMe
i) ArBr, [Pd]/L
ii) BBr3
277
OHOH
278
OMeOMe
n-BuLi, TMEDA;then B(OMe)3
276
Ar
Ar
B(OH)2
B(OH)2
91
Scheme 79. Methoxycarbonylation of 279.
5.4.1 Overview
1,1’-Spirobiindane-7,7’-diol (SPINOL) 111 was first synthesised by Birman in 1999.153 Like
the binaphthyl compounds explored above, SPINOL possesses axial chirality. Chiral biaryl
compunds can epimerise given sufficient thermal input if the barrier to rotation around the
biaryl bond is overcome, however, the enantiomers of SPINOL-derived compounds are not
atropisomers but possess a quaternary centre, thus eliminating this issue.
Figure 17. SPINOL (111).
The spirobiindane scaffold has since been adapted and its derivatives used in a wide range of
transformations, for example: phosphoric acid 281 was used in the enantioselective Friedel-
Crafts reaction of indoles with imines to form chiral secondary amines;154 spiro
phosphoramidite ligands such as SIPHOS (282) were developed for transition metal
catalysed hydrogenation reactions;155 and phosphines such as 283 have been employed as
both ligands and organocatalysts.156,157 Owing to the versatility of this privileged scaffold,
we set out to synthesise Spirobiindanodihydroselenocine 284 (SPISe) by exploiting the
conditions developed for the syntheses of similar catalysts by other groups.
OTfOTf
CO (10 bar)dppp (15 mol%)
Pd(OAc)2 (15 mol%)
DIPEA, MeOHDMSO
279
CO2MeCO2Me
280 (trace)
mes
mes
mes
mes
OH
OH
SPINOL111
92
Figure 18. SPINOL-derived catalysts and ligands.
5.4.2 Synthesis of SPINOL
To begin with, SPINOL was synthesised according to the original procedure developed by
Birman (Scheme 80).
Scheme 80. Synthesis of SPINOL (111).
Dibenzylideneacetone 286 was formed via aldol condensation of acetone with two
equivalents of m-anisaldehyde (285). The double bonds were then hydrogenated using
Raney nickel in order to preserve the carbonyl moiety. The positions para- to the methoxy
groups were selectively brominated with Br2 in order to prevent cyclisation onto these
positions in the next step. Dibromide 288 then underwent a dehydrative-biscyclisation in hot
polyphosphoric acid to afford spirobiindane 289. Removal of the bromides via lithium-
P
283
PhPO
ONMe2
282
PO
O
281
Ar
Ar
OHO
Se
284
OMe
O
H O
NaOHEtOH, H2O
OMe
O
OMe
Raney-NiAcetone
OMe
O
OMe
H2 (balloon)
pyridineCH2Cl2
OMe
O
OMe
Br Br
Br2 (2.5 eq.)MeO
OMe
Br
Br
MeO
OMethen EtOH
n-BuLi (4.0 eq.);OH
OHCH2Cl2
BBr3
105 °CH2O·(HPO3)n
285 286 65% 287 90%
289 59%288 96%
111 72%290 99%
93
halogen exchange followed by demethylation of the methoxy groups with BBr3 gave
racemic SPINOL (111) in 24% overall yield (lit. 28%).
In the original paper, racemate 111 was resolved with L-menthyl chloroformate followed by
column chromatography of the resulting biscarbonate. The carbonate esters were then
cleaved with hydrazine. However, a more straight-forward method, developed by Deng and
co-workers, was followed that involves co-crystallisation of (S)-SPINOL (111) with N-
benzylcinchonidinium chloride 291, Leaving (R)-SPINOL remaining in solution.158 The
solvent is then filtered to give a solution of enantioenriched (R)-SPINOL and a 1:1 two-
component crystal of (S)-SPINOL (111) and 291. The filtrate can be dissolved in aqueous
HCl and extracted with ethyl acetate to afford free (S)-SPINOL (111). This procedure was
replicated, obtaining (S)-111 in 90% ee (Scheme 81). Enantiopure 111 can then be achieved
via subsequent recrystallisation from EtOAc/hexane.
Scheme 81. Separation of the enantiomers of 111.
5.4.3 Spirobiindanodihydroselenocine (SPISe)
With SPINOL in hand, a procedure analogous to that employed in the synthesis of
dihydroselenepine 265 from BINOL was followed (Scheme 82). Triflate 292, formed in
near-quantitative yield from 111 and triflic anhydride, was methoxycarbonylated to afford
diester 293 in 63% yield. Reduction with LiAlH4 followed by bromination with PBr3
provided the dibromide 295 which was cyclised using NaHSe (generated in situ from NaBH4
and elemental selenium) to generate spirobiindanodihydroselenocine (SPISe) 284 in 5 steps
with 27% overall yield from 111. To obtain enantiopure selenide 284, enantiopure SPINOL
N+
N
HO Cl-
291
OH
OH
OH
OH
291 (0.55 eq.)
then filter; extract (HCl/EtOAc)
111 85%(90% ee)
111
94
generated via resolution with N-benzylcinchonidinium chloride 291 can be used in this
synthesis. Alternatively, the enantiomers of 284 could be separated in >99% enantiomeric
excess by preparative chiral HPLC.
Scheme 82. Synthesis of dihydroselenocine 284.
5.4.4 Towards SPINOL-derived diselenide
As there was a sample of triflate 292 in hand, the cross-coupling with alkyl selanyl stannanes
that had been previously developed was attempted for this substrate. Reaction with n-
butylselanyl stannane returned only starting material, however, MeSeSnBu3 afforded mono-
substituted product 296 in fair yield (Scheme 83).
Scheme 83. Cross-coupling of SPINOL-triflate (292).
Unlike in the case with BINOL triflate and the Josiphos ligand, no ee was observed (see
Section 4.4.8) and as no disubstituted product was observed, this route was not investigated
CO (10 bar)DPPP 207 (15 mol%)Pd(OAc)2 (15 mol%)
DIPEA, MeOHDMSO, 80 °C
292 99% 293 63%
Tf2O (2.2 eq.)
pyridine (4.0 eq.)CH2Cl2
111
TfO
OTf
MeO2C
CO2Me
THF, r.t.
294 87%
LiAlH4
OH
HO
THF
295 70%
PBr3 (0.5 eq.)
Br
Br
EtOH, DMF85 °C
NaHSe (1.0 eq.)Se
284 72%
Bu3SnSeMe (2.5 eq.)[Pd(π-cinnamyl)Cl]2 (5 mol%)
PhPF-t-Bu (10 mol%)toluene (0.1 M)
110 °C, 17 h 296 65% (0% ee)
TfO
OTf
MeSe
OTf
292
95
further. It was also proposed that it may be more straightforward to install the selenium at an
earlier stage, and so dibenzylideneacetone 297 was synthesised in two steps from m-
bromobenzaldehyde (232c) (Scheme 84) in order to intercept the previously described
SPINOL synthesis (see Section 5.4.2).
Scheme 84. Double aldol reaction of 3-n-butylselenobenzaldehyde 233c.
The next step was the hydrogenation of 297. For this, various catalysts were trialled
including Pd/C, Rh/Al2O3 and Raney-nickel (Scheme 85a). All of these methods resulted in
cleavage of the Ar-Se bonds. To overcome this a reduction with a copper hydride ‘Stryker-
type’ reagent was attempted, generated in situ from the reduction of stoichiometric
Cu(OAc)2 with polymethylhydrosiloxane in the presence of 10 mol% of the bidentate
phosphine, BDP.159 Unfortunately, this method resulted in complex mixtures of products
with only low yields of partially-reduced substrates such as 300 identified (Scheme 85b).
Scheme 85. Attempted hydrogenations of 297.
222 (1.2 eq.)[Pd(π-cinnamyl)Cl]2
(2.5 mol%)xantphos (5 mol%)
toluene (0.1 M)110 °C, 3 hBr
H
O
Se(n-Bu)
H
O
233c 99%
O
NaOHEtOH, H2O
Se(n-Bu)
O
Se(n-Bu)
297 45%232c
H2 (balloon)
Raney-NiAcetone
Se(n-Bu)
O
Se(n-Bu)
297
O
298 78%
299 (0.1 eq.)
PMHS, t-BuOH (3 eq.)
Se(n-Bu)
O
Se(n-Bu)
297
O
300 (trace)
Se(n-Bu)Se(n-Bu)
P
PCuH
Ph Ph
Ph Ph
a)
b)
96
CHAPTER SIX
Oxidations with cyclic
alkyl selenides
97
6. Oxidations with cyclic alkyl selenides
We had already demonstrated that selenophenes such as VanSe were ineffective in allylic
oxidation with TBHP (see section 3.3), however, the cyclic alkyl selenides will vary greatly
in their reactivity as there is no conjugation of the heteroatom to the aromatic system.
Preliminary studies into allylic oxidation with selenides as opposed to diselenides were
undertaken with the achiral biphenyl catalyst 252 (Scheme 86).
Scheme 86. Oxidation of non-1-ene (171) with catalytic dihydroselenepine 252.
Non-1-ene (171) was used as the model substrate, after 24 hours with one equivalent of
TBHP allylic alcohol 171 was observed in 45% yield in approximately 6:1 ratio with the
enone by-product 173. The remainder of the starting material (approximately 48%) was left
unreacted after this time. With this promising result, the catalyst was replaced with the chiral
unsubstituted binaphthyl (R)-255 (Scheme 87). The oxidation proceeded similarly to that
with the biphenyl catalyst 252 but no stereoinduction was observed when the ratio of
enantiomers was measured using chiral gas chromatography. Allylbenzene was also oxidised
in the same way with no stereoinduction. Lowering the temperature of the reaction resulted
in much increased reaction times but no improvements in ee.
4 4 4OH OCHCl3, 60 °C24 h
252 (20 mol%)TBHP (1.0 eq.)
171 172 45% 173 7%
Se
252
98
Scheme 87. Catalytic oxidations of non-1-ene (171) and allylbenzene (176) with chiral selenide (R)-255.
We also attempted to apply the selenide catalysts to Breder’s allylic imidation but they were
inactive under these conditions (Scheme 88).
Scheme 88. Attempted allylic imidation catalysed by dihydroselenepines 252 or 255.
6.2.1 Initial investigations into propargylic oxidation
The oxidation of propargylic C–H bonds with selenium dioxide has been known for many
years and yet it is rarely exploited and very few developments have been made with respect
to this class of substrates.160 4-Phenyl-1-butyne 301a was initially selected as the substrate as
this would highlight any competing oxidation at the benzylic position and the phenyl group
provided a chromophore as a handle for chiral HPLC.
4 4 4OH OCHCl3, 60 °C24 h
(R)-255 (20 mol%)TBHP (1.0 eq.)
171 172 57% (0% ee) 173 6%Se
(R)-255CHCl3, 60 °C24 h
(R)-255 (20 mol%)TBHP (1.0 eq.)
176 177 42% (0% ee) 178 5%
OH O
OBn
O
OBn
O
NFSI (0.97 eq.)252 or 255 (5 mol%)
4Å mol. sieve, THFr.t., 16 h
N(SO2Ph)2
183 0%182
99
Table 13. Catalytic propargylic oxidations catalysed by organoselenium compounds.
Entry Catalyst Time / h Yield (%)[a] 302:303
1 140 22 16 2:1 2 140 96 57 5:1 3 252 22 53 >20:1 4 252 96 53 18:1 5 (R)-255 24 48 >20:1[b]
[a]Yield calculated using 1H NMR with mesitylene (0.33 eq.) as the internal standard; [b]The ee was 0%.
301a was oxidised at the propargylic position with a diselenide (Table 13, entries 1-2) and
both achiral and chiral alkyl selenides (Table 13, entries 3-5). No benzylic oxidation was
noted. The selenides performed the reaction much more rapidly than diselenide 140,
reaching the end point within 22 hours (Table 13, entry 3). The selenides were also far more
biased towards the desired alcohol product 302a when compared to the diselenide. With the
enantiopure, chiral selenide (R)-255 (Table 13, entry 5), there was no stereoinduction
observed.
6.2.2 Substrate scope
Thus far, only a terminal alkyne had been investigated. To demonstrate the efficacy of the
reaction for internal alkynes TMS alkyne 301b and phenyl substituted alkyne 301c were
synthesised. The alkynes were reacted with unsubstituted binaphthyl catalyst (R)-255 and
3,3’-disubstituted binaphthyl (R)-265 (Table 14).
CDCl3, 60 °C
catalyst (20 mol%)TBHP (1.0 eq.)
OH O
301a 302a 303a
SeSeSe
Se
(R)-255252140
100
Table 14. Substrate scope for catalytic propargylic oxidations.
Entry R = Catalyst Time / h Yield (%)[a] 302:303 ee (%)[b]
1 H (301a) (R)-265 24 60 14:1.0 0 2 TMS (301b) (R)-255 20 54 4.1:1.0 0 3 TMS (301b) (R)-265 72 56 3.0:1.0 0 4 Ph (301c) (R)-255 20 24 2.4:1.0 0 5 Ph (301c) (R)-255 72 59 4.9:1.0 0
[a]Yield calculated using 1H NMR with mesitylene (0.33 eq.) as the internal standard; [b]Measured using chiral HPLC.
Substitution at the terminal position resulted in a marked increase in the amount of over-
oxidised propargylic ketone by-product. Furthermore, addition of a phenyl group at this
position significantly reduced the rate of reaction. Nevertheless, these preliminary results
demonstrate that this procedure is applicable to internal alkynes, albeit with no asymmetric
control using these catalysts.
We initially proposed that the mechanism of oxidation would be similar to that discussed
earlier for diselenides and selenium dioxide (see Section 1.2.1, Scheme 2), except in this
case, the intermediate 307 will be unable to collapse to an allylic selenium oxide. Thus,
hydroxyl transfer and catalyst release would occur in a single, concerted step, removing the
possibility of direct over oxidation of the substrate, leaving only product over oxidation by
reaction of the allylic alcohol with another species (Scheme 89). Initial investigations
CDCl3, 60 °C
catalyst (20 mol%)TBHP (1.0 eq.)
OH O
301b-c 302b-c 303b-c
Se
(R)-265
R R R
R = TMS, Ph
Se
(R)-255
Ph
Ph
101
appeared to be in support of this as the ratio of alcohol 308 to enone 309 was improved with
the selenide catalyst.
Scheme 89. Proposed mechanism for allylic oxidation with dihydroselenepines.
To shed further light on the mechanism, selenoxide 310 was synthesised via oxidation with
mCPBA (Scheme 90).137 310 was used in a stoichiometric reaction with both alkene 171 and
alkyne 301b substrates. In both cases only traces (<5%) of the allylic/propargylic alcohols
were detected by 1H NMR after 72 hours, suggesting that selenoxide 310 is not involved in
the catalytic cycle for allylic C–H oxidation. Further investigations into catalytic
intermediates and the mechanism of this reaction are ongoing within the group.
Scheme 90. Stoichiometric propargylic oxidation with selenoxide 310.
Se+ O-
R
R
enereaction
R'
H
R''
R' R''
RR
OSe
H
SeR
R
catalystoxidation
R'
OH
R'' R'
O
R''over [O]
305
306
307
308 309
304
SemCPBAK2CO3CH2Cl2
Se+ O-
R Se+ O-
72 h
CDCl3R R
OH O
<5% not detected
252 310
310311 312 313
102
Cyclic alkyl selenides have been shown to catalyse allylic and propargylic C–H oxidations
with TBHP. The oxidations demonstrate excellent selectivity for the allylic/propargylic
alcohols with little over-oxidation to the α,β-unsaturated carbonyl products. Where
applicable, no competing benzylic oxidation was observed. However, when using
enantiopure chiral selenides, no asymmetric induction was noted and the mechanism of this
transformation is still unclear. Future work will involve further investigation into the
mechanism in order to provide insight to catalyst design for an enantioselective variant of
this reaction.
103
CHAPTER SEVEN
Tetrahydroselenophenes
104
7. Tetrahydroselenophenes
Figure 19. Chiral tetrahydroselenophenes 313.
Another class of chiral, C2-symmetric selenium compounds are trans-2,5-disubstitued
tetrahydroselenophenes (THSe) 313 (Figure 19). Analogy was drawn from
tetrahydrothiophene (THT) based structures that have been previously applied in
enantioselective organo- and Lewis basic catalysis.161–163 Furthermore, there are also some
instances of catalysis with chiral tetrahydroselenophenes. For example, Metzner and co-
workers employed 2,5-dimethyl catalyst 316 in the enantioselective synthesis of epoxides
from aldehydes via a selenonium ylide (Scheme 91a). Yeung also employed mannitol-
derived 319 in a Lewis base catalysed bromoaminocyclisation (Scheme 91b).128,130
Scheme 91. Use of tetrahydroselenophenes in catalysis.
Other than the above, the tetrahydroselenophene motif has been seldom applied to catalysis
and there are few published synthetic routes. Chiral THSe cores are usually accessed from
sugar precursors, with the structure most commonly found in selenonucleosides explored for
Se RR
313
Ph BrAr H
OSeMe
Me
316 (20 mol%) O
Ph
Ar
317 (1:1 dr)76 - 94% ee (trans)
NaOH
Se
OO
O
O Ar
Ar319
R1 NH(3-Ns)R2 N
NsR2
R1
Br
R1 = AlkylR2 = Aryl 51 - 95% ee
a) Metzner (2001):
b) Yeung (2013):
cat. 319NBS
314 315
318 320
105
medicinal applications.164,165 However, while derived from natural sugars that are readily
available as single enantiomers, these structures feature free hydroxyl groups that add further
complexity and may require protection or removal for our applications. We therefore set out
to establish an enantioselective practical route to enable the direct synthesis of a variety of
trans-2,5-disubstituted tetrahydroselenophenes. Having previously demonstrated the
successful utility of divalent selenium nucleophiles in ring closures, we targeted
intermediates of the type 321.
Scheme 92. Key disconnection in the synthesis of 2,5-disubstituted tetrahydroselenophenes.
7.2.1 Overview
In their work, Metzner synthesised dimethyl catalyst 316 from commercially available
(2S,5S)-hexanediol via activation of both –OH groups as mesylates followed by nucleophilic
substitution with Li2Se in a one-pot procedure. To utilise this method, a general route to
enantiopure 1,4-diols was required. Enantiomerically enriched diols of this type, for
example, 1,4-diphenylbutane-1,4-diol 324, can be accessed via enantioselective reduction of
the corresponding 1,4-diketone 322 and for this transformation the Corey-Itsuno reduction
with a Corey-Bakshi-Shibata reagent 323 (CBS) was selected (Scheme 93).
Scheme 93. Corey-Itsuno reduction of 1,4-diketone 322.
SeRR
RR
X
X
Se2-
321313
324
PhPh
OH
OHPh
PhO
O
NB O
HPh
Ph
R (cat.)
BH3
322
323
106
The Corey-Itsuno reaction is the enantioselective reduction of a prochiral ketone to an
alcohol with an oxazaborolidine catalyst. In 1983 Itsuno reported the asymmetric reduction
of aromatic ketones in high optical yield with a reagent prepared from amino alcohol 325,
derived from (S)-valine (Scheme 94).166,167 During their investigations it was noted that high
enantioselectivity was only achieved when two equivalents of borane were used whereas a
1:1 ratio of aminoalcohol:borane resulted in very low stereoinduction.
Scheme 94. Itsuno’s initial observations in the reduction of ketones with oxazaborolidines.
Building upon the work by Itsuno, in 1987 Corey published the catalytic asymmetric
reduction of ketones employing chiral oxazaborolidines.168 The group were able to isolate
326 and confirm its structure, however, solutions containing only 326 were not able to
reduce acetophenone (327) at room temperature. When further equivalents of borane were
added to the reaction mixture, acetophenone was reduced quantitatively in <1 minute with
95% ee. Corey was able to use 326 catalytically in amounts as low as 2.5 mol% with no
detriment to enantioselectivity. However, reducing the loading further resulted in diminished
ee, probably due to competing background reduction of the substrates by borane. The
group’s investigations led them to discover that proline-derived catalyst 323 was even more
effective, reducing a variety of ketones in high ee with very short (<1 min) reaction times
(Scheme 95).
NH2
OH
PhPhBH3 (2.0 eq.)
HN BH
O
PhPh
326not isolated
325
O
327 (0.8 eq.) OH
328
107
Scheme 95. Corey’s catalytic reduction of ketones with proline-derived oxazaborolidine 323.
In mixtures of 323 and borane, a complex 331, formed through coordination of the nitrogen
lone-pair to a free borane molecule, is observed by 11B NMR. Corey proposed that this
complex is the active reducing agent and from this a mechanistic hypothesis was developed
that could explain both the stereoselectivity of the reaction, and the much-accelerated rate of
reduction relative to BH3·THF alone (Scheme 96).169
Scheme 96. Proposed mechanism for the catalytic Corey-Itsuno reduction.
The mechanism begins with the coordination of BH3 to the Lewis basic nitrogen on the less-
hindered α-face of the molecule, activating the BH3 while also increasing Lewis acidity of
the endocyclic boron. The ketone substrate 332 binds to the Lewis acidic boron with the
less-sterically hindered lone pair such that the larger substituent is angled away from the
oxazaborolidine system. The ketone, now aligned with the coordinated BH3 molecule
R1 R2
O
R1 = t-Bu, arylR2 = alkyl
R1 R2
OH
NB O
HPh
Ph
H 323 (5 mol%)
330 >99%(89 - 97% ee)
BH3·THF (0.6 eq.)THF, 25 °C329
Ph
Ph
NB O
HPh
Ph
H
NB O
HPh
Ph
HH3B
N BO
O
HRS
RLH2B H
Ph
Ph
N+ BO
O
H
BH2
RS
RLH
N BO
H2B
H BH2
O RS
RLH
H PhPh
BH3
RL
O
RS
BH2
RL
OH
RS
HCl, MeOH
323
331
337
333334
335 336
BH3
RL
O
RS
332H
108
undergoes face-selective reduction via a 6-membered transition state 333. The product could
be released either by N- to O- ligand exchange with the exocyclic boron generating
alkoxyboron species 335 and regenerating catalyst 323. Alternatively, attack on 334 by
another BH3 molecule followed by collapse of 6-membered 337 to regenerate the catalyst
could also release alkoxyboron 335. Substoichiometric quantities of borane are employed
due to the alkoxyborane species’ 335 ability to act as an active hydride source. The
mechanistic proposal highlights the dual functionality of the catalyst as both a Lewis base,
activating the BH3 reducing agent, and in turn a Lewis acid, activating the substrate to
reduction through coordination to the ketone. Furthermore, the superiority to Itsuno’s valine-
derived oxazaborolidine 326 is demonstrated as, although disfavoured, BH3 can bind to the
ß-face of this reagent, resulting in the other product enantiomer. In the proline system 323,
ß-coordination is inhibited by the rigid ring system. Further developments to the
aminoalcohol backbone resulting in increased enantioselectivity have been made by various
groups including the original authors, however, use of diphenylprolinol remains widespread
and preferred due to the availability and low cost of proline.
While 323 is isolable, it is extremely air and moisture sensitive. To overcome this CBS
reagent is available commercially as the B-methyl analogue. This reagent is much less
sensitive and can be weighed in air. For the synthesis of tetrahydroselenophenes, however, a
CBS-type reagent was generated inexpensively in situ from diphenylprolinol and
trimethylborate.170
7.2.2 2,5-diaryl tetrahydroselenophenes
Outlined below is a general route to trans-2,5-diaryl tetrahydroselenophenes, exemplified for
diphenyl compound 340 (Scheme 97).
109
Scheme 97. Synthesis of 2,5-diaryl tetrahydroselenophenes exploiting the Corey-Itsuno reaction.
Friedel–Crafts acylation with succinyl chloride (338) enables facile installation of a variety
of aryl groups. The low yield for this step is attributable to the fact that succinyl chloride
exists in equilibrium with dihydrofuranone 342 and, as such, a large amount of by-product
343 was also formed (Scheme 98).
Scheme 98. Succinyl chloride isomers.
Despite this, the availability of the reagents and generality of this step still make it an
attractive route. CBS reduction resulted in only 78% ee for diol 324. It was proposed that
this was due to only a small differentiation in size between RS and RL. Separation of the
diastereomers by flash column chromatography was also problematic due to polarity of the
hydroxyl groups, however, it was envisaged that a single, enantiopure diastereomer could be
isolated through recrystallisation at a later stage. The final ring-closing step resulted in a
mixture of selenide 340 and diselenide 341 that were of very similar polarity. Most of
diselenide 341 could be removed by flash column chromatography followed by two
recrystallisations from n-hexane, affording 340 in 96% ee and ca. 30% yield, albeit with
Ph
OPh
OCl
ClO
O
AlCl3 (2.0 eq.)
benzene Ph
OHPh
OH
NH OH
HPh
Ph
339 (20 mol%)
B(OMe)3 (25 mol%)BH3·SMe2 (2.0 eq.)
THF, r.t.
i) MsCl (2.5 eq.)Et3N (4 eq.)
ii) NaHSe, EtOH SePhPh
322 32% 324 84%(78% ee, 10:1 dr)
340 53% 341 18%
SeSe
Ph
Ph
338
ClCl
O
O
O
O
Cl Cl
AlCl3 (2.0 eq.)
benzeneO
O
Ph Ph
342 343338
110
significant loss of material. The structure and absolute configuration of the selenide and
diselenide were confirmed by X-ray crystallography (Figure 20).
Figure 20. Crystal structures of THSe 340 and diselenide 341 (50% probability ellipsoids).
As well as diphenyl THSe 340 the ditolyl analogue 344 was also prepared in 95% ee
(Scheme 99a), however attempts to produce the mesityl compound were unsuccessful at the
Friedel–Crafts stage, with the only the carboxylic acid 345 isolated in low yield (Scheme
99b).
Scheme 99. Other 2,5-diaryl tetrahydroselenophenes.
XX XX340 341
Se
344 17%(95% ee, >20:1 dr)
ClCl
O
O
AlCl3 (2.0 eq.)
mesitylene
OOH
O
a)
b)
338 345
111
7.3.1 Overview
The “CBS-route” (vide supra) allowed the generation of tetrahydroselenophenes in good
enantiomeric excess, however, it was only generally applicable to 2,5-diaryl compounds as a
key step was the Friedel-Crafts acylation. Furthermore, the low enantiomeric excess
experienced from the CBS reduction (70-80% ee) meant that the final compound required
recrystallisation, resulting in significant reduction of yield. To overcome this issue and
broaden the scope to the synthesis of 2,5-dialkyl products, a new route was devised for the
synthesis of enantiomerically enriched 1,4-diols 346 (Scheme 100).
Scheme 100. a) Alternative retrosynthesis analysis for the synthesis of 2,5-disubstituted
tetrahydroselenophenes; b) Key stereodefining step exploiting enzymatic kinetic resolution of alcohols.
In the retrosynthetic analysis, diols 346 can be accessed via hydrogenation of 1,2-
disubstituted alkene products of olefin metathesis 347. The substrate for the metathesis
would be a vinylic alcohol of the type 348. There are various methods for direct synthesis of
enantiomerically enriched secondary vinylic alcohols, usually involving enantioselective
addition of a vinyl organometallic to an aldehyde.171–173 Alternatively, kinetic resolution of a
vinyl alcohol under Sharpless’ asymmetric epoxidation conditions would yield a single
enantiomer of unreacted alcohol and the 2,3-epoxyalcohol.174 In this synthesis, however, an
enzymatic resolution of racemic (±)-348 was selected as this generally results in extremely
RR
OH
OHR
ROH
OHR
OH
R
O
H
a) Retrosynthetic analysis:
b) Key stereodefining step:
346 347 348 349R = aryl, alkyl
R
OH
(±)-348
OAc (0.5 eq)
Candida antarctica lipase B R
OH
348
R
OAc
350
reductionolefin
metathesisGrignardaddition
112
high enantiopurity, is applicable to a wide variety of substrates and enables the separation of
both enantiomers—a feature that will be useful in order to obtain both enantiomers of the
final compounds. Acylation of the alcohol with a lipase was selected as this method has been
applied extensively to secondary alcohols.175 Transesterification of vinyl acetate with
Novozym 435, an immobilised candida antarctica lipase B (CAL-B), was selected as the
preferred methodology due to the enzyme’s broad functional group tolerance.176,177 While
the enzymatic resolution should provide very enantiopure material, another benefit of this
synthesis is the reaction of two molecules of alcohol 348 in the olefin metathesis. According
to the Horeau principle, dimerisation of molecules results in the statistical amplification of
any pre-existing enantiomeric excess as predicted by Langenbeck and demonstrated
mathematically and synthetically by Horeau.178,179 Although not formally a dimerisation, the
enantiomeric excess should increase after the olefin metathesis step, provided any meso
compound can be separated.
7.3.2 2,5-Diphenyltetrahydroselenophene
The proposed route was exemplified for the 2,5-diphenyl product 324 (Scheme 101).
Benzaldehyde (351) was converted quantitatively into α-vinylbenzyl alcohol (177) via
addition of vinyl magnesium bromide. The enzymatic resolution proceeded as expected,
affording (S)-alcohol 177 in 97% ee. A variety of catalysts were trialled for the metathesis
step, with the 2nd generation Grubbs Catalyst™ producing the best yield of diol 354.
Reduction of the alkene was effected with 5% rhodium on alumina in quantitative yield.
Other hydrogenation catalysts (e.g. Pd/C) and longer reaction times resulted in cleavage of
one or both C–O bonds. Here, the previous route could be intercepted to synthesise the
tetrahydroselenophene 340 (see Section 7.2.2). Although 2 more steps than the previous
route, this procedure afforded diol 324 in far higher ee and as a single diastereomer,
removing the need for several recrystallisations of the final product.
113
Scheme 101. Towards 2,5-diphenyl tetrahydroselenophene (340).
Metathesis of the acetate 353 proceeded similarly to the free alcohol, however using this
reactant would require an additional step to remove the acetate or investigation of conditions
that could remove the acetate in a pan-hydrogenation with the alkene. An alternative
approach to improve the yield of the metathesis step could be to tether the two substrates
together as a dialkoxysilane and effect a ring-closing metathesis (RCM).180
Ph H
O MgBr
THF Ph
OH
(±)-177 99%
Ph
OH
(S)-177 40%(97% ee)
Novozym 435
toluene, r.t.
OAc352
(0.55 eq.)
Ph
OAc
353 46%
Ph
OH Grubbs II (1 mol%)
CH2Cl2, reflux24 h
PhPh
OH
OH354 58%
H2 (balloon)Rh/Al2O3 (10 mol%)
EtOAc, 2 hPh
PhOH
OH324 99%(99% ee)
351
(S)-177
114
7.3.3 2,5-dialkyltetrahydroselenophenes
As mentioned previously, this method is generally applicable to any aldehyde allowing for
the synthesis of 2,5-dialkytetrahydroselenophenes. This was demonstrated with the synthesis
of dicyclohexyl compound 360 (Scheme 102a).
Scheme 102. a) Synthesis of 2,5-dicylcohexyltetrahydroselenophene (360); b) Crystal structure of 360.
Cyclohexane carboxaldehyde 355 was reacted with vinyl magnesium bromide to afford
racemic alcohol 356 in quantitative yield. The racemate was resolved to give (S)-356 in 42%
MgBr
THF
OH
(±)-356 99%
Novozym 435
toluene, r.t.
OAc
Grubbs II (1 mol%)CH2Cl2, reflux
24 h
OH
OH
357 44%
H2 (balloon)Rh/Al2O3 (10 mol%)
EtOAc, 2 h
358 93%
O
H
OH
(S)-356 42%
OH
OH
MsCl (2.5 eq.)
Et3N (4 eq.)THF
OMs
OMs
359
Li2Se (1.2 eq.)
THF Se
360 31%
a) Synthesis of 2,5-dicyclohexyltetrahydroselenophene:
b) ORTEP drawing of 360:
360
355
352(0.55 eq.)
115
yield (maximum theoretical yield = 50%). The enantiopurity was not measured for this
intermediate in this case, however, this is a known substrate for the CAL-B and other groups
have achieved ee’s in excess of 99%.181 Olefin metathesis occurred in only 44% yield but
this was deemed acceptable owing to the ease of the previous steps and availability of
starting materials. Hydrogenation of the alkene proceeded without issue to afford diol 358.
Here, the route deviated slightly to previous syntheses of this class of molecule. It was found
that a one-pot mesylation procedure resulted in an inseparable mixture of products including
the selenide 360 and its diselenide analogue. Ms2Se2 and other oligomers were also detected
and it was proposed that excess MsCl could be responsible for the diselenides observed here
and isolated previously (see Section 7.2.2). To overcome this, the dimesylate 359 was
extracted with CH2Cl2 and HCl (1 M). Although 359 is highly reactive and could not be
isolated it was stable in dilute solution. Following this, an alternative Se2- nucleophile, Li2Se,
generated from LiBHEt3 and elemental selenium, was used to perform the cyclisation.
Pleasingly no diselenide was observed and the only product isolated was THSe 360, albeit in
low yield, with the structure confirmed by X-ray crystallography (Scheme 102b).
7.4.1 Overview
Another route explored was inspired by Hodgson and co-worker’s reports of the
dimerisation of terminal epoxides 361 to afford 2-ene-1,4-diols 362, effected by lithium
tetramethylpiperidide (LiTMP) (Scheme 103).182
Scheme 103. Hodgson’s dimerisation of terminal epoxides.
t-BuO LiTMP (1.3 eq.)
t-BuOMe/hexanes-5 °C
t-But-Bu
OH
OH
Hodgson (2005):
362 86%361
116
The proposed mechanism proceeds via the dimerisation of two α-lithiated terminal epoxides
363 (Scheme 104). Hodgson suggests that oxiranyl anions 364 exhibit carbenoid-like
behaviour, being both nucleophilic and electrophilic.183 Thus, one lithiated species can attack
another to form adduct 365. This species can then undergo syn-elimination to form the (E)-
alkene (E)-366 (Scheme 104b). The group found that when the side chain was very hindered
(e.g. R = t-Bu), the (E)-alkene was the only observed product. However, with less hindered
side chains (e.g. R = n-alkyl, cyclohexyl) some of (Z)-366 was also formed as a minor
product via anti-elimination, due to decreased 1,3-diaxyl strain in the transition state
(Scheme 104c). The configuration of the symmetrical alkenes was initially confirmed by
comparison with 1H NMR data for the known compounds and later by X-ray
crystallography.
Scheme 104. Proposed mechanistic hypothesis for the dimerisation of terminal epoxides.
