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Redox Relay Heck Reaction

Margaret HiltonSigman LabUniversity of Utah

ROH

n

RO

n

R'

[Pd]

ArX

Heck Reaction

Review: Chem. Rev. 2000, 100, 3009.Other Examples and Applications: Overman JACS 1993, 115, 11028 , Sarpong JACS 2008, 130, 7222, Shibasaki JOC 1996, 61, 4876, Sigman JACS 2010, 132, 13981, Sigman JACS 2011, 133, 9692. 2010 Nobel Prize

Since Heck’s seminal publication in 1968, the Heck reaction has been a powerful synthetic tool for the functionalization of olefins with aryl groups.

Heck’s Conditions:

HgCl

Li2PdCl4+MeOH, CuCl2

2 h, rt

O

O O

O57% yield

Heck, along with Negishi and Suzuki, won the Chemistry Nobel Prize in 2010 for their work in cross coupling.

LnPd0

LnPdII X

LnPdIIR

LnPdIIR

LnPdII H

MigratoryInsertion

-HydrideElimination

OxidativeAddition

R

Ar

R

R'

R'

R'

R'

R

ArX

General Mechanism*

*Note: this reaction may also proceed through an oxidative mechanism, where a Pd II

precatalyst , a transmetallating aryl reagent, and a terminal oxidant are used, such as with Heck’s conditions shown.

Chain-Walking

Hayashi JACS 1991, 113, 1417Curran, JACS 2007, 129, 494

MigratoryInsertion

LnPdII-Hydride

Elimination

R'

LnPdII

R

R'

H

R

LnPdII

R'

R

H LnPdII

R'

RHMigratory

Insertion

After the initial migratory insertion, which forms a C-C bond, a β-hydride elimination will occur, producing a Pd-H intermediate. If the alkene remains coordinated to palladium and the hydride reinserts at the opposite carbon, the palladium catalyst is now positioned one more carbon down the alkyl chain. This is called a “relay” or “chain walking” and produces alkene isomers.

Examples of Relay via Palladium Catalysis

O

ArOTf

Pd(OAc)2(R)-BINAP

i-Pr2NEtbenzene

+O Ar O Ar

+

Can chain-walking be controlled?

NMe

O

I Me Me

NMe

OPd2dba3•CHCl3(R)-BINAP

piperidineDMA, 100 °C

Redox-Relay Heck Reaction

B(OH)2

ROH

n

RO

n

R'N N

O

t-BuF3C

Pd(CH3CN)2(OTs)2, DMFCu(OTf)2, O2, 3 Å MS

+

R'n = 0-5up to 99:1 er

Sigman Science 2012, 338, 1455Sigman JACS, 2013, 135, 6830

N2PF6

ROH

n

RO

n

R'N N

O

t-BuF3C

Pd2dba3, DMF+

R'n = 0-2up to 99:1 er

Classical Variant

Oxidative Variant

Sigman and coworkers have developed a redox-relay Heck reaction, where the relay by palladium is controlled by a thermodynamic sink (an alcohol) on the substrate. The unsaturation of the alkene is transferred to the alcohol to form aldehydes or ketones.

Problems

1. Keay, JOC, 2007, 72, 7253

O D O

D

O

D D

ODD

2. The four deuterium-labelled substrates A-D were used to determine theextent of chain-walking under palladium catalysis. Show all the possible productsthat could result from A-D after the initial migratory insertion of an aryl group.

A B C D

OPhOTf +

[Pd]

O Ph O Ph+

1. Draw a general catalytic cycle for the Heck reaction.