A preparative route to methyl 3-(heteroaryl)acrylates using Heck methodology

Article abstract of DOI:10.1021/op050106k

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%.

Full text of DOI:10.1021/op050106k

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.
(1) Tsuji, J. Palladium Reagents and Catalysts; Wiley: New York, 2004.
(2) March, J., Smith, M. B., Eds. March’s AdVanced Organic Chemistry, 5th
ed.; Wiley-Interscience: New York, 2001; p 930.
(5) (a) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989. (b)
Shaughnessy, K. H.; Kim, P.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121,
2123.
(3) (a) Gibson, S. E., Ed. Transition Metals in Organic Synthesis; Oxford
University Press: Oxford, New York, Tokyo, 1997; pp 35-42. (b) Hegedus,
L. S. Transition Metals in the Synthesis of Complex Organic Molecules;
University Science Books: Mill Valley, CA 1994; pp 103-115. (c)
Betletska, J. P.; Cheprakov, A. V. Chem. ReV. 2000, 3009.
(4) (a) Legros, J.-Y.; Primault, G.; Fiaud, J.-C. Tetrahedron 2001, 57, 2507.
(b) Karminski-Zamola, G.; Dogan, J.; Bajic, M. Heterocycles 1994, 38,
759. (c) Bovy, P. R.; Rico, J. G. Tetrahedron Lett. 1993, 34, 8015. (d)
Crisp, G. T.; O’ Donoghue, A. I. Synth. Commun. 1989, 19, 1745. (e)
Nishikawa, Y.; Shindo, T.; Ishii, K.; Kon, T.; Uno, H. Chem. Pharm. Bull.
1989, 37, 684. (f) Eustache, J.; Bernardon, J. M.; Shroot, B. Tetrahedron
Lett. 1988, 29, 4409.
(6) Beller, M.; Zapf, A. Synlett 1998, 792.
(7) (a) Evans, P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581. (b)
Evans, P. A.; Robinson, J. E. Org. Lett. 1999, 1, 1929. (c) Evans, P. A.;
Robinson, J. E.; Moffet, K. K. Org. Lett. 2001, 3, 3269. (d) Baker, M. J.;
Pringle, P. G. J. Chem. Soc., Chem. Commun. 1991, 1292. (e) Hutmacher,
K.; Krill, S. In Applied Homogeneous Catalysis with Organometallic
Compounds: A ComprehensiVe Handbook in Two Volumes; Cornils, B.,
Hermann, W. A., Eds.; VCH: Weinheim, New York, Basel, Cambridge,
UK, Tokyo, 1996; p 465. (f) Horiuchi, T.; Ohta, T.; Shirakawi, E.; Nozaki,
K.; Takaya, H. Tetrahedron 1998, 133, 7795. (g) Kwok, T. J.; Wink, D. J.
Organometallics 1993, 12, 1954.
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10.1021/op050106k CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/24/2005