These products 366 could be used to intercept the previous route, bypassing the low-yielding
olefin metathesis step. The production of a mixture of alkene isomers is inconsequential to
the synthesis of 2,5-disubstituted tetrahydroselenophenes as the double bond is hydrogenated
RO
HH
LiTMPR
OLi
dimerisationR
ROLi
Li
O
a) Dimerization:
b) Syn-elimination:
c) Anti-elimination:
364 365
OLiO
R
H
Li
RR
OLi
OLiR
H
OLi
O
R
Li
R
365 (E)-366
365
R
R
OHOH
(Z)-366
363
117
in the next step. As before, this procedure will also exploit the Horeau principle, enhancing
enantiopurity by means of the dimerisation step. Several chiral terminal epoxides are
commercially available as single enantiomers, or can be readily accessed via hydrolytic
kinetic resolution (HKR) of racemic mixtures.184 First reported in 1997 by Jacobsen and co-
workers, the HKR is the kinetic resolution of terminal epoxides by hydrolysis of one
enantiomer to the corresponding 1,2-diol. The reaction is catalysed by (salen)Co(III)
complexes which are generated in situ from the commercially available Co(II) complexes
via Brønsted acid catalysed aerobic oxidation. Since its development, the HKR has been
widely applied due to its applicability to a variety of electronically and structurally diverse
terminal epoxides. The reaction has very high selectivity with the vast majority of substrates
investigated exhibiting krel > 100.185 Therefore, it was expected that this reaction would
enable the synthesis of a wide range of 2,5-disubstitutedtetrahydroselenophenes in very high
enantiopurity. The reaction is performed at high concentration which permits scalable
reactions. Furthermore, unlike the CBS reagent and lipase enzyme, both enantiomers of the
(salen)Co catalyst are commercially available for a similar price.
7.4.2 2,5-dialkyl tetrahydroselenophenes
The epoxide dimerisation reaction was applied in the syntheses of 2,5-
dialkyltetrahydroselenophenes and the route is exemplified below for the cyclohexyl variant
358 (Scheme 105).
118
Scheme 105. Towards 2,5-dicyclohexyltetrahydroselenophene (360).
Vinylcyclohexane was epoxidised with mCPBA to afford racemic epoxide (±)-368 in high
yield. The racemate was then resolved by HKR to afford the (R)-epoxide (R)-368 in greater
than 99% ee (GC). The absolute configuration of the epoxide was confirmed by comparison
of the optical rotation with the literature. Dimerisation furnished a mixture of alkene isomers
357 in 68% yield (lit. 77%) that were hydrogenated over Rh/Al2O3 to diol 358. The diol can
now intercept the route devised previously (Scheme 102).
In summary, we have developed three complementary routes to enantiopure 2,5-
disubstitutedtetrahydroselenophenes that exploit the Corey-Itsuno reduction, enzymatic
resolution and hydrolytic kinetic resolution as means to access single enantiomers of the
products. The syntheses should allow access to a diverse range of selenide catalysts from
commercially available feedstock starting materials. In the future, these routes will enable
facile catalyst tuning and development.
mCPBACH2Cl2
O O
(±)-368 97% (R)-368 44%(>99% ee)
(R,R)-(salen)Co(II) (0.5 mol%)H2O (0.55 eq.)AcOH (2 mol%)THF, air, 0 °C
LiTMP (1.3 eq.)
t-BuOMe-5 °C
OH
OH
357 68%(2:1 E:Z)
H2 (balloon)
Rh/Al2O3EtOAc
2 h
OH
OH
358 95%
367
119
CHAPTER EIGHT
Lewis base catalysed
cyclisations
120
8. Lewis base catalysed cyclisations
8.1.1 Background
Halofunctionalisations of alkenes are amongst one of the oldest and most widely applied
functional group interconversions in synthetic organic chemistry. The intermediates and
mechanisms of such transformations, where a cyclic halonium ion 370 is trapped by a
nucleophilic species, were first proposed by Roberts and Kimball in 1937 (Scheme 106).186
This hypothesis clearly explained the observation of anti-addition products 371 from these
reactions.
Scheme 106. Halofunctionalisation via halonium intermediates.
Further evidence towards the existence of these species was provided by Winstein and Lucas
in a series of studies on the reactions of bromohydrins with hydrogen bromide, where the
stereochemical outcomes could be explained by an intermediate bromonium ion.187,188 Later,
Olah utilised low temperature 1H and 13C NMR to study halonium ions generated by fluoride
elimination from 1,2-halofluorides 372 (Scheme 107).189–192 For bromine and iodine their
findings were consistent with cyclic species 373a–f (Scheme 107b). Some chloronium ions
were also observed, however 1,2-disubstituted analogues 373h were prone to rearrangement
and the 1,1-disubstituted compound formed an acyclic carbenium species 373i (Scheme
107c). They did not observe any evidence of cyclic fluoronium ions but instead postulated an
acyclic species from 2,3-difluoro-2,3-dimethylbutane, with the fluorine atom exchanging
rapidly between the two sites in a ß-fluorocarbenium species.
RR
"X+" RR
X+
Nu-
370
RR
X
Nu
371X = Cl, Br, I
369
121
Scheme 107. Olah’s study of halonium ions.
More recently, highly hindered iodo- and bromonium ions have been isolated and
characterised by X-ray crystallography, confirming the existence of such species beyond any
reasonable level of doubt.193,194
8.1.2 Configurational stability
The cyclic structure of halonium ions leads to highly stereospecific ring opening by
nucleophiles. Despite this attribute, few examples of enantioselective halofunctionalisation
reactions have been reported due to racemisation of chiral halonium intermediates as their
formation is reversible. This racemisation has been proposed to occur through several
different pathways, the most prevalent and well-studied of which is olefin-to-olefin
exchange of X+. Bromonium ion transfer was first observed by Brown and co-workers
following the observation that addition of small quantities of alkene 375 to the stable
bromonium ion 374, characterised previously, led to a broadening of 1H signals in the NMR
spectrum suggesting a rapid transfer of bromonium from olefin-to-olefin with a second order
rate constant calculated to be ~2.0x107 dm3 mol-1 s-1 at 25 °C (Scheme 108).195 The kinetic
studies indicated that the reaction was first order in added alkene 375, ruling out the
participation of any external species such as free BrOTf in the transfer. These findings,
R
XR
FSbF5
SO2, -78 °C
X = Br, I
+X
R
R
+X +X +X +X+X +X
a) Formation of halonium ions; Olah (1967–1974):
b) Iodonium and bromonium ions:
c) Chlorine analogues:
Cl+ Cl+
Cl
X = Br, I
372 373
373a 373b 373c 373d 373e 373f
373g 373h 373i
122
paired with Ab Initio calculations on a C2H4Br+—C2H4 system enabled the proposal of an
associative mechanism that proceeded via a D2d transition state 376 (Scheme 108b).
Scheme 108. Bromonium olefin to olefin transfer.
Braddock and co-workers have demonstrated that enantiopure bromonium ions 378 may be
generated from optically pure bromohydrins 377 and trapped with a nucleophile to afford
enantiopure products 379 (Scheme 109).196
Scheme 109. 1,2-bromochlorides via enantiopure bromonium ions.
Braddock’s work demonstrated that, in the absence of olefins, halonium ions could be
configurationally stable. This result was corroborated by Denmark and co-workers in the
acetolysis of bromohydrin-derived tosylate 380 (Scheme 110a).197 However, when (E)-
octene 382 was introduced to the reaction an erosion of enantiomeric excess was noted
(Scheme 110b). The enantiospecificity of the reaction was only marginally improved with
additional equivalents of NaOAc. When the corresponding chlorohydrin was used in place of
the bromohydrin, no erosion of enantiomeric excess was observed in the presence of 382,
however, the yield of chloroacetate was low which can be attributed to the instability of
chloronium ions, as alluded to earlier by Olah’s studies (Scheme 107, vide supra).
Br+
TfO-
Br+Br+
374 375
Br+ Br+ Br+ Br+ Br+
a) Olefin–olefin bromonium transfer; Brown (1991):
b) Ab Initio model system:
376
Ph
Br
377 (>98% ee)
PhBr+SOCl2
OHPh
Cl
Br
379 (>98% ee)378
123
Scheme 110. The effect of olefin additives on the acetolysis of 1,2-bromotosylates.
It is clear from these results that the rate of olefin-to-olefin bromonium transfer is extremely
rapid, out-competing nucleophilic attack even when the nucleophile is in excess to any olefin
present. A method to overcome this difference in rate is to use a tethered nucleophile in an
intramolecular halo-functionalisation.
8.1.3 Introduction to Lewis base catalysed halocyclisations
A halocyclisation reaction is the intramolecular trapping of a halonium species, generally
generated from an alkene, with a pendant nucleophile to furnish a halogenated cyclic product
(Scheme 111). The first examples of such a reaction were reported in the early 20th
century,198 however, it was not until the last decade that significant progress has been made
towards enantioselective variants.199,200 The reactions generally proceed with excellent
diastereoselectivity due to the stereospecific opening of halonium intermediates. Depending
on chain length, alkene geometry and electronic effects the products formed may either be
predominantly exo or endo, i.e. the distal alkene carbon may be outside or inside the ring that
is formed.
Scheme 111. General scheme for halocyclisation reactions.
C3H7C3H7
OTs
Br
NaOAc (2.0 eq.)HFIP C3H7
C3H7
OAc
Br380 (94% ee) 381 (94% ee)
a) Enantiospecific acetolysis of 1,2-bromotosylates:
b) Iodonium and bromonium ions:
C3H7C3H7
OTs
BrC3H7
C3H7
OAc
Br
380 (94% ee) 381 (25% ee)
NaOAc (2.0 eq.)HFIPC3H7
C3H7
382 (1.0 eq.)
R+X
NuHn
Nu NuR
X
R
X
or-H+
R NuHn
"X+"n
n383 384 exo-385 endo-386
124
A variety of pendant nucleophiles have been used to generate a range of heterocycles. For
example: alcohols in haloetherification;201,202 amine derivatives in aminohalogenation;203
carbon nucleophiles in halocarbocyclisation;204 and carboxylic acid derivatives in
halolactonisations, which constitute the focus of this study.
A key hurdle in the asymmetric catalysis of bromo- and iodofunctionalisations is
overcoming the racemisation of halonium intermediates, caused by intermolecular halogen
exchange. Denmark proposed that one method to overcome this issue could be the use of a
Lewis basic catalyst that remains bound to the intermediate until attack by the nucleophile.
Thus, a steric barrier to approach by free olefins could be created and a chiral environment
retained.127 In fact, at the time of Denmark’s hypothesis, enantioselective halocyclisations
with stoichiometric pre-formed Lewis base-halogen adducts had already been reported.205,206
Denmark conducted a thorough study of a range of achiral chalcogen and phosphorus Lewis
base catalysts in bromo/iodo-lactonisation (Scheme 112).
Scheme 112. General reaction conditions for Denmark’s study into Lewis base catalysed halolactonisation.
The catalysts had a substantial effect on rate, with the fastest being over 360 times the
uncatalysed rate. A range of O-, S-, Se- and P-based donors were employed with the Se- and
P-based donors exhibiting very high rate acceleration. Several sulfur-based donors, for
example dialkyl- and phosphine-sulfides also performed well. However, the oxygen donors
trialled, including ureas and phosphine oxides, provided only marginal rate enhancement
over background. Furthermore, it was found that the Lewis bases not only had varying
effects on the rate but also on the endo-388:exo-389 composition of product mixtures,
providing evidence that the Lewis bases retained a degree of interaction with the halonium
species during nucleophilic attack.
PhCO2H NXS (1.2 eq.)
Lewis base (5 mol%)CH2Cl2, 23 °C
OO Ph
X
Ph
X+
O O
endo-388 exo-389X = I, Br 387
125
8.1.4 Recent advances in Lewis base catalysed halocyclisations
Since Denmark’s study into the effects of Lewis bases on bromo/iodo-cyclisations, several
chiral Lewis basic catalysts have been developed for a variety of enantioselective
transformations. In most cases these catalysts are based around a bifunctional motif (Scheme
113).207–213
Scheme 113. Examples of bifunctional bromocyclisation catalysts.
A common strategy in the development of bifunctional catalysts for halocyclisation reactions
is to include a pendant hydrogen bonding group that can bind to the nucleophilic part of the
substrate and direct nucleophilic attack onto a preferred enantiomer of the halonium
intermediate. Jacobsen and co-workers reported an enantioselective iodolactionzation with
N-iodo-4-fluorophthalimide (NI(4-F-Phth)) and aminourea catalyst 391 (Scheme 113a).207
The mechanistic hypothesis invokes the tertiary amine as the Lewis basic, iodine transfer
agent while the urea binds to and stabilises the phthalimide in intermediate 399. The alkene
391 (15 mol%)NI(4-F-Phth) (1.0 eq.)
toluene-80 °C
a) Jacobsen (2010):
b) Yeung (2010):
c) Hamashima (2016):
N
O
S
NHMeO
MeO
N
394
HPhOH
O
NBS (1.2 eq.)394 (10 mol%)
NsNH2 (50 mol%)CHCl3/toluene
-78 °C393
O
Ph Br
O
395 98%(90% ee)
PAr2P(O)Ar2
397Ar = 3,5-t-Bu2-4-MeOC6H2
PhHN Ph
O
NBS (1.2 eq.)397 (2 mol%)
CH2Cl2-78 °C
396
NO
Ph Br
Ph
398 98%(99% ee)
Ph
390
OH
O O
Ph
O
I
392 98%(94% ee)
F3C
CF3
NH
NH
O
N(C5H11)2391
126
390 then reacts with this complex, directed by hydrogen-bonding from phthalimide to the
carboxylic acid intermolecular complex 400 (Scheme 114). The key role of the phthalimide
in the mechanism was implied as other I+ sources proved detrimental to the ee.
Scheme 114. Key mechanistic steps in Jacobsen’s iodolactonisation.
Many bifunctional catalysts that have been developed for these applications have exploited a
cinchonine skeleton as source of chirality. Cinchonines feature a quinuclidine that can act as
both a Brønsted and a Lewis base. In Yeung’s bromolactonisation thiocarbamate 394 is
employed as the catalyst (Scheme 113b).208 In this system it is the Lewis basic thiocarbamate
that activates bromine through sulfur, stabilising the succinimide anion through hydrogen
bonding. The proposed mechanism features another hydrogen bond to the carboxylate from
the quinuclidine which here acts as a Brønsted base (Figure 21).
Figure 21. Key mechanistic step in Yeung’s bromolactonisation.
Hamashima has reported an alternative approach in this field in which hydrogen bonding is
not involved in substrate binding (Scheme 113c). Oxazolines such as 398 were synthesised
F3C
CF3
N N
O
N(C5H11)2
NO O
H H
F
I
399
F3C
CF3
N N
O
N(C5H11)2
N-O
O
H H
F400
Ph OH
O
OHO IPh
SO
N
MeO
MeO BrN
OOH
Ph
O
O-
N+
H
401
127
in excellent yield and enantiomeric excess with a dual phosphine/phosphine oxide catalyst
based on chiral binaphthalene 397. The active catalytic species was found to be
dibrominated compound 402 that reacts with the substrate at two sites (Scheme 115).
Stoichiometric studies indicated that mono-brominated catalyst 404, where the PAr2 group is
solely brominated, was inactive towards any bromocylisation, suggesting that bromine is
transferred from the phosphine oxide functionality. In fact, triphenylphosphine was found
not to catalyse this reaction. Furthermore, using alkyl phosphonium salt 405 was detrimental
to both the yield and enantiomeric excess suggesting that interaction of the nucleophile with
the bromophosphonium moiety is essential for catalyst efficacy. In support of this, addition
of PPh3 to the reaction was detrimental to the enantiomeric excess, presumably through
competing O—(PPh3Br)+ interaction.
Scheme 115. Proposed key steps in the mechanism of Hamashima’s bromocyclisation.
There are very few examples of highly enantioselective bromo/iodocyclisations that are
catalysed by monofunctional Lewis bases. As discussed earlier (see Section 7.1, Scheme
91b), Yeung has developed selenide catalyst 319a and employed it in an enantioselective
aminocylisation reaction. The same group have also developed a complementary sulfide
319b for an enantioselective bromo-cycloetherification (Scheme 116).128,214
PAr2
PAr2O
2 NBS PH2Ar2
PAr2O
Br
BrP
PAr2O
Br+
396
Ph
NO
PhAr Ar
403402397
404inactive
405reduced enantioselectivity
PAr2
PAr2O
MePAr2
PAr2O
Br I-
128
Scheme 116. Yeung’s bromocycloetherification using cyclic sulfide 319b.
XO O
OO
t-Bu t-Bu319
319a: X = Se319b: X = S
a) Yeung's monofunctional Lewis basic catalysts:
b) Cycloetherification with 319b:
Ph
Et
OH
OH
OPh
Br
OH
406 407 99%(>99:1 dr, 81% ee)
319b (5 mol%)NBS (1.2 eq.)
CH2Cl2/(CH2Cl)2-78 °C, 3 days
129
8.2.1 Carboxylic acids
To investigate the ability of cyclic selenides to catalyse bromolactonisation reactions,
carboxylic acid 387 was reacted with NBS and 5 mol% of achiral selenide 252 according to
Denmark’s conditions for halocyclisation (Scheme 117).127
Scheme 117. Bromolactonisation of carboxylic acid 387 with achiral dihydroselenepine 252.
Under these conditions the endo-product 388-Br was formed almost exclusively. The
reaction was also very rapid, with complete consumption of the starting material within 20
minutes. To confirm this result and give an indication of any uncatalysed background, the
reaction was repeated in the absence of catalyst (Scheme 118). For both reactions, NBS was
freshly recrystallised from boiling water to ensure there was no Br2 impurity since molecular
bromine can act as a catalyst for this process.
Scheme 118. Uncatalysed background bromolactonisation.
Confident that dihydroselenepines were effective catalysts for this methodology, a survey of
previously synthesised chiral catalysts was undertaken to assess whether an enantioselective
process could be developed (Table 15).
Ph OH
O 252 (5 mol%)NBS (1.2 eq.)
CH2Cl220 mins, r.t.
O O
PhBr
O
Ph
Br
O
92%>20 : 1
388-Br 389-Br
Se
252387
Ph OH
ONBS (1.2 eq.)
CH2Cl220 mins, r.t.
O
PhBr
O
388-Br <1%387
130
Table 15. Towards enantioselective bromolactonisation catalysed by chiral dihydroselenepines.
Entry Catalyst Temp / °C Yield (%)[a] 388:389[b] ee (%)[c]
1 255 23 85 >20:1 11 2 255 -20 80 >20:1 13 3 255 -60 82 19:1 13
4[d] 255 -20 77 >20:1 17 (± 1)[e]
5 265 23 89 >20:1 15 6[d] 265 -20 80 15:1 19 7 268 23 93 >20:1 4 8 272 23 81 18:1 7 9 284 23 84 16:1 3
General procedure: NBS (1.2 eq.) in CH2Cl2 added to solution of 387 (0.5 mmol) and catalyst (5 mol%) at temp in CH2Cl2 (0.1 M); [a]Isolated yield of 388-Br; [b]Ratio determined by 1H NMR spectroscopy of crude product mixture prior to purification by flash column chromatography; [c]Enantiomeric excess determined by chiral HPLC; [d]Solution of NBS pre-cooled to -20 °C before addition; [e]Average of three repeats.
Under all conditions the endo product 388-Br was the major product with a >20:1 ratio to
389-Br in the majority of cases in good to excellent yield. At room temperature,
dinaphthodihydroselenepine 255 provided the endo-product in 11% ee (Table 15, entry 1).
Lowering the temperature to -20 °C and further to -40 °C did not have a large effect on
enantiomeric excess (Table 15, entries 2-3). The procedure for low temperature reactions
involved addition of a solution of NBS to a solution of catalyst and starting material. The
solution of NBS was added down the side of the reaction vessel to effect cooling before the
reagents were mixed. As there appeared to be little change in ee at reduced temperature, it
Se
R
R
265 (R = Ph)268 (R = 3,5-xylyl)272 (R = mesityl)
Se
284
Se
255
Ph OH
O catalyst (5 mol%)NBS (1.2 eq.)
CH2Cl2 (0.1 M)Temp °C
O O
PhBr
O
Ph
Br
O
388-Br 389-Br387
Catalysts:
131
was hypothesised that this cooling was not sufficient due to the rapid rates of reaction and
hence the NBS solution was pre-cooled and transferred via a cold syringe. Under this
procedure, the ee was slightly increased to at –20 °C to 17% (Table 15, entry 4). With 3,3’-
diphenylbinaphthyl catalyst 268, there was a small increase in ee compared to the
unsubstituted catalyst at ambient and reduced temperatures (Table 15, entry 5-6). However,
increasing the bulk at the 3,3’-positions with xylyl 268 or mesityl 272 groups proved
detrimental to enantiomeric excess (Table 15, entries 7-8). SPINOL-derived
dihydroselenocine 284, while effective for the transformation, did not invoke promising
asymmetric induction (Table 15,entry 9).
A 2,5-diaryltetrahydroselenophene was also employed in this process (Scheme 119). Once
again, this proved an effective catalyst for the transformation but stereoinduction was
minimal.
Scheme 119. Tetrahydroselenophene-catalysed bromolactonisation of 387.
Other carboxylic acids trialled included the shorter-chain homologue 408 that furnished 5-
membered lactone 409 as the only detectable regioisomer, however the ee with unsubstituted
binaphthyl 255 at 0 °C was only 3% (Scheme 120).
Scheme 120. Bromolactonisation of (E)-4-phenylbut-3-enoic acid 408.
Ph OH
O 344 (5 mol%)NBS (1.2 eq.)
CH2Cl20 °C, 20 mins
O
PhBr
O
388-Br 85%(2% ee)
387
Se
344
PhOH
255 (5 mol%)NBS (1.2 eq.)
CH2Cl220 mins, r.t.
O
Ph
O
409 72%(3% ee)
408Br
Se
255
O
132
For alkyl substrate 410, the 5-membered exo-product 412 was the major product because the
alkene is no longer conjugated with the aromatic π-system, whereas with aryl substrate 387
used previously, the aromatic system activates one site of the bromonium species towards
nucleophilic attack (Table 16).
Table 16. Bromolactonisation of alkyl substrate 410.
Entry Catalyst Temp / °C Yield (%)[a] 411:412 [b] ee (%)[c]
1 255 23 81 1:15 9 2 265 -20 83 1:14 22
[a]Isolated yield of 412; [b]Ratio determined by 1H NMR spectroscopy of crude product mixture prior to purification by flash column chromatography; [c]Enantiomeric excess determined by chiral HPLC.
Initial trials with the unsubstituted binaphthyl catalyst 255 at ambient temperature gave an ee
of 9% (Table 16, entry 1). The best result of 22% ee at -20 °C was achieved with 3,3’-
diphenyl catalyst 265 (Table 16, entry 2).
8.2.2 Alternative carboxylic acid derivatives
Other carboxylic acid derivatives were also applied to this methodology to highlight the
effects of differing nucleophilicity on the outcome. Employing amide 413 required increased
reaction times and resulted in a diminished yield (Scheme 121). With the achiral biphenyl
catalyst 252, endo-selectivity was maintained, however, 388-Br was isolated in only 35%
yield after hydrolysis during aqueous work-up of the corresponding imine and full
conversion of the starting material was not observed until after 1.5 hours (Scheme 121a).
When chiral catalyst 255 was employed a low ee of 2.5% was achieved at –20 °C (Scheme
121b).
OH
O catalyst (5 mol%)NBS (1.2 eq.)
CH2Cl2 (0.1 M)Temp °C
O
Br
O
411410
PhPh
O
Br
O
412
Ph
133
Scheme 121. Selenide-catalysed bromolactonisation of amide 413.
Another alternative substrate was t-butyl ester 414. Consistent with previous results endo
388-Br was the major product (Scheme 122). This substrate was very slow to react under the
conditions, achieving a yield of 67% with traces of starting material still remaining after 9
hours (Scheme 122a). As with the amide, the enantiomeric excess with binaphthyl catalyst
255 was diminished compared to carboxylic acid 387 with effectively no stereoinduction
after accounting for analytical error. Furthermore, the reaction only proceeded to 30%
completion after 24 hours at 0 °C, precluding any scope for further temperature reduction
(Scheme 122b).
Scheme 122. Selenide-catalysed bromolactonisation of tert-butyl ester 414.
Ph NHPh
O252 (5 mol%)NBS (1.2 eq.)
CH2Cl2r.t., 1.5 h
O
PhBr
O
388-Br 35%413
OPh
Br
O
389-Brnot detected
b) Bromolactonization of amides with a chiral selenide:
a) Bromolactonization of amides:
Se
252
Ph NHPh
O255 (5 mol%)NBS (1.2 eq.)
CH2Cl2-20 °C, 16 h
O
PhBr
O
388-Br 60%(2.5% ee)
413
Se
255
Ph Ot-Bu
O252 (5 mol%)NBS (1.2 eq.)
CH2Cl2r.t., 9 h
O
PhBr
O
388-Br 67%414
OPh
Br
O
389-Brnot detected
b) Bromolactonization of t-butyl esters with a chiral selenide:
a) Bromolactonization of t-butyl esters:
Se
252
Ph Ot-Bu
O255 (5 mol%)NBS (1.2 eq.)
CH2Cl20 °C, 24 h
O
PhBr
O
388-Br 25%(1% ee)
414
Se
255
134
Denmark has reported the catalytic enantioselective thiofunctionalisation of alkenes with N-
phenylsulfenyl-phthalimide 416 using selenophosphoramide catalyst 417 (Scheme 123).215
The study found that a Brønsted acid was necessary to effect the transformation, presumably
via activation of the electrophilic sulfur reagent to the formation of a complex with the
Lewis base.216
Scheme 123. Denmark’s thiofunctionalisation of alkenes.
The conditions were replicated with achiral selenide catalyst 252 on carboxylic acid 387, a
substrate used in the original study (Scheme 124). Interestingly, in accordance with
Denmark’s observations, the regioselectivity for thiolactonisation of this substrate was
reversed, with the exo-isomer the only product isolated. It is unclear where this divergence in
selectivity arises, however, it could be the result of acid-catalysed rearrangement of the 6-
membered endo-product.217,218
Scheme 124. Thiolactonisation catalysed by selenide 252.
Replacing the catalyst with chiral 3,3’-diphenyl 265 or 3,3’-dixylyl 268 catalysts gave low
enantioselectivity of less than 2% ee in both cases. Using TFA instead of MsOH reduced the
rate of reaction but had no effect on asymmetric induction. In this case a challenge to
asymmetric catalysis is racemisation of chiral intermediates before the irreversible
R''R
R'
OH416 (1.0 eq.)417 (10 mol%)MsOH (1.0 eq.)
CH2Cl2
OR
R''
R'
SPh
O
R
PhS R'
R''
up to 92% ee
NSPh
O
O
NP
NMe
MeN
Se
417415 418 419
416 (1.0 eq.)252 (10 mol%)MsOH (1.0 eq.)
CH2Cl2
Ph OH
O OO
Ph
SPh420 74%
Se
252387
135
nucleophilic attack by the pendant nucleophile. In fact, similarly to halofunctionalisation of
alkenes, olefin-to-olefin transfer of chalcogeniranium ions has been documented.219`
In conclusion, cyclic selenides synthesised in this work have demonstrated effective use as
Lewis base catalysts in bromo- and thio-lactonisation reactions. Both 1,2-dialkyl and 1,2-
arylalkyl substrates react with very high regioselectivity and excellent diastereoselectivity.
Modest enantioselectivities were attained for some substrates in bromolactonisation
reactions, highlighting the ability of this class of cyclic selenide catalysts to effect
asymmetric induction and giving scope for catalyst development in the future and
application in other Lewis base catalysed reactions.
136
CHAPTER NINE
Selenonium ylides
137
9. Selenonium ylides
9.1.1 Overview
The synthesis of epoxides via reaction of sulfonium ylides and carbonyl compounds was first
reported in 1961 by Johnson and LaCount.220 The general reaction has since become
commonly known as the Corey-Chaykovsky reaction, following their investigations into the
reactions of dimethylsulfonium methylide (422) and dimethyloxosulfonium methylide (423)
with unsaturated electrophilic species (Scheme 125).221,222
Scheme 125. General scheme for the Corey-Chaykovsky reaction.
There has been some contention as to the specifics of the mechanism of this reaction, with
various practical and computational studies having been conducted.223–226 A simple overview
of the reaction mechanism for 1,2-disubstituted epoxides 428 is displayed below (Scheme
126). The nucleophilic ylide 425 first attacks aldehyde 426, generating an intermediate
betaine 427. Intramolecular Sɴ2 follows, releasing epoxide product 428 and dimethylsulfide.
Although early studies indicated a 4-membered oxathietane intermediate, analogous to a
Wittig reaction, later computational studies favoured a betaine, presumably as there is no
energetic gain in O—S bonding due to ring strain.225,227 Furthermore, the elimination of the
sulfide proceeds through anti-elimination as there is a significant activation barrier to the
complementary syn-elimination.
S+ MeMe
CH2
R R'
X
X = O, N, C
or Me S+Me
O
CH2
R R'
X
421 424
423422
138
Scheme 126. Proposed mechanism for the Corey-Chaykovsky reaction.
General observations from reactions of this type using sulfur ylides have identified trans-
epoxides as the major products in the vast majority of cases. In order to rationalize the
stereochemical outcomes, several available modes of attack have been proposed, leading to
either cis- and trans- diastereomers (Scheme 127).
Scheme 127. Proposed reaction pathways for the Corey-Chaykovsky reaction.
Early attempts to explain the stereochemical outcome featured attack of the aldehyde with
the two R-groups anti to one another, proceeding through transition state 429a, which is
arranged for sulfide elimination to the observed trans-product (Scheme 127a). This
orientation of attack, with oxygen opposite to sulfur, has been dubbed “transoid approach”.
S+
R H H
O
R'R
SMe2
O-
R'O
R'
R425 426 427 428
S+
PhH
O
HPh
S+
PhPh
O
HH
S+
Ph
H
OH
Ph
S+
Ph
Ph
OH
H
transoid approach
transoid approach
cisoid approach
cisoid approach
S+
HPhO-
H Ph
429a
anti-elimination
torsional rotation;
anti-eliminationS+
HPhO-
Ph H
429b
S+
HPhPh
-O H
429c
S+
HPhH
-O Ph
429d
anti-elimination
torsional rotation;anti-elimination
O
Ph Ph
O
Ph Ph
O
Ph Ph
O
Ph Ph
a) Transoid approach:
b) Cisoid approach:
trans-430
cis-430
trans-430
cis-430
139
Similarly, if the R-groups are orientated gauche to one another, as in 429b, the cis-epoxide is
formed and presumably this would be disfavoured due to gauche interactions. While the
transoid hypothesis explains the observed results and visually appears to be less sterically
hindered than attack in an eclipsed fashion, computational studies by Aggarwal and later
Goodman have instead indicated that the aldehyde attacks the ylide in a cisoid orientation,
presumably favoured due to Coulombic interactions between the polarised reactants,
followed by a torsional rotation–elimination sequence (Scheme 127b).225,226 For the trans-
epoxide to be produced under this mechanistic rationale, the two R-groups would have to be
eclipsed as the two reactants come together. Intuition would imply that cis-epoxides would
be formed following cisoid attack due to the steric requirements of this approach. However,
calculations showed that the rates of formation for 429c and 429d were roughly similar and
it was the relative rotational barriers that had a substantial effect on outcome. In 429d the
barrier to rotation to the 429b conformer, which is set up for elimination of the sulfide to the
cis-epoxide, is sufficiently high that betaine formation is reversible. However, the barrier to
rotation from 429c to 429a is lower than that of reversion to reactants and so rotation–
elimination predominates and the trans-epoxide is thus the major product formed. This
computationally-derived hypothesis was confirmed in cross-over experiments with
preformed hydroxysulfonium salts that demonstrated that the syn-betaine 429d was formed
reversibly whereas anti-betaine 429c was formed irreversibly under the reaction
conditions.228
9.1.2 Examples of enantioselective Corey-Chaykovsky epoxidations
A large number of enantioselective examples of the Corey-Chaykovsky reaction involve the
reaction of a preformed stoichiometric chiral sulfonium salt. Aggarwal is prevalent in this
area of the field with a variety of cheaply and easily derived sulfides that can be employed as
stoichiometric chiral reagents.229–232 Most recently sulfide 431, synthesised for <$1 per gram
140
in one step from elemental sulfur and limonene, was reacted with benzylic and allylic
electrophiles to prepare sulfonium salts 432 that were employed directly in enantioselective
epoxidations and aziridinations (Scheme 128).232,233 Epoxides 433 were generally formed as
single trans-diastereomers in very good yield. However, when aliphatic aldehydes (R’ =
alkyl) were used lower yields and diastereoselectivities were observed.
Scheme 128. Aggarwal’s Enantioselective epoxidation with a stoichiometric chiral sulfide.
Development of a catalytic reaction has been met with a number of challenges, for example,
alkylation of sulfides is generally slow, especially under reduced temperatures that may be
required to access higher enantiomeric excess.161 To overcome this, Metzner and co-workers
used stoichiometric n-Bu4NI (TBAI) as an additive with benzyl bromide to effect an in situ
Finkelstein reaction, thereby accelerating sulfide alkylation.234 Later the same group
employed [n-Bu4N]+[HSO4]- in place of TBAI (Scheme 129).235 The role of the ammonium
salt in this case was unclear; it was presumed that it acted as a phase transfer catalyst for
delivery of the hydroxide base, however it was also suggested that HSO4- or SO42- exchange
with the sulfonium bromide anion promotes non-reversible formation of the sulfonium
intermediate.
Scheme 129. Metzner’s asymmetric epoxidation with chiral sulfide 435.
S
431
RCH2Br (2.0 eq.)LiOTf (5.0 eq.)
CH2Cl2/H2OS
R TfO432
R'CHO (1.1 eq.)KOH (1.1 eq.)
MeCN/H2O
O
R R'
433up to 99% ee
R = aryl, alkenylR' = aryl, alkenyl, alkyl
Ar
O
H
BnBr (2.0 eq.)sulfide 435 (10 mol%)
n-Bu4NHSO4 (10 mol%)NaOH (1.0 eq.)
MeCN/H2O (9:1)
O
Ph Ar
436up to 96% ee
S
OO
435434
141
Another approach has been to form the ylide through an alternative process that bypasses the
slow rate of halide displacement. For example, Aggarwal employed a [Rh]/sulfide dual-
catalytic system to generate metallocarbenoids from diazo compounds that can react with the
sulfide 440 to form ylides directly, without the need for a base or use of alkyl electrophiles
(Scheme 130).236,237 As the reaction is now performed under pH-neutral conditions, this
could facilitate the use of enolizable and base-sensitive aldehydes. Side reactions were
controlled by maintaining a low concentration of diazo compounds 437 through slow
addition or in situ generation via thermal decomposition of the corresponding N-tosyl
hydrazone.
Scheme 130. [Rh2(OAc)4]/sulfide dual-catalytic epoxidation of aldehydes.
