Applications of Boronic Acids in Organic Synthesis

A dissertation presented by

Pavel Starkov

in partial fulfilment of the requirements for the award of the degree of

DOCTOR OF PHILOSOPHY

at

UNIVERSITY COLLEGE LONDON

Department of Chemistry

Christopher Ingold Laboratories

University College London

20 Gordon Street

WC1H 0AJ London

ii

Declaration

This dissertation is the result of my own work. Where information has been derived from

other sources it has been clearly indicated so and acknowledged accordingly.

/Pavel Starkov/

iii

Abstract

This thesis describes progress on the application of boronic acids and borate esters as catalysts

and reagents in synthetic organic synthesis, focusing on two areas: one-pot enolate

formation/aldol reactions and amide bond formation.

Chapter 1 introduces the reader to boronic acids and derivatives thereof, their methods of

preparation and their use in synthetic organic chemistry as reactants, reagents and catalysts.

Chapter 2 covers current chemical methods and cellular alternatives for amide bond

formation. Here, we also discuss our use of boron reagents for the activation of carboxylic

acids as well as amides.

Chapter 3 introduces a new concept in catalytic aldol reactions, i.e. an alternative strategy to

access boron enolates in situ. The work covers successful demonstration of the feasibility of

such an approach on an intramolecular system. A novel variation of aerobic Chan–Evans–

Lam coupling, an intramolecular coupling of an aliphatic alcohol with a boronic acid using

catalytic copper, is also introduced

Chapter 4 builds on our observations on gold catalysis and especially that in relation to

electrophilic halogenations.

Chapter 5 contains full details of the experimental procedures.

iv

Contents

Declaration ii

Abstract iii

Contents iv

Abbreviations vi

Acknowledgements vii

1 Boronic Acids in Organic Synthesis 1

1.1 Introduction 2

1.2 Preparation 5

1.2.1 Arylboronic Acids 5

1.2.2 Other Boronic Acids 10

1.3 Boronic Acids as Reactants 12

1.3.1 Transition Metal Catalysed Reactions 12

1.3.2 Chan–Evans–Lam Coupling 15

1.3.3 Converting Boronic Acids 18

1.4 Boronic Acids as Reagents and Catalysts 18

1.4.1 Activation of Carboxylic Acids 21

1.5 Summary 27

2 Development of Boron Based Reagents and Catalysts for 30

Activation of Carboxylic Acids and Amides

2.1 Amide Bond Formation: An Overview 31

2.1.1 Methods for Amide Bond Formation 33

2.1.1.2 Activation of Carboxylic Acids 34

2.1.1.3 Alternative Methods 37

2.1.1.4 Catalytic Methods 38

2.1.1.5 Emerging Methods 38

2.1.2 Amide Bond Formation in Nature 44

2.1.2.1 Ribosomal Peptide Bond Formation 46

2.1.2.2 Nonribosomal Peptide Synthetases 47

2.1.2.3 Acyl Transferases 48

2.1.2.4 Lipases 50

v

2.2 Results and Discussion 53

2.2.1 Introduction 53

2.2.2 Aims and Objectives 55

2.2.3 Synthesis of Boronic Acids 57

2.2.3.1 Synthesis of (1-Hydroxy-1H-benzo[d][1,2,3]triazol-7-yl)boronic Acid 57

2.2.3.2 Synthesis of “Sulfur-Armed” Boronic Acid 63

2.2.4 Evaluation of Boronic Acids and Borates for Catalytic

Amide Bond Formation 64

2.2.5 Borates as a Novel Class of Coupling Reagents for

Amide Bond Formation 74

2.2.6 Tris(2,2,2-trifluoroethyl) Borate as a Reagent

for the Activation of Primary Amides 78

2.2.7 Mechanistic Considerations 80

2.2.8 Conclusions and Outlook 82

3 Gold-Catalysed Boron Enolate Formation 87

3.1 Background 89

3.2 Aims and Objectives 95

3.3 Results and Discussions 97

3.3.1 Gold-Catalysed Boron Enolate Formation 97

3.3.2 One-Pot Boron Enolate Formation/Aldol Reaction 100

3.3.3 Elaboration of Aldol Products:

Oxidation, Suzuki, and Chan–Evans–Lam 112

3.3.4 Miscellaneous 116

3.4 Summary and Outlook 118

4 Observations on the Role of Cationic Gold and

Brønsted Acids in Electrophilic Halogenation 122

4.1 Results and Discussion 123

4.2 Summary and Outlook 133

5 Experimental 134

5.1 General 135

5.2 Procedures for Chapter 2 136

5.2.1 Synthesis of Boron and Silicone Based Reagents 136

5.2.2 Direct Carboxamidation 147

5.2.3 Transamidations of Primary Amides 154

vi

5.3 Procedures for Chapter 3 156

5.3.1 Synthesis of ortho-Alkynylphenylboronic Acids 156

5.3.2 Boron Enolate Formation 161

5.3.3 One-Pot Boron Enolate Formation/Aldol Reaction 164

5.3.4 Aldol/Oxidation 165

5.3.5 Aldol/Suzuki–Miyaura Coupling 168

5.3.6 Aldol/Intramolecular Chan–Evans–Lam Coupling 170

5.3.7 Aldol/Protodeboronation 172

5.4 Procedures for Chapter 4 173

References 175

Appendix 196

vii

Abbreviations

General

ACS American Chemical Society

aq aqueous

bp boiling point

cat catalytic

conc concentrated

conv conversion

DFT density functional theory

DMG directed metalation group

DoE design of experiments

ee enantiomeric excess

EI electron ionisation

equiv equivalent

ESI electrospray ionisation

EWG electron withdrawing group

h hour(s)

HMBC heteronuclear multiple bond connectivity

HMQC heteronuclear multiple quantum connectivity

HRMS high resolution mass spectrometry

IR infrared spectrometry

J coupling constant

LA Lewis acid

lit literature value

LUMO lowest unoccupied orbital

m meta

M+ parent molecular ion

min minute(s)

mp melting point

MS mass spectrometry

MS molecular sieves

MW microwave

NMR nuclear magnetic resonance

viii

NRPS nonribosomal peptide synthetase

o ortho

p para

PNA peptide nucleic acid

ppm part(s) per million

ref reference

rds rate determining step

RT room temperature

sat saturated

tRNA transport ribonucleic acid

quant quantitative

UV ultraviolet

Reagents, ligands and solvents

acac acetylacetonate

AIBN 2,2’-azobis(isobutyronitrile)

BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl.

bmim 1-butyl-3-methylimidazolium

BOP (benzotriazol-1-yloxy)tris(dimethylamino) hexafluorophosphate

BPO benzoyl peroxide.

BQ 1,4-benzoquinone

CDI carbonyldiimidazole

cod 1,5-cyclooctadiene

CuMeSal copper(I) 3-methylsalicylate

CuTC copper(I) thiophen-2-carboxylate

CYC cyanuric chloride

dba dibenzylideneacetone

dtby di-tert-butylbipyridine

DCC dicyclohexylcarbodiimide

DCE 1,2-dichloroethane

DCB o-dichlorobenzene

DCM dichloromethane

DHA dihydroxyacetone

DHAP dihydroxyacetone phosphate

DIC diisopropylcarbodiimide

DIPEA N,N-diisopropylethylamine

DMAD dimethyl acetylenedicarboxylate

ix

DMAP 4-(N,N-dimethylamino)pyridine

DMSO dimethylsulfoxide

DO dioxane

dppe 1,1-bis(diphenylphosphino)ethane

dppf 1,1'-bis(diphenylphosphino)ferrocene

dppm 1,1-bis(diphenylphosphino)methane

dppp 1,3-bis(diphenylphosphino)propane

dtby di-tert-butylbipyridine

DTNO di-tert-butyl nitroxide

EDCl [3-(dimethylamino)propyl]ethylcarbodiimide hydrochloride

HATU O-(7-azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

HBTU 1-[bis(dimethylamino)methylene]-1H-benzotriazolium hexafluorophosphate

HEH Hantzsch ester

HOAt 1-hydroxy-7-azabenzo[d][1,2,3]triazole

HOBt 1-hydroxybenzo[d][1,2,3]triazole

HOI N-hydroxyindolin-2-one

Im imidazole

IMes 1,3-bis(2,4,6-trimethylphenyl)-imidazol-2-ylidene

iPP2BH di(isopropylprenyl)borane

LHMDS lithium hexamethyldisilazide

LTMP lithium 2,2,6,6-tetramethylpiperidide

lut lutidine

MIDA N-methyliminodiacetic acid

MCPBA m-chloroperoxybenzoic acid

MTBE methyl tert-butyl ether

PE petroleum ether (boiling range 60–80 °C)

phen 1,10-phenanthroline

PhMe toluene

Pro proline

PTSA p-toluenesulfonic acid

PyBOP (benzotriazol-1-yloxy)tris(pyrrolidinophosphonium) hexafluorophosphate

nbd norbornadiene

NBP N-butyl-2-pyrrolidinone

NBS N-bromosuccinimide

NHC N-heterocyclic carbene

NMO N-methylmorpholine-N-oxide

NMP N-methyl-2-pyrrolidinone

x

PFP pentafluorophenyl

PNO pyridine N-oxide

PNP p-nitrophenol

SIPr N,N'-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol)-2-ylidene

TCP 2,4,6-trichlorophenyl

TBD 1,5,7- triazabicyclo[4.4.0]dec-5-ene

TEA triethylamine

TEMPO 2,2,6,6-tetramethylpiperidine-1-oxyl

TFA trifluoroacetic acid

THF tetrahydrofuran

Substituents

Ac acetyl

All allyl

An anisyl, 4-methoxyphenyl

Ar aryl

Bn benzyl

Boc tert-butoxycarbonyl

Bu n-butyl

iBu isobutyl

sBu sec-butyl

tBu tert-butyl

Bz benzoyl

cat catecholate

Cbz benzyloxycarbonyl

Cp cyclopentadienyl

Cy cyclohexyl

Cyp cyclopentyl

dan derivative of 1,8-diaminonaphthalene

Et ethyl

Fur furanyl

Hal halide

Me methyl

Mes mesityl, 2,4,6-trimethylphenyl

MOM methoxymethyl

neop neopentandiolate

OTf triflate

xi

PFP pentafluorophenyl

Ph phenyl

pin pinacolato

iPr isopropyl

pza 2-pyrazol-5-ylanilinyl

Sia siamyl, sec-isoamyl,

TCP 2,4,5-trichlorophenyl

Tf triflyl, trifluoromethanesulfonyl

Tol tolyl

Tr trityl, triphenylmethyl

Ts tosyl, p-toluenesulfonyl

xii

Acknowledgements

I would like to thank Dr Tom Sheppard, my PhD thesis supervisor, for his time, patience and

extensive advice.

Also, Dr Abil Aliev and Dr Lisa Harris for help with NMR and MS, respectively.

I thank friends that from time to time have encouraged and/or questioned me, and were

always there with at least a helpful suggestion or a glass of wine, a pint of beer or a shot:

Mikk, Anton, Nadja, Uno, Cindy and Armando, Sonya, Olya, John, Lena, Selene, Albin,

Boaz, Lynsey, Karina, Jon, Sasha, James, Victoria, Lizzie. Also, the guys in the Sheppard lab

(Oz, Fil, Martin, Sam, Matt and the summer students) and the Motherwell group (Matt, Josie,

Helen, Sandra, Chi, Yumi). Last and definitely not least, my family.

Financial support from EPSRC (EP/E052789/1), Estonian Ministry of Education and

Research and Archimedes Foundation is acknowledged.

xiii

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jääb sul tuge liiga vähe,

kui sa kõik tõkked teelt ei talla

ja mööda enesest ei lähe.

Kui suur on korraga su isu!

Hing, ära ohus karda hukku,

vaid senisest end lahti kisu

ja keera vanad uksed lukku!

Sind ümbritsevad jäised tuuled,

ööst kerkib tühi mägiahel.

Sa aimad sügavust ja kuuled

metsloomi kaljuseinte vahel.

Kui sa nüüd minna julgeks! Sillaks

su ees siis kuristikud kaanduks,

hall kivi raskeid vilju pillaks

ja kiskjad alandlikult taanduks.

Betti Alver. "Ekstaas"

v

Chapter 1

Chapter 1

2

1 Boronic Acids and Other Boron-Centred Reagents in

Organic Synthesis

1.1 Introduction

The first boronic acid, ethylboronic acid, was discovered back in 1860,[1]

but it took a long

time for boronic acids to become widely applied in either industrial or academic settings. The

seminal work by Negishi[2]

and Suzuki[3]

on palladium-catalysed arylation of aryl halides[4]

with lithium alkynyl(tributyl)borate 1 and alkenylboronic acid esters 2 (Scheme 1) led to a

substantial increase in interest towards boronic acids and organoboron compounds in general.

Scheme 1. The first two examples[2,3]

of Suzuki–Miyaura coupling. Sia = siamyl, sec-isoamyl, cat =

catecholate.[4]

Structurally, boronic acids [RB(OH)2] contain one carbon–boron bond along with two

hydroxyl groups on boron (Figure 1).[5,6]

The carbon substituents can be greatly varied to

include aryl, alkenyl, alkyl and alkynyl moieties. Boronic acids often undergo trimerisation to

boroxines 7 and water. Other boron based compounds include triorganoboranes [R3B], borinic

acids [R2BOH], and borate esters [B(OR)3], the derivatives of boric acid [B(OH)3].

On condensation of boronic acids with diols, diamines, diacids and hydroxyacids

corresponding boronic acid esters/amides are formed (Figure 2). This conversion is often used

to increase the stability and modify the reactivity of the acids (Scheme 2). For instance,

Suginome demonstrated the use of differentially protected 1-alkene-1,2-diboronic acid

derivatives (Scheme 2a).[7]

The same group reported 2-pyrazol-5-ylaniline as a

protecting/ortho-directing group for ruthenium-catalysed C–H activation/silylation of boronic

Chapter 1

3

Figure 1. (a) Organoboron compounds: triorganoboranes 3, borinic acids 4, boronic acids 5 and borate

esters 6. (b) Boroxine 7 formation from boronic acids.

Figure 2. Boronic acid derivatives. pin = pinacolate, cat = catecholate, neop = neopentandiolate, dan =

derivative of dan 1,8-diaminonaphthalene, pza = 2-pyrazol-5-ylaniline, MIDA = N-methyliminodiacetic

acid.

acids 9 (Scheme 2b).[8]

In recent work by Dennis Hall, diaminonaphthalene-protection was

crucial to achieve high enantioselectivities in conjugate addition of Grignard reagents to β-

boronyl unsaturated (thio)esters 10.[9]

Potassium organofluoroborates[10]

are a compelling alternative to boronic acids and esters

(Scheme 3a). They show increased stability, greater efficiency in Pd-catalysed cross-

couplings, and often do not require additional base and/or ligand. For instance,

alkynyltrifluoroborates were recently demonstated to undergo copper-catalysed coupling with

amides at ambient temperature in the absence of base.[11]

However, due to fluorine’s high

electronegativity, nucleophilicity of the carbon adjacent to boron is decreased. To solve this,

sodium trihydroxyborates [R(OH)3Na] and cyclic triolborates [RB(O3R’)Li, where triol is 2-

(hydroxymethyl)-2-methylpropane-1,3-diol] were prepared by Cammidge[12]

and Miyaura,[13]

respectively. For example, a cyclic triolborate of 2-pyridineboronic acid 11, which as the free

Chapter 1

4

Scheme 2. Applications of protected boronic acids. cod = 1,5-cyclooctadiene, dppf = 1,1'-

bis(diphenylphosphino)ferrocene, BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl.

Scheme 3. Applications of (a) trifluoroborates,[11]

(b) cyclic triolborates[13b]

and (c) MIDA boronates.[14]

Chapter 1

5

acid is sensitive to protodeboronation, successfully underwent C–N coupling with morpholine

(Scheme 3b).[13]

Martin Burke’s group developed N-methyliminodiacetic acid (MIDA) based protection of

boronic acids.[14]

This allowed them to carry out transformations that otherwise were

incompatible with boronic acids, including selective cross-coupling of haloaryl [14a]

and

haloalkenyl[14b]

MIDA boronates 12 with boronic acids (Scheme 3c). This methodology was

extended to the synthesis of natural products[14a-c,e]

and used to improve the reactivity profiles

of less stable 2-heteroarylboronic acids.[14d]

1.2 Preparation

In the past decade, significant advances have been made in the synthesis of boronic acids.

These include Hosomi–Miyaura and Hartwig borylations (discussed below). These

advancements allow more straightforward synthesis of functionalised boronic acids. While

most of examples mentioned below are for the generation of arylboronic acids many methods

may well be extended to alkenyl-, alkynyl- and, to a lesser extent, alkylboronic acids.

1.2.1 Arylboronic Acids

Traditionally, arylboronic acids are prepared by borylation of metalated species such as

organolithium[15]

and Grignard reagents 13 (Scheme 4).[16]

Both of these reagents can be

generated in situ by halogen–metal exchange[17]

or metal insertion.[18]

Where an arene of

interest bears a directing metalation group (DMG), organolithiums 14 can be accessed by

directed ortho-lithiation.[19]

Scheme 4. Synthesis of arylboronic acids using main group metals via (a) halogen–metal exchange and

metal insertion, and (b) directed ortho-lithiation.

Chapter 1

6

Another popular method employs palladium catalysis (Scheme 5). In Hosomi–Miyaura

borylation,[20]

bis(pinacolato)diboron (B2pin2) is cross-coupled with aryl halides and

pseudohalides 15 (Table 1, entries 1–6).[21]

The borylation of the latter substrates is often

referred to as Miyaura–Masuda borylation. The choice of an appropriate base (e.g. KOAc or

PhOK) and a ligand for Pd (usually, dppf 16) plays a crucial role in achieving good

conversions. Notably, a few examples employing aryl halides as substrates have also been

reported.[22–24]

Miyaura used Pd(dba)2 as catalyst source along with trialkylphosphine ligand

(Cy3P).[22]

Fürstner exploited an NHC ligand 17 and Pd(OAc)2 as catalyst precursor under

both thermal and microwave conditions.[23]

Finally, Buchwald and co-workers employed

dialkylphosphinobiphenyl ligand 18 to give good yields with aryl chlorides at 110 ºC.[24]

Switching to a more electron-rich ligand allowed them to conduct Miyaura borylations at

ambient temperature.

Scheme 5. Synthesis of arylboronic acids using palladium-catalysed cross-coupling.

Alternatively, cheaper sources of boron such as pinacolborane (HBpin)[25–31]

and

catecholborane (HBcat)[26]

are used instead of bis(pinacolato)diboron (Table 1, entries 7–12).

In these instances a tertiary amine such as Et3N is required as a base,[25b]

while reactions

conducted in ionic liquids can proceed in under an hour.[30]

Murata et al. showed that

bisphosphine 19 can serve as an efficient ligand for Pd-catalysed borylation of iodides,

bromides and notably, electron-rich chlorides.[28]

Furthermore, for both diboron and borane

cases, palladium can be effectively substituted with copper.[29,32]

Nickel is yet another transition metal that efficiently catalyses borylation of aryl halides with

HBpin and related compounds. Back in 2000, Tour employed nickel catalysts, Ni(dppe)Cl2

and Ni(dppp)Cl2, to access di- and triboronylarenes in reasonable yields (Scheme 6).[33]

In

2007, Mindiola showed that the pincer-liganded boryl–nickel complex 20, (PNP)Ni(Bcat),

reacts with bromobenzene to give the corresponding B–C coupled product 21 (Scheme 7).[34]

They were, however, unable to establish a catalytic procedure via in situ regeneration of

nickel hydride precursor. Later, Percec neopentylglycolborylated aryl halides (X = I, Br) with

a corresponding borane (HBneop), which was generated directly from BH3·DMS and

neopentyl glycol prior to the coupling step (Scheme 8).[35]

The transformation was catalysed

by Ni complexes initially reported by Tour in the presence of equimolar amounts of ligand.

Chapter 1

7

Table 1. Palladium and copper-catalysed borylation of aryl halides and pseudohalides with diboron and

borane reagents. bmim = 1-butyl-3-methyl-imidazolium, cat = catheholate, DO =dioxane, dba =

dibenzylideneacetone, neop = neopentandiolate, pin = pinacolate, TEA = triethylamine.

entry X boron source (equiv)

metal source and ligand

conditions ref

1 I, Br B2pin2 (1.1) Pd(dppf)Cl2

3 mol% [Pd], 3 eq KOAc, DO, 80 ºC

[21a]

2 OTf B2pin2 (1.1) Pd(dppf)Cl2 dppf

3 mol% [Pd], 3 mol% ligand, 3 eq KOAc, DO, 80ºC

[21b]

3

Cl, Br, I, OTf B2pin2 (1.1) Pd(dba)2

Cy3P 3 mol% [Pd], 3.3-7.2 mol% ligand,

1.5 eq KOAc, DO, 80 ºC [22]

4 Cl B2pin2 (1.16) Pd(OAc)2

SIPr·HCl (17) thermal: 3 mol% [Pd], 6 mol% ligand, 2.5 equiv KOAc, THF, rfx; MW: 2× 3 mol% [Pd], 6 mol% ligand, 2.5 equiv

KOAc, THF, 110 ºC, 2×10 min

[23]

5 Cl B2pin2 (1.2-3.0) Pd2dba3

18a and 18b 0.1–4.0 mol% [Pd], 0.2–8.0 mol%

ligand, 3 equiv KOAc or K3PO4, DO, 110 ºC with 18a or RT with 18b

[24]

6 I, Br B2pin2 or B2(neop)2 (1.5)

CuI Bu3P

10 mol% [Cu], 13 mol% ligand, 1.5 KO

tBu, THF, RT

[32]

7 Br, I, OTf HBpin or HBcat (1.5)

Pd(dppf)Cl2 3 mol% [Pd], 3 equiv TEA, DO, 80-110 ºC

[25a,26]

8 I, Br HBpin (7.0) Pd(OAc)2

18c or Pd(dppf)Cl2

5 mol% [Pd], 20 mol% ligand, 3 equiv TEA, DO, 80-100 ºC

[31]

9 Cl, Br, I HBpin (2.0) Pd(dba)2 19

5 mol% [Pd], 5 mol% ligand, 3 equiv TEA, DO, 80-100ºC

[28]

10 I, Br HBpin (1.3) Pd(dppf)Cl2 3 mol% [Pd], 3 equiv TEA, [bmim][BF4], 100 ºC

[30]

11 Cl, Br, I HBpin (1.5)

PdCl2(MeCN)2

18b 0.1–4 mol% [Pd], 0.4–16 mol%

ligand, 3 equiv TEA, DO, 110 ºC [27]

12 I HBpin (1.5) CuI 10 mol% [Cu], 1.5 equiv TEA, THF, RT

[29]

Chapter 1

8

Scheme 6. First examples of Ni-catalysed borylation of aryl halides.[33]

dppp = 1,3-bis(diphenyl-

phosphino)propane

Scheme 7. Synthesis of the first nickel-boryl complex, B–C coupling on nickel-boryl complex (neat PhBr,

120ºC, 18 h, 68%) and attempted catalytic cycle formation with a reducing agent (NaBH4).[34]

Scheme 8. Nickel-catalysed borylations. (a) Borane reagent, neopentylglycolborane, was generated

prior to (b) C–B coupling of aryl bromides, chlorides, and pseudo halides.[35–37]

DMS =dimethylsulfide.

Chapter 1

9

This methodology was then extended to aryl chlorides[36]

and pseudohalides[37]

by applying

mixed ligands. Addition of metallic zinc led to drastic improvements in the case of mesylates

and tosylates.[37]

While in every example above, aryl halides and pseudohalides were utilised as starting

materials, it is also possible to use other aryl donors. Metal-free borylation of arylamines 22

with tert-butyl nitrite and B2pin2 was recently developed (Scheme 9).[38]

Alternatively, several

strategies provide ways to derivatise existing boronic acids.[7, 9,14,39]

For example, by silver-

mediated ortho-bromination and iodination (Scheme 10)[39]

or via cycloaddition of

alkynylboronic esters with a diene (Scheme 11).[40]

Scheme 9. Metal-free synthesis of arylboronates.[38]

BPO = benzoyl peroxide.

Scheme 10. Silver-mediated halogenations of boronic acids.[39]

Scheme 11. Synthesis of pyrazole boronic esters from sydnones.[40]

DCB = o-dichlorobenzene.

A direct approach to access arylboronates from arenes, alkenes and alkanes via C–H

activation/functionalisation is known as Smith–Miyaura–Hartwig borylation.[41]

Hartwig led

the field by introducing iron, rhenium, tungsten and ruthenium based catalysts for catalytic

photoactivated, and later thermal, C–H derivatization of alkanes with B2pin2 (Scheme

12).[42,43]

Later, Smith developed a highly selective “solventless” iridium-based process for

direct synthesis of arylboronates (Scheme 13).[44]

Miyaura used 3 mol% Pd/C (10 mol%

loading) to C–H activate/borylate benzylic positions (Scheme 14).[45]

Within the recent

decade, many other improvements (importantly the introduction of bipyridine ligands)[46]

have

been

Chapter 1

10

Scheme 12. First thermal examples of alkane C-H activation/borylation.[43]

Scheme 13. Iridium-catalysed solventless direct borylation of arenes.[44]

Scheme 14. Pd-catalysed C-H activation/borylation of benzylic positions.[45]

explored to control and enhance both selectivity and reactivity of this transformation. These

have also been documented in a thorough review.[41]

1.2.2 Other Boronic Acids

Boronic acids carrying moieties other than aryl groups, are often synthesised in similar ways

to those described in the section above. For instance, alkenylboronic acids may be accessed

from corresponding alkenyl bromides and iodides by halogen/metal exchange with sBuLi and

borylated with trialkylborate.[46]

Examples of Hosomi–Miyaura Pd-catalysed borylations

include reactions using alkenyl triflates[21c,48,49]

and phosphonates[49]

as well as benzyl

halides[50]

as substrates. Recently, Duñach reported magnesium-catalysed borylation of

benzylic halides with pinacolborane (Scheme 15).[51]

Chapter 1

11

Scheme 15. Magnesium-catalysed borylation of benzyl halides.[51]

Alkynylboronic acids are less stable and usually only their corresponding esters can be

obtained. They are synthesised by deprotonation and subsequent borylation with borate

esters.[52]

Addition of B–H across multiple bonds was first noted by Brown in 1956 (Scheme 16).[53]

It

represents yet another strategy to access alkenyl and alkylboronic acids. The process with

terminal alkynes is especially effective and, depending on the choice of conditions, both trans

and cis-alkenylboronic acids/esters can be obtained. In case of non-catalysed cis-

hydroborylation, bulky dialkylboranes like 9-BBN[54]

, dicyclohexylborane[55]

and

di(isopropylprenyl)borane (iPP2BH)[56]

are used to avoid multiple addition of borane to the

alkyne. Subsequent mild oxidation with trimethylamine oxide[57]

gives the boronic acid that is

usually esterified with a diol to give a more stable alkenylboronate. Often, iPP2BH is used as

a milder alternative. In that case, acetaldehyde can be used as an oxidant.[56]

Alkenylboronic

esters can be accessed directly using HBpin[58]

and HBcat[59]

to provide the boronic esters

under thermal conditions. To accelerate this process, HZrCp2Cl,[60]

Cp2Ti(CO)2,[61]

Rh(CO)(PPh3)2Cl,[62]

Rh(PPh3)3Cl,[63]

and CpNi(PPh3)Cl[62]

as well many other early and late

transition metals were employed.[64]

Scheme 16. Hydroboration of alkenes and alkynes.[64]

Notable is Suginome’s nickel-catalysed addition of alkynylborones across carbon–carbon

triple bonds (Scheme 17).[65]

This was achieved with pronounced regioselectivities to give

predominantly a cis-addition product 23.

Chapter 1

12

Scheme 17. Ni-catalysed regioselective cis-addition of alkynylboranes to alkynes.[65]

Alkylboronic acids and esters are used to a lesser extent than their alkenyl and aryl

equivalents. This is due to their decreased shelf-stability and the strong tendency of

alkylmetal species to undergo β-hydride elimination in the cross-coupling reactions.[66]

Nevertheless, such derivatives can be accessed via hydroboration of alkenes,[64]

borylation of

organolithium and organomagnesium reagents with borate esters,[67]

and Pd[68]

and Rh[69]

-

catalysed hydrogenation of alkenylboronic acids.

1.3 Boronic Acids as Reactants

Traditionally, the synthetic value of boronic acid derivatives as reactants is demonstrated by

numerous examples of transition-metal catalysed processes. This is due to (a) the relative ease

of the transmetalation step to a variety of metals (Pd, Cu, Hg, Pb, Ir, Co, Zn, Fe, Cu, Au),[5]

(b) greater atom-economy of boronic acids in comparison to other organometallics (c.f.

organobismuthanes[70,71]

and organostibanes[72]

), and (c) their low toxicity and increased

stability (c.f. organostibanes and organoplumbanes[71]

).

1.3.1 Transition Metal Catalysed Reactions

In cross-coupling reactions, two reactants are combined to make a product. The “coupling

portfolio” of boronic acids caters a wide variety of chemistries, and we will briefly discuss

most interesting examples below.

Palladium-catalysed Suzuki–Miyaura coupling was one the first major applications of boronic

acids and it is perhaps the most widely used today.[4]

In this reaction, a boronic acid is coupled

with a halide or pseudohalide to give a biaryl. In 2005, Buchwald reported a highly efficient

class of phosphorus-based bulky palladium ligands 18 for this transformation, efficient

enough to catalyse coupling between unactivated aryl bromides and chlorides with

arylboronic acids (Scheme 18)[73]

Chapter 1

13

Scheme 18. Buchwald’s SPhos ligand 18b for the Suzuki–Miyaura reaction.[73]

Another popular transformation involving boronic acids is their conjugative 1,4-addition to

enones, developed by Hayashi and Miyaura.[74]

For this process, rhodium is often the

preferred catalyst. In conjunction with a chiral ligand (e.g. olefin, phosphine, or

phosphoramidite) products with high enantioselectivities are obtained (Scheme 19).[75]

Scheme 19. (a) First rhodium-catalysed asymmetric conjugate addition of boronic acids to enones[76]

and (b) its application in a tandem intramolecular 1,4-addition–aldol cyclisation process.[77]

acac =

acetylacetonate.

Also of note is the nickel-catalysed arylation of aryl[78]

and alkenyl[79]

methyl ethers 24

reported by Chatani (Scheme 20).

Scheme 20. Ni-catalysed cross-coupling of (a) aryl and (b) alkenyl methyl ethers with arylboronic

esters.[78,79]

Arylboronic acids are useful partners in the Liebeskind–Srogl ketone synthesis (Scheme 21).

Notably, unlike Suzuki–Miyaura coupling, this transformation does not require the presence

of a base. It has been applied in the total synthesis of litseaverticillol B[80]

and (-)-D-erythro-

Chapter 1

14

sphingosine.[81]

The first generation coupling system was catalysed by Pd(0) and mediated by

copper(I) via C–S addition to Pd(0), transmetallation of an arylcopper(I) species (generated in

situ from the boronic acid) and reductive elimination.[82]

The second generation system is

based on aerobic copper(I) catalysis, however, use of a sacrificial equivalent of boronic acid

and a specifically funtionalised thiol ester is required.[83]

Scheme 21. (a) First[82]

and (b) second[83]

generation Liebeskind–Srogl coupling reactions. (c) Two

natural products, for the synthesis of which, Liebeskind-Srogl coupling was employed.[80,81]

CuTC =

copper(I) thiophen-2-carboxylate. CuMeSal = copper(I) 3-methylsalicylate.

In the recent years, a number of oxidative coupling reactions were developed, where boronic

acids or esters act as aryl donors (Scheme 22). Yu showed palladium(II/IV)-catalysed direct

arylation of sp2 and sp

3 C–H bonds in simple carboxylic acids.

[84] Zhang found that in the

presence of a gold catalyst and Selectfluor®

, propargylic acetates not only rearrange to give

enones but the intermediate vinyl gold species can be trapped and arylated with arylboronic

acids to give 2-arylenones 24 .[85]

Later, using analogous conditions but a different gold

source, Toste reported three component oxyarylation of alkenes.[86]

Recently, Baran

demonstrated Ag-catalysed direct arylations of heteroarenes, which proceed at ambient

temperature with persulfate as a terminal oxidant.[87]

Chapter 1

15

Scheme 22. Boronic acids in oxidative couplings: (a) Directed Pd-catalysed C–H activation/arylation of

carboxylic acids (10 mol% Pd(OAc)2, 1 equiv PhBneop, 0.5 equiv BQ, 1 equiv Ag2CO3, tBuOH, 120 ºC,

3 h, 63%); (b) Au-catalysed cross-coupling (5 mol% Ph3PAuCl, 4 equiv ArB(OH)2, 2 equiv Selectfluor®,

MeCN/H2O 20:1, 80 °C, 30 min, 68%); (c) Au-catalysed three component reaction (5 mol%

dppm(AuBr)2, 2 equiv PhB(OH)2, 2 equiv Selectfluor®, MeCN:ROH 9:1, 50 ºC, 14 h, 66%); (d) Ag-

catalysed arylation of pyridine (1.5 equiv PhB(OH)2, 20 mol% AgNO3, 3 equiv K2S2O8, 1 equiv TFA, 23

ºC, 12 h, 80%). BQ = 1,4-benzoquinone, dppm = 1,1-bis(diphenylphosphino)methane. TFA =

trifluoroacetic acid

1.3.2 Chan–Evans– Lam Coupling

Apart from carbon–carbon bond forming reactions, boronic acids also participate in carbon–

heteroatom bond construction, where nitrogen, oxygen, and less frequently sulphur,[88]

can act

undergo arylation. The first examples of such copper-mediated processes (now known as

Chan–Evans–Lam or Chan–Lam coupling[89]

) where reported back in 1998 in three back-to-

back communications (Scheme 23).[90]

At that time, palladium ligands were not sophisticated

enough to offer a sound alternative for the synthesis of diaryl ethers. Another reason why this

reaction became popular was an easy access to N-arylated heterocycles.[89]

Chapter 1

16

Scheme 23. (a) Chan–Evans Lam coupling reaction and (b) proposed mechanism.[91]

This practical procedure is carried out under mild conditions and boronic acids, unlike

organobismuthanes, organostannanes, organolead, iodonium salts and organoantimony

compounds, are “aryl-economic”, that is they bear only one equivalent of aryl moiety and do

not require 'dummy ligands'. In the majority of examples, at least an equimolar quantity of

copper salt (preferably, Cu(OAc)2 or its crystallohydrate) and a nitrogen-base/promoter

(triethylamine and/or pyridine, and recently, alkynes[92b]

) are used. Lam et al. also looked into

the possibility of using co-oxidants to establish a catalytic copper protocol (Scheme 24).

Pyridine N-oxide, TEMPO and N-methylmorpholine oxide gave the best improvements.[93]

Scheme 24. Co-oxidant screening in Chan–Evans–Lam reaction.[93]

Chapter 1

17

In 2003, Lan et al. found that the reaction can be most effectively carried out in methanol as

solvent without any additives or enhancers and using air as the terminal oxidant. Methanol

and to some extent ethanol are believed to (a) activate the carbon–boron bond towards

transmetallation via coordination to boron and also (b) enhance the aerobic oxidation of

copper.[90]

Initially, the methodology was developed for arylation of amines, sulphonamides and

phenols. Recently, however, reports on monoalkylation of anilines[94]

and alkenylation of

alcohols[92]

have been reported. In addition to that, with potassium alkenyltrifluoroborates,

Batey was able to alkenylate amides and imides[95]

and arylate alcohols[96]

efficiently.

Chan–Evans–Lam coupling has also found use in the synthesis of macrocyclic structures.

Evans and co-workers were the first to exercise such a strategy, delivering macrocyclic

diethers 25, the hydroxamic acids of which, represented a new chemical scaffold for

inhibitors of matrix metalloproteinases (MMP) (Scheme 25).[97]

Scheme 25. Synthesis of the first macrocyclic diaryl ethers.[97]

The only major limitation in the substrate scope are aliphatic alcohols.[96]

In 2010, Merlic was

able to demonstrate a few copper-promoted examples, but the reactions were conducted in

neat alcohol and often limited to activated (allyl alcohol, 2-chloroethanol and 2-

trimethylsilylethanol) or simple (methanol, ethanol) examples.[92a,b]

Work on Chan–Evans–Lam coupling reactions also led to several reports on regioselective

1,2-additions of boronic acid to azo[97]

and nitroso[98]

compounds, aromatic aldehydes[99]

and

alkynoates.[100]

Chapter 1

18

1.3.3 Converting Boronic Acids

In addition to various coupling reactions, boronic acids can be readily and efficiently

transformed into many other functionalities (Scheme 26, Table 2).[101–120]

Taking into

consideration, the ease of preparation of boronic acids and importance of structure–activity

relationships, in the future, the boronic acid moiety may serve as an important starting point

for various divergent transformations. In that regard, the ability to encode a para-

boronylsubstituted phenylalanine (Phe) into the protein is perhaps most exciting.[121]

Scheme 26. Conversion of boronic acids.

1.4 Boron-Based as Reagents and Catalysts

There is only a limited body of work on boron-based systems acting as catalysts and

promoters. The first such example was demonstrated by Letsinger in 1963, when 8-

quinolineboronic acid enhanced the rate of hydrolysis of some chloroalcohols.[122]

In 1979,

Nagata reported phenylboronic acids-mediated ortho-α-hydroxyalkylation of phenols by

aldehydes (Scheme 27).[123]

This condensation was used in the synthesis of the decaline

portion of (+)-compactin[124]

and hexahydrocannabinoids.[125]

Scheme 27. (a) Boronic acid-medited ortho-α-hydroxyalkylation of phenols [123]

and (b) its application.

Chapter 1

19

Table 2. Conversion of boronic acids. aBoronic ester used as substrate. phen = 1,10-phenanthroline

entry X X source (equiv)

metal source (equiv)

conditions ref

1 NO2 AgNO3 or NH4NO3

(2.2) – [Ag] or [NH4], 2 equiv TMSCl,

DCM, RT–50 ºC, 30–72 h [101]

2 NH2 NH3·H2O

(5.0)

Cu2O (0.1) MeOH, air, RT [102]

3 N3 NaN3

(1.2–1.5) CuSO4 or

Cu(OAc)2 (0.1) MeOH, RT–55°C, 24 h [103]

4 N3 TMSN3 (1.2)

CuCl (0.1)

1.2 equiv TBAF, MeOH, reflux

[104]

5 OH KOH (3.0)

CuSO4 (0.1) 0.2 equiv phen, H2O, RT, 1-10 h [105]

6 SR

R = Alk, Ar

CuMeSal (0.3)

2 equiv RB(OH)2, THF, 45–50 °C, 2-18

[106]

7 CN RS–CN (1.0) R = Alk, Ar

Pd(PPh3)4 (0.03), CuTC (1.5–3.0)

1.5 equiv RB(OH)2, DO, 100 ºC, 12 h

[107]

8 CN Zn(CN)2

(3.0) Cu(NO3)2∙H2O

(2.0) 1 equiv CsF, MeOH/H2O,

80 ºC, 3-6 h [108]

9* COOH CO2 [Rh(OH)(cod)]2

(0.03–0.05) CO2 (1 atm), 7-10 mol% dppp,

3 equiv CsF, DO, 60 °C

[109]

10a COOH CO2

iPrCuCl (0.01)

CO2 (1 atm), 1.05 equiv tBuOK,

THF, reflux, 24 h [110]

11* COOR CO, ROH Pd(OAc)2

(0.05–0.08) CO (1 atm),10–16 mol% PPh3,

1 equiv BQ [111]

12 F CsOSO3F – 1.5 equiv RB(OR’)2, MeCN, reflux [112]

13 a F

Selectfluor®

(1.05) AgOTf (2.0)

(i) 1 equiv NaOH, MeOH; [Ag], 0 ºC; (ii) Selectfluor

®, 3Å MS, Me2CO, 3 h

[113]

14 F Selectfluor

®

(1.0) – MeCN, RT, 24 h [114]

15 Cl, Br CuX2

(3.0) – MeOH/H2O [115]

16 I NaI

(excess) 2 equiv TsNNaCl, NaOH,

THF/H2O, RT 5 min [116]

17 Br, I NBS, NIS (1.0–2.0)

– MeCN, 25–81 °C, 1–24 h [117]

continued on next page

Chapter 1

20

continued from previous page

entry X X source (equiv)

metal source (equiv)

conditions ref

18 Cl, Br

– 5 mol% NaOMe, MeCN, RT [118]

17 Cl, Br, I NCS, NBS, NIS

(1.0) CuCl or CuCl2

(0.1–1.0) MeCN, 80 °C, 1–24 h [119]

18 CF3 TMSCF3

(5.0) [Cu(OTf)]2∙PhH

(0.6) 1.2 equiv phen, 5 equiv KF, 3 equiv

K3PO4, DMF, 45ºC, 4 h [120]

Nagasaki introduced boronic acids as templates in the Diels–Alder reaction,[126]

which

Nicolaou later used in the total synthesis of Taxol (Scheme 28).[127]

Chiral boron-based Lewis

acids, especially acyloxyboranes and oxazaborolidines, are extensively employed in

asymmetric reductions and Diels–Alder reactions.[128]

Scheme 28. Use of boronic acid as a template for the Diels–Alder reaction.[127]

Recently, Štefane demonstrated that 1,3-dioxa-BF2 complexes 26 are readily accessible from

aryl 3-oxopropanoates and BF3·OEt2. These undergo highly chemoselective addition of

organolithium reagents to give 1,3-diketones 27 (Scheme 29).[129]

Scheme 29. Selective addition of organolithium reagents to BF2-chelates of β-ketoesters.[129]

Suginome’s group employed trimethyl borate as a nonacidic iminium ion generator for both

Mannich and Ugi-type reactions (Scheme 30).[130]

Chapter 1

21

Scheme 30. Trimethyl borate mediated Mannich and Ugi reactions.[130]

During the past decade, several groups have noted that boron-based systems can activate

carboxylic acids. One of the most studied applications is direct amide bond formation.[131]

In a

similar fashion, unsaturated carboxylic acids are activated towards cycloadditions.[132]

Moreover, several substoichiometic reagents and catalysts have been devised. We will discuss

this mode of activation in more detail below.

1.4.1 Activation of Carboxylic Acids

A number of boron based reagents (Scheme 31) react with carboxylic acids to give

acyloxyboronate/acyloxyborane intermediates, which undergo aminolysis to give an

amide.[133]

In most cases, reaction conditions are mild and neutral, and often no or

insignificant epimerisation is observed. However, the main drawbacks of these stoichiometric

reagents are low conversions, incompatibility with several functional groups, and the fact that

often an excess of either an amine or a carboxylic acid is required to achieve good yields.

Scheme 31. Simple boron reagents for stoichiometric amide bond formation.

The first substoichiometric boron reagents for direct carboxamidation were reported in 1996.

Hisashi Yamamoto and co-workers demonstrated that electron-deficient arylboronic acids act

Chapter 1

22

as catalysts for direct amide bond formation (Scheme 32).[134]

They showed that 3,4,5-

trifluorobenzeneboronic acid 28 showed superior activities. While the initial screening gave

excellent results, most of the reactions were carried out under harsh conditions. Namely,

heating under reflux in toluene (bp 110 C), xylene (bp 140 C), anisole (154 C) and

mesitylene (bp 164 C) was required along with concomitant removal of water (4 Å MS in a

Soxhlet thimble or azeotropic reflux) and prolonged reaction times (ca 20 h). However, even

under these conditions practically no racemisation was observed.

Further work carried out by Yamamoto aimed at identifying better boron-based catalysts

(Figure 3)[131c, 135]

as well as their use for the synthesis of polyamidic polymers[136]

and urea

derivatives.[137]

In 2001, they showed that 3,5-bis(perfluorodecyl)phenylboronic acid 32 was

immobile in the fluorous recyclable phase and possessed catalytic activity similar to that of 28

and 30.[138]

In 2005, they reported N-alkyl-4-boronopyridinium salts 33 and 34 as thermally

stable and reusable catalysts for direct amidation.[135]

Interestingly, 4,5,6,7-

tetrachlorobenzo[d][1,3,2]dioxaborole 35 was shown to be superior for the direct amidation

Scheme 32. Boronic acid-catalysed direct amide bond formation. (a) Catalytic activity of various

arylboronic acids. (b) Efficacy of 1 mol% 28 as a catalyst. In the last example, starting material was

>98% ee and 10 mol% of 28 was used.

Chapter 1

23

Figure 3. Arylboronic acids for direct amide bond formation.

Scheme 33. Catalytic activities of boron compounds for direct amidation of cyclohexanecarboxylic acid

with benzylamine.

of only sterically hindered carboxylic acids (Scheme 33).[135]

However, no explanation to

account for such a reactivity profile was provided.

While Yamamoto and co-workers were investigating various arylboronic acids, Tang

demonstrated that boric acid alone is a sufficient substoichiometric catalyst for direct amide

bond formation in some cases.[139]

However, extensive heating under reflux in high boiling

point solvents was required.

Historically, bringing the reaction temperature below 100 °C for this transformation was

challenging. Whiting et al. proposed that having an additional N,N-dialkylaminomethyl in the

ortho-position to the boronyl moiety would promote the reaction by abstracting a proton from

an amine during the formation of a tetrahedral intermediate. In order to test this hypothesis,

they prepared five “Wulff-type”[140]

arylboronic acids 38 (Figure 4).[141,142]

In the N,N-

dimethylaminomethyl variant 39, chelation of nitrogen to boron led to low catalytic activity.

