Palladium-catalysed α-arylation of esters and amides under microwave conditions

Article abstract of DOI:10.1016/j.tetlet.2004.08.074

A rapid and convenient approach for the α-arylation of esters and amides using Reformatsky reagents under a microwave accelerated reaction protocol has been established.

Full text of DOI:10.1016/j.tetlet.2004.08.074

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7395–7397
Palladium-catalysed a-arylation of esters and amides
under microwave conditions
Emilie Bentz, Mark G. Moloney* and Susan M. Westaway
The Department of Chemistry, Central Research Laboratory, The University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
Department of Medicinal Chemistry, Neurology and GI CEDD, GlaxoSmithKline Research Ltd, New Frontiers
Science Park, Third Ave, Harlow, Essex, CM19 5AW, UK
Received 29 June 2004; revised 3 August 2004; accepted 16 August 2004
Abstract—A rapid and convenient approach for the a-arylation of esters and amides using Reformatsky reagents under a microwave
accelerated reaction protocol has been established.
Ó 2004 Elsevier Ltd. All rights reserved.
The nucleophilic character coupled with low basicity
and ease of preparation of Reformatsky reagents has
resulted in their renewed interest as enolate sources. For
example, they have been found to be effective in conju-
gate addition reactions with reactive enones, and more
recently as nucleophilic partners in ligand coupling reac-
tions with aryl halides mediated by palladium, chemistry
extensively developed by Hartwig,1–4 Buchwald5–11 and
others.12,13 This latter reaction affords a-arylated esters
and amides, a structural type which has hitherto been
directly accessed by ligand coupling reactions making
use of aryllead(IV) intermediates.14 In view of the
importance of this recently established Pd-mediated
approach, it was of interest to us to examine the appli-
cation of well-precedented microwave technology in
combination with readily accessible Pd(0) catalysts to
this reaction;15,16 success would significantly simplify
the existing protocol. The application of microwave
acceleration to a variety of palladium-catalysed proc-
esses was demonstrated some time ago17–20 and has been
recently extended.21–23 We report here the results of this
investigation, detailing the efficiency and scope of a sim-
ple alternative procedure.
at 100°C; addition of this Reformatsky reagent to the
coupling partner, an aryl bromide and the relevant cata-
lyst/ligand in THF was followed by further irradiation
for 5–10min at 120°C, and the reaction worked-up and
the product obtained by chromatography25 (Scheme 1).
In this way, a number of substituted aryl bromides were
converted to the corresponding arylacetic esters or
amides (Table 1), generally in good yield and with short
reaction times. However, some substrates with active
hydrogens or reactive functions, such as ketones, alcoh-
ols and amines, were unsuitable, returning starting
material or by-products, and in some cases isolation of
the product was problematic due to difficulties removing
phosphine residues. The requirement for microwave
irradiation in these reactions was indicated by a control
experiment (ethyl p-bromobenzoate, tert-butyl bromo-
acetate, Pd(0)(PPh3)4, THF, 70°C, 18h) but with no
irradiation, which gave a mixture consisting mostly of
unreacted starting material (58%) with only a small
amount of the desired product (6%). Anhydrous THF
proved to be the most effective solvent for the reaction,
and DMF, DME, and CH3CN all returned unreacted
starting ethyl p-bromobenzoate.
The required Reformatsky reagent was readily prepared
by microwave irradiation of tert-butyl bromoacetate or
dibenzyl bromoacetamide24 with zinc in THF for 5min
The generality of this procedure was then examined;
interestingly we found that the Reformatsky reagent
derived from tert-butyl bromopropionate was unreactive
with ethyl p-bromobenzoate under the microwave con-
ditions, and dibenzyl bromopropionamide gave only a
5% yield of the expected product; thus, substitution at
the a-position on the Reformatsky reagent was tolerated
poorly. Noteworthy also is that the reaction proceeds
Keywords: Arylation; Reformatsky; Catalysis; Microwave.
*
Corresponding author. Tel.: +44 01865 275656; fax: +44 0186
5275674; e-mail: mark.moloney@chem.ox.ac.uk
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.074

7396
E. Bentz et al. / Tetrahedron Letters 45 (2004) 7395–7397
Scheme 1.
Table 1. Yields for coupling of Reformatsky reagents and aryl
bromides according to Scheme 1
References and notes
R1
Y
Z
XR2
Yielda (%)
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We have shown that microwave accelerated reactions
leading to a-arylation of ester and amide enolates using
readily available Pd(0)(PPh3)4 catalyst is possible, and
although the scope of these reactions is currently limi-
ted, microwave acceleration is likely to permit further
enhancements of these useful coupling reactions.
25. Typical procedure: Step 1. Preparation of the Reformat-
sky reagent: To a suspension of zinc (50mg, 0.8mmol) in
THF (0.7mL) was added a few crystals of iodine, followed
by tert-butyl bromoacetate (59lL, 0.4mmol). The mixture
was placed in a Personal Chemistry EmrysTM Optimizer
EXP microwave reactor and irradiated for 5min to
achieve a temperature of 100°C. Step 2. Conjugate
Acknowledgements
We gratefully acknowledge EPSRC and GSK for a
DTA/CASE award to E.B., and the EPSRC Chemical
Database Service at Daresbury.28

E. Bentz et al. / Tetrahedron Letters 45 (2004) 7395–7397
7397
addition reaction: To a solution of ethyl bromobenzoate
(33lL, 0.2mmol) in THF (0.8mL) was added a solution of
the Reformatsky reagent in THF previously prepared (it is
important not to add excess zinc reagent), followed by
Pd(PPh3)4 (24mg, 0.2mmol). The mixture was replaced
into the microwave reactor for 5min to achieve a
temperature of 120°C. The reaction mixture was quenched
with a saturated solution of ammonium chloride (3mL)
and extracted with EtOAc (4mL). The organic layer was
dried over MgSO4, filtered and concentrated. The residue
was purified by flash column chromatography to afford
the desired product.
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