While the majority of research in this field has involved use of sulfonium and oxosulfonium
ylides, other heteroatoms have been explored to mediate this process including the other
chalcogens, selenium and tellurium,238,239 as well as arsenic.240 Most relevant to this work is
Metzner’s use of a chiral C2-symmetric tetrahydrothiophene 316 (Scheme 131).241
Scheme 131. Asymmetric epoxidation of aldehydes with a chiral selenide catalyst 316.
Metzner and co-workers were able to achieve high enantioselectivities using chiral selenide
316, however, long reaction times of up to seven days were required and the
R
N2 H
N2
[Rh2(OAc)4] 438
[Rh=CHR] 439
S
O
R2S 440
R2S-–CHR 441
Ph
O
H
O
Ph R
440
442up to 94% ee
437351
Se
316Ar
O
H
BnBr (2.0 eq.)selenide 316 (20 mol%)
NaOH (2.0 eq.)t-BuOH/H2O (9:1)
O
Ph Ar
436 1:1 drup to 94% ee
434
142
diastereoselectivity was not highly controlled—a feature that is common to all reported non-
sulfur mediated processes. Furthermore, only aromatic aldehydes were used and BnBr was
the only halide reagent explored. Thus, this work will aim to build upon this process with the
aim of improving diastereoselectivity as well as broadening the substrate scope.
9.2.1 Epoxidations with BnBr and Benzaldehyde
Benzyl bromide and benzaldehyde were reacted under Metzner’s conditions using catalytic
dihydroselenepine 252. After 24 hours at room temperature, stilbene oxide 430 was obtained
in 93% yield (Scheme 132). However, in accordance with Metzner’s selenium-catalysed
epoxidation, the diastereoselectivity was low, only slightly in favour of the trans epoxide
with a ratio of 1.2:1 (trans:cis).
Scheme 132. Corey-Chaykovsky epoxidation with catalytic dihydroselenepine 252.
For the selenonium intermediate 443, the benzylic protons in the catalyst scaffold (Hb) may
have a similar pKa to the protons adjacent to the phenyl ring (Ha) and thus ylide formation
could take place on the scaffold, resulting in destruction of the catalyst (Scheme 133).
Scheme 133. Alternative sites for deprotonation of selenonium ylide 443.
Considering the high yields achieved in this reaction and the observation of 252 in crude 1H
NMR following the reaction, it must be assumed that this process does not occur to any
252
Ph
O
H
BnBr (2.0 eq.)selenide 252 (10 mol%)
NaOH (2.0 eq.)t-BuOH/H2O (9:1)
24 h
O
Ph Ph
430 93%(1.2:1 dr)
Se
351
SeBnBr
Se
Ph
HaHa
Hb
Hb
Br Ph
OSe Ph
252 443 444
143
synthetically significant extent and that any deprotonation of Hb is either not productive or
that betaines are formed reversibly at these positions.
With this result in hand, the reaction was repeated with several enantiopure chiral selenide
catalysts (Table 17). With unsubstituted dinaphthodihydroselenepine 255 an enantiomeric
excess of 23% was obtained while the yield and diastereoselectivity were comparable to the
achiral catalyst 252 (Table 17, entry 1). With the more hindered catalyst 265 there was no
reaction at 23 °C (Table 17, entry 2). When the temperature was raised to 50 °C, the BnBr
was consumed entirely, however, no products were observed (Table 17, entry 3). Employing
tetrahydroselenophene 360 gave the highest ee of 66% but resulted in a reduction of yield
and diastereoselectivity (Table 17, entry 4).
Table 17. Epoxidation of benzaldehyde with chiral selenides.
Entry Catalyst Temp / °C Yield (%)[a] dr (trans:cis)[b] ee (trans) (%)[c]
1 255 23 89 1.3:1 23 2 265 23 No reaction n/a n/a 3 265 50 0 n/a n/a 4 360 23 77 1:1 66
[a]Total yield of both diastereomers; [b]dr measured by 1H NMR of the crude mixture prior to purification by flash column chromatography; [c]ee measured using chiral HPLC.
Furukawa has reported a moderately enantioselective epoxidation of sulfonium ylides under
solid-liquid phase-transfer conditions (Scheme 134).242
Ph
O
H
BnBr (2.0 eq.)catalyst (10 mol%)
NaOH (2.0 eq.)t-BuOH/H2O (9:1)temp, 24 h
O
Ph Ph
O
Ph Phtrans-430 cis-430
SeCyCy
360
Se
Ph
Ph265
Se
255
351
144
Scheme 134. Furukawa’s solid/liquid phase-transfer Corey-Chaykovsky epoxidation.
Although the reported turn-over numbers were low (2.3 turn-overs in the best case),
Furukawa’s result demonstrates that the hydroxide source does not need to be in solution,
opening up the scope for other organic solvents. A variety of solvents were thus investigated
with achiral selenide 252 (Table 18).
Table 18. Effect of solvent on the epoxidation of benzaldehyde.
Entry Solvent Yield (%)[a] dr (trans:cis)[b]
1 MeCN 55 1.3:1 2 CH2Cl2 32 1.3:1 3 THF <1 n/a 4 toluene <1 n/a 5 t-BuOMe <1 n/a
[a]Total yield of both diastereomers; [b]dr measured by 1H NMR of the crude mixture prior to purification.
With acetonitrile and CH2Cl2 there was no effect on diastereoselectivity and yields were
diminished to 55% and 32% respectively with full consumption of benzaldehyde (Table 18,
entries 1-2). For THF, toluene and t-BuOMe, only traces of the products were observed by
1H NMR (Table 18, entries 3-5). Taking the above results into account along with
Furukawa’s low turn-over numbers, it is apparent that these solid/liquid phase transfer
conditions are not optimal for this reaction. Nevertheless, MeCN was assessed using chiral
selenide 255, affording the trans-epoxide in slightly improved diastereoselectivity of 1.2:1
compared to t-BuOH/H2O (Scheme 135). However, the yield and enantioselectivity were
diminished (cf. Table 17, entry 4).
Ph H
OBnBr (1.0 eq.)
sulfide 445 (10 mol%)
KOH(s)MeCN
O
Ph Phtrans-430 10%
(47% ee)
SMe
OMe
445351
Ph
O
H
BnBr (2.0 eq.)selenide 252 (10 mol%)
NaOH(s)solvent
O
Ph Ph
O
Ph Ph
trans-430a
cis-430
145
Scheme 135. Epoxidation of benzaldehyde using the chiral catalyst 360.
A survey of bases in CH2Cl2 was conducted as it was proposed that if an organic-soluble
base were effective for this transformation then a wider range of solvents could be accessed
(Table 19).
Table 19. Effect of base on the epoxidation of benzaldehyde.
Entry Base Yield (%)[a] dr (trans:cis)[b]
1 DIPEA 2 1.4:1 2 DIPEA[c] 1 1.4:1 3 DBU 0 n/a 4 DBN 0 n/a 5 TBD 0 n/a 6 P2-Et 0 n/a 7 Cs2CO3 9 1.5:1 8 Cs2CO3
[c] 28 1.2:1 [a]Total yield of both diastereomers; [b]dr measured by 1H NMR of the crude mixture prior to purification; [c]Solvent was t-BuOH/H2O (9:1).
Hünig's base gave very low yields in both CH2Cl2 and t-BuOH/H2O (Table 19, entries 1-2).
Amidine bases DBU, DBN and guanidine base TBD did not result in any production of the
epoxides although there was some consumption of the starting materials in these cases
(Table 19, entries 3-5). The phosphazene base, P2-Et, resulted in a complex mixture of
products but no stilbene oxide was observed (Table 19, entry 6). Phosphazene bases have
been used in stoichiometric epoxidations with pre-formed sulfonium compounds, however,
the reactions were conducted at low temperatures that would make formation of the
selenonium species extremely slow.243 More promising results were achieved using caesium
Ph
O
H
BnBr (2.0 eq.)selenide 360 (10 mol%)
NaOH (2.0 eq.)MeCN
O
Ph Ph
430 64%(1.2:1 dr, 32% ee)
SeCyCy
360351
Ph
O
H
BnBr (2.0 eq.)selenide 252 (10 mol%)
base (2.0 eq.)CH2Cl2
O
Ph Ph
O
Ph Ph
trans-430a
cis-430351
146
carbonate with yields of 9% and 28% in CH2Cl2 and t-BuOH/H2O respectively (Table 19,
entries 7-8). Furthermore, in CH2Cl2, the trans-diastereoselectivity was slightly improved.
The promising results achieved with caesium carbonated prompted further investigation of
this base in alternative solvents as it has a relatively high solubility in organic solvents for an
inorganic base (Table 20).
Table 20. Epoxidations of benzaldehyde with Cs2CO3 in various solvents.
Entry Solvent Yield (%)[a] dr (trans:cis)[b]
1 t-BuOH 85 1.3:1 2 MeCN 62 1.3:1 3 MeCN/H2O (9:1) 5 1.3:1 4 THF 7 3.2:1 5 DMF 26 1.8:1 6 t-BuOMe <1 n/a
[a]Total yield of both diastereomers; [b]dr measured by 1H NMR of the crude mixture prior to purification.
Without a water co-solvent, the yield in t-BuOH was greatly improved to 85% (Table 20,
entry 1). MeCN resulted in a moderate yield of 62% that similarly was diminished upon the
addition of water (Table 20, entries 2-3). Low yields were obtained with THF and DMF,
however the trans-diastereoselectivity was improved in both cases (Table 20, entries 4-5).
Unfortunately, the yields were not improved with increased reaction time. The ethereal
solvent t-BuOMe was ineffective under these conditions (Table 20, entry 6).
9.2.2 Epoxidations with BnBr and Formaldehyde
A single trial reaction was attempted with benzyl bromide and formaldehyde to synthesise
styrene oxide (Scheme 136).
Scheme 136. Synthesis of (±)-styrene oxide from benzyl bromide and paraformaldehyde.
Ph
O
H
BnBr (2.0 eq.)selenide 252 (10 mol%)
Cs2CO3 (2.0 eq.)solvent
O
Ph Ph
O
Ph Ph
trans-430a
cis-430351
Br
paraformaldehyde (6.0 eq.)selenide 252 (10 mol%)
Cs2CO3 (2.0 eq.)MeCN
O
446 74%
147
Full conversion of benzyl bromide was achieved following the addition of 6.0 equivalents of
benzaldehyde, affording styrene oxide 446 in 74% yield (GC).
9.2.3 Epoxidations with allylic bromides
Previous reports of this class of reaction have found that modification of the aldehyde
substrate is limited to aromatic aldehydes and those that bear no alpha protons due to the
basic conditions employed. The few reports of reactions with aliphatic aldehydes have
resulted in diminished yields and selectivity. Thus, the initial investigations into expansion
of the substrate scope focused on the bromide reactant. Cinnamyl bromide (447) was reacted
with benzaldehyde under the original conditions to afford allylic epoxide 448 in a 1.7:1
trans- to cis-epoxide diastereomeric ratio (Table 21, entry 1). Using NaOH in other solvents
that had been effective for benzyl bromide resulted in no trace of products (Table 21, entries
2-3). Caesium carbonate was found to only be effective in t-BuOH, with only traces of
products observed by NMR in acetonitrile and t-BuOH/H2O (Table 21, entries 4-6). When
the reaction was repeated with allyl bromide, no epoxide products were observed.
Table 21. Epoxidation of cinnamyl bromide with benzaldehyde.
Entry Base Solvent Yield (%)[a] dr (trans:cis)[b]
1 NaOH t-BuOH/H2O (9:1) 63 1.7:1 2 NaOH MeCN 0 n/a 3 NaOH MeCN/H2O (9:1) 0 n/a 4 Cs2CO3 t-BuOH 30 1.6:1 5 Cs2CO3 t-BuOH/H2O (9:1) <1[c] n/a 6 Cs2CO3 MeCN <1[c] n/a 7 Cs2CO3 MeCN/H2O (9:1) 0 n/a
[a]Yield of both diastereomers; [b]dr measured by 1H NMR of the crude mixture prior to purification; [c]Trace.
9.2.4 Epoxidations with propargylic bromides
Two equivalents of propargylic bromide 449 were reacted with benzaldehyde (351) in the
presence of achiral selenide 252 and Cs2CO3 (Scheme 137). Pleasingly, propargylic epoxide
Ph
O
H
selenide 252 (10 mol%)
base (2.0 eq.)solvent (9:1), 24 h
O
PhPh Br Ph448447 351
148
450 was formed in 91% yield after 24 hours, however, there was minimal
diastereoselectivity.
Scheme 137. Epoxidation of propargylic bromide 449.
With this result in hand, unsubstituted propargyl bromide (451) was applied to the same
reaction conditions. The reaction proceeded more slowly but after 48 hours with 20 mol%
catalyst, the epoxide 452 was isolated in 84% yield with slightly improved
diastereoselectivity compared to the phenyl analogue (Scheme 138).
Scheme 138. Epoxidation of propargyl bromide 452.
Methyl substrate 453 reacted under the same conditions, affording epoxide 454 in 93% yield
but with no diastereoselectivity demonstrating that alkyl substitution on the alkyne could be
tolerated (Scheme 139)
Scheme 139. Epoxidation of alkyl-substituted propargylic bromide 454.
Silylated alkyne 455 reacted with 71% overall yield with some desilylation observed under
the reaction conditions (Scheme 140). Where the silyl group remained attached, there was
negligible diastereoselectivity.
Ph
O
HPhBr selenide 252 (10 mol%)
Cs2CO3 (2.0 eq.)MeCN
O
Ph
450 91%(1.2:1 dr)
Ph
252
Se
449 351
Ph
O
HHBr selenide 252 (20 mol%)
Cs2CO3 (2.0 eq.)MeCN
O
Ph
452 84%(1.5:1 dr)
H
252
Se
451 (2.0 eq.) 351
Ph
O
HMeBr selenide 252 (20 mol%)
Cs2CO3 (2.0 eq.)MeCN
O
Ph
454 93%(1:1 dr)
Me
252
Se
453 (2.0 eq.) 351
149
Scheme 140. Epoxidation of silylated propargylic bromide 455.
Secondary bromide 457 was synthesised from the corresponding alcohol with PBr3 and used
in this reaction in an attempt to synthesis 1,1,2-trisubstituted epoxides (Scheme 141).
Interestingly, the only products isolated were 1,2-disubstituted epoxides 454, albeit in a low
yield of 26%, however the diastereomeric ratio was improved compared to reaction of the
linear, primary propargylic bromide 453 (cf. Scheme 139). This presumably occurs through
conjugate attack of the ylide on the aldehyde through the terminal position (Scheme 141b)
Scheme 141. Epoxidation of a secondary propargylic bromide 457.
The reaction with methyl substituted propargyl bromide 453 was repeated using chiral
tetrahydroselenophene 360 and the ee of the epoxide was 9% (Scheme 142). While the
enantioselectivity with this catalyst was low there is clearly some stereoinduction, which is
promising for future development of an enantioselective process.
Ph
O
HTMSBr selenide 252 (20 mol%)
Cs2CO3 (2.0 eq.)MeCN
O
Ph
456 71%(1:1 dr)
TMS
252
Se
455 (2.0 eq.) 351
Ph
O
HH
selenide 252 (20 mol%)
Cs2CO3 (2.0 eq.)MeCN
O
Ph
454 26%(1.5:1 dr)
Me457 (2.0 eq.)
BrO
Ph
458 0%H
a)
b)
SeR2
Ph H
O •Ph
OSeR2 O
PhMe
351 459 460 454
150
Scheme 142. Epoxidation of propargylic bromide 453 with a chiral tetrahydroselenophene 360.
As this is the first instance of propargylic bromides undergoing Corey-Chaykovsky
epoxidations with chalcogenide catalysts, the reaction was repeated using
tetrahydrothiophene (THT) as the catalyst to determine whether the reactivity was unique to
selenium (Table 22). THT is often used as a “model” catalyst in this and similar processes
but to ensure the reactions were comparable, tetrahydroselenophene (THSe) was synthesised
from 1,4-dibromobutane.244 Under two sets of conditions, THT failed to produce significant
amounts of epoxide. With Cs2CO3 in MeCN, traces of the trans-452 were observed in the
crude 1H NMR after 24 h, however, increasing the reaction time had no noticeable effect on
the conversion of starting materials.
Table 22. Comparison of THT and THSe in the epoxidation of propargyl bromide.
Entry Catalyst Base Solvent Yield (%)[a] dr (trans:cis)
1 462 NaOH t-BuOH/H2O (9:1) 4 n/a 2 462 Cs2CO3 MeCN 78 1.4:1 3 461 NaOH t-BuOH/H2O (9:1) 0 n/a 4 461 Cs2CO3 MeCN <1[b] 1:0
[a]Total yield of both diastereomers; [b]Traces of trans-epoxide only.
In summary, cyclic alkyl selenides have been applied successfully as catalysts in the Corey-
Charkovsky epoxidation. Compared to their sulfur-based equivalents the selenides exhibit
much lower diastereoselectivity, implying lower barrier to rotation following betaine
formation or a distinct mechanism, perhaps via a 4-membered oxaselenetane intermediate.245
Ph
O
HMeBr selenide 360 (20 mol%)
Cs2CO3 (2.0 eq.)MeCN, 48 h
O
Ph
454 89%(1.1:1 dr, 9% ee)
Me453 (2.0 eq.)
SeCyCy
360351
Ph
O
HHBr catalyst (20 mol%)
base (2.0 eq.)solvent
O
PhH
451 (2.0 eq.) 452
X
461 (X = S)462 (X = Se)
351
151
Investigations into diversification of the substrate scope demonstrated applicability of this
process to both 3-aryl- and 3-alkyl-propargylic bromides and preliminary studies suggest
that dialkyl sulfides do not catalyse this transformation for these substrates. To our
knowledge this is the first example of a chalcogenide-catalysed synthesis of propargylic
epoxides from propargylic electrophiles. Additional substrates trialled were unsuccessful and
are listed in the appendices (see Section 13.2).
152
CHAPTER TEN
Selenium(IV) salts
153
10. Selenium(IV) salts
10.1.1 Alkenyl sulfonium salts
Alkenylsulfonium salts are electrophilic at the ß-position since the sulfonium can stabilise an
α-anion by means of sulfur ylide resonance forms. This reactivity enables access to sulfur
ylide chemistry through an initial nucleophilic attack. For example, vinylsulfonium salts
were first applied by Jimenez and co-workers during the preparation of fused heterocycles
for the synthesis of mitomycins (Scheme 143).246 Nucleophilic attack by the deprotonated
indole on the sulfonium salt affords ylide 466, which undergoes intramolecular cyclisation
with the pendant aldehyde forming betaine 467. Intramolecular Sɴ2 yields fused epoxide
464.
Scheme 143. Proposed mechanism for the reaction of vinylsulfonium salts with indole-2-carboxaldehyde 463.
When the R-groups on sulfur featured α- or ß-hydrogens, yields were diminished due to
side-reactions of the ylide 468 (Scheme 144). Where α-protons were accessible, proton-
transfer occurred, followed by undesired nucleophilic attack (Scheme 144a). With ß-
hydrogens, a [2,3]-sigmatropic shift could occur, forming an olefin and sulfide (Scheme
144b).
NH
H
O
SR2 OTf
NaH, THF;
then: N O
464
N H
O
SR2
N H
O
SR2
NSR2
O
466 467
463
465
154
Scheme 144. Proposed mechanisms for observed side-reactions of intermediate sulfur ylides.
This process was later adapted by Aggarwal and co-workers into a more general method of
synthesising epoxide or aziridine-fused pyrrolidines, piperidines and azepines (Scheme
145).247
Scheme 145. Aggarwal’s synthesis of epoxide-fused heterocycles using vinylsulfonium salts.
Diphenylvinylsulfonium triflate was very effective for this transformation, furnishing the
products in good to excellent yields. Using chiral sulfide 440 resulted in high
enantioselectivities, however, the yields of products were significantly lower due to
decomposition of the dialkylvinylsulfonium salt, potentially through side-reactions described
above (Scheme 144).
Alkenylsulfonium salts will also react with nucleophiles bearing two acidic protons, for
example primary amines and malonates react to form aziridines and cyclopropanes (Scheme
146).248,249 The nucleophile is deprotonated once, then reacts with the sulfonium salt at the ß-
N H
O
SH
N H
O
S CH2
NS
O
Me
N
SMe
O
a) Side reaction with α-protons:
N H
O
S
b) Side reaction with β-protons:
H N H
O
S+
468 469 470 471
468 472
TsHNR
O
n
SR2
DBU, THFN
OR
R = H, Me, Et, Phn = 1, 2, 3
SR2 = Ph2S: 67 – 96%SR2 = 440: 30 – 80% (up to 99% ee)
nTs
S
O
440
OTf
473 474
155
position, generating a sulfur ylide. Deprotonation of the nucleophile by the ylide then sets up
an ensuing Sɴ2 displacement of the sulfide to afford a 3-membered ring, analogous to the
Corey-Chaykovsky reaction (see Scheme 126, vide supra).
Scheme 146. Proposed mechanism for the reaction of alkenylsulfonium salts with diprotic nucleophiles.
Aggarwal and co-workers have also employed 1,2-dinucleophiles with diphenylvinyl
sulfonium salts to afford morpholines 480, thiomorpholines 482 and piperazines 484
(Scheme 147).250 In the case of morpholines 480, protection of the nitrogen as a sulfonamide
was essential to prevent aziridine formation. This was not the case for thiomorpholines 482,
suggesting that the more nucleophilic sulfur atom attacks first. For piperazines 484 it was
also not essential for the amines to be protected.
Scheme 147. Synthesis of 6-membered heterocycles from diphenylvinyl sulfonium triflate.
The same group have also published a complementary synthesis of 6- and 7-membered
heterocycles from a 1-styrylsulfonium salt 488 (Scheme 148).251 In general, high
regioselectivities and diastereoselectivities were observed. Morpholine products that were
SPh2R
NuH2base
HNu
R
Nu
SPh2
H
R
Nu
SPh2 RNu
NuH2 = RNH2, (EtO2C)2CH2 etc.
475
476 477
478
R'RHN
HO
R = Ts, Ns
R''
R'H2N
HS R''
R'RHN
RHN
R = H, Ts
R''
R'NR
O R''
R'NH
S R''
R'NR
RN R''
SPh2
Et3N or DBU (2.0 eq.)CH2Cl2
R', R'' = alky, aryl, CO2Me
OTf
479
481
483
480
482
484
485
156
obtained indicated that attack of the sulfonium species occurred first through oxygen in most
cases, contrary to the findings of the previous study. Six-membered products 489 were
mostly obtained with the 2,6-cis product as the major diastereomer, however, a notable
exception to this occurred when R’ was an ester (R’ = t-BuCO2) where a 1:1 cis:trans
mixture of the 2,6-morpholine was obtained. Only benzo-fused azepines and oxazapines 490
were synthesised and so no indication was made as to diastereoselectivity. In order to
achieve the best results, portion-wise addition of the sulfonium salt 488 and base was
required due to side-reactions of the dialkyl sulfonium species.
Scheme 148. Formation of 6- and 7-membered heterocycles from alkenylsulfonium salts.
When a 2-styrylsulfonium salt 492 was used, the corresponding 2,3,5-trisubstituted
morpholines were formed in moderate yields due to competing elimination of the
alkylsulfonium intermediate (Scheme 149).
Scheme 149. Reaction of 2-styrylsulfonium salt 492 with 1,2-dinucleophiles.
10.1.2 Alkenyl selenonium salts
Comparatively few investigations have been made into the reactions of alkenyl selenonium
species. Kataoka and co-workers have reported the synthesis of cyclopropanes from 1,3-
dicarbonyls and 2-styrylselenonium salt (Scheme 150). Interestingly, malonates reacted as
S
BPh4Ph
R'TsHN
XH R''
N
X
X = O, NTs
R'
R''
PhTs
orN
X
Ts Ph
488Cs2CO3CH2Cl2
489 490
orNHTs
XH
486 487
PhS
Ph
Ph
BPh4
NHTs
Ph OH492
NTs
Ph O
NHTs
Ph OPh Ph
493 53%(1.1:1 dr)
494 21%
DBU, CH2Cl2
491
157
NuH2 species, forming 1,1-disubstituted cyclopropanes 498 (Scheme 150a), whereas, 1,3-
diketones underwent a tandem Favorskii-type rearrangement to afford 1,2-disubstituted
products 501 (Scheme 150b).252 In the latter case, the major diastereomer was that with the
ketone groups cis- to one another.
Scheme 150. Proposed mechanisms for the reactions of 2-styrylselenonium salts with 1,3-dicarbonyls.
Another example of an application of alkenylselenonium salts is the three-component
reaction with an alkoxide and aldehyde to form epoxides 503 and 504 (Scheme 151).253 The
reaction proceeds first by nucleophilic attack of the alkoxide, forming an ylide that
undergoes epoxidation with benzaldehyde. The epoxides were formed as 1:1 mixtures of cis-
and trans-diastereomers. Modification of the nucleophilic alkoxide to methoxide and carbon-
based nucleophiles resulted in demethylation of 502 through an Sɴ2 displacement of
styrylphenylselenide. Presumably adding a more sterically hindered alkyl substituent or
employing a diarylselenide could overcome this side reaction.
Scheme 151. Three-component reaction of alkenyl selenonium salts.
PhSe
Ph
Ph
EtO OEt
O O
Ph
CO2EtEtO2C
SePh2
HPh
CO2EtEtO2C
SePh2 Ph
CO2EtCO2Et
498
PhSe
Ph
Ph
O O
PhSePh2
O O
Ph
OO
SePh2 Ph
O
O
501
a) Reaction of 2-styrylselenonium salts with malonates:
b) Reaction of 2-styrylselenonium salts with 1,3-diketones:
495
496 497
495
499 500
PhSe
Ph
Me
ONa
PhCHOTHF/HMPA Ph
OO
Ph
502 503 35%Ph
OO
Ph+
504 35%
158
10.2.1 Iodine(III) reagents
Triarylselenonium salts can be synthesised from diarylselenides using aryl iodine(III)
reagents in the presence of a copper(I) catalyst.254 However, this method has not been
applied to dialkyl selenides, or for alkenylation of a selenide. Thus, to test the applicability
of the methodology to dialkylselenides, tolyl selenonium salt 506 was synthesised from
cyclic dialkyl selenide 252 and diaryliodonium triflate 505. The structure of 506 was
confirmed by X-ray crystallography (Scheme 152).
Scheme 152. Copper-catalysed synthesis of selenonium salts.
The mechanism of this reaction is still under debate, however, the reaction is presumed to
proceed via either a Cu(I)/Cu(III) or radical pathway, with copper(I) generated in situ by a
disproportionation process.255 More recently, Ciufolini has demonstrated that at elevated
temperatures this process does not require a copper catalyst and that aryl transfer can occur
directly from the iodonium reagent to the sulfide or selenide.256 Using the above method,
alkenyl selenonium salt 508 was prepared from iodine(III) reagent 507 in 82% yield
(Scheme 153). In the absence of copper(II) the yield was 47% when performed at 110 °C.
Scheme 153. Copper-catalysed preparation of an alkenyl selenonium salt.
The product was purified by flash column chromatography on SiO2 and found to be stable
for >6 months at –20 °C, however, some visual decomposition was noted at ambient
Se IOTf
Cu(OAc)2 (5 mol%)toluene, 70 °C
Se
506 73%252 505
OTf
Se IOTf
Cu(OAc)2 (5 mol%)toluene, 70 °C
Se
508 82%252 507
OTf
PhPh
159
temperatures when exposed to light. The structure was confirmed by single crystal X-ray
diffraction (Figure 22). The structure shows that the triflate anion is only loosely coordinated
(shortest Se–O contact = 2.94 Å) with the [SeR3]+ cation adopting a pyramidal structure.
Figure 22. Crystal structure of alkenylselenonium triflate 508 (50% probability ellipsoids).
In the presence or absence of a copper catalyst, when the procedure was applied to 2,5-
diphenyltetrahydroselenophene 340 a complex mixture of products was formed containing a
significant quantity of the starting material was obtained but no Se(IV) salt identified.
10.2.2 Alkylation–elimination
Vinyl sulfonium salts were originally prepared by Jimenez, and later Aggarwal, by
alkylation with 2-bromoethyl triflate followed by mild base-induced elimination.246,247 This
procedure was employed to synthesise vinylselenonium salt 510 in 42% yield (Scheme 154).
Scheme 154. Synthesis of vinylselenonium salt 510.
Se Se
510 60%252
OTf
Se
509 71%
OTf
Br
BrOTf
C6H5CF3
KHCO3
THF/H2O (2:1)
160
Following the elimination step, approximately 40% of selenide 252 was recovered. This was
thought to be due to elimination of the selenide from the bromoselenonium species 509 or
due to reaction of the vinyl selenonium salt under the conditions.
10.2.3 From pre-oxidised selenium species
Selenonium salts can also be prepared from selenoxides by first reacting the selenoxide with
triflic anhydride and then treatment of the resultant species with an alkene or alkyne
(Scheme 155).257,258 The bis(triflate) 512 is thought to undergo formal addition across the
double bond, forming 513, followed by elimination of the triflate to reform the alkene
moiety.
Scheme 155. Proposed mechanism for the formation of alkenylselenonium species from selenoxides.
The reaction is performed in one-pot, with all reagents added simultaneously. Selenoxide
515 was synthesised using mCPBA and then converted into vinyl and styryl selenonium salts
516 and 517 (Scheme 156). In the case of vinyl compound 516, vinyltrimethylsilane was
used as a surrogate for gaseous ethylene.
Scheme 156. Synthesis of alkenylselenonium salts 516 and 517.
RSe
R
O Tf2ORSe
R
OTf
OTf
R'
SeR2OTf
R'
TfO
-TfOHR2Se
TfO
R'
H
511 513 514512
Se
Ph
Ph
mCPBAK2CO3 (aq.)
CH2Cl2
Se
Ph
Ph
O
TMS
Se
Ph
Ph
340 515Se
Ph
PhPh
Tf2O
CH2Cl2
Ph
516 38% (2 steps)
517 43% (2 steps)
OTf
OTf
161
Preliminary investigations into the reactivity of selenonium species are detailed below
(Table 23). With tert-butylamine 518, diethyl malonate 519 and aminoalcohol 520, none of
the expected products were formed.
Table 23. Preliminary investigations into the reactivity of alkenylselenonium species.
Entry Selenonium salt Nucleophile Conditions[a] Comments
1 508 (R = Ph) 518 CH2Cl2 No aziridine formation
2 508 (R = Ph) 519 NaH, DMF No cyclopropane formation
3 508 (R = Ph) 520 Et3N, CH2Cl2 No morpholine
formation
4 508 (R = Ph) 520 Et3N, (CH2Cl)2, 80 °C No morpholine formation
5 510 (R = H) 520 Et3N, CH2Cl2 No morpholine formation
6 510 (R = H) 520 Et3N, (CH2Cl)2, 80 °C No morpholine formation
[a]Reactions performed at ambient temperature unless otherwise stated.
Studies of the crude 1H NMR of the reaction mixtures indicated that the selenonium species
were decomposing by some other reaction pathway. It was suspected that Sɴ2 attack by
nucleophiles at the benzylic position, displaces the neutral selenide leaving group. This was
confirmed by further investigation of the reaction with tert-butylamine, where the only
product isolated was aminoselenide 521 (Scheme 157).
Se
OTf
R
NuH2
R
508 (R = Ph)510 (R = H)
conditions
Nu or
X
X R
Nucleophiles:
NH2
518
EtO OEt
O O
519
HONHTs
520
162
Scheme 157. Reaction of styrylselnonium salt 508 with tert-butylamine.
It is clear from these results that the back-bone structure of the selenonium salts is highly
susceptible to unfavourable side-reactions due to the activated sp3 carbon atoms that are both
benzylic and attached to an excellent selenide leaving group. Future work with this class of
compounds will focus on perturbing reaction at these position by: a) adding steric bulk to
hinder Sɴ2 substitution; b) replacing the aromatic substituents with aliphatic so as to remove
the benzylic activation. For example, selenonium salts produced from 2,5-
dicyclohexyltetrahydroselenophene (360) would satisfy both of these conditions and these
will feature centrally in the future investigations into the reactivity of these species.
Se
OTf
Ph
t-BuNH2
CH2Cl2
508 521
NH
SePh
163
CHAPTER ELEVEN
Conclusions and Future
Work
164
11. Conclusions and Future Work
11.1.1 Diselenides
Allylic C-H oxidations with SeO2 and BSA have been known for some time.17,19,23 Attempts
to develop an enantioselective variant of these reaction by employing chiral C2-symmetric
diaryl diselenides have thus far been unsuccessful, due to the propensity of these species to
eliminate a selenium upon oxidation forming selenophenes and generating SeO2 which is
able to oxidise substrates efficiently and in a non-enantioselective fashion. With respect to
diselenides, future work must focus on preventing this elimination pathway, most probably
achievable through steric constraint or by using employing a non-biaryl catalyst. For
example, spirobiindane based diselenide 119 could satisfy both of these constraints as a) the
aromatic rings are no longer conjugated and therefore there is no gain in aromaticity through
elimination of a selenium atom; b) the two arenes in spirobiindanes have a dihedral angle of
approximately 60-70° and so excessive contortion of bond angles would be required to join
the rings with a single atom to bring the rings essentially co-planar (Figure 23). It is hoped
that synthesis of this compound will be possible through a cross-coupling with the bistriflate.
Figure 23. Spirobiindane based diselenide 119 for future investigations into enantioselective oxidations.
11.1.2 Dialkyl selenides
Dialkyl selenides also showed that they were able to catalyse allylic and propargylic C–H
oxidations efficiently and this is believed to be the first report of this mode of reactivity.
However, no stereoinduction was observed in any case and the mechanism of oxidation is
SeSe
119
165
unknown. Before any developments can be made towards an enantioselective variant of
these oxidations, further insights into the mode and mechanism of reaction must be made.
A versatile Pd-catalysed cross-coupling of selanylstannanes and aryl halides and triflates has
been developed and its synthetic utility demonstrated on a range of electron-rich and
deficient arenes 249 (Scheme 158).
Scheme 158. General procedure for the cross-coupling of aryl halides and triflates with selanylstannanes.
Future work will involve investigations into increasing the scope of the nucleophilic
coupling partner. Tin selenolates could be accessed from any halide via a Grignard reagent
523 (Scheme 159). However, due to the stability of the resulting selanylstannanes,
purification may prove problematic and it is likely that the reagents would be used in situ.
Scheme 159. Route to a wider range of selanylstannanes.
Alternatively, preliminary experiments have shown that diselenides can be converted into
selanylstannanes by reaction with bis(tributyltin) through a radical process, initiated by
either visible light or a radical initiator. Such a process would theoretically allow the use of
any diselenide. To determine the effectiveness of crude solutions of selanylstannane
generated in this way, diselenide 526 and bis(stannane) 527 were allowed to react under
varying conditions before being added to a mixture of triflate and Pd/xantphos (Table 24).