In 40, however, the two bulky isopropyl groups on nitrogen prevent N→B chelation. As a

result, 40 showed improved activity at lower temperatures (in refluxing fluorobenzene, bp 84

Chapter 1

24

ºC). Additionally, with 40 carboxamidation of a less reactive acids such as benzoic acid was

more successful then with other catalysts. However, under higher temperature conditions both

boric acid and 30 were superior to 40.[141]

Figure 4. ortho-(N,N-Diisopropyl)methylphenylboronic acids.

Further introduction of electron-deficient groups into the phenyl ring raised the catalytic

activity of ortho-(N,N-diisopropyl)methylphenylboronic acids. The yields for the catalysed

condensation between benzoic acid and benzylamine in refluxing fluorobenzene using 5

mol% of arylboronic acid decreased in the following row 43> 40 > 41 >> 42 >> thermal.[142]

Some interesting observations were reported by Hall et al. in 2008 (Scheme 34).[132b]

. Firstly,

they found that boronic acid catalysed carboxamide formation can be carried out at ambient

temperature (25 °C), but in dilute solutions and in the presence of molecular sieves (both for

the sake of effective water removal). Secondly, they identified ortho-iodoboronic acid 47 as a

superior catalyst under these conditions. They examined the catalytic efficiency of 45 diverse

arylboronic acids but no obvious direct correlation between the reactivity and the substituents’

steric or inductive effects could easily be drawn. For example, the fact that among ortho-

halide derivatives ortho-iodophenylboronic acid 47 is the most efficient catalyst, while the

fluoro analogue 44 is not, rules out the possibility that inductive effects account solely for the

catalytic properties. While iodine is the most bulky substituent in the halogen row,

comparison of activities of o-methyl and o-isopropylphenylboronic acids 49 and 50 confirmed

that steric effects alone could not have explained the catalyst efficiency (Figure 5). The

acidity of the boronic acids was also unlikely to provide a rationalisation as pKas of 47 and

inactive phenylboronic acid are 9.80 and 9.90, respectively. Since the X-ray crystal structure

of 47 showed an angular distortion of the B-C-C bonds (117°, 126°), the authors conclude that

“subtle electronic or structural effects may be at play”.

Chapter 1

25

Scheme 34. Boronic acids as catalysts for room temperature direct amidation.[132b]

(a) (b)

Figure 5. (a) Catalytic activities of ortho-alkylboronic acids. Reaction conditions: 10 mol% catalyst, 0.07

M DCM, 25 h. (b) Crystal structure of 47.

The explanation of this reactivity was recently provided by Marcelli.[143]

His computational

studies indicated that the halogen acts as a Lewis base, promoting hydrogen abstraction from

nitrogen in the tetrahedral intermediate 51 (Figure 6). The precise spatial positioning of the

halogen in relation to the boron may be the reason why Hall’s catalyst outperforms Wulff-

type boronic acids, which might be expected to be superior bifunctional Lewis acid/Lewis

base catalysts. We will return to the mechanistic considerations in Chapter 2.

Chapter 1

26

Figure 6. Iodine-assisted direct carboxamidation. Simplified model using methylamine, acetic acids,

ortho-iodophenylboronic acid. Hydrogen bond patterns are shown in green.

In additional to amidation Hall showed that ortho-iodophenylboronic acid promotes Diels–

Alder reactions between α, -unsaturated acids and dienes (Scheme 35) at ambient

temperatures.[132b]

Formation of a mixed anhydride 52 would lower the LUMO of a

dienophile, which would then more readily undergo [4+2] cycloaddition. This concept was

essentially borrowed from Yamamoto, who successfully used diborane-THF complex to

achieve similar reactivities.[132a]

Hall expanded this methodology to include a series of [3+2]

dipolar cycloadditions involving azides, nitrile oxides and nitrones.[132c]

Scheme 35. Boronic acid-catalysed Diels-Alder reaction with acrylic acid as a dienophile.

Apart from direct carboxamidation, boron-based catalysts were shown to promote several

specific cases of esterfication. In 2004, Houston et al. reported that α-hydroxyacids 53 (but

not succinic or benzoic acids) can be converted to the corresponding esters 54 with boric acid

as a catalyst in an excess of alcohol (Scheme 36).[144]

This was despite the fact that some

earlier reports claimed that the use of alcohols as solvents deactivated arylboronic acids by

forming alkylesters of the boronic acids. This enhanced reactivity can be explained by the

formation of cyclic borates and acyloxyboronates. This was further supported by the fact that

while monoesters of maleic and malonic acids 55 and 56, respectively, were obtained under

similar conditions, while fumaric acid remained unreacted.[145]

Chapter 1

27

Scheme 36. Esterification of (a) α-hydroxycarboxylic acids,[144]

(b) monoesterification of maleic and

malonic acids.[145]

Later, Yamamoto showed that 33 was superior to boric acid and gave methyl esters at ambient

temperatures.[131c]

Other coordinating functionalities on the α-carbon also promoted

esterification (Scheme 37).[135]

No similar effect was reported for amidation of α-

functionalised carboxylic acids.

Scheme 37. Methyl esterification α-functionalised carboxylic acids.

Other boronic acid-catalysed reactions include (a) synthesis of oxalinone and thiazolines from

carboxylic acids and 1,2-aminoalcohols and 1,2-aminothiols, respectively;[146]

(b) preparation

of acyl azides from carboxylic acids;[147]

and (c) reduction of carboxylic acids to alcohols.[148]

1.5 Summary

The chemistry of boronic acids has advanced substantially during the past decade.[5]

A

number of new strategies for the synthesis of a variety of boronic acids have been developed.

Several new conditions allow the introduction of boron in the presence of several otherwise

Chapter 1

28

restrictive functionalities. Numerous strategies for the conversion of boronic acids to other

useful derivatives (e.g. halides including fluorides, azides, carboxylic esters etc.) have also

been introduced. Major progress was made in understanding and controlling the reactivity of

boronic acids and esters in transition metal catalysed processes.[149]

Furthermore, aerobic

catalytic systems (e.g. for Chan–Lam coupling) were devised[142,150]

and experimentally

studied.[90]

The mechanistic details of these transformations significantly contributed to the

design of other aerobic systems.[151]

As a result of these advances, boronic acids and their

surrogates are often used in the total syntheses of complex natural products, including for late

stage transformations, an indicator of the maturation of the field (Scheme 38).[14e,152,153]

Furthermore, the use of boronic acids has also been extended to the development of

carbohydrate sensors[154]

and pharmaceuticals (Figure 7).[155]

For example, bortezomib is a

first-in-class proteasome inhibitor,[156]

while other boron-based substances currently under

development may find their niche as anti-infectives (e.g. AN-2690 is a highly potent

antifungal agent[157]

).

In spite of all these accomplishments, applications of boronic acids and other boron-centred

systems as catalysts and reagents are rather underexplored. In the next chapters, we will

introduce and discuss new applications of boron-centred reagents and assess their potential in

catalysis.

Chapter 1

29

Scheme 38. (a) Miyaura borylation was crucial to Nicolaou’s second generation total synthesis of

Diazonamide A.[152]

(b) Late stage Ir-catalysed C–H activation/borylation in Sarpong’s total synthesis of

Complanadine A.[153]

(c) Total synthesis of (–)-Peridinin via iterative cross-coupling strategy.[14e]

dtby =

di-tert-butylbipyridine

Figure 7. Structures of Bortezomib, a proteasome inhibitor and AN-2690, an antifungal.

Chapter 2

Chapter 2

31

2 Development of Boron Based Reagents and Catalysts

for Activation of Carboxylic Acids and Amides

2.1 Amide Bond Formation: An Overview

The amide bond is one of the most fundamental and widely occurring bond types in

nature.[158,159]

Not only is it the “linking” bond in peptides, related conjugates (e.g. peptide

nucleic acids[160]

), and polymers, it is also found in a vast number of natural and unnatural

compound, e.g. polyketides, cyclopeptides, antibiotics, and pharmaceuticals (Figure 8). In

addition, amides are commonly used as protecting and/or directing groups (Scheme 39) and as

starting materials for functional group interconversions leading to ketones, acids and amines,

to name just a few (Scheme 40).

A recently conducted analysis of the reactions used for the preparation of drug candidates[161]

as well as commercially available drugs,[162]

indicated a significant use of amide bond

formation in industry. Namely, 9.1% of all reactions involved amide formation, and the

carboxamide unit was found in 25% of all marketed drugs.[163]

Despite the vast number of methods available to construct an amide bond, most have

disadvantages such as high substrate dependence and poor atom[164]

and redox[165]

economy.

Other commonly encountered problems are substrate racemisation and the toxicity of the

reagents used. As a result, amide bond formation was ranked the highest among the reactions

that are “already in use but require better reagents” by the ACS Green Chemistry Institute

Pharmaceuticals Roundtable as well as by other bodies.[166]

While numerous strategies have been developed for the chemical synthesis of carboxamides,

few of them have any resemblance to the catalytic methods of enzymes/ribozymes employed

in in vivo amide and peptide bond formation. This, perhaps, may also be attributed to

difficulties in obtaining the crystal structures of the respective ribozymes/protein complexes

with transition-state analogues.[167]

Chapter 2

32

Figure 8. A selection of bioactive compounds containing amide bonds. (a) Trapoxin, 57, a fungal natural

product, known to inhibit histone deacetylases.[168]

(b) Vancomycin, 58, a glucopeptidic antibiotic.[169]

(c)

Tacrolimus, 59, a polyketide, an immunosuppressive drug.[170]

(d) Valsartan, 60, an angiotensin II

receptor antagonist, a multibillion-dollar drug.[171]

Scheme 39. Amide-directed chemical transformations. (a) Directed ortho-lithiation.[172]

(b)

Regioselective oxidation of a benzylic position.[173]

(c) Catalytic asymmetric hydroboration of alkenes.[174]

Chapter 2

33

Scheme 40. Synthetic utility of amines: (a) Hofmann rearrangement.[175]

(b) Petasis–Tebbe

olefination.[176]

(c) Myers asymmetric alkylation.[177]

2.1.1 Methods for Amide Bond Formation

Carboxamide formation has been studied extensively over the last century and as a result,

there are a number of reviews published in this area.[178]

Below, the existing methods will be

classified and their main limitations will be outlined. Several emerging alternative and/or

catalytic methods will also be covered.

Direct amide formation, which essentially is a simple condensation, is a thermodynamically

favoured process with the overall free energy of formation of an amide being negative.

However, mixing a carboxylic acid with an amine results in spontaneous ammonium salt 62

formation (Scheme 41, route a).[179]

Further condensation to give an amide is then kinetically

disfavoured. There are a few examples of thermally driven direct carboxamidations,[180]

however, the temperatures required for these processes to occur are often substantially high.

Chapter 2

34

Scheme 41. Strategies for amide bond formation from carboxylic acids and amides via (a) thermal

condensation and (b) activation of carboxyl by introducing a good leaving group.

2.1.1.2 Activation of Carboxylic Acids

Most synthetic routes make use of pre-formed or in situ generated activated acyl derivatives

63 (Scheme 41, route b).[178d]

This helps to prevent ammonium salt formation and provides a

good leaving group at the acyl carbon. These methods may be further classified based on the

stability of the acyl derivative. Firstly, acyl derivatives that have a long shelf-life can be used

including acyl halides and esters of electron-deficient phenols such as 64–66 (Figure 9).

Secondly, acyl derivatives that have to be pre-formed before an amine is added (Scheme 42).

These include acyl halides (e.g. 67 although a few of acyl halides can often be isolated and

stored or are commercially available), a wide selection of mixed anhydrides (e.g. 68) and

imidazolium salts 69. In the third case, the activated acyl derivative is formed in situ from a

so-called coupling reagent, and this then reacts with an amine present in the reaction mixture.

These commonly used reagents include carbodiimides 70–72, phosphonium salts 73–74,

uronium/guanidinium salts 75–76 and ammonium salts, e.g. 77 and Mukaiyama‟s reagent 78

(Figure 10).

Figure 9. Phenols used to prepare activated esters with a long shelf-life. PNPOH = p-nitrophenol,

PFPOH = pentafluorophenol, TCPOH = 2,4,5-trichlorophenol.

Chapter 2

35

With all of these acyl activation techniques, at least a stoichiometric amount of an activating

or coupling reagent is required. In many cases, additional bases, dehydrating agents and

promoters are employed. This all contributes to a significant amount of waste and by-products

are also often generated.

Scheme 42. Preparation of halides and mixed anhydrides. CDI = 1,1'-carbonyldiimidazole, CYC =

cyanuric chloride.

Figure 10. Common coupling reagents.

Another frequent drawback is racemisation at the α-carbon (Scheme 43). For example, acyl

chlorides with an α-hydrogen 79 can racemise via ketenes 80. In the C→N peptide synthesis,

the oxygen of the carboxamide may intramolecularly attack an activated acyl intermediate 81

to form an oxazolone 82, which would undergo racemisation via formation of a conjugated

Chapter 2

36

anionic/aromatic intermediate 83. When a racemic oxazolone then reacts with an amine, it

gives a racemic product 84. Hence, that is why peptides are usually synthesised from the N-

terminus (N→C). Moreover, to suppress the racemisation process additives such as 85–87 are

used in conjunction with carbodiimides (Figure 11). More “powerful” coupling reagents (e.g.

73–76) already carry a HOBt/HOAt unit for this reason.

Scheme 43. Racemisation of an asymmetric carbon adjacent to a carboxyl group via (a) ketene and (b)

oxazolone.

Figure 11. (a) Peptide coupling additives: HOBt,[181]

HOAt, [182]

HOI.[183]

(b) Yield and racemisation

during formation of Cbz-Phg-Pro-NH2 (DMF, RT).[183]

The recent analysis of reactions employed in the pharmaceutical industry showed that only a

handful of reagents meet the three requirements of sustainability, wide usability and

scalability (Figure 12).[166]

However, the “ideal” reagents in this study – thionyl chloride, CDI

and iBuOCOCl – are used in equimolar amounts and generate toxic and corrosive waste

products. Thus, they are far from ideal, and the environmental and economic need for the

development of sustainable and efficient catalysts for direct amide bond formation is still

great.

Chapter 2

37

(a) (b)

Figure 12. Venn diagrams that form the basis for the reagent guide depending on wide utility, scalability

and sustainability. (a) Venn diagram for amide formation from acids and amines (only examples that are

not prone to racemisation are included). (b) Venn diagram for amide formation from acids and amines

(examples that are prone to racemisation are included). Adopted with changes from ref. [166] –

Reproduced with permission of the Royal Society of Chemistry.

2.1.1.3 Alternative Methods

Alternatively, amides can be synthesised thermally (pyrolysis of the ammonium salts,[180]

in

the presence of silica gel[184]

), under microwave conditions[185]

, by amine activation,[186]

or

biocatalytically.[187]

However, these methods are often unreliable as they require harsh

conditions and/or have narrow substrate scope.

CDI-mediated amide coupling is a rare example of dual activation. First, an amine reacts with

CDI to give an amine/CDI surrogate, that is subsequently methylated to give a stable

crystalline carbamoylimidazolium salt 88 (Scheme 44).[188]

This salt readily reacts with an

acid in the presence of a mild base and proceeds via an in situ formed activated acyl

derivative 89.

Scheme 44. CDI-mediated amide synthesis via amide activation.[188]

Chapter 2

38

2.1.1.4 Catalytic Methods

Apart from boron-based systems, which were discussed in Chapter 1, catalytic methods for

direct carboxamide formation are limited to only a few examples.

Nomura et al. reported antimony-based catalysts (Scheme 45).[189]

In their studies,

triphenylantimony oxide 90 reacted with an acid in situ to give triphenylantimony

dicarboxylate 91. This organoantimony(V) compound 91 then reacted with an amine to yield

a corresponding amide and regenerate Ph3SbO. The initial reactions were carried out with 10

mol% of Ph3SbO and a slight excess of a primary amine in pyridine at elevated temperatures.

Under optimised conditions using P4S10 as a dehydrating agent, they showed that the catalyst

was active at 30–60 C for the acylation of dialkylamines and anilines and also the formation

of dipeptides.[190]

To a certain extent the reaction was taking place even without Ph3SbO.

However, the high toxicity of antimony and tetraphosphorus decasulfide limits the

employment of this chemistry. Dialkyltin oxide was also shown to be active for

lactamisation.[191]

Scheme 45. Catalytic cycle for triphenylantimony oxide catalysed direct amide formation.[189]

In 1988, Mader and Helquist found that titanium(IV) isopropoxide (50 mol%) but not TiCl4

mediated formation of five and six-membered lactams from ω-amino acids in good yields.[192]

2.1.1.5 Emerging Methods

In this section, we will briefly review approaches that exploit unactivated alkyl carboxylic

esters,[193–196]

carboxylates,[197]

aldehydes[198-201]

, ketones[202]

, alcohols[203-206]

and α-bromo

nitroalkanes[207]

as acyl precursors. The main disadvantages of these methods are that they

have only been demonstrated on a range of simple and often unfunctionalised substrates, or

Chapter 2

39

ones that are, on the contrary, laborious to access. However, most of the examples below

represent new strategies for amide formation.

Yamamoto et al. used tris(dimethylamino)borane[193]

and Sb(OEt)3[194]

for templated[208]

macrolactamisation (macrocyclic amide formation), which was a crucial step in the synthesis

of spermine-derived alkaloids (Scheme 46). The boron reagent was effective only for the

cyclisation of triamino esters 92 giving a 13-membered lactam 94. This lactamisation

proceeded through boron compound 93, which was isolated in a separate experiment (93%)

and was stable to hydrolysis (4.5 M HCl/MeOH, reflux, 4 h and glacial AcOH, reflux, 4 h).

To access 17-membered lactams such as 95, Sb(OEt)3 was used as the boron reagent proved

to be ineffective. Some activity was also observed with titanium(IV) ethoxide and

zirconium(IV) isopropoxide.[194]

Scheme 46. Boron[193]

and antimony[194]

templated syntheses of macrolactams.

Although the above transformations required stoichiometric use of reagent, they inspired

further work into metal-catalysed amidation of esters. In 2005, Porco et al. screened transition

metal salts and alkoxides for catalytic ester–amide exchange (Scheme 47). They found that

group (IV) alkoxides were the most efficient and that their activity was significantly raised if

additives such as HOAt, HOBt, PFPOH and 2-hydroxypyridine were used.[195]

Mechanistic

studies showed that both an additive and an amine coordinated to the metal centre resulting in

the dimeric species 96, which was characterised by X-ray crystallography. Further

coordination of an ester and nucleophilic attack by the amine gave the desired amide. These

ester amidations occurred at RT, 60 ºC or 100 ºC, depending on the substrate pair, and with

good functional group tolerance (e.g. OH, NHBoc, ketals).

Chapter 2

40

Scheme 47. (a) Zirconium(IV) tert-butoxide catalysed ester amidation. (b) Isolated zirconium dimeric

species.

Yang and Birman showed that a 1,2,4-triazole anion can act as a substoichiometric catalyst

for ester amidation (Scheme 48).[196]

Scheme 48. Catalytic ester amidation with 1,2,4-triazole.[196]

A number of catalytic routes to carboxamides involving N-heterocyclic carbenes (NHC) have

been reported. In 2005, Movassaghi and Schmidt showed that NHCs promoted amidation of

unactivated esters by 1,2-amino alcohols (Scheme 49).[198]

In the first step, the alcohol is

activated by the virtue of formation of an NHC–alcohol complex 97. Oxygen then attacks the

ester to give the tetrahedral intermediate 98 that yields an O-acylated amine 99. Finally, an

intramolecular N→O acyl transfer takes place to furnish the corresponding N-acylated alcohol

100.

Further concomitant reports by Rovis and Bode showed that a wide variety of α-

functionalised aldehydes underwent NHC-catalysed redox amidation (Scheme 50).[199,200]

. The

reaction was co-catalysed by HOBt, HOAt, PFPOH, DMAP and imidazole. These small

molecules effectively act as acyl acceptors forming either activated esters or acyl pyridinium

or imidazolium salt,[209]

which then easily undergo amidation.

Chapter 2

41

Scheme 49. (a) NHC-catalysed amidation of an unactivated ester with a -amino alcohols and (b) the

proposed mechanism. IMes = 1,3-bis(2,4,6-trimethylphenyl)-imidazol-2-ylidene.

Scheme 50. (a) NHC-catalysed redox amidation of α-functionalised aldehydes.[199,200]

(b) Proposed

catalytic cycle for 101a with 1-HOBt as a co-catalyst for acyl transfer.

Later, Bode came up with α‟-hydroxyenones 102 as an alternative for enals 101b (Scheme

51).[202]

These substrates can be readily accessed from condensation of an aromatic aldehyde

with 3-hydroxy-3-methyl-2-butanone. Unfortunately, derivatives of aliphatic aldehydes gave

poor yields in the NHC-catalysed amidation step.

Scheme 51. NHC-catalysed redox amidation of α’-hydroxyenones.[202]

Chapter 2

42

In 2006, Yoo and Li described the first system for oxidative amidation, employing aldehydes

and amine hydrochloride salts (Scheme 52).[201]

The oxidation of the intermediate aminol was

achieved in the presence of CuI and AgIO3 as co-catalysts and tert-butyl hydroperoxide

(TBHP) as the terminal oxidant. However, this process was limited to aromatic aldehydes.

Scheme 52. CuI/AgIO3-catalysed oxidative amination of aldehydes.[201]

Cy = cyclohexyl.

In 2007, Milstein reported the first example of direct dehydrative coupling of amines and

alcohols that proceeded via aminol and led to liberation of two equivalents of dihydrogen

(Scheme 53).[203]

This transformation was achieved using a low loading of PNN-type pincer

ruthenium complex 103 (0.1 mol%) to yield carboxamides under mild conditions. However,

only primary unfunctionalised amines were reported to work.

Scheme 53. Direct amide synthesis of secondary amides from alcohols and amines catalysed by a

Milstein catalyst 103 that carries a dearomatised PNN-type pincer ligand.[203]

Fur = furanyl.

In 2008, Madsen devised a mixed ligand (carbene and phosphine) Ru-based system (Scheme

54) that showcased a more diverse set of alcohol/amine partners.[204]

While aryl chlorides, and

secondary/tertiary amines were well tolerated, double bonds were not. Amidations with

secondary amines and anilines were also unsuccessful. The phosphine ligand was proposed to

stabilise ruthenium-catalyst resting states and not be involved in the catalytic cycle itself.

Chapter 2

43

Scheme 54. Madsen’s Ru-based system for oxidative amide synthesis from amines and alcohols.[204]

cod = 1,5-cyclooctadiene, IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidine, Cyp = cyclopentyl.

Later, Williams et al. came up with another ruthenium-based system that used methyl

isopropyl ketone (MIPK) as a dihydrogen acceptor (Scheme 55).[205]

Scheme 55. Oxidative coupling of alcohols and amines using hydrogen transfer conditions.[205]

dppb =

1,4-bis(diphenylphosphino)butane, MIPK = methyl isopropyl ketone, Ind = indolyl.

Grützmacher and co-workers reported the first rhodium-based system for this type of

transformation.[206]

For coupling of primary alcohols with amines, they used

[Rh(trop2N)(PPh3)] along with methylmethacrylate (MMA) as a terminal dihydrogen acceptor

(Scheme 56). While only five examples were reported, the reaction proceeded at low

temperatures and showed good functional group tolerance.

Scheme 56. Rhodium-catalysed oxidative coupling of alcohols and amines using hydrogen transfer

conditions.[206]

trop2NH = bis(5H-dibenzo[a,d]cyclohepten-5-yl)amine, MMA = methylmethacrylate.

Chapter 2

44

Recently, Johnston reported an umpolung-based strategy for amide bond formation, where an

α-bromo nitroalkane, a nucleophilic component, serves as a masked acyl group and an in situ

generated N-iodo amine is an electrophilic component (Scheme 57).[207]

To support this

approach, an efficient protocol was developed to access α-bromo nitroalkanes using chiral

proton catalysis from N-Boc imines. These substrates are, however, not always readily

available and those derived from aliphatic aldehydes are much less stable and their reactivity

profile was not reported. The amide coupling reaction requires prolonged reaction times (48

h) and, interestingly, the presence of water. In that regard, water is important for hydrolysis

but it may also be possible that this transformation is a metal-catalysed process. For instance,

Norrby and Bolm have shown that ppm copper loadings present in water are sufficient enough

to catalyse carbon–heteroatom coupling reactions.[210]

No sound experimental or

computational evidence was provided by Johnston et al. to support their mechanism

(nitronate‟s nucleophilic attack at the nitrogen of the N-iodo amine).

Scheme 57. (a) Generation of α-bromo nitroalkane precursor via chiral proton catalysis. (b) Umpolung

amide coupling.[207]

2.1.2 Amide Bond Formation in Nature

Amide bond formation within the cell is carried out in a number of ways. These vary

depending on the substrate‟s biological function. Long peptidic chains, which form proteins,

are synthesised in the ribosomes (Section 2.1.6.1). Nonribosomal peptides, which often have

branched and/or cyclic structures and may contain non-proteinogenic amino acids, are

synthesised by highly specific nonribosomal peptide synthetases (NRPSs) (Section 2.1.6.2).

These multifunctional enzyme complexes are found in fungi and bacteria and are responsible

Chapter 2

45

for making many biologically active and complex compounds. In a cell, a vast number of

heteroatom-acylations also take place. These events are carried out by numerous enzymes,

which are collectively known as acyltransferases (Section 2.1.6.3).

All of the above-mentioned processes require different sets of co-factors and acyl donors. In

addition, the structures of the catalytic sites and, as a consequence, the reaction mechanisms

vary considerably. However, in nearly all the cases, a carboxyl moiety of an amino acid is

initially activated to form an acyl-adenylate or an acyl-phosphate at the expense of high-

energy bonds within ATP, and this intermediate may or may not be converted to a thioester

(Scheme 58). Observation of an ATP-independent strategy for amide bond formation in the

capuramycin-type antibiotic biosynthesis was reported recently (Scheme 59).[211]

Funabashi et

al. found that in the NRPS cluster, CapS, acts not as a β-lactamase but as an S-

adenosylmethionine-dependent carboxyl methyltransferase (i.e. methylates a carboxylic acid

to give a methyl ester). CapW then catalyses the intermolecular amidation of the resulting

unactivated ester by an unknown mechanism.

Scheme 58. Strategies for carboxylic acid activation and amide bond formation in Nature. ATP =

adenosine triphosphate, ADP = adenosine diphosphate, SAM = S-Adenosyl-L-methionine, SAH = S-

adenosyl-L-homocysteine.

Chapter 2

46

Scheme 59. Proposed biosynthetic pathway to A-503083 B.

2.1.2.1 Ribosomal Peptide Bond Formation

Protein synthesis is performed on the ribosome, which consists of three RNA molecules and

more than 50 proteins.[167]

The active site is 15 Å wide and incorporates only RNA residues.

The amine equivalent is delivered to the peptidyl-tRNA site (P site) 106 in the form of an

aminoacyl-tRNA (A site), which is a ribose ester 105 (Figure 13). Then substrate 106 assisted

nucleophilic attack takes place to give prolonged peptidic chain and the free tRNA.

It is believed that peptide bond formation is in part driven by lowering the transition state‟s

entropy via effective positioning of substrates, reacting groups and organisation of water

molecules.[212]

However, it was also shown by numerous experimental and theoretical studies

that the 2‟-hydroxyl group[213]

is essential for the reaction to take place. The 2‟-OH functions

by providing an organised hydrogen bond network that stabilises the transition state.

Figure 13. (a) Aminoacyl-tRNA 105. (b) Concerted proton shuttle mechanism of peptide bond formation

(dashed lines represent the new bonds, which are forming).

Chapter 2

47

2.1.2.2 Nonribosomal Peptide Synthetases

NRPSs are multiprotein complexes, which consist of a series of repeating enzymes fused

together. There are three main domains found in NPRS: the adenylation (A), the peptidyl

carrier (PCP) and the condensation (C) domains (Figure 14).[214]

In the A domain, an amino

acid is activated by adenylation, resulting in an aminoacyl adenylate (Scheme 60). The

resulting highly reactive intermediate can then react with the thiol of a phosphopantetheinyl

linker (that is attached to a serine residue in the PCP domain) to form a thioester. The free

amino group of the newly formed thioester then attacks a thioester linked to another PCP

domain. This process takes place in the C domain, where the basic residue (e.g. His195 in

structurally related chloramphenicol acetyl transferase (CAT)) acts as a general base

deprotonating the ammonium group to give an amino group (not shown), which subsequently

attacks the thioester. This attack forms a negatively charged tetrahedral intermediate, which is

stabilised by other residues (e.g. Asn355 in VibH, a condensation domain in vibriobactin

synthetase, or Ser148 in CAT).

In the further steps a number of additional domains (fused enzymes) catalyse a variety of

transformations including epimerisation of the α-carbon of the amino acid (E domain),

intramolecular heterocyclisation of serine, cysteine or threonine residues (cyclisation (Cy)

domain), N-methylation of the amine (methyltransferase (MT) domain) and others. Finally,

the fully assembled peptide is cleaved from the PCP domain by the thioesterase (TE) domain.

The fold of the TE domain belongs to the α,β-hydrolase containing the conventional catalytic

triad comprising serine, histidine and aspartic acid residues (see Section 2.1.6.4). The first

step of the reaction is the formation of a tetrahedral enzyme-linked intermediate, in which the

negative charge is stabilised by an oxyanion hole. The intermediate is decomposed losing the

phosphopantetheinyl thiol to give an acyl enzyme intermediate that subsequently undergoes

nucleophilic attack by water (giving a linear peptide) or an internal nucleophile (giving a

cyclic peptide).

Figure 14. General schematic representation of NRPS, a multienzyme collinear complex.

Chapter 2

48

Scheme 60. General schematic representation of peptide bond formation in a NRPS.

In all, the limitations in structural and biochemical characterisation of NRPSs as well as

complications with their genetic engineering have greatly restricted the understanding of the

reaction mechanisms underlying these processes.[214]

2.1.2.3 Acyl Transfer

The most common N-acyl transfer process in the cell is the acetyl transfer from acetyl CoA

107 (Figure 15) to the ε-amino group of lysine residues of histones and many other proteins,

which is catalysed by histone acetyltransferases (HATs). Based on their structure and

homology, the nuclear HATs are divided into three families (Gcn5/PCAF, MYST, and

p300/CBP) that are governed by different catalytic mechanisms (Scheme 61).[215]

For

example, in yeast HAT Esa1 the ping-pong mechanism involves acetyl transfer from CoA to

an enzyme nucleophile (cysteine) prior to transfer to the amino group. Site-directed

Chapter 2

49

mutagenesis showed that Cys307 was crucial for the enzyme activity and the crystal structure

of the acylated enzyme intermediate was obtained.[216]

However, in yeast HAT Gcn5, which

belongs to a different family, the ternary mechanism is employed.[217]

The acetyl group does

not form any enzyme intermediate but is directly transferred to the ε-amino group.

Figure 15. Acetyl Coenzyme A (AcCoA).

Scheme 61. Mechanisms of acetyl transfer. (a) Ping-pong mechanism in yeast Esa1. (b) Ternary

complex mechanism in yeast Gcn5. “simplified” denotes that protonation/deprotonation steps are

missed out.

Chapter 2

50

2.1.2.4 Lipases

There is one more biocatalytic approach to carboxamides. It is not observed in nature but has

been successfully employed in chemistry.[218]

Lipases catalyse the hydrolysis of esters. They function by forming a tetrahedral intermediate,

which is subsequently hydrolysed (Scheme 62). It was envisaged that an analogical route

(formation of a tetrahedral intermediate from a carboxylic acid or an ester followed by

nucleophilic attack by an amine) could be used for the biocatalytic amide bond formation.[187]

Scheme 62. Schematic mechanism of serine hydrolase biocatalysis. 108: Michaelis complexes; 109:

tetrahedral intermediate; 110: acyl-enzyme covalent intermediate; 11: free enzyme. Hydrogen bonds are

shown in green. They play crucial role in ester recognition, correct positioning in the catalytic pocket and

stabilisation of the negatively charged tetrahedral intermediate.

In fact, lipases are potentially ideal because they have been shown to be active in organic

solvents.[219]

The use of organic solvents is often essential because most organic substrates are

insoluble in water. It also excludes the reverse process, namely, the hydrolysis of the newly

formed amide. Proteolysis (peptide bond hydrolysis) is catalysed in the cell by a closely

related class of proteins, proteases, which share a mechanism that is similar to that of lipases

and involves the catalytic triad.

The catalytic triad refers to the three amino acid residues (Asp-His-X, where X is Ser, Asp or

Cys) that are commonly found in the active site of the α, -hydrolase superfamily. They work

together via formation of a tetrahedral intermediate and activation of small molecules

Chapter 2

51

(Scheme 63).[220]

The carboxylic group of aspartic acid forms a low-barrier hydrogen bond

with histidine, increasing the pKa of the imidazole nitrogen from 7 to about 12. This makes

His act as a strong general base which can deprotonate the acidic hydrogens of serine,

cysteine, aspartic acid and acidic substrates.

Scheme 63. Diverse catalytic activities of the α, -hydrolase superfamily. Simplified mechanisms for (a)

“classical” serine hydrolase–protease, (b) C-C hydrolase, (c) hydroxynitrile lyase.

Recently, Ema et al. reported the first hydrolase inspired biomimetic trifunctional

organocatalysts 112 and 113 (Figure 16), which significantly increased the reaction rate

between vinyltrifluoroacetate 114 and methanol or iso-propanol (Scheme 64).[221]

Control

compounds, lacking either the hydroxyl, pyridine or urea/thiourea moiety were inefficient.

This example of trifunctional organocatalysis is perhaps one of the most impressive ones.

However, it is very limited. Firstly, vinyl alcohol tautomerises to acetaldehyde and does not

act as a competitive nucleophile. Secondly, although vinyltrifluoroacetate 114 showed

impressive rate acceleration (reaction was complete in 30 min at 22 °C with 1 mol% 113 and

in 1 h with 112), the less reactive vinylacetate remained unreacted even with 1 equiv of 112.

Chapter 2

52

Figure 16. (a) Lipase active site catalytic triad. (b) Ema’s biomimetic trifunctional organocatalysts for

transesterication.

Scheme 64. Rate constants for catalysed transesterification. Urea derivative 113 accelerates reaction

3–5 times compared to thiourea-based catalyst 112 The kun values for acylations of MeOH and iPrOH

are 7.6·10–5

and 4.0·10–6

M–1

s–1

, respectively. un = uncatalysed.

Chapter 2

53

2.2 Results and Discussion

2.2.1 Introduction

The amide bond is prevalent in nature and its formation is heavily utilised in synthetic organic

chemistry.[158,159,178]

Despite the multitude of existing methods and strategies, there is a high

level of interest, particularly by the industrial community in more cost-efficient ways to

perform an amide coupling.[161,166,222]

There are many factors that come into play when determining the cost-efficiency of a

process.[222]

For chemists, the main issue is of course, atom efficiency, which may be equated

in this particular case to sustainability. However, one should not forget about the ease of

manipulation, purification and scaling-up, which all contribute to labour and engineering

costs; cost of coupling reagent, additives or catalyst; waste disposal costs including solvents;

and the energy costs (e.g. cooling or heating the reaction mixture). In this regard, the

employment of boronic acids as substoichiometric catalysts and perhaps, other simple boron

reagents represents an attractive alternative[131]

to already established methods.

In 2007, when this project was initiated, only Yamamoto‟s work,[131a,133,134–138]

Tang‟s note of

the activity of boric acid[139]

and Whiting‟s preliminary results on “Wulff-type” boronic

acids[141]

were available. Arylboronic/boric acids were shown to act as direct amidation

catalysts, however, somewhat inefficiently. In most of the examples, reaction mixtures were

heated at temperatures above 100 °C in high boiling point solvents and with water removal

using Dean–Stark apparatus. The use of such high temperatures is undesired because of

incompatibility with a number of protective and functional groups (e.g. N-Boc). Under these

conditions complex starting materials as well as arylboronic acids[140–142,223]

may also

decompose.

As for the mechanistic rationale behind the direct catalytic amidation of carboxylic acids at

that time, Yamamoto was able to synthesise and characterise by crude 1H NMR and IR a

monoacyloxyarylboronic ester 115 on heating 4-phenylbutyric acid with 3,5

bis(trifluoro)phenylboronic acid (in ratio 2:1) under reflux in toluene-d8 (Scheme 65).

Interestingly, intermediate 115 was very susceptible to hydrolysis and was able to react with

benzylamine at ambient temperature. Based on these results, a catalytic cycle, where in situ

generation of monoacyloxyarylboronic ester was assumed to be a rate-determining step, was

proposed.

Chapter 2

54

Scheme 65. Proposed mechanism for catalytic boron-based amide bond formation.[134]

The mixed anhydride 115 was supposedly stabilised by an intramolecular hydrogen bond.

Later, Whiting and co-workers stated that they could not observe such an intermediate by

ESI/MS and 1H NMR.

[141] In fact, they detected bis(acyloxy)arylboronate species 116,

diboronate 117 and boroxine 118 (Figure 17).

Figure 17. Observed intermediates and species in boronic-acid catalysed carboxamidtions: by (a)

Yamamoto and (b) Whiting.

The use of elevated temperatures alongside water removal also raised the question whether a

carboxylic acid anhydride could be formed in situ at higher temperatures. Direct condensation

of ammonium salts has also been achieved under high temperatures without a catalyst,[180]

although this process is highly substrate and temperature-dependent. [185]

Notably, the boronic

and boric acid-catalysed amidations are also substrate and temperature-dependent.[141,142]

Another interesting issue is solvent effects. Most reactions using arylboronic acids were

carried out in arenes (e.g. fluorobenzene, toluene, mesitylene), out of which at ambient

temperatures the ammonium salt precipitates rapidly and quantitatively.[244]

Improved

catalyst, N-methyl-4-boronopyridinium iodide 33, reportedly[224]

showed better performance

in polar aprotic solvents such as NMP and N-benzylpyrrolidone.[135a]

Unfortunately, no

Chapter 2

55

solvent screening data was provided and boronic acid 33 was used in toluene/[emim][OTf]

5:1 mixture as solvent.

2.2.2 Aims and Objectives

Initially, this project aimed to improve the catalytic performance of boronic acids in direct

carboxamidation. This was to be achieved through design and evaluation of a small set of

boronic acids, which would also incorporate a general base (Figure 18). Such a strategy is in

fact nature-inspired as similar catalytic triads/diads (such as those described in the earlier

sections) are found in hydrolases. However, later work by Ema et al. on trifunctional

hydrolase-like organocatalysis, showed how highly substrate-dependent these systems are.[221]

Figure 18. Envisaged potential catalysts for direct amide bond formation.

The strategy was based on incorporating additional functionalities into an arylboronic acid

skeleton to enhance the overall reaction rate. It was hoped that an intermolecular transfer of

the acyl moiety from the acyloxyboron species (regardless whether it is mono or bis) to

another intramolecular nucleophile would yield a more readily reactive intermediate 124

(Scheme 66). The transfer step could be favoured as the change in entropy for the

intramolecular step would be minimal.

It was envisaged that the additional functionalities (X in Scheme 65) would be based on

common acyl transfer reagents, such as 1-hydroxybenzotriazole (catalyst 119) and N,N-

dimethylaminopyridine (catalyst 122). In addition, since aminolysis of thioesters is a fast

process in comparison to that of oxoesters,[225,226]

incorporation of a thiol moiety into the

boronic acid‟s skeleton was also pursued.

Chapter 2

56

Scheme 66. Proposed modified catalytic cycle.

Although the structures of the proposed catalysts might look simple, as we found out, they

are not easy to prepare. Firstly, because they contain a number of functional groups in close

proximity to each other. Secondly, this sets strict limits on how they can be assembled so as

not to compromise the neighbouring groups. For instance, we have looked into construction

of DMAP-type quinoline-based boronic acid 122 (Scheme 667).[227–231]

The original strategy

was based on successive intramolecular cyclisation/aromatisation reactions. However, both

the corresponding ester and amide failed to cyclise. Another route attempted was via

quinoline oxidation, analogous to that reported for a similar substrate.[231]

Later in the

programme, it was recognised that the proposed catalysts 120–122 were perhaps s too rigid to

act as effective catalysts. These conclusions were drawn in part from Hall‟s work that

appeared in 2008.[132b]

Nevertheless, a full discussion of the strategies employed and/or

attempted to synthesise catalysts 119 and 123 are provided below.

Chapter 2

57

Scheme 67. Strategies to catalyst (4-(dimethylamino)quinolin-8-yl)boronic acid.

2.2.3 Synthesis of Boronic Acids

The high reactivity of boronic acids especially in the presence of transition metals and acids

(e.g. protodeboronation) dictated that the boronyl moiety should be introduced towards the

end of the synthesis.

2.2.3.1 Synthesis of (1-Hydroxy-1H-benzo[d][1,2,3]triazol-7-yl)boronic acid

It was thought that 1-hydroxybenzotriazole derivative 119 would be accessed via borylation

of 7-halosubstituted 125, which would be prepared from 2,6-dihalonitrobenzene 126 (Scheme

68).

Chapter 2

58

Scheme 68. Principal retrosynthetic analysis for (1-hydroxy-1H-benzo[d][1,2,3]triazol-7-yl)boronic acid.

Having taken into consideration that several methods for borylation of aryl chlorides

exist,[18,22–24,28]

the first strategy that was pursued used commercially available 2,6-

dichloroaniline 127a as a starting material. It was oxidised with NaBO3/AcOH to give the

corresponding nitro compound 126a (Scheme 69).[232]

While this protocol was previously

reported to give 126a in an 87% crude yield, the two unoptimised runs in our hands afforded

126a only in 24% and 31% yields after purification. The starting material was not consumed

even after prolonged reaction times and the use of further excess of sodium perborate.

Scheme 69. Synthesis of 7-chloro-1H-benzo[d][1,2,3]triazol-1-ol.

Next, 2,6-dichloronitrobenzene 126a was converted to 7-chloro-1-hydroxybenzotriazole

125a. [223–234]

Under optimised conditions, the reaction was carried out under argon in

anhydrous ethanol with an excess of hydrazine monohydrate (15–20 equiv) and 5 mol%

NaOAc. The reaction mixture was then quenched with NaHCO3 solution, the aqueous layer

was washed with ether, and the product was precipitated out of solution by addition of

concentrated HCl solution. The two separate runs afforded 125a in 61% and 58% yields.

The conversion of aryl chloride 125a to arylboronic acid or ester, however, proved

unsuccessful (Table 3). Although precedented with aryl chlorides, both insertion of lithium

and magnesium into carbon–chlorine bond[18]

and Pd-catalysed Miyaura borylation,[22–24,28]

did not lead to any detectable formation of boronic acid or ester, respectively.

Chapter 2

59

Table 3. Attempted routes to borylation of 7-chloro-1-benzotriazole 125a.

entry conditions observations ref

1 Pd(dba)2, PCy3, B2pin2,

KOAc, 48h, DO, 80 ºC

complex mixture,

starting material not consumed

[22]

2 (i) BuLi, THF, –78 °C;

(ii) B(OMe)3

no indication of Cl/Li exchange;

when quenched with D2O, no

deuterated product was observed

[17]

3 (i) Li granula, THF, –40 °C;

(ii) B(OMe)3

no indication of Cl/Li exchange [18]

4 (i) Mg, THF, 70 °C;

(ii) B(OMe)3, 16 h, 70 °C

no indication of Cl/Mg exchange [18]

5 Pd(OAc)2, IMes, B2pin2,

KOAc, THF, 10 min, 110 ˚C,

MW

no product formation [23]

Next, a directed metalation strategy was explored. It was hypothesised that the hydroxyl of 1-

hydroxybenzotriazole 85 or its MOM-protected variant 128 could act as a directing group for

ortho-lithiation (Scheme 70). However, no formation of the desired products 119 or 129 was

observed in either of the cases. In addition to standard sequential borylation procedure, an in

situ trapping directed lithiation/borylation protocol[235]

was tested.

Scheme 70. Attempts towards directed ortho-lithiation/borylation. MOM = methoxymethyl, LTMP =

lithium 2,2,6,6-tetramethylpiperidide.

The rising popularity of oxidative C–H activation/functionalisation, tempted us to explore an

approach in analogy with Sanford‟s and Yu‟s Pd-catalysed halogenation reports (Scheme

71).[236–239]

Ideally, the hydroxyl group could act as a directing group in a manner shown in

Scheme 33 promoting C–H activation at the C7 position (Scheme 72). Then, an electrophilic

Chapter 2

60

halogenating agent (NBS or NIS in our case) could oxidatively add to palladium(II) system

130 to give a Pd(IV) complex 131. As the successive reductive elimination of aryl halide is

more favoured from Pd(IV) rather than Pd(II), the reaction would afford the corresponding

aryl halide 125. Unfortunately, in systems with glacial acetic acid or acetonitrile as a solvent

and NBS, NIS and IOAc (generated in situ from I2 and PhI(OAc)2) as oxidants, only

nitrogen–oxygen bond cleavage products were observed by LC/MS. Interestingly, several

groups later successfully utilised such N–O bond cleavage in a number of palladium-catalysed

oxidative C-H activation/derivatisation approaches (Scheme 73).[240–242]

Scheme 71. (a) Sanford’s and (b) Yu’s approaches to C–H activation/halogenation.[236–239]

Scheme 72. Proposed mechanism for Pd-catalysed C–H activation/halogenation of 30.

