An optimized process for formation of 2,4-disubstituted imidazoles from condensation of amidines and α-haloketones

Article abstract of DOI:10.1021/op025552b

The preparation of 2,4-disubstituted imidazoles from the condensation of α-haloketones with amidines is described. The optimal reaction protocol is to add the α-bromoketone solution to the amidine in aqueous tetrahydrofuran in the presence of potassium bi

Full text of DOI:10.1021/op025552b

Organic Process Research & Development 2002, 6, 682−683
An Optimized Process for Formation of 2,4-Disubstituted Imidazoles from
Condensation of Amidines and r-Haloketones
Bryan Li,* Charles K.-F. Chiu, Richard F. Hank, Jerry Murry,† Joshua Roth, and Harry Tobiassen
Pfizer Global Research and DeVelopment, Groton Laboratories, Eastern Point Road, Groton, Connecticut 06340, U.S.A.
Scheme 1
Abstract:
The preparation of 2,4-disubstituted imidazoles from the
condensation of r-haloketones with amidines is described. The
optimal reaction protocol is to add the r-bromoketone solution
to the amidine in aqueous tetrahydrofuran in the presence of
potassium bicarbonate under vigorous reflux. Imidazole was
isolated in 83-91% yield with >95% purity without column
chromatography.
Results and Discussion
Our initial attempts to optimize this reaction focused on
utilizing anhydrous reaction conditions due to stability
concerns of R-bromoketones under basic aqueous conditions.
Condensations using a variety of bases (potassium tert-
butoxide, potassium carbonate, cesium carbonate, etc.) in
THF, DMF, CH3CN, or CH2Cl2 gave low yields. Reactions
in alcohols (ethanol, 2-propanol, and tert-butyl alcohol) were
also unsatisfactory. We then investigated mixed organic/
aqueous reaction media, as we reasoned that amidines are
stronger nucleophiles than water, and therefore the condensa-
tion rate of R-bromoketones with amidines should be faster
than the decomposition rate of the bromoketone in water. A
series of reactions using THF, DMF, or alcohols as the
organic solvent were conducted, and from these experiments
we made a number of observations.
(1) Aqueous THF is a suitable media to bring the very
polar amidines and nonpolar R-bromoketones in the same
phase, and it is superior to aqueous DMF or alcohol.
(2) Higher reaction temperatures in aqueous THF ac-
celerates the condensation.
(3) Bicarbonate is the base of choice, as it only serves to
scavenge the acid produced during the condensation reaction.
(4) As R-bromoketones decompose under the reaction
conditions, their concentrations in the reaction should be
minimized.
Introduction
The imidazole nucleus is often found in biologically active
molecules,1 and a large variety of methods have been
employed for their synthesis.2 We recently had a need to
develop a more viable process for the preparation of
multikilogram quantities of 2,4-disubstituted imidazoles. The
condensation of amidines, which are readily accessible from
nitriles,3 with R-haloketones has become a widely used
method for the synthesis of 2,4-disubstituted imidazoles
(Scheme 1). A literature survey showed that chloroform was
the most commonly used solvent for this reaction.4 In
addition to the use of a nonbenign solvent, yields of the
reaction varied from poor to moderate, and column chro-
matography was often needed for product isolation. Use of
other solvents such as alcohols,5 DMF,6 and acetonitrile7 have
also been reported for this reaction, but yields are also
frequently poor.
* To whom correspondence should be addressed. Fax: (860) 715-7305.
E-mail: bryan_li@groton.pfizer.com.
† Current Address: Process Research Department, Merck Research Labora-
tories, Merck and Co. Inc., Rahway, NJ, U.S.A.
(1) Kudzma, L. V.; Turnbull, S. P.,Jr. Synthesis 1991, 1021. (b) Compagnone,
R. S.; Rapport, H. J. Org. Chem. 1986, 51, 1713 and references therein.
(c) Shapiro, S.; Enz, A. Drugs Future 1992, 17, 489.
(2) For examples, see: (a) Grimmett, M. R. In ComprehensiVe Heterocycle
Chemistry; Katritzky, A. R., Rees, C., Eds.; Pergamon Press: Elmsford,
NY, 1984; Vol. 5 and references therein. (b) Grimmet, M. R. In
ComprehensiVe Heterocycle Chemistry II; Katritzky, A. R., Rees, C.,
Scriven, E. F. V., Eds.; Pergamon Press: Elmsford, NY, 1996; Vol. 3, and
references therein. (c) Varma, R. S.; Kumar, D. Tetrahedron Lett. 1999,
40, 7665. (d) Heras, M.; Ventura, M.; Linden, A.; Villalgordo, J. M.
Synthesis 1999, 9, 1613. (e) Lengeler, D.; Weisz, K. Nucleosides Nucleotides
1999, 18, 1657. (f) Batanero, B.; Escudero, J.; Barba, F. Org. Lett. 1999,
1, 1521. (g) Bergemann, M.; Neidlein, R. HelV. Chim. Acta 1999, 82, 909.
(3) (a) Boere, R. T.; Oakley, T. T.; Reed, R. W. J. Organomet. Chem. 1987,
331, 161. (b) Thurkauf, A.; Hutchison, A.; Peterson, J.; Cornfield, L.;
Meade, R. J. Med. Chem. 1995, 38, 2251.
(4) (a) Kempter, G.; Spindler, J.; Fiebig, H. J.; Sarodnick, G. J. Prakt. Chem.
1971, 313, 977. (b) Baldwin, J. J.; Christy, M. E.; Denny, G. H.; Habecker,
C. N.; Freedman, M. B. J. Med. Chem. 1986, 29, 1065. (c) Nagao, Y.;
Takahashi, K.; Torisu, K.; Kondo, K.; Hamanaka, N. Heterocycles 1996,
42, 517. (d) Baldwin, J. J.; Engelhardt, E. L.; Hirschmann, R.; Lundell, G.
F.; Ponticello, G. S. J. Med. Chem. 1979, 22, 687.
We found that the optimal reaction protocol was to add
a solution of R-bromoketone in THF to the amidine in
aqueous THF in the presence of potassium bicarbonate under
vigorous reflux. Once the reaction was complete, the THF
was removed, and the product crystallized directly out of
the remaining solvent. Using this protocol, 2,4-disubstituted
(6) Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tokuhara, N.; Tai, K.; Hida, T.;
Yamauchi, T.; Nagai, M. J. Med. Chem. 2000, 43, 409.
(7) Moody, C. J.; Roffey, J. R. A. Chem. Abstr. 2000, 134, 71748.
(8) Burtles, P. J. Chem. Soc. 1923, 123, 362.
(9) Lombardino, J. G.; Wiseman, E. H. J. Med. Chem. 1974, 17, 1182.
(10) Baldwin, J. J.; Lumma, P. K.; Novello, F. C.; Ponticello, G. S.; Sprague,
J. M.; Duggan, D. E. J. Med. Chem. 1977, 20, 1189.
(11) Baldwin, J. J.; Engelhardt, E. L.; Hirschmann, R.; Lundell, G. S.; Ponticello,
G. S. J. Med. Chem. 1979, 22, 687.
(5) Baldwin, J. E.; Fryer, A. M.; Pritchard, G. J. J. Org. Chem. 2001, 66, 2588.
(12) Nakanish, S.; Nantaku, J.; Otsuji, Y. Chem. Lett. 1983, 3, 341.
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10.1021/op025552b CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/23/2002

