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:!