Scheme 73. Cleavage of N–O bond in palladium-catalysed (a) amination of aromatic C−H bonds with

oxime esters,[240]

(b) C−H amidation N-nosyloxycarbamate,[241]

(c) synthesis of heteroaryl ethers from

pyridotriazol-1-yloxy heterocycles and boronic acids.[242

Chapter 2

61

Since borylation of the aryl chloride 125a was troublesome, an aryl bromide analogue 125b

was synthesised in a similar fashion (Scheme 74). Oxidation of 2,6-dibromoaniline with either

sodium perborate[232]

or Oxone® in a biphasic system

[243] were both unsuccessful. Oxidation

with TFA/H2O2[244]

in contrary to a previous report, gave a nitroso compounds 132. Therefore,

a two-step oxidation protocol in order to access 126b was applied.[245]

Aniline was first

converted with MCPBA to the nitroso compound, which was then oxidised to the nitro

derivative with catalytic nitric acid and hydrogen peroxide as a terminal oxidant. We

subsequently found that 2,6-dibromoaniline could also have been oxidised in one step, if

treated with MCPBA for 48 h rather than 4 h (98%).

Scheme 74. Successful synthesis of 7-bromo-1-hydroxybenzotriazole 171.

When 126b was subjected to the same reaction conditions as the dichloro analogue 126a

(benzotriazole formation), the product did not precipitate out of the aqueous phase upon

treatment with concentrated HCl. The water was therefore removed under reduced pressure

and the resulting residue was re-dissolved in a minimum amount of water and only then

treated with acid to give the product in 58–65% yield.

To deliver the desired boronic acid via halogen/metal exchange-borylation sequence, the

benzotriazole derivative 125b was first protected with a benzyl group (Scheme 75). To avoid

tele-substitution on the heteroaromatics, the Mitsunobu protocol was employed.[246]

Such a

conversion was thought to be feasible, as the pKa of 1-BtOH was reported to be 4.60;[247]

and

indeed, the protection worked smoothly. The difficulties with the benzyl-protected compound

133, however, arose on the lithiation/borylation step. Namely, compound 134 was identified

as a major product. It formed as a consequence of base promoted formation of benzaldehyde,

which was later trapped by the aryl lithium species. A number of attempts was made to

optimise the reaction. However, conducting the reaction at –100 ºC, slow addition of BuLi as

well as addition of BuLi to a mixture of aryl bromide and borate did not lead to detectable

amounts of the desired product (by LC/MS and 1H NMR). The use of „turbo-Grignard‟

reagent, iPrMgCl∙LiCl,

[248] was also explored. In addition to benzaldehyde-derived

Chapter 2

62

benzotriazole, formation of 135 was observed by LC/MS and confirmed by HRMS (for

C6H5BrN3 [M+H]+ found 197.9663, calc. 197.9667).

Scheme 75. Reactions with 1-benzyloxy-1H-benzo[d][1,2,3]triazole.

Hence, there was a need to switch to a protecting group that bears no protons on the carbon

adjacent to oxygen and is easily cleavable, i.e. tert-butyl (Scheme 76). Because the Mitsunobu

protocol would not lead to the formation of the desired borylated product, to protect the

hydroxybenzotriazole 125b Widmer‟s esterification procedure with N,N-dimethylformamide

di-tert-butyl acetal was employed.[249]

This gave a mixture of 136 and 137. The latter product

arises from N-attack (Scheme 77) and was identified by characteristic signal shifts in 1H NMR

spectrum in agreement with the previous work by Katritzky.[250]

Additionally, it is known that

N-oxides arise in alkylation of hydroxybenzotriazoles.[251]

Subsequent lithiation/borylation of 136 gave the corresponding boronic acid 138.

Deprotection of the tert-butyl moiety was conducted in the TFA/DCM system. Initially, 138

was treated with 2 equiv of TFA in DCM for ten minutes, however, simultaneous tert-butyl

deprotection and protodeboronation was observed. Reducing the amount of acid employed

down to 0.2 equiv led to clean formation of the desired material 139 in quantitative yield.

Scheme 76. Synthesis of (1-hydroxy-1H-benzo[d][1,2,3]triazol-7-yl)boronic acid.

Chapter 2

63

Scheme 77. Proposed mechanism for N-oxide formation.

2.2.3.2 Synthesis of “Sulfur-Armed” Boronic Acid

Thioesters are known to undergo aminolysis much faster than their oxoester counterparts.

Hence, it was deemed useful to explore the effect of a sulfhydryl-bearing substituent in the

boronic acid. (2-(Mercaptomethyl)phenyl)boronic acid 123 was selected as a most convenient

structure to assess the feasibility of the effect (Scheme 78).

Scheme 78. (2-(Mercaptomethyl)phenyl)boronic acid.

Initially, a number of aryl bromides with a free or S-protected thiol were prepared (Scheme

79). Tritylthiol and thioacetate were installed by nucleophilic substitution of 2-bromobenzyl

bromide. Thioacetate 141 also underwent deprotection under basic conditions to free thiol

142. However, attempted lithiation/borylation of these aryl bromides failed to give the desired

product.

Scheme 79. Synthesis of sulphur-containing bromides.

Chapter 2

64

However, a complementary route was based on elaboration of benzylic protons in ortho-

tolylboronic acid, which exists in the boroxine form (ArBO)3 (Scheme 80). Radical

bromination by N-bromosuccinimide in the presence of AIBN as initiator led to benzyl

bromide 143,[252–253]

which was successfully converted to the corresponding S-protected

boronic acid 144.[254]

However, attempted deprotection with K2CO3/MeOH led to the

formation of a complex mixture of products. As the free thiol 123 could not be isolated in a

clean form, it was decided to use the crystalline S-acetylated boronic acid as a pre-catalyst. In

the actual amidation system, a sacrificial amount of amine should readily deprotect the

thioacetate 144 generating the active catalyst 123 in situ (Scheme 81).

Scheme 80. Synthesis of sulphur-containing bromides.

Scheme 81. Thioacetate-based pre-catalyst activation.

2.2.4 Evaluation of Boronic Acids and Borates for Catalytic Amide Bond Formation

All the experiments, including the screening reactions, discussed below were performed with

equimolar amounts of amine and carboxylic acid. In the very first screen, several small

molecules (loading 5 mol%) were screened for catalytic activity in amide formation between

of 4-phenylbutyric acid and benzylamine (Table 4). These results indicated that at least for

this combination of amide coupling partners, the condensation reaction proceeded without a

catalyst to a reasonable extent (80% conv). As expected, both PhB(OH)2 and boric acid

enhance the reaction progression to give essentially full conversions. Additionally, some

catalytic activity was observed with silicon-based reagents (Ph2SiCl2 and PhSi(OH)3). The

silicon-based reagents were screened as phenylsilane, PhSiH3, has been reported as a reagent

Chapter 2

65

for amide bond formation that acted in a fashion similar to that of boranes, i.e. the reaction

proceeded via acyloxysilanes.[255]

Table 4. The extent of background reaction in carboxamidation at high temperature.a

entry catalyst conv%b

1 – 80

2 PhB(OH)2 99

3 B(OH)3 97

4 Ph2SiCl2 92

5 PhSi(OH)3

88

6 Ph2Si(OH)2

70

a Reaction conditions: acid (1 equiv), amine (1 equiv), catalyst (5 mol%), PhMe, 130 ºC, carousel tube, 20 h.

b Determined by

1H NMR (DMSO-d6).

Due to the high level of the background reaction, another set of experiments was conducted at

lower temperature (80 °C) and shorter reaction times (Table 5). In this case the thermal

reaction was suppressed. The activities of phenylboronic acid and boric acid fell drastically in

comparison to the reactions at higher temperature, indicating that the reaction temperature has

a drastic effect on progression of both the thermal and catalysed reactions. Both trimethyl

borate and tetrachlorosilane, although employed in stoichiometric amounts, showed superior

results. In addition to activating carboxylic acids directly by forming acyloxyboron and

acyloxysilicon species, respectively, they may also promote the reaction by serving as

effective dehydrating agents. The use of SiCl4 in pyridine as a reagent for amide formation

was reported in the late 1960s.[256]

The conditions used for screening were later modified to allow faster data acquisition and

fewer sampling errors, especially to minimise the impact of various work-up manipulations.

Hence, amidations were conducted in a microwave (CEM, 150 W) at 100 ºC for 10 min.

Then, DMSO was added to dissolve the insoluble material that usually crystallised on cooling

to RT. A small sample was then transferred to an NMR tube and diluted with DMSO-d6. In

Chapter 2

66

the 1H NMR spectrum (600 MHz), a doublet for the benzylic methylene of the product lies

downfield of that of the starting material. The ratio of integrals for these two signals was used

to determine the extent of the reaction.

Table 5. Progress of the direct carboxamidation under milder conditions.a

a

Reaction conditions: acid (1 equiv), amine (1 equiv), reagent (x mol%), 0.5 M PhMe, 80 ºC, 3 h.

b Determined by

1H NMR (DMSO-d6).

Next, a focused subset of boronic acids and boroxoaromatic compounds was screened under

these microwave conditions (Table 6). Yamamoto‟s catalyst 28 proved to be superior.

Interestingly, Hall‟s ortho-iodophenylboronic acid 47 showed diminished results in

comparison to the bromo analogue 48. The sulfur-containing boronic acid 144 was ineffective

and this may be due to S→B coordination.

The hydroxybenzotriazole-based boronic acids 138 and 119 did not show significant catalytic

effect. This perhaps can be explained by protodeboronation of both 138 and 119, as based on

further examination of 1H NMR spectra recorded of the reaction mixtures of these amidation

reactions. Namely, the doublet at > 8 ppm, characteristic for the hydrogen bonded to carbon

ortho to the carbon–boron bond, had disappeared during the attempted reaction.

entry catalyst/reagent mol% conv%b

1 – 5 2

2 PhB(OH)2 5 6

3 3-NO2C6H4B(OH)2 5 8

4 3-NO2C6H4B(OH)2/PhSH 5/5 8

5 B(OH)3

5 5

6 B(OMe)3

100 38

7 Ph2SiCl2 5 3

8 SiCl4 100 76

9 Ph2Si(OH)2 5 4

Chapter 2

67

Gratifyingly, alkylboronic acids were also catalytically active. No-one has explored them as

potential catalysts because they are regarded to be somewhat unstable. However, they are

considerably stable under transition metal-free conditions and are able to catalyse the reaction

better than simple arylboronic acids. Hence, it may serve as a good basis for developing new

catalysts for carboxamidation. Not only because their aliphatic scaffold allows easier

introduction of functional groups, but also the arrangement and placing of these groups can be

varied to a larger degree in the three-dimensional space.

Table 6. Focused library screen of potential boron-based catalystsa,b

Conversions are shown in blue.

a Conversions were determined by

1H NMR (DMSO-d6).

b Reaction conditions: acid (1 equiv), amine (1 equiv), reagent (5 mol%), 0.5 M MeCN, 100 ºC, MW, 10 min.

c with 1 equiv of reagent instead of 5 mol%.

However, we decided to concentrate our efforts on borate esters. They could provide us with a

better understanding of factors contributing to successful boron-mediated and/or catalysed

direct carboxamidation. Additionally, though required in equimolar amounts, a number of low

cost and sustainable borate esters are commercially available except for B(OCH2CF3)3. This,

in fact, could facilitate their acceptance as a convenient alternative to the already known

classes of coupling agents.

Chapter 2

68

To date, a single example of direct amidation using trimethyl borate was presented by Pelter

et al. in 1970 (Scheme 82).[257]

Namely, caproic acid and N-butylamine were heated under

reflux in trimethyl borate for 25 h in the presence of catalytic amounts of para-

toluenesulfonic acid to gave a mixture of N-butylcaproamide and methyl caproate. In the forty

years that followed this precedent, no further use of borate esters as amide coupling agents

has been reported.

Scheme 82. Carboxamidation in refluxing trimethyl borate.[257]

Firstly, a number of commonly used solvents were screened (Table 7). At 80 ºC, in the

absence of drying agents and/or apparatus, toluene – the most commonly used solvent in

boronic acid-catalysed amidations – was one of the least efficient solvents (entry 8). In

methanol, no reaction was observed presumably because MeOH coordinated to the borate

ester, diminishing its reactivity (entry 10). Amidation reaction conducted in methyl tert-butyl

ether (MTBE) turned out to be inefficient as well (entry 9). However, aprotic polar solvents

(NMP, MeCN, DMSO, THF and DCE) proved to be significantly better for this

transformation (entries 1–2, 4–7). Since both NMP and DMSO are somewhat practically

inconvenient due to their high boiling points, acetonitrile was selected as the best solvent for

this process. When B(OMe)3 was used as a solvent (at the same concentration, i.e. 18 equiv of

borate), a conversion of only 30% was achieved.

We then examined the amount of borate ester added vs. the conversion after three hours under

thermal conditions (Graph 1). As expected, an equimolar amount of trimethyl borate was

required to reach significant conversion (36%). However, further increasing the amount of

borate ester up to two and three equivalents did not lead to any major improvements.

The solvent screen results pointed out a pronounced deactivation of the borate ester by

potential by-products of the reaction such as MeOH. This may involve formation of stable

tetrahedral alcohol–borate complexes.

Chapter 2

69

Table 7. Solvent effects in B(OMe)3-mediated carboxamidations.a

a Reaction conditions: acid (1 equiv), amine (1 equiv), B(OMe)3 (1 equiv), 0.5 M solvent, 100 ºC, MW, 10 min.

b

Determined by 1H NMR (DMSO-d6).

c 1,3,5-(MeO)3C6H3 used as an internal standard.

d BnNHCHO, a transamidation

product arising from DMF, was the major product. e In the absence of B(OMe)3.

Graph 1. Progression of carboxamidation in relation to amount of B(OMe)3 employed with the same

initial concentration of phenylacetic acid and benzylamine.a,b

a Reaction conditions: acid (1 equiv), amine (1 equiv), B(OMe)3 (1 equiv), 0.5 M MeCN, 80 ºC, 3 h.

b Conversions

determined by 1H NMR (DMSO-d6).

entry solvent conv%b entry solvent conv%

b

1 NMP 40

7c DCE 19

2 MeCN 36 8 PhMe 12

3 B(OMe)3 30 9 MTBE 4

4 DMSO 27 10 MeOH 0

5 THF 20 11 DMF –d

6 THF (dry) 17 12 MeCN 2e

Chapter 2

70

We then screened for an additive that could potentially enhance borate ester-mediated

carboxamidation (Table 8). At first, we observed that protic additives, especially alcohols,

strongly diminished conversions (entries 5–13, 15–18). Among compounds screened were

diols (entries 11–13), which are known to give rise to boronate esters in situ.[258]

It was hoped

that they could aid transfer of the carboxylic acid onto boron as shown in Scheme 83a. Use of

Brønsted and Lewis acids could potentially stabilise the tetrahedral intermediates as shown in

Scheme 83b but this was also ineffective (entries 17–19 and 30–33, respectively). Addition of

bases (entries 21–29) or using 0.2 equiv excess of either carboxylic acid or amine (entries 2–

3) did not improve conversion.

Scheme 83. Strategies to affect borate ester-mediated amidation.

We also examined 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) and 2,3-dihydro-1,4-

phthalazinedione as additives (entries 20, 27–28). Although hydrogen bonding catalysis is

very rarely observed in amidation reactions,[259]

Mioskowski showed that TBD stabilised the

tetrahedral intermediate by internal hydrogen bonding in the case of ester amidation (Scheme

84a).[260]

Additionally, Iwata and Kuzuhara employed 2,3-dihydro-1,4-phthalazinedione in N-

formylation of primary amines (Scheme 84b).[261]

However, neither of the reagents proved to

be beneficial in our hands.

Finally, the only combination that led to an increase in conversion was the use of 0.2 equiv

excess of both the acid and the borate ester.

Chapter 2

71

Table 8. Assessment of various additives in B(OMe)3-mediated carboxamidations.a

a Reaction conditions: acid (1 equiv), amine (1 equiv), B(OMe)3 (1 equiv), additive (x equiv), 0.5 M MeCN, 100 ºC,

MW, 10 min. b Determined by

1H NMR (DMSO-d6).

entry additive x equiv conv%b

1 – – 36

2 BnNH2 0.2 24

3 BnCOOH 0.2 33

4 BnCOOH + B(OMe)3 0.2 + 0.2 42

5 H2O 1 19

6 MeOH

1 6

7 B(OH)3 1 14

8 CF3CH2OH 1 15

9 PhOH 1 30

10 4-NO2C6H4OH 0.2 1

11 catechol 0.2 36

12 catechol 1 9

13 (CH2OH)2 1 1

14 DMSO-d6 0.2 24

15 PhSH 0.2 28

16 3,4,5-F3C6H2B(OH)2 0.1 8

17 BtOH 0.2 28

18 TsOH∙H2O 0.2 18

19 HCl∙Et2O 0.2 26

20 phthNHNH 0.2 28

21 DMAP 0.2 29

22 Im 0.2 27

23 N-MeIm 0.2 31

24 N-MeIm 1 29

25 TEA 0.2 37

26 TEA 1 31

27 TBD 0.2 6

28 TBD 1 4

29 DIPEA 1 24

30 LiCl 0.2 6

31 MgCl2 0.2 6

32 MgSO4 0.2 28

33 Mg(ClO4)2 1 11

Chapter 2

72

Scheme 84. Hydrogen bonding catalysis in amidations: (a) TBD-catalysed ester amidation and (b) 2,3-

dihydro-1,4-phthalazinedione-catalysed N-formylation of primary amines.

Several boron and silicon reagents were then screened as stoichiometric reagents under

microwave conditions (Table 9). Both triphenyl and tris(2,2,2-trifluoroethyl) borates showed

significantly improved reactivities (entries 7–8). However, only B(OCH2CF3)3 was chosen to

study scope and limitations. Yamamoto‟s catalyst (3,4,5-trifluorophenylboronic acid) did not

serve as a good promoter under these reaction conditions (entry 5).

Activation of the carboxylic acid presumably occurs via in situ generation of a four or three-

coordinated boron species 145a or 145b (Scheme 85).

Chapter 2

73

Table 9. Assessment of various simple borate esters and orthosilicate as reagents carboxamidations.a

a Reaction conditions: acid (1 equiv), amine (1 equiv), reagent (1 equiv), 0.5 M MeCN, 100 ºC, MW, 10 min.

b Determined by

1H NMR (DMSO-d6).

Scheme 85. Plausible mechanism of borate ester mediated carboxamidation. rds = rate-determining

step.

entry reagent conv%b

1 – 2

2 B(OMe)3 36

3 B(OiPr)3 9

4 B(OTMS)3

9

5 3,4,5-F3C6H2B(OH)2 19

6 Si(OMe)4

22

7 B(OCH2CF3)3 63

8 B(OPh)3 73

Chapter 2

74

2.2.5 Borates as a Novel Class of Coupling Reagents for Amide Bond Formation

With the optimised results in hand, it was insightful to look at the substrate scope of both

B(OMe)3 and the borate derived from a more electron-deficient alcohol B(OCH2CF3)3 In

order to do so, reactions were carried out with two equivalents of the borate ester. An excess

of borate ester ensures that the overall conversion is not compromised by coordination of a

by-product (an alcohol or boric acid) to the remaining borate. Additionally, for each

carboxylic acid–amine combination, we tested borate-free reaction conditions to assess the

thermal contribution towards the carboxamidation reaction.

Tris(2,2,2-trifluoroethyl) borate showed superior activities throughout the series, however, in

a number of cases low cost and commercially available B(OMe)3 was sufficient to promote

amidation in satisfactory to very good yields (Table 10, entries 1–3, 7–9, 11, 15–16).

Reactions with less reactive acids, such as benzoic and pivalic acids were conducted at higher

temperatures (entries 5–6); while p-aniside also gave the amide 146n in a good yield (entry

14).

Both volatile substrates (entries 9–10) and those containing polar groups such as free

hydroxyl and unprotected indole (entries 7, 11) were tolerated. Tris(2,2,2-trifluoroethyl)

borate showed the most improvement over B(OMe)3 in the case of α,β-unsaturated carboxylic

acids (Entries 12–14). However, coupling of 3-thiophenylcinnamic acid and pyrrolidine gave

only 10% of product 146q (Scheme 86).

Scheme 86. Amide coupling between 3 thiophenylcinnamic acid and pyrrolidine. aIsolated yield.

Importantly, α-branched carboxylic acids and amines were reactive under these conditions. Of

note are also results with Boc-L-alanine (enry 16). Trimethyl borate promoted reaction in a

reasonable conversion and with no racemisation as determined on Diacel® Chiralpak

® OD-H

column (7–10% iPrOH/hexane). It was gratifying to see that B(OCH2CF3)3 was also able to

promote amidation without N-Boc cleavage. This result is somewhat unexpected as

B(OCH2CF3)3 may act as a strong Lewis acid and this is supported by its Gutmann Acceptor

Chapter 2

75

Number (AN) value of 66.4.[262]

However, under unoptimised conditions, the product was

obtained in good yield with a minor loss in enantiopurity (88% ee). The small degree of

epimerisation indicates that it takes place in the early steps of amidation, most likely when the

carboxylic acid is activated, i.e. forms acyloxyboron species (Scheme 85). Hence, the

racemisation-sensitive amidations can be optimised by controlled addition of a borate ester

and/or lowering the reaction temperature.

Table 10. Borate-promoted direct amide bond formation.

entry product isolated yield, %

a

B(OCH2CF3)3b B(OMe)3

b thermal

c

1

146a 91 (74)d 92 (66)

d 18

2

146b 70 73 <1

3

146c 70 51 7

4

146d 76 44 5

5

146e 14 (50)e 2 0

6

146f 27 (71)e 12 <1

7

146g 92 45 9

8

146h 82 51 6

9

146i 66 66 6

continued on next page

Chapter 2

76

a Purified by acid-base extraction, except for entry 14, where flash chromatography was used.

b Reaction conditions:

acid (1 equiv), amine (1 equiv), borate (2 equiv), 0.5 M MeCN, 80 ºC, 15 h. c

Reaction conditions: acid (1 equiv),

amine (1 equiv), 0.5 M MeCN, 80 ºC, 15 h. d Reaction conditions: acid (1 equiv), amine (1 equiv), borate (1 equiv), 0.5

M MeCN, 80 ºC, 15 h. e

Reaction conditions: acid (1 equiv), amine (1 equiv), borate (2 equiv), 0.5 M MeCN, 100 ºC,

caurosel tube, 15 h. f From amine-HCl salt, with

iPr2NEt (1 equiv).

g 88% ee.

h >99% ee.

Hydrochloride salts of amines can also be used as starting materials, although an equivalent of

Hünig‟s base is additionally required (entry 15). The base deprotonates the ammonium salt

resulting in a free amine that goes into the solution phase. In the absence of a base, the

starting material was not soluble and no reaction was observed.

Encouraged by the compatibility of B(OCH2CF3)3 with the Lewis and Brønsted acid-sensitive

N-Boc moiety and the low degree of racemisation in the case of N-Boc-L-alanine (entry 16),

an experiment to test direct amidation of an unprotected amino acid, namely, L-alanine was

conducted with benzylamine (Scheme 87). In the absence of base, the amino acid remained

insoluble in acetonitrile and no product was formed. However, when 1 equiv of Hünig‟s base

continued from previous page

entry product isolated yield, %

a

B(OCH2CF3)3b B(OMe)3

b thermal

c

10

146j 61 36 3

11

146k 70 quant 9

12

146l 71 17 8

13

146m 95 11 6

14

146n 72 4 0

15f

146o 94 60 5

16

146p 81g 49

h 7

Chapter 2

77

was added, pleasingly, the desired amide 146r was observed as a major product in 1H NMR

(DMSO-d6). Dipeptide Ala–Ala was the minor product. Due to time restriction, no further

experiments with free amino acids were conducted, though it should be noted that

racemisation of the unprotected α-amino acid is not expected to occur under these conditions.

Scheme 87. Amide synthesis from free α-amino acid. a Determined by

1H NMR (DMSO-d6).

A similar protection/activation[263]

strategy was reported by Liskamp and co-workers (Scheme

88).[264]

They first prepared a BF2-complex 147 from lithium salt of (S)-phenylalanine, and

after purification by flash chromatography treated with 2 equiv of benzylamine, to give the

desired amide in 45% over two steps. The same strategy was also pursued with

dichlorosilanes (e.g. Ph2SiCl2) in pyridine followed by an excess of amine (3–5 equiv).[265]

Unfortunately, couplings with secondary amines were rather poor (with maximum yield up to

17%).

Scheme 88. Stepwise simultaneous protection-activation strategy for amide coupling of amino

carboxylates.

It was expected that the Lewis acidity of B(OCH2CF3)3 would be higher than that of other

borate esters and boronic acids. Hence, this reagent could potentially activate other carboxyl

compounds such as esters and/or amides. When methyl phenylacetate was treated with

benzylamine in the presence of B(OCH2CF3)3, no amidation product was observed (Scheme

89). This allowed us to successfully couple L-phenylalanine ethyl ester hydrochloride with

phenylacetic acid (Table 10, entry 15) without formation of by-products arising from ester

amidation. However, as expected, B(OCH2CF3)3 proved to be successful in activating more

nucleophilic primary amides and in the section below we demonstrate several examples of

transamidation reaction (Section 2.2.6).

Chapter 2

78

Scheme 89. Attempted ester amidation.

2.2.6 Tris(2,2,2-trifluoroethyl) Borate as a Reagent for the Activation of Primary

Amides

Amides are one of the most widely employed bond types in natural systems. They are often

used as linkers in medicinal chemistry and chemical biology because they are stable in the

cellular environment, i.e. they do not get readily reduced or hydrolysed. In synthetic

chemistry, transformations of amides often require highly nucleophilic reagents or pre-

activation (Scheme 90). There are two major strategies for this latter approach: (a) use of

Lewis acidic catalyst or promoter to generate an activated intermediate 148;[266–268]

or (b)

formation of an iminium salt 149 upon treatment with triflic anhydride.[269–270]

Additionally,

amides can be activated with oxalyl chloride[271]

but this approach is not compatible with

reductions and transamidation reactions.

Scheme 90. Activation of amides. All = allyl, HEH = Hantzsch ester.

In our hands, primary but not secondary or tertiary amides were activated in situ by

B(OCH2CF3) towards transamidation reactions (Table 11). Substrates containing polar groups

such as free hydroxyl and indole were tolerated. Moreover, several other boron reagents such

Chapter 2

79

as Yamamoto and Hall boronic acids, borate esters, B(OR)3 (where R = TMS, Ph, Me) and

tetramethyl orthosilicate, Si(OMe)4 did not promote transamidation. Essentially, this is the

first example of boron-promoted transamidation as well as a very rare example of the

transamidation of primary amides. Notably, Tf2O-mediated activation of primary amides was

not reported and metal systems, e.g. Ti(NMe)4 or and Zr(NMe)4 react with primary amides to

form imido species ([M]=N) which react further to give amidines.[266]

Myers developed a

strategy to circumvent this event by pre-forming N‟-acyl-N,N-dialkylformamidines 150 that

eventually react with amines in the presence of 0.5 equiv of ZrCl4 (Scheme 91).[268]

Bertrand

showed that stoichiometric use of AlCl3 can promote such amidations, but the amide/amine

ratio was 1:2.5–3.5 (Scheme 92).[266e]

Table 11. Transamidation of primary amides.a,b

a Reaction conditions: amide (1 equiv), amine (1 equiv), borate (2 equiv), 0.5 M MeCN, 100 ºC, carousel tube, 15 h.

b Transamidations were performed on 0.5–3.0 mmol scale. cIsolated yield.

entry product yieldc

1

146s 73

2

146t 63

3

146u 82

4

146v 62

Chapter 2

80

Scheme 91. Myers approach to transamidation of primary amides by in situ formation of N’-acyl-N,N-

dialkylformamidines.[268]

Scheme 92. Aluminum chloride-mediated transamidation of acetamide.[266e]

2.2.7 Mechanistic Considerations

As this report was in the final stages, a computational study on the mechanism of boronic

acid-catalysed direct amidations was reported (Scheme 93).[143]

Marcelli used DFT-

experiments (MPW1K, gas-phase) to construct a likely catalytic cycle and interpret the high

catalytic ability of ortho-haloboronic acids in this transformation.

Marcelli proposed that the carboxylic acid and not the carboxylate reacts with the boronic

acid to give the acyloxyboronate species 151. This is due to a significantly higher activation

barrier if the reaction were to proceed from the carboxylate, regardless of several groups'

reports that ammonium salt formation on mixing of primary amine and carboxylic acid is

instantaneous.[134,141–142]

It was then estimated that conversion between acyloxyboronate 151

and acyloxyborate 152 has a low energetic barrier (1.4 kcal/mol), however, nucleophilic

attack on the four-coordinated boron species 151 is favoured by 6.8 kcal/mol. The expulsion

of water is next, and it is the rate-determining step, at least as calculated for primary amines

(Ea = 20.1 kcal/mol). Hall's ortho-halophenylboronic acids catalyse direct carboxamidation at

this stage by acting as mild Lewis bases. Further dissociation of amide from boron is fast.

These calculations do not exclude nucleophilic attack on the bisacyloxyboronate species 153.

Chapter 2

81

Scheme 93. (a) Lowest-energy calculated catalytic cycle.[143]

(b) Diagram of the catalytic reaction

proceeding via acyloxyboronate species 151 (energy vs. reaction progression)

Chapter 2

82

These finding are in agreement with previous observations. In his work on boronic acid-

catalysed 1,3-dipolar additions to unsaturated carboxylic acids, Hall observed only a three-

coordinated species similar to 152 but 13

C NMR.[132b]

This can be explained by a low

energetic barrier between tetra and three-coordinated species 151 and 152 (1.2 kcal/mol) as

calculated by Marcelli.

However, in all reported cases employing boronic acid-catalysis removal of water is required

to achieved high conversions. This may mean that water and/or other protic substrates may

intervene with the catalytic cycle by coordinating to boron or hydrolysing the resulting

carboxylic acid/boric acid mixed anhydride. Moreover, our screening data support this for

both boronic acid-catalysed and borate ester-mediated conditions. Another factor worth

considering is the equilibrium between boronic acids and their trimers, boroxines.

Furthermore, dimeric and/or oligomeric species might be involved in catalysis,[141]

while for

electron-rich boronic acids and some boroxoaromatics protodeboronation may be a reactivity-

determining factor .

Additional design of experiments (DoE) experiments were conducted using triphenyl borate

under microwave conditions (Table 12). A number of parameters was varied such as initial

concentration of the starting material (c 0.15, 1.08 and 2.0 M), reaction temperatures (80, 115

and 150 ºC) and time (5, 18 and 30 min). It was shown that reaction progression did not

depend on either concentration or reaction times (Graph 2). However, there was a high

correlation with the temperature, the reaction was conducted at. Background reaction, thermal

carboxamidation, did not take place at milder temperatures (80 ºC, 115 ºC).

2.2.8 Conclusions and Outlook

From screening a focused library of boronic acids, we have learned that protodeboronation,

boroxine formation and complexation of by-products such as water, methanol and boric acid

itself may play a substantial role in limiting the overall progression of carboxamidation

(Scheme 94). We have shown that alkylboronic acids may act as catalysts in this

transformation, opening new possibilities to improve the existing catalytic systems.

Chapter 2

83

Table 12. Data collected from DoE study by varying concentration, reaction time and temperature

demonstrate that there is a dependence on reaction temperature.a,b

a Reaction conditions: amine (1 equiv), acid (1 equiv), B(OPh)3 (1 equiv)

b Determined by

1H NMR (DMSO-d6).

c Without B(OPh)3.

Graph 2. (a) Temperature effect on reaction progression (see Table 12). All data points have varying

concentration (0.5, 1.08 or 2.0 M). (b) Temperature effect in borate ester mediated and non-mediated

reactions (c = 1.08 M, t = 18 min).

entry c,

x M

t,

y ºC

time,

z min

conv%b entry c,

x M

t,

y ºC

time,

z min

conv%b

1 0.15 80 18 61 11 1.08 150 18 85

2 0.15 115 5 73 12 1.08 150 30 85

3 0.15 115 30 76 13 2.0 80 18 62

4 0.15 150 18 83 14 2.0 115 5 75

5 1.08 80 5 61 15 2.0 115 30 79

6 1.08 80 18 62 16 2.0 150 18 84

7 1.08 80 30 67

8 1.08 115 18 78 17c 1.08 80 18 0

9 1.08 115 18 77 18c 1.08 115 18 4

10 1.08 150 5 81 19c 1.08 150 18 24

Chapter 2

84

Scheme 94. Factors involved in the boronic acid-catalysed carboxamidation.

As a part of work towards rationally designed boronic acid for the catalysis of direct amide

bond formation, it was found that simple borates can serve as effective carboxamidation

promoters. They act at 80 ºC, a temperature much lower than the one typically used for

boronic acid- catalysis and in the absence of any additional drying apparatus or agent.

Borate esters can be easily fine-tuned to deliver a right combination of reactivity. They make

up a new family of amide coupling reagents, which are environmentally benign and allow

easy purification using aqueous work-up.

Tri(2,2,2-trifluoroethyl) borate, was shown to be superior to trimethyl borate. Not only did it

promote carboxamidation with good to excellent yields, it also activated primary but not

secondary or tertiary amides towards transamidation. While promoting carbox- and

transamidations, it did not cleave the Lewis acid-sensitive N-Boc moiety, pointing out to a

window of potential chemoselectivity. This subtle trade-off in the Lewis acidity should be

further explored in application to a new platform for oligopeptide synthesis directly from

unprotected α-amino acids. The borate reagent in this case will act as a dual C-activation/N-

protecting agent (Scheme 95).[263–265]

Apart from surrogate systems for amidations such as (CF3CH2O)2BOBt, a number of

transformations, can be envisaged and/or pursued. Most notably, the activation of alcohols

and related compounds towards nucleophilic substitution or transmetalation reactions

(Scheme 96). The currently employed methods for these reactions are limited to Mitsunobu

protocol and formation of pseudohalides (e.g. tosylates, mesylates, nosylates). A process

involving borates is most likely to require an additional equivalent of base as depicted in

Chapter 2

85

Scheme 96 to stabilise the boronate 155. Simple heating of 4-phenyltetrazole, benzyl alcohol

and B(OCH2CF3)3 in acetonitrile at 100 ºC in a carousel tube was not effective (Scheme 97).

However, due to the severe limitations of alternative methods and their rather poor

sustainability it is desirable to look for further elaboration of this system.

Scheme 95. (a) Classical approach to peptide synthesis. (b) Approach incorporating dual C-

activation/N-protection strategy.

Scheme 96. Plausible modes of RXH activation by Lewis acid borate towards nucleophilic attack.

Chapter 2

86

Scheme 97. Attempted direct N-benzylation of 4-phenyltetrazole.

It is of note that a boron-based system, a simple borate buffer, was used in another

transformation, where an otherwise hard-to-access phosphorylated substrate,

dihydroxyacetone phosphate (DHAP), is required.[272]

RhaD, an aldolase, can accept

dihydroxyacetone as a substrate when it was in a borate buffer, presumably in the form of a

reversible DHA borate (Scheme 98).

Scheme 98. Borate as a phosphate ester mimic in aldolase-catalysed reaction. DHAP =

dihydroxyacetone phosphate.

In summary, boron reagents can provide an important tool to mimic the natural reactivity of

phosphates. Phosphorylation is one of the prevalent ways of activating carboxylic, hydroxyl

and keto-substrates in biological systems. Advances in boron catalysis and mediation can

provide the synthetic community with better control over desired reactivities in addition to

novel reactions.

Chapter 3

Chapter 3

88

3 Gold-Catalysed Boron Enolate Formation

In the previous Chapter, the Lewis acidity of the boron atom was used to activate carboxylic

acids and primary amides and thus promote elimination of a small molecule (water or

ammonia), i.e. a condensation reaction. However, boron based systems may be useful in the

reverse process; namely, delivering a small molecule in an addition reaction, e.g. water.

Boronic acids bear two hydroxyl groups and they may act as nucleophiles (Scheme 99). So

far, few reports of using this reactivity pattern have appeared. Additionally, a water molecule

or other oxygen, nitrogen, or sulphur compound (alcohols, amines, thiols, respectively) can

coordinate to boron. By donating electron density into the boron system, it may increase the

nucleophilicity of the most electronegative substituent, i.e. the hydroxyls. Otherwise, boron

may serve as a tether to deliver the O, N, S-nucleophiles from a tetrahedral boronate

intermediate to the substrate. An interesting example of hydroxylation would be that of

addition of boronic acids across a multiple bond as shown in Scheme 100. This could generate

a boron enolate species 156, a highly useful intermediate in synthetic organic chemistry.

Scheme 99. Increasing the nucleophilicity of boronic acids via activation.

Chapter 3

89

Scheme 100. Trapping an in situ generated boron enolate.

3.1 Background

In the aldol reaction, a β-hydroxy carbonyl compound is produced from two carbonyl-

containing compounds (Scheme 101). It is perhaps one of the most widely used methods for

new carbon–carbon bond formation.[273]

The first notion of such reactivity was described by

Borodin[274]

and Wurtz[275]

independently in 1872. They observed that under acidic conditions

aldehydes self-condense giving rise to a new product 157 that acts both as aldehyde and

alcohol (hence, the product was named aldol).

A cross-condensation product 158 arising from two different carbonyl compounds is

synthetically more valuable than a self-condensation (Scheme 101a). The simplest example of

cross-aldol reaction is that between an aromatic and an aliphatic aldehyde (Scheme 101b).[276]

Benzaldehyde is not enolisable and thus can only act as an electrophile.

Scheme 101. (a) Self vs. cross-aldol reactions. (b) Proline-catalysed cross-aldol reaction.[276]

Chapter 3

90

To achieve an effective crossed aldol reaction, one of the carbonyl compounds (donor) must

be activated as an enolate. A diverse array of enolate equivalents has been explored

synthetically (Figure 19). Some of them are commercially available and/or have long shelf-

life (e.g. silyl enolates) and can be used directly. Additionally, within the last decade, a

number of organocatalytic approaches to crossed aldol reactions have been developed. They

often allow perfect control of chemo- and stereoselectivity under milder conditions in a

straightforward one-pot manipulation.[273]

However, out of a wide choice of enolate equivalents, boron enolates remain one of most

effective ones. Usually, they are generated in situ prior to addition of the aldehyde (acceptor),

which itself is added in a controlled fashion and at low temperatures. This prevents transfer of

the enolate from one partner to the other and usually gives rise to the kinetic product.

Figure 19. Enolate equivalents and their relative nucleophilicity.

Apart from ascertaining which partner will act as an electrophile and which as a nucleophile,

in simple systems the enolate’s geometry controls the stereochemical outcome of the reaction.

Up to two new stereocentres can be created and their relative stereochemistry, i.e. syn or anti,

is controlled by selective generation of either (E)– or (Z)–enolate, respectively (Scheme

102).[277]

To accomplish this, for instance, an appropriate combination of dialkyl boron

(pseudo)halide and a base are used. This methodology is largely robust and has been a true

workhorse for stereocontrolled aldol reactions and has been widely applied in the synthesis of

complex molecules such as natural products.[278]

Chapter 3

91

Scheme 102. Control of relative stereoselectivity through enolate geometry.[279]

Nevertheless, even for this well established protocol, Abiko et al. reported that in certain

cases products of the double aldol reaction 159 are observed. This process was rationalised to

proceed via carbon-bound boron enolates 160 (Scheme 103).[280]

Scheme 103. Boron-mediated double aldol reaction of carboxylic esters.

Alternative approaches aim to generate enolates catalytically and by-pass conventional

stoichiometric deprotonation at the α-carbon adjacent to the carbonyl.[281]

For instance,

Motherwell and co-workers[282]

pursued a transition metal-catalysed isomerisation of allylic

alkoxides (Scheme 104).[283]

Lithium alkoxides and potassium triethylboronates were

successfully isomerised with [Rh(dppe)(thf)2][ClO4],[282a,b]

Wilkinson’s catalyst[282a]

and

(Cy3P)2NiCl2[282b]

and trapped with aldehydes to give aldol products.

Scheme 104. (a) Rhodium promoted isomerisation of allylic alkoxides[282a]

and (b) plausible mechanism.

TM = transition metal.

Chapter 3

92

In 2001, Uma et al. demonstrated that under UV irradiation, Fe(CO)5 can catalyse similar

transformation without the need for base (Scheme 105).[284]

Next, they introduced a

modification for Ru and Rh-catalysed protocols. Hydride, alkyl or aryl-metal species,

generated in situ from simple chloride complexes with an equivalent of RLi, catalysed the

transformation without stoichiometric amount of base.[285]

Scheme 105. Tandem isomerisation of allylic alcohols/aldol reaction in the absence of base.

Later, Li showed that this transformation can be carried out using commercially available

ruthenium-based catalyst in aqueous solvent mixtures or ionic liquids without any other

additives (Scheme 106).[286]

Scheme 106. Ruthenium-catalysed aldol-type reactions via olefin migration in polar media.

An approach combining rhodium-catalysed hydrogenation of enones and aldol reaction was

thoroughly explored by Krische.[287]

In a recent instalment, a diastereo- and enatioselective

hydrogenative protocol was developed (Scheme 107).[287h]

Namely, TADDOL-like

phosphonite ligands allowed smooth hydrogenative aldol coupling between aldehydes and

vinyl ketones.

Scheme 107. First enantioselective reductive aldol couplings of vinyl ketones.

Chapter 3

93

In addition to development of transition metal-catalysed processes, alternative generation of

boron enolates were explored by several groups. Hoffmann[288]

and Trombini[289]

exploited

mild oxidation of vinyl boronic esters (Scheme 108). Lipshutz[290]

used Stryker’s reagent,

[(Ph3P)CuH]6,[291]

to reductively alkylate enones with aldehydes (Scheme 109). Reaction

proceeded via copper hydride-catalysed 1,4-hydroboration of enones to give boron

enolates[292]

in situ. A similar process was developed with organosilanes but lacked

stereospecifity in the aldol step.[293]

Further examples of copper[294]

and palladium[295]

catalysis

have been reported by Koskinen and Oshima, respectively.

Scheme 108. Access to boron enolates via mild oxidation of vinyl boronic acids.

Scheme 109. Stryker's reagent-catalysed reductive hydroalkylation of enones via boron and silyl

enolates.

The Reformatsky reaction, zinc-promoted hydroxyalkylation of α-haloesters, can be viewed

as another way to construct aldol products.[296]

Moreover, other metal systems based on

indium,[297]

titanium[298]

and copper or iron[299]

(Scheme 110a) have been used for this

transformation. For the synthesis of UCS1025A, a telomerase inhibitor, Danishefsky

employed triethylborane as mediator and α-iodoamide 161 as a substrate (Scheme 110b).[300]

Chapter 3

94

Scheme 110. (a) Indium and (b) triethylborane-mediated Reformatsky-type reactions.

Mukaiyama explored one-pot deiodination of α-iodoketones by organoboranes (Scheme

111).[301]

The enolates thus generated gave preferentially syn-aldol products on reacting with

aldehydes. Yanagisawa used activated barium for a similar process employing α-

chloroketones (Scheme 112).[302]

Importantly, in both these examples, the aldehyde

component was present in the reaction mixture from the start.

Scheme 111. Reformatsky-type reaction with α-iodoketone and organoborane.[301]

Scheme 112. One-pot Reformatsky-type reaction with α-chloroketones via barium enolates.[302]

Finally, in 1982, Mukaiyama reported a mercury-mediated stoichiometric hydroboroxylation

of an activated alkyne by diphenylborinic acid with subsequent trapping with an aldehyde

Chapter 3

95

(Scheme 113).[303]

Use of equimolar amounts of Hg(OAc)2 led to formation of a partially

acetylated aldol product 163.

Scheme 113. Mercury-mediated hydration of an activated acetylene and trapping with aldehyde.[303]

Yet another demonstration of the hydration of activated alkynes was recently reported by

Gaunt (Scheme 114).[304]

Scandium triflate (or possibly, HOTf) catalysed hydration of

ynamide 164 by a silanol to give a silyl enol ether 165, which then underwent scandium-

catalysed aldol reaction with an aldehyde present in the reaction mixture.

Scheme 114. Scandium triflate-catalysed silanol-mediated stereoselective anti-aldol reaction of

ynamides.[304]

3.2 Aims and Objectives

Cationic gold[305]

can efficiently catalyse highly regioselective Markovnikov hydration[306]

of

unactivated alkynes. At present, it is a highly active area of research because gold offers large

functional group tolerability and unlike mercury, is largely non-toxic. Acetylenes are an

abundant hydrocarbon source,[307]

and their use as starting material for active intermediates is

of interest to the chemical community. This can be achieved by design of new dual catalytic

Chapter 3

96

cycles based on gold and another metal or small molecule. Currently, gold co-catalysed

processes are limited to only a few Pd/Au and secondary amine/Au examples.[308–309]

It was envisaged that a boronic acid in combination with gold can lead to an efficient

formation of a boron enolate, which, if the aldehyde were present, would undergo an aldol

reaction (Scheme 115). Ideally, boronic acid would be regenerated in the presence of a small

amount of moisture and thus forming a dual catalytic cycle for both gold and boron catalysts.

Scheme 115. Schematic representation of envisaged gold and boronic acid co-catalysed aldol reaction

with alkyne as a starting material.

Earlier in the Sheppard group,[310]

it was shown that enolate formation could be achieved

intermolecularly (Scheme 116). In the presence of catalytic amounts of PPh3AuCl and AgOTf

(used to generate a cationic gold species), ortho-(1-hex-1-enyl)phenylboronic acid cyclised to

give a stable boron enolate. In a separate step, on mixing the resulting boron enolate with

butyraldehyde for 18 h at RT, a mixture of cis and trans-aldol products was isolated (total

53%). A one-pot transformation starting from boronic acid (–40 ºC to RT, 18 h) afforded the

desired products in 70% yield.