Table 1. Amidine and r-haloketone condensations
a It was reported that the results were irreproducible. b 3 equiv of 2-thiophenylamidine was used, yield was based on R-bromoketone. c From condensation of
amidine and R-halooxime.
imidazoles were isolated in excellent yields with >95%
purity without column chromatography. Aromatic and ali-
phatic R-haloketones participate in this reaction with a variety
of aromatic amidines, as indicated in Table 1. We note that
reactions involving pyridylamidines or chloroacetone are
substantially more robust using this protocol (entries 3 and
4). We have successfully used this protocol on multikilogram
scale.
In conclusion, a scaleable process for the preparation of
2,4-subsituted imidazole from amidines and R-haloketones
has been described. This method avoids the use of chloroform
as solvent and affords the desired products in consistently
good-to-excellent yields.
Spectroscopic data of all products were consistent to those
reported.
Typical Procedure. A mixture of 3-amidinopyridine
hydrochloride (150 g, 0.95 mol) and potassium bicarbonate
(381 g, 3.80 mol) in 1.6 L of THF and 400 mL of water
was heated at vigorous reflux. Chloroacetone (80 mL, 0.95
mol) in THF (400 mL) was added over a period of 30 min,
while keeping the reaction mixture at reflux. After the
addition, the reaction was heated at reflux for 2 h until HPLC
assay showed reaction completion. THF was then removed
by distillation, and the solids that crystallized out were
collected by filtration and rinsed once with water. The crude
product (94.3% pure by HPLC) was repulped in isopropyl
ether/hexanes(1:1 mixture, 600 mL) for 2 h, filtered, and
dried under vacuum to give 126.4 g (82.7% yield, 99.1%
pure by HPLC) of the desired product as an off-white solid.
Experimental Section
HPLC analyses were carried out using a Zorbax SB-CN
column (4.6 mm × 250 mm), eluting with acetonitrile/water
(30/70, 2 mL/min) monitored at 210 nm wavelength. A
Finnigan (San Jose, CA) LCQ ion trap instrument coupled
to an HP 1100 liquid chromatograph was used for all MS
data acquisition. NMR spectra were recorded in DMSO-d6
with DMSO-d6 (1H, 2.49 ppm, 13C, 39.5 ppm) as an internal
reference, using Varian 400. 2,4-Disubstituted imidazoles in
Table 1 were previously characterized in the literature.
Acknowledgment
We thank Dr. Martin A. Berliner for his comments on
the manuscript.
Received for review May 22, 2002.
OP025552B
Vol. 6, No. 5, 2002 / Organic Process Research & Development
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