Direct displacement of -OH by nucleophiles in hydroxymethylimidazoles

Article abstract of DOI:10.1016/S0040-4039(00)00262-8

Direct displacement of -OH from 4- and 5-hydroxymethylimidazoles is achieved in good to excellent yields simply by heating a 4- or 5- hydroxymethylimidazole in the presence of an appropriate nucleophile in refluxing basic water. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00262-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2777–2779
Direct displacement of –OH by nucleophiles in
hydroxymethylimidazoles
John E. Macor,∗ Lyndon A. M. Cornelius and Jacques Y. Roberge
Bristol-Myers Squibb, Pharmaceutical Research Institute, Discovery Chemistry, PO Box 5400, Princeton,
NJ 08543-5400, USA
Received 13 December 1999; accepted 8 February 2000
Abstract
Direct displacement of –OH from 4- and 5-hydroxymethylimidazoles is achieved in good to excellent yields
simply by heating a 4- or 5-hydroxymethylimidazole in the presence of an appropriate nucleophile in refluxing
basic water. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: aminomethylimidazole; hydroxymethylimidazole; imidazole; nucleophilic displacement.
Simple chemical transformations can be very powerful tools in organic synthesis. We needed to
make a series of substituted imidazoles, and sought a direct method to access a multitude of imida-
zole derivatives from a common precursor. In addition to our needs for this class of compounds, 4-
aminomethylimidazoles have recently been claimed as potent farnesyl transfer inhibitors for the treatment
of cancer.1 Thus, we sought an expedient method for functionalizing certain imidazoles using a readily
available common starting material. Hydroxymethyimidazoles (1) came to mind, and using analogy with
the instability of 3-hydroxymethylindoles,2 we envisioned that we could develop conditions under which
direct –OH displacement could be achieved from hydroxymethylimidazole (1, Scheme 1). Our hypothesis
was further supported by the observation that naturally occurring 4-hydroxymethylimidazoles tended to
racemize in solution,3 thus supporting the hypothesized lability of the –OH group. Recognizing that an
elimination/addition equilibrium of the HO– group in hydroxymethylimidazole would likely exist under
Scheme 1.
∗
Corresponding author. E-mail: john.macor@bms.com (J. E. Macor)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00262-8
tetl 16542

2778
Table 1
Synthesis of functionalized imidazoles
basic conditions, we sought to establish the equilibrium such that a nucleophile present in the reaction
would have an opportunity to capture the vinylogous iminium intermediate (2, Scheme 1). Using basic
aqueous conditions (1 M K2CO3 or Na2CO3), we were able to directly displace the hydroxy group in

2779
hydroxymethylimidazoles with a variety of nitrogen nucleophiles forming functionalized imidazoles (3)
in moderate to excellent yields (Table 1).
Table 1 summarizes the results of our methodological study. In a typical experiment,4 the hydroxy-
methylimidazole hydrochloride (1 equiv.) is heated at reflux in an aqueous solution of K2CO3 (3 equiv.)
along with the desired nucleophile (excess, typically 2 equiv.). Nucleophiles included amines (entries
A–F), methoxylamine (entry G), and sulfonamides (entries H and I). Only water has been used as the
reaction solvent, and for the cases studied, no other solvents were needed. Extremely volatile nucleophiles
(i.e. dimethylamine) require the reaction to be run in a sealed tube, but generally no other special
requirements are needed. Within 24 hours, the reaction is typically complete. Purification depends on
the nature of the nucleophile. With most amines, the reaction could be simply evaporated under reduced
pressure, and the desired product isolated via washing the solid residue with ethyl acetate; evaporation
of the ethyl acetate afforded the desired aminomethylimidazole. Both 4- and 5-hydroxymethyimidazoles
can participate in this reaction.
We have not attempted the reaction with a 2-hydroxymethyimidazole as yet. It should also be noted
that no attempt has been made to optimize the conditions of the individual reactions. Furthermore, only
nitrogen nucleophiles have been tested thus far in this method. We are presently exploring the activity
of other nucleophiles (oxygen, sulfur and carbon nucleophiles), and will report those results upon their
completion.
In summary, we have demonstrated an expedient synthesis of functionalized imidazole derivatives
arising from the direct nucleophilic displacement of hydroxide from hydroxymethylimidazoles. We are
presently studying the full scope of this powerful but simple transformation.
References
1. (a) Williams, T. M.; Bergman, J. M.; Brashear, K.; Breslin, M. J.; Dinsmore, C. J.; Hutchinson, J. H.; MacTough, S. C.;
Stump, C. A.; Wei, D. D.; Zartman, C. B.; Bogusky, M. J.; Culberson, J. C.; Buser-Doepner, C.; Davide, J.; Greenberg, I. B.;
Hamilton, K. A.; Koblan, K. S.; Kohl, N. E.; Liu, D.; Lobell, R. B.; Mosser, S. D.; O’Neill, T. J.; Rands, E.; Schaber, M. D.;
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2. Remers, W. A. In Properties and Reactions of Indoles, Vol. 25, Part 1 of the series Chemistry of Heterocyclic Compounds;
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4. A typical procedure was as follows: a solution of the hydroxymethylimidazole (10 mmol), amine (25 mmol, 2.5 equiv.),
potassium or sodium carbonate (30 mmol, 3 equiv.) and water (20 mL) was heated at reflux under nitrogen for 24 h. Water
was removed from the reaction via evaporation under reduced pressure, and the residue was vigorously stirred in ethyl acetate
(50 mL). The ethyl acetate was removed and evaporated under reduced pressure to afford the desired aminomethylimidazole.
Alternatively, the aqueous reaction solution could be extracted with 5% methanol in ethyl acetate (3×50 mL), the extracts
combined, dried (Na2SO4) and evaporated under reduced pressure to afford the desired aminomethylimidazole. The
sulfonamides were further purified by passing an aqueous solution of the sulfonamide through a column of acidic ion exchange
resin (Bio-Rad AG 50W-X2, 35 g). The resin was then washed with water (2×200 mL, discarded), methanol (2×200 mL,
discarded), and the product was obtained by releasing the imidazole from the acidic resin with methanolic ammonia (200 mL,
3.5 N). This solution was then evaporated under reduced pressure to afford the desired sulfonamide.