Scheme 116. Early results in the Sheppard group.

We therefore wished to optimise the conditions and see whether the reaction can effectively

be performed as a one-pot procedure. Additionally, the exploration of ways to improve the

diastereoselectivity and define the scope and limitations was desirable.

Chapter 3

97

3.3 Results and Discussion

The required ortho-alkynylboronic acids 167–171 were prepared in a two-step procedure

(Scheme 117). First, 2-iodobromobenzene was alkynylated with terminal acetylenes using a

standard Sonogashira coupling protocol.[311,312]

Then, the corresponding bromoarenes 166

were subjected to a lithiation/borylation sequence.[15]

In the case of TMS-protected boronic

acid 171, upon borylation the reaction mixture was quenched with sat. NH4Cl instead of 1 M

HCl to avoid protodesilylation.

Scheme 117. Synthesis of ortho-alkynylboronic acids. aIsolated yields over two steps.

3.3.1 Gold-Catalysed Boron Enolate Formation

When 167 was subjected to cationic gold catalysis (1 mol% of both AgOTf and Ph3PAuCl or

0.5 mol% Ph3PAuNHTf2, 10 min), only the 6-endo-dig, i.e. anti-Markovnikov product 172a

was formed (Scheme 118). This 6-endo cyclisation was a somewhat unexpected outcome

because in several analogous cases, e.g. cyclisation of ortho-alkynylbenzoic acids, usually a

mixture of 5-exo and 6-endo-dig products was observed (Scheme 119).[313]

For ortho-

alkynylbenzyl alcohols, Hashmi observed only the rather unstable 6-endo products, and no

reaction was detected when the substituent on the alkyne was hydrogen, TMS or alkynyl.

Moreover, intramolecular hydroxylation and hydroamination reactions are believed to

proceed via an energetically more viable 5-exo-dig cyclisation followed by gold-catalysed

oxygen migration to give the 6-endo product.[314]

Scheme 118. Gold-catalysed cyclisation of ortho-(ethynylphenyl)boronic acid (isolated yields: 84% with

1 mol% Ph3PAuCl, 1 mol% AgOTf and 90% with 0.5 mol% Ph3PAuNTf2).

Chapter 3

98

Scheme 119. Gold-catalysed cyclisation of ortho-alkynylbenzoic acids. [313]

All the other boronic acids 168–170 smoothly cyclised to give the corresponding 6-endo-dig

products 172 which were isolated in excellent yield by column chromatography or, when R =

Ph, p-An, by decantation (Scheme 120). In the case of the cyclisation of (2-

(cyclopropylethynyl)phenyl)boronic acid 168, both 3-cyclopropyl-1H-

benzo[c][1,2]oxaborinin-1-ol 172a and its dimer 173b were obtained and characterised as an

inseparable mixture.

Scheme 120. Gold-catalysed intramolecular boron enolate formation. aIsolated yields.

Similarly, another π-acid, commonly used to activate alkynes, PtCl2,[305d]

also led to the

formation of the 6-endo product (on reaction with 169). However, this transformation was

considerably slower and took 17 h to complete at ambient temperature.

Interestingly, although we expected 5-exo-dig cyclisation to occur with TMS-protected 2-

ethynylphenylboronic acid, clean formation of 6-endo-dig protodesilylated enolate (R = H)

was detected (Scheme 121). The mechanism is further discussed in Chapter 4.

Scheme 121. Gold-catalysed one-pot silyl-deprotection/enolate formation.

Chapter 3

99

The stability of these compounds on silica gel as well as their tolerance of air- and moisture,

can perhaps be attributed to aromatic stabilisation, which has been a focus of several

theoretical and experimental studies in the past.[315–316]

Based on ab initio and DFT calculations,[316f]

Minyaev et al. predicted that hypothetical 1,2-

oxaborabenzene 178 (Figure 20), the simplest ring system not subject to additional

stabilisation by fused rings, possesses stable aromatic structure. Relative stabilization energy

arising from cyclic π-electron delocalization in 178, ΔEarom, was to calculated to be ca. 50–56

kcal/mol and in the range typical for other cyclic systems exhibiting π-electron

delocalisation.[317]

Later, Ashe III et al. experimentally studied 179, a chromium tricarbonyl

complex of a B-phenylated analogue of 1,2-oxaborabenzene.[316d]

Although 179 readily

participated in the Diels–Alder reaction with dimethyl acetylenedicarboxylate (DMAD) and

was protodeboronated with TFA, its crystal structure revealed that there are features

attributable to delocalised π-bonding. Firstly, the endocyclic boron-carbon bond (1.48Ǻ) was

significantly shorter than the exocyclic one (1.57 Å), and was closely in line with that

calculated by DFT values. Secondly, the oxoborabenzene ring was completely planar.

Figure 20. 1,2-Oxaborabenzenes.

Hence, our boron enolates are potentially boroxoaromatic compounds, similar to

borazaaromatics[318]

and are isosteric with naphthanols (Figure 21). This feature also

influenced the reactivity of the intermediates in the subsequent aldol reactions and will be

discussed in the next section.

Figure 21. B–O and B–N as isosteres of a carbon–carbon double bond in aromatic systems.

Chapter 3

100

3.3.2 One-Pot Boron Enolate Formation/Aldol Reaction

At first, it was decided to work on (2-ethynylphenyl)boronic acid 167, as it bears a small

substituent on the alkyne and may result in higher diastereoselectivities upon reaction with

aldehyde. However, while this substrate did cyclise to form a boron enolate, no aldol reaction

was observed in 24 h (Scheme 122). Numerous attempts to activate the system were made

with a number of Brønsted and Lewis bases and acids as well as increasing the reaction

temperature. However, the enolate proved to be exceptionally stable and remained unreacted.

When strong acids/bases were applied the boron compounds underwent protodeboronation.

Similarly, the aryl-substituted boronic acid 175 (R = Ph) did not undergo aldol reaction.

Scheme 122. Unreactive cyclic boron enolates.

It was then necessary to re-examine the original system, that of ortho-(1-

hexynyl)phenylboronic acid 169 and butyraldehyde, to learn more about controlling this

process. Interestingly, while the results provided earlier were generally reproducible, i.e. the

desired product was formed, there was certain variation in isolated yields of the aldol

products. Additionally, the cyclic boronic monoesters, e.g. 180 in Figure 22, proved to be

difficult to isolate, decomposing both on the silica gel column and under vacuum. Hence, to

gain control over this system, we needed to understand it in greater detail.

Gratifyingly, the progression of the reaction could easily be tracked by 1H NMR experiments

conducted on a 600 MHz spectrometer equipped with Cryoprobe® that ensured good

separation of signals, especially in the aromatic region (Figure 22). When the starting

material, i.e. boronic acid 169, was fully consumed, signals for the ortho aromatic protons Ha

in the enolate 174a and the trans- and cis-aldol products could be easily resolved for all

boronic acid–aldehyde combinations. Signals for hydrogens Hb and Hc bonded to the carbons

involved in the new carbon–carbon bond formation were also distinguished. The aldol

reaction gave the trans-product 180a as the major product. The stereochemical assignment of

the trans- and cis-isomers required follow-on derivatisation and is discussed later in this

section.

Chapter 3

101

Figure 22. Typical 1H NMR (600 MHZ, CDCl3) spectrum of the reaction mixture (note that starting

material 169 is fully consumed). Red, blue and green arrows as well as en, tr and cis labels denote 1H

NMR signals corresponding to enolate, trans- and cis-aldol products, respectively. pba = phenylboronic

acid.

The choice of solvent was dictated by two factors (Table 13). First was the overall

conversion, i.e. from boronic acid to the aldol products, and second was the ratio of

diastereomers formed. In regard to conversion, no aldol products 180a and 180b were

obtained in trimethyl borate or DMSO, although the cyclisation to form enolate 174a did take

place. Diethyl ether, though providing the best diastereomeric ratio, was least efficient in the

overall conversion. DCM and nitromethane were identified as optimal solvents with

acceptable diastereomeric ratio. DCM was selected as it is the most widely used solvent in

gold-catalysed processes. All reactions were conducted at ambient temperature.

nPrCHO

CH2Cl2

CHCl3

en

aH

c

tr

aH

cis

aH

en

bH

c

cis

bH

tr

bH

tr

cH cis

cH

Chapter 3

102

Table 13. Solvent screen.a

aReaction conditions: boronic acid (1 equiv), butyraldehyde (1 equiv), Ph3PAuNTf2 (1 mol%), 0.5 M solvent, RT, 16h.

bDiastereomeric ratios and conversions were determined by

1H NMR (CDCl3).

Over the course of these reactions, it was noted that there were variations in the conversion to

the aldol products and subsequently in the isolated yield. These differed depending on both

reaction times and the amount of aldehyde employed. Interestingly, in the case of 180, highest

isolated yields were obtained when products were isolated after 5 h and 48 h but not within

10–15 h after the start of reaction. We reasoned that one of the contributing factors might be

retro-aldol reaction. However, more information on the progression of the reaction was

required.

To find optimal conditions with regard to aldehyde amount, reaction time and gold source,

time tracking experiments were conducted. Namely, small aliquots of the reaction mixture (ca

0.2 mL) were collected at different time intervals, diluted in CDCl3 and characterised by 1H

NMR spectroscopy. As mentioned above, the proton signals for the enolate and the trans- and

cis-aldol products were easily distinguishable. For the boronic acid, the proton peak for pba

aH

entry solvent

product (180)

trans/cisb conv%

b

1 DCM 73:27 30

2 MeNO2 70:30 36

3 PhMe 63:37 26

4 MeCN 70:30 10

5 Et2O 79:21 7

6 B(OMe)3 – 0

7 DMSO – 0

Chapter 3

103

(Figure 22), partially overlaid with the one for the enolate, i.e. en

aH . However, the amount of

the remaining boronic acid was estimated by subtracting the integral for en

bH from the sum of

integrals for the two overlaying peaks (en

aH +

pba

aH ). Further numerical data are provided in

the Appendix.

At first, the effect of varying the initial amount/concentration of aldehyde was examined with

Ph3PAuNTf2 serving as a cationic gold source (Graph 3). When 1.2 equivalents of aldehyde

were used, the peak for the aldol product was observed after one hour. At the same time, it

was noted that the cyclisation to give the boron enolate was complete and no boronic acid

remained in the mixture. Over time, however, the product appeared to revert to the enolate

and did so rather quickly. Later, the aldol product started to build up again. When two

equivalents of aldehyde were used, the peak conversion was observed after three to four

hours. After that, it seems that the retro-aldol took place and the enolate became the major

species. Only later did the system equilibrate back to give the aldol products 180a and 180b

as the predominant species. A dynamic behaviour like this is not common in synthetic

chemistry and does not follow monotonic/linear kinetics. However, note that the

diastereomeric ratio of the aldol products also changed slowly over time. Further discussion

will be provided later in this Section.

It was decided to use 2 equiv of aldehyde in view of the fact that aldol products 180a and

180b were rather unstable and required further derivatisation, for instance, by oxidation (see

Section 3.3.3). This would allow a time window of approximately 1 h (s) to trap them in situ,

Allowing the reaction mixture to stir for three to four hours proved to be essential in getting

high conversions and isolated yields of 180a and 180b.

Finding the optimal gold source was considered next (Graph 4). Of three gold sources

compared, AuCl was the only noncationic one and did not allow full conversion of starting

boronic acid to boron enolate. Meanwhile, the two cationic gold catalysts – Ph3PAuNTf2 and

Ph3PAuCl/AgOTf – converted boronic acid to enolate in less than one hour. Gagozs catalyst,

Ph3PAuNTf2, was preferred to the Au/Ag system for two reasons: firstly, the NMR spectra of

the crude reactions were considerably cleaner, suggesting there were fewer potential by-

products; secondly, it was rational not to use Au/Ag because silver triflate, an oxophilic Lewis

acid, could influence the progression and/or the outcome of the reaction.

Chapter 3

104

Graph 3. Progression of one-pot enolate formation/aldol reaction depending on an initial amount of

aldehyde ( ∑ [boron-based compounds] = 100).a, b

with 1.2 equiv nPrCHO

with 2.0 equiv nPrCHO

aReaction conditions: boronic acid (1 equiv), butyraldehyde (1.2 or 2.0 equiv), Ph3PAuCl (2 mol%), AgOTf (2 mol%), 1

M DCM, RT. b Conversions and diastereomeric ratios were determined by

1H NMR (CDCl3).

time, h 169 174a 180a+180b trans cis

1 2 19 78 62 38

3 0 77 23 67 33

3 0 76 24 68 32

5 0 42 58 56 44

23 0 30 70 70 30

time, h 169 174a 180a+180b trans cis

1 0 34 66 71 29

3 0 14 86 75 25

4 0 13 87 74 26

7 0 50 50 56 44

24 0 48 52 55 45

Chapter 3

105

Graph 4. Progression of one-pot enolate formation/aldol reaction in relation to the gold source.a, b

with AuCl

with Ph3PAuNTf2

with Ph3PAuCl/AgOTf

aReaction conditions: boronic acid (1 equiv), butyraldehyde (2.0 equiv), Au salt (2 mol%), 0.5 M DCM, RT.

b Conversions and diastereomeric ratios were determined by

1H NMR (CDCl3).

time, h 169 174a 180a+180b trans cis

1 77 0 23 79 21

2 73 1 26 78 22

3 70 2 28 78 22

4 69 2 30 77 23

7 69 2 29 75 25

20.5 44 7 49 61 39

time, h 169 174a 180a+180b trans cis

1 0 28 72 74 26

3 0 15 85 75 25

4 0 19 81 73 27

7 0 50 50 62 38

24 0 30 70 67 33

time, h 169 174a 180a+180b trans cis

1 0 34 66 71 29

3 0 14 86 75 25

4 0 13 87 74 26

7 0 50 50 56 44

24 0 48 52 55 45

Chapter 3

106

In a small number of cases, while trying to optimise the reaction, it was noted that the

diastereomeric ratio had reversed. As one of the potential sources leading to this effect could

have been moisture, the effect of water on diastereoselectivity was examined (Graph 5). In the

presence of water (5 equiv) and AuCl as the gold source, the cis-aldol product 180b was the

major product.

Graph 5. Effect of water on diastereomeric ratio of aldol-product in AuCl-catalysed process.a, b

without H2O

with H2O (5 equiv)

aReaction conditions: boronic acid (1 equiv), butyraldehyde (2.0 equiv), water (none or 5.0 equiv), AuCl (2 mol%), 1 M

DCM, RT. b Conversions and diastereomeric ratios were determined by

1H NMR (CDCl3).

time, h 169 174a 180a+180b trans cis

1 77 0 23 79 21

2 73 1 26 78 22

3 70 2 28 78 22

4 69 2 30 77 23

7 69 2 29 75 25

20.5 44 7 49 61 39

time, h 169 174a 180a+180b trans cis

1 84 0 16 62 38

2 42 36 22 47 53

3 36 36 28 36 64

4 36 36 29 36 64

7 36 28 36 31 69

20.5 36 20 44 30 70

Chapter 3

107

Altogether, a better understanding of the reaction system allowed us to isolate both trans- and

cis-cyclic aldol products as separate compounds in 86% combined yield (Scheme 123).

Scheme 123. Preparation of aldol product 181 under optimised conditions.

What remains is the interpretation of the initial data (Graphs 2 and 3), which implied that the

optimal reaction conditions require precise timing. At present, there are not enough data

points in Graphs 2 and 3 to unequivocally support the fact that these fluctuations in

conversion are systematic. However, reactions done on numerous occasions indicated that

leaving the mixture to stir for longer than 5 h always resulted in low conversions and/or

isolated yield.

Further examination of the data suggested that in reactions employing 2 equiv of aldehyde in

the presence of cationic gold source such as Ph3PAuNTf2 and Ph3PAuCl/AgOTf, the absolute

amount of cis-aldol remained constant (ca. 20%) throughout ca. 24 h. The increase and

subsequent decrease in the amount of enolate 174a came at the expense of trans-aldol

product. In the presence of water with AuCl as a catalyst, on the contrary, it was the trans-

isomer 180a whose levels remained constant at ca. 10%, while the amount of cis-isomer

increased over time. It is most likely that the changes arise from variation in rates of

formation/retro-aldol reaction of the trans and cis-aldol products.

Further experiments on the tandem enolate formation/aldol reaction were conducted in an

NMR tube with one and two equivalents of butyraldehyde (i.e. in a sealed tube). The spectra

were recorded every ten minutes over the first two hours and are presented in Graph 7.

Notably, no epimerisation of the aldol products was observed and the product formation

followed linear kinetics.

However, these results cannot be directly compared to the reactions conducted on the bench.

In the NMR experiments, stirring was not continuous and the reaction vial was capped.

Chapter 3

108

Graph 7. Progression of one-pot enolate formation/aldol reaction in an NMR tube.a

with 1 equiv nPrCHO

with 2 equiv nPrCHO

aReaction conditions: boronic acid (1 equiv), aldehyde (1 or 2 equiv), Ph3PAuNTf2 (1 mol%), 0.5 M CD2Cl2, RT.

bConversions and diastereomeric ratios were determined by

1H NMR (CDCl3).

time, min 169 174a 180a+180b trans cis

10 28 46 26 83 17

20 3 57 40 82 18

30 0 55 45 82 18

40 0 53 47 81 19

50 0 53 47 81 19

60 0 53 47 81 19

70 0 52 48 81 19

80 0 53 47 81 19

90 0 52 48 80 20

100 0 52 48 80 20

210 0 50 50 78 22

time, min 169 174a 180a+180b trans cis

15 46 38 16 81 19

25 23 48 29 80 20

35 11 50 39 81 19

45 4 47 48 81 19

55 0 45 55 80 20

65 0 43 57 80 20

75 0 42 58 79 21

85 0 42 58 79 21

95 0 41 59 79 21

105 0 41 59 79 21

115 0 41 59 78 22

215 0 37 63 76 24

Chapter 3

109

Hence, the reaction mixture was not exposed to evaporation and/or adventitious moisture.

Notably, the conversion to aldol product was only 50–60% (after ca 4 h), which is less than

was afforded under standard reaction conditions (>90 conv%, isolated yield 86% ). This

indicates that in bench-top reactions external factors such as the presence of Brønsted or

Lewis acids and/or moisture may play a crucial role in driving the system initially out of

equilibrium allowing higher than expected conversion to the aldol products.

Overall, this particular system behaves as if it were following either overshoot–undershoot

kinetics or damped oscillatory kinetics in respect to 180a (Graph 6).[321]

In both of these cases,

the product concentration would first overshoot the equilibrium concentration and then

undershoot it. Only later would it reach the equilibrium.

Graph 6. Types of kinetics: (a) linear (monotonic), (b) overshoot–undershoot, (c) damped oscillatory, (d)

sustained ossicilations. [P] = product concentration, t = time.

This dynamic behaviour was observed exclusively for the combination of 169 and

butyraldehyde and keeping track of the reaction time was crucial to obtaining good results in

the follow-on one-pot derivatisations described in Section 3.3.3.

Chapter 3

110

The proposed enolate formation/aldol reaction mechanism is shown in Scheme 124. For

aliphatic systems, the enolate is formed within the first ten minutes and is followed by the

aldol step to give a mixture of trans and cis isomers of the cyclic boronic monoester.

However, based on this data alone, it is unclear whether aldol reaction proceeds via open or

closed transition state.

Scheme 124. Proposed mechanism.

To determine which diastereomer is formed as a major product, a previously reported[319]

mixture of compounds 182a and 182b was prepared via an enolate formation/aldol sequence

followed by protodeboronation (Scheme 125). This step had to be performed under mild

conditions to avoid retro-aldol and potential dehydration. Kuivila et al. showed that copper is

the most effective cation for protodeboronation (ca. 0.2 mol%, pH 6.7, 90 ºC, kcat ~40 M–1

s–

1).

[320] Our protodeboronation was conducted with copper(II) sulfate in water as sulfate would

lead to slightly acidic pH, and in comparison to other copper salts, minimise formation of

undesired Chan–Lam coupling products. Heating at 60 ºC was required as no reaction was

detected at 40 ºC. Coupling constants for β-ketoalcohols 182a and 182b were found to be in

line with those originally reported by Mukaiyama.[319]

Retrospectively, as the anti-isomer

182a was the major product after protodeboronation, trans- boronate 181a was the major

aldol-product.

Chapter 3

111

Scheme 125. Synthesis of 4-hydroxy-3-phenylpentan-2-one via copper(II)-catalysed protodeboronation.

The boronic acid used for this determination was prepared from ((2-

bromophenyl)ethynyl)trimethylsilane by TMS deprotection, deprotonation/methylation and

subsequent lithiation/borylation (Scheme 126).

Scheme 126. Synthesis of (2-(prop-1-yn-1-yl)phenyl)boronic acid.

Chapter 3

112

3.3.3 Elaboration of Aldol Products: Oxidation, Suzuki, and Chan-Evans-Lam

As mentioned above, the aldol products were not stable and decomposed on storage and under

prolonged exposure to vacuum. It was deemed rational to convert them into more stable

derivatives. This was not a straightforward process as the material was susceptible to

decomposition and retro-aldol reaction.

Initially, it was proposed to trap the intermediate by acetylating the resulting free alcohol 186

(Scheme 127). Although no free alcohol was observed in crude 1H NMR, it was still assumed

that a small proportion might be present. Acetic anhydride and acetyl chloride were used as

projected acetylating agents, in the presence of DMAP, tBuOK and CsF both at ambient

temperatures and at 37 ºC. The combinations of these reagents were added at the start of the

reaction or 3 h later. However, only retro-aldol and/or dehydration products were observed.

Scheme 127. Attempted trapping of the aldol product by in situ O-acylation.

Next, the oxidation strategy was explored. Standard conditions for oxidation of boronic acids

(30% H2O2/1 M NaOH (5 equiv each), RT, 1 h) were first employed (Scheme 128). Although

after flash chromatography the oxidised product was obtained, the diastereomeric ratio could

not readily be determined in the 1H NMR spectrum prior to isolation.

Scheme 128. Oxidation of cyclic boron aldol under basic conditions.

Chapter 3

113

Milder oxidants such as sodium perborate and trimethylamine N-oxide (3 equiv, 16 h, RT or

37 ºC), did not cleave the carbon–boron bond. However, in the absence of base, treatment

with 30% H2O2, (5 equiv) at ambient temperature for 8 h led to full conversion of aldol

product to phenol with unaltered diastereomeric ratio (Scheme 129).

Scheme 129. Telescoping cyclic aldol products to the corresponding phenols using H2O2. *no change in

diastereomeric ratio after the derivatisation step.

Having mastered the oxidation, it was thought to be useful to provide an example of a more

strategic derivatisation; for example, a Suzuki–Miyaura coupling.[4]

Usually this

transformation requires a strong base, which in our case would have destroyed the aldol

product and/or altered the diastereomeric ratio. With 1 equivalent of p-tolyliodide,

Pd(PPh3)2Cl2 was used as a palladium source, while base, solvent system and reaction

temperature were varied (Table 14). Previously reported mild system for Suzuki–Miyaura

coupling using sodium borate[322a]

as base was tried out first, however, without success. Our

attention was then turned to fluorides, namely CsF (entries 2–3), as they were previously

reported to activate boronic acids.[322b]

Although no coupling was detected at room

temperature, heating the same system under reflux in DCM led to clean conversion.

Importantly, in one of these examples, the use of acetaldehyde was demonstrated. This is a

good measure of the mildness[323]

of these reaction conditions for both the Au-catalysed

enolate formation/aldol reaction and subsequent coupling. Acetaldehyde is known to be hard

to handle as it easily undergoes acid or base-catalysed self-condensation.

Chapter 3

114

Table 14. Optimisation of one-pot aldol/Suzuki–Miyaura coupling.a,b

aOptimisation of reaction conditions for 189a/189b: (i) boronic acid (1 equiv), aldehyde (2 equiv), Ph3PAuNTf2 (1

mol%), DCM, RT, 3 h. (ii) p-MeC6H4I (1 equiv), Pd(PPh3)2Cl (3 mol%), base (2–3 equiv), solvent, RT–50 ºC, 15 h.

bReaction conditions for one-pot aldol/Suzuki–Miyaura coupling: (i) boronic acid (1 equiv), aldehyde (2 equiv),

Ph3PAuNTf2 (1 mol%), DCM, RT, 3 h. (ii) p-MeC6H4I (1 equiv), Pd(PPh3)2Cl (3 mol%), CsF (2 equiv), solvent, 37 ºC,

15 h.c nr = no reaction.

d Isolated yield. DO = dioxane.

Finally, it was appealing to explore the possibility of B–O ring contraction (Scheme 130). It

was envisaged that such transformation might be mediated or perhaps even catalysed by

copper(II) acetate (for a discussion of Chan–Evans–Lam coupling, see Chapter 1.3.2). It

would allow an elegant entry into 2,3-disubstituted-2,3-dihydrobenzofurans. Further

inspection of literature (mid-2009) implied that this type of core structures has been

underexplored in medicinal chemistry due to the limitations of the synthetic methods

available to access them. However, an interesting and diverse biological profile has been

associated with this scaffold. A selection of natural products isolated to date (Figure 23) have

already shown a valuable spectrum of immunosuppressive, antiproliferative, and anti-

infective activities such as antimicrobial[325,327,328]

, antiviral (e.g. anti-HIV activity of (+)-

Lithospermic acid[326]

) and growth suppression in a human lung adenocarcinoma cell line

(A549).[325a]

entry base solvent t, ºC

comments

1 3 equiv Na2B4O7 DO/EtOH 5/1

50 nrc

2 2 equiv CsF DCM 23 nrc

3 2 equiv CsF DCM 37 78%d

Chapter 3

115

Scheme 130. Plausible mechanism for copper-catalysed B-O ring contraction/Chan–Lam–Evans

coupling.

Figure 23. Dihydrobenzofuran core-containing natural products and their biological activity.

It was envisioned that Cu(II) will react with the arylboronic acid to give the arylcopper(II)

species 191, stabilised by an intramolecular alkoxide (Scheme 128). The initial set up with 5

mol% Cu(OAc)2 was highly likely to fail, because ortho-substituted boronic acids are known

Chapter 3

116

to give poor conversions under copper catalysis (Scheme 131),[90]

and it was also known that

aliphatic alcohols are very poor coupling partners.[96]

Gratifyingly, the reaction conducted in

methanol at 40 ºC was successful from the very first attempt, and the desired product was

isolated in 81% yield (192, R1 =

cPr, R

2 = Me).

Presumably, in the presence of methanol, the cyclic boronic monoester is cleaved, which

allowed for copper(II) acetate or methoxide, to exchange ligand with the substrate's free

hydroxyl, and that substantially enhances the reactivity. Notably, this process requires only a

catalytic amount of copper salt, uses dioxygen as terminal oxidant and does not require any

additional base or ligand. However, methanol is essential for this transformation as no

reaction took place in DCM, and only partial progression was observed in a 1:1 DCM/MeOH

solvent mixture. These products were collected as an inseparable mixture of the cis and trans

isomers. However, the cis-product is more stable so that when a mixture of products was

treated with TEA and silica gel, only the cis-product was observed. Notably, in 2,3-

disubstituted 2,3-dihydrobenzofurans, the dihedral torsion angles are such that the spin–spin

coupling constant for the cis-isomer is greater than that for the trans-isomer. This is also in

line with the data for several reported natural products containing this core[326,328]

and ensure

that under our copper-catalysed conditions the substrates do not epimerise.

Scheme 131. Aerobic copper-catalysed B–O ring contraction via Chan–Lam–Evans coupling.

3.3.4 Miscellaneous

Attempts were made to further broaden the scope of reactivity of these enolate systems, and

they are discussed below.

Apart from, aldehydes, other potential electrophiles were briefly explored (Scheme 132). No

reaction was detected with nitrosobenzene and Eschenmoser’s salt (CH2=N+Me2I

–).

Chapter 3

117

Nevertheless, boron enolate 174a reacted with PhCH=NPh, presumably giving rise to 194 (1H

NMR). However, on initial attempts the conversion remained below 10% and did not increase

on heating to 60 ºC (MeCN) or on addition of 5 mol% Y(OTf)3, which is often used to

improve the reactivity of imines in carbon–carbon bond forming reactions.[329]

Scheme 132. Probing other electrophiles.

When BocN=NBoc was used, broad signals were observed in the 1H NMR and a complex

inseparable mixture was obtained. It was later proposed that in addition to rotamers (which

could explain broadening of the signals in the 1H NMR spectra), the vinyl gold intermediate

itself might be trapped by the dialkyl azodicarboxylate reagent giving rise to a complex

mixture of products.

It was observed that with methanol, the boron enolates easily form boron enolate esters, so it

was interesting to see whether in the presence of allylic alcohol a rearrangement might take

place, either by treatment with allyl alcohol prior to cyclisation or by mixing it with the boron

enolate itself (Scheme 133). In both cases, only esterification product was observed.

Interestingly, not a long time later Blum reported that gold/palladium co-catalysis can address

a similar reactivity challenge in ortho-alkynyl allyl benzoates 196 (Scheme 134).[309b]

Scheme 133. Attempted allylation of enolate/hydroxyallylation of alkynylboronic acid.

Chapter 3

118

Scheme 134. Synthesis of substituted isocoumarin using carbophilic Lewis acidic gold and palladium.

A few experiments to establish conditions for intermolecular enolate formations were

conducted but were unsuccessful (Scheme 135). At ambient temperature, alkyne remained

mostly unhydrolysed after 24 h and did not incorporate aldehyde when heated in DCM at 37

ºC for the same period of time. Boron compounds screened were 10-hydroxy-10,9-

boroxophenanthrene, 2-iodophenylboronic acid, 3,4,5-trifluorophenylboronic and boric acids.

It may be that large presence of boronic acid deactivates the catalyst (Ph3PAuNTf2) and that

increased π back donation of boronyl oxygens into the vacant orbital on three-coordinated

boron.

Scheme 135. Attempted set up for intermolecular enolate formation/aldol reaction. For variations of

boronic acids, see the text.

3.4 Summary and Outlook

Cationic gold catalysts can promote highly regioselective hydration of alkynes, which makes

this process very valuable for further development into an aldol reaction procedure.

Environmentally benign variants of aldol reaction, especially the ones compatible with

moisture and air conditions, would be a significant step towards more sustainable formation

of carbon–carbon bonds.

Chapter 3

119

Having spotted this opportunity, an intramolecular system was devised to assess the formation

of enolates from a boronic acid and an alkyne. Although initially aiming to simplify the

system, additional factors such as boroxoaromaticity came into play and somewhat limited the

process to alkynes with alkyl and electron-rich aryl substituents. Nevertheless, the work laid

out above, demonstrated the proof-of-concept, namely, that such a multicomponent reaction is

feasible. However, the intermolecular version of reaction will face other challenges, such as

competing alkyne hydration.

Essentially this strategy builds on gold's ability to activate alkynes towards hydroxylation,

while the role of the complementary non-gold co-catalyst is to deliver a water equivalent.

Apart from hydration, it also facilitates aldol reaction; and hence, may serve as the most

convenient means to control the absolute stereochemistry. This catalyst should be rationally

designed to fulfill both of these functions (Scheme 136).

Scheme 136. Hydration/aldol strategy towards one-pot aldol reaction from alkynes. M = metal, L =

ligand, X = charged ligand.

It seems reasonable to build such a co-catalyst around a high-valent metal. To control

absolute chemistry, it must carry a chiral ligand, bidentate or pincer-like. The complex must

have an exposed hydroxyl moiety or coordinated water molecule, to allow participation in

Au-catalysed hydration to give a metal enolate directly. To ensure that the process goes via a

closed transition state, there needs to be an extra vacant site for aldehyde coordination.

Hence, boron-based catalysts may not be the optimal co-catalysts for this tandem

transformation. One of the potential metals is rhodium, as its enolates are rather stable and

Chapter 3

120

undergo aldol reaction. Additionally, a great number of alternative methods for aldol reactions

already exploit rhodium chemistry. Lanthanide-based catalysis, often moisture-tolerant, may

serve as yet another option.

Alternatively, hydration can be achieved by one species and then be transmetalated to another

for efficient aldol reaction to take place as shown in Scheme 137). However, such step-wise

systems are less innovative, as they combine two previously well-described steps.

Scheme 137. Hydration/transmetalation/aldol strategy towards one-pot aldol reaction from alkynes. M =

metal, L = ligand, S = solvent., X = charged ligand.

As for the ortho-alkynylboronic acids, it was shown that they can serve as precursors to a

variety of scaffolds (Scheme 138). In a simple manipulation, but with accurately chosen

conditions, they take place without detectable racemisations. Furthermore, we have gained

access to 2,3-disubstitued-2,3-dihydrobenzofurans via an aerobic copper-catalysed ring

contraction in a one-pot process. To the best of our knowledge, this constitutes the only

example of Chan–Lam coupling of aliphatic alcohols using catalytic Cu. Additionally,

preliminary experiments suggest that aza-analogues (2,3-dihydroindoles) can also be

accessed.

Chapter 3

121

Scheme 138. Transformation of ortho-alkynylboronic acids.

Taking into consideration the number of natural products with intriguing biological activities,

it might be worth pursuing an asymmetric variant of this enol formation/aldol condensation.

Options to control absolute stereochemistry in case of ortho-alkynylboronic acids

(presumingly directing aldol reaction to go via open transition state) include employment of

chiral organocatalysts (thioureas),[330]

Lewis acids (metal–ligand pairs)[331]

and Brønsted

acids[332]

to activate/coordinate to an aldehyde (Figure 24).

Figure 24. Proposed systems to execute stereochemical control in intramolecular enolate

formation/aldol reaction via (a) hydrogen bonding and (b) Lewis acid catalysis.

Chapter 4

Chapter 4

123

4 Observations on the Role of Cationic Gold and

Brønsted Acids in Electrophilic Halogenation

4.1 Results and Discussion

In the course of work on gold-catalysed formation of boron enolates, a trimethylsilyl-

protected ortho-ethynylphenylboronic acid 171 was subjected to the cationic gold catalysis

with the overall goal to drive the 5-exo-dig cyclisation. However, only formation of the

desilylated boron enolate 172 was observed (Scheme 139).

Scheme 139. (a) Gold-catalysed protodesilylation/boron enolate formation. aConversion was determined

by 1H NMR (CDCl3).

bIsolated yield.

Scheme 140. Plausible mechanism for tandem desilylation/boron enolate formation.

To verify that this process proceeds via hydroxyl coordination to silicon as shown in Scheme

140, silylation of 2-iodophenol with various trialkylsilylacetylenes was examined (Scheme

141). As expected, silylation was less efficient with the alkynyltrialkylsilanes that carried

bulkier alkyl substituents.

Chapter 4

124

Scheme 141. Gold-catalysed silylation of phenols. aConversions were determined by

1H NMR (CDCl3).

A more practically interesting example involving silylation of a secondary alcohol, namely, 2-

butanol, was attempted with triethylethynylsilane; however, no product formation was

observed (Scheme 142).

Scheme 142. Attempted triethylsilylation of 2-butanol.

Next, the focus was drawn to the opposite process, i.e. deprotection of silyl-protected

acetylenes. Most oftenly, K2CO3/MeOH and TBAF/THF systems[333]

are used to deblock

silylacetylenes, which are widely used as ethyne equivalents. Due to the extremely mild

conditions, the gold-catalysed process could be of value in the total syntheses of complex

targets, for instance, those involving differentially substituted acetylenes, e.g. in

neocarzinostatin[334]

or a combination of C– and O–silyl groups.

In the presence of 0.5 mol% Ph3PAuNTf2 and 5 equiv of methanol, TMS cleavage proceeded

cleanly and was complete within 2 h at ambient temperature in either DCM or acetonitrile

(Scheme 143).[335]

No reaction took place when either catalyst or methanol were absent or

when AuCl (3 mol%) was used.

Scheme 143. Gold-catalysed TMS-deprotection with methanol. aConversion was determined by

1H

NMR (CDCl3).

Chapter 4

125

It was possible that desilylation proceeded via gold(I) acetylide 198 as shown in Scheme 144.

If it were so, we could trap 198 by N-iodosuccinimide (NIS), which is often used to trap

vinyl/aryl gold species in situ.[304d,l]

Indeed, in the presence of both methanol and NIS (0.5

equiv each), a mixture of proto- and iododesilylated products was afforded. This result alone

could not prove direct iodination of proposed Au(I) acetylide 198 because halogenating

reagents can also react with TMS-protected acetylene 197 (Scheme 145). Reaction with NIS

was complete within 3 h, N-bromosuccinimide (NBS) was less reactive affording the

corresponding alkynyl bromide (33 conv% after 3 h; 66 conv% after 15 h). No reaction was

observed with N-chlorosuccinimide (NCS).

Scheme 144. Plausible mechanism for protodesilylation.

Scheme 145. Gold-catalysed halodesilylation of TMS-protected alkynes. aConversions were determined

by 1H NMR (CDCl3).

A plausible mechanism for this transformation would involve aurodesilylation followed by

iododeauration (Scheme 146). However, there could be another pathway leading to the

desired product (Scheme 147). Namely, catalysed by minute amounts of

bis(trifluoromethane)-sulfonamide, HNTf2 (pKa 1.7),[336]

generated in situ from the gold

catalyst.[337]

In this case, protonation of N-halosuccinimide's nitrogen or oxygen would

increase the electrophilicity of the halo-compound and catalyse halodesilylation.

Chapter 4

126

Scheme 146. Plausible mechanism for halodesilylation via gold intermediate.

Scheme 147. Plausible mechanism for Brønsted acid catalysed halodesilylation.

Indeed, triflic acid (HOTf) alone was competent to catalyse halodesilylations (Scheme 148).

Interestingly, the reactivity of N-halosuccinimides in comparison of that with the gold

catalysed examples, was reversed. Chlorination proceeded the fastest, while complete

iododesilylation was achieved only after 16 h. This shift in catalytic activity between gold and

an acid indicates that different reaction mechanisms are in place. Finally, there were no

halogenations observed in the absence of either gold or Brønsted acid catalyst.

Scheme 148. Triflic acid catalysed halodesilylation. aConversions were determined by

1H NMR (CDCl3).

Chapter 4

127

To explore alternative means to confirm that gold(I) acetylenide can be present in the system,

direct halogenation of terminal alkynes was examined (Scheme 149). Phenylacetylene was

treated with NIS in the presence of either Gagozs catalyst or triflic acid at ambient

temperature in DCM. Importantly, formation of iodoalkyne was observed only when the

gold(I) catalyst was used. While for phenylacetylene halogenation with NIS was complete in

under an hour, a bromination reaction with NBS stopped at 66% conversion (also with 2

mol% of Gagosz catalyst), and no chlorinated product formation was observed with NCS.

Scheme 149. Gold-catalysed direct halogenations of alkynes. Isolated yield in parentheses.

aConversions were determined by

1H NMR (CDCl3).

b Isolated yield.

c Conducted at 37 ºC. I

An alkylacetylene, 1-hexyne, did not react with N-bromosuccinimide at either room

temperature or when heated under reflux in DCM (Scheme 147). Despite this, it did react with

N-iodosuccinimide when the mixture was heated overnight.

Direct iodination of several other arylacetylenes was examined (Figure 25). While the

reactions proceeded readily, the signals in the 1H NMR spectra for these compounds were

broad and not always clean. Only one further example, that of 4-methoxyacetylene, was fully

characterised. Furthermore, the electron-rich substrates underwent partial decomposition on

exposure to light, heat and drying under high vacuum. In the later stages, it was found that

longer exposure (e.g. for 4-methoxyacetylene, 3 h instead of 1 h) led to decolouration of the

reaction mixture, which subsequently led to better spectral data. It is highly likely that for

isolation of alkynyl iodides it is important to wait until cationic gold is reduced to the

colloidal gold. This ensures that no Au/acetylene complexes are present, and thus the product

is more stable.

Figure 25. Products from the substrates explored further for direct iodination (the identity of the

corresponding products was proved by HRMS).

Chapter 4

128

Mechanistically, there are two possibilities for the conversion of gold(I) acetylide 198 to

haloalkynes (Scheme 150). In one case, acetylides are undergoing halodeauration via 199. In

the other case, gold may be oxidised by NIS to gold(III) species 200, which subsequently

undergo fast reductive elimination to form Ar–C≡C–X. Traditionally, gold(I) is known to be

resistant to oxidation,[304]

so the first explanation could be intuitively favoured. However, a

few reports on oxidation of gold(I) complexes with iodine exist,[338–340]

and catalytic cycle

involving Au(III) cannot be easily disproved.

Scheme 150. Possible mechanisms for halodeauration.

Importantly, in none of the above-mentioned examples for both halodesilylation and direct

halogenation, either homocoupled or hydrated products was observed. This is a strong

prerequisite to incorporation of gold-catalysed activation of acetylenes into more

sophisticated catalytic cycles. Moreover, it may allow controlled oxidation to Au(III)

acetylenides and further modifications through Au(III) chemistry.

From a synthetic prospective, haloalkynes are useful intermediates, and the method above

potentially provides a very convenient method to access them. During the past decade,

alkynyl halides (R–C≡C–X) have found new applications in various transformations,[341]

e.g.

indium-mediated alkynylation of carbonyl compounds (X = I),[342]

rapid and highly

regioselective Huisgen azide/alkyne cycloaddition (X = I),[343]

zirconocene-catalysed

cyclobutene formation on reaction with EtMgBr (X = Cl, Br, I),[344]

synthesis of

alkynylepoxides,[345]

copper-mediated[346]

and catalysed[347]

N-alkynylation (X = Cl, Br, I),

copper-catalysed cross-coupling with Grignard reagents (X = Cl, Br),[348]

rhodium-catalysed

intramolecular [4+2] cycloadditions (X = Cl, Br, I),[349]

and formal reverse Sonogashira

coupling (X = Cl, Br).[350]

As the development of novel C–H activation approaches is in great demand, the reverse

Sonogashira cross-coupling reactions caught our attention, In this field, gold catalysis was

reported quite recently by two groups (Scheme 151). Waser et al. demonstrated alkynylation

Chapter 4

129

of heteroaromatics by a hypervalent iodine-based reagent 201,[351]

while Nevado showed that

alkynes bearing electron withdrawing groups can be used to alkynylate electron-rich arenes

and some heterocycles.[352]

Scheme 151. First examples of gold-catalysed alkynylation by (a) Waser[351a]

and (b) Nevado.[352]

Encouraged by these two reports, an experiment to investigate the reactivity of an in situ

generated haloalkyne with N-methyl and unprotected indoles were set up (Scheme 152). The

rationale was that alkynyl iodode would act as an oxidant and add to the indole, after alkynyl-

shift delivering the oxidative coupling product 202. However, these initial experiments were

not as successful as hoped.

Scheme 152. Attempted one-pot gold-catalysed alkynylation of indoles with in situ generated

haloalkynes.

Chapter 4

130

Another system that was briefly examined was a combination of Au-catalysed in situ alkynyl

halide formation/Pd-catalysed direct C–H alkynylation (Scheme 153). In a simplistic set up,

only the first transformation took place smoothly. No reaction took place with 2-

phenylpyridine; however, with O-methyl benzaldehyde oxime, a complex mixture of

products was obtained. Nevertheless, it is worth exploring this directed alkynylation strategy

further in the future (e.g. addition of Ag2CO3 as a base), as both the Waser and Nevado

systems have great limitations in scope. Waser’s chemistry is based on a single example of an

expensive alkynyl derivative. It is far from ideal synthesis as it already incorporates an

equivalent of oxidant, and the reaction protocol is limited to heteroaryl systems. Nevado’s

catalytic system also has a narrow substrate scope, namely, only electron-rich arenes.

Additionally, both of these methods do not allow the introduction of an alkynyl moiety using

a more efficient directing metalation group strategy.

Scheme 153. Attempted one-pot directed alkynylation of arenes.

To explore whether haloalkynes may act as oxidants in a fashion similar or perhaps different

to that of N-halosuccinimides, we conducted an experiment with a boronic acid as a substrate

(Scheme 154). Uncatalysed halogenation of boronic acids was previously reported by Olah to

be proceed somewhat slow,[117]

so it was decided to set up a competition experiment with a

dropwise addition of NIS to a mixture of phenylacetylene and 4-anisylboronic acid over one

hour (Scheme 155).

Scheme 154. Uncatalysed coupling of boronic acids and alkynyl halides.

Chapter 4

131

Scheme 155. Iodination competition experiments. a

Conversion was determined by 1H NMR (CDCl3).

Interestingly, the only product formed was 4-anisyliodide. Further experiments showed that

electron-rich boronic acids underwent rapid halodeboronation at ambient temperature and

that these reactions were also catalysed by triflic acid (Scheme 156). Due to the time

restriction, reactions at elevated temperatures were not examined.

Scheme 156. Halodeboronation: (a) the competition experiment with acetylene, (b) limitations of triflic

acid catalysed process at RT. aConversions were determined by

1H NMR (CDCl3).

bIsolated yield.

At this stage, it is questionable whether this strategy could be of use in converting generally

electron-rich alkylboronic acids/esters to the corresponding halides. Such a transformation is

not feasible with transition metal catalysts, because many alkylmetal species, for example,

alkylcopper and alkylpalladium, would readily undergo β-hydride elimination.[119]

Moreover,

the synthetic utility of this conversion is potentially enhanced by Hartwig’s highly efficient

direct C–H activation/borylation of alkanes.[41–43]

Mechanistically, the Brønsted acid probably activates the electrophile (NXS), and an electron-

rich substituent in ortho- and para-positions activates the boronic acid (Scheme 157). For

Chapter 4

132

activation of an alkylboronic acid, use of electron-donating groups is not a feasible strategy

but these boronic acids are more electron-rich than unsubstituted phenylboronic acids in the

first place. Secondly, the rate of the reaction may also be enhanced by controlling the

borophilic ligand (L).