For comparison, reaction with selanylstannane generated from Bu3SnCl and identical cross-
Bu3SnSeR' (1.5 eq.)[Pd(π-cinnamyl)Cl]2 (5 mol%)
xantphos or PhPF-t-Bu (10 mol%)toluene (0.1 M)
110 °C
XR
R = alkyl, aryl, -CHO, -OMe, -NO2, -NH2X = I, Br, OTfR' = Me, n-Bu, t-Bu, Ph
SeR'R
249 250
R X R MgXMgTHF
X = Cl, Br, I
R SeMgXSe Bu3SnCl
R SeSnBu3
522 523 524 525
166
coupling conditions provided the product in 92% yield (see Section 4.4.5, Table 11, entry
10). With a 40 W filament lamp at 40 °C, the cross-coupling product was generated in 31%
yield (Table 24, entry 1). In the dark at 80 °C, there was very little reaction (Table 24, entry
2), however, with the addition of AIBN as a radical initiator, the yield of cross-coupling
product improved (Table 24, entry 3). LiCl was a by-product of the formation of
selanylstannanes in the earlier study and pleasingly, using this as an additive in the cross-
coupling improved the yield (Table 24, entry 4). Finally, excess diselenide 526 was
detrimental to the yield, essential halting the cross-coupling, whereas, excess bis(stannane)
527 had little effect on the cross-coupling (Table 24, entries 5-6). These results form a
promising foothold for future investigation, with the hope being that this can eventually be
developed into a one-pot process.
Table 24. Preliminary investigations into generation of selanylstannanes from bis(tributyltin).
Entry Conditions[a] Additive Yield (%)[b]
1 40 W filament lamp, 40 °C - 31 2 Dark, 80 °C - 2 3 AIBN (2.5 mol%), 80 °C - 27 4 AIBN (2.5 mol%), 80°C LiCl (1.5 eq.) 53 5 AIBN (2.5 mol%), 80°C (BuSe)2 (0.1 eq.) 1 6 AIBN (2.5 mol%), 80°C (Bu3Sn)2 (0.1 eq.) 30
[a]1:1 ratio of diselenide and bis(stannane) in toluene (0.15 M); [b]Measured by GC analysis with decane as internal standard.
Ultimately, the removal of tin would enable this methodology to be more atom-economical
and less hazardous, thus making it more accessible to general use. Therefore, future work
will also involve investigation into alternative selenium nucleophiles, for example there
(BuSe)2 + (Bu3Sn)2
OTf SeBu
222 (1.5 eq.)[Pd(π-cinnamyl)Cl]2 (5 mol%)
XantPhos (10 mol%)additive?toluene
110 °C, 24 h
conditionstoluene, 2 h526 527
230 231
167
could be the possibility of using selanylcuprates, selanylzincs and selanylboronic
acids/esters. Additionally, modification of the nucleophilic component may also allow for
reduction in catalyst loading which will be a further aim of any future studies.
11.3.1 Dihydroselenepines and Dihydroselenocines
This work presents several routes to dibenzodihydroselenepines and dihydroselenocines. For
example, there is now a clear route to 3,3’-disubstituted dinaphthoselenepines 120 and we
have also demonstrated the synthesis of dihydroselenocine SPISe 284 (Figure 24).
Figure 24. Dihydroselepine 120 and dihydroselenocine 284.
Future work in this area will focus on creating a diverse library of catalysts based on these
scaffolds including routes to alkyl/heteroatom substitution at the 3,3’-positions of 10 and
introducing substitution onto the aromatic rings in the spirobiindane scaffold of 284.
11.3.2 Tetrahydroselenophenes
Three distinct routes to 2,5-disubstitutedtetrahydroselenphenes have been presented. The
products are formed in excellent diastereo- and enantioselectivity (Scheme 160).
Enantioselective steps in all the processes (CBS reduction, enzymatic resolution and HKR)
are all well precedented for a wide range of substrates and thus this will enable easy and
diverse modification of catalyst structures in the future. Furthermore, two routes involve a
dimerisation after the enantioselective step that enables further enhancement in enantiopurity
to be gained through the Horeau principle.
Se
284120
R
R
Se
168
Scheme 160. Routes to 2,5-disubstituted tetrahydroselenophenes.
Future developments in this area of work will investigate improvements to the overall yield
of the syntheses, for example, the cross-metathesis step following the enzymatic resolution
could be improved by employing a tethered RCM approach (Scheme 161). Furthermore, the
feasibility of adding further substitution to the selenophene ring in order to increase rigidity
of the catalyst structure will be investigated.
Scheme 161. RCM approach to the synthesis of 1,4-diols.
11.4.1 Bromolactonisation
Cyclic selenides synthesised in this work have been applied successfully as catalysts in the
bromolactonisations of unsaturated carboxylic acid derivatives. For the substrates tested,
high endo:exo regioselectivity was observed, following expected and precedented reactivity.
R
OR
OR
OHR
OH
NH OH
HPh
Ph
(20 mol%)
R
(R,R)-(salen)Co(II) (0.5 mol%)H2O (0.55 eq.)AcOH (2 mol%)THF, air, 0 °C
OR
O
(±)-363SeR
R4 steps
R H
O MgBr
THF R
OH
(±)-348
Novozym 435
toluene, r.t.
OAc
(0.55 eq.)
R
OH
SeRR4 steps
SeRR2 steps
a) CBS reagent:
c) Hydrolytic kinetic resolution:
b) Enzymatic resolution:
528 346 313
313348349
363 313
B(OMe)3 (25 mol%)BH3·SMe2 (2.0 eq.)
THF, r.t.
R
OH R'2SiCl2OSiO
R'R' RR RCM O OSiR'R'
RR
529 530348
169
The syn-diastereomer was not observed in any of the reactions. Using enantiopure
dihydroselenepines, modest enantioselectivity was observed, with the best results obtained
using 3,3’-diphenyl binaphthyl derivative 365 (Scheme 162). This result demonstrates that
the catalyst is involved, at least to some extent, in the stereodefining step.
Scheme 162. Highest ee obtained for the bromolactonisation of 410.
The low enantioselectivities encountered could be due to non-stereospecific olefin to olefin
bromonium transfer. To overcome this, future work will focus on steric and electronic
properties of the catalysts in an effort to increase the strength of interaction between the
catalyst and the reaction intermediates. Modifications could include the incorporation of
hydrogen bonding sites at the 3,3’-positions to bind to the pendant nucleophile in substrates.
11.5.1 Corey-Chaykovsky reaction
11.5.1.1 1,2-Diphenylepoxides
Dialkyl, cyclic selenides synthesised in this project have been shown to successfully catalyse
the reaction of benzyl bromide and benzaldehyde to form stilbene oxide (430). Akin to other
groups’ research, low or negligible diastereoselectivity was observed, however, both chiral
dihydroselenepines and tetrahydroselenophenes were shown to induce a degree of
enantioselectivity in the process. The best result in terms of enantioselectivity for these
substrates was obtained using 2,5-dicyclohexyltetrahydroselenophene 360 (Scheme 163).
OH
O 365 (5 mol%)NBS (1.2 eq.)
CH2Cl2 (0.1 M)–20 °C
410
PhO
Br
O
412 83%(22% ee)
Ph Se
Ph
Ph365
170
Scheme 163. Highest ee obtained in this project for the synthesis of trans-stilbene oxide 430.
Future work in this area will investigate methods to improve the diastereoselectivity through
modification of reaction conditions and catalyst design. Focus will need to be given to
elucidation of any selenide-specific mechanistic nuances in order to drive progress in this
area. Catalyst modifications could include trialling alternative ring sizes in order to alter the
steric environment around the intermediate ylide. As with the Lewis basic catalysts used in
halocylisations the incorporation of distal hydrogen bonding sites will be investigated, in this
case to direct addition of the aldehyde to the ylide. Additionally, expansion of the substrate
scope to include substituted arenes, as well as alkyl substrates will be investigated.
11.5.1.2 Allylic and propargylic bromides
This process was also successful when benzyl bromide was replaced with other activated
bromides. Particularly of note is the reaction of propargylic bromides 531 to from alkynyl
oxiranes 532 as, after preliminary investigations, this process appears to be specific to
selenide catalysis and has not been reported previously (Scheme 164).
Scheme 164. Selenium-catalysed epoxidations of propargylic bromides with benzaldehyde.
The reaction was applicable to 3-aryl, 3-alkyl and unsubstituted propargylic bromides,
however, secondary propargyl bromides led to rearranged products. When chiral selenide
360 was employed to catalyse the reaction of these substrates, only single-digit
enantioselectivities were obtained and improving this will be the main feature of any future
work into this area.
Ph
O
H
BnBr (2.0 eq.)selenide 360 (10 mol%)
NaOH (2.0 eq.)t-BuOH/H2O (9:1)
23 °C, 24 h
O
Ph Ph SeCyCy
360430 77%(1:1 dr, 66% eetrans)
351
Ph
O
HRBr selenide 252 (20 mol%)
Cs2CO3 (2.0 eq.)MeCN
O
Ph
53284-93%
(1 to 1.5:1 dr)
R351
R = H, Me, Ph531
171
Over the course of this work, several novel chiral selenides and diselenides have been
synthesised and their synthetic routes optimised. Their application in several classes of
transformation has been demonstrated, such as: Csp3–H oxidation; Lewis basic catalysis; and
Corey-Chaykovsky epoxidations. This work provides a foundation for the further expansion
of the applications of these compounds as catalysts, as well as providing a comprehensive
account of their synthesis upon which to base future derivatisation of catalyst structure.
Additionally, an effective palladium-catalysed formation of arylalkyl selenides has been
developed and its exploitation will facilitate any future catalyst synthesis.
172
CHAPTER TWELVE
Experimental
173
12. Experimental
All reactions were carried out under an atmosphere of nitrogen or argon and in oven-dried
glassware, unless otherwise stated. Flame- and oven-dried glassware was cooled under
vacuum (ca. 1 mbar). Where anhydrous conditions were necessary, standard Schlenk
techniques were used with flame-dried glassware under a positive pressure of nitrogen.
Anhydrous DMF, THF, CH2Cl2, toluene, hexane and Et2O were dried by passing through a
modified Grubbs system of alumina columns manufactured by LC Technology Solutions
Ltd. H2O refers to redistilled H2O. Other solvents and all reagents were obtained from
commercial suppliers and used as obtained unless stated otherwise. References in the
experimental to petroleum ether indicate use of petroleum spirit (b.p. 40–60 °C).
Room/ambient temperature was taken as 23 °C, where no external heating or cooling was
applied. Reactions at temperatures from –20 °C to ambient temperature were performed in
an ice/water/NaCl(s) bath and –78 °C was achieved using an acetone/CO2(s) bath. Prolonged
periods of reaction cooling were accomplished through the use of cryocool apparatus
manufactured by Huber. 1H NMR spectra were recorded at 400 MHz. Chemical shifts (δ) are
quoted to two decimal places in parts per million (ppm) with signal splittings recorded as
singlet (s), doublet (d), triplet (t), quartet (q), quintet (p), sextet (h), heptet (hept) and
multiplet (m). Coupling constants, J, are quoted to one decimal place in Hertz (Hz) and are
uncorrected. 13C NMR spectra were recorded at 101 MHz. Chemical shifts are quoted to one
decimal place in ppm. The solvent used in each case is specified. 1H spectra are referenced to
residual solvent peaks (for CDCl3: δ H =7.26). 13C spectra were referenced to CDCl3 (δ C =
77.0 ppm). Compounds 165, 233d, 233f, 233g, 233l, 237 and 268 were submitted for HRMS
but experienced high fragmentation with no molecular ion peaks identified.
174
Infrared (IR) spectra were recorded on a PerkinElmer FT-IR spectrometer with an ATR
accessory and were recorded neat as thin films or solids. Indicative features of spectrum are
given with adsorptions reported in wavenumbers (cm-1).
High resolution mass spectra (HRMS) (EI, CI, ESI) were recorded by the Imperial College
Mass Spectrometry Service.
Melting points were obtained using a Reichert-Thermovar melting point apparatus and are
uncorrected.
Optical rotations were recorded on a Perkin-Elmer 241 Polarimeter with a path length of 0.5
dm. Concentrations (c) are quoted in g/mL.
X-ray diffraction data was recorded by the Imperial College Department of Chemistry X-ray
diffraction service.
Flash column chromatography was performed according to the procedures used by Still and
co-workers using Merck silica gel 60 (particle size 40–63 µm) unless otherwise stated.259
Thin layer chromatography (TLC) was performed on Merck Kiesegel 60 F254 0.25 mm
precoated aluminium backed plates. Product spots were visualised under UV light (λmax =
254 nm) and/or by staining with aqueous potassium permanganate solution or vanillin.
Chiral HPLC was performed on a HP Agilent 1260 infinity series system employing Daicel
Chiralcel columns eluting with i-PrOH/hexane at 35 °C and monitored by a DAD (Diode
Array Detector).
Chiral GC was performed on an Agilent 7890 system (H2 Flow Rate = 0.88 mL/min, Inlet
Temperature = 250 °C) employing an Agilent CP-ChiraSil Dex CB column (25 m x 0.25
mm x 0.25 µm) and monitored by a FID (Flame Ionisation Detector).
175
Representative procedure for the preparation of sodium hydrogen selenide (NaHSe)
A flame-dried 50 mL two-neck round-bottomed flask was fitted with a rubber septum and a
nitrogen inlet. The flask was evacuated (ca. 1 mbar) and back-filled with nitrogen three
times and cooled to 0 °C in an ice/water bath. The septum was removed under a heavy flow
of nitrogen and the flask charged with selenium (237 mg, 3.0 mmol) and NaBH4 (125 mg,
3.3 mmol). In a separate flask EtOH (15 mL) was pre-cooled to 0 °C and then added to the
reaction flask via syringe. The reaction was stirred at 0 °C for 15 minutes and then the
cooling bath was removed and the suspension stirred vigorously for 1 hour, over which time
it warmed to room temperature and became a very pale red/colourless solution. The solution
of NaHSe was prepared as required and used subsequently without any further purification
or characterisation.67
Representative procedure for the preparation of tri-n-butyl(n-butylselanyl)stannane
(n-Bu3SnSe-n-Bu) – 222
A flame-dried 50 mL two-neck round-bottomed flask was fitted with a rubber septum and
nitrogen inlet and charged with selenium (1.2 g, 15 mmol). The flask was evacuated (ca. 1
mbar) and back-filled with nitrogen three times before the addition of anhydrous THF (10
mL). The suspension was cooled to –78 °C and n-butyllithium (6 mL, 15 mmol, 2.5 M in
hexanes) added dropwise via syringe over 10 minutes. The reaction mixture was stirred at
this temperature until complete consumption of selenium and a colourless solution was
obtained (ca. 30 minutes). Tributyltin chloride (4.1 mL, 4.9 g, 15 mmol) was added and the
flask was removed from the cooling bath and stirred for 1 hour, over which time it warmed
to ambient temperature, to obtain a solution of the title product 222 (15 mmol, 0.94 M in
THF/hexanes).
176
Representative procedure for the preparation of tri-n-butyl(methylselanyl)stannane (n-
Bu3SnSeMe) – 236-Me
A flame-dried 10 mL two-neck round-bottomed flask was fitted with a rubber septum and
nitrogen inlet and charged with selenium (95 mg, 1.2 mmol). The flask was evacuated (ca. 1
mbar) and back-filled with nitrogen three times before the addition of anhydrous THF (1
mL). The suspension was cooled to –78 °C and methyllithium (0.75 mL, 1.2 mmol, 1.6 M in
Et2O) added dropwise via syringe. The reaction mixture was stirred at this temperature until
complete consumption of selenium and a colourless solution was obtained (ca. 30 minutes).
Tributyltin chloride (325 µL, 290 mg, 1.2 mmol) was added and the flask was removed from
the cooling bath and stirred for 1 hour, over which time it warmed to ambient temperature, to
obtain a solution of the title product 236-Me (1.2 mmol, 0.69 M in THF/Et2O).
Representative procedure for the preparation of tri-n-butyl(t-butylselanyl)stannane (n-
Bu3SnSe-t-Bu) – 236-(t-Bu)
A flame-dried 10 mL two-neck round-bottomed flask was fitted with a rubber septum and
nitrogen inlet and charged with selenium (142 mg, 1.8 mmol). The flask was evacuated (ca.
1 mbar) and back-filled with nitrogen three times before the addition of anhydrous THF (1.5
mL). The suspension was cooled to –78 °C and tert-butyllithium (1.1 mL, 1.8 mmol, 1.7 M
in pentane) added dropwise via syringe. The reaction mixture was stirred at this temperature
until complete consumption of selenium and a yellow suspension was obtained (ca. 30
minutes). Tributyltin chloride (488 µL, 586 mg, 1.8 mmol) was added and the flask was
removed from the cooling bath and stirred for 1 hour, over which time it warmed to ambient
temperature and the mixture became a colourless solution, to obtain a solution of the title
product 236-(t-Bu) (1.8 mmol, 0.69 M in THF/pentane).
177
Representative procedure for the preparation of tri-n-butyl(phenylselanyl)stannane (n-
Bu3SnSePh) – 236-Ph
A flame-dried 10 mL two-neck round-bottomed flask was fitted with a rubber septum and
nitrogen inlet and charged with selenium (118 mg, 1.5 mmol). The flask was evacuated (ca.
1 mbar) and back-filled with nitrogen three times before the addition of anhydrous THF (1
mL). The suspension was cooled to –78 °C and phenyllithium (0.79 mL, 1.5 mmol, 1.9 M in
n-Bu2O) added dropwise via syringe. The reaction mixture was stirred at this temperature
until complete consumption of selenium and a yellow solution was obtained (ca. 30
minutes). Tributyltin chloride (488 µL, 586 mg, 1.8 mmol) was added and the flask was
removed from the cooling bath and stirred for 1 hour, over which time it warmed to ambient
temperature and the solution became colourless, to obtain a solution of the title product 236-
Ph (1.5 mmol, 0.84 M in THF/n-Bu2O).
178
Representative procedure for the preparation of magnesium bis(2,2,6,6-
tetramethylpiperidinide), Mg(TMP)2
Anhydrous MgBr2:
A flame-dried two-neck 50 mL round-bottomed flask was charged with magnesium turnings
(243 mg, 10 mmol) and fitted with a reflux condenser and rubber septum. The flask was
evacuated (ca. 1 mbar) and back-filled with nitrogen three times before the addition of
anhydrous THF (8 mL). The reaction vessel was placed in a water bath at ambient
temperature and 1,2-dibromoethane (862 µL, 10 mmol) was added via syringe dropwise
until the reaction initiated. Once the reaction had initiated, effervescence was controlled by
varying dropwise addition. After all of the 1,2-dibromoethane had been added, the reaction
was heated to reflux and stirred for 4 hours before cooling to 0 °C to afford a suspension of
MgBr2.
Mg(TMP)2:
A separate flame-dried two-neck 25 mL round-bottomed flask was evacuated (ca. 1 mbar)
and back-filled with nitrogen three times. The flask was charged with freshly-distilled
2,2,6,6-tetramethylpiperidine (3.38 mL, 20 mmol) and anhydrous THF (7 mL). The solution
was cooled to –78 °C before the addition of n-butyllithium (8 mL, 20 mmol, 2.5 M in
hexane) dropwise via syringe. After stirring at this temperature for 10 minutes, the solution
was warmed to 0 °C and stirred for 30 minutes to afford a solution of Li(TMP).
The solution of Li(TMP) was added to the freshly-prepared suspension of MgBr2 via syringe
and stirred at 0 °C for 30 minutes. The resulting solution of Mg(TMP)2 was used in the next
step immediately.146
179
General procedure A for the synthesis of aryl n-butyl selenides
A two-neck round-bottomed flask was fitted with a reflux condenser and rubber septum and
charged with [Pd(π-cinnamyl)Cl]2 (5 mol%) and the appropriate ligand (10 mol%). The flask
was evacuated (ca. 1 mbar) and back-filled with nitrogen three times before the addition of
anhydrous toluene (8 mL/mmol). The palladium and ligand were pre-mixed for 30 minutes
at 30 °C before the addition of a solution of the appropriate aryl electrophile (1.0 eq., 0.5 M
in toluene) followed by a solution of tri-n-butyl(n-butylselanyl)stannane 222 (1.5 eq., 0.94 M
in THF/hexanes). The reaction mixture was heated to 110 °C and stirred overnight. The
reaction mixture was allowed to cool to ambient temperature, diluted with Et2O (5
mL/mmol) and extracted three times with potassium fluoride (3 x 10 mL/mmol, 7 M in
H2O). The organic phase was separated and washed with brine (10 mL/mmol), dried
(MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column
chromatography to afford the appropriate aryl-n-butyl selenide.
General procedure B for the synthesis of cyclic dialkyl selenides
A solution of NaHSe (2.0 eq., 0.2 M in EtOH) was prepared in a two-neck round-bottomed
flask fitted with a reflux condenser and septum. The septum was removed under a heavy
flow of nitrogen and the appropriate dibromide (1.0 eq.) added as a solid. The reaction
mixture was heated to reflux and stirred at this temperature for 4 hours. The reaction was
allowed to cool to room temperature and quenched cautiously by dropwise addition of HCl
(20 mL/mmol, 1 M in H2O). The resulting suspension was diluted with EtOAc (20
mL/mmol) and the organic layer separated. The aqueous phase was extracted with CH2Cl2 (2
x 20 mL/mmol) and the combined organic extracts washed with saturated aqueous NaHCO3
(20 mL/mmol), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash
column chromatography to afford the appropriate cyclic selenide.136
180
General procedure C for the bis(methoxycarbonylation) of aryl bis(triflates)
A two-neck round-bottomed flask was fitted with a nitrogen inlet and rubber septum and
evacuated (ca. 1 mbar) and back-filled with nitrogen three times. N-ethyldiisopropylamine
(0.77 mL/mmol), methanol (2.0 mL/mmol) and DMSO (5.0 mL/mmol) were added via
syringe. The resulting solution was sparged with nitrogen through a needle for 30 minutes.
A Parr Split-Ring pressure vessel was charged with a stirrer bar, Pd(OAc)2 (15 mol%), 1,3-
bis(diphenylphosphino)propane (15 mol%) and the appropriate bistriflate (1.0 eq.). The
DMSO solution was then added via syringe and the head of the vessel was secured onto the
base with a nitrogen line attached to the inlet. The vessel was partially evacuated (ca. 300
mbar) and back-filled with nitrogen five times. The vessel was partially evacuated a final
time (ca. 300 mbar) and the inlet valve closed. The nitrogen line was removed and the inlet
attached to a CO cylinder regulated at 10 bar. The inlet valve of the reaction vessel was
opened and the pressure vessel filled with CO (10 bar). The inlet valve was closed, the CO
line removed and the closed reaction was heated to 80 °C with stirring for 24 hours. The
pressure vessel was allowed to cool to ambient temperature, carefully vented and the head
removed. The progress of the reaction was elucidated through TLC analysis and the vessel
refilled with CO as above if required. When complete, the reaction mixture was diluted with
CH2Cl2 (20 mL/mmol) and washed with brine (5 x 20 mL/mmol). The organic layer was
dried (MgSO4) and concentrated in vacuo. The residue was adsorbed onto silica and purified
by flash column chromatography to afford the bismethylester.136
181
General procedure D for the reduction of binaphthyl diesters
A flame-dried two-neck round-bottomed flask was fitted with a reflux condenser and rubber
septum. The flask was evacuated (ca. 1 mbar) and back-filled with nitrogen three times
before the addition of a solution of LiAlH4 (6.0 eq., 1 M in THF). The solution was cooled to
0 °C and a solution of the starting material (1.0 eq., 0.15 M in anhydrous THF) was added
dropwise via syringe. The reaction was heated to reflux and stirred at this temperature
overnight then cooled to room temperature. The reaction mixture was diluted sequentially
with Et2O (10 mL/mmol), H2O (1 mL/mmol), NaOH (1 mL/mmol, 4.4 M in H2O) and H2O
(2 mL/mmol). The resulting mixture was stirred at ambient temperature overnight and then
filtered through Celite® with Et2O. The filtrate was concentrated in vacuo to afford the
appropriate diol that was used in the next step without further purification.
General procedure E for the dibromination of diols
A round-bottomed flask was charged with the appropriate diol, fitted with a rubber septum
and evacuated (ca. 1 mbar) and back-filled with nitrogen three times through a needle.
Anhydrous THF (10 mL/mmol) was added and the resulting solution cooled to 0 °C. PBr3
(1.0 eq.) was added dropwise via syringe and the reaction mixture allowed to warm to room
temperature and stirred for 2 hours. The reaction was quenched with H2O (10 mL/mmol) and
extracted with EtOAc (2 x 10 mL/mmol). The combined organic extracts were washed with
brine (10 mL/mmol), dried (MgSO4) and concentrated in vacuo. The residue was purified by
flash column chromatography to afford the required dibromide.146
182
General procedure F for the synthesis of 1,4-diaryl-1,4-diketones
A 25 mL two-neck round-bottomed flask was fitted with a reflux condenser and rubber
septum and charged with AlCl3 (2 eq.) and evacuated (ca. 1 mbar) and back-filled with
nitrogen three times. The appropriate arene (7.5 eq) was added as the solvent via syringe and
the flask cooled to 0 °C. Succinyl chloride (1 eq.) was added dropwise via syringe at a rate
as to control the exotherm. Once all of the succinyl chloride had been added, the resulting
slurry was stirred for 2 hours and then quenched with HCl (4 mL/mmol, 1 M in H2O). The
mixture was extracted with CH2Cl2 (2 x 5 mL/mmol) and the combined organic extracts
washed with brine (5 mL/mmol), dried (MgSO4) and concentrated in vacuo. The residue was
purified by flash column chromatography to afford the desired product.260
General procedure G for the Corey-Itsuno reduction of 1,4-diketones
A flame-dried 25 mL two-neck round-bottomed flask was charged with (S)-α,α-
diphenylprolinol (20 mol%) and fitted with a nitrogen inlet and a rubber septum. The flask
was evacuated (ca. 1 mbar) and back-filled with nitrogen three times. Anhydrous THF (2
mL) followed by trimethylborate (25 mol%) were added and the resulting solution stirred for
1 hour at ambient temperature. BH3·SMe2 (2.0 eq.) was added via and syringe followed by a
solution of the appropriate 1,4-diketone (1.0 eq., 0.15 M in THF) and the reaction mixture
was stirred for 2 hours. The reaction was quenched with addition of HCl (8 mL/mmol, 1 M
in H2O) and extracted with EtOAc (3 x 10 mL/mmol). The combined organic extracts were
washed with brine (10 mL/mmol), dried (MgSO4) and concentrated in vacuo. The residue
was purified by flash column chromatography to afford the desired product.261
183
General procedure H for the synthesis of tetrahydroselenophenes from 1,4-diols
A two-neck round-bottomed flask was charged with the appropriate diol (1.0 eq.) and fitted
with a nitrogen inlet and rubber septum. CH2Cl2 (5 mL/mmol) and Et3N (3.0 eq.) were added
via syringe and the flask was cooled to –20 °C. MsCl (2.5 eq.) was added dropwise and the
reaction mixture stirred for 2.5 hours. A solution of NaHSe (4.0 eq., vide supra) in EtOH (5
mL/mmol) was added and the reaction mixture was warmed to 0 °C and stirred for 24 hours.
The reaction was quenched with HCl (10 mL/mmol, 1 M in H2O) and extracted with CH2Cl2
(2 x 10 mL/mmol). The combined organic extracts were washed with brine (10 mL/mmol),
dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column
chromatography to yield the desired product.241
General procedure I for the preparation of α-vinyl alcohols
A flame-dried two-neck round-bottomed flask was fitted with a nitrogen inlet and rubber
septum and evacuated (ca. 1 mbar) and back-filled with nitrogen three times. THF (2
mL/mmol) and the appropriate aldehyde (1.0 eq.) were added via syringe and the flask was
cooled to 0 °C. Vinyl magnesium bromide (1.2 eq., 1.0 M in THF) was added dropwise via
syringe and the reaction mixture stirred for 4 hours, over which time it warmed to room
temperature. The reaction was quenched via cautious addition of a solution of NH4Cl (2
mL/mmol, sat. aq.). The mixture was extracted with Et2O (2 x 2 mL/mmol) and the
combined organic extracts washed with brine (2 mL/mmol), dried (MgSO4) and
concentrated in vacuo. The residue was purified by flash column chromatography or used in
the next step without further purification.
184
General procedure J for the enzymatic resolution of α-vinyl alcohols
A round-bottomed flask was charged with toluene (1 mL/mmol), the appropriate alcohol (1.0
eq.) and vinyl acetate (0.52 eq.). Novozym 435 (10% wt.) was added and the reaction stirred
at ambient temperature for 24 hours. The reaction mixture was filtered through cotton wool
with Et2O and concentrated in vacuo. The residue was purified by flash column
chromatography to afford first the enantioenriched acetate followed by the enantioenriched
alcohol.181
General procedure K for alkene metathesis of α-vinyl alcohols
A two-neck round-bottomed flask was charged with 2nd Generation Grubbs Catalyst™ (1
mol%) and fitted with a reflux condenser and rubber septum. The flask was evacuated (ca. 1
mbar) and back-filled with nitrogen three times before the addition of CH2Cl2 (4 mL/mmol)
and the appropriate (1.0 eq.) via syringe. The reaction mixture was heated to reflux and
stirred for 24 hours. The reaction was concentrated in vacuo and the residue purified by flash
column chromatography to afford the desired 1,2-disubstituted alkene.262
185
General procedure L for the hydrogenation of alkenes over Rh/Al2O3
A round-bottomed flask was charged with 5% Rh/Al2O3 (10 mol%) and fitted with a rubber
septum. The flask was evacuated (ca. 1 mbar) and back-filled with nitrogen three times
through a needle before the addition of EtOAc (10 mL/mmol) followed by a solution of the
appropriate alkene (1.0 eq. in 2 mL EtOAc). The suspension was sparged with nitrogen
through a needle for 30 minutes and then the nitrogen line replaced with a H2 balloon. H2
was bubbled through the solvent for 10 minutes and then the reaction was stirred under a
hydrogen atmosphere for 1 hour. The reaction was filtered through Celite® with EtOAc and
the filtrate concentrated in vacuo to afford the desired saturated diol without the need for
further purification.
General procedure M for the selenium-catalysed Corey-Chaykovsky epoxidation of
aldehydes
A two-neck round-bottomed flask was charged with Cs2CO3 (2.0 eq.), the appropriate
selenide (10–20 mol%) and fitted with a nitrogen inlet and rubber septum. The flask was
evacuated (ca. 1 mbar) and back-filled with nitrogen three times before the addition of
CH2Cl2 (4 mL/mmol), benzaldehyde (1.0 eq.) and the appropriate bromide (2.0 eq.) via
syringe. The reaction was stirred at room temperature overnight and then diluted with
CH2Cl2 (10 mL/mmol) and washed with brine (5 mL/mmol). The organic layer was
separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash
column chromatography or preparatory TLC to afford the desired epoxides.
186
General procedure N for the preparation of alkenyl selenonium salts from selenides
Selenoxides from selenides:
A round-bottomed flask was charged with mCPBA (1.1 eq, <77% wt.), the appropriate
selenide (1.0 eq.) and CH2Cl2 (20 mL/mmol). K2CO3 (5 mL/mmol, sat. aq.) was added and
the resulting suspension stirred at ambient temperature for 1 hour. The reaction mixture was
diluted with saturated aqueous Na2CO3 (10 mL/mmol, sat. aq.) and the organic layer
separated, dried (MgSO4) and concentrated in vacuo. The selenoxide was used in the next
step without any further purification.136
Alkenyl selenonium triflates:
A two-neck round-bottomed flask was charged with the appropriate selenoxide (1.0 eq.) and
fitted with a nitrogen inlet and rubber septum. The flask was evacuated (ca. 1 mbar) and
back-filled with nitrogen three times before the addition of CH2Cl2 (7.5 mL/mmol). The
flask was cooled to 0 °C and the alkene (1.1 eq.) followed by Tf2O (1.1 eq.) were added
dropwise via syringe. The reaction mixture was stirred for 4 hours over which time it
warmed to room temperature. The reaction was concentrated in vacuo and the residue
adsorbed onto silica. The product was purified by flash column chromatography (20–40%
acetone in CH2Cl2) to afford the desired alkenyl selenonium triflate.258
187
Di(3,5-bis(trifluoromethyl)phenyl)diselenide – 23
A 100 mL two-neck round-bottomed flask was fitted with a reflux condenser and rubber
septum and purged with nitrogen. The flask was charged with selenium (790 mg, 10 mml),
NaOH (600 mg, 15 mmol) and DMF (40 mL). Hydrazine hydrate (490 µL, 10 mmol) was
added by syringe and the reaction mixture stirred at room temperature for 2 hours. 3,5-
bis(trifluoromethyl)bromobenzene (1.71 mL, 10 mmol) was added dropwise via syringe to
the deep red solution and the reaction mixture was heated to reflux for 13 hours before being
cooled to room temperature. The reflux condenser and septum were removed and the
mixture stirred vigorously under air for 1 hour. The resulting suspension was concentrated in
vacuo and the residue purified by flash column chromatography (10:1 hexane:Et2O) to
afford the desired product 23 as a yellow crystalline solid (2.10 g, 72%).
1H NMR (400 MHz, CDCl3) δ 8.05 (s, 4H), 7.81 (s, 2H);
13C NMR (101 MHz, CDCls) δ 132.5, 132.4, 131.6, 122.6 (q, 1JC–F = 274 Hz), 122.2.
The data are consistent with that reported in the literature.29
F3C
CF3
Se2
188
Dibenzo[c,e][1,2]diselenine – 140
A flame-dried 500 mL two-neck round-bottomed flask was fitted with a rubber septum and a
reflux condenser. The flask was evacuated (ca. 1 mbar) and back-filled with nitrogen three
times before being charged with TMEDA (18.9 mL, 126 mmol) followed by anhydrous
hexane (120 mL) and then n-BuLi (78.8 mL, 126 mmol, 1.6 M in hexane) at room
temperature. The septum was removed and biphenyl (9.25 g, 60 mmol) was added, the
septum replaced and the reaction mixture stirred 60 °C for 2 hours. The reaction mixture was
cooled to −78 °C and anhydrous THF (60 mL) was added via syringe (3 x 20 mL). The
septum was removed and selenium (9.48 g, 120 mmol) was added portionwise over 20
minutes. The flask was removed from the cooling bath and stirred for 1.5 hours over which
time it warmed to ambient temperature. The reaction mixture was poured onto NH4Cl (100
mL, 8 M in H2O) in a 1 L flask and stirred vigorously under air for 13 hours. The organic
phase was separated and the aqueous layer extracted with Et2O (2 x 250 mL). The combined
organic extracts were washed with brine (300 mL), dried (MgSO4), filtered and concentrated
in vacuo. The resulting red-brown residue was recrystallised from Et2O to yield product 140
as a red crystalline solid (5.22 g, 16.8 mmol, 28%).
