Organic Process Research & Development 2005, 9, 694−696
Technical Notes
A Preparative Route to Methyl 3-(Heteroaryl)acrylates Using Heck Methodology
Thomas J. Kwok*,† and Joseph A. Virgilio*,‡
SynDesign, LLC, 11 Melanie Lane, Suite 23, East HanoVer, New Jersey 07936
Scheme 1
Abstract:
Methyl 3-(heteroaryl)acrylates were prepared using Heck
coupling of heteroarene halides with methyl acrylate mediated
by Pd(OAc)2/P(OCH3)3. Reactions were highly efficient (reaction
times between 60 and 120 min) and scalable to 100 g of
heteroarene halide. The isolated yields are from 76 to 99%.
Scheme 2
Palladium complexes have been extensively utilized in
organic synthesis for the generation of carbon-carbon
bonds.1 A commonly used procedure is the arylation of
alkenes using an “aryl palladium” reagent which can be
generated in situ by several methods.2 Regardless of the
method used, all of these reactions are known as Heck
reactions.3 The reaction is generally carried out by combining
an organic halide with a slight excess of the olefin, a slight
excess of an amine base, and 1 mol % of palladium acetate
and 2 mol % of a triarylphosphine (usually triphenyl- or tri-
o-tolylphosphine).
the heteroarene halides would make this route prohibitively
expensive.
We needed to prepare a number of methyl 3-(heteroaryl)-
acrylates for use as intermediates for the production of
pharmaceutical scaffolds. Surprisingly the reaction failed
when run under the standard Heck conditions.4 For example,
the reaction of 5-bromopyrimidine with methyl acrylate using
triphenylphosphine yielded none of the desired product.4e An
alternate approach using acrylic acid in the place of methyl
acrylate under standard Heck conditions at 160 °C followed
by esterification of the crude product with methanol/HCl
afforded the product in a disappointing 25% overall yield
(Scheme 1). On a large preparative scale the high cost of
Recent reports have indicated that bulky and electron-
rich phosphorus ligands produce highly active catalysts;
however, the examples described involved non-heteroarene
chlorides and bromides.5 Beller demonstrated that bulky
phosphite compounds were good ligands for Heck reactions
using chlorobenzene but did not study heteroarenes.6 Phos-
phites have also been reported to enhance the reactivity of a
variety of other processes mediated by transition metals.7
We screened a number of different phosphorus-based ligands
and found that trimethyl phosphite activated the palladium
acetate-catalyzed coupling to give the desired methyl 3-(het-
eroaryl)acrylates in good yield (Scheme 2 and Table 1).
The reactions were effected by heating a 3-fold excess
of methyl acrylate and the bromoheteroarene in DMF under
* To whom correspondence should be addressed.
† Current address for this author: Cornerstone Pharmaceuticals Inc., Synthetic
and Medicinal Chemistry Group, 25 E. Loop Rd., Stony Brook, NY 11790.
E-Mail: tom@cornerstonepharma.com.
‡ E-mail: syndesign@hotmail.com.
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Vol. 9, No. 5, 2005 / Organic Process Research & Development
10.1021/op050106k CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/24/2005