Scheme 157. Double activation in halodeboronation of arylboronic acids via electron-rich substituent in

the substrate and protonation of NXS reagent.

Another conceptually interesting experiment for hydroalkynylation was set up with a styrene

derivative (Scheme 158). The idea was to construct a catalytic cycle, where in situ generated

HOTf, protonates styrene to give a benzyl cation, which is then trapped by gold acetylide.

However, an electron-rich styrene, 4-methoxystyrene, was used as substrate; and only

polymerization of this starting material was observed.

Scheme 158. (a) Attempted hydroalkynylation of alkenes and (b) proposed catalytic cycle.

Chapter 4

133

4.2 Summary and Outlook

In this section, cationic gold and triflic acid were both shown to accelerate halodesilylation

and halodeborylation (Scheme 159). This catalysis may well be of synthetic value. Firstly,

halodesilylation of silyl-protected alkynes delivers haloalkynes in a simple transformation

avoiding common desilylation/deprotonation/halogenation sequence. Secondly,

halodeboronation under substantially mild and metal free conditions may allow a simple

conversion of boronic acids to the corresponding halides, although the substrate scope

remains largely to be determined.

Scheme 159. (a) Triflic acid an (b) cationic gold-catalysed halogenations.

Importantly, free terminal alkynes were activated in the presence of cationic gold and in the

presence of an electrophile, NBS or NIS, and gave the corresponding alkynyl halides (Scheme

159b). Typically, gold catalysts are used to activate acetylenes towards nucleophilic attack,

but this reaction is most likely proceeding via intermediate gold acetylide, and is

mechanistically distinct. Controlling the distribution of intermediate gold–acetylene π-

complex vs. gold acetylide will be the key to exploiting this new mechanistic pathway. From

a practical prospective, this transformation yields a wide range of alkynyl halides with no

homocoupling products observed. The haloalkynes and/or Au-haloalkyne complexes are not

very stable (light and temperature-sensitive), and their subsequent use (e.g. alkynylation,

heterocycle formation) will fully demonstrate the practical application of this reaction.

Chapter 5

Chapter 5

135

5 Experimental

5.1 General

Unless otherwise stated all chemicals were used as supplied. THF was used following

purification from a zeolite drying apparatus (Anhydrous Engineering, USA). Sonogashira

coupling[311]

and lithiation/borylation reactions[15]

were carried out in dry glassware under a

positive pressure of argon.

Chromatographic separations were performed on silica gel (VWR/BDH Prolabo® (40–63

μm) and Merck Silica gel 60 (40–63 μm). Thin-layer chromatography was performed on

Merck TLC Silica gel 60 F254 and visualised by UV (254 nm) and/or 10% PMA ethanolic

solution (PMA = phosphomolybdic acid).

Melting points were determined using a Gallenkamp apparatus and are uncorrected. Infrared

spectra were recorded on Perkin–Elmer Spectrum 100 FTIR ATR spectrometer and are

quoted in cm–1

. Optical rotations were measured using Perkin–Elmer 343 polarimeter (sodium

D-line, 529 nm) and [α]D values are reported in 10–1

deg cm2 g

–1, c is concentration (g/100

mL). 1H (

13C) NMR spectra were recorded at 300 (75), 400 (100), 500 (125) and 600 (150)

MHz on Bruker AMX400, Bruker Avance 500 and Bruker Avance 600 spectrometers,

respectively. 11

B and 19

F NMR spectra were recorded at 192 (160) and 282 MHz on Bruker

Avance 600 (Bruker Avance 500) and Bruker 300 spectrometers, respectively. Residual

solvent peak was used as an internal standard[353]

. Chemical shifts are quoted in ppm using the

following abbreviations: s singlet, d doublet, t triplet, q quartet, qn quintet, sx sextet, non

nonet, m multiplet, br broad; or a combination thereof. The coupling constants J are measured

in Hz. Mass spectra were recorded in the Department of Chemistry, University College

London.

Chapter 5

136

5.2 Procedures for Chapter 2

5.2.1 Synthesis of Boron and Silicone Based Reagents

7-Chloro-1H-benzo[d][1,2,3]triazol-1-ol (125a)

A solution of 2,6-dichloroaniline (5.20 g, 32.1 mmol) in glacial acetic acid (50 mL) was

added slowly to a stirred suspension of sodium perborate tetrahydrate (24.6 g, 160 mmol, 5.0

equiv) in glacial acetic acid (100 mL) maintained at 55 °C. The reaction mixture was stirred at

50 °C for 21 h and since starting material has not been consumed, additional sodium

perborate (5.24 g, 34.1 mmol, 1.06 equiv) was added. The mixture was cooled to RT and the

inorganic salts were removed by filtration. Distilled water (50 mL) was added to the filtrate

and the mixture was extracted with ether (4×50 mL), washed with brine (30 mL), dried over

MgSO4, filtered and concentrated. The residue was purified by column chromatography

(EtOAc/PE 1:25) to give the product as a colourless solid (1.97 g, 32%).

1,3-Dichloro-2-nitrobenzene (126a):[354]

Colourless solid. Mp 70–71°C (PE). Lit Mp 71–72 °C (EtOH).[354]

1H NMR (CDCl3, 400 MHz) δ 7.48–7.33 (m, 3H, ArH).

13C NMR (CDCl3, 125 MHz) δ 131.1, 129.0, 126.5, carbon adjacent to nitrogen not observed.

IR ν 1527, 1372, 1203, 776.

HRMS for C6H3Cl2NO2 [M]+ found 278.85178, calc. 278.85251.

2,6-Dichloronitrobenzene (484 mg, 2.52 mmol) and hydrazine monohydrate (1.56 mL, 20

equiv) were heated under reflux in anhydrous ethanol (4 mL) in the presence of sodium

acetate trihydrate (17 mg, 5 mol%) for 62 h under argon. After removal of the solvent under

reduced pressure, the residue was dissolved in 1 M NaHCO3 (20 mL). the solution was

washed with ether (2×10 mL) and acidified with conc HCl to precipitate the product,[234]

which was washed with water and dried under reduced pressure to give the product as a

colourless solid (264 mg, 62%).

Chapter 5

137

7-Chloro-1H-benzo[d][1,2,3]triazol-1-ol (125a):[233]

Colourless solid. Mp 184°C (H2O). Lit Mp 184–185 °C (EtOH/H2O).[233]

1H NMR (DMSO-d6, 300 MHz) δ 13.88 (s, 1H, OH), 7.98 (dd, 1H, J = 8.4, 0.4, ArH), 7.62

(dd, 1H, J = 7.4, 0.4, ArH), 7.39 (dd, 1H, J = 8.4, 7.4, ArH).

13C NMR (DMSO, 125 MHz) δ 128.0, 125.4, 124.5, 118.6.

IR ν 3089, 2322, 1420, 1360, 1167, 979, 783.

HRMS for C6H4ClN3O [M] +

found 169.00283, calc. 169.00374.

1-(Methoxymethoxy)-1H-benzo[d][1,2,3]triazole (128)

K2CO3 (608 mg, 4.40 mmol), TBAB (35 mg, 0.11 mmol, 5 mol%) and MOMCl (184 μL, 2.42

mmol, 1.10 equiv) were added to a solution of 1-HOBt (297 mg, 2.20 mmol) in MeCN (3

mL) and the mixture was stirred for 1h. The solvent was removed under reduced pressure and

the solid residue was dissolved in water and DCM, and extracted with DCM (3 x 10 mL),

washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to

give the product as a colourless solid (319 mg, 81%).

Yellow oil.

1H NMR (CDCl3, 600 MHz) δ 8.02 (d, 1H, J = 8.4, ArH), 7.58 (d, 1H, J = 8.4, ArH), 7.52 (td,

1H, J = 6.6, 0.9, ArH), 7.39 (td, 1H, J = 6.6, 0.9, ArH), 5.47 (s, 2H, CH2), 3.74 (s, 3H, CH3).

13C NMR (CDCl3, 150 MHz) δ 143.7, 128.4, 128.2, 124.7, 120.4, 108.7, 103.8, 58.2.

IR ν 2944, 1445, 1368, 1166, 1081, 921, 882.

HRMS for C8H9N3O2 [M]+ found 179.06680, calc. 179.06893.

7-Bromo-1H-benzo[d][1,2,3]triazol-1-ol (125b)

Chapter 5

138

30% H2O2 (8.0 mL, 0.26 mol) was added to a solution of 2,6-dibromoaniline (1.03 g, 4.09

mmol) in TFA (7 mL) and the mixture was stirred for 16 h at rt. It was then transferred into

ice-cold water and the precipitate was collected by filtration and dried to afford the nitroso-

compound 132 as a colourless solid (1.08 g, quant).

2,6-Dibromonitrosobenzene (132):[245]

Colourless solid. Mp 134–135°C (H2O). Lit Mp 132–133°C (hexane).[245]

1H NMR (CDCl3, 400 MHz) δ 7.78–7.70 (m, 2H, ArH), 7.31–7.24 (m, 1H, ArH).

13C NMR (CDCl3, 125 MHz) δ 134.5, 134.2, 133.4, 132.5, 119.4, 116.7.

IR ν 3068, 1562, 1290, 1199, 846, 777.

MCPBA (77%, 7.92 g, 35.4 mmol) was added to a solution of 2,6-dibromoaniline (2.52 g,

10.0 mmol) in DCM (70 mL) and the mixture was left to stir overnight at 40 °C. The

precipitate was filtered off. The solution was extracted with 1 M KOH (4×50 mL) until no

MCPBA could be detected by TLC. The combined organic layers were concentrated under

reduced pressure and the residue was dissolved in glacial AcOH (50 mL) and a solution of

30% H2O2 (25 mL) in glacial AcOH (25 mL) was added at rt. Then HNO3 (1.6 mL) was

added. The mixture was left to stir at 90 °C overnight. Water (50 mL) was added, and the

precipitate was collected by filtration to give the product as colourless needles (2.29 g, 81%).

2,6-Dibromonitrobenzene (126b):[245]

Colourless solid. Mp 77 °C (H2O). Lit Mp 78–79 °C (hexane).[245]

1H NMR (CDCl3, 400 MHz) δ 7.62 (d, 2H, J = 8.1, ArH), 7.24 (t, 1H, J = 8.1, ArH).

13C NMR (CDCl3, 75 MHz) δ 151.6 132.7, 131.8, 113.8.

IR ν 3078, 1562, 1527, 1436, 1277, 1201, 846, 770.

HRMS for C6H3Br2NO2 [M]+ found 190.95533, calc. 190.95354.

2,6-Dibromonitrobenzene (2.97 g, 10.6 mmol), hydrazine monohydrate (1.6 mL, 32 mmol)

and NaOAc·3H2O (72 mg, 0.53 mmol) were heated under reflux in dry EtOH (2 mL) for 16 h.

The mixture was dissolved in sat NaHCO3 and washed with Et2O. The aqueous phase was

concentrated and dissolved in a minimum amount of water. The precipitate formed on

addition of conc HCl was filtered off, washed with water and Et2O. It was then washed off the

filter with MeOH into a different flask and concentrated to give the product as a colourless

solid (1.57 g, 69 %).

Chapter 5

139

7-Bromo-1H-benzo[d][1,2,3]triazol-1-ol (125b):

Colourless solid. Mp 164 °C (dec; H2O).

1H NMR (DMSO-d6, 600 MHz) δ 8.02 (d, 1H, J = 8.4, ArH), 7.76 (d, 1H, J = 7.4, ArH), 7.31

(dd, 1H, J = 8.4, 7.4, ArH).

13C NMR (DMSO-d6, 150 MHz) δ 144.2, 131.3, 126.1, 125.9, 119.0, 101.5.

IR ν 3083, 1564, 1419, 1236, 1166, 960, 847.

HRMS for C6H5BrN3O [M+H]+ found 213.96164, calc. 213.96160.

Attempted Borylation of 1-(Benzyloxy)-7-bromo-1H-benzo[d][1,2,3]triazole (133)

DEAD (1.7 mL, 10.5 mmol) was added to a slurry of 7-bromo-1-hydroxybenzotriazole (1.49

g, 6.97 mmol), PPh3 (2.75 g, 10.5 mmol) and benzyl alcohol (1.08 mL, 10.5 mmol) in THF

(10 mL) at 0 °C and the mixture was left to stir for 10 h at RT. The reaction mixture purified

by column chromatography (EtOAc/PE 1:30) to give the product as a colourless solid (1.68 g,

79%).

1-(Benzyloxy)-7-bromo-1H-benzo[d][1,2,3]triazole (133):

Colourless solid. Mp 120–121 °C (PE/EtOAc).

1H NMR (DMSO-d6, 600 MHz) δ 8.11 (d, 1H, J = 8.3, ArH), 7.87 (d, 1H, J = 7.4, ArH),

7.60–7.56 (m, 2H, ArH), 7.46–7.43 (m, 3H, ArH), 7.40 (dd, 1H, J = 8.3, 7.4, ArH), 5.61 (s,

2H, CH2).

13C NMR (DMSO-d6, 150 MHz) δ 144.0, 132.7, 132.3, 130.4, 129.7, 128.7, 126.5, 125.9,

119.4, 101.1, 83.9.

IR ν 3036, 1575, 1455, 1345, 1246, 1097, 904, 841.

HRMS for C13H10BrN3O [M]+ found 303.00143, calc. 303.00018.

A 1.6 M solution of BuLi in hexanes (380 μL, 0.62 mmol, 0.95 equiv) was added dropwise at

–78 ºC to a solution of 1-(benzyloxy)-7-bromo-1H-benzo[d][1,2,3]triazole (198 mg, 0.65

mmol) and B(OiPr)3 (180 μL, 0.78 mmol, 1.2 equiv) in THF (7 mL) and the mixture was left

to stir overnight. The reaction mixture was quenched with sat NH4Cl solution and extracted

Chapter 5

140

with ether (3×10 mL), dried over MgSO4, filtered, concentrated and purified by flash

chromatography (EtOAc/PE 1:7) to give the product as a colourless solid (64 mg, 59%)

(1-(Benzyloxy)-1H-benzo[d][1,2,3]triazol-7-yl)(phenyl)methanol (134):

Colourless solid. Mp 112–113 °C (PE/EtOAc).

1H NMR (CDCl3, 500 MHz) δ 7.94 (dd, 1H, J = 6.0, 0.8, ArH), 7.46–7.22 (m, 12 H, ArH),

6.35 (d, 1H, J = 4.6, CHOH), 5.40 (d, 1H, J = 10.0, PhCH), 5.37 (d, 1H, J = 10.0, PhCH),

2.66 (d, 1H, J = 4.6, OH).

13C NMR (CDCl3, 125 MHz) δ 145.5, 143.3, 134.0, 131.23, 131.17, 130.3, 130.1, 129.5,

128.3, 128.2, 128.1, 126.7, 126.2, 121.1, 84.4, 72.6.

IR ν 3308, 3027, 1570, 1451, 1343, 1240, 1090/

HRMS ([M+H]+ for C20H17N3O2 found 331.13179, calc. 331.13153

(1-Hydroxy-1H-benzo[d][1,2,3]triazol-7-yl)boronic acid (139)

Dimethylformamide di-tert-butyl diacetate (1.6 mL, 6.69 mmol, 4.0 equiv) was added

dropwise over 20 min to a solution of 7-bromo-1-hydroxybenzotrizole (352 mg, 1.67 mmol)

in toluene (3 mL) and the mixture was left to stir for 4 h at 80 ºC. The mixture was then

concentrated and purified by column chromatography (EtOAc/PE 1:20) to give 7-bromo-1-

(tert-butoxy)-1H-benzo[d][1,2,3]triazole 136 as a colourless oil (244 mg, 55%) and 4-bromo-

1-(tert-butyl)-1H-benzo[d][1,2,3]triazole 3-oxide 137 as a colourless solid (200 mg, 45%).

7-Bromo-1-(tert-butoxy)-1H-benzo[d][1,2,3]triazole (136):

Colourless oil.

1H NMR (CDCl3, 600 MHz) δ 8.00 (dd, 1H, J = 8.3, 0.5, ArH), 7.67 (dd, 1 H, J = 7.4, 0.5,

ArH), 7.25 (dd, 1H, J = 8.3, 7.4, ArH), 1.56 (s, 9H, CH3).

Chapter 5

141

13C NMR (CDCl3, 125 MHz) δ 144.1, 132.2, 127.9, 125.4, 119.5, 101.9, 91.0, 27.1.

IR ν 2991, 1604, 1555, 1441, 1381, 1372, 1246, 1185, 943.

HRMS for C10H13BrN3O [M+H]+ found 270.02494, calc. 270.02420.

4-Bromo-1-(tert-butyl)-1H-benzo[d][1,2,3]triazole 3-oxide (137):

Colourless solid. Mp 149–151 °C (PE/EtOAc).

1H NMR (CDCl3, 600 MHz) δ 7.67 (d, 1H, J = 8.6, ArH), 7.46 (d, 1H, J = 7.3, ArH), 7.21

(dd, 1H, J = 8.6, 7.3, ArH), 1.93 (s, 9H, CH3)

13C NMR (CDCl3, 125 MHz) δ 140.5, 129.7, 128.5, 125.2, 118.5, 106.4, 67.3, 27.0.

IR ν 2982, 1575, 1371, 1248, 1162, 1090, 1040, 939.

HRMS for C10H13BrN3O [M+H]+ found 270.02451, calc. 270.02420.

A 1.6 M solution of BuLi in hexanes (328 μL, 0.525 mmol, 1.1 equiv) and B(OiPr)3 (121 μL,

0.525 mmol, 1.1 equiv) were added dropwise to a solution of 7-bromo-O-tert-

butyloxybenzotriazole (129.0 mg, 0.478 mmol) in THF (3 mL) at –78 °C and the mixture was

left to stir for 16 h. The mixture was quenched with 1 M HCl and extracted with Et2O. The

combined organic layers were dried over Na2SO4, filtered, concentrated and purified by flash

chromatography (EtOAc/PE 1:10 then with EtOAc/PE/MeOH 1:10:0.01) to give the product

as a colourless solid (71 mg, 63%).

(1-(tert-Butoxy)-1H-benzo[d][1,2,3]triazol-7-yl)boronic acid (138):

Colourless solid. Mp 71–72 °C (PE/EtOAc; dec).

1H NMR (DMSO-d6, 600 MHz) δ 8.50 (s, 2H, B(OH)2), 8.00 (d, 1H, J = 8.3, ArH), 7.59 (d,

1H, J = 6.7, ArH), 7.38 (dd, 1H, J = 8.3, 6.7, ArH), 1.39 (s, 9H, CH3).

13C NMR (DMSO-d6, 150 MHz) δ 141.3, 132.4, 131.1, 124.1, 119.7, 89.6, 26.7, carbon

adjacent to boron not observed.

IR ν 3356, 2984, 1599, 1412, 1373, 1329, 1249, 1163, 1105.

HRMS for C10H14BN3O3 [M]+ found 235.11309, calc. 235.11227.

0.2 M TFA/DCM solution (300 μL, 0.063 mmol, 0.2 equiv) was added to a solution of (1-

(tert-butoxy)-1H-benzo[d][1,2,3]-triazol-7-yl)boronic acid (74 mg, 0.31 mmol) in DCM (2

mL) and left to stir for 10 minutes. The mixture was then concentrated to give the product as a

colourless solid (56 mg, quant).

(1-Hydroxy-1H-benzo[d][1,2,3]triazol-7-yl)boronic acid (139):

Colourless solid. Mp 121–123 °C (DCM, dec).

Chapter 5

142

(DMSO-d6, 600 MHz) δ 8.46 (s, 2H, B(OH)2), 8.05 (d, 1H, J = 8.2, ArH), 7.57 (d, 1H, J =

6.5, ArH), 7.38 (dd, 1H, J = 8.2, 6.5, ArH).

13C NMR (DMSO-d6, 150 MHz) δ 141.2, 132.7, 131.0, 124.3, 119.5, carbon adjacent to boron

not observed.

IR ν 3350, 3293, 1579, 1432, 1370, 1245, 1161, 1090.

HRMS for C6H7N3O3B [M+H] +

found 180.05763, calc. 180.05805.

2-Iodophenylboronic acid (47)[132b]

iPrMgCl (2.0 M in THF, 1.75 mL, 3.50 mmol) was added dropwise to a solution of 1,2-

diiodobenzene (1.156 g, 3.50 mmol) in THF/Et2O (1:1, 30 mL) at –78 °C. The mixture was

stirred at –78 °C for 2 h and then B(OiPr)3 (2.43 mL, 11.50 mmol) was added. The mixture

was stirred for further 2h at –78 °C and then was allowed to warm up to RT while being

stirred for 16 h. The mixture was acidified with HCl (10%, 40 mL) and extracted with ether (3

x 30 mL). The combined organic layers were dried over Na2SO4, and purified by column

chromatography (PE then EtOAc/PE 1:5) to give product as a colourless solid (309 mg, 36%).

Colourless solid. Mp 121–122 °C (PE/EtOAc).

1H NMR (DMSO-d6, 400 MHz) δ 8.25 (s, 2H, B(OH)2), 7.74 (dd, 1H, J = 7.5, 0.5, ArH), 7.33

(td, 1H, J = 7.5, 1.0, ArH), 7.22 (dd, 1H, J = 7.5, 1.0, ArH), 7.06 (td, 1H, J = 7.5, 0.5, ArH).

13C NMR (DMSO-d6, 125 MHz) δ 137.6, 133.1, 130.0, 126.8, 99.2, carbon adjacent to boron

not observed.

Attempted synthesis of (2-(mercaptomethyl)phenyl)boronic acid

Chapter 5

143

TrSH (1.34 g, 4.84 mmol) was added to slurry of 2-bromobenzyl bromide (1.21 g, 4.84

mmol) and K2CO3 (1.34 g, 9.68 mmol, 2.0 equiv) in DMF (7 mL) and left to stir at RT for 17

h. The mixture was then washed with 10% LiCl aqueous solution (3×10 mL) and 1 M

NaHCO3 (2×10 mL), dried over MgSO4, concentrated under reduced pressure to give the

product as colourless solid (2.12 g, 98%).

(2-Bromobenzyl)(trityl)sulfane (140):

1H NMR (CDCl3, 400 MHz) δ 7.54–7.48 (m, 7H, ArH), 7.35–7.29 (m, 6H, ArH), 7.27–7.21

(m, 3H, ArH), 7.16 (td, 1H, J = 7.6, 1.3, ArH), 7.05 (td, 1H, J = 7.6, 1.7, ArH), 7.00 (dd, 1H,

J = 7.6, 1.7, ArH), 3.44 (s, 2H, CH2).

1H NMR (CDCl3, 125 MHz) δ 144.6, 136.9, 131.4, 129.8, 128.7, 128.0, 127.5, 126.8, 124.6,

67.6, 37.3.

IR ν 3062, 1487, 1463, 1440, 1023, 766.

HRMS for C20H17BrS [M–PhH]+ found 368.02260, calc. 368.02289

A mixture of 2-bromobenzyl bromide (1.68 g, 4.67 mmol) and potassium thioacetate (587

mg, 5.14 mmol) was heated under reflux in dry THF (20 mL) for 4 h under argon. The

solution was filtered, and the filtrate was concentrated under reduced pressure. The residue

was dissolved in ether and washed with sat NH4Cl (10 mL), dried over MgSO4, filtered and

concentrated under reduced pressure to give the product as a light brown viscous oil (1.14 g,

quant).

S-2-Bromobenzyl ethanethioate (141):

1H NMR (CDCl3, 600 MHz) δ 7.56 (dd, 1H, J = 7.7, 1.2, ArH), 7.46 (dd, 1H, J = 7.7, 1.7,

ArH), 7.26 (td, 1H, J = 7.7, 1.2, ArH), 7.13 (td, 1H, J = 7.7, 1.7, ArH), 4.25 (s, 2H, ArCH2),

2.36 (s, 3H, CH3).

13C NMR (CDCl3, 150 MHz) δ 195.1, 137.3, 133.0, 131.3, 129.1, 127.8, 124.6, 34.2, 30.5.

IR ν 1687, 1469, 1440, 1353, 1130, 1026.

HRMS for C9H9BrOS [M+H] +

found 244.96357, calc. 244.96333.

S-2-Bromobenzyl ethanethioate (207 mg, 0.844 mmol) and K2CO3 (117 mg, 0.844 mmol)

were stirred in MeOH (3 mL) for 2 h at RT. The mixture then purified by flash

chromatography (Et2O/PE 1:10) to give the product as a pale yellow oil (162 mg, 94%).

Chapter 5

144

(2-Bromophenyl)methanethiol (142):[355]

Pale yellow oil.

1H NMR (CDCl3, 400 MHz) δ 7.56 (dd, 1H, J = 7.7, 1.2, ArH), 7.39 (dd, 1H, J = 7.7, 1.6,

ArH), 7.30 (td, 1H, J = 7.7, 1.2, ArH), 7.12 (td, 1H, J = 7.7, 1.6, ArH), 3.85 (d, J = 8.1, 2H,

ArCH2SH), 2.02 (t, 1H, J = 8.1, SH).

13C NMR (CDCl3, 125 MHz) δ 140.6, 133.2, 130.1, 128.8, 128.0, 123.7, 29.7.

(2-((Acetylthio)methyl)phenyl)boronic acid

2-Tolylboronic acid:[356]

Colourless solid. Mp 164–166 °C (PE/EtOAc). Lit Mp 168 °C (H2O).[356]

1H NMR (CDCl3, 600 MHz) δ 8.22 (d, 1H, J = 7.5, ArH), 7.46 (t, 1H, J = 7.5, ArH), 7.31 (t,

1H, J = 7.5, ArH), 7.25 (d, 1H, J = 7.5, ArH), 2.82 (s, 3H, CH3).

13C NMR (CDCl3, 150 MHz) δ 146.4, 137.4, 132.3, 129.4, 125.3, 23.3.

2-Tolylboronic acid (197 mg, 1.45 mmol), NBS (310 mg, 1.74 mmol, 1.2 equiv), and AIBN

(24 mg, 0.15 mmol) were heated in CCl4 (3 mL) at 80 °C for 2 h. The reaction mixture was

then cooled to RT, preabsorbed onto silica gel and purified by flash chromatography

(EtOAc/PE 1:5) to give the product as a colourless solid (223 mg, 71%).

(2-(Bromomethyl)phenyl)boronic acid (143):[252]

Colourless solid. Mp 138–139 °C (EtOAc/PE). Lit Mp 138 °C (DCM/Et2O).[253]

1H NMR (CDCl3, 400 MHz) δ 8.39 (dd, 1H, J = 7.4, 1.3, ArH), 7.59 (td, 1H, J = 7.4, 1.3,

ArH), 7.53 (dd, 1H, J = 7.4, 1.3, ArH), 7.49 (td, 1H, J = 7.4, 1.3, ArH), 5.16 (s, 2H, CH2).

13C NMR (CDCl3, 125 MHz) δ 145.5, 138.04, 133.0, 131.0, 128.3, 33.8, carbon adjacent to

boron not observed.

IR ν 3215, 1597, 1487, 1444, 1335, 1301, 1017, 805

(2-(Bromomethyl)phenyl)boronic acid (724 mg, 3.37 mmol) and potassium thioacetate (423

mg, 3.71 mmol) were heated under reflux in anhydrous THF (6 mL) for 8 h. The reaction

Chapter 5

145

mixture was then cooled to RT, preabsorbed onto silica gel and purified by flash

chromatography (EtOAc/PE 1:1) to give the product as a colourless solid (568 mg, 80%).

(2-((Acetylthio)methyl)phenyl)boronic acid (144):

Colourless solid. Mp 46–47 °C (EtOAc/PE).

1H NMR (CDCl3, 600 MHz) δ 8.01 (dd, 1H, J = 7.6, 1.2, ArH), 7.55 (td, 1H, J = 7.6, 1.2,

ArH), 7.54 (dd, 1H, J = 7.6, 1.2, ArH), 7.47 (td, 1H, J = 7.6, 1.2, ArH), 4.23 (s, 2H, ArCH2),

2.35 (s, 3H, CH3)

13C NMR (CDCl3, 150 MHz) δ 194.9, 143.4, 137.0, 133.2, 130.8, 128.1, 34.4, 29.9. carbon

adjacent to boron not observed.

IR 3220, 1594, 1485, 1446, 1334, 1030.

HRMS for C9H11O3BS [M]+ found 210.05139, calc. 210.05165.

Phenylsilanetriol[357]

PhSi(OMe)3 (1.25 mL, 6.57 mmol) was added dropwise into a 0.5% acetic acid solution (0.75

mL) at 5 °C. The reaction mixture was stirred for 4 h at 5 °C. A colourless crystalline product

precipitated. The reaction mixture was cooled to –18 °C for 30 min and then filtered, washed

with cold water, toluene and hexane to give the product as colourless needle-like crystals (253

mg, 26%).

Mp 129–130°C (PE). Lit Mp 130 °C (MeOAc, acetone).[358]

1H NMR (DMSO-d6, 300 MHz) δ 7.62–7.54 (m, 2H, ArH), 7.36–7.26 (m, 3H, ArH), 6.36 (s,

3H, 3×OH).

13C NMR (DMSO, 125 MHz) δ 137.4, 134.0, 129.0, 127.2.

Phenylsilanediol[359]

Ph2SiCl2 (870 μL, 4.14 mmol) in Et2O (2 mL) was added dropwise over 10 min into a rapidly

stirred biphasic system consisting of brine (10 mL), ether (10 mL) and (NH4)2CO3 (240 mg,

3.04 mmol). When addition was complete, the aqueous layer was extracted with ether (3 x 20

mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated

under reduced pressure to give the product a colourless solid (872.3 mg, 97%).

Chapter 5

146

Mp 164–165°C (Et2O). Lit Mp 161–165 °C (benzene, PE).[360]

1H NMR (DMSO-d6, 300 MHz) δ 7.71 (d, 4H, J = 7.8, ArH), 7.50–7.30 (t, 6H, J = 7.8, ArH),

2.93 (br s, 2H, 2×OH).

13C NMR (DMSO-d6, 125 MHz) δ 137.8, 134.1, 129.3, 127.4.

6H-Dibenzo[c,e][1,2]oxaborinin-6-ol[316a]

A solution of 2-hydroxybiphenyl (1.0046 g, 5.90 mmol) in dry hexane (total 80 mL) was

added dropwise to a solution of 1 M BCl3 in hexane (9.0 mL, 9.0 mmol, 1.52 equiv) and

hexane (40 mL). After the reaction mixture was stirred at 25 ºC for 10 min, AlCl3 (39 mg, 5

mol%) was added. The reaction mixture was heated to 80 ºC for 15 h, and then cooled down.

Ice was added to quench the reaction. Diethyl ether (20 mL) was added, and the mixture was

stirred for 15 min. The organic layer was separated, and the aqueous phase was extracted with

diethyl ether (2×15 mL). Combined organic layers were dried over MgSO4, filtered and

concentrated in vacuum to give the product as a colourless solid (1.15 g, quant).

Colourless solid. Mp 213–214 °C (PE). Lit Mp 214–216 °C (PE).[361]

1H NMR (CDCl3, 600 MHz) δ 8.19 (d, 1H, J = 8.2, ArH), 8.16 (dd, 1H, J = 8.2, 1.4, ArH),

8.09 (d, 1H, J = 7.4, ArH), 7.74 (td, 1H, J = 7.8, 1.4, ArH), 7.50 (td, 1H, J = 7.4, 1.0, ArH),

7.40 (td, 1H, J = 7.4, 1.4, ArH), 7.29 (dd, 1H, J = 7.8, 1.4, ArH), 7.25 (td, 1H, J = 7.4, 1.4,

ArH), 4.72 (br s, 1H, OH).

13C NMR (CDCl3, 150 MHz) δ 151.12, 140.33, 133.34, 132.6, 129.0, 127.3, 123.6, 123.0,

122.7, 121.6, 119.6, carbon adjacent to boron not observed.

IR ν 3449, 1604, 1487, 1392, 1018.

Tris(2,2,2-trifluoroethyl) borate[361, 362]

2,2,2-Trifluroethanol (42.7 mL, 58.6 mmol, 3.0 equiv) was added via syringe pump over 30

min to neat BBr3 (48.9 g, 19.5 mmol, 1.0 equiv) at –78 °C and the mixture was allowed to

Chapter 5

147

warm up to RT overnight under argon flow. The mixture was heated for 1 h at 70 °C under

argon before being distilled (120–123 °C; 760 Torr) to give the product as a colourless liquid

(54.0 g, 90%).

Colourless liquid. Lit Bp 77 ºC (200 Torr)[362]

1H NMR (CDCl3, 600 MHz) δ 4.22 (q, 6H, J = 8.4, CH2CF3).

13C NMR (CDCl3, 150 MHz) δ 123.3 (q, J = 278), 61.9 (q, J = 36).

19F NMR (CDCl3, 282 MHz) δ –77.2.

11B NMR (CDCl3, 160 MHz) δ 15.3.

IR ν 2974, 1429, 1390, 1264, 1161, 1079, 964, 907, 840, 731.

HRMS for C6H7O3F9B [M]+ found 309.03461, calc. 309.03445.

5.2.2 Direct carboxamidation

Amidations were performed on 0.5–3.0 mmol scale.

Representative Procedure: Borate (2 equiv) was added to a solution/suspension of carboxylic

acid (1 equiv) and amine (1 equiv) in MeCN (0.5 M) and the mixture was heated at 80 °C.

After 15 h, the solvent was removed under reduced pressure. The residue was redissolved in

DCM and washed with NaHCO3 (1 M) and HCl (1 M) aqueous solutions, dried over MgSO4,

filtered and concentrated under reduced pressure to give the clean amide product.

N-Benzyl-2-phenylacetamide (146a)[204a]

Colourless solid. Mp 118–120 °C (DCM). Lit Mp 118–119 °C (PE/EtOAc).[204a]

1H NMR (CDCl3, 600 MHz) δ 7.36–7.32 (m, 2H, ArH), 7.32–7.22 (m, 6H, ArH), 7.19–7.15

(d, 2H, J = 7.1, ArH), 5.79 (br s, 1H, NH), 4.41 (d, 2H, J = 5.8, CH2NH), 3.63 (s, 2H,

CH2CO).

13C NMR (CDCl3, 150 MHz) δ 171.1, 138.2, 134.9, 129.6, 129.2, 128.8, 127.61, 127.56,

127.55, 43.9, 43.7.

1H NMR (DMSO-d6, 600 MHz) δ 8.56 (br t, 1H, J = 5.5, NH), 7.33–7.26 (m, 6H, ArH), 7.25–

7.20 (m, 4H, ArH), 4.26 (d, 2H, J = 6.0, CH2NH), 3.47 (s, 2H, CH2CO).

13C NMR (DMSO-d6, 150 MHz) δ 170.1, 139.5, 136.4, 129.0, 128.3, 128.2, 127.2, 126.8,

126.4, 42.4, 42.2.

Chapter 5

148

IR ν 3286, 1637, 1551.

HRMS for C15H15NO [M]+ found 225.11483, calc. 225.11482.

N-Butyl-2-phenylacetamide (146b)[363]

Colourless solid. Mp 49–50 °C (DCM). Lit Mp 49°C.[363]

1H NMR (CDCl3, 600 MHz) δ 7.34–7.30 (m, 2H, ArH), 7.30–7.21 (m, 3H, ArH), 5.71 (br s,

1H, NH), 3.53 (s, 2H, CH2CO), 3.17 (q, 2H, J = 6.5, NHCH2), 1.38 (qn, 2H, J = 7.3, CH2Et),

1.23 (sx, 2H, J = 7.3, CH2CH3), 0.85 (t, 3H, J = 7.3, CH3).

13C NMR (CDCl3, 150 MHz) δ 171.2, 135.2, 129.5, 129.1, 127.4, 43.9, 39.5, 31.6, 20.1, 13.8.

IR ν 3294, 1642, 1549.

HRMS for C12H17NO [M]+ found 191.12961, calc. 191.13047.

N-Benzyl-3-methylbutanamide (146c)[364]

Colourless solid. Mp 58–59 °C (DCM). Lit Mp 58–60°C.[364]

1H NMR (CDCl3, 600 MHz) δ 7.34–7.29 (m, 2H, ArH), 7.28–7.23 (m, 3H, ArH), 5.97 (br s ,

1H, NH), 4.41 (d, 2H, J = 5.7, CH2NH), 2.13 (non, 1H, J = 6.7, CHMe2), 2.06 (d, 2H, J = 7.1,

CH2CO), 0.94 (d, 6H, J = 6.6, CH3).

13C NMR (CDCl3, 150 MHz) δ 172.5, 138.5, 128.8, 127.9, 127.6, 46.2, 43.6, 26.3, 22.6.

IR ν 3289, 1635, 1543.

HRMS for C12H17NO [M]+ found 191.13126, calc. 191.13047.

N-Butyl-3-methylbutanamide (146d)[365]

Colourless oil.

1H NMR (CDCl3, 600 MHz) δ 5.79 (br s, 1H. CONH), 3.20 (q, 2H, J = 6.7, NHCH2), 2.07

(non, 1H, J = 6.7, CH(CH3)3), 1.99 (d, 2H, J = 6.7, CH2CO), 1.44 (qn, 2H, J = 7.2,

NHCH2CH2), 1.30 (sx, 2H, J = 7.2, CH2CH3), 0.90 (d, 6H, J = 6.7, CH(CH3)2), 0.88 (t, 3H, J

= 7.2, CH2CH3).

13C NMR (CDCl3, 150 MHz) δ 172.7, 46.3, 39.2, 31.9, 26.3, 22.5, 20.2, 13.9.

IR ν 3284, 2957, 2871, 1641, 1550, 1465, 1368.

HRMS for C9H20NO [M+H]+ found 158.15521, calc. 157.15449.

Chapter 5

149

N-Benzylpivalamide (146e)[366]

Colourless solid. Mp 80–81 °C (DCM). Lit Mp 80–82°C.[366]

1H NMR (CDCl3, 600 MHz) δ 7.36–7.30 (m, 2H, ArH), 7.30–7.23 (m, 3H, ArH), 5.92 (br s,

1H, NH), 4.43 (d, 2H, J = 5.6, CH2NH), 1.22 (s, 9H, CH3).

13C NMR (CDCl3, 150 MHz) δ 178.5, 138.7, 128.8, 127.8, 127.6, 43.7, 38.8, 27.7.

IR ν 3293, 1634, 1540.

HRMS for C12H17NO [M]+ found 191.12954, calc. 191.13047.

N-Benzylbenzamide (146f)[204a]

Colourless solid. Mp 100–101°C (DCM). Lit Mp 98–100°C (H2O/EtOH).[204a]

1H NMR (CDCl3, 600 MHz) δ 7.90–7.76 (m, 2H, ArH), 7.52–7.46 (m, 1H, ArH), 7.45–7.39

(m, 2H, ArH), 7.37–7.32 (m, 4H, ArH), 7.32–7.26 (m, 1H, ArH), 6.56 (br s, 1H, NH), 4.63 (d,

2H, J = 5.1, CH2CO).

13C NMR (CDCl3, 150 MHz) δ 167.5, 138.3, 134.5, 131.7, 128.9, 128.7, 128.0, 127.7, 127.1,

44.2.

IR ν 3318, 1639, 1540.

HRMS for C14H14NO [M+H]+ found 212.10846, calc. 212.10754.

N-(2-Hydroxyethyl)-2-phenylacetamide (146g)[198]

Colourless solid. Mp 64–66 °C. Lit Mp 65–66 °C.[198]

1H NMR (CDCl3, 600 MHz) δ 7.38–7.25 (m, 5H, ArH), 5.98 (br s, 1H, CONH), 3.68 (t, 2H, J

= 5.0, CH2OH), 3.61 (s, 2H, PhCH2), 3.38 (q, 2H, J = 5.0, NHCH2), 2.46 (br s, 1H, OH).

13C NMR (CDCl3, 150 MHz) δ 172.8, 134.6, 129.6, 129.2, 127.6, 62.5, 43.7, 42.9.

IR ν 3397, 3278, 3090, 2931, 1635, 1540, 1495, 1454, 1429, 1345, 1061.

HRMS for C10H14NO2 [M+H]+ found 180.10266, calc. 180.10245.

Chapter 5

150

(R)-2-Phenyl-N-(1-phenylethyl)acetamide (146h)[204a]

Colourless solid. Mp 116–117 °C (DCM). Lit Mp 115-116 °C (H2O/EtOH).[204a]

25

D +3.3 (c 1.0, CHCl3). Lit

25

D +3.3 (c 1.0, CHCl3).

[204a]

1H NMR (CDCl3, 600 MHz) δ 7.37–7.33 (m, 2H, ArH), 7.32–7.27 (m, 3H, ArH), 7.27–7.21

(m, 3H, ArH), 7.20–7.16 (m, 2H, ArH), 5.66 (br s, 1H, CONH), 5.12 (qn, 1H, J = 7.1,

CHCH3), 3.60(d, 1H, J = 16.3, PhCHH)3.58 (d, 1H, J = 16.3, PhCHH), 1.39 (d, 3H, J = 7.1,

CH3).

13C NMR (CDCl3, 150 MHz) δ 170.2, 143.1, 134.9, 129.5, 129.2, 128.7, 127.5, 127.4, 126.1,

48.9, 43.9, 21.9.

IR ν 3284, 3062, 3030, 2974, 1641, 1543, 1495, 1453.

HRMS for C16H18NO [M+H]+ found 240.13757, calc. 240.13884.

N-Allylhex-5-enamide (146i)

Pale yellow oil.

1H NMR (CDCl3, 600 MHz) δ 6.09 (br s, 1H, CONH), 5.83–5.66 (m, 2H, 2×CH=CH2), 5.12

(d, 1H, J = 17.2, NHCH2CH=CHH-trans), 5.07 (d, 1H, J = 10.4, NHCH2CH=CHH-cis), 4.97

(d, 1H, J = 17.2, (CH2)2CH=CHH-trans), 4.92 (d, 1H, J = 10.4, (CH2)2CH=CHH-cis), 3.81 (t,

2H, J = 5.6, NHCH2), 2.16 (t, 2H, J = 7.6, COCH2), 2.04 (q, 2H, J = 7.2, CH2CH=CH2), 1.70

(qn, 2H, J = 7.5, CH2CH2CH2).

13C NMR (CDCl3, 150 MHz) δ 173.0, 138.0, 134.4, 116.3, 115.4, 41.9, 35.9, 33.3, 24.9.

IR ν 3289, 3077, 2927, 1640, 1543, 911.

HRMS for C9H14NO [M–H]+ found 152.10643, calc. 152.10699.

N-Cyclopropylbut-3-enamide (146j)

Yellow oil.

1H NMR (CDCl3, 600 MHz) δ 6.53 (br s, 1H, CONH), 5.82 (ddt, 1H, J = 17.1, 10.7, 7.1,

CH=CH2), 5.10–5.05 (m, 2H, CH=CH2), 2.88 (d, 2H, J = 7.1, CH2CO), 2.59 (tq, J = 7.3, 3.7,

1H, CHN), 0.66–0.62 (m, 2H, cPr–H), 0.40 (m, 2H,

cPr–H).

13C NMR (CDCl3, 150 MHz) δ 172.5, 131.6, 119.2, 41.4, 22.7, 6.4.

Chapter 5

151

IR ν 3275, 3081, 1647, 1537, 913.

HRMS for C7H11NO [M]+ found 125.08291, calc. 125.08352.

N-(2-(1H-Indol-3-yl)ethyl)-4-phenylbutanamide (146k)

Pale yellow solid. Mp 110–111 °C (PE/Et2O). Lit Mp 112–113 °C (MeOH)[367]

1H NMR (CDCl3, 600 MHz) δ 8.59 (br s, 1H, indole-NH), 7.60 (d, 1H, J = 7.9, indole-CH),

7.37 (d, 1H, J = 7.9, indole-CH), 7.29–7.24 (m, 2H, ArH), 7.24–7.17 (m, 2H, indole-CH),

7.15–7.10 (m, 3H, ArH), 6.97 (s, 1H, indole-CH), 5.69 (br s, 1H, CONH), 3.59 (q, 2H, J =

6.6, NHCH2), 2.98 (t, 2H, J = 6.6, NHCH2CH2), 2.60 (t, 2H, J = 7.6, PhCH2), 2.11 (t, 2H, J =

7.6, CH2CO), 1.94 (qn, 2H, J = 7.6, CH2CH2CH2).

13C NMR (CDCl3, 150 MHz) δ 173.2. 141.6, 136.5, 128.6, 128.5, 127.5, 126.1, 122.4, 122.2,

119.5, 118.8, 112.8. 111.6, 40.0, 36.1, 35.3, 27.3, 25.4.

IR ν 3407, 3284, 2924, 1644, 1526, 1455.

HRMS for C20H22N2ONa [M+Na]+ found 329.1628, calc. 329.1630.

N-Benzylbut-2-ynamide (146l)

Pale yellow solid. Mp 114–115 °C (DCM).

1H NMR (CDCl3, 600 MHz) δ 7.37–7.31 (m, 2H, ArH), 7.31–7.26 (m, 3H, ArH), 6.02 (br s,

1H, CONH), 4.47 (d, 2H, J = 5.9, CH2Ph), 1.93 (s, 3H, CH3).