1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 7.6, 1.4 Hz, 2H), 7.65 (dd, J = 7.6, 1.5 Hz, 2H),
7.39 (app. td, J = 7.6, 1.4 Hz, 2H), 7.26 (app. td, J = 7.6, 1.5 Hz, 2H);
13C NMR (101 MHz, CDCl3) δ 141.9, 131.8, 131.2, 129.6, 128.9, 127.6;
77Se NMR (76 MHz, CDCl3) δ 347.49 (d, 3JSe–C = 5.7 Hz).
The data are consistent with that reported in the literature.263
SeSe
189
Dinaphtho[2,1-b:1',2'-d]selenophene – 142
A flame-dried 50 mL two-neck round-bottomed flask was fitted with a reflux condenser and
rubber septum and charged with magnesium turnings (73 mg, 3 mmol). The flask was
evacuated (ca. 1 mbar) and back-filled with nitrogen three times. A solution of 2,2'-dibromo-
1,1'-binaphthalene (412 mg, 1 mmol) in anhydrous THF (10 mL) was added via syringe. 1,2-
Dibromoethane (18 µL, 0.2 mmol) was added to initiate the reaction and the reaction
mixture was heated to reflux (70 °C) with stirring for 5 hours. The reaction mixture was
cooled slightly to 50 °C before the rubber septum was removed under a heavy flow of
nitrogen and selenium (197 mg, 2.5 mmol) was added in one portion. The septum was
replaced and the suspension heated to reflux (70 °C) for 12 hours. The reaction mixture was
allowed to cool to ambient temperature and diluted with NH4Cl (50 mL, sat. aq.) and Et2O
(100 mL). The organic phase was separated and the aqueous extracted with Et2O (2 x 100
mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4),
filtered and concentrated in vacuo. The residue was purified by flash column
chromatography (20:1 hexane:EtOAc) to afford the product 142 as a colourless crystalline
solid (60 mg, 0.18 mmol, 18%).
1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 8.4 Hz, 2H), 8.06 – 8.00 (m, 4H), 7.90 (d, J = 8.5
Hz, 2H), 7.59 (ddd, J = 8.1, 6.8, 1.3 Hz, 2H), 7.52 (ddd, J = 8.4, 6.8, 1.5 Hz, 2H);
13C NMR (101 MHz, CDCl3) δ 140.0, 133.9, 132.3, 131.1, 128.5, 127.2, 126.5, 125.2,
124.6, 123.6;
77Se{1H} NMR (76 MHz, CDCl3) δ 484.6.
The data are consistent with that reported in the literature.60
Se
190
Sodium hydrogen selenide (NaHSe)
A 500 mL round-bottomed flask was charged with selenium (2.37 g, 30 mmol) and 2-
propanol (75 mL). The suspension was degassed by purging with a flow of nitrogen (20
minutes) and NaBH4 (1.13 g, 30 mmol) added. After stirring for 1 hour, the product was
used in situ without need for purification.
O-(4-Nitrophenyl) N,N-dimethylselenocarbamate – 151
A 250 mL, two-neck round-bottomed flask was charged with anhydrous CH2Cl2 (140 mL),
4-nitrophenol (5.56 g, 40 mmol) and N-(dichloromethylene)-N-methylmethanaminium
chloride (3.25 g, 20 mmol) under a nitrogen atmosphere. The suspension was heated to
reflux (45 °C) for 1 hour before being cooled to room temperature. The resulting solution
was added to a solution of NaHSe (80 mL, 30 mmol, 0.4 M in 2-propanol) dropwise via
syringe over 10 minutes and stirred at room temperature for 1.5 hours. The reaction mixture
was filtered through Celite®, concentrated in vacuo and purified by flash column
chromatography (CH2Cl2 + 1% Et3N) to afford the desired product 151 as a pale yellow
solid (890 mg, 3.25 mmol, 16%).
1H NMR (400 MHz, CDCl3) δ 8.35 – 8.29 (m, 2H), 7.32 – 7.25 (m, 2H), 3.61 (s, 3H), 3.40
(s, 3H);
13C NMR (101 MHz, CDCl3) δ 159.5, 145.7, 124.9, 124.1, 110.0, 46.0, 39.2.
The data are consistent with that reported in the literature.32
O2N
O NMe2
Se
191
Se-(4-Nitrophenyl) N,N-dimethylselenocarbamate – 152
A flame-dried 25 mL two-neck round-bottomed flask was fitted with a rubber septum and
nitrogen inlet and charged with O-(4-nitrophenyl) N,N-dimethylselenocarbamate (151) (50
mg, 0.18 mmol). The flask was evacuated (ca. 1 mbar) and back-filled with nitrogen three
times before the addition of anhydrous N,N-dimethylacetamide (3 mL) via syringe. The
resulting solution was heated to 130 °C for 15 hours and then allowed to cool to ambient
temperature. The solution was transferred to a 20 mL vial, warmed to 40 °C and the solvent
blown down under a flow of nitrogen overnight to afford a mixture of the desired product
152 (0.167 mmol, 92%) and 4-nitrophenyl N,N-dimethylcarbamate (0.0145 mmol, 8%). The
yields of the products were calculated by the relative intensities of product peaks in the 1H
NMR spectrum.
1H NMR (400 MHz, CDCl3) δ 8.20 – 8.15 (m, 2H), 7.80 – 7.75 (m, 2H), 3.07 (s, 6H);
13C NMR (101 MHz, CDCl3) δ 162.5, 147.9, 136.8, 135.9, 123.6, 37.2 (2C).
The data are consistent with that reported in the literature.32
O2N
Se NMe2
O
192
O-(2'-Hydroxy-biphenyl-2-yl) N,N-dimethylselenocarbamate – 156
A 250 mL, two-neck round-bottomed flask was charged with anhydrous CH2Cl2 (140 mL),
2,2’-biphenol (3.72 g, 20 mmol) and N-(dichloromethylene)-N-methylmethanaminium
chloride (6.5 g, 40 mmol) under a nitrogen atmosphere. The suspension was heated to reflux
(45 °C) for 1.5 hours before being cooled to room temperature. The resulting solution was
added to a solution of NaHSe (160 mL, 60 mmol, 0.4 M in 2-propanol) dropwise via syringe
over 10 minutes and stirred at room temperature for 3 hours. The reaction mixture was
filtered through Celite®, concentrated in vacuo and purified by flash column chromatography
(CH2Cl2 + 1% Et3N) to afford the desired product 156 as a pale yellow oil (3.50 g, 10.9
mmol, 55%).
1H NMR (400 MHz, CDCl3) δ 7.49 (ddd, J = 8.1, 6.0, 3.2 Hz, 1H), 7.41 – 7.38 (m, 2H),
7.31 – 7.23 (m, 2H), 7.17 (ddd, J = 7.6, 1.8, 0.4 Hz, 1H), 7.02 (ddd, J = 8.2, 1.2, 0.4 Hz, 1H),
6.95 (td, J = 7.4, 1.2 Hz, 1H), 3.41 (s, 3H), 3.10 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 190.3, 153.4, 132.1, 130.9, 130.8, 129.5, 129.2, 126.8,
124.4, 124.3, 120.2, 117.0, 45.8, 38.7;
77Se{1H} NMR (76 MHz, CDCl3) δ 276.1;
HRMS (ES+) calculated for C15H16NO2Se [M+H]+: 322.0346; Found: 322.0342;
IR νmax/cm-1 (neat): 3315 (br.), 1542, 1475, 1398, 1198, 1121, 747.
OHO NMe2
Se
193
1,4-Diphenylbuta-1,3-diyne – 162
A 500 mL round-bottomed flask was charged with CuI (286 mg, 1.5 mmol), acetone (150
mL) and TMEDA (450 µL, 3 mmol) to afford a blue-black solution. Phenylacetylene (3.3
mL, 30 mmol) was added to the solution dropwise over 5 minutes during which time the
colour changed to pale blue. The reaction was stirred vigorously under air until the blue-
black colour returned (ca. 3 hours) and then concentrated in vacuo. The residue was
dissolved in Et2O (100 mL) and washed with H2O (50 mL). The aqueous was extracted with
Et2O (100 mL) and the combined organic layers washed with brine, dried (MgSO4) and
concentrated in vacuo. The residue was purified by flash column chromatography
(petroleum ether) to afford the title compound 162 as a colourless, crystalline solid (2.65 g,
87%).
1H NMR (400 MHz, CDCl3) δ 7.57 – 7.51 (m, 4H), 7.42 – 7.32 (m, 6H);
13C NMR (101 MHz, CDCl3) δ 132.5, 129.2, 128.5, 121.8, 81.6, 73.9;
The data are consistent with that reported in the literature.264
Ph
Ph
194
2-(Phenylethynyl)benzaldehyde – 163
A two-neck 100 mL round-bottomed flask was fitted with a reflux condenser and rubber
septum. The flask was charged with Pd(PPh3)2Cl2 (420 mg, 0.6 mmol) and CuI (190 mg, 1.0
mmol) and then evacuated (ca. 1 mbar) and back-filled with nitrogen three times. THF (25
mL), 2-bromobenzaldehyde (2.3 mL, 20 mmol), phenylacetylene (2.6 mL, 24 mmol) and
Et3N (5.6 mL, 40 mmol) were added and the flask was heated to reflux for 3 hours. The
reaction mixture was allowed to cool to room temperature and diluted with Et2O (50 mL),
filtered through Celite® with Et2O and the resulting solution concentrated in vacuo. The
residue was purified by flash column chromatography (0–5% EtOAc in petroleum ether) to
afford the title compound 163 as a brown oil (4.0 g, 97%).
1H NMR (400 MHz, CDCl3) δ 10.69 (d, J = 0.8 Hz, 1H), 8.03 – 7.93 (m, 1H), 7.70 – 7.66
(m, 1H), 7.64 – 7.57 (m, 3H), 7.51 – 7.46 (m, 1H), 7.45 – 7.39 (m, 3H);
13C NMR (101 MHz, CDCl3) δ 191.7, 135.8, 133.8, 133.2, 131.7, 129.1, 128.6, 128.5,
127.3, 126.9, 122.3, 96.3, 84.9;
The data are consistent with that reported in the literature.265
O
H
Ph
195
1,1'-Dibromo-3,3'-diphenyl-2,2'-binaphthalene – 164
A 100 mL two-neck round-bottomed flask was charged with CuBr2 (2.2 g, 10 mmol) and
diyne 152 (400 mg, 2 mmol). The flask was fitted with a reflux condenser and rubber septum
and evacuated (ca. 1 mbar) and back-filled with nitrogen three times. (CH2Cl)2 (20 mL)
followed by 2-(phenylethynyl)benzaldehyde 153 (1.0 g, 5 mmol) were added via syringe and
the reaction was heated to 100 °C and stirred for 3 hours. The reaction mixture was allowed
to cool to room temperature and washed with NH4Cl (50 mL, sat. aq.). The aqueous was
extracted with Et2O (80 mL) and the combined organic layers were washed with brine (50
mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column
chromatography (5% CH2Cl2 in hexane) to afford the title compound 164 as a colourless
solid (460 mg, 41%).
1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 7.9 Hz, 2H), 7.82 (d, J = 8.1 Hz, 2H), 7.65 (ddd,
J = 8.5, 6.9, 1.4 Hz, 2H), 7.62 (s, 2H), 7.57 (ddd, J = 8.1, 6.9, 1.2 Hz, 2H), 7.11 – 7.06 (m,
2H), 7.01 – 6.96 (m, 4H), 6.75 (d, J = 8.2 Hz, 4H);
13C NMR (101 MHz, CDCl3) δ 140.1 (2C), 139.3, 133.7, 131.3, 129.4, 129.1, 128.3, 128.0,
127.5, 127.3, 127.1, 126.8;
The data are consistent with that reported in the literature.80
PhPh
BrBr
196
6,7-Diphenyldinaphtho[1,2-c:2',1'-e][1,2]diselenine – 165
A flame-dried 250 mL two-neck round-bottomed flask was fitted with a nitrogen inlet and
rubber septum and evacuated (ca. 1 mbar) and back-filled with nitrogen three times. A
solution of the dibromide 164 (1.8 g, 3.2 mmol) in anhydrous THF (100 mL) was added via
syringe and the flask cooled to –78 °C. tert-Butyllithium (7.5 mL, 12.8 mmol, 1.7 M in
pentane) was added dropwise and the reaction mixture stirred for 3 hours. The septum was
removed under a flow of nitrogen and selenium (560 mg, 7.0 mmol) was added. The septum
was replaced and the reaction mixture allowed to warm to room temperature and stirred for 2
hours. The reaction was quenched with NH4Cl (50 mL, sat. aq.), diluted with Et2O (50 mL)
and stirred vigorously under air overnight. The organic layer was separated and the aqueous
extracted with Et2O (3 x 50 mL). The combined organic extracts were washed with brine (50
mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column
chromatography (1% Et2O in hexane) to afford the title compound 165 as an orange solid
(701 mg, 39%).
1H NMR (400 MHz, CDCl3) δ 8.45 (dd, J = 8.4, 1.0 Hz, 2H), 7.78 (app. dt, J = 7.9, 0.7 Hz,
2H), 7.64 (ddd, J = 8.4, 6.9, 1.3 Hz, 2H), 7.52 (ddd, J = 8.1, 6.8, 1.2 Hz, 2H), 7.44 (d, J = 0.8
Hz, 2H), 7.10 – 7.05 (m, 2H), 6.92 (dd, J = 8.1, 7.2 Hz, 4H), 6.54 – 6.46 (m, 4H);
13C NMR (101 MHz, CDCl3) δ 141.6, 141.2, 140.7, 140.6, 132.5, 132.4, 129.9, 129.7,
128.8, 128.3, 127.2, 126.7 (2C), 126.5;
77Se{1H} NMR (76 MHz, CDCl3) δ 375.9;
m.p. (EtOH): 164 °C (decomposed);
PhPh
SeSe
197
IR νmax/cm-1 (neat): 3051, 3025, 1482, 884, 780, 740, 697.
198
6,7-Diphenyldinaphtho[1,2-b:2',1'-d]selenophene – 179
When the diselenide 165 was stored as a solid, slow decomposition to the selenophene 179
was observed. Furthermore, oxidations with the diselenide 165 led to observation of
increased concentrations of selenophene 179 in the reaction mixture.
The structure was confirmed by single crystal X-ray crystallography and characteristic 1H
NMR data is displayed below.
1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.1, 2H), 7.91 – 7.84 (m, 2H), 7.63 – 7.58 (m,
2H), 7.55 (ddd, J = 8.1, 6.9, 1.4 Hz, 2H), 7.47 (d, J = 0.7 Hz, 2H), 7.10 – 7.04 (m, 2H), 7.02
– 6.95 (m, 4H), 6.79 – 6.74 (m, 4H).
SePh
Ph
199
n-Butyl(p-tolyl)selenide – 218
Prepared from p-tolyl triflate 219 (240 mg, 1.0 mmol) according to general procedure A
using [Pd(π-cinnamyl)Cl]2 (26 mg, 0.05 mmol) and xantphos 224 (58 mg). The crude
product mixture was purified by flash column chromatography (petroleum ether) to afford
the title compound 218 as a colourless oil (223 mg, 98%).
1H NMR (400 MHz, CDCl3) δ 7.39 (app. dt, J = 8.1, 1.9 Hz, 2H), 7.07 (d, J = 7.8 Hz, 2H),
2.87 (t, J = 7.5 Hz, 2H), 2.32 (s, 3H), 1.72 – 1.62 (m, 2H), 1.48 – 1.36 (m, 2H), 0.90 (t, J =
7.4 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 136.7, 133.0, 132.4, 129.8, 32.4, 28.0, 22.9, 22.7, 21.1;
77Se{1H} NMR (76 MHz, CDCl3) δ 283.0;
HRMS (ES+) calculated for C11H17OSe [M+OH]+: 245.0445; Found: 245.0448;
IR νmax/cm-1 (neat): 3070, 3018, 2957, 2926, 1579, 1489, 1458, 1016, 734.
SeBu
200
n-Butyl(o-tolyl)selenide – 231
Prepared from o-tolyl triflate 230 (240 mg, 1.0 mmol) according to general procedure A
using [Pd(π-cinnamyl)Cl]2 (26 mg, 0.05 mmol) and xantphos 224 (58 mg). The crude
product mixture was purified by flash column chromatography (petroleum ether) to afford
the title compound 231 as a colourless oil (208 mg, 92%).
1H NMR (400 MHz, CDCl3) δ 7.42 (dd, J = 6.8, 2.3 Hz, 1H), 7.22 –7.10 (m, 3H), 2.90 (t, J
= 7.4 Hz, 2H), 2.40 (s, 3H), 1.76 – 1.65 (m, 2H), 1.51 – 1.40 (m, 2H), 0.93 (t, J = 7.4 Hz,
3H);
13C NMR (101 MHz, CDCl3) δ 139.1, 131.9, 130.9, 129.9, 126.4, 126.3, 32.0, 26.5, 23.1,
22.3, 13.6;
77Se{1H} NMR (76 MHz, CDCl3) δ 242.0;
HRMS (ES+) calculated for C11H17OSe [M+OH]+: 245.0445; Found: 245.0448;
IR νmax/cm-1 (neat): 3059, 2957, 2928, 1591, 1464, 1037, 739.
SeBu
201
3-(Butylselanyl)benzaldehyde – 233c
Prepared from 3-bromobenzaldehyde 232c (184 mg, 1.0 mmol) according to general
procedure A using [Pd(π-cinnamyl)Cl]2 (26 mg, 0.05 mmol) and xantphos 224 (58 mg). The
crude product mixture was purified by flash column chromatography (petroleum ether) to
afford the title compound 233c as a colourless oil (235 mg, 98%).
1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 7.96 (td, J = 1.7, 0.5 Hz, 1H), 7.74 – 7.69 (m,
2H), 7.42 (app. t, J = 7.7 Hz, 1H), 2.98 (t, J = 7.4 Hz, 2H), 1.75 – 1.66 (m, 2H), 1.50 – 1.39
(m, 2H), 0.92 (t, J = 7.4 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 191.8, 137.7, 137.0, 132.5, 130.4, 129.5, 128.0, 32.1, 27.6,
22.9, 13.5;
77Se{1H} NMR (76 MHz, CDCl3) δ 296.8;
HRMS (ES+) calculated for C11H15O2Se [M+OH]+: 259.0237; Found: 259.0242;
IR νmax/cm-1 (neat): 2957, 2723, 1694, 1573, 1464, 1376, 1192, 782.
SeBuO
H
202
n-Butyl(2-methoxyphenyl)selenide – 233d
Prepared from 2-bromoanisole 232d (187 mg, 1.0 mmol) according to general procedure A
using [Pd(π-cinnamyl)Cl]2 (26 mg, 0.05 mmol) and xantphos 224 (58 mg). The crude
product mixture was purified by flash column chromatography (1% Et2O in petroleum ether)
to afford the title compound 233d as a colourless oil (115 mg, 47%).
1H NMR (400 MHz, CDCl3) δ 7.33 (dd, J = 7.5, 1.7 Hz, 1H), 7.19 (ddd, J = 8.3, 7.5, 1.7 Hz,
1H), 6.91 (app. td, J = 7.5, 1.2 Hz, 1H), 6.83 (dd, J = 8.3, 1.2 Hz, 1H), 3.88 (s, 3H), 2.90 (t, J
= 7.8 Hz, 2H), 1.76 – 1.66 (m, 2H), 1.51 – 1.41 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 131.8, 130.6, 127.2, 121.4, 110.3, 108.7, 55.8, 31.8 24.8,
23.1, 13.5;
77Se{1H} NMR (76 MHz, CDCl3) δ 225.3;
IR νmax/cm-1 (neat): 2957, 2924, 1594, 1466, 841, 766.
SeBu
OMe
203
n-Butyl(3-methoxyphenyl)selenide – 233e
Prepared from 3-bromoanisole 232e (187 mg, 1.0 mmol) according to general procedure A
using [Pd(π-cinnamyl)Cl]2 (26 mg, 0.05 mmol) and xantphos 224 (58 mg). The crude
product mixture was purified by flash column chromatography (1% Et2O in petroleum ether)
to afford the title compound 233e as a colourless oil (191 mg, 78%).
1H NMR (400 MHz, CDCl3) δ 7.17 (app. t, J = 7.9 Hz, 1H), 7.08 – 7.01 (m, 2H), 6.76 (ddd,
J = 8.2, 2.6, 1.0 Hz, 1H), 3.80 (s, 3H), 2.92 (t, J = 7.4 Hz, 2H), 1.76 – 1.61 (m, 2H), 1.49 –
1.37 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 159.7, 131.8, 129.7, 124.3, 117.6, 112.3, 55.3, 32.2, 27.5,
23.0, 13.6;
77Se{1H} NMR (76 MHz, CDCl3) δ 296.0;
HRMS (ES+) calculated for C11H17O2Se [M+OH]+: 261.0394; Found: 261.0387;
IR νmax/cm-1 (neat): 2956, 2928, 1587, 1475, 1040, 839, 686.
SeBuMeO
204
n-Butyl(4-nitrophenyl)selenide – 233f
Prepared from 1-bromo-4-nitrobenzene 232f (202 mg, 1.0 mmol) according to general
procedure A using [Pd(π-cinnamyl)Cl]2 (26 mg, 0.05 mmol) and xantphos 224 (58 mg). The
crude product mixture was purified by flash column chromatography (5% Et2O in petroleum
ether) to afford the title compound 233f as a yellow oil (184 mg, 71%).
1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 9.0 Hz, 2H), 7.50 (d, J = 9.0 Hz, 2H), 3.08 – 3.00
(m, 2H), 1.81 – 1.70 (m, 2H), 1.54 – 1.41 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 142.6, 130.0, 129.1, 123.8, 31.7, 26.9, 23.0, 13.5;
77Se{1H} NMR (76 MHz, CDCl3) δ 315.2;
IR νmax/cm-1 (neat): 2957, 2927, 2871, 1573, 1509, 1340, 1066, 850, 758.
SeBu
O2N
205
3-(n-Butylselanyl)aniline – 233g
Prepared from 3-bromoaniline 232g (172 mg, 1.0 mmol) according to general procedure A
using [Pd(π-cinnamyl)Cl]2 (26 mg, 0.05 mmol) and xantphos 224 (58 mg). The crude
product mixture was purified by flash column chromatography (10% EtOAc in petroleum
ether) to afford the title compound 233g as a brown oil (134 mg, 59%).
1H NMR (400 MHz, CDCl3) δ 7.03 (app. t, J = 7.8 Hz, 1H), 6.89 – 6.81 (m, 2H), 6.54 (ddd,
J = 7.8, 2.3, 1.0 Hz, 1H), 2.89 (t, J = 7.4 Hz, 2H), 1.74 – 1.64 (m, 2H), 1.48 – 1.36 (m, 2H),
0.91 (t, J = 7.4 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 146.8, 130.6, 129.7, 122.3, 118.6, 113.5, 32.3, 27.4, 23.0,
13.6;
77Se{1H} NMR (76 MHz, CDCl3) δ 291.3;
IR νmax/cm-1 (neat): 3451, 3355, 3217, 2956, 2925, 1588, 1478, 1261, 863, 768.
SeBuH2N
206
n-Butyl(2-methylnaphthalen-1-yl)selenide – 233h
Prepared from 1-bromo-2-methylnaphthalene 232h (221 mg, 1.0 mmol) according to general
procedure A using [Pd(π-cinnamyl)Cl]2 (26 mg, 0.05 mmol) and xantphos 224 (58 mg). The
crude product mixture was purified by flash column chromatography (petroleum ether) to
afford the title compound 233h as a colourless oil (171 mg, 62%).
1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.73 (d, J
= 8.3 Hz, 1H), 7.54 (ddd, J = 8.6, 6.8, 1.4 Hz, 1H), 7.44 (ddd, J = 8.1, 6.9, 1.3 Hz, 1H), 7.40
(d, J = 8.3 Hz, 1H), 2.80 (s, 3H), 2.75 (t, J = 7.4 Hz, 2H), 1.61 – 1.50 (m, 2H), 1.42 – 1.31
(m, 2H), 0.84 (t, J = 7.3 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 141.7, 135.9, 132.5, 129.0, 128.8, 128.4, 128.3, 128.2,
126.7, 125.0, 32.6, 28.7, 25.1, 23.0, 13.6;
77Se{1H} NMR (76 MHz, CDCl3) δ 146.1;
HRMS (ES+) calculated for C15H19OSe [M+OH]+: 295.0601; Found: 295.0596.
SeBu
207
2,2'-Bis(butylselanyl)-1,1'-biphenyl – 233l
Prepared from (1,1'-biphenyl)-2,2'-diyl bis(triflate) 232l (221 mg, 1.0 mmol) and n-Bu3SnSe-
n-Bu 222 (3.0 mmol, 3.0 eq.) according to general procedure A using [Pd(π-cinnamyl)Cl]2
(26 mg, 0.05 mmol) and Josiphos PhPF-t-Bu 221 (54 mg). The crude product mixture was
purified by flash column chromatography (5% toluene in petroleum ether) to afford the title
compound 233l as a colourless oil that solidified upon standing (390 mg, 90%).
1H NMR (400 MHz, CDCl3) δ 7.49 (dd, J = 7.8, 1.5 Hz, 2H), 7.33 – 7.22 (m, 4H), 7.17 (dd,
J = 7.3, 1.8 Hz, 2H), 2.85 – 2.74 (m, 4H), 1.67 – 1.52 (m, 4H), 1.40 – 1.29 (m, 4H), 0.87 (t, J
= 7.4 Hz, 6H);
13C NMR (101 MHz, CDCl3) δ 143.3, 132.2, 130.3, 130.1, 128.3, 125.7, 31.7, 26.7, 23.1,
13.6;
77Se{1H} NMR (76 MHz, CDCl3) δ 261.7.
SeBuSeBu
208
2,2'-Bis(butylselanyl)-1,1'-binaphthalene – 246
Prepared from 2,2'-dibromo-1,1'-binaphthalene 141 (412 mg, 1.0 mmol) and n-Bu3SnSe-n-
Bu 222 (3.0 mmol, 3.0 eq.) according to general procedure A using [Pd(π-cinnamyl)Cl]2 (26
mg, 0.05 mmol) and xantphos 224 (58 mg). The crude product mixture was purified by flash
column chromatography (5–20% toluene in petroleum ether) to afford the title compound
246 as a pale orange solid (437 mg, 83%).
1H NMR (400 MHz, CDCl3) δ 7.91 – 7.87 (m, 4H), 7.70 (d, J = 8.7 Hz, 2H), 7.41 (ddd, J =
8.1, 6.8, 1.2 Hz, 2H), 7.23 (ddd, J = 8.3, 6.8, 1.3 Hz, 2H), 7.03 (d, J = 8.5 Hz, 2H), 2.96 –
2.83 (m, 4H), 1.65 – 1.55 (m, 4H), 1.37 – 1.24 (m, 4H), 0.82 (t, J = 7.4 Hz, 6H);
13C NMR (101 MHz, CDCl3) δ 137.3, 132.9, 132.0, 131.5, 128.4, 128.1, 127.3, 126.7,
125.5, 125.4, 32.1, 26.1, 23.0, 13.5;
77Se{1H} NMR (76 MHz, CDCl3) δ 282.1;
m.p. (hexane): 145–146 °C
HRMS (EI+) calculated for C28H30Se2 [M]+: 526.0678; Found: 526.0694;
IR νmax/cm-1 (neat): 3051, 2948, 2925, 1258, 1174, 1037, 804, 740.
SeBuSeBu
209
Methyl(o-tolyl)selenide – 237
A 25 mL two-neck round-bottomed flask was fitted with a reflux condenser and rubber
septum and charged with [Pd(π-cinnamyl)Cl]2 (26 mg, 0.05 mmol) and PhPF-t-Bu (54 mg).
The flask was evacuated (ca. 1 mbar) and back-filled with nitrogen three times before the
addition of anhydrous toluene (8 mL). The palladium and ligand were pre-mixed for 30
minutes at 30 °C before the addition of a solution of o-tolyl triflate 230 (2 mL, 240 mg, 1.0
mmol, 0.5 M in toluene) followed by a solution of tri-n-butyl(methylselenyl)stannane 236-
Me (1.75 mL, 1.2 mmol, 0.69 M in THF/Et2O). The reaction mixture was heated to 110 °C
and stirred overnight. The reaction mixture was allowed to cool to ambient temperature,
diluted with Et2O (10 mL) and extracted three times with potassium fluoride (3 x 10 mL, 7
M in H2O). The organic phase was separated and washed with brine (10 mL), dried
(MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column
chromatography (hexane) to afford the title compound 237 as a colourless oil (175 mg,
95%).
1H NMR (400 MHz, CDCl3) δ 7.33 (dd, J = 7.4, 1.9 Hz, 1H), 7.20 – 7.12 (m, 3H), 2.40 (s,
3H), 2.34 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 137.8, 133.2, 129.8, 128.4, 126.6, 125.8, 21.7, 6.3;
IR νmax/cm-1 (neat): 2921, 2851, 1458, 1211, 1031, 744.
SeMe
210
t-Butyl(p-tolyl)selenide – 238
A 50 mL two-neck round-bottomed flask was fitted with a reflux condenser and rubber
septum and charged with [Pd(π-cinnamyl)Cl]2 (19 mg, 0.038 mmol) and xantphos (43 mg,
0.075 mmol). The flask was evacuated (ca. 1 mbar) and back-filled with nitrogen three times
before the addition of anhydrous toluene (12 mL). The palladium and ligand were pre-mixed
for 30 minutes at 30 °C before the addition of a solution of p-tolyl triflate 219 (3 mL, 360
mg, 1.5 mmol, 0.5 M in toluene) followed by a solution of tri-n-butyl(t-
butylselenyl)stannane 236-(t-Bu) (2.6 mL, 1.8 mmol, 0.69 M in THF/pentane). The reaction
mixture was heated to 110 °C and stirred overnight. The reaction mixture was allowed to
cool to ambient temperature, diluted with Et2O (20 mL) and extracted three times with
potassium fluoride (3 x 20 mL, 7 M in H2O). The organic phase was separated and washed
with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was
purified by flash column chromatography (hexane) to afford the title compound 238 as a
pale yellow oil (326 mg, 96%).
1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 2.39 (s,
3H), 1.42 (s, 9H);
13C NMR (101 MHz, CDCl3) δ 138.1, 133.0, 130.1, 129.5, 42.8, 32.1, 21.3;
77Se{1H} NMR (76 MHz, CDCl3) δ 511.3;
HRMS (EI+) calculated for C11H16Se [M]+: 228.0417; Found: 228.0426;
IR νmax/cm-1 (neat): 2951, 2925, 2854, 1448, 1048, 847, 804.
Se(t-Bu)
211
Phenyl(o-tolyl)selenide – 239
A 25 mL two-neck round-bottomed flask was fitted with a reflux condenser and rubber
septum and charged with [Pd(π-cinnamyl)Cl]2 (26 mg, 0.05 mmol) and xantphos (58 mg).
The flask was evacuated (ca. 1 mbar) and back-filled with nitrogen three times before the
addition of anhydrous toluene (8 mL). The palladium and ligand were pre-mixed for 30
minutes at 30 °C before the addition of a solution of o-tolyl triflate 230 (2 mL, 240 mg, 1.0
mmol, 0.5 M in toluene) followed by a solution of tri-n-butyl(phenylselenyl)stannane 236-
Ph (1.8 mL, 1.2 mmol, 0.84 M in THF/n-Bu2O). The reaction mixture was heated to 110 °C
and stirred overnight. The reaction mixture was allowed to cool to ambient temperature,
diluted with Et2O (10 mL) and extracted three times with potassium fluoride (3 x 10 mL, 7
M in H2O). The organic phase was separated and washed with brine (10 mL), dried
(MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column
chromatography (petroleum ether) to afford the title compound 239 as a colourless oil (224
mg, 91%).
1H NMR (400 MHz, CDCl3) δ 7.44 – 7.37 (m, 2H), 7.34 (dd, J = 7.8, 1.3 Hz, 1H), 7.29 –
7.17 (m, 5H), 7.10 – 7.04 (m, 1H), 2.40 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 139.1, 133.7, 133.0, 132.8, 131.7, 130.2, 129.4, 127.8,
127.2, 126.7, 22.4;
77Se{1H} NMR (76 MHz, CDCl3) δ 374.9.
The data are consistent with that reported in the literature.87
SePh
212
5,7-Dihydrodibenzo[c,e]selenepine – 252
Prepared from 2,2'-bis(bromomethyl)-1,1'-biphenyl (6.8 g, 20 mmol) and NaHSe (40 mmol)
according to general procedure B. The crude product mixture was adsorbed onto silica and
purified by flash column chromatography (3% Et2O in petroleum ether) to afford the title
compound 252 as a pale yellow solid (4.4 mg, 85%).
1H NMR (400 MHz, CDCl3) δ 7.39 – 7.30 (m, 6H), 7.28 – 7.21 (m, 2H), 3.62 (d, J = 11.5
Hz, 2H), 3.38 (d, J = 11.5 Hz, 2H);
13C NMR (101 MHz, CDCl3) δ 140.5, 136.7, 128.8, 128.3, 127.9, 127.5, 22.8;
77Se{1H} NMR (76 MHz, CDCl3) δ 439.2;
m.p. (hexane): 67–68 °C (lit. 65–66 °C);266
HRMS (EI+) calculated for C14H12Se [M]+: 260.0104; Found: 260.0119;
IR νmax/cm-1 (neat): 2991, 2925, 1475, 1448, 1428, 754, 740.
Se
213
(R)-3,5-Dihydrodinaphtho[2,1-c:1',2'-e]selenepine – 255
Prepared from (R)-2,2'-bis(bromomethyl)-1,1'-binaphthalene (110 mg, 0.25 mmol) and
NaHSe (0.5 mmol) according to general procedure B. The crude product mixture was
adsorbed onto silica and purified by flash column chromatography (3% Et2O in petroleum
ether) to afford the title compound 255 as a colourless solid (68 mg, 76%).
1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.3 Hz, 2H), 7.56 (d, J
= 8.4 Hz, 2H), 7.44 (ddd, J = 8.1, 6.2, 1.8 Hz, 2H), 7.30 – 7.18 (m, 4H), 3.52 (d, J = 11.2 Hz,
2H), 3.47 (d, J = 11.2 Hz, 2H);
13C NMR (101 MHz, CDCl3) δ 134.6, 133.4, 132.8, 132.0, 129.1, 128.2, 126.6, 126.3,
126.1, 125.4, 24.7;
77Se{1H} NMR (76 MHz, CDCl3) δ 437.2;
m.p. (hexane): 180–181 °C;
HRMS (EI+) calculated for C22H16Se [M]+: 360.0417; Found: 360.0411;
IR νmax/cm-1 (neat): 3038, 2941, 1589, 1508, 1428, 827, 750;
The data are consistent with that reported in the literature.136
Se
214
Dimethyl (R)-[1,1'-binaphthalene]-2,2'-dicarboxylate – 260
Prepared from (R)-[1,1'-binaphthalene]-2,2'-diyl bis(triflate) (3.0 g, 5.45 mmol) according to
general procedure C. After reacting for 72 hours the crude product mixture was adsorbed
onto silica and purified by flash column chromatography (5–10% EtOAc in petroleum ether)
to afford the title compound 260 as a colourless solid (1.58 g, 78%).
