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Redox Relay Heck Reaction

Margaret HiltonSigman Lab

University of Utah2014

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

*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.

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.

General Mechanism*

Chain-Walking

Examples of Relay via Palladium Catalysis

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

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.

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

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

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

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.

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Contributed by: Margaret HiltonSigman LabUniversity of Utah2014