13C NMR (CDCl3, 150 MHz) δ 153.4, 137.4, 128.9, 128.0, 127.9, 83.9, 74.8, 43.9, 3.8.

IR ν 3266, 3062, 2253, 1631, 1532, 1287.

HRMS for C11H11NO [M]+ found 173.08273, calc. 173.08352.

Chapter 5

152

(E)-N-Benzyl-3-(3-nitrophenyl)acrylamide (146m)[368]

Pale yellow solid. Mp 185–186 °C (DCM). Lit Mp 184–185 °C.[368]

1H NMR (CDCl3, 600 MHz) δ 8.31 (s, 1H, ArH), 8.15 (d, 1H, J = 8.2, ArH), 7.71 (d, 1H, J =

7.7, ArH), 7.66 (d, 1H, J = 15.6, ArCH=CH), 7.52 (t, 1H, J = 8.2, ArH), 7.34–7.24 (m, 4H,

ArH), 6.60 (d, 1H, J = 15.6, ArCH=CH), 6.48 (br s, 1H, NH), 4.57 (d, 2H, J = 5.8, NHCH2).

13C NMR (CDCl3, 150 MHz) δ 165.1, 148.7, 138.8, 138.0, 136.7, 134.1, 130.0, 128.9, 128.0,

127.8, 124.1, 123.7, 121.8, 44.8.

IR ν 3283, 1656, 1619, 1525, 1349, 1221.

HRMS for C16H15NO [M]+ found 282.09909, calc. 282.09989.

(E)-N-(4-Methoxyphenyl)-3-(4-(trifluoromethyl)phenyl)acrylamide (146n)

Purified by column chromatography (PE/EtOAc 1:2).

Colourless solid. Mp 191–192 °C (EtOAc/PE).

1H NMR (DMSO-d6, 600 MHz) δ 10.2 (s, 1H, CONH), 7.84 (d, 2H, J = 8.5, ArH), 7.80 (d,

2H, J = 8.5, ArH), 7.66–7.60 (m, 3H, PMPH and ArCH=CH), 6.96–6.90 (m, 3H, PMPH and

ArCH=CH), 3.74 (s, 3H, OCH3).

13C NMR (DMSO-d6, 150 MHz) δ 162.6, 155.5, 138.9, 137.9, 132.3, 129.4 (J = 32.2), 128.3,

125.9 (J = 3.9), 125.3, 124.2 (J = 271.8), 120.7, 114.0, 55.2.

IR ν 3294, 1658, 1622, 1537, 1511, 1326, 1125, 1070.

HRMS for C17H15F3NO2 [M+H]+ found 322.1057, calc. 322.1055.

(R)-Methyl 3-phenyl-2-(2-phenylacetamido)propanoate (146o)[369]

Chapter 5

153

Colourless solid. Mp 93–94 °C (DCM). Lit Mp 92–94 °C (EtOAc/hexane).[369]

αD25

(c 1.0, CHCl3) = – 49.1. Lit. αD25

(c 1.0, CHCl3) = – 49.5.[369]

1H NMR (CDCl3, 600 MHz) δ 7.36.–7.27 (m, 3H, ArH), 7.21–7.16 (m, 5H, ArH), 6.90–6.85

(m, 2H, ArH), 5.80 (d, 1H, J = 7.0, CONH), 4.85 (dt, 1H, J = 7.0, 5.8, NHCH), 3.70 (s, 3H,

CH3), 3.56 (d, 1H, J = 15.9, PhCHHCO), 3.53 (d, 1H, J = 15.9, PhCHHCO), 3.06 (dd, 1H, J =

13.8, 5.8, CHHPh), 2.99 (dd, 1H, J = 13.8, 5.8, CHHPh).

13C NMR (CDCl3, 150 MHz) δ 171.9, 170.6, 135.6, 134.5, 129.5 129.3, 129.1, 128.7, 127.5,

127.2, 53.1, 52.46, 43.8, 37.7.

IR ν 3287, 3063, 3029, 2951, 1744, 1651, 1537, 1496, 1217.

HRMS for C18H20NO3 [M+H]+ found 298.14468, calc. 298.14431.

tert-Butyl (1-(benzylamino)-1-oxopropan-2-yl)carbamate (146p)[370]

Colourless solid. Mp 100–102 °C (DCM). Lit Mp 104–106 °C (EtOAc/hexane).[370]

For B(OCH2CF3)3, αD22

(c 1.9, CHCl3) = – 22.1. For B(OMe)3, αD

22 (c 1.9, CHCl3) = – 24.1.

Lit. αD22

(c 1.9, CHCl3) = – 24.5.[363]

HPLC chromatograms can be found in appendix.

1H NMR (CDCl3, 600 MHz) δ 7.33–7.28 (m, 2H, ArH), 7.28–7.22 (m, 3H, ArH), 6.63 (br s,

1H, CONHBn), 5.07 (m, 1H, CHCH3), 4.43 (br s, 2H, CH2Ph), 4.20 (br s, 1H, BocNH), 1.40

(s, 9H, C(CH3)3), 1.37 (d, 3H, J = 6.8, CHCH3).

13C NMR (CDCl3, 150 MHz) δ 172.7, 155.7, 138.1, 128.8, 127.7, 127.6, 80.3, 50.3, 43.5,

28.4, 18.3.

IR ν 3304, 1695, 1591, 1497, 1365, 1162.

HRMS for C15H22N2O3Na [M+Na]+ found 301.15319, calc. 301.15280.

(E)-1-(Pyrrolidin-1-yl)-3-(thiophen-3-yl)prop-2-en-1-one (146q)

Chapter 5

154

Colourless solid. Mp 94–95 °C (DCM).

1H NMR (CDCl3, 600 MHz) δ 7.68 (d, 1H, J = 15.5, ArCH=CH), 7.45 (d, 1H, J = 1.8, ArH),

7.33–7.27 (m, 2H, ArH), 6.56 (d, 1H, J = 15.5, ArCH=CH), 3.60 (t, 2H, J = 6.8, NCH2), 3.58

(t, 2H, J = 6.8, N CH2), 1.99 (qn, 2H, J = 6.8, NCH2CH2), 1.89 (qn, 2H, J = 6.8, NCH2CH2).

13C NMR (CDCl3, 150 MHz) δ 165.1, 138.4, 135.5, 127.2, 126.7, 125.2, 118.5, 46.7, 46.2,

26.3, 24.5.

IR ν 2953, 2924, 2872, 1647, 1598, 1436, 1404, 783.

HRMS for C11H14NSO [M]+ found 208.0805, calc. 208.0796.

5.2.3 Transamidations of Primary Amides

Transamidations were performed on 0.5–3.0 mmol scale.

Representative Procedure: Borate (2 equiv) was added to a solution/suspension of amide (1

equiv) and amine (1 equiv) in MeCN (0.5 M) and the mixture was heated at 100 °C in

carousel tube. After 15 h, solvent was removed under reduced pressure. The residue was

purified by column chromatography (EtOAc/PE 1:1) to give the product.

N-Benzylpropionamide (146s)[371]

Colourless solid. Mp 51 °C (EtOAc/PE). Lit Mp 49–50 ºC (EtOAc/hexane).[371]

1H NMR (DMSO-d6, 600 MHz) δ 8.28 (br t, 1H, J = 6.0, CONH), 7.34–7.29 (m, 2H, ArH),

7.25–7.21 (m, 3H, ArH), 4.25 (d, 2H, J = 6.0, NHCH2), 2.14 (q, 2H, J = 7.7, CH2CH3), 1.02

(t, 3H, J = 7.7, CH3).

13C NMR (DMSO-d6, 150 MHz) δ 172.9, 139.8, 128.3, 127.2, 126.7, 42.0, 28.5, 10.0.

IR ν 3282, 3066, 3031, 2977, 2938, 1642, 1541, 1454, 1234, 1029.

HRMS for C10H13NO [M]+ found 163.09931, calc. 163.09917.

N-Butylpropionamide (146t) [372]

Chapter 5

155

Colourless oil.

1H NMR (CDCl3, 600 MHz) δ 5.55 (br s, 1H, CONH), 3.23 (q, 2H, J = 6.5, NHCH2), 2.18 (q,

2H, J = 7.5, CH2CO), 1.46 (qn, 2H, J = 7.5, NHCH2CH2), 1.32 (sx, 2H, J = 7.5,

CH2CH2CH3), 1.13 (t, 3H, J = 7.5, CH3CH2CO), 0.90 (t, 3H, J = 7.5, NH(CH2)3CH3).

13C NMR (CDCl3, 150 MHz) δ 174.2, 39.3, 31.7, 29.7, 20.1, 13.8, 10.1.

IR ν 3292, 2960, 2933, 1644, 1550, 1464, 1236.

HRMS for C7H15NO [M]+ found 129.11468, calc. 129.11468.

N-Benzyl-2-hydroxyacetamide (146u)[373]

Colourless solid. Mp 102–103 °C (EtOAc/hexane). Lit Mp 102–103 °C (DCM).[373]

1H NMR (CDCl3, 600 MHz) δ 7.35–7.30 (m, 2H, ArH), 7.29–7.24 (m, 3H, ArH), 6.99 (br s,

1H, CONH), 4.45 (d, 2H, J = 5.9, NHCH2), 4.09 (s, 2H, HOCH2), OH not observed.

13C NMR (CDCl3, 150 MHz) δ 172.0, 137.8, 128.9, 127.9, 127.8 , 62.2, 43.1.

IR ν 3317, 3208, 3058, 3031, 2933, 2857, 1633, 1562, 1453, 1424, 1342, 1082.

HRMS for C9H11NO2 [M]+ found 165.07859, calc. 165.07843.

N-((1H-Indol-3-yl)methyl)-2-hydroxyacetamide (146v)

Purified by column chromatography (PE/EtOAc/MeOH 5:5:1).

Colourless solid. Mp 141–142 °C (PE/MeOH).

1H NMR (DMSO-d6, 600 MHz) δ 10.81 (s, 1H, indole-NH), 7.81 (t, 1H, J = 5.8, CONH),

7.56 (d, 1H, J = 7.9, ArH), 7.33 (d, 1H, J = 7.9, ArH), 7.16 (d, 1H, J = 2.2, ArH), 7.06 (td,

1H, J = 7.4, 0.9, ArH), 6.97 (td, 1H, J = 7.4, 0.9, ArH), 5.49 (t, 1H, J = 5.8, CH2OH), 3.79 (d,

2H, J = 5.8, CH2OH), 3.39 (q, 2H, J = 7.1, NHCH2), 2.83 (t, 2H, J = 7.1, ArCH2)

13C NMR (DMSO-d6, 150 MHz) δ 171.6, 136.3, 127.2, 122.6, 121.0, 118.4, 118.2, 111.7,

111.4, 61.5, 38.8, 25.4.

IR ν 3391, 3301, 3260, 1644, 1619, 1543, 1455, 1353, 1223, 1072.

Chapter 5

156

4.3 Procedures for Chapter 3

4.3.1 Synthesis of ortho-Alkynylphenylboronic Acids

Representative procedure for Sonogashira coupling: Pd(PPh3)2Cl2 (522 mg, 0.74 mmol, 2

mol%) and CuI (142 mg, 0.74 mmol, 2 mol%) were added to a solution of 2-

bromoiodobenzene (10.515 g, 37.17 mmol) in Et2NH (120 mL). After 10 min a solution of 1-

hexyne (6.4 mL, 55.8 mmol, 1.5 eq) in Et2NH (3.6 mL) was added dropwise over 3 h via

syringe pump and the reaction mixture was left to stir for 18 h. Sat. NH4Cl solution (80 mL)

was added and the mixture was extracted with PE (3×60 mL), dried over Na2SO4, filtered,

concentrated and purified by flash chromatography (PE) to give the product as a colourless oil

(8.81 g, quant).

Representative procedure for lithiation/borylation: A 1.6 M solution of BuLi in hexanes (8.0

mL, 12.8 mmol, 1.2 equiv) was added dropwise to a solution of 1-bromo-2-(hex-1-

ynyl)benzene (2.537 g, 10.70 mmol) in THF (60 mL) at –78 °C. After 30 min, B(OiPr)3 (4.9

mL, 21.4 mmol, 2.0 eq) was added and the reaction mixture was left to stir at –78 °C

gradually warming up to RT over 16 h. The reaction was quenched with 1 M HCl aq solution

(40 mL) and then extracted with Et2O (3×30 mL), dried over MgSO4, filtered and

concentrated. The residue was purified by flash chromatography (first PE, then PE/Et2O 5:1)

to give the product as a colourless solid (1.785 g, 83%).

2-((Trimethylsilyl)ethynyl)phenylboronic acid (171)[374–376]

((2-Bromophenyl)ethynyl)trimethylsilane (183):[374–376]

Yield 78%. Yellow oil.

1H NMR (CDCl3, 600 MHz) δ 7.58 (dd, 1 H, J = 7.7, 1.2, ArH), 7.51 (dd, 1H, J = 7.7, 1.7,

ArH), 7.26 (td, 1H, J = 7.7, 1.2, ArH), 7.17 (td, 1H, J = 7.7, 1.7, ArH), 0.29 (s, 9H, Si(CH3)3).

13C NMR (CDCl3, 125 MHz) δ 133.7, 132.4, 129.6, 126.9, 125.8, 125.3, 103.1, 99.7, –0.1.

IR υ 2959, 2163, 1465, 1248.

HRMS for C11H13BrSi [M]+ found 251.99521, calc. 251.99644.

Chapter 5

157

2-((Trimethylsilyl)ethynyl)phenylboronic acid (171):

Yield 63%. Colourless solid. Mp 68–69 ºC (PE/Et2O).

1H NMR (CDCl3, 600 MHz) δ 7.98 (dd, 1H, J = 7.3, 1.5, ArH), 7.51 (dd, 1H, J = 7.3, 1.5,

ArH), 7.42 (td, 1h, J = 7.3, 1.5, ArH), 7.38 (td, 1H, J = 7.3, 1.5, ArH), 5.92 (br s, 2H,

B(OH)2), 0.30 (s, 9H, Si(CH3)3).

13C NMR (CDCl3, 150 MHz) δ 135.6, 132.6, 130.7, 128.6, 126.6, 106.5, 98.9. –0.3, carbon

adjacent to boron not observed.

IR υ 3497, 3383, 2143, 1335, 1250.

HRMS for C11H15BO2Si [M]+ found 218.09185, calc. 218.09289.

2-Ethynylphenylboronic acid (167)[377]

The reaction was quenched with 1 M HCl aq solution (50 mL) and allowed to stir for 30 min.

Yield 92%. Colourless solid. Mp 95–96 ºC (PE). Lit Mp 93–95 ºC (THF).[377]

1H NMR (CDCl3, 600 MHz) δ 8.01 (m, 1H, ArH), 7.56 (m, 1H, ArH), 7.44 (m, 1H, ArH),

7.43 (td, 1H, J = 7.4, 1.9, ArH), 6.19 (br s, 2H, B(OH)2), 3.49 (s, 1H, C≡CH).

13C NMR (CDCl3, 100 MHz) δ 135.7, 133.2, 130.8, 128.9, 125.3, 85.1, 81.3, carbon adjacent

to boron not observed.

IR υ 3497, 3358, 3267, 1391, 1339.

HRMS for C24H14O3B3 [3M–3H2O]+ found 383.12072, calc. 383.12220.

2-(Phenylethynyl)phenylboronic acid (170)[378]

1-Bromo-2-(phenylethynyl)benzene:[375–376]

Yield 95%. Yellow oil.

1H NMR (CDCl3, 600 MHz) δ 7.64 (dd, 1H, J = 7.6, 1.1, ArH), 7.62–7.60 (m, 2H, ArH), 7.58

(dd, 1H, J = 7.6, 1.6, ArH), 7.41–7.37 (m, 3H, ArH), 7.31 (td, 1H, J = 7.6, 1.1, ArH), 7.20 (td,

1H, J = 7.6, 1.7, ArH).

Chapter 5

158

13C NMR (CDCl3, 150 MHz) δ 133.2, 132.4, 131.7, 129.4, 128.7, 128.4, 127.1, 125.7, 125.4,

122.9, 93.9, 88.0.

IR υ 3058, 2220, 1491

HRMS for C14H9Br [M]+ found 255.98796, calc. 255.98821.

2-(Phenylethynyl)phenylboronic acid (170):[378]

Yield 88%. Yellow solid. Mp 105–106 ºC

(PE/Et2O). Lit Mp 160–161 ºC (EtOH).[378]

1H NMR (CDCl3, 600 MHz) δ 8.04 (dd, 1 H, J = 7.5, 1.2, ArH), 7.61 (dd, 1H, J = 7.5, 1.0,

ArH), 7.59–7.56 (m, 2H, ArH), 7.49 (td, 1H, J = 7.5, 1.2, ArH), 7.43 (td, 1H, J = 7.5, 1.0,

ArH), 7.44–7.39 (m, 3H, ArH), 6.04 (br s, 2H, B(OH)2).

13C NMR (CDCl3, 150 MHz) δ 138.7, 132.6, 131.6, 130.9, 129.1, 128.7, 128.3, 126.7, 121.9,

93.5, 89.8, carbon adjacent to boron not observed.

IR υ 3468, 3347, 3055, 2928, 1590, 1333.

HRMS for C14H11O2B [M]+ found 222.08524, calc. 222.08466.

2-(Hex-1-ynyl)phenylboronic acid (169)

1-Bromo-2-(hex-1-ynyl)benzene:[374]

Yield quant. Colourless oil.

1H NMR (CDCl3, 600 MHz) δ 7.58 (dd, 1H, J = 7.7, 1.2, ArH), 7.46 (dd, 1H, J = 7.7, 1.7,

ArH), 7.23 (td, 1H, J = 7.7, 1.2, ArH), 7.12 (td, 1H, J = 7.7, 1.7, ArH), 2.51 (t, 2H, J = 7.2,

C≡CCH2), 1.66 (qn, 2H, J = 7.2, CH2Et), 1.57 (sx, 2H, J = 7.2, CH2Me), 1.00 (t, 3H, J = 7.2,

CH3).

13C NMR (CDCl3, 150 MHz) δ 133.3, 132.3, 128.7, 126.9, 126.1, 125.5, 95.6, 79.5, 30.7,

22.1, 19.3, 13.7.

IR υ 2958, 2931, 2235, 1468, 1026.

HRMS for C12H13Br [M]+ found 236.02063, calc. 236.01951.

2-(Hex-1-ynyl)phenylboronic acid (169): Yield 93%. Colourless solid. Mp 34–35 ºC

(PE/Et2O).

1H NMR (CDCl3, 600 MHz) δ 7.96 (dd, 1H, J = 7.6, 1.4, ArH), 7.47 (dd, 1H, J =7.6, 1.2,

ArH), 7.41 (td, 1H, J = 7.6, 1.4, ArH), 7.36 (td, 1H, J = 7.6, 1.2, ArH), 5.83 (br s, 2H,

Chapter 5

159

B(OH)2), 2.51 (t, 2H, J = 7.4, CH2C≡C), 1.65 (qn, 2H, J = 7.4, CH2Et), 1.51 (sx, 2H, J = 7.4,

CH2Me), 0.98 (t, 3H, J = 7.4, CH3).

13C NMR (CDCl3, 150 MHz) δ 135.4, 132.6, 130.8, 127.63, 127.56, 95.1, 81.7, 30.6, 22.1,

19.1, 13.6, carbon adjacent to boron not observed.

IR υ 3504, 3392, 2213, 1560, 1333, 1059.

HRMS for C12H15O2B [M]+

found 202.11549, calc. 202.11596.

2-(Cyclopropylethynyl)phenylboronic acid (168)

Sonogashira coupling gave an inseparable mixture of 1-bromo-2-

(cyclopropylethynyl)benzene (HRMS for C11H9Br [M]+ found 219.98782, calc. 219.98821)

and 1,4-dicyclopropylbuta-1,3-diyne as a yellow oil that was carried forward to the

lithiation/borylation step.

Yield over two steps 74%. Colourless solid. Mp 56–57 ºC (Et2O).

1H NMR (CDCl3, 600 MHz) δ 7.96 (dd, 1 H, J = 7.5, 1.4, ArH), 7.45 (dd, 1H, J = 7.5, 1.3,

ArH), 7.40 (td, 1H, J = 7.5, 1.4, ArH), 7.35 (td, 1H, J = 7.5, 1.3, ArH), 5.95 (br s, 2H,

B(OH)2), 1.54 (tt, 1H, J = 8.3, 5.0, CH2CHCH2), 0.97 (ddd, 2H, J = 8.3, 4.2, 2.0, CHH trans

CH), 0.88 (ddd, 2H, J = 5.0, 4.2, 2.0, CHH cis to CH).

13C NMR (CDCl3, 150 MHz) δ 135.4, 132.7, 130.7, 127.6, 127.4, 98.0, 76.64, 8.9, 0.05,

carbon adjacent to boron not observed.

IR υ 3417, 3092, 3059, 3015, 2221, 1592, 1444, 1335.

HRMS for C11H11BO2 [M]+ found 186.08512, calc. 186.08512.

2-(Prop-1-ynyl)phenylboronic acid (181)

Chapter 5

160

(2-Bromophenylethynyl)trimethylsilane (1.621 g, 6.40 mmol) and K2CO3 (0.885 g, 6.40

mmol, 1 eq) were stirred in MeOH (10 mL) for 2 h. The reaction mixture was then filtered,

concentrated and purified by flash chromatography (PE) to give the product as a yellow oil

(0.841 g, 67%).

1-Bromo-2-ethynylbenzene (184):[379]

Yellow oil.

1H NMR (CDCl3, 600 MHz) δ 7.61 (dd, 1 H, J = 7.6, 1.2, ArH), 7.55 (dd, 1H, J = 7.6, 1.7,

ArH), 7.29 (td, 1H, J = 7.6, 1.2, ArH), 7.22 (td, 1H, J = 7.6, 1.7, ArH), 3.40 (s, 1H, C≡CH).

13C NMR (CDCl3, 150 MHz) δ 134.1, 132.5, 130.0, 127.0, 125.6, 124.3, 81.9, 81.8.

IR υ 3291, 1466, 1027.

HRMS for C8H5Br [M]+ found 179.95617, calc. 179.95691.

A solution of LHMDS in THF (1.0 M, 6.7 mL, 6.7 mmol, 1.5 eq) was added to a solution of

1-bromo-2-ethynylbenzene (0.807 g, 4.46 mmol) in THF (20 mL) at 0 ºC. After 1 h

iodomethane (444 µL, 7.13 mmol, 1.6 eq) was added at 0 ºC and the mixture was left to stir

for 16 h. The mixture was quenched with sat. NH4Cl aq solution (7 mL) and extracted with

Et2O (3×10 mL). The combined organic fractions were dried over MgSO4, filtered,

concentrated and purified by flash chromatography (PE) to give the product as a colourless oil

(598 mg, 69%).

1-Bromo-2-(prop-1-ynyl)benzene (185):[374]

Colourless oil.

1H NMR (CDCl3, 600 MHz) δ 7.57 (1H, dd, J = 7.7, 1.2, ArH), 7.44 (1H, dd, J = 7.7, 1.7,

ArH), 7.24 (td, 1H, J = 7.7, 1.2, ArH), 7.13 (td, 1H, J = 7.7, 1.7, ArH), 1.00 (s, 3H, CH3).

13C NMR (CDCl3, 150 MHz) δ 133.4, 132.3, 128.7, 126.9, 126.0, 125.3, 91.0, 78.5, 4.6.

IR υ 2916, 2232, 1470, 1433.

HRMS for C9H7Br [M]+ found 193.97225, calc. 193.97256.

2-(Prop-1-ynyl)phenylboronic acid (181): Yield 86%. Colourless solid. Mp 165–166 ºC.

1H NMR (CDCl3, 600 MHz) δ 7.97 (dd, 1H, J = 7.5, 1.3, ArH), 7.47 (dd, 1H, J = 7.5, 1.2,

ArH), 7.42 (td, 1H, J = 7.5, 1.3, ArH), 7.36 (td, 1H, J = 7.5, 1.2, ArH), 5.92 (br s, 2H,

B(OH)2), 2.16 (s, 3H, CH3).

13C NMR (CDCl3, 150 MHz) δ 135.4, 132.6, 130.8, 127.7, 127.5, 90.5, 80.9, 4.4, carbon

adjacent to boron not observed.

IR υ 3499, 3363, 1442, 1337.

HRMS for C9H7O2B [M]+ found 160.06829, calc. 160.06901.

Chapter 5

161

5.3.2 Boron Enolate Formation

Representative procedure: 2-(Cyclopropylethynyl)phenylboronic acid (105.0 mg, 0.564

mmol) and [Ph3PAuNTf]2∙PhMe (4 mg, 2.8 µmol, 0.5 mol%) were mixed in DCM (0.5 mL)

at RT for 1 h. The reaction mixture was preabsorbed onto silica gel and purified by flash

chromatography (PE/Et2O 7:1) to give the product as a colourless solid (91.5 mg, 87 %).

1H-Benzo[c][1,2]oxaborinin-1-ol (172a)

Yield 90%. Colourless oil. Characterised as a mixture of monomer/dimer 1:0.2

IR υ 3527, 1585, 1488, 1438, 1401, 1348, 1210, 1132, 961.

1H NMR (CDCl3, 500 MHz, major) δ 7.99 (d, 1H, J = 7.6, ArH), 7.59 (dd, 1H, J = 7.6, 1.4,

ArH), 7.41–7.34 (m, 2H, ArH), 7.03 (d, 1H, J = 5.5, ArCH=CH), 6.30 (d, 1H, J = 5.5,

CH=CHO), 4.63 (br s, 1H, OH).

13C NMR (CDCl3, 150 MHz) 156.1, 144.2, 131.3, 131.9, 125.6, 125.0, 104.8, carbon adjacent

to boron not observed.

11B NMR (CDCl3, 192 MHz) δ 26.0

HRMS for C16H12O3B2 [2M–H2O]+ found 274.09596, calc. 274.09670.

3-Cyclopropyl-1H-benzo[c][1,2]oxaborinin-1-ol and its dimer (173a+173b)

Yield 87%. Colourless solid. Mp 71–72 ºC (Et2O). Characterised as a mixture of 173a/173b =

major/minor 1:0.36).

11B NMR δ (CDCl3, 192 MHz, 173a+173a) δ 26.1

IR (173a+173b) υ 3377, 3091, 3056, 3013, 1640, 1478, 1350, 1297.

Chapter 5

162

3-Cyclopropyl-1H-benzo[c][1,2]oxaborinin-1-ol (173a):

1H NMR (CDCl3, 600 MHz) δ 7.92 (d, 1H, J = 7.6, ArH), 7.55 (td, 1H, J = 7.6, 1.4, ArH),

7.32–7.28 (m, 2H, ArH), 6.20 (s, 1H, ArCH=C), 4.49 (br s, 1H, OH), 1.79 (tt, 1H, J = 8.3,

5.0, CH2CHCH2), 0.98–0.94 (m, 2H, cPr-H), 0.85–0.80 (m, 2H,

cPr-H).

13C NMR (CDCl3, 150 MHz) δ 154.7, 143.3, 132.5, 132.4, 125.0, 124.48, 104.2, 14.7, 6.0,

carbon adjacent to boron not observed.

HRMS for C11H11O2B [M]+ found 186.08523, calc. 186.08466.

1,1'-Oxybis(3-cyclopropyl-1H-benzo[c][1,2]oxaborinine) (173b)

1H NMR (CDCl3, 600 MHz) δ 7.97 (d, 1H, J = 7.6, ArH), 7.59 (td, 1H, J = 7.6, 1.3, ArH),

7.36 (d, 1H, J = 7.6, ArH), 7.32–7.28 (m, 1H, ArH), 6.32 (s, 1H, ArH), 1.83 (tt, 1H, J = 8.2,

5.1, CH2CHCH2), 0.98–0.94 (m, 2H, cPr-H), 0.85–0.80 (m, 2H,

cPr-H).

13C NMR (CDCl3, 150 MHz) δ 155.4, 144.0, 133.5, 132.6, 124.9, 124.46, 104.6, 14.9, 6.3,

carbon adjacent to boron not observed.

HRMS for C22H20O3B2 [M]+ found 354.15931, calc. 354.15849.

3-Butyl-1H-benzo[c][1,2]oxaborinin-1-ol (174a)

Yield 85%. Colourless oil.

1H NMR (CDCl3, 600 MHz) δ 7.93 (d, 1H, J = 7.5, ArH), 7.31 (td, J = 7.5, 1.4, ArH), 7.33–

7.28 (m, 2H, 2×ArH), 6.08 (s, 1H, ArCH=C), 4.47 (s, 1H, BOH), 2.44 (t, 2H, J = 7.6, CH2Pr),

1.64 (qn, 2H, J = 7.6, CH2CH2Et), 1.38 (sx, 2H, J = 7.6, CH2CH3), 0.94 (t, 3H, J = 7.6,

CH2CH3).

13C NMR (CDCl3, 150 MHz) δ 155.1, 143.2, 132.4, 132.3, 125.4, 124.9, 105.4, 34.7, 29.3,

22.2, 13.9, carbon adjacent to boron not observed.

11B NMR (CDCl3, 192 MHz) δ 25.9

IR υ 3416, 1645, 1480, 1396, 1302.

HRMS for C12H15O2B [M]+ found 202.11534, calc. 202.11596.

Chapter 5

163

3-Phenyl-1H-benzo[c][1,2]oxaborinin-1-ol (175a)

2-(Phenylethynyl)phenylboronic acid (142 mg, 0.639 mmol) and [Ph3PAuNTf2]2-PhMe (5.0

mg, 3.2 µmol, 0.5 mol%) were mixed in DCM (0.6 mL) at RT for 1 h. The reaction mixture

was concentrated and the crude residue washed with PE to give the product as colourless

needles (113.9 mg, 80 %).

3-Phenyl-1H-benzo[c][1,2]oxaborinin-1-ol: Colourless needles. Mp 144–145 ºC (PE).

1H NMR (DMSO-d6, 600 MHz) δ 9.35 (s, 1H, BOH), 8.04 (d, 1H, J = 7.6, ArH), 7.93 (dd,

1H, J = 7.6, 1.3, ArH) 7.61 (td, 1H, J = 7.6, 1.3, ArH), 7.53 (d, 1H, J = 7.6, ArH), 7.48 (t, 2H,

J = 7.6, ArH), 7.39 (td, 1H, J = 7.6, 1.0, ArH), 7.37 (td, 1H, J = 7.6, 1.0, ArH), 7.14 (s, 1H,

ArCH=C).

13C NMR (DMSO-d6, 150 MHz) δ 149.7, 142.6, 134.9, 132.9, 132.2, 128.8, 128.7, 126.1,

126.0, 124.7, 104.3, carbon adjacent to boron not observed.

IR υ 3206, 1626, 1475, 1369, 1263, 1003, 767.

HRMS for C14H11O2B [M]+ found 222.08562, calc. 222.08466.

3-(4-Methoxyphenyl)-1H-benzo[c][1,2]oxaborinin-1-ol (176a)

Yield 82%.

Colourless solid. Mp 167–168 °C (DCM).

1H NMR (DMSO-d6, 600 MHz) δ 9.29 (s, 1H, BOH), 8.01 (d, 1H, J = 7.6, ArH), 7.86 (d, 2H,

J = 9.0, ArH), 7.59 (td, 1H, J = 7.6, 1.0, ArH), 7.48 (d, 1H, J =7.6, ArH), 7.32 (td, 1H, J =

7.6, 1.0, ArH), 7.04 (d, 2H, J = 7.6, ArH), 6.99 (s, 1H, ArCH=C), 3.81 (s, 3H, OCH3).

13C NMR (DMSO-d6, 150 MHz) δ 159.8, 149.9, 142.9, 132.9, 132.1, 127.5, 126.2, 125.8,

125.6, 114.1, 102.6, 55.3, carbon adjacent to boron not observed.

IR υ 3391, 2931, 2840, 1625, 1601, 1510, 1450, 1357, 1246, 1174, 1035, 990, 898, 758.

HRMS for C15H13O3B [M+] found 252.09632, calc. 252.09632.

Chapter 5

164

3-Methyl-1H-benzo[c][1,2]oxaborinin-1-ol (177a)

Yield 92%.

1H NMR (CDCl3, 600 MHz) δ 7.94 (d, 1H, J = 7.8, ArH), 7.54 (td, 1H, J = 7.8, 1.2, ArH),

7.31 (t, 1H, J = 7.8, ArH), 7.28 (d, 1H, J = 7.8, ArH), 6.09 (s, 1H, ArCH=C), 4.61 (br s, 1H,

BOH), 2.19 (s, 3H, CH3).

13C NMR (CDCl3, 150 MHz) δ 151.5, 143.3, 132.6, 132.4, 125.5, 124.8, 106.2, 21.2, carbon

adjacent to boron not observed.

11B NMR (DMSO-d6, 192 MHz) δ 26.2

IR υ 3141, 3055, 2917, 1651, 1604, 1476, 1346, 1302, 1245, 918.

HRMS for C9H10O2B [M+H]+ found 161.07590, calc. 161.07684.

5.3.3 One-Pot Boron Enolate Formation/Aldol Reaction

Representative procedure: Butyraldehyde (107 µL, 1.19 mmol, 2 equiv) and

[Ph3PAuNTf2]2∙PhMe (5 mg, 3 µmol, 0.5 mol%, 1 mol% [Au]) were added to a solution of 2-

(hex-1-ynyl)phenylboronic acid (120 mg, 0.59 mmol) in DCM (0.5 mL) and the mixture was

allowed to stir at RT for 3 h. The mixture was concentrated and purified by flash

chromatography (PE/Et2O 9:1 to 4:1) to give trans (112 mg) and cis (28 mg) aldol products

(combined 140 mg, 86%).

trans-1-(1-Hydroxy-3-propyl-3,4-dihydro-1H-benzo[c][1,2]oxaborinin-4-yl)pentan-1-one

(171a): Colourless viscous oil.

1H NMR (CDCl3, 600 MHz) δ 7.81 (dd, 1H, J = 7.5, 1.0, ArH), 7.45 (td, 1H, J = 7.5, 1.4,

ArH), 7.35 (td, 1H, J = 7.5, 1.0, ArH), 7.16 (d, 1H, J = 7.5, ArH), 4.97 (br s, 1H, BOH), 4.63

(ddd, 1H, J = 8.5, 5.2, 2.2, 1H, CHOB), 3.68 (d, 1H, J = 2.2, ArCH), 2.43 (dt, 1H, J = 17.5,

7.4, COCHH), 2.37 (dt, 1H, J = 17.5, 7.4, COCHH), 1.56–1.52 (m, 1H, CHCHH), 1.50–1.45

Chapter 5

165

(m, 3H, COCH2CH2 and CHCH2CHH), 1.39-1.32 (m, 2H, CHCHHCHHCH3), 1.25–1.18 (m,

2H, COCH2CH2CH2), 0.89 (t, 3H, J = 7.2 Hz, CH(CH2)2CH3), 0.81 (t, 3H, J = 7.2 Hz,

CO(CH2)3CH3).

13C NMR (CDCl3, 125 MHz) δ 209.8, 141.2, 133.2, 132.1, 128.6, 127.6, 74.7, 59.3, 41.4,

38.0, 25.6, 22.2, 19.1, 13.9, 13.8, carbon adjacent to boron not observed.

IR υ 3387, 3062, 2958, 2932, 2871, 1706, 1605, 1450.

HRMS for C16H23O3B [M]+ found 274.17436, calc. 274.17348.

cis-1-(1-Hydroxy-3-propyl-3,4-dihydro-1H-benzo[c][1,2]oxaborinin-4-yl)pentan-1-one

(171b):

Colourless viscous oil.

1H NMR (CDCl3, 600 MHz) δ 7.84 (dd, 1H, J = 7.4, 1.1, ArH), 7.41 (td, 1H, J = 7.4, 1.4,

ArH), 7.35 (td, 1H, J = 7.4, 1.1, ArH), 7.15 (d, 1H, J = 7.4, ArH), 4.53 (br s, 1H, BOH), 4.33

(ddd, 1H, J = 8.7, 4.4, 3.4, CHOB), 3.83 (d, 1H, J = 3.4, ArCH), 2.44 (ddd, 1H, J = 17.9, 8.2,

6.4, COCHH), 2.35 (ddd, 1H, J = 17.9, 8.2, 6.4, COCHH), 1.67–1.57 (m, 3H, CHCH2CHH),

1.48–1.35 (m, 3H, COCH2CH2 and CHCH2CHH), 1.22–1.14 (m, 2H, COCH2CH2CH2), 0.95

(t, 3H, J = 7.2, CH(CH2)2CH3), 0.81 (t, 3H, J = 7.2, CO(CH2)3CH3).

13C NMR (CDCl3, 125 MHz) δ 209.1, 143.6, 133.7, 131.7, 127.6, 127.2, 75.8, 59.5, 42.7,

36.5, 25.3, 22.2, 19.4, 13.9, 13.8, carbon adjacent to boron not observed.

IR υ 3422, 3061, 2959, 2933, 2871, 1701, 1603, 1451

HRMS for C16H23O3B [M]+ found 274.17372, calc. 274.17348.

5.3.4 Aldol/Oxidation

Representative procedure: Butyraldehyde (134 µL, 1.5 mmol, 2 equiv) and

[Ph3PAuNTf2]2∙PhMe (6 mg, 4 µmol, 0.5 mol%) were added to a solution of 2-(hex-1-

ynyl)phenylboronic acid (151 mg, 0.75 mmol) in DCM (0.5 mL) and the mixture was left to

stir for 3 h at RT (crude aldol product dr trans/cis 79:21). Then, 30% H2O2 (200 μL, 1.9

mmol) and 100 μL MeOH were added and the mixture was left to stir for 8 h. The reaction

mixture was purified by flash chromatography (Et2O/PE 1:7) to give anti (149 mg) and syn

aldol (37 mg) products (combined 186 mg, 94%).

Chapter 5

166

7-Hydroxy-6-(2-hydroxyphenyl)decan-5-one (187)

Aldol reaction time 3 h.

anti-7-Hydroxy-6-(2-hydroxyphenyl)decan-5-one (187a): Colourless oil.

1H NMR (CDCl3, 600 MHz) δ 8.92 (br s, 1H, ArOH), 7.24 (td, 1H, J = 7.8, 1.5, ArH), 7.10

(dd, 1H, J = 7.8, 1.5, ArH), 6.95 (dd, 1H, J = 7.8, 1.2, ArH), 6.92 (td, 1H, J = 7.8, 1.2, ArH),

4.57–4.52 (m, 1H, CHOH), 4.07 (br s, 1H, CHOH), 3.51 (d, 1H, J = 3.6, COCH), 2.32–2.25

(m, 2H, COCH2), 1.50–1.44 (m, 3H, COCH2CH2 and CH(OH)CH2CHH), 1.39–1.29 (m, 2H,

CH(OH)CHHCHHCH3), 1.24–1.16 (m, 3H, COCH2CH2CH2 and CH(OH)CHH), 0.88 (t, 3H,

J = 7.2, CH(OH)(CH2)2CH3), 0.80 (t, 3H, J = 7.4, CO(CH2)3CH3).

13C NMR (CDCl3, 125 MHz) δ 213.2, 155.4, 133.7, 129.8, 120.6, 118.7, 122.0, 71.3, 62.7,

41.2, 36.0, 25.9, 22.1, 18.9, 13.9, 13.7.

IR υ 3302, 2958, 2932, 2873, 1698, 755.

HRMS for C16H24O3 [M]+ found 264.17194, calc. 264.17200.

syn-7-Hydroxy-6-(2-hydroxyphenyl)decan-5-one (187b):

Colourless needles. Mp 50 ºC (PE/Et2O).

1H NMR (CDCl3, 600 MHz) δ 7.81 (br s, 1H, ArOH), 7.19 (td, 1H, J = 7.8, 1.7, ArH), 7.02

(dd, 1H, J = 7.8, 1.6, ArH), 6.91–6.87 (m, 2H, ArH), 4.36 (td, 1H, J = 7.8, 2.9, CHOH), 3.87

(d, 1H, J = 7.8, COCH), 2.93 (br s, 1H, CHOH), 2.56–2.44 (m, 2H, COCH2), 1.58–1.48 (m,

3H, COCH2CH2 and CH(OH)CH2CHH), 1.30–1.18 (m, 5H, CH(OH)CH2CHH and

CO(CH2)2CH2), 0.82 (t, 6H, J = 7.2, CO(CH2)3CH3 and CH(OH)(CH2)2CH3).

13C NMR (CDCl3, 125 MHz) δ 215.4, 155.1, 131.3, 129.4, 120.8, 118.0, 122.3, 72.3, 61.9,

43.4, 37.1, 25.7, 22.1, 18.7, 14.0, 13.8.

IR υ 3276, 3068, 2958, 2933, 2873, 1698.

HRMS for C16H24O3 [M]+ found 264.17148, calc. 264.17200.

Chapter 5

167

1-Cyclopropyl-3-hydroxy-2-(2-hydroxyphenyl)hexan-1-one (188)

Aldol reaction time 1 h.

anti-1-Cyclopropyl-3-hydroxy-2-(2-hydroxyphenyl)hexan-1-one (188a):

Colourless needles. Mp 72 ºC.

1H NMR (CDCl3, 600 MHz) δ 8.94 (br s, 1H, ArOH), 7.28 (td, 1H, J = 7.8, 1.6, ArH), 7.16

(dd, 1H, J = 7.8, 1.6, ArH), 6.98 (dd, 1H, J = 7.8, 1.2, ArH), 6.94 (td, 1H, J = 7.8, 1.2, ArH),

4.53–4.50 (m, 1H, CHOH), 4.20 (br s, 1H, CHOH), 3.74 (d, 1H, J = 3.7, ArCH), 1.82 (tt, 1H,

J = 7.3, 4.6, COCH(CH2)2), 1.54–1.46 (m, 1H, CH(OH)CH2CHH), 1.40–1.33 (m, 2H,

CH(OH)CHHCHHMe), 1.28–1.23 (m, 1H, CH(OH)CHH), 1.13–1.10 (m, 1H,

COCH(CHHCH2)), 1.05–1.00 (m, 1H, COCH(CH2CHH)), 0.85–0.82 (m, 1H,

COCH(CHHCH2)), 0.79–0.74 (m, 1H, COCH(CH2CHH)), 0.89 (t, 3H, J = 7.2 Hz, CH3).

13C NMR (CDCl3, 125 MHz) δ 212.5, 155.7, 134.0, 129.9, 120.6, 121.9, 118.7, 71.2, 63.6,

36.0, 20.1, 18.9, 13.9, 12.6, 12.0.

IR υ 3304, 3012, 2958, 2926, 2873, 1677, 1456.

HRMS for C15H20O3 [M]+ found 248.14097, calc. 248.14069.

syn-1-Cyclopropyl-3-hydroxy-2-(2-hydroxyphenyl)hexan-1-one (188b):

Colourless viscous oil.

1H NMR (CDCl3, 600 MHz) δ 7.90 (br s, 1H, ArOH), 7.19 (td, 1H, J = 7.8, 1.0, ArH), 7.06

(dd, 1H, J = 7.8, 1.0, ArH), 6.91–6.87 (m, 2H, ArH), 4.35–4.31 (m, 1H, CHOH), 4.11 (d, 1H,

J = 7.4, ArCH), 3.50 (br s, 1H, CHOH), 1.94 (tt, 1H, J = 7.8, 4.5, COCH(CH2)2), 1.56–1.49

(m, 1H, CH2CH3), 1.45–1.37 (m, 1H, CH(OH)CHH), 1.35–1.29 (m, 2H, CHHCHHCH3),

1.16–1.07 (m, 2H, COCH(CHHCHH)Me), 0.94–0.91 (m, 1H, COCH(CHHCH2), 0.85–0.80

(m, 1H, COCH(CH2CHH), 0.85 (t, 3H, J = 7.3 Hz, CH3).

13C NMR (CDCl3, 125 MHz) δ 214.6, 155.2, 131.2, 129.3, 120.8, 117.5, 122.8, 72.5, 61.4,

36.7, 21.7, 19.6, 13.9, 12.36, 12.33.

IR υ 3241, 2976, 2872, 1683, 1455.

HRMS for C15H21O3 [M+H]+ found 249.15021, calc 249.14907.

Chapter 5

168

5.3.5 Aldol/Suzuki–Miyaura Coupling

Representative procedure: Acetaldehyde (71 µL, 1.269 mmol, 2 eq) and

[Ph3PAuNTf2]2∙PhMe (5 mg, 3 µmol, 0.5 mol%) were added to a solution of 2-

(cyclopropylethynyl)phenylboronic acid (118 mg, 0.634 mmol) in DCM (0.5 mL) and the

mixture was allowed to stir at RT for 1 h (crude aldol product dr trans/cis 62:38). p-

Iodotoluene (138 mg, 0.634 mmol, 1 eq), CsF (193 mg, 1.27 mmol, 2 eq) and Pd(PPh3)2Cl2

(13 mg, 19 mmol, 3 mol%) were then added and the mixture was heated at 40 ºC for 10 h

(Suzuki coupling product with dr anti/syn 62:38). The reaction mixture was then cooled to

RT, absorbed onto silica gel and purified by flash chromatography (PE/Et2O 10:1) to give the

product as a yellow oil (139 mg, 74%).

1-Cyclopropyl-3-hydroxy-2-(4'-methylbiphenyl-2-yl)butan-1-one (190)

1-Cyclopropyl-3-hydroxy-2-(4'-methylbiphenyl-2-yl)butan-1-one: Yellow oil. Characterised

as a mixture of diastereomers (190a/190b= anti/syn 59:41).

