Page 1 - From -Arylation of Olefins to Acylation with Aldehydes: A Journey in Regiocontrol of the Heck Reaction

From r-Arylation of Olefins to Acylation with
Aldehydes: A Journey in Regiocontrol of the

Heck Reaction

JIWU RUAN AND JIANLIANG XIAO*
Department of Chemistry, University of Liverpool, Liverpool L69 7ZD,
United Kingdom
RECEIVED ON MARCH 1, 2011

CONSPECTUS

he Pd-catalyzed MizorokiHeck reaction of olefins with aryl
T halides, more often simply called the Heck reaction, was
recently recognized with the 2010 Nobel Prize in chemistry.
Although highly selective with electron-deficient olefins, which
generally yield the linear β-arylated product exclusively, the
Heck reaction is less satisfactory with electron-rich olefins. This
substrate typically generates a mixture of both r- and β-arylated
regioisomeric products, hampering wider application of the reaction in chemical synthesis.
Pioneering studies by a number of researchers revealed that high r-regioselectivity could be obtained under Pddiphosphine
catalysis either through (i) the substitution of aryl triflates for halides or (ii) the addition of stoichiometric silver or thallium salts
when aryl halides are used. Under these conditions, the arylation is believed to proceed via an ionic pathway. However,
silver introduces added cost, thallium salts are toxic, and triflates are generally commercially unavailable, base sensitive, and
thermally labile.
Believing that the ionic pathway would be promoted in an ionic medium, in the early 2000s, we attempted the Pd-catalyzed
arylation of the benchmark electron-rich olefin butyl vinyl ether with aryl bromides in an imidazolium ionic liquid. We were delighted
to observe thathighly regioselective r-arylation couldreadily be accomplished, with no need for silver additives, thallium additives,or
aryl triflates. A range of other electron-rich olefins has since been shown to be viable as well. The high r-selectivity probably results
from the high ionic strength of the medium, which facilitates the dissociation of halide anions from the [L 2 Pd(Ar)X] intermediate,
channeling the arylation into the ionic pathway. Hydrogen bonding interactions may also play a role, however.
We subsequently discovered that the r-arylation can indeed be significantly accelerated by a hydrogen bond donor salt, in both
ionic liquids and common solvents. Evidence shows that the concentration of the cationic Pd(II)olefin species along the ionic
pathway is increased as a result of hydrogen bonding between the hydrogen bond donor and the halide anion.
More recently, we reported that cheaper and greener alcohols allow the Heck arylation of electron-rich olefins to proceed in a
much faster, productive, and totally r-regioselective manner, circumventing the need for an ionic medium or hydrogen bond donor
salt. In particular, aryl chlorides with diverse properties have been demonstrated to be viable substrates for the first time.
Significantly, it appears that ethylene glycol facilitates both the oxidative addition of ArCl to Pd(0) and the subsequent dissociation
of chloride from Pd(II).
A closely related reaction, acylation of aryl halides with aldehydes, was also developed. Proceeding via the intermediacy of an
electron-rich enamine, this Pdpyrrolidine cooperative catalysis affords alkyl aryl ketones in a straightforward manner, extending
the Heck reaction from olefins to aldehydes.

Introduction Its significance has been highlighted by the 2010 Nobel Prize

The palladium-catalyzed MizorokiHeck, or more often in chemistry to Professor Richard Heck alongside Professors
the Heck, arylation of olefins with aryl halides was in- Ei-ichi Negishi and Akira Suzuki.
2
1
dependently discovered by Heck and Mizoroki ca. 40 years
ago (eq 1). It has since become one of the most celebrated
2
tools for constructing sp CC bonds in synthetic chemistry. 3
614 ’ ACCOUNTS OF CHEMICAL RESEARCH ’ 614–626 ’ 2011 ’ Vol. 44, No. 8 Published on the Web 05/25/2011 www.pubs.acs.org/accounts
10.1021/ar200053d & 2011 American Chemical Society