1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.7 Hz, 2H), 8.01 (d, J = 8.7 Hz, 2H), 7.94 (app.
dt, J = 8.3, 0.9 Hz, 2H), 7.51 (ddd, J = 8.2, 6.8, 1.2 Hz, 2H), 7.24 (ddd, J = 8.3, 6.9, 1.4 Hz,
2H), 7.07 (d, J = 8.6 Hz, 2H), 3.49 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 167.1, 140.3, 134.8, 132.9, 128.0, 127.9, 127.7, 127.3,
127.2, 126.7, 125.9, 51.9;
The data are consistent with that reported in the literature.136
CO2MeCO2Me
215
(R)-[1,1'-Binaphthalene]-2,2'-dicarboxylic acid
A two-neck round-bottomed flask was fitted with a reflux condenser and charged with
methyl ester 260 (1.0 g, 2.7 mmol), KOH (530 mg, 9.4 mmol) and 4:1 MeOH/H2O (35 mL).
The suspension was heated to reflux and stirred for 6 hours at this temperature. The reaction
mixture was cooled to ambient temperature and concentrated in vacuo. The residue was
suspended in H2O (50 mL), acidified with HCl (20 mL, 1 M in H2O) and extracted with
EtOAc (3 x 125 mL). The combined organic extracts were dried (MgSO4) and concentrated
in vacuo to afford the title compound as a colourless solid (910 mg, 98%). The product was
used in the next step without further purification.
CO2HCO2H
216
Diisopropyl (R)-[1,1'-binaphthalene]-2,2'-dicarboxylate – 261
A 25 mL round-bottomed flask was charged with the bis(acid) (910 mg, 2.7 mmol) and fitted
with a reflux condenser. The flask was evacuated (ca. 1 mbar) and back-filled with nitrogen
three times before the addition of SOCl2 (5 mL, 70 mmol) via syringe. The reaction mixture
was heated to 80 °C and stirred for 4 hours. The reaction was allowed to cool to ambient
temperature and concentrated in vacuo to remove the remaining SOCl2. The residue was
dissolved in iso-propanol (8 mL) and pyridine (2 mL), heated to reflux and stirred for 2
hours. The reaction mixture was allowed to cool to ambient temperature, diluted with brine
(30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried
(MgSO4), concentrated in vacuo and the residue purified by flash column chromatography
(5–10% EtOAc in hexane) to afford the title compound 261 as a pale yellow solid (848 mg,
75%).
1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.7 Hz, 2H), 8.03 (d, J = 8.7 Hz, 2H), 7.95 (dt, J
= 8.2, 0.9 Hz, 2H), 7.53 (ddd, J = 8.2, 6.8, 1.2 Hz, 2H), 7.29 – 7.23 (m, 2H), 7.18 – 7.12 (m,
2H), 4.78 (hept, J = 6.2 Hz, 2H), 0.78 (d, J = 6.2 Hz, 6H), 0.46 (d, J = 6.2 Hz, 6H);
The data are consistent with that reported in the literature.146
CO2(i-Pr)CO2(i-Pr)
217
Diisopropyl (R)-3,3'-dibromo-[1,1'-binaphthalene]-2,2'-dicarboxylate – 262
A solution of diisopropyl (R)-[1,1'-binaphthalene]-2,2'-dicarboxylate 261 (1.0 g, 2.4 mmol)
in anhydrous THF (8 mL) was added to a solution of Mg(TMP)2 (9.75 mmol) prepared as
above at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred
for 4 hours. The reaction was cooled to –78 °C before the addition of Br2 (1.0 mL, 3.1 g,
19.5 mmol). The reaction was removed from the cooling bath and stirred for 1 hour, over
which time it warmed to room temperature. The reaction was quenched cautiously with HCl
(20 mL, 1 M in H2O) and extracted with EtOAc (3 x 100 mL). The combined organic
extracts were washed successively with Na2S2O3 (100 mL, sat. aq.) and brine (100 mL),
dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column
chromatography (5–10% EtOAc in petroleum ether) to afford the title compound 262 as a
colourless solid (1.1 g, 82%).
1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 0.8 Hz, 2H), 7.85 – 7.79 (d, J = 8.2 Hz, 2H), 7.53
(ddd, J = 8.2, 6.8, 1.2 Hz, 2H), 7.35 (ddd, J = 8.2, 6.8, 1.3 Hz, 2H), 7.19 (d, J = 8.6, 2H),
4.78 (hept, J = 6.3 Hz, 2H), 0.78 (d, J = 6.2 Hz, 6H), 0.67 (d, J = 6.3 Hz, 6H);
The data are consistent with that reported in the literature.146
CO2(i-Pr)CO2(i-Pr)
Br
Br
218
Diisopropyl (R)-3,3'-diphenyl-[1,1'-binaphthalene]-2,2'-dicarboxylate – 263
A 10 mL round-bottomed flask was charged with dibromide 262 (147 mg, 0.25 mmol),
phenylboronic acid (74 mg, 0.61 mmol), K2CO3 (105 mg, 0.76 mmol), Pd(OAc)2 (5.6 mg,
0.013 mmol) and PPh3 (20 mg, 0.075 mmol). The flask was fitted with a rubber septum and
evacuated (ca. 1 mbar) and back-filled with nitrogen three times through a needle. DMF (3
mL) was added and the resulting suspension degassed by sparging with nitrogen for 20
minutes. The reaction mixture was heated to 90 °C and stirred for 4 hours. The reaction was
allowed to cool to room temperature and diluted with EtOAc (20 mL) and NH4Cl (20 mL,
sat. aq.). The organic layer was separated and the aqueous extracted with EtOAc (2 x 10
mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4) and
concentrated in vacuo. The residue was purified by flash column chromatography (5–8%
EtOAc in petroleum ether) to afford the title compound 263 as a colourless solid (120 mg,
83%).
1H NMR (400 MHz, CDCl3) δ 7.96 (s, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.56 – 7.49 (m, 6H),
7.43 – 7.30 (m, 10H), 4.49 (hept, J = 6.3 Hz, 2H), 0.55 (d, J = 6.3 Hz, 6H), 0.50 (d, J = 6.3
Hz, 6H);
13C NMR (101 MHz, CDCl3) δ 167.4, 141.2, 137.4, 134.6, 133.2, 132.9, 132.1, 129.2,
128.8, 128.2, 127.8, 127.7, 127.3, 127.3, 126.7, 67.9, 20.6;
The data are consistent with that reported in the literature.267
CO2(i-Pr)CO2(i-Pr)
Ph
Ph
219
(R)-(3,3'-Diphenyl-[1,1'-binaphthalene]-2,2'-diyl)dimethanol
Prepared from diisopropyl (R)-3,3'-diphenyl-[1,1'-binaphthalene]-2,2'-dicarboxylate 263
(115 mg, 0.20 mmol) according to general procedure D to afford the title compound as a
colourless solid (88 mg, 95%). The material was used in the next step without further
purification.
1H NMR (400 MHz, CDCl3) δ 7.95 (s, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.72 – 7.65 (m, 4H),
7.52 – 7.34 (m, 8H), 7.31 – 7.22 (m, 2H), 7.05 (dd, J = 8.5, 1.0 Hz, 2H), 4.39 (d, J = 11.3
Hz, 2H), 4.15 (d, J = 11.3 Hz, 2H);
13C NMR (101 MHz, CDCl3) δ 141.7, 141.2, 136.8, 136.0, 133.0, 132.6, 130.1, 130.0,
128.3, 128.2, 127.6, 126.9, 126.8, 126.5, 60.0;
The data are consistent with that reported in the literature.268
Ph
Ph
OH
OH
220
(R)-2,2'-Bis(bromomethyl)-3,3'-diphenyl-1,1'-binaphthalene – 264
Prepared from (R)-(3,3'-diphenyl-[1,1'-binaphthalene]-2,2'-diyl)dimethanol (85 mg, 0.18
mmol) according to general procedure E. The crude product mixture was purified by flash
column chromatography (5% EtOAc in petroleum ether) to afford the title compound 264 as
a colourless solid (94 mg, 88%).
1H NMR (400 MHz, CDCl3) δ 7.95 – 7.87 (m, 4H), 7.66 – 7.60 (m, 4H), 7.56 – 7.41 (m,
8H), 7.30 (ddd, J = 8.3, 6.8, 1.3 Hz, 2H), 7.18 (dd, J = 8.4, 1.1 Hz, 2H), 4.32 – 4.25 (m, 4H);
13C NMR (101 MHz, CDCl3) δ 141.1, 140.5, 136.5, 133.3, 132.4, 132.0, 130.5, 129.7,
128.2, 128.0, 127.8, 127.6, 127.5, 126.7, 32.1;
The data are consistent with that reported in the literature.268
Ph
Ph
Br
Br
221
(R)-2,6-Diphenyl-3,5-dihydrodinaphtho[2,1-c:1',2'-e]selenepine – 265
Prepared from (R)-2,2'-bis(bromomethyl)-3,3'-diphenyl-1,1'-binaphthalene 264 (72 mg, 0.12
mmol) and NaHSe (0.36 mmol) according to general procedure B with the addition of
anhydrous DMF (2 mL) to aid solubility of the dibromide. The crude product mixture was
adsorbed onto silica and purified by flash column chromatography (5% EtOAc in petroleum
ether) to afford the title compound 265 as a colourless solid (44 mg, 72%).
1H NMR (400 MHz, CDCl3) δ 7.95 – 7.87 (m, 4H), 7.70 (d, J = 7.4 Hz, 4H), 7.52 – 7.39 (m,
8H), 7.30 – 7.21 (m, 2H), 7.19 (dd, J = 8.4, 1.2 Hz, 2H), 3.63 (d, J = 11.4 Hz, 2H), 3.40 (d, J
= 11.4 Hz, 2H);
13C NMR (101 MHz, CDCl3) δ 141.3, 139.1, 134.3, 132.5, 132.4, 131.4, 130.1, 129.7,
128.2, 128.2, 127.3, 126.7, 126.1, 125.8, 22.3;
77Se{1H} NMR (76 MHz, CDCl3) δ 440.5;
m.p. (EtOH): 221–222 °C;
HRMS (EI+) calculated for C34H24Se [M]+: 512.1043; Found: 512.1064;
IR νmax/cm-1 (neat): 3676, 2971, 2921, 1492, 1395, 1064, 894, 747.
Ph
Ph
Se
222
Diisopropyl (R)-3,3'-bis(3,5-xylyl)-[1,1'-binaphthalene]-2,2'-dicarboxylate – 267
A 10 mL round-bottomed flask was charged with dibromide 262 (100 mg, 0.17 mmol), 3,5-
xylylboronic acid (103 mg, 0.69 mmol), Ba(OH)2·H2O (130 mg, 0.69 mmol) and Pd(PPh3)4
(40 mg, 0.034 mmol). The flask was fitted with a rubber septum and evacuated (ca. 1 mbar)
and back-filled with nitrogen three times through a needle. 1:1 DME/H2O (2.6 mL) was
added and the resulting suspension degassed by sparging with nitrogen for 20 minutes. The
reaction mixture was heated to 90 °C and stirred overnight. The reaction was allowed to cool
to room temperature and diluted with EtOAc (20 mL) and saturated aqueous NH4Cl (20
mL). The organic layer was separated and the aqueous extracted with EtOAc (2 x 10 mL).
The combined organic extracts were washed with brine (30 mL), dried (MgSO4) and
concentrated in vacuo. The residue was purified by flash column chromatography (7–10%
EtOAc in petroleum ether) to afford the title compound 267 as a colourless solid (82 mg,
76%).
1H NMR (400 MHz, CDCl3) δ 7.94 (s, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.50 (ddd, J = 8.1, 5.5,
2.3 Hz, 2H), 7.36 – 7.28 (m, 4H), 7.16 (app. dt, J = 1.6, 0.8 Hz, 4H), 6.99 (dd, J = 1.6, 0.8
Hz, 2H), 4.51 (hept, J = 6.2 Hz, 2H), 0.57 (d, J = 6.3 Hz, 6H), 0.55 (d, J = 6.3 Hz, 6H);
13C NMR (101 MHz, CDCl3) δ 167.5, 141.0, 137.7, 134.4, 133.2, 133.0, 132.0, 129.0,
128.9, 127.7 (2C), 127.1, 126.6, 126.5, 67.8, 21.3, 20.8, 20.7;
The data are consistent with that reported in the literature.145
CO2(i-Pr)CO2(i-Pr)
223
(R)-(3,3'-Bis(3,5-xylyl)-[1,1'-binaphthalene]-2,2'-diyl)dimethanol
Prepared from diisopropyl (R)-3,3'-bis(3,5-xylyl)-[1,1'-binaphthalene]-2,2'-dicarboxylate
267 (148 mg, 0.23 mmol) according to general procedure D to afford the title compound as a
colourless solid (122 mg, 99%). The material was used in the next step without further
purification.
1H NMR (400 MHz, CDCl3) δ 7.91 – 7.88 (m, 4H), 7.47 (ddd, J = 8.3, 6.3, 1.3 Hz, 2H),
7.32 – 7.29 (m, 2H), 7.28 – 7.24 (m, 2H), 7.06 (s, 4H), 7.03 (s, 2H), 4.44 (d, J = 11.5 Hz,
2H), 4.12 (d, J = 11.5 Hz, 2H), 2.40 (s, 12H);
The data are consistent with that reported in the literature.146
OH
OH
224
(R)-2,2'-Bis(bromomethyl)-3,3'-bis(3,5-xylyl)-1,1'-binaphthalene
Prepared from (R)-(3,3'-bis(3,5-xylyl)-[1,1'-binaphthalene]-2,2'-diyl)dimethanol (120 mg,
0.23 mmol) according to general procedure E. The crude product mixture was purified by
flash column chromatography (2.5% EtOAc in petroleum ether) to afford the title compound
as a colourless solid (117 mg, 78%).
1H NMR (400 MHz, CDCl3) δ 7.92 – 7.87 (m, 4H), 7.50 (ddd, J = 8.2, 6.7, 1.3 Hz, 2H),
7.33 – 7.27 (m, 2H), 7.25 – 7.23 (m, 4H), 7.18 – 7.13 (m, 2H), 7.08 (s, 2H), 4.33 – 4.23 (m,
4H), 2.41 (s, 12H);
13C NMR (101 MHz, CDCl3) δ 141.3, 140.4, 137.6, 136.4, 133.2, 132.3, 131.8, 130.2,
129.1, 127.9, 127.4, 127.3, 127.1, 126.3, 32.1, 21.4;
The data are consistent with that reported in the literature.146
Br
Br
225
(R)-2,6-Bis(3,5-xylyl)-3,5-dihydrodinaphtho[2,1-c:1',2'-e]selenepine – 268
Prepared from (R)-2,2'-bis(bromomethyl)-3,3'-bis(3,5-xylyl)-1,1'-binaphthalene (115 mg,
0.18 mmol) and NaHSe (0.54 mmol) according to general procedure B with the addition of
anhydrous DMF (2 mL) to aid solubility of the dibromide. The crude product mixture was
adsorbed onto silica and purified by flash column chromatography (10–20% CH2Cl2 in
hexane) to afford the title compound 268 as a colourless solid (49 mg, 48%).
1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.2 Hz, 2H), 7.87 (s, 2H), 7.43 (ddd, J = 8.1, 6.7,
1.3 Hz, 2H), 7.34 – 7.28 (br. s, 4H), 7.23 (ddd, J = 8.1, 6.7, 1.3 Hz, 2H), 7.17 – 7.13 (m,
2H), 7.05 (s, 2H), 3.64 (d, J = 11.4 Hz, 2H), 3.37 (d, J = 11.4 Hz, 2H), 2.39 (s, 12H);
13C NMR (101 MHz, CDCl3) δ 141.2, 139.3, 137.6, 134.3, 132.6, 132.3, 131.3, 129.8,
128.9, 128.1, 127.5, 126.7, 125.9, 125.7, 22.3, 21.4;
77Se{1H} NMR (76 MHz, CDCl3) δ 440.5;
m.p. (EtOH): 218–219 °C;
IR νmax/cm-1 (neat): 3021, 2945, 2915, 1602, 887, 847, 747.
Se
226
Diisopropyl (R)-3,3'-dimesityl-[1,1'-binaphthalene]-2,2'-dicarboxylate – 270
A 10 mL round-bottomed flask was charged with dibromide 262 (265 mg, 0.45 mmol),
mesitylboronic acid (372 mg, 2.27 mmol), K3PO4 (765 mg, 3.6 mmol) SPhos (19 mg, 0.045
mmol) and Pd(OAc)2 (5.2 mg, 0.023 mmol). The flask was fitted with a rubber septum and
evacuated (ca. 1 mbar) and back-filled with nitrogen three times through a needle. Dioxane
(3 mL) was added and the resulting suspension degassed by sparging with nitrogen for 20
minutes. The reaction mixture was heated to reflux and stirred overnight. The reaction was
allowed to cool to room temperature and filtered through Celite® with EtOAc. The filtrate
was concentrated in vacuo, the residue adsorbed onto silica and purified by flash column
chromatography (3% EtOAc in petroleum ether) to afford the title compound 270 as a
colourless solid (261 mg, 87%).
1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.3 Hz, 2H), 7.71 (s, 2H), 7.54 – 7.46 (m, 2H),
7.36 – 7.31 (m, 4H), 6.91 (s, 2H), 6.87 (s, 2H), 4.36 (hept, J = 6.3 Hz, 2H), 2.30 (s, 6H), 2.10
(s, 6H), 2.05 (s, 6H), 0.66 (d, J = 6.2 Hz, 6H), 0.21 (d, J = 6.2 Hz, 6H);
13C NMR (101 MHz, CDCl3) δ 166.8, 137.2, 136.9, 136.3, 136.0, 134.2, 133.6, 133.4,
132.4, 128.9, 127.8, 127.8, 127.6, 126.9, 126.2, 67.7, 21.1, 20.9, 20.8, 20.6, 20.1;
The data are consistent with that reported in the literature.269
CO2(i-Pr)CO2(i-Pr)
227
((R)-3,3'-Dimesityl-[1,1'-binaphthalene]-2,2'-diyl)dimethanol – 271
Prepared from diisopropyl (R)-3,3'-dimesityl-[1,1'-binaphthalene]-2,2'-dicarboxylate 270
(180 mg, 0.27 mmol) according to general procedure D with DIBAL-H (5.4 mL, 5.4 mmol,
1 M solution in heptane) in place of LiAlH4. The crude product was adsorbed onto silica and
purified by flash column chromatography (10–20% EtOAc in hexane) to afford the title
compound 271 as a colourless solid (137 mg, 92%).
1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.2 Hz, 2H), 7.73 (s, 2H), 7.49 (ddd, J = 8.2, 6.8,
1.2 Hz, 2H), 7.32 – 7.26 (m, 2H), 7.14 (d, J = 8.5 Hz, 2H), 6.97 (br. s, 4H), 4.05 – 3.92 (m,
4H), 2.31 (s, 6H), 2.08 (s, 6H), 2.04 (s, 6H);
13C NMR (101 MHz, CDCl3) δ 139.6, 137.1, 137.0 (2C), 136.4, 136.3, 135.4, 133.5, 132.5,
129.0, 128.5, 128.0, 127.9, 126.4, 60.4, 21.1, 21.0, 20.7;
m.p. (EtOAc): 288–290 °C;
HRMS (ES+) calculated for C40H37O [M-OH]+: 533.2839; Found: 533.2839;
IR νmax/cm-1 (neat): 3676, 3198, 2988, 1395, 1064, 747.
CH2OHCH2OH
228
(R)-2,2'-Bis(bromomethyl)-3,3'-dimesityl-1,1'-binaphthalene
Prepared from (R)-(3,3'-bis(3,5-xylyl)-[1,1'-binaphthalene]-2,2'-diyl)dimethanol 271 (135
mg, 0.24 mmol) according to general procedure E. The product was not purified by flash
column chromatography and the crude product was used immediately in the next step.
1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.2 Hz, 2H), 7.78 (s, 2H), 7.52 (ddd, J = 8.1, 6.8,
1.2 Hz, 2H), 7.31 (ddd, J = 8.3, 6.9, 1.3 Hz, 2H), 7.17 (dd, J = 8.4, 1.2 Hz, 2H), 7.03 (s, 4H),
4.17 (d, J = 9.8 Hz, 2H), 4.05 (d, J = 9.8 Hz, 2H), 2.38 (s, 6H), 2.17 (s, 6H), 2.16 (s, 6H);
The crude product was used in the next step without further purification.
CH2BrCH2Br
229
(R)-2,6-Dimesityl-3,5-dihydrodinaphtho[2,1-c:1',2'-e]selenepine – 272
Prepared from (R)-2,2'-bis(bromomethyl)-3,3'-dimesityl-1,1'-binaphthalene (159 mg, 0.24
mmol) and NaHSe (1.44 mmol) according to general procedure B with the addition of
anhydrous DMF (4 mL) to aid solubility of the dibromide. The crude product mixture was
adsorbed onto silica and purified by flash column chromatography (3% EtOAc in hexane) to
afford the title compound 272 as a colourless solid (58 mg, 41%).
1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.3 Hz, 2H), 7.72 (s, 2H), 7.47 (ddd, J = 8.1, 6.3,
1.6 Hz, 2H), 7.33 – 7.20 (m, 4H), 7.03 – 6.98 (m, 2H), 6.97 – 6.92 (m, 2H), 3.29 (d, J = 11.1
Hz, 2H), 3.18 (d, J = 11.1 Hz, 2H), 2.36 (s, 6H), 2.22 (s, 6H), 1.98 (s, 6H);
13C NMR (101 MHz, CDCl3) δ 137.5, 137.1, 136.9, 136.9, 136.0, 134.3, 133.1, 132.8,
131.3, 129.3, 128.8, 128.1, 127.8, 126.7, 125.8, 125.5, 21.3, 21.1, 21.0, 20.4;
77Se{1H} NMR (76 MHz, CDCl3) δ 407.4;
m.p. (EtOH): 232–233 °C;
HRMS (EI+) calculated for C40H36Se [M]+: 596.1982; Found: 596.1993;
IR νmax/cm-1 (neat): 3048, 2925, 2854, 1615, 1442, 854, 750.
Se
230
2,2',3,3'-Tetrahydro-1,1'-spirobi[indene]-7,7'-diyl bis(triflate) – 292
A flame-dried 100 mL two-neck round-bottomed flask was fitted with a nitrogen inlet and a
rubber septum. The flask was evacuated (ca. 1 mbar) and back-filled with nitrogen three
times before the addition of a solution of 2,2',3,3'-tetrahydro-1,1'-spirobi[indene]-7,7'-diol
111 (719 mg, 2.85 mmol) in anhydrous CH2Cl2 (50 mL). The flask was cooled to –5 °C and
pyridine (922 µL, 11.4 mmol) was added via syringe. Triflic anhydride (1.15 mL, 6.84
mmol) was added to the solution dropwise via syringe and the reaction stirred at –5 °C for
45 minutes. After this time, the reaction was allowed to warm to room temperature and
stirred for 2 hours. The reaction mixture was quenched with HCl (40 mL, 1 M in H2O) and
the organic layer was separated, washed with brine, dried (MgSO4) and concentrated in
vacuo to afford the title compound 292 as a colourless solid (1.47 g, 99%) that was used in
the next step without the need for further purification.
TfO
OTf
231
Dimethyl 2,2',3,3'-tetrahydro-1,1'-spirobi[indene]-7,7'-dicarboxylate – 293
Prepared from 2,2',3,3'-tetrahydro-1,1'-spirobi[indene]-7,7'-diyl bis(triflate) 292 (516 mg, 1.0
mmol) according to general procedure C. After reacting for 120 hours the crude product
mixture was adsorbed onto silica and purified by flash column chromatography (10% EtOAc
in petroleum ether) to afford the title compound 293 as a colourless solid (212 mg, 63%).
1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.6 Hz, 2H), 7.44 (dd, J = 7.5, 1.2 Hz, 2H), 7.22
(app. t, J = 7.6 Hz, 2H), 3.16 (s, 6H), 3.13 – 2.96 (m, 4H), 2.65 – 2.52 (m, 2H), 2.30 (ddd, J
= 12.0, 7.4, 1.4 Hz, 2H);
13C NMR (101 MHz, CDCl3) δ 168.0, 149.8, 145.3, 128.5, 128.2, 126.8, 126.5, 63.3, 51.3,
38.4, 31.1;
The data are consistent with that reported in the literature.270
MeO2C
CO2Me
232
(2,2',3,3'-Tetrahydro-1,1'-spirobi[indene]-7,7'-diyl)dimethanol – 294
Prepared from dimethyl 2,2',3,3'-tetrahydro-1,1'-spirobi[indene]-7,7'-dicarboxylate 293 (97
mg, 0.29 mmol) according to general procedure D. The crude product was purified by flash
column chromatography (30% EtOAc in petroleum ether) to afford the title compound 294
as a colourless solid (71 mg, 87%).
1H NMR (400 MHz, CDCl3) δ 7.33 – 7.20 (m, 6H), 4.26 (d, J = 11.9 Hz, 2H), 4.19 (d, J =
11.9 Hz, 2H), 3.09 – 2.96 (m, 4H), 2.33 (ddd, J = 12.9, 6.0, 3.1 Hz, 2H), 2.08 – 1.95 (m,
2H);
13C NMR (101 MHz, CDCl3) δ 147.3, 143.5, 136.4, 128.4, 127.7, 124.3, 61.1, 60.5, 39.6,
30.7;
The data are consistent with that reported in the literature.156
OH
HO
233
7,7'-Bis(bromomethyl)-2,2',3,3'-tetrahydro-1,1'-spirobi[indene] – 295
Prepared from (2,2',3,3'-tetrahydro-1,1'-spirobi[indene]-7,7'-diyl)dimethanol 294 (68 mg,
0.24 mmol) according to general procedure E. The crude product mixture was purified by
flash column chromatography (3% EtOAc in petroleum ether) to afford the title compound
295 as a colourless solid (67 mg, 70%).
1H NMR (400 MHz, CDCl3) δ 7.29 – 7.21 (m, 6H), 4.13 (d, J = 10.3 Hz, 2H), 4.05 (d, J =
10.3 Hz, 2H), 3.11 – 2.96 (m, 4H), 2.44 – 2.25 (m, 4H);
13C NMR (101 MHz, CDCl3) δ 147.0, 144.1, 133.8, 130.6, 128.2, 125.2, 61.6, 38.2, 30.7,
30.3;
The data are consistent with that reported for the dichloride analogue in the literature.156
Br
Br
234
4,5,6,7-Tetrahydro-11H,13H-diindeno[7,1-cd:1',7'-ef]selenocine (SPISe) – 284
Prepared from 7,7'-bis(bromomethyl)-2,2',3,3'-tetrahydro-1,1'-spirobi[indene] 295 (42 mg,
0.1 mmol) and NaHSe (0.31 mmol) according to general procedure B with the addition of
anhydrous DMF (1 mL) to aid solubility of the dibromide. The crude product mixture was
adsorbed onto silica and purified by flash column chromatography (3% EtOAc in hexane) to
afford the title compound 284 as a colourless solid (24 mg, 72%).
1H NMR (400 MHz, CDCl3) δ 7.21 (app. t, J = 7.5 Hz, 2H), 7.10 (d, J = 7.4 Hz, 2H), 7.04
(d, J = 7.6 Hz, 2H), 3.57 (d, J = 11.8 Hz, 2H), 3.52 (d, J = 11.8 Hz, 2H), 3.06 – 2.94 (m,
2H), 2.89 (dd, J = 15.9, 8.2 Hz, 2H), 2.26 (dd, J = 12.3, 6.8 Hz, 2H), 1.95 – 1.81 (m, 2H);
13C NMR (101 MHz, CDCl3) δ 147.0, 142.6, 134.0, 128.3, 127.7, 123.1, 60.8, 38.5, 30.5,
22.9;
77Se{1H} NMR (76 MHz, CDCl3) δ 403.1;
m.p. (EtOH): 179–180 °C;
HRMS (EI+) calculated for C19H18Se [M]+: 326.0574; Found: 326.0580;
IR νmax/cm-1 (neat): 2955, 2935, 2921, 1428, 1161, 780, 747.
Se
235
7'-(Methylselanyl)-2,2',3,3'-tetrahydro-1,1'-spirobi[inden]-7-yl triflate – 296
A 25 mL two-neck round-bottomed flask was fitted with a reflux condenser and rubber
septum and charged with [Pd(π-cinnamyl)Cl]2 (6.2 mg, 0.012 mmol) and PhPF-t-Bu (13 mg,
0.024 mmol). The flask was evacuated (ca. 1 mbar) and back-filled with nitrogen three times
before the addition of anhydrous toluene (3.5 mL). The palladium and ligand were pre-
mixed for 30 minutes at 30 °C before the addition of 2,2',3,3'-tetrahydro-1,1'-
spirobi[indene]-7,7'-diyl bis(triflate) 292 (123 mg, 0.24 mmol) followed by a solution of tri-
n-butyl(methylselenyl)stannane 236-Me (0.87 mL, 0.6 mmol, 0.69 M in THF/Et2O). The
reaction mixture was heated to 110 °C and stirred overnight. The reaction mixture was
allowed to cool to ambient temperature, diluted with Et2O (10 mL) and extracted three times
with potassium fluoride (3 x 20 mL, 7 M in H2O). The organic phase was separated and
washed with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue
was purified by flash column chromatography (10–20% toluene in petroleum ether) to afford
the title compound 296 as a colourless solid (72 mg, 65%).
1H NMR (400 MHz, CDCl3) δ 7.33 – 7.23 (m, 2H), 7.19 – 7.08 (m, 4H), 3.14 – 3.08 (m,
2H), 3.07 – 3.00 (m, 2H), 2.56 – 2.45 (m, 1H), 2.39 – 2.19 (m, 3H), 2.16 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 148.2, 146.3, 145.4, 143.9, 139.7, 129.1, 128.6, 128.1,
126.7, 124.3, 122.0, 119.5 (q, 1JC–F = 217 Hz), 118.0, 61.7, 38.2, 36.8, 31.4, 31.0, 6.6;
19F NMR (376 MHz, CDCl3) δ -75.1;
77Se NMR (76 MHz, CDCl3) δ 160.2;
m.p. (CH2Cl2): 124–126 °C;
HRMS (EI+) calculated for C19H18F3O3SSe [M]+: 463.0088; Found: 463.0085;
IR νmax/cm-1 (neat): 3055, 2941, 2848, 1392, 1204, 1131, 927, 847, 767.
TfO
SeMe
236
1,4-Diphenylbutane-1,4-dione – 322
Prepared from benzene (6.7 mL, 75 mmol) and succinyl chloride (1.1 mL, 10 mmol)
according to general procedure F. The crude mixture was purified by flash column
chromatography (10% EtOAc in petroleum ether) to afford the title compound 322 as a
colourless solid (760 mg, 32%).
1H NMR (400 MHz, CDCl3) δ 8.08 – 8.02 (m, 4H), 7.63 – 7.55 (m, 2H), 7.52 – 7.46 (m,
4H), 3.47 (s, 4H);
13C NMR (101 MHz, CDCl3) δ 198.7, 136.8, 133.2, 128.6, 128.1, 32.6;
The data are consistent with that reported in the literature.271
O
O
237
(1R,4R)-1,4-Diphenylbutane-1,4-diol – 324
Prepared from 1,4-diphenylbutane-1,4-dione 322 (240 mg, 1 mmol) according to general
procedure G. The crude mixture was purified by flash column chromatography (30–40%
EtOAc in petroleum ether) to afford the title compound 324 as a colourless solid (208 mg,
84%, 78% ee).
The ee was determined on a Chiralcel IF column (hexane/i-PrOH = 9:1; 35 ºC; 1.0 mL/min);
tR (major) = 14.8 min; tR (minor) = 16.5 min.
1H NMR (400 MHz, CDCl3) δ 7.35 – 7.24 (m, 10H), 4.78 – 4.64 (m, 2H), 1.99 – 1.77 (m,
4H);
13C NMR (101 MHz, CDCl3) δ 144.6, 128.5, 127.5, 125.8, 74.6, 35.8;
The data are consistent with that reported in the literature.272
OH
OH
238
(2S,5S)-2,5-Diphenyltetrahydroselenophene – 340
Prepared from (1R,4R)-1,4-diphenylbutane-1,4-diol 324 (740 mg, 3.1 mmol) according to
general procedure H. The crude mixture was purified by flash column chromatography (0–
15% toluene in hexane) to afford diselenide, (3S,6S)-3,6-diphenyl-1,2-diselenane 340 as a
yellow solid (204 mg, 18%) followed by the title compound 341 as a colourless solid (470
mg, 53%).
1H NMR (400 MHz, CDCl3) δ 7.50 – 7.45 (m, 4H), 7.36 – 7.29 (m, 4H), 7.26 – 7.21 (m,
2H), 5.13 – 5.05 (m, 2H), 2.75 – 2.67 (m, 2H), 2.31 – 2.22 (m, 2H);
13C NMR (101 MHz, CDCl3) δ 142.6, 128.5, 127.9, 127.0, 50.1, 42.1;
77Se{1H} NMR (76 MHz, CDCl3) δ 486.2;
m.p. (hexane): 87–89 °C;
HRMS (EI+) calculated for C16H16Se [M]+: 288.0417; Found: 288.0420;
IR νmax/cm-1 (neat): 2931, 1599, 1488, 1452, 1111, 750, 693;
[α]24D = +78.0 (c = 1.0, CHCl3).
(3S,6S)-3,6-diphenyl-1,2-diselenane – 341
1H NMR (400 MHz, CDCl3) δ 7.43 – 7.38 (m, 4H), 7.38 – 7.32 (m, 4H), 7.31 – 7.24 (m,
2H), 4.68 – 4.45 (m, 2H), 2.78 – 2.52 (m, 4H);
13C NMR (101 MHz, CDCl3) δ 142.4, 128.9, 127.7, 127.1, 43.0, 37.9;
77Se{1H} NMR (76 MHz, CDCl3) δ 415.5;
m.p. (hexane): 144 °C (decomposed);
HRMS (EI+) calculated for C16H16Se2 [M]+: 367.9582; Found: 367.9576;
SePhPh
SeSe
Ph
Ph
239
IR νmax/cm-1 (neat): 2935, 1492, 1452, 1118, 750, 693
1,4-Di-p-tolylbutane-1,4-dione
Prepared from toluene (8.0 mL, 75 mmol) and succinyl chloride (1.1 mL, 10 mmol)
according to general procedure F. The crude mixture was purified by flash column
chromatography (10% EtOAc in petroleum ether) to afford the title compound as a
colourless solid (759 mg, 36%).