1H NMR (CDCl3, 600 MHz, 190a) δ 7.50–7.11 (m, 8H, Ar), 4.39 (app qn, 1H, J = 6.3,

CHOH), 4.18 (d, 1H, J = 6.0, ArCHCO), 2.72 (br s, 1H, OH), 2.45 (s, 3H, ArCH3), 1.72 (tt,

1H, J = 7.8, 4.5, CH2CHCH2), 1.08–0.94 (m, 2H, cPr–H), 1.00 (d, 3H, J = 6.4, CHCH3), 0.88–

0.72 (m, 2H, cPr–H).

1H NMR (CDCl3, 600 MHz, 190b) δ 7.50–7.11 (m, 8H, Ar), 4.32 (app qn, 1H, J = 8.8,

CHOH), 4.07 (d, 1H, J = 8.7, ArCHCO), 3.49 (br s, 1H, OH), 2.45 (s, 3H, ArCH3), 1.80 (tt,

1H, J = 7.8, 4.5, CH2CHCH2), 1.08–0.94 (m, 2H, cPr–H), 0.91 (d, 3H, J = 6.4, CHCH3), 0.88–

0.72 (m, 2H, cPr–H).

13C NMR (CDCl3, 150 MHz, 190a+190b, overlapping peaks) δ 213.2, 211.7, 144.0, 143.3,

138.5, 138.2, 137.1, 137.0, 134.1, 132.7, 131.0, 129.6, 129.4, 129.14, 129.05, 128.8, 127.9,

127.8, 127.7, 127.3, 127.2, 70.0, 68.0, 62.1, 60.55, 21.22, 21.20, 21.2, 20.5, 19.8, 12.3, 12.0,

11.9, 11.8.

IR (190a+190b) υ 3459, 3020, 2972, 2926, 1682, 1481, 1379, 1050.

HRMS (190a+190b) for C20H22O2Na [M+Na]+ found 317.1510, calc. 317.1517.

Chapter 5

169

7-Hydroxy-6-(4'-methylbiphenyl-2-yl)decan-5-one (189)

Aldol reaction time 3 h. Yield 78%.

7-Hydroxy-6-(4'-methylbiphenyl-2-yl)decan-5-one: Yellow oil. Characterised as a mixture of

diastereomers (major/minor = anti/syn 77:23).

1H NMR (CDCl3, 600 MHz, 189a) δ 7.50–7.1 (m, 8H, Ar), 4.26 (td, 1H, J = 6.8, 2.7, CHOH),

4.04 (d, 1H, J = 6.6, ArCHCO), 2.45 (s, 3H, ArCH3), 2.30–2.14 (m, 2H, CH2CO), 1.69 (br s,

1H, OH), 1.52–1.30 (m, 8H, 4×CH2), 0.88–0.76 (m, 6H, 2×CH3).

1H NMR (CDCl3, 600 MHz, 189b) δ 7.50–7.1 (m, 8H, Ar), 4.18 (td, 1H, J = 8.9, 2.8, CHOH),

3.94 (d, 1H, J = 8.8, ArCHCO), 3.03 (br s, 1H, OH), 2.44 (s, 3H, ArCH3), 2.30–2.14 (m, 2H,

CH2CO), 1.52–1.30 (m, 8H, 4×CH2), 0.88–0.76 (m, 6H, 2×CH3).

13C NMR (CDCl3, 150 MHz, 189a+189b, overlapping peaks) δ 213.1, 212.0, 143.9, 143.2,

138.3, 138.1, 137.1, 137.0, 133.9, 132.7, 131.0, 130.9, 129.6, 129.4, 129.1, 129.0, 128.3,

128.2, 127.9, 127.8, 127.4, 127.21, 127.17, 73.2, 71.8, 60.0, 58.7, 42.4, 42.3, 37.0, 35.7, 25.7,

25.6, 22.1, 21.3, 19.1, 19.0, 14.0, 13.82, 13.79.

IR (189a+189b) υ 3503, 2957, 2931, 2871, 1705.

HRMS (189a+189b) for C23H30O2Na [M+Na]+ found 361.2142, calc. 361.2144.

Chapter 5

170

5.3.6 Aldol/Intramolecular Chan–Evans–Lam Coupling

Representative procedure: Butyraldehyde (86 µL, 0.97 mmol, 2 eq) and

[Ph3PAuNTf2]2∙PhMe (4 mg, 2 µmol, 0.5 mol%) were added to a solution of 2-(hex-1-

ynyl)phenylboronic acid (97 mg, 0.48 mmol) in DCM (0.5 mL) and the mixture was allowed

to stir at RT for 3 h (crude aldol product dr trans/cis 79:21). Cu(OAc)2∙H2O (5 mg, 24 µmol,

5 mol%) and MeOH (1 mL) were then added and the mixture was heated at 40 ºC for 10 h

(Chan–Lam coupling product dr trans/cis 79:21). The reaction mixture was then cooled to

RT, absorbed onto silica gel and purified by flash chromatography (PE/Et2O 25:1) to give the

product as a yellow oil (89 mg, 75%).

1-(2-Propyl-2,3-dihydrobenzofuran-3-yl)pentan-1-one (192)

Aldol reaction time 1h.

1-(2-Propyl-2,3-dihydrobenzofuran-3-yl)pentan-1-one: Yellow oil. Characterised as a mixture

of diastereomers (192a/192b= trans/cis 79:21).

1H NMR (CDCl3, 600 MHz, 192a) δ 7.20–7.15 (m, 2H, ArH), 6.86 (td, 1H, J = 7.5, 1.0,

ArH), 6.81 (dd, 1H, J = 7.7, 1.0, ArH), 5.02 (dt, 1H, J = 7.7, 5.6, CHOAr), 3.95 (d, 1H, J =

5.6, ArCHCO), 2.59 (dt, 1H, J = 17.5, 7.4, COCHH), 2.49 (dt, 1H, J = 17.5, 7.4, COCHH),

1.82–1.38 (6H, 3×CH2), 1.27 (sxd, 2H, J = 7.4, 1.8, CH2Me), 0.96 (t, 3H, J = 7.4, CH3), 0.87

(t, 3H, J = 7.4, CH3).

1H NMR (CDCl3, 600 MHz, 192b) δ 7.20 (t, 1H, J = 7.5, ArH), 7.12 (d, 1H, J = 7.5, ArH),

6.89 (td, 1H, J = 7.5, 1.0, ArH), 6.88–6.84 (m, 1H, ArH), 4.83 (td, 1H, J = 8.7, 4.3, CHOAr),

4.10 (d, 1H, J = 8.6, ArCHCO), 2.29 (ddd, 1H, J = 17.8, 8.8, 6.8, COCHH), 2.23 (ddd, 1H, J

= 17.8, 8.8, 6.8, COCHH), 1.82–1.38 (6H, 3×CH2), 1.21 (sxd, 2H, J = 7.3, 1.5, CH2Me),

0.98–0.95 (m, 3H, CH3), 0.82 (t, 3H, J = 7.3, CH3).

13C NMR (CDCl3, 150 MHz, 192a) δ 207.8, 159.7, 129.57, 125.5, 124.88, 120.5, 110.3, 84.4,

61.2, 40.3, 38.0, 25.7, 22.4, 18.5, 14.00, 13.98.

13C NMR (CDCl3, 150 MHz, 192b) δ 209.7, 160.6, 129.60, 126.8, 124.85, 121.1, 110.4, 86.2,

58.9, 42.0, 33.0, 25.5, 22.3, 20.0, 14.00, 13.98.

IR (192a +192b) υ 2958, 2932, 2872, 1715, 1675, 1479, 1462, 1236.

HRMS (192a +192b) for C16H22O2 [M]+ found 246.16143, calc. 246.16143.

Chapter 5

171

Cyclopropyl(2-methyl-2,3-dihydrobenzofuran-3-yl)methanone (193)

Aldol reaction time 1 h. Yield 81%.

Cyclopropyl(2-methyl-2,3-dihydrobenzofuran-3-yl)methanone: Colourless oil. Characterised

as a mixture of diastereomers (193a/193b= trans/cis 67:33).

1H NMR (CD2Cl2, 600 MHz, 193a) δ 7.28 (d, 1H, J = 7.6, ArH), 7.24–7.17 (m, 1H, ArH),

6.94–6.85 (m, 1H, ArH), 6.84 (d, 1H, J = 7.9, ArH), 5.25 (qn, 1H, J = 6.3, CHCH(OAr)Me),

4.09 (d, 1H, J = 6.3, COCHCH), 2.07 (tt, 1H, J = 7.7, 4.5, CH2CHCH2), 1.49 (d, 3H, J = 6.3,

CH3), 1.16–1.09 (m, 1H, c

Pr-H), 1.09–1.02 (m, 1H, cPr-H), 1.02–0.95 (m, 1H,

cPr-H), 0.95–

0.90 (m, 1H, cPr-H).

1H NMR (CD2Cl2, 600 MHz, 193b) δ 7.24–7.17 (m, 2H, 2× ArH), 6.94–6.85 (m, 2H,

2×ArH), 5.11 (dq, 1H, J = 9.1, 6.7, CHCH(OAr)Me), 4.25 (d, 1H, J = 9.1, CHCHMe), 1.78

(tt, 1H, J = 7.7, 4.4, CH2CHCH2), 1.53 (d, 3H, J = 6.7, CH3), 1.16–1.09 (m, 1H, cPr-H), 1.09–

1.02 (m, 1H, cPr-H), 0.91–0.86 (m, 1H,

cPr-H), 0.86–0.79 (m, 1H,

cPr-H).

13C NMR (CDCl3, 150 MHz, 193a) δ 207.5, 160.4, 129.48, 125.8, 125.1, 120.6, 110.2, 80.8,

63.2, 21.3, 19.1, 12.2, 11.7.

13C NMR (CDCl3, 150 MHz, 193b) δ 209.0, 159.4, 129.46, 126.5, 125.0, 121.1, 110.1, 81.7,

60.0, 20.2, 16.8, 12.8, 12.1.

IR (193a+193b) υ 3008, 2979, 2929, 1694, 1595, 1477, 1380, 1232.

HRMS (193a+193b) for C13H14O2 [M]+ found 202.09792, calc. 202.09883.

Chapter 5

172

5.3.7 Aldol/Protodeboronation

Representative procedure: Acetaldehyde (69 µL, 1.2 mmol, 2.0 eq) was added to a

suspension of 2-(prop-1-ynyl)phenylboronic acid (99 mg, 0.62 mmol) and

[Ph3PAuNTf2]2∙PhMe (5 mg, 3 µmol, 0.5 mol%) in DCM (0.5 mL) and the mixture was

allowed to stir at RT for 10 h (crude aldol product dr trans/cis 75:25). H2O (1 mL) and

CuSO4∙5H2O (15 mg, 0.062 mmol, 10 mol%) were added and the mixture was heated at 60 ºC

for 16 h (crude protodeborylation product dr anti/syn 75:25). The reaction mixture was

extracted with DCM (3×5 mL), dried over MgSO4, concentrated and purified by flash

chromatography (PE/Et2O/Et3N 50:50:1) to give the product as a colourless oil (61 mg, 55

%).

4-Hydroxy-3-phenylpentan-2-one (182)[319]

4-Hydroxy-3-phenylpentan-2-one:

Colourless oil. Characterised as a mixture of diastereomers (182a/182b= anti/syn 75:25).

IR (182a+182b) υ 3412, 2971, 2927, 1705, 1355.

HRMS (182a+182b) for C11H14O2 [M]+ found 178.09810, calc. 178.09883.

anti–4-hydroxy-3-phenylpentan-2-one (182a):

1H NMR (CDCl3, 600 MHz) δ 7.38–7.24 (m, 5H, ArH), 4.43 (app qn, 1H, J = 6.0, CHOH),

3.61 (d, 1H, J = 5.4, ArCHCO), 2.66 (br s, 1H, OH), 2.08 (s, 3H, COCH3), 1.09 (d, 3H, J =

6.3, CHCH3).

13C NMR (CDCl3, 150 MHz) δ 210.0, 134.5, 129.8, 129.1, 128.01, 67.5, 65.6, 30.2, 20.5.

syn–4-hydroxy-3-phenylpentan-2-one (182b):

1H NMR (CDCl3, 600 MHz) δ 7.38–7.24 (m, 3H, ArH), 7.18–7.14 (m, 2H, ArH), 4.36 (dq,

1H, J = 9.2, 6.2, CHOH), 3.56 (d, 1H, J = 9.2, ArCHCO), 3.11 (br s, 1H, OH), 2.05 (s, 3H,

COCH3), 0.98 (d, 3H, J = 6.2, CHCH3).

13C NMR (CDCl3, 150 MHz) δ 210.3, 136.0, 129.3, 128.8, 127.95, 69.0, 67.9, 29.9, 20.0.

Chapter 5

173

5.4 Procedures for Chapter 4

Protodesilylation procedure: [Ph3PAuNTf]2∙PhMe (0.5 mol%) was added to a solution of ((2-

bromophenyl)ethynyl)trimethylsilane (1 equiv) and MeOH (5 equiv) in DCM (1 M) and was

left to stir at RT. After designated time, the mixture was filtered through a silica pad and

concentrated to afford the product.

Representative procedure for halogenations: [Ph3PAuNTf]2∙PhMe (0.5 mol%) or TfOH (1

mol%) was added to a solution of trimethylsilylalkyne, a terminal alkyne or a boronic acid (1

equiv) in DCM (1 M) and was left to stir at RT. After designated time and if reaction was

complete, the mixture was filtered through a silica pad and concentrated to afford the product.

(2-Iodophenoxy)trimethylsilane: [380]

Colourless oil.

1H NMR (CDCl3, 600 MHz) δ 7.67 (dd, 1H, J = 7.8, 1.5, ArH), 7.25 (td, 1H, J = 7.8, 1.2,

ArH), 7.00 (d, 1H, J = 7.8, ArH), 6.69 (td, 1H, J = 7.8, 1.5, ArH), 0.21 (s, 9H, CH3).

13C NMR (CDCl3, 150 MHz) δ 155.2, 139.3, 129.3, 123.2, 119.1, 91.3, 0.5.

1-Bromo-2-(iodoethynyl)benzene:[381]

Colourless oil

1H NMR (CDCl3, 600 MHz) δ 7.60 (d, 1H, J = 7.7, ArH), 7.47 (d, 1H, J = 7.7, ArH), 7.25 (t,

1H, J = 7.7, ArH), 7.15 (t, 1H, J = 7.7, ArH).

13C NMR (CDCl3, 150 MHz) δ 132.4, 129.1, 128.3, 123.7, 94.3, 6.4.

HRMS for C8H4BrI [M]+ found 305.85391, calc. 305.85356.

1-Bromo-2-(bromoethynyl)benzene:[382]

Yellow oil.

1H NMR (CDCl3, 600 MHz) δ 7.57 (d, 1H, J = 7.7, ArH), 7.47 (d, 1H, J = 7.7, ArH), 7.25 (t,

1H, J = 7.7, ArH), 7.19 (t, 1H, J = 7.7, ArH).

13C NMR (CDCl3, 150 MHz) δ 134.1, 132.6, 130.0, 127.2, 125.8, 124.9, 78.8, 55.0.

HRMS for C8H4Br2 [M+H] +

found 257.86812, calc. 257.86743.

(Iodoethynyl)benzene:[343]

Yellow oil. Mp 118–120 °C (DCM). Lit Mp 118–119 °C (PE).[343]

1H NMR (CDCl3, 600 MHz) δ 7.45–7.41 (m, 2H, ArH), 7.33–7.28 (m, 3H, ArH).

Chapter 5

174

13C NMR (CDCl3, 150 MHz) δ 132.4, 128.9, 128.4, 123.5, 94.2, 6.3.

IR ν 3055, 1597, 1488, 1442, 753, 689.

HRMS for C8H5I [M]+ found 227.94390, calc. 227.94304.

1-(Iodoethynyl)-4-methoxybenzene:[383]

Yellow solid. Mp 62–63 °C (PE/DCM). Lit Mp 61–62°C (DCM).[383]

1H NMR (CDCl3, 600 MHz) δ = 7.38 (d, 2H, J = 7.8, ArH), 6.84 (d, 2H, J = 7.8, ArH), 3.82

(s, 3H, CH3).

13C NMR (CDCl3, 150 MHz) δ 160.0, 133.7, 115.5, 94.0, 55.3, 3.7.

HRMS for C9H7IO [M]+ found 257.95290, calc. 257.95361.

References

References

176

References

[1] (a) Frankland, E.; Duppa, B. F. Justus Liebigs Ann. Chem. 1860, 115, 319. (b)

Frankland, E.; Duppa, B. F. Proc. Royal Soc. (Lond.) 1860, 10, 568. (c) Frankland, E.

J. Chem. Soc. 1862, 15, 363.

[2] Negishi, E. Aspects of Mechanism and Organometallic Chemistry; Brewster, J. H.,

Ed.; Plenum Press: New York, 1978; p 285.

[3] (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20, 3437. (b)

Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866.

[4] For review, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b) Kotha,

S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633.

[5] Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine.

Hall, D. G., Ed.; Wiley-VCH, Weinheim, 2005.

[6] Organoboranes for Syntheses. Ramachandran, P. V.; Brown, H. C., Eds.; ACS,

Washington, DC, 2001.

[7] Iwadate, N.; Suginome, M. J. Am. Chem. Soc. 2010, 132, 2548.

[8] Ihara, H.; Suginome, M. J. Am. Chem. Soc. 2009, 131, 7502.

[9] Lee, J. C. H.; Hall, D. G. J. Am. Chem. Soc. 2010, 132, 5544.

[10] For reviews, see: (a) Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108, 288. (b)

Molander, G. A.; Sandrock, D. L. Curr. Opin. Drug Disc. Dev. 2009, 12, 811.

[11] Jouvin, K.; Couty. F.; Evano, G. Org. Lett. 2010, 12, 3272.

[12] Cammidge, A. N.; Goddard, V. H. M.; Gopee, H.; Harrison, D. L.; Hughes, D. L.;

Schubert, C. J.; Sutton, B. M.; Watts, G. L.; Whitehead, A. J. Org. Lett. 2006, 8,

4071.

[13] (a) Yamamoto, Y.; Takizawa, M.; Yu, Q.-X.; Miyaura, N. Angew. Chem. Int. Ed.

2008, 47, 928. (b) Yu, Q.-X.; Yamamoto, Y.; Miyaura, N. Chem. – Asian J. 2008, 3,

1517.

[14] (a) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716. (b) Lee, S. J.;

Gray, K. C.; Paek, J. S.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 466. (c) Gillis, E.

P.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 14084. (d) Knapp, D. M.; Gillis, E. P.;

Burke, M. D. J. Am. Chem. Soc. 2009, 131, 6961. (e) Woerly, E. M.; Cherney, A. H.;

Davis, E. K.; Burke, M. D. J. Am. Chem. Soc. 2010, 132, 6941. (f) Gillis, E. P.;

Burke, M. D. Aldrichim. Acta, 2009, 42, 17.

References

177

[15] Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.; Cai, D.; Larsen, R. D.; Reider,

P. J. J. Org. Chem. 2002, 67, 5394.

[16] (a) Seaman, W.; Johnson, J. R. J. Am. Chem. Soc. 1931, 53, 711. For a procedure

carried out at ambient temperature, see: (b) Wang, X.-J.; Sun, X.; Zhang, L.; Xu, Y.;

Krishnamurthy, D.; Senanayake, C. H. Org. Lett. 2006, 8, 305.

[17] For a review on halogen–metal exchange in preparation of organolithiums, see: (a)

Sotomayor, N.; Lete, E. Curr. Org. Chem. 2003, 7, 275. For Grignard reagents, see:

(b) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.;

Sapountzis, I.; Vu, V. A. Angew. Chem. Int Ed. 2003, 42, 4302.

[18] Meudt, A.; Erbes, M.; Forstinger, K. US Patent Appl. 0161230 A1, 2002.

[19] (a) Nerdinger, S.; Kendall, C.; Cai, X.; Marchart, R.; Riebel, P.; Johnson, M. R.; Yin,

C.-F.; Hénaff, N.; Eltis, L. D.; Snieckus, V. J. Org. Chem. 2007, 72, 5960. (b) Alessi,

M.; Larkin, A. L.; Ogilvie, K. A.; Green, L. A.; Lai, S.; Lopez, S.; Snieckus, V. J.

Org. Chem. 2007, 72, 1588. (c) Sharp, M. J.; Cheng, W.; Snieckus, V. Tetrahedron

Lett. 1987, 28, 5093.

[20] Merino, P.; Tejero, T. Angew. Chem. Int. Ed. 2010, 49, 7164.

[21] (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508. (b)

Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett. 1997, 38, 3447. (c)

Takagi, J.; Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Am. Chem. Soc. 2002, 124,

8001.

[22] Ishiyama, T.; Ishida, K.; Miyaura, N. Tetrahedron 2001, 57, 9813.

[23] Fürstner, A.; Günter, S. Org. Lett. 2002, 4, 541.

[24] Billingley, K. L.; Barder, T. E.; Buchwald, S. L. Angew. Chem. Int. Ed. 2007, 46,

5369.

[25] (a) Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997, 62, 6458. For recent

mechanistic considerations, see: (b) Lam, K. C.; Marder, T. B.; Lin, Z.

Organometallics 2010, 29, 1849.

[26] Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J. Org. Chem. 2000, 65, 164.

[27] Billingsley, K. L.; Buchwald, S. L. J. Org. Chem. 2008, 73, 5589.

[28] Murata, M.; Sambommatsu, T.; Watanabe, S.; Masuda, Y. Synlett 2006, 1867.

[29] Zhu, W.; Ma, D. Org. Lett. 2006, 8, 261.

[30] Wolan, A.; Zaidlewicz, M. Org. Biomol. Chem. 2003, 1, 3724.

[31] Baudoin, O.; Guénard, D.; Guéritte, F. J. Org. Chem. 2000, 65, 9268.

[32] Kleeberg, C.; Dang, L.; Lin, Z.; Marder, T. B. Angew. Chem. Int. Ed. 2009, 48, 5350.

[33] Morgan, A. B.; Jurs, J. L.; Tour, J. M. J. Appl. Polym. Sci. 2000, 76, 1257.

[34] Debashis, A.; Huffman, J. C.; Mindiola, D. J. Chem. Commun. 2007, 4489.

References

178

[35] (a) Rosen, B. M.; Huang, C.; Percec, V. Org. Lett. 2008, 10, 2597. (b) Wilson, D. A.;

Wilson, C. J.; Rosen, B. M.; Percec, V. Org. Lett. 2008, 10, 4879.

[36] Moldoveanu, C.; Wilson, D. A.; Wilson, C. J.; Corcoran, P.; Rosen, B. M.; Percec, V.

Org. Lett. 2009, 11, 4974.

[37] Wilson, D. A.; Wilson, C. J.; Moldoveanu, C.; Resmerita, A.-M.; Corcoran, P.;

Hoang, L. M.; Rosen, B. M.; Percec, V. J. Am. Chem. Soc. 2010, 132, 1800.

[38] Mo, M.; Jiang, Y.; Qiu, D.; Zhang, Y.; Wang, J. Angew. Chem. Int. Ed. 2010, 49,

1846.

[39] Al-Zoubi, R. M.; Hall, D. G. Org. Lett. 2010, 12, 2480.

[40] Browne, D. L.; Helm, M. D.; Plant, A.; Harrity, J. P. A. Angew. Chem. Int. Ed. 2007,

46, 8656.

[41] Mkhalid, I. A. I.; Barnard, J. H.; Marder, T .B.; Murphy, J. M.; Hartwig, J .F. Chem.

Rev. 2010, 110, 890.

[42] Waltz, K. M.; Hartwig, J. F. Science 1997, 277, 211.

[43] Chen, H.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000, 287, 1995.

[44] Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E. Jr.; Smith, M. R., III. Science

2002, 295, 305.

[45] Ishiyama, T.; Ishida, K.; Takagi, J.; Miyaura, N. Chem. Lett. 2001, 30, 1082.

[46] Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. J.

Am. Chem. Soc. 2002, 124, 390.

[47] Brown, H. C.; Bhat, N. G. Tetrahedron Lett.1988, 29, 21.

[48] Takagi, J.; Kamon, A.; Ishiyama, T.; Miyaura, N. Synlett 2002, 1880.

[49] Occhiato, E. G.; Galbo, F. L.; Guarna, A. J. Org. Chem. 2005, 70, 7324.

[50] Ishiyama, T.; Oohashi, Z.; Ahiko, T.; Miyaura, N. Chem. Lett. 2002, 31, 780.

[51] Pintaric, C.; Olivero, S.; Gimbert, Y.; Chavant, P. Y.; Duñach, E. J. Am. Chem. Soc.

2010, 132, 11825.

[52] (a) Brown H. C.; Bhat, N. G.; Srebnik, M. Tetrahedron Lett. 1988, 29, 2631. (b)

Nishihara, Y.; Miyasaka, M.; Okamoto, M.; Takahashi, H.; Inoue, E.; Tanemura, K.;

Takagi, K. J. Am. Chem. Soc. 2007, 129, 12634.

[53] Brown, H. C.; Subba Rao, B. C. J. Am. Chem. Soc. 1956, 78, 5694.

[54] Brown, H. C.; Scouten, C. G.; Liotta, R. J. Am. Chem. Soc. 1979, 101, 96.

[55] Zweifel, G.; Clark, G. M.; Polston, N. L. J. Am. Chem. Soc. 1971, 93, 3395.

[56] Kalinin, A. V.; Scherer, S.; Snieckus, V. Angew. Chem. Int. Ed. 2003, 42, 3399.

[57] Miyaura, N.; Suzuki, A. Chem. Lett. 1981, 879.

[58] Tucker, C. E.; Davidson, J.;. Knochel, P. J. Org. Chem. 1992, 57, 3482.

References

179

[59] (a) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1972, 94, 4370. (b) Brown, H. C.;

Gupta, S. K. J. Am. Chem. Soc. 1975, 97, 5249. (c) Lane, C. F.; Kabalka, G. W.

Tetrahedron 1976, 32, 981.

[60] Pereira, S.; Srebnik, M. Organometallics 1995, 14, 3127.

[61] He, X. M.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 1696

[62] Pereira, S.; Srebnik, M. Tetrahedron Lett. 1996, 37, 3283.

[63] Pereira, S.; Srebnik, M. J. Am. Chem. Soc. 1996, 118, 909.

[64] For reviews on hydroboration, see: (a) Vogels, C.M.; Westcott, S.A. Curr. Org.

Chem. 2005, 9, 687. (b) Trost, B. M.; Ball, T. Z. Synthesis 2005, 853. (c) Beletskaya,

I.; Pelter, A. Tetrahedron 1997, 53, 4957.

[65] Suginome, M.; Shirakura, M.; Yamamoto, A. J. Am. Chem. Soc. 2006, 128, 14438.

[66] (a) Crabtree, R. H. The Organometallic Chemistry of the Transition Metals; 5th Ed.;

Wiley & Sons, Ltd: New Jersey, 2009. (b) Spessard, G. O.; Miessler, G. L.

Organometallic Chemistry, 1st Ed.; Prentice Hall: New Jersey, 1996. (c) Powell, P.

Principles of Organometallic Chemistry, 2nd Ed.; Chapman and Hall: New York,

1988. (d) Tsuji, J. Palladium Reagents and Catalysts: New Perspectives for the 21st

Centry, 2nd Ed.; John Wiley & Sons, Ltd: Chichester, 2004. (e) Zhao, H.; Ariafard,

A.; Lin, Z. Organometallics 2006, 25, 812.

[67] Brown, H. C.; Cole, T. E. Organometallics 1983, 2, 1316.

[68] Hupe, E.; Marek, I.; Knochel, P. Org. Lett. 2002, 4, 2861.

[69] Ueda, M.; Satoh, A.; Miyaura, N. J. Organomet. Chem. 2002, 642, 145.

[70] Organobismuth Chemistry. Suzuki, H.; Matano, Y., Eds.; Elsevier, Amsterdam, 2001.

[71] Elliott, G. I.; Konopelski, J. P. Tetrahedron 2001, 57, 5683.

[72] Finet, J. P.; Fedorov, A. Y.; Combes, S.; Boyer, G. Curr. Org. Chem. 2002, 6, 597.

[73] Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc.

2005, 127, 4685.

[74] Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16, 4229.

[75] For reviews, see: (a) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829. (b)

Edwards, H. J.; Hargrave, J. D.; Penrose, S. D.; Frost, C. G. Chem. Soc. Rev. 2010,

39, 2093. (c) Yoshida, K.; Hayashi, T. In Modern Rhodium-Catalyzed Organic

Reactions; Evans, P. A.; Tsuji, J., Eds.; Wiley-VCH: Weinheim, 2005, pp 55–78.

[76] Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N. J. Am. Chem. Soc.

1998, 120, 5579.

[77] (a) Cauble, D. F.; Gipson, J. D.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 1110.

(b) Bocknack, B. M.; Wang, L. C.; Krische, M. J. Proc. Natl. Acad. Sci. U. S. A.

2004, 101, 5421.

[78] Tobisu, M.; Shimasaki, T.; Chatani, N. Angew. Chem. Int. Ed. 2008, 47, 4866.

References

180

[79] Shimasaki, T.; Konno, Y.; Tobisu, M.; Chatani, N. Org. Lett. 2009, 11, 4890.

[80] Morita, A.; Kuwahara, S. Org. Lett. 2006, 8, 1613.

[81] Yang, H.; Liebeskind, L. S. Org. Lett. 2007, 9, 2993.

[82] Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260.

[83] Villalobos, J. M.; Srogl, J.; Liebeskind, L. S. J. Am. Chem. Soc. 2007, 129, 15734.

[84] Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-

Q. J. Am. Chem. Soc. 2007, 129, 3510.

[85] Zhang, G.; Peng, Y.; Cui, L.; Zhang, L. Angew. Chem. Int. Ed. 2009, 48, 3112.

[86] (a) Melhado, A. D.; Brenzovich, W. E., Jr.; Lackner, A. D.; Toste, F. D. J. Am.

Chem. Soc. 2010, 132, 8885. (b) Brenzovich, W. E., Jr.; Benitez, D.; Lackner, A. D.;

Shunatona, H. P.; Tkatchouk, E.; Goddard, W. A., III; Toste, F. D. Angew. Chem. Int.

Ed. 2010, 49, 5519.

[87] Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.; Fujiwara, Y.; Sobel, A. L.;

Baran, P. S. J. Am. Chem. Soc. 2010, 132, 13194.

[88] Herraduea, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett. 2000, 2, 2019.

[89] For reviews, see: (a) Chan, D. M. T.; Lam, P. Y. S. In Boronic Acids – Preparation

and Applications in Organic Synthesis and Medicine; Hall, D. G., Ed.; Wiley:

Weinheim, 2005, pp 205–232. (b) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed.

2003, 42, 5400. (c) Thomas, A. W.; Ley, S. V. In Modern Arylation Methods;

Achkermann, L., Ed.; Wiley-VCH: Weinheim, 2009, pp 121–154. (d) Das, P.;

Sharma, D.; Kumar, M.; Singh, B. Curr. Org. Chem. 2010, 14, 754.

[90] For back-to-back original reports, see: Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.;

Winters, M. P. Tetrahedron Lett. 1998, 39, 2933. (b) Evans, D. A.; Katz, J. L.; West,

T. R. Tetrahedron Lett. 1998, 39, 2937. (c) Lam, P. Y. S.; Clark, C. G.; Saubern, S.;

Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39,

2941.

[91] King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131, 5044.

[92] (a) Shade, R. E.; Hyde, A. M.; Olsen, J.-C.; Merlic, C. A. J. Am. Chem. Soc. 2010,

132, 1202. (b) Winternheimer, D. J.; Merlic, C. A. Org. Lett. 2010, 12, 2508. (c)

Lam, P Y. S.; Vincent, G.; Bonne, D.; Clark, C. G. Tetrahedron Lett. 2003, 44, 4927.

[93] Lam, P. Y. S.; Vincent. G.; Clarck, C. G.; Deudon, S.; Jadhav, P K. Tetrahedron Lett.

2001, 42, 3415.

[94] (a) González, I.; Mosquera, J.; Guerrero, C.; Rodríguez, R.; Cruces, J. Org. Lett.

2009, 11, 1677. (b) Larossa, M.; Guerrero, C.; Rodríguez, R.; Cruces, J. Synlett 2010,

2105.

[95] Bolshan, Y.; Batey, R. A. Tetrahedron 2010, 66, 5283.

[96] Quachg, T. D.; Batey, R. A. Org. Lett. 2001, 5, 1381.

References

181

[97] (a) Uemura, T.; Chatani, N. J. Org. Chem. 2005, 70, 8361. (b) Kisseljova, K.;

Tšubrik, O.; Sillard, R.; Mäeorg, S.; Mäeorg, U. Org. Lett. 2006, 8, 43.

[98] Yu, Y.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2004, 6, 2631.

[99] Zheng, H.; Zhang, Q.; Chen, J.; Liu, M.; Cheng, S.; Ding, J.; Wu, H.; Su, W. J. Org.

Chem. 2009, 74, 943.

[100] Yamamoto, Y.; Kirai, N.; Harada, Y. Chem. Commun. 2008, 2010.

[101] Prakash, G. K. S.; Panja, C.; Mathew, T.; Surampudi, V.; Petasis, N. A.; Olah, G. A.

Org. Lett. 2004, 6, 2205.

[102] Rao, H.; Fu, H.;Jiang, Y.; Zhao, Y. Angew. Chem. Int. Ed. 2009, 48, 1114.

[103] (a) Tao, C.-Z.; Cui, X.; Li, J.; Liu, A.-X.; Liu, L.; Guo, Q.-X. Tetrahedron Lett. 2007,

48, 3525. (b) Grimes, K. D.; Gupte, A.; Aldrich, C. C. Synthesis 2010, 9, 1441.

[104] Li, Y.; Gao, L.-Z.; Han, F. S. Chem. Eur. J. 2010, 16, 7969.

[105] Xu, J.; Wang, X.; Shao, C.; Su, D.; Cheng, G.; Hu, Y. Org. Lett. 2010, 12, 1964.

[106] Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2002, 4, 4309.

[107] Zhang, Z.; Liebeskind, L. S. Org. Lett. 2006, 8, 4331.

[108] Liskey, C. W.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 11389.

[109] Ukai, K.; Aoki, M.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2006, 128, 8706.

[110] (a) Ohishi, T.; Nishiura, M.; Hou, Z. Angew. Chem. Int. Ed. 2008, 47, 5792. (b)

Takaya, J.; Tadami, S.; Ukai, K.; Iwasawa, N. Org. Lett. 2008, 10, 2697.

[111] Yamamoto, Y. Adv. Synth. Catal. 2010, 352, 478.

[112] (a) Diorazio, L. J.; Widdowson, D. A.; Clough, J. M. Tetrahedron 1992, 48, 8073. (b)

Clough, J. M.; Diorazio, L. J.; Widdowson, D. A. Synlett 1990, 761.

[113] Furuya, T.; Ritter, T. Org. Lett. 2009, 11, 2860.

[114] Cazorla, C.; Métay, E.; Andrioletti, B.; Lemaire, M. Tetrahedron Lett. 2009, 50,

3936.

[115] (a) Murphy, J. M.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 15434. (b)

Thompson, A. L. S.; Kabalka, G. W.; Akula, M. R.; Huffman, J. W. Synthesis 2005,

457. (c) Ainley, A. D.; Challenger, F. J. J. Chem. Soc. 1930, 2171.

[116] Kabalka, G. W.; Akula, M. R.; Zhang, J. Nucl. Med. Biol. 2002, 29, 841.

[117] Thiebes, C.; Praksh, G. K. S.; Petasis, N. A.; Olah, G. A. Synlett 1998, 141.

[118] Szumigala, R. H., Jr.; Devine, P. N.; Gauthier, D. R., Jr.; Volante, R. P. J. Org. Chem.

2004, 69, 566.

[119] Wu, H.; Hynes, J., Jr. Org. Lett. 2010, 12, 1192.

[120] (a) Chu, L.; Qing, F.-L. Org. Lett. 2010, 12, 5060. (b) Senecal, T. D.; Parson, A. T.;

Buchwald, S. L. J. Org. Chem. 2011, 76, DOI:10.1021/jo1023377

[121] Brustad, E.; Bushey, M. L.; Lee, J. W.; Groff, D.; Liu, W.; Schultz, P. G. Angew.

Chem. Int. Ed. 2008, 47, 8220.

References

182

[122] (a) Letsinger, R. L.; Dandegaonker, S.; Vullo, W. J.; Morrison, J. D. J. Am. Chem.

Soc. 1963, 85, 2223. (b) Letsinger, R. L.; Morrison, J. D. J. Am. Chem. Soc. 1963, 85,

2227.

[123] Nagata, W.; Okada, K.; Aoki, T. Synthesis 1979, 365.

[124] Dufresne C.; Cretney D.; Lau C. K.; Mascitti V.; Tsou N. Tetrahedron: Asymmetry

2002, 13, 1965.

[125] Mufphy, W. S.; Tuladhar, S. M.; Duffy, B. J. Chem. Soc., Perkin Trans. 1 1992, 605.

[126] Narasaka, K.; Shimada, G.; Osoda, K.; Iwasawa, N. Synthesis 1991, 1171.

[127] Nicolaou, K. C.; Liu, J.-J.; Yang, Z.; Ueno, H.; Sorensen, E. J.; Claiborne, C. F.; Guy,

R. K.; Hwang, C.-K.; Nakada, M.; Nantermet, P. G. J. Am. Chem. Soc. 1995, 117,

634.

[128] (a) Yamamoto, H.; Fitatsugi, K. Angew. Chem. Int. Ed. 2005, 44, 1924. (b) Ishihara,

K.; Yamamoto, H. Eur. J. Org. Chem. 1999, 3, 527. (c) Corey, E. J.; Helal, C. J.

Angew. Chem. Int. Ed. 1998, 37, 1986.

[129] Štefane, B. Org. Lett. 2010, 12, 2900.

[130] Tanaka, Y.; Hidaka, K.; Hasui, T.; Suginome, M. Eur. J. Org. Chem. 2009, 1148.

[131] For reviews, see: (a) Charville, H.; Jackson, D.; Hodges, G.; Whiting, A. Chem.

Commun. 2010, 46, 1813. (b) Georgiou, I.; Ilyashenko, G.; Whiting, A. Acc. Chem.

Res. 2009, 42, 756. (c) Maki, T.; Ishihara, K.; Yamamoto, H. Tetrahedron 2007, 63,

8645.

[132] (a) Furuta, K.; Miwa, Y.; Iwanaga, K.; Yamamoto, H. J. Am. Chem. Soc. 1988, 110,

6254. (b) Al-Zoubi, R. M.; Marion, O.; Hall. D. G. Angew. Chem. Int. Ed. 2008, 47,

2876. (c) Zheng, H.; McDonald, R.; Hall, D. G. Chem. Eur. J. 2010, 16, 5454.

[133] (a) Levitt, T.; Pelter, A. Nature 1966, 21, 299. (b) Tani, J.; Oine, T.; Junichi, I.

Synthesis 1975, 714. (c) Trapani, G.; Reho, A.; Latrofa, A. Synthesis 1983, 1013. (d)

Huang, Z.; Reilly, J. E.; Buckle, R. N. Synlett 2007, 1026. (e) Collum, D. B.; Chen,

S.; Ganem, B. J. Org. Chem. 1978, 43, 4393

[134] Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996, 61, 4196.

[135] (a) Maki, T.; Ishihara, K.; Yamamoto, H. Org. Lett. 2005, 7, 5043. (b) Maki, T.;

Ishihara, K.; Yamamoto, H. Org. Lett. 2006, 8, 1431.

[136] Ishihara, K.; Ohara, S.; Yamamoto, H. Macromolecules 2000, 33, 3511.

[137] Maki, T.; Ishihara, K.; Yamamoto, H. Synlett 2004, 1355.

[138] Ishihara, K.; Kondo, S.; Yamamoto, H. Synlett 2001, 1371.

[139] Tang, P. Org. Synth. 2005, 81, 262.

[140] (a) Wulff, G. Pure App. Chem. 1982, 54, 2093. (b) Zhu, L.; Shabbir, S. H.; Gray, M.;

Lynch, V. M.; Sorey, S.; Anslyn, E. V. J. Am. Chem. Soc. 2006, 128, 1222.

References

183

[141] Arnold, K.; Davies, B.; Giles, R. L.; Grosjean, C.; Smith, G. E.; Whiting, A. Adv.

Synth. Catal. 2006, 348, 813.

[142] Arnold, K.; Batsanov, A. S.; Davies, B.; Whiting, A. Green Chem. 2008, 10, 124.

[143] Marcelli, T. Angew. Chem. Int. Ed. 2010, 49, 6840.

[144] Houston, T. A.; Wilkinson, B. L.; Blanchfield, J. T. Org. Lett. 2004, 6, 679.

[145] Houston, T. A.;. Levonis, S. M. Kiefel, M. J. Aust. J. Chem. 2007, 60, 811.

[146] Wang, X.; Wipf, P. J. Comb. Chem. 2002, 4, 656.

[147] Tale, R. H.; Patil, K. M. Tetrahedron Lett. 2002, 43, 9715.

[148] Tale, R. H.; Patil, K. M.; Dapurkar, S. E. Tetrahedron Lett. 2003, 44, 3427.

[149] Miyaura, N. Bull. Chem. Soc. Jpn. 2008, 81, 1535; and references therein.

[150] (a) Lan, J.-B.; Chen, L.; Yu, X. Q.; You, J. S.; Xie, R. G. Chem. Commun. 2004, 188.

(b) Lan, J.-B.; Zhang, G.-L.; Yu, X.-Q.; You, J.-S.; Chen, L.; Yan, M.; Xie, R.-G.

Synlett 2004, 1095. (b) Sreedhar, B.; Venkanna, G. T.; Kumar, K. B. S.;

Balasubrahmanyam, V. Synthesis 2008, 795.

[151] (a) King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J.

Am. Chem. Soc. 2010, 132, 12068. (b) Yang, L.; Lu, Z.; Stahl, S. S. Chem. Commun.

2009, 6460. (c) Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas,

X. Chem. Sci. 2010, 1, 326.

[152] Nicolaou, K. C.; Bheema Rao, P.; Hao, J.; Reddy, M. V.; Rassias, G.; Huang, X.;

Chen, D. Y.-K.; Snyder, S. A. Angew. Chem. Int. Ed. 2003, 42, 1753.

[153] Fischer, D. F.; Sarpong, R. J. Am. Chem. Soc. 2010, 132, 5926.

[154] James, T. D.; Phillips, M. D.; Shinkai, S. Boronic Acids in Saccharide Recognition.

RSC, Cambridge, 2006.

[155] Hunter, P. EMBO Rep. 2009, 10, 125.

[156] Richardson, P. G, Mitsiades, C.; Hideshima, T.; Anderson, K. C.. Annu. Rev. Med.

2006, 57, 33.

[157] Rock, F. L.; Mao, W.; Yaremchuk, A.; Tukalo, M.; Crépin, T.; Zhou, H.; Zhang, Y.

K.; Hernandez, V.; Akama, T.; Baker, S. J.; Plattner, J. J.; Shapiro, L.; Martinis, S.

A.; Benkovic, S. J.; Cusack, S.; Alley, M. R. Science 2007, 316, 1759.

[158] Greenberg, A.; Breneman, C. M.; Liebman, J. F. The Amide Linkage: Selected

Structural Aspects in Chemistry, Biochemistry, and Material Science. Wiley, New

York, 2000.

[159] Sewald, N.; Jakubke, H.-D. Peptides: Chemistry and Biology. Wiley-VCH Verlag

GmbH, Weinheim, 2002.

[160] Nielsen, P. E.; Egholm, M.; Berg, R. H.; Buchardt, O. Science 1991, 254, 1497.

[161] (a) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006,

4, 2337. (b) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.; Leazer,

References

184

J. L.; Linderman, R. J.; Lorenza, K.; Manley, J.; Pearlman, B. A.; Wells, A.; Zaks, A.;

Zhang, T. Y. Green Chem. 2007, 9, 411.

[162] Dugger, R. W.; Ragan, J. A.; Ripin, D. H. B. Org. Proc. Res. Dev. 2005, 9, 253.

[163] Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. J. Comb. Chem. 1999, 1, 55.

[164] Trost, B. M. Science 1991, 254, 1471.

[165] Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem. Int. Ed. Engl. 2009, 48,

2854.

[166] Alfonsi, K.; Colberg, J.; Dunn, P. J.; Fevig, T.; Jennings, S.; Johnson, T. A.; Kleine,

H. P.; Knight, C.; Nagy, M. A.; Perry, D. A.; Stefaniak, M. Green Chem. 2008, 10,

31.

[167] (a) Rodnina, M. A.; Beringer, M.; Wintermeyer. W. Quar. Rev. Biophys. 2006, 39,

203. (b) Polacek, N.; Mankin, A. Crit. Rev. Biochem. Mol. Biol. 2005, 20, 285. (c)

Beringer, M.; Rodnina, M. V. Mol. Cell. 2007, 26, 311. (d) Steitz, T. A. Nat. Rev.

Mol. Cell Biol. 2008, 9, 242. (e) Simonovic, M.; Steitz, T. A. Biochim. Biophys. Acta

2009, 1789, 612.

[168] Kijima, M.; Yoshida, M.; Sugita, K.; Horinouchi, S.; Beppu T. J. Biol. Chem. 1993,

268, 22429.

[169] Levine, D. P. Clin. Infect. Dis. 2006, 42, S5.

