aryne insertions into σ-bondsdonohoe.chem.ox.ac.uk/resources/270312chris.pdf · examples of the...
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Aryne Insertions into σ-Bonds!
Chris R Jones!TJD group!
!March 27th 2012!
XY
X
Y
Insertion+
§ Formal triple bond of aryne is highly strained - powerful electrophile!
§ Nucleophilic addition to aryne generates carbanion that can be trapped by an electrophile!
For useful reviews on insertion reactions see: !Peña & Guitián, ACIE, 2006, 45, 3579!Yoshida & Kunai, Bull. Chem. Soc. Jpn. 2010, 83, 199!!For an exhaustive review on aryne chemistry see:!Sanz, Org. Prep & Proc. Int. 2008, 40, 215!!!
Background!
NuE
Nu
E
Insertion+
NuE
ENu
§ Insertions reactions were not that well exploited until a mild method to generate benzyne was reported by Kobayashi!
Background!
Kobayashi, Chem Lett. 1983, 1211!!!
OTf
SiMe3
F-?
Many examples!
§ Examples of the insertion of benzyne into σ-bonds (Nu = heteroatom)!
σ-Bond Insertions!
Peña & Guitián, ACIE, 2006, 45, 3579!
OTf
SiMe3
F-
§ Examples of the insertion of benzyne into σ-bonds (Nu = carbon)!
σ-Bond Insertions!
Peña & Guitián, ACIE, 2006, 45, 3579!
OTf
SiMe3
F-
§ Examples of the insertion of benzyne into σ-bonds (catalytic palladium)!
σ-Bond Insertions!
Peña & Guitián, ACIE, 2006, 45, 3579!
OTf
SiMe3
F-
§ Plausible mechanistic cycles for Pd-catalysed insertion reactions - both cycles have been invoked!
Mechanism!
Yoshida & Kunai, Bull. Chem. Soc. Jpn. 2010, 83, 199!
§ Is it possible to insert directly into the C-H σ-bond?!
Proposal!
OTf
SiMe3
F- HC
H
C
Insertion+
§ Is it possible to insert directly into the C-H σ-bond?!
Proposal!
OTf
SiMe3
F- HC
H
C
Insertion+
§ If metal free then essentially “C(δ+)” and “H(δ -)” (i.e. an intermolecular hydride transfer)!
H R'
R''
RH
R'
R''
RH
R
R''R'
Ph
OMe
Ph HPh
Ph
Ph H PhPh H
R3Si
Suitable cation stabilising groups?!
§ Examples of good hydride transfer compounds!
Proposal!
Hantzsch ester! 10-Methylacridin!Nicotinamide! Benzothiazoline!
NH
Me Me
CO2EtEtO2CH H
S
HN
Ph
H
NH
CONH2H H
NMe
H H
§ Examples of good hydride transfer compounds!
Proposal!
§ e.g. Possible target: Nifedipine (treats hypertension) - $1 billion drug in 1999!
Hantzsch ester! 10-Methylacridin!Nicotinamide! Benzothiazoline!
NH
Me Me
CO2EtEtO2CH H
S
HN
Ph
H
NH
CONH2H H
NMe
H H
NH
MeO2C
Me
CO2Me
Me
O2N H
NH
MeO2C
Me
CO2Me
Me
O2N
sterically & electronically favoured
NO2
NH
Me Me
CO2MeMeO2CH H
§ Will any heteroatom be tolerated in substrate - competing nucleophile?!
§ How feasible is an intermolecular hydride shift? No examples onto arynes. !
Proposal!
§ Two reports of intramolecular hydride transfer involving benzyne - but only as side reactions.!
Proposal!
e.g. 1: Tetrahedron, 1977, 581!
NEtCl
CN
HH
NEt
CN
HH
NEt
CN
HH
NHEt
H
11 % 60 % ~1 %
NaNH2 + +
NH2
e.g. 2: Tetrahedron, 1968, 6223!
N
OBr
HH N
OH
N
OH
KNH2
38 %
Oxidation of indoline!
§ Intramolecular hydride transfer to benzyne - potential dual role:!- alcohol oxidation (also indoline, amines etc.)!- protecting group (can be used for regio- and chemoselective oxidation)!
Proposal - Self-Oxidising Protecting Groups!
Oxidation of alcohol!
TMS
TfO
OR OR
H
OR
R R'
OHOR' R'
+HF-
R R'
OHR'
Protected alcohol!
§ c.f. 1,5-Hydrogen atom transfer: Curran, Synthesis, 1992, 123!
Oxidation of alcohol!
Ph OH
Ph O Ph O
BrH H H Ph O
AIBN, Bu3SnHBenzene, ∆
[c = 0.001M]50-70 %
few examples
- employed in Nicoloau and Baran’s synthesis of the CP-Molecules, JACS, 2002, 124, 2190!
§ Intramolecular hydride transfer to benzyne - potential dual role:!- alcohol oxidation (also indoline, amines etc.)!- protecting group (can be used for regio- and chemoselective oxidation)!
Proposal - Self-Oxidising Protecting Groups!
TMS
TfO
OR OR
H
OR
R R'
OHOR' R'
+HF-
R R'
OHR'
Protected alcohol!
X
Y
Z
X = leaving groupY = TMS & Z = OTfor Y = OTf & Z = TMS
§ Require benzylic electrophile of the general structure:!
Proposal - Self-Oxidising Protecting Groups!
§ Synthesis?!
OH
Br
OH
Br
HO
OH
TMS
HO
OTf
TMS
TfO1. PhB(OH)2(CHO)n
2. H2O2
1. BuLi, TMS
2. TBAF
Tf2O
Eur. J. Org. Chem. 2006, 197
OH
CO2RO
CO2R
O NEt2
OHTES
OH
OTfTES
OTf
Et2NCOCl1. BuLi thenTESCl
2. LiAlH4
Tf2O
or!
Any suggestions, observations, criticisms etc.?!
Proposal - Self-Oxidising Protecting Groups!
Oxidation of alcohol!
TMS
TfO
OR OR
H
OR
R R'
OHOR' R'
+HF-
R R'
OHR'
Protected alcohol!
Further ideas for aryne insertions (C-H or otherwise)?!Different coupling partners for arynes?!
Tandem processes - what concurrent reactions could F- be used for?!
§ This project:!
§ In general:!