1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.2 Hz, 4H), 7.26 (d, J = 7.9 Hz, 4H), 3.42 (s,
4H), 2.40 (s, 6H);
The data are consistent with that reported in the literature.273
(1R,4R)-1,4-Di-p-tolylbutane-1,4-diol
Prepared from 1,4-di-p-tolylbutane-1,4-dione (1.86 g, 7 mmol) according to general
procedure G. The crude mixture was purified by flash column chromatography (30–40%
EtOAc in petroleum ether) to afford the title compound as a colourless solid (1.47 mg, 79%,
87% ee).
The ee was determined on a Chiralcel IE column (hexane/i-PrOH = 9:1; 35 ºC; 1.0 mL/min);
tR (major) = 15.2 min; tR (minor) = 12.9 min.
1H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 8.1 Hz, 4H), 7.14 (d, J = 8.1 Hz, 4H), 4.72 – 4.61
(m, 2H), 2.60 (br. s, 2H), 2.34 (s, 6H), 1.97 – 1.72 (m, 4H);
13C NMR (101 MHz, CDCl3) δ 141.7, 137.2, 129.1, 125.8, 74.5, 35.9, 21.1;
The data are consistent with that reported in the literature.274
O
O
OH
OH
240
(2S,5S)-2,5-Di-p-tolyltetrahydroselenophene – 344
Prepared from (1R,4R)-1,4-di-p-tolylbutane-1,4-diol (1.0 g, 3.7 mmol) according to general
procedure H. The crude mixture was purified by flash column chromatography (0–15%
toluene in hexane) to afford the title compound 344 as a pale yellow solid (200 mg, 17%).
1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.1 Hz, 4H), 7.14 (d, J = 8.1 Hz, 4H), 5.10 – 5.02
(m, 2H), 2.73 – 2.61 (m, 2H), 2.33 (s, 6H), 2.29 – 2.20 (m, 2H);
13C NMR (101 MHz, CDC l3) δ 139.6, 136.7, 129.2, 127.8, 49.9, 42.1, 21.1;
77Se{1H} NMR (76 MHz, CDCl3) δ 485.6;
m.p. (hexane): 122–123 °C;
HRMS (EI+) calculated for C18H20Se [M]+: 316.0730; Found: 316.0724;
IR νmax/cm-1 (neat): 2941, 2918, 1512, 1118, 807, 760, 717;
[α]24D = +74.4 (c = 0.5, CHCl3).
Se
241
(±)-1-Phenylprop-2-en-1-ol – 348
Prepared from benzaldehyde (5.1 mL, 50 mmol) according to general procedure I. The
product was used in the next step without further purification.
1H NMR (400 MHz, CDCl3) δ 7.41 – 7.27 (m, 5H), 6.06 (ddd, J = 17.2, 10.4, 5.9 Hz, 1H),
5.41 – 5.30 (m, 1H), 5.25 – 5.16 (m, 2H);
13C NMR (101 MHz, CDCl3) δ 142.6, 140.3, 128.6, 127.8, 126.3, 115.1, 75.4;
The data are consistent with that reported in the literature.275
(S)-1-Phenylprop-2-en-1-ol – 348
Prepared from (±)-1-phenylprop-2-en-1-ol (±)-348 (3.0 g, 23 mmol) according to general
procedure J. The crude product was purified by flash column chromatography (5–15 % Et2O
in petroleum ether) to afford the title compound as a colourless oil (1.2 g, 40%, 97% ee).
The ee was determined on a Chiralcel IB column (hexane/i-PrOH = 19:1; 35 ºC; 1.0
mL/min); tR (major) = 7.3 min; tR (minor) = 6.7 min.
NMR data consistent with that of the racemate (vide supra).
OH
OH
242
(1S,4S,E)-1,4-Diphenylbut-2-ene-1,4-diol – 354
Prepared from (S)-1-phenylprop-2-en-1-ol 348 (130 mg, 1 mmol) according to general
procedure K. The crude product was purified by flash column chromatography (30 % EtOAc
in hexane) to afford the title compound 354 as a colourless solid (70 mg, 58%).
1H NMR (400 MHz, CDCl3) δ 7.44 – 7.27 (m, 10H), 6.02 (dd, J = 3.3, 1.5 Hz, 2H), 5.25
(dd, J = 3.3, 1.5 Hz, 2H);
13C NMR (101 MHz, CDCl3) δ 142.6, 133.1, 128.6, 127.8, 126.3, 74.4;
The data are consistent with that reported in the literature.276
OH
OH
243
(±)-1-Cyclohexylprop-2-en-1-ol – 356
Prepared from cyclohexanecarboxaldehyde 355 (3.0 mL, 25 mmol) according to general
procedure I. The crude product was purified by flash column chromatography (10% EtOAc
in petroleum ether) to afford the title compound 356 as a colourless oil (3.5 g, 99%).
1H NMR (400 MHz, CDCl3) δ 5.88 (ddd, J = 17.1, 10.4, 6.6 Hz, 1H), 5.22 (app. dt, J = 17.2,
1.5 Hz, 1H), 5.16 (ddd, J = 10.4, 1.7, 1.1 Hz, 1H), 3.91 – 3.83 (m, 1H), 1.93 – 0.95 (m,
12H);
13C NMR (101 MHz, CDCl3) δ 139.8, 115.5, 43.5, 28.8, 28.3, 26.5, 26.1;
The data are consistent with that reported in the literature.181
(S)-1-Cyclohexylprop-2-en-1-ol – 356
Prepared from (±)-1-cyclohexylprop-2-en-1-ol (±)-356 (2.5 g, 18 mmol) according to
general procedure J. The crude product was purified by flash column chromatography (5–20
% Et2O in petroleum ether) to afford the title compound 356 as a colourless oil (1.1 g, 42%,
98% ee).
[α]24D = –14.4 (c = 1.0, CHCl3) (lit. (R)-356 [α]25D = +14.7 (99% ee));277
NMR data consistent with that of the racemate (vide supra).
OH
OH
244
(1R,4R,E)-1,4-Dicyclohexylbut-2-ene-1,4-diol – 357
Prepared from (S)-1-cyclohexylprop-2-en -1-ol 356 (800 mg, 5.7 mmol) according to general
procedure K. The crude product was purified by flash column chromatography (20–30 %
EtOAc in hexane) to afford the title compound 357 as a colourless solid (320 mg, 44%).
1H NMR (400 MHz, CDCl3) δ 5.65 (dd, J = 4.1, 2.0 Hz, 2H), 3.85 (ddd, J = 6.2, 4.1, 2.0 Hz,
2H), 1.91 – 0.89 (m, 24H);
13C NMR (101 MHz, CDCl3) δ 133.3, 77.1, 43.7, 28.8, 28.6, 26.5, 26.1, 26.0;
[α]24D = –24.3 (c = 1.0, CHCl3);
The data are consistent with that reported in the literature.182
OH
OH
245
(1S,4S)-1,4-Dicyclohexylbutane-1,4-diol – 358
Prepared from (1R,4R,E)-1,4-dicyclohexylbut-2-ene-1,4-diol 357 (300 mg, 1.2 mmol)
according to general procedure K. The product was obtained as a colourless solid (285 mg,
93%) that was used in the next step without further purification.
1H NMR (400 MHz, CDCl3) δ 3.41 – 3.31 (m, 2H), 1.93 – 0.95 (m, 28H);
13C NMR (101 MHz, CDCl3) δ 76.7, 44.0, 31.0, 29.2, 28.0, 26.6, 26.4, 26.2;
[α]24D = –19.7 (c = 1.0, CHCl3);
The data are consistent with that reported in the literature.182
OH
OH
246
(2R,5R)-2,5-Dicyclohexyltetrahydroselenophene – 360
A two-neck round-bottomed flask was charged with (1S,4S)-1,4-dicyclohexylbutane-1,4-diol
358 (189 mg, 0.74 mmol) and fitted with a nitrogen inlet and rubber septum. CH2Cl2 (10
mL) and Et3N (0.63 mL, 4.5 mmol) were added via syringe and the flask was cooled to –20
°C. MsCl (0.23 mL, 3.0 eq.) was added dropwise and the reaction mixture stirred for 2.5
hours. The reaction mixture was allowed to warm to 0 °C and quenched via the addition of
HCl (5 mL, 1 M in H2O). The organic layer was separated and the aqueous extracted with
CH2Cl2 (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried
(MgSO4) and concentrated to approximately 2 mL volume. THF (20 mL) was added and the
solution concentrated to approximately 5 mL volume.
A separate flame-dried 25 mL two-neck round-bottomed flask was fitted with a rubber
septum and a nitrogen inlet. The flask was evacuated (ca. 1 mbar) and back-filled with
nitrogen three times and cooled to 0 °C in an ice/water bath. LiBHEt3 (1. mL, 1.6 mmol, 1.0
M in THF) was added to the flask via syringe. The septum was removed under a heavy flow
of nitrogen and selenium (58 mg, 0.74 mmol) was added as a solid. The resulting suspension
was stirred at 0 °C for 30 minutes, resulting in a clear, colourless solution of Li2Se. The
reaction mixture was cooled to –10 °C and the solution of bis(mesylate) (0.74 mmol, 0.15 M
in THF) was added dropwise via syringe. The mixture was stirred for 23 hours, over which
time it warmed to room temperature. The reaction was quenched via dropwise addition of
HCl (10 mL, 1 M in H2O) and extracted with CH2Cl2 (2 x 20 mL). The combined organic
extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The
residue was purified by flash column chromatography (0–1% Et2O in hexane) to afford the
title compound 360 as a colourless solid (47 mg, 31%).
Se
247
1H NMR (400 MHz, CDCl3) δ 3.36 – 3.25 (m, 2H), 2.44 – 2.29 (m, 2H), 2.03 – 0.80 (m,
24H);
13C NMR (101 MHz, CDCl3) δ 52.8, 45.6, 37.3, 34.8, 32.3, 26.4;
77Se{1H} NMR (76 MHz, CDCl3) δ 290.9;
m.p. (hexane): 119 – 120 °C;
HRMS (EI+) calculated for C16H28Se [M]+: 300.1356; Found: 300.1362;
IR νmax/cm-1 (neat): 2931, 2915, 2844, 1432, 1181, 1118, 964, 653;
[α]24D = –183.5 (c = 0.3, CHCl3).
248
(±)-2-Cyclohexyloxirane – 368
A two-neck 500 mL round-bottomed flask was fitted with a nitrogen inlet and rubber
septum. The flask was evacuated (ca. 1 mbar) and back-filled with nitrogen three times
before the addition of CH2Cl2 (180 mL) and vinylcyclohexane (4.9 mL, 36 mmol). The
septum was removed under a flow of nitrogen and mCPBA (13 g, 58 mmol, < 77% wt.) was
added as a solid. The resulting suspension was stirred for 16 hours at ambient temperature.
The reaction was quenched with Na2SO3 (100 mL, sat. aq.) and the organic layer washed
with NaHCO3 (100 mL, sat. aq.), dried (MgSO4) and concentrated in vacuo. The residue was
purified by Kugelrohr distillation (30 °C, 0.3 mbar) to afford the desired product 368 as a
colourless oil (4.4 g, 97%).
1H NMR (400 MHz, CDCl3) δ 2.76 – 2.68 (m, 2H), 2.53 (dd, J = 4.5, 3.3 Hz, 1H), 1.91 –
1.59 (m, 5H), 1.32 – 1.05 (m, 6H);
The data are consistent with that reported in the literature.278
O
249
(R)-2-Cyclohexyloxirane – 368
A 50 mL two-neck round-bottomed flask was charged with (R,R)-(−)-N,N′-Bis(3,5-di-tert-
butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) (290 mg, 0.48 mmol) and the racemic
epoxide (±)-368 (12.1 g, 96 mmol). A solution of AcOH (115 mg 1.9 mmol) in THF (0.96
mL) was added and the flask was cooled to 0 °C. H2O (950 mg, 53 mmol) was added via
syringe and the reaction stirred rapidly under air for 22 hours. The reaction mixture was
transferred into a Kugelrohr bulb and purified by Kugelrohr distillation (30 °C, 0.3 mbar) to
afford the desired product 368 as a colourless oil (5.3 g, 44%, >99% ee).
The ee was determined using chiral GC (80 °C isothermal): tR (major) = 23.9 min; tR (minor)
= 24.7 min.
[α]24D = –2.2 (c = 1.0, CHCl3) (lit. (S)-368 [α]24D = +2.2 (99.9% ee));279
NMR data consistent with that of the racemate (vide supra).
O
250
(1R,4R)-1,4-Dicyclohexylbut-2-ene-1,4-diol – 357
A flame-dried 50 mL two-neck round-bottomed flask was fitted with a nitrogen inlet and
rubber septum. The flask was evacuated (ca. 1 mbar) and back-filled with nitrogen three
times before the addition of t-BuOMe (8 mL) and 2,2,6,6-tetramethylpiperidine (3.5 mL, 21
mmol). The flask was cooled to –5 °C and n-butyllithium (8.3 mL, 21 mmol, 2.5 M in
hexanes) was added dropwise via syringe. The reaction mixture was stirred for 30 minutes
over which time it warmed to room temperature. The flask was cooled to –5 °C and a
solution of the epoxide 368 (2.0 g, 16 mmol) in t-BuOMe (4 mL) was added dropwise over
10 minutes. The reaction was stirred for 23 hours at –5 °C and then quenched via addition of
MeOH (5 mL). The solvents were removed in vacuo and the residue dissolved in CH2Cl2 (50
mL), washed with brine (30 mL), dried (MgSO4) and the organic layer concentrated in
vacuo. The crude product was recrystallised from CH2Cl2/pentane to afford pure (E)-alkene
(E)-357 (920 mg, 46%). The mother liquors were concentrated and the resulting oil triturated
with cold pentane to afford mostly (Z)-357 (430 mg, 22%) with traces of the other alkene
isomer.
Data for (E)-357:
1H NMR (400 MHz, CDCl3) δ 5.65 (dd, J = 4.1, 2.0 Hz, 2H), 3.85 (ddd, J = 6.2, 4.1, 2.0 Hz,
2H), 1.91 – 0.89 (m, 24H);
13C NMR (101 MHz, CDCl3) δ 133.3, 43.7, 28.8, 28.6, 26.5, 26.1, 26.0;
Data for (Z)-357:
1H NMR (400 MHz, CDCl3) δ 5.53 (dd, J = 5.8, 2.0 Hz, 2H), 4.12 (ddd, J = 7.4, 5.8, 2.0 Hz,
2H), 1.99 – 0.89 (m, 24H);
The data are consistent with that reported in the literature.182
OH
OH
251
2-Phenyl-3-(phenylethynyl)oxirane – 450
Prepared from (3-bromoprop-1-yn-1-yl)benzene 449 (78 mg, 0.4 mmol) according to general
procedure M using 5,7-dihydrodibenzo[c,e]selenepine 252 (5 mg, 0.02 mmol) as the
catalyst. The product was purified by preparative TLC (2% Et2O in pentane) to afford first
the trans-epoxide, trans-450 (22 mg, 50%) followed by cis-450 (18 mg, 41%).
Data for trans-450:
1H NMR (400 MHz, CDCl3) δ 7.52 – 7.27 (m, 10H), 4.15 (d, J = 2.0 Hz, 1H), 3.58 (d, J =
2.0 Hz, 1H);
Data for cis-450:
1H NMR (400 MHz, CDCl3) δ 7.52 – 7.30 (m, 10H), 4.22 (d, J = 3.9 Hz, 1H), 3.97 (d, J =
3.9 Hz, 1H);
The data are consistent with that reported in the literature.280
O
PhPh
252
2-Ethynyl-3-phenyloxirane – 452
Prepared from propargylbromide 451 (300 mg, 2 mmol) according to general procedure M
using 5,7-dihydrodibenzo[c,e]selenepine 252 (50 mg, 0.2 mmol) as the catalyst. The product
was purified by flash column chromatography (1–2% Et2O in pentane) to afford first the
trans-epoxide, trans-452 (72 mg, 51%) followed by cis-452 (48 mg, 33%).
Data for trans-452:
1H NMR (400 MHz, CDCl3) δ 7.39 – 7.21 (m, 5H), 4.05 (d, J = 2.0 Hz, 1H), 3.36 (dd, J =
2.0, 1.6 Hz, 1H), 2.40 (d, J = 1.6 Hz, 1H);
Data for cis-452:
1H NMR (400 MHz, CDCl3) δ 7.45 – 7.26 (m, 5H), 4.12 (d, J = 4.0 Hz, 1H), 3.76 (dd, J =
4.0, 1.8 Hz, 1H), 2.24 (d, J = 1.8 Hz, 1H);
The data are consistent with that reported in the literature.281
O
PhH
253
2-Phenyl-3-(prop-1-yn-1-yl)oxirane – 454
Prepared from 1-bromobut-2-yne 452 (22 mg, 0.4 mmol) according to general procedure M
using 5,7-dihydrodibenzo[c,e]selenepine 252 (10 mg, 0.04 mmol) as the catalyst. The
product was purified by preparative TLC (2% Et2O in hexane) to afford first the trans-
epoxide, trans-454 (15 mg, 47%) followed by cis-454 (14 mg, 44%).
Data for trans-454:
1H NMR (400 MHz, CDCl3) δ 7.44 – 7.23 (m, 5H), 3.98 (d, J = 2.0 Hz, 1H), 3.31 (dq, J =
2.0, 1.8 Hz, 1H), 1.89 (d, J = 1.8 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 136.0, 128.6 (2C), 125.5, 80.8, 75.6, 60.0, 49.8, 3.7;
Data for cis-454:
1H NMR (400 MHz, CDCl3) δ 7.45 – 7.26 (m, 5H), 4.06 (d, J = 4.0 Hz, 1H), 3.74 (dq, J =
4.0, 1.8 Hz, 1H), 1.74 (d, J = 1.8 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 134.5, 128.2, 127.8, 126.9, 83.3, 73.4, 58.8, 48.7, 3.7;
The data are consistent with that reported in the literature.282
O
PhMe
254
(E)-6-Styryl-6,7-dihydro-5H-6λ4-dibenzo[c,e]selenepin-6-yl triflate – 508
Prepared from 5,7-dihydrodibenzo[c,e]selenepine 252 (259 mg, 1.0 mmol) and styrene (127
µL, 1.1 mmol) according to general procedure N. The title compound 508 was isolated
following flash column chromatography (20–40% acetone in CH2Cl2) as a pale pink foam
(400 mg, 78%).
1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.6 Hz, 1H), 7.62 – 7.50 (m, 3H), 7.47 – 7.22 (m,
10H), 6.80 (d, J = 15.7 Hz, 1H), 5.06 (d, J = 10.8 Hz, 1H), 4.59 (d, J = 13.0 Hz, 1H), 3.92
(d, J = 13.0 Hz, 1H), 3.66 (d, J = 10.7 Hz, 1H);
13C NMR (101 MHz, CDCl3) δ 148.2, 140.9, 140.5, 133.3, 131.4, 131.2, 131.0, 130.9 (2C),
130.2, 129.8, 129.5, 129.0, 127.9, 127.6, 127.0, 120.6 (q, 1JC–F = 320 Hz), 111.6, 42.6, 40.2;
19F NMR (376 MHz, CDCl3) δ -78.2;
77Se{1H} NMR (76 MHz, CDCl3) δ 551.3;
m.p. (CH2Cl2): 75 °C (decomposed);
HRMS (ES+) calculated for C22H19Se [M-OTf]+: 363.0636; Found: 363.0652;
IR νmax/cm-1 (neat): 2935, 2918, 2848, 1245, 1181, 1024, 964, 734.
Se
OTf
Ph
255
6-Vinyl-6,7-dihydro-5H-6λ4-dibenzo[c,e]selenepin-6-yl triflate – 510
Prepared from 5,7-dihydrodibenzo[c,e]selenepine 252 (259 mg, 1.0 mmol) and
trimethyl(vinyl)silane (161 µL, 1.1 mmol) according to general procedure N. The title
compound 510 was isolated following flash column chromatography (20–40% acetone in
CH2Cl2) as a brown solid (178 mg, 41%).
1H NMR (400 MHz, CDCl3) δ 7.74 – 7.69 (m, 1H), 7.58 (app. tdd, J = 7.6, 2.9, 1.3 Hz, 2H),
7.43 – 7.51 (m, 2H), 7.42 – 7.35 (m, 3H), 6.70 – 6.59 (m, 1H), 6.45 – 6.37 (m, 2H), 4.96 (d,
J = 10.8 Hz, 1H), 4.56 (d, J = 13.1 Hz, 1H), 4.03 (d, J = 13.0 Hz, 1H), 3.61 (d, J = 10.7 Hz,
1H);
13C NMR (101 MHz, CDCl3) δ 140.8, 140.4, 134.6, 131.6, 131.3, 131.0, 131.0, 130.2,
129.9, 129.6, 129.0, 127.3, 126.7, 123.0, 41.6, 40.0;
19F NMR (376 MHz, CDCl3) δ -78.1;
77Se{1H} NMR (76 MHz, CDCl3) δ 437.4;
m.p. (CH2Cl2): 70 °C (decomposed);
HRMS (ES+) calculated for C16H15Se [M-OTf]+: 287.0333; Found: 287.0344;
IR νmax/cm-1 (neat): 3065, 2935, 1228, 1178, 1027, 750, 740.
Se
OTf
256
(2S,5S)-2,5-Diphenyl-1-((E)-styryl)tetrahydro-1H-1λ4-selenophen-1-yl triflate – 517
Prepared from (2S,5S)-2,5-diphenyltetrahydroselenophene 340 (172 mg, 0.6 mmol) and
styrene (69 µL, 0.6 mmol) according to general procedure N. The title compound 517 was
isolated following flash column chromatography (20% acetone in CH2Cl2) as a brown solid
(138 mg, 43%).
1H NMR (400 MHz, CDCl3) δ 7.70 – 7.61 (m, 2H), 7.60 – 7.53 (m, 2H), 7.41 – 7.25 (m,
12H), 6.52 (d, J = 15.7 Hz, 1H), 3.40 – 3.22 (m, 2H), 2.95 – 2.77 (m, 4H);
13C NMR (101 MHz, CDCl3) δ 135.9, 133.4, 133.0, 131.5, 131.4, 130.2, 129.9, 129.7,
129.6, 129.3, 129.0, 128.6, 128.1, 111.4, 38.7, 35.1, 30.9;
19F NMR (376 MHz, CDCl3) δ -78.1;
77Se{1H} NMR (76 MHz, CDCl3) δ 381.9;
m.p. (CH2Cl2): 79 °C (decomposed);
HRMS (ES+) calculated for C24H23Se [M-OTf]+: 391.0959; Found: 391.0969;
IR νmax/cm-1 (neat): 2935, 2918, 2848, 1432, 1275, 1255, 1118, 1027, 964, 757.
Se
Ph
PhPh
OTf
257
APPENDICES
258
13. Appendices
The following ligands were also trialed in the cross-coupling reaction developed earlier (see
Section 4). The Buchwald ligands 533–541 and NHC precursors 542–543 were inferior
compared to Josiphos/xantphos and therefore were not investigated further (Table 25).
Figure 25. Ligands trialed.
PCy2NMe2
DavePhos533
PCy2OMe
SPhos534
MeOP(t-Bu)2
JohnPhos535
PCy2i-Pr
XPhos536
i-Pr
i-Pr
P(t-Bu)2i-Pr
(t-Bu)XPhos537
i-Pr
i-Pr
PCy2O(i-Pr)
RuPhos538
(i-Pr)O
PCy2i-Pr
BrettPhos539
i-Pr
i-Pr
OMe
MeO
N
O
P(1-adam)2
morDalPhos540
P(t-Bu)2N
N
Ph
Ph
TrippyPhos541
N+ NCl-
N+ N
i-Pr
i-Pr
i-Pr
i-PrCl-
IMes•HCl542
IPr•HCl543
259
Table 25. Alternative ligands trailed in the cross-coupling of selenylstannes and aryl electrophiles.
Entry Ligand Conversion (%)[a] Yield (%)[a]
1 DavePhos 533 10 6 2 SPhos 534 8 3 3 JohnPhos 535 4 <1 4 XPhos 536 10 5 5 (t-Bu)XPhos 537 6 1 6 RuPhos 538 12 7 7 BrettPhos 539 47 46 8 morDalPhos 540 8 4 9 TrippyPhos 541 2 <1
10 IMes·HCl 542[b] 4 <1 11 IPr·HCl 543[b] 2 <1
[a]Measured by GC analysis with decane as internal standard; [b]Ligand premixed with KO(t-Bu) (1:1) prior to the addition of any other reagents to generate the free NHC.
n-BuSeSn(n-Bu)3 (1.5 eq.)[Pd(π-cinnamyl)Cl]2 (5 mol%)
Ligand (10 mol%)toluene (0.1 M)
110 °C, 18 h
OTf Se230 231
260
13.2.1 Bromide modifications
Replacing benzyl bromide with methyl bromoacetate 544 resulted initially in promising
results, however, it was found that the background Darzens reaction was occurring rapidly
and the selenide did not appear to be participating in the transformation (Scheme 165).
Scheme 165. α-haloesters.
Background Darzens reaction was found to be prevalent for a bromoacetonitrile 546 as well
as several other α-haloesters (Figure 26).
Figure 26. Other halides trialled.
Modification of the base to prevent this process was either ineffective or resulted in no
conversion of the starting materials (Table 26).
BrOMe
O O
Ph
CO2Me
545 81%(1.2:1 dr)544
BrOMe
Oselenide 252 (10 mol%)
PhCHO 351 (0.5 eq.)
Cs2CO3 (1 eq.)MeCN
O
Ph
CO2Me
545 89%(1.2:1 dr)544
PhCHO 351 (0.5 eq.)
Cs2CO3 (1 eq.)MeCN
a) In presence of catalyst:
b) no catalyst:
Se
252
NBr Br
OEt
OBr
OEt
O
546 548547
261
Table 26. Modifications to the base.
Entry Base Solvent Yield (%)[a]
1 NaOH toluene 74 2[b] NaOH toluene 70 3 Na2CO3 MeCN <1 4 NaHCO3 MeCN <1 5 Ag2CO3 MeCN <1 6 Ag2CO3 toluene <1 7 Ag2CO3 dioxane <1 8 Ag2CO3 EtOH 4 9 DIPEA MeCN 3
10 2,6-lutidine MeCN 0 [a]Total yield of both diastereomers; [b]Reaction preformed without catalyst 252.
13.2.2 Aldehyde modifications
The substrates listed below were used in place of benzaldehyde but all were unproductive in
this process (Scheme 166).
Scheme 166. Replacements for benzaldehyde 351 in Corey-Chaykovsky reactions.
NBr
selenide 252 (10 mol%)PhCHO 351 (0.5 eq.)
base (1.0 eq.)
546
Se
252549
O
Ph
CN
substrate (0.5 eq.)selenide 252 (10 mol%)
Cs2CO3 (1 eq.)MeCN
X
Ph
RSe
252
Ph Br
550
HOEt
O
O
OEtO
O Ph H
NPh
Ph H
NTs
551 552 553 554
substrates:
262
13.2.3 Towards cyclopropanation
Several α,ß-unsaturated carbonyl compounds were also trialled in this reaction in the hope of
generating cyclopropanes, however, no products were observed in the preliminary
investigations (Scheme 167).
Scheme 167. Initial investigations towards cyclopropanation.