[170] Wallemacq, P. E.; Reding, R. Clin. Chem. 1993, 39, 2219.

[171] Black, H. R.; Bailey, J.; Zappe, D.; Samuel, R. Drugs, 2009, 69, 2393.

[172] For reviews, see: (s) Snieckus, V. Chem Rev. 1990, 90, 879. (b) Hartung, C. G.;

Snieckus, V. In Modern Arene Chemistry; Astruc, D., Ed.; Wiley-VCH: Weinheim,

Germany, 2002; Chapter 10.

[173] Nguyen, P.; Corpuz, E.; Heidelbaugh, T. D.; Chow, K.; Garst, M. E. J. Org. Chem.

2003, 68, 10195.

[174] Smith, S. M.; Thacker, N. C.; Takacs, J. M. J. Am. Chem. Soc. 2008, 130, 3734.

[175] Shioiri, T. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I, Eds.;

Pergamon, Oxford, 1991; Vol. 6, pp 800–806.

[176] (a) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978, 100, 3611.

(b) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392. (c) Takeda, T.;

Tsubouchi, A. In Modern Carbonyl Olefination; Takeda, T., Ed.; Wiley-VCH:

Weinheim, Germany, 2004; Chapter 4.

[177] (a) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc. 1994, 116,

9361. (b) Mikami, K.; Shimizu, M.; Zhang, H. C.; Maryanoff, B. E. Tetrahedron

2001, 57, 2917.

[178] (a) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827. (b) Bode, J. W.

Curr. Opin. Drug. Disc. Dev. 2006, 9, 765. (c) Valeur, E.; Bradley, M. Chem Soc.

References

185

Rev. 2009, 38, 606. (d) Bailey, P. D.; Collier, I. D.; Morgan, K. M. In Comprehensive

Organic Functional Group Transformations; Katritzky, A. R.; Meth-Cohn, O.; Rees,

C. W., Eds.; Pergamon: Cambridge, 1995; Vol. 5; Chapter 6. (e) Bailey, P. D.; Mills,

T. J.; Pettercrew, R.; Price, R. A. In Comprehensive Organic Functional Group

Transformations II; Katritzky, A. R.; Taylor, R. J. K., Eds.; Elsevier: Oxford, 2005;

Vol. 5; Chapter 7.

[179] Boldeskul, I. E.; Egorov, Yu. P.; Ryltsev, E. V. Theor. Exp. Chem. 1975, 10, 133.

[180] (a) Jursic, B. S.; Zdravkovski, Z. Synth. Commun. 1993, 23, 2761. (b) Gooßen, L. J.;

Ohlmann, D. M.; Lange, P. P. Synthesis 2009, 160.

[181] König, W.; Geiger, R. Chem. Ber. 1970, 103, 788.

[182] Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397.

[183] El-Faham. A.; Albericio, F. Eur. J. Org. Chem. 2009, 1499.

[184] (a) Comerford, J. W.; Clark, J. H.; Macquarrie, D. J.; Breeden, S. W. Chem. Commun.

2009, 2562. (b) Yang, X.-D.; Zeng, X.-H.; Zhao, Y.-H.; Wang, X.-Q.; Pan, Z.-Q.; Li,

L.; Zhang, H.-B. J. Comb. Chem. 2010, 12, 307.

[185] For recent catalysed and non catalysed microwave-assisted amidations, see: (a)

Perreux, L.; Loupy, A.; Volatron, F. Tetrahedron 2002, 58, 2155. (b) Vázquez-Tato,

M. P.; Synlett 1993, 506. (c) Marrero-Terrero, A. L.; Loupy, A. Synlett 1996, 245. (d)

Seijas, J. A.; Vázquez-Tato, M. P.; Martinez, M. M.; Nunez-Corredoira, G. J. Chem.

Res. (S) 1999, 7, 420. (e) Baldwin, B. W.; Hirose, T.; Wang, Z.-H. Chem. Commun.

1996, 23, 2669.

[186] For a recent example, see: (a) Gustafsson, T.; Ponten, F.; Seeberger, P. H. Chem.

Commun. 2008, 1100. (b) Burnell-Curty, C.; Roskamp, E. J. Tetrahedron Lett. 1993,

34, 5193.

[187] (a) Gotor, V. Bioorg. Med. Chem. 1999, 7, 2189. (b) van Rantwijk, F.; Hacking, M.

A. P. J.; Sheldon, R. A. Monatsh. Chem. 2000, 131, 549. (c) Alfonso, I.; Gotor, V.

Chem. Soc. Rev. 2004, 33, 201.

[188] (a) Grzyb, J. A.; Batey, R. A.. Tetrahedron Lett 2003, 44, 7485. (b) Grzyb, J. A.;

Shen, M.; Yoshina-Ishii, C.; Chi, W.; Brown, R. S.; Batey, R. A. Tetrahedron 2005,

61, 7153.

[189] Nomura, R.; Wada, T.; Yamada, Y.; Matsuda, H. Chem. Lett. 1986, 1901.

[190] (a) Nomura, R.; Yamada, Y.; Matsuda, H. Appl. Organomet. Chem. 1989, 3, 355. (b)

Nomura, R.; Nakano, T.; Yamada, Y.; Matsuda, H. J. Org. Chem. 1991, 56, 4076.

[191] Steliou, K.; Poupart, M.-A. J. Am. Chem. Soc. 1983, 105, 7130.

[192] Helquist, P.; Mader, M. Tetrahedron Lett. 1988, 29, 3049.

[193] Yamamoto, H.; Maruoka, K. J. Am. Chem. Soc. 1981, 103, 6133.

References

186

[194] Ishihara, K.; Kuroki, Y.; Hanaki, N.; Ohara, S.; Yamamoto, H. J. Am. Chem. Soc.

1996, 118, 1569.

[195] Han, C.; Lee, J. P.; Lobkovsky, E.; Porco, J. A. J. Am. Chem. Soc. 2005, 127, 10039.

[196] Yang, Y.; Birman, V. B. Org. Lett. 2009, 11, 1499.

[197] Kunishima, M.; Imada, H.; Kikuchi, K.; Hioki, K.; Nishida, J.; Tani, S. Angew.

Chem. Int. Ed. 2005, 44, 7254.

[198] Movassaghi, M.; Schmidt, M. A. Org. Lett. 2005, 7, 2453.

[199] Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2007, 129, 13796.

[200] Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798.

[201] Yoo, W.-J.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 13064.

[202] Chiang, P.-C.; Kim, Y.; Bode, J. W. Chem. Commun. 2009, 4566.

[203] Guanathan, C.; Ben-David, Y.; Milstein. D. Science 2007, 317, 790.

[204] (a) Nordstrøm, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc. 2008, 130, 17672. (b)

Dam, J. H.; Osztrovszky, G.; Nordstrøm, L. U.; Madsen, R. Chem. Eur. J. 2010, 16,

6820.

[205] Watson, A. J.; Maxwell, A. C.; Williams, J. M. J. Org. Lett. 2009, 11, 2667.

[206] Zweifel, T.; Naubron, J.-V.; Grützmacher, H. Angew. Chem. Int. Ed. 2009, 48, 559.

[207] Shen, B.; Makley, D. M.; Johnston, J. N. Nature 2010, 465, 1027.

[208] For a review on selective metal-templated/mediated reactions of amino groups, see:

Lee, S. H.; Cheong, C. S. Tetrahedron 2001, 57, 4801.

[209] (a) Kostin, A. I.; Sheinkman, A. K.; Savchenko, A. S. Chem. Heterocycl. Comp.

1987, 23, 417. (b) Cherkasova, E. M.; Bogatkov, S. V.; Golovina, Z. P. Russ. Chem.

Rev. 1977, 46, 246.

[210] Larsson, P.-F.; Correa, A.; Carril, M.; Norrby, P.-O.; Bolm, C. Angew. Chem. Int. Ed.

2009, 48, 5691.

[211] Funabashi, M.; Yang, Z.; Nonaka, K.; Hosobuchi, M.; Fujita, Y.; Shibata, T.; Chi, X.;

van Lanen, S. G. Nat. Chem. Biol. 2010, 6, 581.

[212] (a) Sievers, A.; Beringer, M.; Rodnina, M. V.; Wolfenden, R. Proc. Natl. Acad. Sci.

U. S. A. 2004, 101, 7891. (b) Trobso, S.; Åqvist, J. Proc. Natl. Acad. Sci. U. S. A.

2005, 102, 12395.

[213] (a) Weinger, J. S.; Parnell, K. M.; Dorner, S.; Green, R.; Strobel, S. A. Nat. Struct.

Mol. Biol. 2004, 11, 1101. (b) Bayryamov, S. G.; Rangelov, M. A.; Mladjova, A. P.;

Yomtov, V.; Petkov, D. D. J. Am. Chem. Soc. 2007, 129, 5790.

[214] For reviews, see: (a) Finkin, R.; Marahiel, M. A. Ann. Rev. Microbiol. 2004, 58, 453.

(b) Challis, G. L.; Naismith, J. H. Curr. Opin. Struct. Biol. 2004, 14, 748. (c)

Fischbach, M. A.; Walsh, C. T. Chem. Rev. 2006, 106, 3468.

[215] Hodawadekar, S. C.; Marmorstein, R. Oncogene 2007, 26, 5528.

References

187

[216] Yan, Y.; Harper, S.; Spreicher, D. W.; Marmorstein, R. Nat. Struct. Biol. 2002, 9,

862.

[217] (a) Tanner, K. G.; Trievel, R. C.; Kuo.; Howards, R. M.; Berger, S. L.; Allis, D. C.;

Maromorstein, R.; Denu, J. M. J. Biol. Chem. 1999, 274, 18157. (b) Trievel, R. C.;

Rojas, J. R.; Sterner, D. E.; Venkataramani, R. N.; Wang, L.; Zhou, J.; Allis, D. C.;

Berger, S. L.; Marmorstein, R. Proc. Natl. Acad. Sci. USA 1999, 96, 8931.

[218] Schmid, A.; Dordick, J. S.; Hauer, B.; Kiener, A.l.; Wubbolts, W.; Withold, B.

Nature 2001, 409, 258.

[219] (a) Inada, Y.; Nishimura, H.; Takahashi, K.; Yoshimoto, T.; Saha, A. R.; Saito, Y.

Biochem. Biophys. Res. Commun. 1984, 122, 845. (b) Zaks, A.; Klibanov, A. M.

Proc. Natl. Acad. Sci. U. S. A. 1985, 82, 3192.

[220] Bugg, T. D. H. Bioorg. Chem. 2004, 32, 367.

[221] Ema, T.; Tanida, D.; Matsukawa, T.; Sakai, I. Chem Commun. 2008, 957.

[222] Green Chemistry in the Pharmaceutical Industry. Dunn, P. J.; Wells, A. S.; Williams,

M. T.; Eds.; Wiley–VCH, Weinheim, 2010.

[223] Arnold, K.; Davies, B.; Herault, D.; Whiting, A. Angew. Chem. Int. Ed. 2008, 27,

2673.

[224] (a) Ohara, S.; Ishihara, K.; Yamamoto, H. The 78th Spr. Meet. Chem. Soc. Jpn. 2000,

3-B5-10. (b) Ishihara, K.; Yamamoto, H. JP 2001-270939, 2001.

[225] (a) Yang, W.; Drueckhammer, D. G. J. Am. Chem. Soc. 2001, 123, 11004. (b) Yang,

W.; Drueckhammer, D. G. Org. Lett. 2000, 2, 4133.

[226] Connors, K. A.; Bender, M. L. J. Org. Chem. 1961, 26, 2498.

[227] Wolfe, S.; Sterzycki, R. Can. J. Chem. 1987, 65, 26.

[228] Sezer, O.; Anac, O. Helv. Chim. Acta 1994, 77, 2323.

[229] Kasahara, A.; Izumi, T.; Murakami, S.; Yanai, H.; Takatori, M. Bull. Chem. Soc. Jpn.

1986, 59, 927.

[230] Wada, K.; Mizutani, T.; Kitagawa, S. J. Org. Chem. 2003, 68, 5123.

[231] Rodriguez, J. G.; Rios, C.; Lafuente, A. Tetrahedon 2005, 61, 9042.

[232] McKillop, A.; Tarbin, J. A. Tetrahedron 1987, 43, 1753.

[233] (a) Savrda, J.; Ziane, N.; Guilhem, J.; Wakselman, M. J. Chem. Res. (S) 1991, 36. (b)

Savrda, J.; Ziane, N.; Guilhem, J.; Wakselman, M. J. Chem. Res. (M) 1991, 379.

[234] Takeda, K.; Tsuboyama, K.; Yamaguchi, K.; Ogura, H. J. Org. Chem. 1985, 50, 273.

[235] Kristensen, J.; Lysen, M.; Vedsø, P; Begtrupt, M. Org. Lett. 2001, 3, 1435.

[236] Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Org. Lett. 2006, 8, 2523.

[237] Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Tetrahedron 2006, 62, 11483.

[238] Mei, T.-S.; Giri, R.; Maugel, N.; Yu, J.-Q. Angew. Chem. Int. Ed. 2008, 47, 5215.

[239] Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem. Int. Ed. 2005, 44, 2112.

References

188

[240] Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 3676.

[241] Ng, K.-H.; Chan, A. S. C.; Yu, W.-Y. J. Am. Chem. Soc. 2010, 132, 12862.

[242] Wacharasindhu, S.; Bardhan, S.; Wan, Z.-K.; Tabei, K.; Mansour, T. S. J. Am. Chem.

Soc. 2009, 131, 4174.

[243] Zabrowski, D. L.; Moormann, A. E.; Beck, K. R. Tetrahedron Lett. 1988, 29, 4501.

[244] Emmons, W. D.; Ferris, A. F. J. Am. Chem. Soc. 1953, 75, 4623.

[245] Shen, D.; Diele, S.; Pelzl, G.; Wirth, I.; Tschierske, C. J. Mater. Chem. 1999, 9, 661.

[246] (a) Mitsunobu, O. Synthesis 1981, 1. (b) Swamy, K. C.; Kumar, N. N. B.; Balaraman,

E.; Kumar, K. V. P. P. Chem. Rev. 2009, 109, 2551.

[247] (a) .Koppel, I.; Koppel, J.; Leito, I.; Pihl, V.; Grehn, L.; Ragnarsson, U. J. Chem Res.

(S) 1993, 446. (b) Carpino, l. A.; Imazumi, H.; Foxman, B. M.; Vela, M. J.; Henklein,

P.; El-Faham, A.; Klose, J.; Bienert, M. Org. Lett. 2000, 2, 2253.

[248] (a) Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333. (b)

Krasovskiy, A.; Straub, B. F.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 159.

[249] Widmer, U. Synthesis 1983, 135.

[250] Katritzky, A. R.; Maimait, R.; Denisenko, S. N.; Steel, P. J.; Akhmedov, N. G. J.

Org. Chem. 2001, 66, 5585.

[251] (a) Brady, O. L.; Day, J. N. E. J. Chem. Soc. 1923, 2258. (b) Brady, O. L.; Reynolds,

C. V. J. Chem. Soc. 1928, 193. (c) Brady, O. L.; Jakobovits, J. J. Chem. Soc. 1950,

767.

[252] Takeuchi, M.; Mizuno, T.; Shinmori, H.; Nakashima, M.; Shinkai, S. Tetrahedron

1996, 52, 1195.

[253] Fedorov, A. Y.; Shchepalov, A. A.; Bolshakov, A. V.; Shavyrin, A. S.; Kurskii, Y.

A.; Finet J.-P.; Zelentsov S. V. Russ. Chem. Bull. 2004, 53, 370.

[254] Sakata, T.; Maruyama, S.; Veda, A.; Otsuka, H.; Miyahara, Y. Langmuir 2007, 23,

2269.

[255] Ruan, Z.; Lawrence, R. M.; Cooper, C. B. Tetrahedron Lett. 2006, 47, 7649.

[256] Chan, T. -H.; Wog, L. T. L. J. Org. Chem. 1969, 34, 2766.

[257] Pelter, A.; Levitt, T. E.; Nelson, P. Tetrahedron 1970, 26, 1539.

[258] Springsteen, G.; Wang, B. Tetrahedron 2002, 58, 5291.

[259] Hydrogen Bonding in Organic Synthesis. Pihko, P., Ed.; Wiley-VCH Verlag GmbH

& Co. KGaA, Weinheim, 2009.

[260] (a) Sabot, C.; Kumar, K. A.; Meunier, S.; Mioskowski, C. Tetrahedron Lett. 2007, 48,

3863. (b) Kiesewetter, M. K.; Scholten, M. D.; Kirn, N.; Weber, R. L.; Hedrick, J. L.;

Waymouth, R. M. J. Org. Chem. 2009, 74, 9490.

[261] Iwata, M.; Kuzuhara. H. Chem. Lett. 1989, 11, 2029.

References

189

[262] Beckett, M. A.; Rugen-Hankey, M. P.; Strickland, G. C.; Varma, K. S. Phosphorus,

Sulfur Silicon Relat. Elem. 2001, 169, 113.

[263] Spengler, J.; Böttcher, C.; Albericio, F.; Burger, K. Chem. Rev. 2006, 106, 4728.

[264] (a) van Leeuwen, S. H.; Quaedflieg, P. J. L. M.; Broxterman, Q. B.; Milhajlovic, Y.;

Liskamp, R. M. J. Tetrahedron Lett. 2005, 46, 653. (b) Wang, J.; Okada, Y.; Wang,

Z,; Wang, Y,; Li, W. Chem. Pharm. Bull. 1996, 44, 2189.

[265] (a) Quaedflieg, P. J. L. M.; Broxterman, Q. B.; van Leeuwen, S. H.; Liskamp, R. M.

J. PCT Int. Appl. WO 0037484 A1, 2000. (b) van Leeuwen, S. H.; Quaedflieg, P. J.

L. M.; Broxterman, Q. B.; Liskamp, R. M. J. Tetrahedron Lett. 2002, 43, 9203.

[266] For examples of metal-mediated/catalysed amide activation/transamidation, see: (a)

Stephenson, N. S.; Zhu, J.; Gellman, S. H.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131,

10003. (b) Hoerter, J. M.; Otte, K. M.; Gellman, S. H.; Cui, Q.; Stahl, S. S. J. Am.

Chem. Soc. 2008, 130, 647. (c) Kissounko, D. A.; Hoerter, J. M.; Guzei, I. A.; Cui,

Q.; Gellman, S. H.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 1776. (d) Eldred, S. E.;

Stone, D. A.; Gellman, S. H.; Stahl, S. S. J. Am. Chem. Soc. 2003, 125, 3422. (e) Bon,

E.; Bigg, D. C. H.; Bertrand, G. J. Org. Chem. 1994, 59, 4035.

[267] For thermally driven transamidations, see: Mucsi, Z.; Chass, G. A.; Csizmadia, I. G.

J. Phys. Chem. B 2008, 112, 7885.

[268] For amidine formation/zirconium-catalysed amidation starting from primary amides,

see: Dineen, T. A.; Zajac, M. A.; Myers, A. G. J. Am. Chem. Soc. 2006, 128, 16406.

[269] For examples of metal-catalysed amide activation/amide reduction, see: (a) Zhou, S.;

Junge, K.; Addis, D.; Das, S.; Beller, M. Angew. Chem. Int. Ed. 2009, 48, 9507. (b)

Das, S.; Addis, D.; Zhou, S.; Junge, K.; Beller, M. J. Am. Chem. Soc. 2010, 132,

1770. (c) Hanada, S.; Tsutsumi, E.; Motoyama, Y.; Nagashima, H. J. Am. Chem. Soc.

2009, 131, 15032.

[270] For examples of Tf2O-mediated amide activation/amide reduction, see: (a) Barbe. G.;

Charette, A. B. J. Am. Chem. Soc. 2008, 130, 18. (b) Pelletier, G.; Bechara, W. S.;

Charette, A. B. J. Am. Chem. Soc. 2010, 132, 12817.

[271] (a) Speziale, A. K.; Smith, L. R.; Fedder, J. E. J. Org. Chem. 1965, 30, 4306. (b)

Speziale, A. J.; Smith, L. R. J. Org. Chem. 1963, 28, 1805.

[272] Sugiyama, M.; Hong, Z.; Whalen, L. J.; Greenberg,W. A.; Wong, C.-H. Adv. Synth.

Catal. 2006, 348, 2555.

[273] Modern Aldol Reactions, Vol. 1 and 2. Mahrwald, R., Ed; Wiley-VCH Verlag GmbH

& Co., Weinheim, Germany, 2004.

[274] (a) Gordin, M. D. J. Chem. Ed. 2006, 83, 561. (b) Podlech, J. Angew. Chem. Int. Ed.

2010, 49, 6490.

References

190

[275] (a) Wurtz, C. A. Bull. Soc. Chim. Fr. 1872, 17, 436. (b) Wurtz, C. A. J. Prakt. Chem.

1872, 5, 457. (c) Wurtz, C. A. Comp. Rend. 1872, 74, 1361.

[276] Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798.

[277] Fenzl, W.; Köster, R. Justus Liebigs Ann. Chem. 1975, 1322.

[278] For review, see: (a) Dias, L. C.; Aguilar, A. M. Chem. Soc. Rev. 2008, 37, 451. (b)

Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1. (c). Yeung, K.-S; Paterson, I.

Chem. Rev. 2005, 105, 4237.

[279] Brown, H. C.; Dhar, R. K.; Bakshi, R. K.; Pandiarajan, P. K.; Singaram, B. J. Am.

Chem. Soc. 1989, 111, 3441.

[280] (a) Abiko, A.; Inoue, T.; Masamune, S. J. Am. Chem. Soc. 2002, 124, 10759. (b)

Abiko, A.; Inoue, T.; Furuno, H.; Schwalbe, H.; Fieres, C.; Masamune, S. J. Am.

Chem. Soc. 2001, 123, 4605. (c) Abiko, A.; Liu, J.-F.; Buske, D. C.; Moriyama, S.;

Masamune, S. J. Am. Chem. Soc. 1999, 121, 7168.

[281] Mestres, R. Green Chem. 2004, 6, 583.

[282] (a) Edwards, G. L.; Motherwell, W. B.; Powell, D. M.; Sandham, D. A. J. Chem.

Soc., Chem. Commun. 1991, 1399. (b) Motherwell, W. B.; Sandham, D. A.

Tetrahedron Lett. 1992, 33, 6187. (c) Gazzard, L. J.; Motherwell, W. B.; Sandham, D.

A. J. Chem. Soc., Perkin Trans. 1, 1999, 979.

[283] (a) Uma, R.; Crévisy, C.; Grée, R. Chem. Rev. 2003, 103, 27. (b) Yanovskaya, L. A.;

Shakhidayatov, K. Russ. Chem. Rev. 1970, 39, 859. (c) van der Drift, R. C.;

Bouwman, E.; Drent, E. J. Organomet. Chem. 2002, 650, 1.

[284] Crévisy, C.; Wietrich, M.; le Boulaire, V.; Uma, R.; Grée, R. Tetrahedron Lett. 2001,

42, 395.

[285] (a) Uma, R.; Davies, M.; Crévisy, C.; Grée, R. Tetrahedron Lett. 2001, 42, 3069. (b)

Uma, R.; Davies, M. K.; Crévisy, C.; Grée, R. Eur. J. Org. Chem. 2001, 3141.

[286] (a) Wang, M.; Li, C. J. Tetrahedron Lett. 2002, 43, 3589. (b) Yang, X. F.; Wang, M.;

Varma, R. S.; Li, C. J. Org. Lett. 2003, 5, 657.

[287] (a) Jang, H. Y.; Huddleston, R. R.; Krische, M. J. J. Am. Chem. Soc. 2002, 124,

15156. (b) Huddleston, R. R.; Krische, M. J. Org. Lett. 2003, 5, 1143. (c) Marriner,

G. A.; Garner, S. A.; Jang, H. Y.; Krische, M. J. J. Org.Chem. 2004, 69, 1380. (d)

Koech, P. K.; Krische, M. J. Org. Lett. 2004, 6, 691. (e) Jung, C.-K.; Krische, M. J. J.

Am. Chem. Soc. 2006, 128, 17051. (f) Han, S. B.; Krische, M. J. Org. Lett. 2006, 8,

5657. (g) Jung, C.-K.; Garner, S. A.; Krische, M. J. Org. Lett. 2006, 8, 519. (h) Bee

C.; Han, S. B.; Hassan, A.; Ioda, H.; Krische, M. J. J. Am. Chem. Soc. 2008, 130,

2746.

[288] (a) Hoffmann, R. W.; Ditrich, K. Tetrahedron Lett. 1984, 25, 1781. (b) Hoffmann, R.

W.; Ditrich, K.; Froech, S. Tetrahedron 1985, 41, 1985.

References

191

[289] Basile, T.; Biondi, S.; Boldrini, G. P.; Tagliavini, E.; Trombini, C.; Umani–Ronchi. J.

Chem. Soc., Perkin Trans. 1 1989, 1025.

[290] Lipshutz, B. H.; Papa, P. Angew. Chem. Int. Ed. 2002, 41, 4580.

[291] (a) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem. Soc. 1988, 110,

291. (b) Mahoney, W. S.; Stryker, J. M. J. Am. Chem. Soc. 1989, 111, 8818. (c)

Brestensky, D. M.; Stryker, J. M. Tetrahedron Lett. 1989, 30, 5677.

[292] Boldrini, G. P.; Bortolotti, M.; Mancini, F.; Tagliavini, E.; Trombini, C.; Umani-

Ronchi, A. J. Org. Chem. 1991, 56, 5820.

[293] Lipshutz, B. H.; Chrisman, W.; Noson, K.; Papa, P.; Sclafani, J. A.; Vivian, R. W.;

Keith, J. M. Tetrahedron 2000, 56, 2779.

[294] Pelss, A.; Kumpulainen, E. T. T.; Koskinen, A. M. P. J. Org. Chem. 2009, 74, 7598.

[295] Sumida, Y.; Yorimitsu, H.; Oshima, K. J. Org. Chem. 2009, 74, 7986.

[296] Ocampo, R.; Dolbier, W. R, Jr. Tetrahedron 2004, 60, 9325.

[297] Babu, S. A.; Yasusa, M.; Shibata, I.; Baba, A. J. Org. Chem. 2005, 70, 10408. (b)

Babu, S. A.; Yasuda, M.; Okabe, Y.; Shibata, I.; Baba, A. Org. Lett. 2006, 8, 3029.

[298] Parrish, J. D.; Shelton, D. R.; Little, R. D. Org. Lett. 2003, 5, 3615.

[299] Chattopadhyay, A.; Dubey, A. K. J. Org. Chem. 2007, 72, 9357.

[300] Lambert, T. H.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 426.

[301] (a) Mukaiyama, T.; Takuwa, T.; Yamane, K.; Imachi, S. Bull. Chem. Soc. Jpn. 2003,

76, 813. (b) Mukaiyama, T.; Imachi, S.; Yamane, K.; Mizuta, M. Chem. Lett. 2002,

698.

[302] Yanagisawa, A.; Takahashi, H.; Arai, T. Chem. Commun. 2004, 580.

[303] Mukaiyama, T. Chem. Lett. 1982, 241.

[304] Grimster, N. P.; Wilton, D. A. A.; Chana, L. K. M.; Godfreyb, C. R. A.; Green, C.;

Owen, D. R.; Gaunt, M. J. Tetrahedron 2010, 66, 6429.

[305] (a) Hoffmann-Röder, A.; Krause, N. Org. Biomol. Chem. 2005, 3, 387. (b) Zhang, L.;

Sun, J.; Kozmin, A. S. Adv. Synth. Catal. 2006, 348, 2271. (c) Hashmi, A. S. K.;

Hutchings, G. J. Angew. Chem. Int. Ed. 2006, 45, 7896. (d) Fürstner, A.; Davies, P.

W. Angew. Chem. Int. Ed. 2007, 46, 3410. (e) Jimnez-Nez, E.; Echavarren, A. M.

Chem. Commun. 2007, 333. (f) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395. (g)

Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180. (h) Skouta, R.; Li, C.-J. Tetrahedron

2008, 64, 4917. (i) Shen, H. C. Tetrahedron 2008, 64, 3885. (j) Shen, H. C.

Tetrahedron 2008, 64, 7847. (k) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108,

3239. (l) Hashimi, A. S. K. Angew. Chem. Int. Ed. 2010, 49, 5232.

[306] Hintermann, L.; Labonne, A. Synthesis 2007, 1121.

[307] Acetylene Chemistry: Chemistry, Biology, and Material Science. Diederich, F.; Stang,

P. J.; Tykwinski, R. R., Ed.; Wiley-VCH, Weinheim, 2005.

References

192

[308] (a) Lauterbach, T.; Livendahl, M.; Roselln, A.; Espinet, P.; Echavarren, A. M. Org.

Lett. 2010, 12, 3006; and references therein. (b) Duschek, A.; Kirsch, S. F. Angew.

Chem. Int. Ed. 2008, 47, 5703.

[309] (a) Shi, Y.; Peterson, S. M; Haberacker, W. W.; Blum, S. A. J. Am. Chem. Soc. 2008,

130, 2168. (b) Shi, Y.; Roth, K. E.; Ramgren, S. D.; Blum, S. A. J. Am. Chem. Soc.

2009, 131, 18022.

[310] Körner, C.; Sheppard, T. D. Unpublished observations.

[311] Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467.

[312] Chinchilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874.

[313] Marchal, E.; Uriac, P.; Legouin, B.; Toupet, L.; van de Weghe, P. Tetrahedron 2007,

63, 9979.

[314] (a) For DFT calculations on Pd-catalysed cyclisation of ortho-alkynylnitrobenzenes,

see: Ramana, C. V.; Patel, P.; Vanka, K.; Miao, B.; Degterev, A. Eur. J. Org. Chem.

2010, 31, 5955. (b) Hashmi, A. S. K.; Ramamurthi, T. D.; Rominger, F. Adv. Synth.

Catal. 2010, 352, 971. (c) Jadhav, A. M.; Bhunia, S.; Liao, H.-Y.; Liu, E.-S. J. Am.

Chem. Soc. 2011, 133, DOI:/10.1021/ja110514s.

[315] Zhou, Q. J.; Worm, K.; Dolle, R. E. J. Org. Chem. 2004, 69, 5147.

[316] (a) Greig, L. M.; Kariuki, B. M.; Habershon, S.; Spencer, N.; Johnston, R. L.; Harris,

K. D. M.; Philp, D. New J. Chem. 2002, 26, 701. (b) Arcus, V. L.; Main, L.;

Nicholson, B. K. J. Organomet. Chem. 1993, 460, 139. (c) Letsinger, R. L.; Nazy, J.

R. J. Am. Chem. Soc. 1959, 81, 3013. (d) Chen, J.; Bajko, Z.; Kampf, J. W.; Ashe, A.

J., III. Organometallics 2007, 26, 1563. (e) Carnevale, D.; del Amo, V.; Philp, D.;

Ashbrook, S. E. Tetrahedron 2010, 66, 6238. (f) Minyaev, R. M.; Minkin, V. I.;

Gribanova, T. N.; Starikov, A. G. Mendeleev Commun. 2001, 2, 43. (g) Köster, R.;

Pourzal, A. A. Synthesis 1973, 674.

[317] Krygowski, T. M.; Cyranski, M. K.; Czarnocki, Z.; Hafelinger, G.; Katritzky, A. R.

Tetrahedron, 2000, 56, 1783.

[318] Bosdet, M. J. D.; Piers, W. Can. J. Chem. 2009, 87, 8; and references therein.

[319] Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503.

[320] Kuivila, H. G.; Reuwer, J. F.; Mangravite, J. A. J. Am. Chem. Soc. 1964, 86, 2666.

[321] (a) Higgins, J. Ind. Eng. Chem. 1967, 59, 18. (b) Erdi, P.; Toth, J. Mathematical

models of chemical reactions: Theory and applications of deterministic and

stoichastic models. Manchester University Press: Manchester, 1989.

[322] (a) Avitabile, B.; Smith, C. A.; Judd, D. B. Org. Lett. 2005, 7, 843. (b) Wright S.

W.; Hageman D. L.; McClure L. D. J. Org. Chem. 1994, 59, 6095.

References

193

[323] For recent catalytic reactions of acetaldehyde, see: (a) Hayashi, Y.; Itoh, T.; Ohkubo,

M.; Ishikawa, H. Angew. Chem. Int. Ed. 2008, 47, 4722. (b) Yang, J. W.; Chandler,

C.; Stadler, M.; Kampen, D.; List, B. Nature 2008, 452, 453.

[324] (a) For recent synthesis and platelet activating factor antagonist activity, see: (a) Coy,

E. D.; Cuca, L. E.; Sefkow, M. Org. Biomol. Chem. 2010, 8, 2003. (b) Coy, E. D.;

Cuca, L. E.; Sefkow, M. J. Nat. Prod. 2009, 72, 1245. (c) Coy, E. D.; Cuca, L. E.;

Sefkow, M. Bioorg. Med. Chem. Lett. 2009, 19, 6922.

[325] Jang, J.-H.; Kanoh, K.; Adachi, K.; Shizuri, Y. J. Antibiot. 2006, 59, 428.

[326] O'Malley, S. J.; Tan, K. L.; Watzke, A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.

Soc. 2005, 127, 13496.

[327] (a) Snider, B. B.; Han, L.; Xie, C. J. Org. Chem. 1997, 62, 6978; and references

therein. (b) Sawasdee, K.; Chaowasku, T.; Likhitwitayawuid, K. Molecules 2010, 15,

639.

[328] Pongcharoen, W.; Rukachaisirikul, V.; Phongpaichit, S.; Sakayaroj, J. Chem. Pharm.

Bull. 2007, 55, 1404.

[329] (a) Kobayashi, S. In Lanthanides: Chemistry and use in organic synthesis,

Kobayashi, S.; Ed. Springer-Verlag, Heidelberg, 1999, pp 63–118. (b) Molander, G.

A. Chem. Rev. 1992, 92. 29.

[330] Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187.

[331] Acid Catalysis in Modern Organic Synthesis Vol 1-2. Yamamoto, H.; Ishihara, K.

Wiley-VCH, Weinheim, 2008.

[332] Terada, M. Synthesis 2010, 1929.

[333] Wuts, G. M.; Greene, T. W. Greene's Protective Groups in Organic Synthesis.

Wiley–Interscience: Weinheim, 2006.

[334] Myers, A. G.; Liang, J.; Hammond, M.; Harrington, P. M.; Wu, Y.; Ku, E. Y. J. Am.

Chem. Soc. 1998, 120, 5319.

[335] For similar observation of cationic gold-catalysed protodesilylation example in the

presence of water, see: Leyva, A.; Corma, A. J. Org. Chem. 2009, 74, 2067.

[336] Chipanina, N. N.; Sterkhova, I. V.; Aksamentova, T. N.; Sherstyannikova, L. V.;

Kukhareva, V. A.; Shainyan, B. A. Russ. J. Gen. Chem. 2008, 78, 2363.

[337] (a) Taylor, J. G.; Adrio, L. A.; Hii, K. K. Dalton Trans. 2010, 39, 1171. (b) Krische,

M. J.; Rhee, J. U. Org. Lett. 2005, 7, 2493.

[338] Schneider, D.; Schier, A.; Schmidbaur, H. Dalton Trans. 2004, 1995.

[339] Espinet, P.; Martin-Barrois, S.; Villafane, F. Organometallics 2000, 19, 290.

[340] Scott, V. J.; Labinger, J. A.; Bercaw, J. E. Organometallics 2010, 29, 4090.

[341] For reviews of the chemistry of haloacetylenes, see: (a) Hopf, H.; Witulski, B. In

Modern Acetylene Chemistry; Stang, P. J.; Diederich, F., Eds.; VCH: Weinheim,

References

194

1995; pp 33-66. (b) Brandsma, L. Preparative Acetylenic Chemistry; Elsevier: New

York, 1988.

[342] Augé, J.; Lubin-Germaina, N.; Seghrouchnia, L. Tetrahedron Lett. 2002, 43, 5255.

[343] Hein, J. E.; Tripp, J.; Krasnova, L.; Sharpless, K. B.; Fokin, V. V. Angew. Chem. Int.

Ed. 2009, 48, 8018.

[344] Kasai, K.; Liu, Y.; Harab, R.; Takahashi, T. Chem. Commun. 1998, 1989.

[345] Trofimov, A.; Chernyak, N.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 13538.

[346] Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5, 4011.

[347] (a) Hirano, S.; Tanaka, R.; Urabe, H.; Sato, F. Org. Lett. 2004, 6, 727. (b) Zhang, Y.;

Hsung, R. P.; Tracey, M. R.; Kurtz, K. M. C.; Vera, E. L. Org. Lett. 2004, 6, 1151.

[348] (a) Cahier, G.; Gager, O.; Buendia, J. Angew. Chem. Int. Ed. 2010, 49, 1278. (b)

Ishihara, T.; Yamamoto, A.; Taguchi, K. US Patent 4,391,984, 1983.

[349] Yoo, W.-J.; Allen, A.; Villeneuve, K.; Tam, W. Org. Lett. 2005, 7, 5853.

[350] (a) Dudnik, A. S.; Gevorgyan, V. Angew. Chem. Int. Ed. 2010, 49, 2096. (b) Garcia,

P.; Malacria, M.; Aubert, C.; Gandon, V.; Fensterbank, L. ChemCatChem 2010, 2,

493.

[351] (a) Brand, J. P.; Charpentier, J.; Waser, J. Angew. Chem. Int. Ed. 2009, 48, 9346. (b)

Brand, J. P.; Waser, J. Angew. Chem. Int. Ed. 2010, 49, 7304.

[352] de Haro, T.; Nevado, C. J. Am. Chem. Soc. 2010, 132, 1512.

[353] Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, 7512.

[354] Suzuki, H.; Mori, T.; Maeda, K. Synthesis 1994, 841.

[355] Parham, W. E.; Egberg, D. C.; Sayed,Y. A.; Thraikill, R. W.; Keyser, G. E.; Neu, M.;

Montgomery, W. C.; Jones, L. D. J. Org. Chem. 1976, 41, 2628.

[356] Faraoni, M. B.; Koll, L. C.; Mandolesi, S. D.; Zuniga, A. E.; Podesta, J. C. J.

Organomet. Chem. 2000, 613, 236.

[357] Korkin, S. D.; Buzin, M. I.; Matukhina, E. V.; Zherlitsyna, L. N.; Auner, N.;

Shchegolikhina, O. I. J. Organomet. Chem. 2003, 686, 313.

[358] Takiguchi, T. J. Am. Chem. Soc. 1959, 81, 2359.

[359] Cella, J. A.; Carpenter, J. C. J. Organomet. Chem. 1994, 480, 23.

[360] Steward, O. W.; Williams, J. L. J. Organomet. Chem. 1988, 341, 199.

[361] Schroeder, H. J. Org. Chem. 1960, 25, 1682.

[362] Abel, E. W.; Gerrard, W.; Lappert, M. F.; Shafferman, R. J. Chem. Soc. 1958,

2895.

[363] Hassen, Z.; Akacha, A. B.; Zantour, H. Phosphorus, Sulfur Silicon Relat. Elem. 2003,

178, 2241.

[364] Mahajan, R. K.; Gupta, N; Uppal, S. K. Coll. Czech. Chem. Commun. 1985, 50, 690.

References

195

[365] Gu, L.; Wang, B.; Kulkarni, A.; Geders, T. W.; Grindberg, R. V.; Gerwick, L.;

Hkansson, K.; Wipf, P.; Smith, J. L.; Gerwick, W. H.; Sherman, D. H. Nature 2009,

459, 731.

[366] Martínez, R.; Ramón, D. J.; Yus, M. Adv. Synth. Catal. 2008, 350, 1235.

[367] Protiva, M; Jilek, J. O.; Hachova, E.; Adlerova, E.; Vejdelek, Z. J. Czechoslovak

Patent, CS86787, 1960.

[368] Chen, C.-C.; Ho, J.-H.; Chang, N.-C. Tetrahedron 2008, 64, 10350.

[369] Thalhammer, A.; Mecinović, J.; Schofield, C. J. Tetrahedron Lett. 2009, 50, 1045.

[370] Saito, Y.; Ouchi, H.; Takahata, H. Tetrahedron 2008, 64, 11129.

[371] Lee, S. Y.; Lee, C.-W.; Oh, D. Y. J. Org. Chem. 1999, 64, 7017.

[372] Steffel, L. R.; Cashman, T. J.; Reutershan, M. H.; Linton, B. R. J. Am. Chem. Soc.

2007, 129, 12956.

[373] Zamudio Rivera, L. S.; Carrillo, L.; Mancilla, T. Org. Prep. Proc. Int. 2000, 32, 84.

[374] Sashida, H.; Sadamori, K.; Tsuchiya, T. Synth. Commun. 1998, 28, 713.

[375] Verma, A. K.; Kesharwani, T.; Singh, J.; Tandon, V.; Larock, R. C. Angew. Chem.

Int. Ed. 2009, 48, 1138.

[376] Huynh, C.; Linstrumelle, G. Tetrahedron 1988, 44, 6337.

[377] Laus, G.; Müller, A. G.; Schottenberger, H.; Wurst, K.; Buchmeiser, M. R.; Ongania,

K.-H. Monatsh. Chem. 2006, 137, 69.

[378] Letsinger, R. L.; Feare, T. E.; Savereide, T. J.; Nazy, J. R. J. Org. Chem. 1961, 26,

1271.

[379] van Meurs, P. J.; Janssen, R. A. J. J. Org. Chem. 2000, 65, 5712.

[380] Brathe, A.; Gundersen, L.-L.; Rise. F.; Eriksen, A. B.; Vollsnes, A. V.; Wang, L.

Tetrahedron 1999, 55, 211.

[381] Meng, L.-G.; Cai, P.-J.; Guo, Q.-X.; Xue, S. Synth. Commun. 2008, 38, 225.

[382] Shastin, A. V.; Korotchenko, V. N.; Nenajdenko, V. G.; Balenkova, E. S. Synthesis

2001, 2081.

[383] Abe, H.; Suzuki, H. Bull. Chem. Soc. Jpn. 1999, 72, 787.

Appendix

Appendix

197

B(OCH2CF3)3

Racemate Spiking experiment

Appendix

198

B(OMe)3

Racemate Spiking experiment

Appendix

199

time, h 180 174a 180a+180b trans cis

1 2 19 78 62 38

3 0 77 23 67 33

3 0 76 24 68 32

5 0 42 58 56 44

23 0 30 70 70 30

Reaction conditions: boronic acid (1 equiv), aldehyde (1.2 equiv), Ph3PAuCl (2 mol%), AgOTf (2 mol%),

1 M DCM, RT.

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25

time, h

aldol

enolate

pba

Appendix

200

time, h 180 174a 180a+180b trans cis

1 0 34 66 71 29

3 0 14 86 75 25

4 0 13 87 74 26

7 0 50 50 56 44

22 0 48 52 55 45

Reaction conditions: boronic acid (1 equiv), aldehyde (2 equiv), Ph3PAuCl (2 mol%), AgOTf (2 mol%), 1

M DCM, RT.

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25

time, h

aldol

enolate

pba

Appendix

201

time, h 180 174a 180a+180b trans cis

1 0 28 72 74 26

3 0 15 85 75 25

4 0 19 81 73 27

7 0 50 50 62 38

24 0 30 70 67 33

Reaction conditions: boronic acid (1 equiv), aldehyde (2 equiv), Ph3PAuNTf2 (2 mol%), 1 M DCM, RT.

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25

time, h

aldol

enolate

pba

Appendix

202

time, h 180 174a 180a+180b trans cis

1 77 0 23 79 21

2 73 1 26 78 22

3 70 2 28 78 22

4 69 2 30 77 23

7 69 2 29 75 25

20.5 44 7 49 61 39

Reaction conditions: boronic acid (1 equiv), aldehyde (2 equiv), AuCl (2 mol%), 1 M DCM, RT.

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25

time, h

aldol

enolate

pba

Appendix

203

time, h 180 174a 180a+180b trans cis

1 84 0 16 62 38

2 42 36 22 47 53

3 36 36 28 36 64

4 36 36 29 36 64

7 36 28 36 31 69

20.5 36 20 44 30 70

Reaction conditions: boronic acid (1 equiv), aldehyde (2 equiv), AuCl (2 mol%), H2O (5 equiv), 1 M DCM,

RT.

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25

time, h

aldol

enolate

pba

Appendix

204

time, min 180 174a 180a+180b trans cis

10 28 46 26 83 17

20 3 57 40 82 18

30 0 55 45 82 18

40 0 53 47 81 19

50 0 53 47 81 19

60 0 53 47 81 19

70 0 52 48 81 19

80 0 53 47 81 19

90 0 52 48 80 20

100 0 52 48 80 20

210 0 50 50 78 22

Reaction conditions: boronic acid (1 equiv), aldehyde (1 equiv), Ph3PAuNTf2 (1 mol%), 0.5 M, CD2Cl2,

RT.

0

10

20

30

40

50

60

0 50 100 150 200 250

time, min

aldol

enolate

pba

Appendix

205

time, min 180 174a 180a+180b trans cis

15 46 38 16 81 19

25 23 48 29 80 20

35 11 50 39 81 19

45 4 47 48 81 19

55 0 45 55 80 20

65 0 43 57 80 20

75 0 42 58 79 21

85 0 42 58 79 21

95 0 41 59 79 21

105 0 41 59 79 21

115 0 41 59 78 22

215 0 37 63 76 24

Reaction conditions: boronic acid (1 equiv), aldehyde (2 equiv), Ph3PAuNTf2 (1 mol%), 0.5 M, CD2Cl2,

RT.

0

10

20

30

40

50

60

70

0 50 100 150 200 250

time, min

aldol

enolate

pba