Table 1. Heteroarene Halides and Heck Reaction Products
The use of DIPEA in place of TEA had no effect on the
other reactions. The N-H group of the pyrazoles (entries
2-4) was protected by an acetyl group to prevent undesired
coupling reactions. It was removed by hydrolysis with 2 M
methanolic potassium hydroxide in quantitative yield. All
1
products were characterized by mass spectrometry and H
NMR spectroscopy. The NMR spectra indicated the products
were the expected E-olefins.
There are some practical aspects for using trimethyl
phosphite as a ligand in the place of conventional phosphines.
The highly volatile phosphite is readily separated during the
removal of the DMF. Conventional triarylphosphines can
remain in trace amounts after isolation of the product, and
removal may require more rigorous and costly procedures
to meet product purity specifications. Phosphines can also
undergo oxidative cleavage forming undesirable cross-
coupling products that can lead to catalyst deactivation.8 No
side-reaction products associated with the decomposition of
trimethyl phosphite were detected in our reactions.
Experimental Section
General. The heteroarene halides were obtained from
Aldrich or Alfa-Aesar. Palladium acetate was obtained from
Strem Chemicals. Other reagents and anhydrous solvents
were from Aldrich and were used as received. TLC was
performed on Macherey-Nagel 40 mm × 80 mm silica gel
plates with UV indicator (254 nm) using ethyl acetate-
a The yields are based on isolated product after recrystallization. b Determined
by GC (area %).
1
hexanes (1:2). H NMR spectra were acquired on a Varian
XL-300 spectrometer at 300 MHz. Mass spectra were
recorded on a HP-5890 GC with a HP 5972 mass selective
detector or by the Mass Spectral Services Unit, Department
of Chemistry, CUNY Hunter College, New York, NY.
General Procedure for a Heck Coupling Using
5-Bromopyrimidine. A 5-L multineck flask was fitted with
a mechanical stirrer, glycol-chilled (-10 °C) condenser, gas
inlet adapter, and a thermometer. The system was purged
with dry N2 for a few minutes and then charged with
5-bromopyrimidine (100 g, 0.64 mol) dissolved in 1.5 L of
DMF, methyl acrylate (165.2 g, 1.92 mol), diisopropylethyl-
amine (120 mL), trimethyl phosphite (4.0 g, 32 mmol), and
palladium acetate (3.6 g, 16 mmol). The mixture was warmed
to 110°. The reaction was monitored by removing an aliquot
under N2 and analyzing by TLC. When the reaction was
complete as determined by the disappearance of the 5-bromo-
pyrimidine, the mixture was cooled to room temperature and
the DMF removed under reduced pressure. The residue was
stirred with 1.5 L of methylene chloride, and the suspension
was filtered through a bed of silica gel. The filtrate was
washed with 1 L of 3% hydrochloric acid, 1 L of water, and
1 L of saturated brine. The solution was dried over MgSO4
and filtered; the solvent was removed under reduced pressure.
nitrogen with either triethylamine (TEA) or diisopropylethyl-
amine (DIPEA) as the base. Trimethyl phosphite and pal-
ladium acetate were used in a 2:1 ratio with a catalyst loading
of 1-5 mol %. Reaction temperature was 80-120 °C,
depending on the particular heteroarene with reaction times
of 60-120 min as determined by gas chromatography or
thin-layer chromatography. Longer reaction times or a higher
catalyst load had no effect on the yield. Workup involved
removal of the DMF under reduced pressure and extraction
of the residue with methylene chloride. The resulting
suspension was filtered through a bed of silica and the
methylene chloride solution washed with water. After drying
and evaporation of the solvent, the crude product was purified
by crystallization. The process was scaled to 100 g without
any lowering of the yield.
Table 1 summarizes the yields obtained from various
heteroarenes using this procedure. The yields were good for
a variety of substrates except for N-acetyl-4-bromo-3,
5-dimethylpyrazole (entry 3). It is unclear whether this was
due to the electron-releasing character of the methyl groups
or to steric hindrance, although the corresponding iodo
compound gave a nearly quantitative yield (entry 4). In the
case of 4-bromoisoquinoline (entry 7) and 3-bromo-7-
methylisoquinoline (entry 8) the use of triethylamine required
a longer reaction time and gave lower yields. Diisopropyl-
ethylamine gave improved reaction rates and higher yields.
(8) (a) McGuiness, D. S.; Saendig, N.; Yates, B. F.; Cavell, K. J. J. Am. Chem.
Soc. 2001, 123, 4029. (b) Garrou, P. E. Chem. Rev. 1985, 85, 171.
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The crude solid was crystallized from ethyl acetate-hexane
Supporting Information Available
to yield 93.4 g (89%) of the product.
1H NMR chemical shifts and mass spectral data of all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment
We thank Dr. James F. Marecek, Director of the Chemical
Synthesis Center at SUNY Stony Brook, NY, for reviewing
our manuscript.
Received for review June 26, 2005.
OP050106K
696
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Vol. 9, No. 5, 2005 / Organic Process Research & Development