substrate (0.5 eq.)selenide 252 (10 mol%)
Cs2CO3 (1 eq.)MeCN Ph
R'
R = CN, Ph, CO2Me
Se
252
R Br
555not observed
556 557
substrates:
R
OEt
O O
263
Crystal structure of dibenzo[c,e][1,2]diselenine – 140
Empirical formula C12H8Se2 Formula weight 310.10 Temperature 173 K Crystal system, space group Tetragonal Space group P41212 Unit cell dimensions a = 14.0472(2) Å α = 90° b = 14.0472(2) Å ß = 90° c = 21.3601(6) Å γ = 90° Volume 4214.87(17) Å3, Z 16 Density (calculated) 1.955 g/cm3 Absorption coefficient 6.971 mm-1 F(000) 2368 Crystal colour / morphology Red blocks Crystal size 0.58 x 0.45 x 0.37 mm3 θ range for data collection 2.800 to 28.205° Index ranges -17<=h<=18, -17<=k<=17, -28<=l<=17 Reflns collected / unique 24222 / 4614 [R(int) = 0.0471] Reflns observed [F>σ (F)] 3509 Absorption correction Analytical Max. and min. transmission 0.203 and 0.085 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4614 / 0 / 254 Goodness-of-fit on F2 1.016 Final R indices [F>4σ (F)] R1 = 0.0343, wR2 = 0.0492 R indices (all data) R1 = 0.0642, wR2 = 0.0548 Absolute structure parameter -0.030(10) Largest diff. peak, hole 0.483, -0.534 eÅ-3
264
Bond lengths / Å Bond angles / ° Se(1A)-C(1A) 1.923(5) Se(1A)-Se(2A) 2.3230(10) Se(2A)-C(12A) 1.920(5) C(1A)-C(2A) 1.378(8) C(1A)-C(6A) 1.394(7) C(2A)-C(3A) 1.374(8) C(3A)-C(4A) 1.375(9) C(4A)-C(5A) 1.382(8) C(5A)-C(6A) 1.389(7) C(6A)-C(7A) 1.489(7) C(7A)-C(8A) 1.396(7) C(7A)-C(12A) 1.406(7) C(8A)-C(9A) 1.378(8) C(9A)-C(10A) 1.382(8) C(10A)-C(11A) 1.372(7) C(11A)-C(12A) 1.377(7) Se(1B)-C(1B) 1.909(5) Se(1B)-Se(1B)#1 2.3250(14) C(1B)-C(2B) 1.381(7) C(1B)-C(6B) 1.415(7) C(2B)-C(3B) 1.379(8) C(3B)-C(4B) 1.369(8) C(4B)-C(5B) 1.381(8) C(5B)-C(6B) 1.389(7) C(6B)-C(6B)#1 1.484(11) Se(1C)-C(1C) 1.909(5) Se(1C)-Se(1C)#2 2.3231(14) C(1C)-C(6C) 1.381(7) C(1C)-C(2C) 1.398(8) C(2C)-C(3C) 1.382(9) C(3C)-C(4C) 1.380(9) C(4C)-C(5C) 1.364(8) C(5C)-C(6C) 1.392(7) C(6C)-C(6C)#2 1.496(11)
C(1A)-Se(1A)-Se(2A) 93.21(18) C(12A)-Se(2A)-Se(1A) 93.23(18) C(2A)-C(1A)-C(6A) 121.3(5) C(2A)-C(1A)-Se(1A) 117.5(5) C(6A)-C(1A)-Se(1A) 121.2(4) C(3A)-C(2A)-C(1A) 120.1(6) C(2A)-C(3A)-C(4A) 120.1(6) C(3A)-C(4A)-C(5A) 119.5(6) C(4A)-C(5A)-C(6A) 121.8(6) C(5A)-C(6A)-C(1A) 117.1(5) C(5A)-C(6A)-C(7A) 118.8(5) C(1A)-C(6A)-C(7A) 124.1(5) C(8A)-C(7A)-C(12A) 116.9(5) C(8A)-C(7A)-C(6A) 118.9(5) C(12A)-C(7A)-C(6A) 124.2(5) C(9A)-C(8A)-C(7A) 121.3(5) C(8A)-C(9A)-C(10A) 119.9(5) C(11A)-C(10A)-C(9A) 120.4(6) C(10A)-C(11A)-C(12A) 119.6(5) C(11A)-C(12A)-C(7A) 121.7(5) C(11A)-C(12A)-Se(2A) 117.9(4) C(7A)-C(12A)-Se(2A) 120.3(4) C(1B)-Se(1B)-Se(1B)#1 94.00(18) C(2B)-C(1B)-C(6B) 120.9(5) C(2B)-C(1B)-Se(1B) 118.3(4) C(6B)-C(1B)-Se(1B) 120.7(4) C(3B)-C(2B)-C(1B) 119.9(5) C(4B)-C(3B)-C(2B) 120.5(6) C(3B)-C(4B)-C(5B) 119.6(6) C(4B)-C(5B)-C(6B) 122.1(5) C(5B)-C(6B)-C(1B) 116.8(5) C(5B)-C(6B)-C(6B)#1 118.6(4) C(1B)-C(6B)-C(6B)#1 124.6(4) C(1C)-Se(1C)-Se(1C)#2 92.70(19) C(6C)-C(1C)-C(2C) 120.9(5) C(6C)-C(1C)-Se(1C) 121.3(4) C(2C)-C(1C)-Se(1C) 117.8(5) C(3C)-C(2C)-C(1C) 119.5(6) C(4C)-C(3C)-C(2C) 120.1(6) C(5C)-C(4C)-C(3C) 119.5(6) C(4C)-C(5C)-C(6C) 122.3(6) C(1C)-C(6C)-C(5C) 117.7(5) C(1C)-C(6C)-C(6C)#2 123.4(4) C(5C)-C(6C)-C(6C)#2 118.9(4)
265
Crystal structure of dinaphtho[2,1-b:1',2'-d]selenophene – 142
Formula C20H12Se Formula weight 331.26 Temperature 173 K Crystal system, space group Orthorhombic, Pbcn Unit cell dimensions a = 21.1026(10) Å α = 90° b = 8.5519(4) Å ß = 90° c = 7.4095(4) Å γ = 90° Volume 1337.17(11) Å3
Z 4 Density (calculated) 1.645 g/cm3
Absorption coefficient 2.796 mm-1
F(000) 664 Crystal colour / morphology Colourless thin plates Crystal size 0.67 x 0.47 x 0.01 mm3
θ range for data collection 2.570 to 28.205° Index ranges -26<=h<=27, -11<=k<=11, -7<=l<=8 Reflns collected / unique 6869 / 1437 [R(int) = 0.0386] Reflns observed [F>4σ (F)] 1079 Absorption correction Analytical Max. and min. transmission 0.961 and 0.359 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 1437 / 0 / 96 Goodness-of-fit on F2 1.024 Final R indices [F>4σ (F)] R1 = 0.0318, wR2 = 0.0583 R indices (all data) R1 = 0.0536, wR2 = 0.0653 Largest diff. peak, hole 0.406, -0.289 eÅ-3
266
Bond lengths / Å Bond angles / ° Se(1)-C(2) 1.872(2) Se(1)-C(2)#1 1.872(3) C(1)-C(2) 1.397(3) C(1)-C(10) 1.442(3) C(1)-C(1)#1 1.471(5) C(2)-C(3) 1.423(3) C(3)-C(4) 1.355(4) C(4)-C(5) 1.419(4) C(5)-C(6) 1.411(4) C(5)-C(10) 1.433(3) C(6)-C(7) 1.365(4) C(7)-C(8) 1.410(4) C(8)-C(9) 1.368(3) C(9)-C(10) 1.418(3)
C(2)-Se(1)-C(2)#1 86.57(16) C(2)-C(1)-C(10) 117.0(2) C(2)-C(1)-C(1)#1 112.78(14) C(10)-C(1)-C(1)#1 129.70(15) C(1)-C(2)-C(3) 123.0(2) C(1)-C(2)-Se(1) 113.39(18) C(3)-C(2)-Se(1) 123.55(19) C(4)-C(3)-C(2) 118.3(2) C(3)-C(4)-C(5) 121.4(2) C(6)-C(5)-C(4) 120.6(2) C(6)-C(5)-C(10) 119.3(2) C(4)-C(5)-C(10) 119.9(2) C(7)-C(6)-C(5) 121.6(2) C(6)-C(7)-C(8) 119.5(3) C(9)-C(8)-C(7) 120.4(2) C(8)-C(9)-C(10) 121.9(2) C(9)-C(10)-C(5) 117.2(2) C(9)-C(10)-C(1) 123.9(2) C(5)-C(10)-C(1) 118.5(2)
267
Crystal structure of dibenzo[c,e][1,2,7]oxadiselenepine 5,7-dioxide – 170
Formula C12H8O3Se2, CH2Cl2 Formula weight 443.03 Temperature 173 K Crystal system Monoclinic Space group P21/n Unit cell dimensions a = 10.8124(4) Å α = 90° b = 9.9864(3) Å ß = 105.386(4)° c = 13.9570(5) Å γ = 90° Volume 1453.01(9) Å3 Z 4 Density (calculated) 2.025 g/cm3 Absorption coefficient 5.459 mm-1 F(000) 856 Crystal colour / morphology Colourless blocks Crystal size 0.63 x 0.32 x 0.12 mm3 θ range for data collection 2.771 to 27.969° Index ranges -9<=h<=14, -8<=k<=12, -17<=l<=11 Reflns collected / unique 4928 / 2889 [R(int) = 0.0242] Reflns observed [F>4σ (F)] 2312 Absorption correction Analytical Max. and min. transmission 0.521 and 0.231 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2889 / 0 / 182 Goodness-of-fit on F2 1.024 Final R indices [F>4σ (F)] R1 = 0.0271, wR2 = 0.0560 R indices (all data) R1 = 0.0418, wR2 = 0.0616 Largest diff. peak, hole 0.405, -0.591 eÅ-3
268
Bond lengths / Å Bond angles / ° Se(1)-O(1) 1.628(2) Se(1)-O(3) 1.8460(19) Se(1)-C(1) 1.953(3) Se(2)-O(2) 1.631(2) Se(2)-O(3) 1.795(2) Se(2)-C(12) 1.954(3) C(1)-C(2) 1.387(4) C(1)-C(6) 1.392(4) C(2)-C(3) 1.380(4) C(3)-C(4) 1.382(4) C(4)-C(5) 1.380(4) C(5)-C(6) 1.393(4) C(6)-C(7) 1.484(4) C(7)-C(8) 1.395(4) C(7)-C(12) 1.404(4) C(8)-C(9) 1.379(4) C(9)-C(10) 1.378(4) C(10)-C(11) 1.384(4) C(11)-C(12) 1.389(4) C(20)-Cl(22) 1.751(4) C(20)-Cl(21) 1.758(4)
O(1)-Se(1)-O(3) 97.65(10) O(1)-Se(1)-C(1) 102.86(12) O(3)-Se(1)-C(1) 95.74(11) O(2)-Se(2)-O(3) 101.15(9) O(2)-Se(2)-C(12) 101.25(12) O(3)-Se(2)-C(12) 98.80(11) Se(2)-O(3)-Se(1) 122.33(11) C(2)-C(1)-C(6) 121.5(3) C(2)-C(1)-Se(1) 117.5(2) C(6)-C(1)-Se(1) 120.8(2) C(3)-C(2)-C(1) 119.3(3) C(2)-C(3)-C(4) 120.2(3) C(5)-C(4)-C(3) 120.3(3) C(4)-C(5)-C(6) 120.7(3) C(1)-C(6)-C(5) 118.0(3) C(1)-C(6)-C(7) 122.2(3) C(5)-C(6)-C(7) 119.7(3) C(8)-C(7)-C(12) 117.5(3) C(8)-C(7)-C(6) 120.4(3) C(12)-C(7)-C(6) 122.1(3) C(9)-C(8)-C(7) 120.7(3) C(10)-C(9)-C(8) 121.0(3) C(9)-C(10)-C(11) 119.8(3) C(10)-C(11)-C(12) 119.2(3) C(11)-C(12)-C(7) 121.6(3) C(11)-C(12)-Se(2) 116.9(2) C(7)-C(12)-Se(2) 121.1(2) Cl(22)-C(20)-Cl(21) 111.3(2)
269
Crystal structure of 6,7-diphenyldinaphtho[1,2-b:2',1'-d]selenophene – 179
Formula C32H20Se Formula weight 483.44 Temperature 173(2) K Crystal system Monoclinic Space group P21/c Unit cell dimensions a = 7.40759(17) Å α = 90° b = 22.3900(6) Å ß = 95.209(2)° c = 13.1501(3) Å γ = 90° Volume 2172.01(9) Å3
Z 4 Density (calculated) 1.478 g/cm3 Absorption coefficient 2.466 mm-1 F(000) 984 Crystal colour / morphology Colourless thin plates Crystal size 0.30 x 0.20 x 0.01 mm3 θ range for data collection 3.910 to 74.137° Index ranges -9<=h<=5, -25<=k<=27, -16<=l<=14 Reflns collected / unique 7184 / 4187 [R(int) = 0.0329] Reflns observed [F>4σ (F)] 3273 Absorption correction Analytical Max. and min. transmission 0.970 and 0.706 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4187 / 1110 / 431 Goodness-of-fit on F2 1.021 Final R indices [F>4σ (F)] R1 = 0.0501, wR2 = 0.1321 R indices (all data) R1 = 0.0630, wR2 = 0.1454 Largest diff. peak, hole 1.493, -0.565 eÅ-3
270
Bond lengths / Å Bond angles / ° Se(1)-C(2) 1.882(3) Se(1)-C(22) 1.882(3) C(1)-C(2) 1.382(4) C(1)-C(10) 1.443(4) C(1)-C(21) 1.472(4) C(2)-C(3) 1.428(4) C(3)-C(4) 1.403(5) C(3)-C(8) 1.421(4) C(4)-C(5) 1.374(5) C(5)-C(6) 1.407(5) C(6)-C(7) 1.366(5) C(7)-C(8) 1.423(4) C(8)-C(9) 1.425(4) C(9)-C(10) 1.378(4) C(10)-C(11) 1.491(4) C(11)-C(12) 1.391(5) C(11)-C(16) 1.405(5) C(12)-C(13) 1.394(5) C(13)-C(14) 1.390(5) C(14)-C(15) 1.386(5) C(15)-C(16) 1.385(5) C(21)-C(22) 1.390(4) C(21)-C(30) 1.440(4) C(22)-C(23) 1.430(4) C(23)-C(24) 1.403(5) C(23)-C(28) 1.415(5) C(24)-C(25) 1.372(5) C(25)-C(26) 1.408(5) C(26)-C(27) 1.377(5) C(27)-C(28) 1.417(4) C(28)-C(29) 1.424(5) C(29)-C(30) 1.380(4) C(30)-C(31) 1.492(4) C(31)-C(32) 1.396(5) C(31)-C(36) 1.401(4) C(32)-C(33) 1.388(5) C(33)-C(34) 1.390(6) C(34)-C(35) 1.382(5) C(35)-C(36) 1.386(5) Se(1')-C(2') 1.890(16) Se(1')-C(22') 1.893(16) C(1')-C(2') 1.386(17) C(1')-C(10') 1.449(17) C(1')-C(21') 1.473(17) C(2')-C(3') 1.427(17) C(3')-C(4') 1.401(18) C(3')-C(8') 1.417(18) C(4')-C(5') 1.377(19) C(5')-C(6') 1.400(19) C(6')-C(7') 1.364(19) C(7')-C(8') 1.429(18)
C(2)-Se(1)-C(22) 86.16(14) C(2)-C(1)-C(10) 118.0(3) C(2)-C(1)-C(21) 113.4(3) C(10)-C(1)-C(21) 128.4(3) C(1)-C(2)-C(3) 124.0(3) C(1)-C(2)-Se(1) 113.4(2) C(3)-C(2)-Se(1) 122.6(2) C(4)-C(3)-C(8) 119.6(3) C(4)-C(3)-C(2) 124.2(3) C(8)-C(3)-C(2) 116.1(3) C(5)-C(4)-C(3) 120.8(3) C(4)-C(5)-C(6) 120.1(3) C(7)-C(6)-C(5) 120.4(3) C(6)-C(7)-C(8) 120.9(3) C(3)-C(8)-C(7) 118.2(3) C(3)-C(8)-C(9) 119.5(3) C(7)-C(8)-C(9) 122.2(3) C(10)-C(9)-C(8) 122.6(3) C(9)-C(10)-C(1) 118.2(3) C(9)-C(10)-C(11) 117.7(3) C(1)-C(10)-C(11) 123.1(3) C(12)-C(11)-C(16) 118.2(3) C(12)-C(11)-C(10) 122.2(3) C(16)-C(11)-C(10) 119.2(3) C(11)-C(12)-C(13) 121.0(3) C(14)-C(13)-C(12) 119.9(3) C(15)-C(14)-C(13) 119.8(3) C(16)-C(15)-C(14) 120.2(3) C(15)-C(16)-C(11) 120.9(3) C(22)-C(21)-C(30) 118.0(3) C(22)-C(21)-C(1) 112.9(3) C(30)-C(21)-C(1) 129.0(3) C(21)-C(22)-C(23) 123.7(3) C(21)-C(22)-Se(1) 113.4(2) C(23)-C(22)-Se(1) 122.9(2) C(24)-C(23)-C(28) 120.0(3) C(24)-C(23)-C(22) 123.8(3) C(28)-C(23)-C(22) 116.2(3) C(25)-C(24)-C(23) 120.9(3) C(24)-C(25)-C(26) 119.6(3) C(27)-C(26)-C(25) 120.7(3) C(26)-C(27)-C(28) 120.4(3) C(23)-C(28)-C(27) 118.4(3) C(23)-C(28)-C(29) 119.8(3) C(27)-C(28)-C(29) 121.7(3) C(30)-C(29)-C(28) 122.5(3) C(29)-C(30)-C(21) 118.1(3) C(29)-C(30)-C(31) 117.8(3) C(21)-C(30)-C(31) 123.3(3) C(32)-C(31)-C(36) 118.0(3) C(32)-C(31)-C(30) 121.4(3)
271
C(8')-C(9') 1.422(18) C(9')-C(10') 1.381(18) C(10')-C(11') 1.488(17) C(11')-C(12') 1.397(18) C(11')-C(16') 1.403(18) C(12')-C(13') 1.396(19) C(13')-C(14') 1.39(2) C(14')-C(15') 1.383(19) C(15')-C(16') 1.389(19) C(21')-C(22') 1.388(17) C(21')-C(30') 1.440(17) C(22')-C(23') 1.426(17) C(23')-C(24') 1.409(18) C(23')-C(28') 1.416(18) C(24')-C(25') 1.373(19) C(25')-C(26') 1.406(19) C(26')-C(27') 1.377(19) C(27')-C(28') 1.417(18) C(28')-C(29') 1.428(18) C(29')-C(30') 1.371(18) C(30')-C(31') 1.495(17) C(31')-C(32') 1.394(19) C(31')-C(36') 1.404(19) C(32')-C(33') 1.382(19) C(33')-C(34') 1.40(2) C(34')-C(35') 1.38(2) C(35')-C(36') 1.382(19)
C(36)-C(31)-C(30) 120.2(3) C(33)-C(32)-C(31) 121.0(3) C(32)-C(33)-C(34) 120.3(3) C(35)-C(34)-C(33) 119.2(3) C(34)-C(35)-C(36) 120.7(3) C(35)-C(36)-C(31) 120.7(3) C(2')-Se(1')-C(22') 84.9(7) C(2')-C(1')-C(10') 118.1(15) C(2')-C(1')-C(21') 111.2(14) C(10')-C(1')-C(21') 130.4(16) C(1')-C(2')-C(3') 124.3(15) C(1')-C(2')-Se(1') 115.2(12) C(3')-C(2')-Se(1') 120.6(13) C(4')-C(3')-C(8') 118.1(16) C(4')-C(3')-C(2') 126.1(18) C(8')-C(3')-C(2') 115.8(15) C(5')-C(4')-C(3') 123(2) C(4')-C(5')-C(6') 120(2) C(7')-C(6')-C(5') 118(2) C(6')-C(7')-C(8') 124(2) C(3')-C(8')-C(9') 118.8(17) C(3')-C(8')-C(7') 117.2(16) C(9')-C(8')-C(7') 123.4(18) C(10')-C(9')-C(8') 124(2) C(9')-C(10')-C(1') 116.5(16) C(9')-C(10')-C(11') 120.2(18) C(1')-C(10')-C(11') 122.7(17) C(12')-C(11')-C(16') 118.9(18) C(12')-C(11')-C(10') 120.2(19) C(16')-C(11')-C(10') 120.8(19) C(13')-C(12')-C(11') 120(2) C(14')-C(13')-C(12') 120(2) C(15')-C(14')-C(13') 121(2) C(14')-C(15')-C(16') 119(2) C(15')-C(16')-C(11') 121(2) C(22')-C(21')-C(30') 118.5(15) C(22')-C(21')-C(1') 113.8(14) C(30')-C(21')-C(1') 127.3(16) C(21')-C(22')-C(23') 124.8(15) C(21')-C(22')-Se(1') 113.1(12) C(23')-C(22')-Se(1') 121.6(13) C(24')-C(23')-C(28') 120.5(16) C(24')-C(23')-C(22') 124.6(17) C(28')-C(23')-C(22') 114.7(16) C(25')-C(24')-C(23') 121(2) C(24')-C(25')-C(26') 119(2) C(27')-C(26')-C(25') 120(2) C(26')-C(27')-C(28') 121(2) C(23')-C(28')-C(27') 116.9(17) C(23')-C(28')-C(29') 119.3(18) C(27')-C(28')-C(29') 121.1(19) C(30')-C(29')-C(28') 123.0(19) C(29')-C(30')-C(21') 117.5(17)
272
C(29')-C(30')-C(31') 119(2) C(21')-C(30')-C(31') 119.6(18) C(32')-C(31')-C(36') 118.1(18) C(32')-C(31')-C(30') 120.3(19) C(36')-C(31')-C(30') 121(2) C(33')-C(32')-C(31') 121(2) C(32')-C(33')-C(34') 120(2) C(35')-C(34')-C(33') 118(2) C(34')-C(35')-C(36') 122(2) C(35')-C(36')-C(31') 120(2)
273
Crystal structure of (2S,5S)-2,5-diphenyltetrahydroselenophene – 340
Formula C16H16Se Formula weight 287.25 Temperature 173(2) K Crystal system Monoclinic Space group P21 Unit cell dimensions a = 13.6821(5) Å α = 90° b = 5.6693(2) Å ß = 99.756(4)° c = 17.1924(6) Å γ = 90° Volume 1314.30(9) Å3 Z 4 Density (calculated) 1.452 g/cm3 Absorption coefficient 2.832 mm-1 F(000) 584 Crystal colour / morphology Colourless blocky needles Crystal size 0.59 x 0.16 x 0.08 mm3 θ range for data collection 2.404 to 28.186° Index ranges -18<=h<=12, -4<=k<=7, -14<=l<=21 Reflns collected / unique 4809 / 3676 [R(int) = 0.0207] Reflns observed [F>4σb(F)] 3289 Absorption correction Analytical Max. and min. transmission 0.808 and 0.434 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 3676 / 1 / 307 Goodness-of-fit on F2 1.012 Final R indices [F>4σ (F)] R1 = 0.0316, wR2 = 0.0541 R indices (all data) R1 = 0.0397, wR2 = 0.0567 Absolute structure parameter -0.019(10) Largest diff. peak, hole 0.413, -0.391 eÅ-3
274
Bond lengths / Å Bond angles / ° Se(1A)-C(5A) 1.982(4) Se(1A)-C(2A) 1.992(5) C(2A)-C(3A) 1.511(6) C(2A)-C(6A) 1.518(6) C(3A)-C(4A) 1.528(6) C(4A)-C(5A) 1.533(6) C(5A)-C(12A) 1.512(5) C(6A)-C(11A) 1.377(7) C(6A)-C(7A) 1.396(7) C(7A)-C(8A) 1.394(7) C(8A)-C(9A) 1.368(8) C(9A)-C(10A) 1.363(7) C(10A)-C(11A) 1.388(6) C(12A)-C(17A) 1.386(6) C(12A)-C(13A) 1.389(6) C(13A)-C(14A) 1.389(6) C(14A)-C(15A) 1.380(7) C(15A)-C(16A) 1.380(7) C(16A)-C(17A) 1.393(6) Se(1B)-C(5B) 1.982(4) Se(1B)-C(2B) 1.987(5) C(2B)-C(6B) 1.514(6) C(2B)-C(3B) 1.527(6) C(3B)-C(4B) 1.526(6) C(4B)-C(5B) 1.525(5) C(5B)-C(12B) 1.508(6) C(6B)-C(7B) 1.377(6) C(6B)-C(11B) 1.386(7) C(7B)-C(8B) 1.387(6) C(8B)-C(9B) 1.369(7) C(9B)-C(10B) 1.385(8) C(10B)-C(11B) 1.395(6) C(12B)-C(13B) 1.385(6) C(12B)-C(17B) 1.395(6) C(13B)-C(14B) 1.378(6) C(14B)-C(15B) 1.382(7) C(15B)-C(16B) 1.382(9) C(16B)-C(17B) 1.387(6)
C(5A)-Se(1A)-C(2A) 90.62(19) C(3A)-C(2A)-C(6A) 116.5(4) C(3A)-C(2A)-Se(1A) 103.9(3) C(6A)-C(2A)-Se(1A) 111.0(3) C(2A)-C(3A)-C(4A) 108.1(4) C(3A)-C(4A)-C(5A) 108.3(4) C(12A)-C(5A)-C(4A) 113.6(3) C(12A)-C(5A)-Se(1A) 114.8(3) C(4A)-C(5A)-Se(1A) 104.2(3) C(11A)-C(6A)-C(7A) 118.3(5) C(11A)-C(6A)-C(2A) 120.0(5) C(7A)-C(6A)-C(2A) 121.7(5) C(8A)-C(7A)-C(6A) 120.4(5) C(9A)-C(8A)-C(7A) 119.9(5) C(10A)-C(9A)-C(8A) 120.0(5) C(9A)-C(10A)-C(11A) 120.8(5) C(6A)-C(11A)-C(10A) 120.5(5) C(17A)-C(12A)-C(13A) 118.2(4) C(17A)-C(12A)-C(5A) 118.2(4) C(13A)-C(12A)-C(5A) 123.4(4) C(14A)-C(13A)-C(12A) 121.4(4) C(15A)-C(14A)-C(13A) 119.6(5) C(14A)-C(15A)-C(16A) 119.9(4) C(15A)-C(16A)-C(17A) 120.2(5) C(12A)-C(17A)-C(16A) 120.7(4) C(5B)-Se(1B)-C(2B) 90.88(18) C(6B)-C(2B)-C(3B) 117.0(4) C(6B)-C(2B)-Se(1B) 110.9(3) C(3B)-C(2B)-Se(1B) 103.7(3) C(4B)-C(3B)-C(2B) 107.4(4) C(5B)-C(4B)-C(3B) 108.8(3) C(12B)-C(5B)-C(4B) 114.9(3) C(12B)-C(5B)-Se(1B) 112.1(3) C(4B)-C(5B)-Se(1B) 104.0(3) C(7B)-C(6B)-C(11B) 119.7(4) C(7B)-C(6B)-C(2B) 122.0(4) C(11B)-C(6B)-C(2B) 118.4(4) C(6B)-C(7B)-C(8B) 120.2(5) C(9B)-C(8B)-C(7B) 120.2(5) C(8B)-C(9B)-C(10B) 120.4(4) C(9B)-C(10B)-C(11B) 119.4(5) C(6B)-C(11B)-C(10B) 120.1(5) C(13B)-C(12B)-C(17B) 118.1(4) C(13B)-C(12B)-C(5B) 121.4(4) C(17B)-C(12B)-C(5B) 120.5(5) C(14B)-C(13B)-C(12B) 121.3(4) C(13B)-C(14B)-C(15B) 120.0(5) C(14B)-C(15B)-C(16B) 119.9(5) C(15B)-C(16B)-C(17B) 119.8(5) C(16B)-C(17B)-C(12B) 120.9(5)
275
Crystal structure of (3S,6S)-3,6-diphenyl-1,2-diselenane – 341
Formula C16H16Se2 Formula weight 366.21 Temperature 173(2) K Crystal system Trigonal, Space group P3121 Unit cell dimensions a = 9.28979(15) Å α = 90° b = 9.28979(15) Å ß = 90° c = 14.6496(3) Å γ = 120° Volume 1094.88(4) Å3 Z 3 Density (calculated) 1.666 g/cm3 Absorption coefficient 6.151 mm-1 F(000) 540 Crystal colour / morphology Yellow blocks Crystal size 0.45 x 0.35 x 0.25 mm3 θ range for data collection 5.499 to 73.799° Index ranges -11<=h<=9, -7<=k<=11, -18<=l<=16 Reflns collected / unique 6078 / 1474 [R(int) = 0.0217] Reflns observed [F>4σ (F)] 1427 Absorption correction Analytical Max. and min. transmission 0.372 and 0.182 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 1474 / 0 / 83 Goodness-of-fit on F2 1.078 Final R indices [F>4σ (F)] R1 = 0.0290, wR2 = 0.0741 R indices (all data) R1 = 0.0304, wR2 = 0.0757 Absolute structure parameter 0.00(2) Largest diff. peak, hole 0.631, -0.566 eÅ-3
276
Bond lengths / Å Bond angles / ° Se(1)-C(2) 1.978(4) Se(1)-Se(1)#1 2.3210(8) C(2)-C(4) 1.501(5) C(2)-C(3) 1.521(6) C(3)-C(3)#1 1.530(9) C(4)-C(5) 1.377(7) C(4)-C(9) 1.393(6) C(5)-C(6) 1.396(8) C(6)-C(7) 1.369(8) C(7)-C(8) 1.372(7) C(8)-C(9) 1.385(6)
C(2)-Se(1)-Se(1)#1 96.82(11) C(4)-C(2)-C(3) 114.9(4) C(4)-C(2)-Se(1) 104.8(3) C(3)-C(2)-Se(1) 110.0(3) C(2)-C(3)-C(3)#1 116.1(4) C(5)-C(4)-C(9) 117.8(4) C(5)-C(4)-C(2) 120.7(4) C(9)-C(4)-C(2) 121.5(4) C(4)-C(5)-C(6) 121.3(5) C(7)-C(6)-C(5) 120.2(5) C(6)-C(7)-C(8) 119.2(4) C(7)-C(8)-C(9) 120.9(5) C(8)-C(9)-C(4) 120.7(4)
277
Crystal structure of (2R,5R)-2,5-dicyclohexyltetrahydroselenophene – 360
Formula C16H28Se Formula weight 299.34 Temperature 173(2) K Crystal system Orthorhombic Space group C2221 Unit cell dimensions a = 4.6582(2) Å α = 90° b = 11.5702(5) Å ß = 90° c = 27.3504(13) Å γ = 90° Volume 1474.08(12) Å3 Z 4 Density (calculated) 1.349 g/cm3 Absorption coefficient 2.527 mm-1 F(000) 632 Crystal colour / morphology Colourless blocks Crystal size 0.632 x 0.395 x 0.134 mm3 θ range for data collection 2.979 to 28.704° Index ranges -6<=h<=5, -15<=k<=14, -33<=l<=35 Reflns collected / unique 9353 / 1664 [R(int) = 0.0502] Reflns observed [F>4σ (F)] 1612 Absorption correction Analytical Max. and min. transmission 0.739 and 0.346 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 1664 / 0 / 78 Goodness-of-fit on F2 1.341 Final R indices [F>4σ (F)] R1 = 0.0595, wR2 = 0.1169 R indices (all data) R1 = 0.0614, wR2 = 0.1177 Absolute structure parameter 0.004(10) Largest diff. peak, hole 0.871, -2.103 eÅ-3
278
Bond lengths / Å Bond angles / ° Se(1)-C(2)#1 1.984(7) Se(1)-C(2) 1.984(7) C(2)-C(4) 1.510(9) C(2)-C(3) 1.531(10) C(3)-C(3)#1 1.513(11) C(4)-C(5) 1.533(9) C(4)-C(9) 1.546(9) C(5)-C(6) 1.519(10) C(6)-C(7) 1.517(10) C(7)-C(8) 1.525(10) C(8)-C(9) 1.523(10)
C(2)#1-Se(1)-C(2) 91.7(4) C(4)-C(2)-C(3) 115.2(6) C(4)-C(2)-Se(1) 111.6(5) C(3)-C(2)-Se(1) 103.8(5) C(3)#1-C(3)-C(2) 109.8(6) C(2)-C(4)-C(5) 113.6(5) C(2)-C(4)-C(9) 110.5(5) C(5)-C(4)-C(9) 109.5(5) C(6)-C(5)-C(4) 112.2(6) C(7)-C(6)-C(5) 112.2(6) C(6)-C(7)-C(8) 111.0(6) C(9)-C(8)-C(7) 111.8(6) C(8)-C(9)-C(4) 112.2(6)
279
Crystal structure of
6-(p-tolyl)-6,7-dihydro-5H-dibenzo[c,e]selenepin-6-ium triflate
Formula C21H19Se, CF3O3S Formula weight 499.39 Temperature 173(2) K Crystal system Monoclinic Space group C2/c Unit cell dimensions a = 16.2065(7) Å α = 90° b = 13.7833(5) Å ß = 99.585(4)° c = 19.4913(7) Å γ = 90° Volume 4293.2(3) Å3
Z 8 Density (calculated) 1.545 g/cm3 Absorption coefficient 1.893 mm-1 F(000) 2016 Crystal colour / morphology Colourless blocky needles Crystal size 0.45 x 0.10 x 0.09 mm3 θ range for data collection 2.549 to 28.377° Index ranges -21<=h<=14, -18<=k<=11, -25<=l<=21 Reflns collected / unique 7732 / 4290 [R(int) = 0.0140] Reflns observed [F>4σ (F)] 3638 Absorption correction Analytical Max. and min. transmission 0.851 and 0.610 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4290 / 0 / 272 Goodness-of-fit on F2 1.043 Final R indices [F>4σ (F)] R1 = 0.0304, wR2 = 0.0724 R indices (all data) R1 = 0.0409, wR2 = 0.0777 Largest diff. peak, hole 0.929, -0.283 eÅ-3
280
Bond lengths / Å Bond angles / ° Se(1)-C(16) 1.917(3) Se(1)-C(2) 1.965(2) Se(1)-C(15) 1.976(2) C(2)-C(3) 1.500(3) C(3)-C(4) 1.384(4) C(3)-C(8) 1.405(3) C(4)-C(5) 1.381(4) C(5)-C(6) 1.382(4) C(6)-C(7) 1.378(4) C(7)-C(8) 1.392(4) C(8)-C(9) 1.481(4) C(9)-C(10) 1.392(3) C(9)-C(14) 1.405(3) C(10)-C(11) 1.376(4) C(11)-C(12) 1.375(4) C(12)-C(13) 1.387(4) C(13)-C(14) 1.383(4) C(14)-C(15) 1.489(3) C(16)-C(17) 1.386(3) C(16)-C(21) 1.389(3) C(17)-C(18) 1.374(4) C(18)-C(19) 1.387(3) C(19)-C(20) 1.387(4) C(19)-C(22) 1.500(4) C(20)-C(21) 1.382(4) S(30)-O(33) 1.428(2) S(30)-O(32) 1.4297(19) S(30)-O(31) 1.4315(19) S(30)-C(30) 1.809(3) C(30)-F(32) 1.319(3) C(30)-F(33) 1.324(3) C(30)-F(31) 1.330(3)
Se(1)-C(16) 1.917(3) Se(1)-C(2) 1.965(2) Se(1)-C(15) 1.976(2) C(2)-C(3) 1.500(3) C(3)-C(4) 1.384(4) C(3)-C(8) 1.405(3) C(4)-C(5) 1.381(4) C(5)-C(6) 1.382(4) C(6)-C(7) 1.378(4) C(7)-C(8) 1.392(4) C(8)-C(9) 1.481(4) C(9)-C(10) 1.392(3) C(9)-C(14) 1.405(3) C(10)-C(11) 1.376(4) C(11)-C(12) 1.375(4) C(12)-C(13) 1.387(4) C(13)-C(14) 1.383(4) C(14)-C(15) 1.489(3) C(16)-C(17) 1.386(3) C(16)-C(21) 1.389(3) C(17)-C(18) 1.374(4) C(18)-C(19) 1.387(3) C(19)-C(20) 1.387(4) C(19)-C(22) 1.500(4) C(20)-C(21) 1.382(4) S(30)-O(33) 1.428(2) S(30)-O(32) 1.4297(19) S(30)-O(31) 1.4315(19) S(30)-C(30) 1.809(3) C(30)-F(32) 1.319(3) C(30)-F(33) 1.324(3) C(30)-F(31) 1.330(3)
281
Crystal structure of
(E)-6-styryl-6,7-dihydro-5H-6λ4-dibenzo[c,e]selenepin-6-yl triflate – 508
Formula C22H19Se, CF3O3S Formula weight 511.40 Temperature 173(2) K Crystal system Monoclinic Space group P21/c Unit cell dimensions a = 12.6901(4) Å α = 90° b = 9.1311(3) Å ß = 102.350(3)° c = 18.9851(7) Å γ = 90° Volume 2148.99(13) Å3
Z 4 Density (calculated) 1.581 g/cm3 Absorption coefficient 1.893 mm-1 F(000) 1032 Crystal colour / morphology Colourless blocks Crystal size 0.44 x 0.37 x 0.22 mm3 θ range for data collection 2.771 to 28.197° Index ranges -9<=h<=16, -11<=k<=11, -25<=l<=23 Reflns collected / unique 7371 / 4276 [R(int) = 0.0223] Reflns observed [F>4σ (F)] 3472 Absorption correction Analytical Max. and min. transmission 0.762 and 0.606 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4276 / 0 / 280 Goodness-of-fit on F2 1.046 Final R indices [F>4σ (F)] R1 = 0.0351, wR2 = 0.0718 R indices (all data) R1 = 0.0513, wR2 = 0.0783 Largest diff. peak, hole 0.424, -0.442 eÅ-3
282
Bond lengths / Å Bond angles / ° Se(1)-C(16) 1.904(2) Se(1)-C(2) 1.969(2) Se(1)-C(15) 1.970(2) C(2)-C(3) 1.504(3) C(3)-C(8) 1.398(4) C(3)-C(4) 1.398(4) C(4)-C(5) 1.383(4) C(5)-C(6) 1.377(4) C(6)-C(7) 1.383(4) C(7)-C(8) 1.394(3) C(8)-C(9) 1.492(3) C(9)-C(10) 1.390(4) C(9)-C(14) 1.406(3) C(10)-C(11) 1.386(4) C(11)-C(12) 1.385(4) C(12)-C(13) 1.377(4) C(13)-C(14) 1.389(3) C(14)-C(15) 1.490(3) C(16)-C(17) 1.321(3) C(17)-C(18) 1.466(4) C(18)-C(19) 1.390(4) C(18)-C(23) 1.394(4) C(19)-C(20) 1.375(4) C(20)-C(21) 1.384(4) C(21)-C(22) 1.370(4) C(22)-C(23) 1.384(4) S(30)-O(33) 1.431(2) S(30)-O(31) 1.4329(19) S(30)-O(32) 1.438(2) S(30)-C(30) 1.809(4) C(30)-F(31) 1.323(4) C(30)-F(33) 1.330(3) C(30)-F(32) 1.330(4)
C(16)-Se(1)-C(2) 97.88(11) C(16)-Se(1)-C(15) 97.96(11) C(2)-Se(1)-C(15) 95.17(10) C(3)-C(2)-Se(1) 111.53(17) C(8)-C(3)-C(4) 119.4(2) C(8)-C(3)-C(2) 120.8(2) C(4)-C(3)-C(2) 119.8(2) C(5)-C(4)-C(3) 120.6(3) C(6)-C(5)-C(4) 119.9(3) C(5)-C(6)-C(7) 120.1(3) C(6)-C(7)-C(8) 120.8(3) C(7)-C(8)-C(3) 118.9(2) C(7)-C(8)-C(9) 120.0(2) C(3)-C(8)-C(9) 121.1(2) C(10)-C(9)-C(14) 119.0(2) C(10)-C(9)-C(8) 120.8(2) C(14)-C(9)-C(8) 120.2(2) C(11)-C(10)-C(9) 120.7(3) C(12)-C(11)-C(10) 119.9(3) C(13)-C(12)-C(11) 120.0(3) C(12)-C(13)-C(14) 120.8(2) C(13)-C(14)-C(9) 119.5(2) C(13)-C(14)-C(15) 119.6(2) C(9)-C(14)-C(15) 120.8(2) C(14)-C(15)-Se(1) 113.41(17) C(17)-C(16)-Se(1) 121.0(2) C(16)-C(17)-C(18) 125.8(2) C(19)-C(18)-C(23) 118.2(3) C(19)-C(18)-C(17) 122.2(2) C(23)-C(18)-C(17) 119.5(2) C(20)-C(19)-C(18) 121.0(3) C(19)-C(20)-C(21) 120.1(3) C(22)-C(21)-C(20) 119.9(3) C(21)-C(22)-C(23) 120.3(3) C(22)-C(23)-C(18) 120.5(3) O(33)-S(30)-O(31) 115.50(13) O(33)-S(30)-O(32) 114.82(14) O(31)-S(30)-O(32) 114.53(13) O(33)-S(30)-C(30) 102.98(15) O(31)-S(30)-C(30) 102.25(14) O(32)-S(30)-C(30) 104.37(15) F(31)-C(30)-F(33) 107.4(3) F(31)-C(30)-F(32) 107.8(3) F(33)-C(30)-F(32) 106.5(3) F(31)-C(30)-S(30) 111.7(3) F(33)-C(30)-S(30) 112.0(2) F(32)-C(30)-S(30) 111.2(2)
283
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