Organic Process Research & Development 2002, 6, 674−676
Efficient Synthesis of 1-Substituted-5-Hydroxymethylimidazole Derivatives:
1
Clean Oxidative Cleavage of 2-Mercapto Group
Jay Hyok Chang, Kyu Woong Lee, Do Hyun Nam, Won Sup Kim, and Hyunik Shin*
LGCI Ltd. / Life Science R & D, 104-1 Moonji-dong, Yusung-gu, Taejon 305-380, Korea
Abstract:
-Substituted-5-hydroxymethylimidazoles were prepared through
green desulfurization of their 2-mercapto derivatives by the
treatment of 30% hydrogen peroxide in the presence of a
catalytic amount of transition metal catalysts.
been reported by Merck process chemists. However the
method is still complicated with the use of excess hydrogen
peroxide (7-8 equiv) and organic acid as reaction medium,
which inevitably calls for the subsequent quench of excess
hydrogen peroxide by a reducing agent and for neutralization
of the organic acid by the excess of base in the workup
procedure. In this report we would like to disclose safe and
clean desulfurization conditions of 2-mercapto-5-hydroxy-
methylimidazole derivatives.
It was speculated that the reaction mechanism of the
nitrite/nitric acid method would involve a sequence of
reactions, oxidation of the mercapto group of 2-mercap-
toimidazole to a sulfinic or sulfonic acid group through
oxygen transfer from nitrogen to sulfur and subsequent
elimination of these groups to afford imidazole. This
assumption led us to test various thiol- or sulfide-oxidizing
reagents for desulfurization.
1
Recently we have published the discovery of a series of
1
,5-disubstituted imidazole derivatives as potent and selective
2
farnesyl transferase inhibitors. For the proper supply of this
class of compounds in reasonable quantity, it is a prerequisite
to establish a scalable route towards 1-substituted-5-hy-
droxymethylimidazoles.
In the literature various procedures are known for the
preparation of 1-substituted-5-hydroxymethylimidazoles, which
3
are via oxidative desulfurization of 1-substituted-2-mercapto-
5
-hydroxymethylimidazole, selective alkylation of 4-hy-
4
droxymethylimidazole, and less commonly, via the reduc-
tion of 5-substituted-1-carboxylates. Among these methods,
5
The starting materials, 2-mercapto-imidazole derivatives
(2a-f) were prepared according to literature precedents.2a
For oxidative desulfurization, we have employed a tungstic
acid/hydrogen peroxide system based on the literature
the last two routes are not viable for the large-scale prepa-
ration due to the lack of bulk availablility of 4-hydroxy-
methylimidazole and because of lengthy steps, respectively.
Accordingly we have chosen the oxidative desulfurization
route of readily available 1-substituted-2-mercapto-5-hy-
droxymethylimidazole under the known conditions, employ-
ing nitrite/nitric acid or fuming nitric acid (Scheme 1).
However, we found that the reaction conditions were quite
exothermic and accompanied by a vigorous evolution of a
stoichiometric amount of nitrous oxide gas to render the
reaction improper for a large-scale preparation in terms of
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precedents which demonstrated clean and efficient oxidation
of sulfide groups to sulfone derivatives. As expected,
desulfurization of 2-mercapto imidazole derivatives pro-
ceeded smoothly in methanol or ethanol with slow addition
of 30% hydrogen peroxide (3.0-3.5 equiv) in the presence
of catalytic amounts of tungstic acid (Table 1). In general 1
mol % of catalyst was employed, but the amount could be
reduced to 0.1 mol % with comparable results. It is also
worth mentioning that there was neither hydroxyl group
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safety and environmental concerns. Recently, an improved
7
8
10
procedure using hydrogen peroxide in acidic medium has
oxidation of the 5-hydroxymethyl fragment of 2a-f nor
1
1
epoxidation of the double bond of 2e. After all the starting
material was consumed, the reaction mixture was neutralized
with aqueous base, and the formed solid was filtered to give
the product. In most cases, the purity of the products was
*
To whom correspondence should be addressed. E-mail: hisin@lgci.co.kr.
(
1) The result was published as a part of patent. Refer to: Shin, H.; Chang, J.
H.; Lee, K. W.; Lee, H. I.; Kim, S. K.; Nam, D. H. WO 0117974.
2) Lee, H. I.; Koh, J. S.; Lee, J. H.; Jung, W. H.; Shin, Y. S.; Chung, H. H.;
Kim, J. H.; Ro. S. G.; Choi, T. S.; Jeong, S. W.; Lee, S. H.; Kim, K. W.
WO9928315, 9938862, 9905117, and 0064891.
(
>95% by HPLC analysis.
(
3) (a) Aulaskari, P.; Ahlgren, M.; Roubinen, J.; Vainiotalo, P.; Pohjala, E.;
Vepsaelaeinen, J. J. Heterocycl. Chem. 1996, 33(4), 1345. (b) Dodson, R.
M.; Ross, F. J. Am. Chem. Soc, 1950, 72, 1478. (b) Jones, R. G. ibid,
Other transition metal catalysts were also tested. Vanadyl
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sulfate showed almost the same reactivity of tungstic acid.
13
14
Vanadium oxide and methyltrioxorhenium revealed slightly
1
952, 74, 1085. (c) Mhasalkar, M. Y. et al. J. Med. Chem. 1971, 14, 260.
(4) (a) Antonini, I.; Cristalli, G.; Franchetti, P.; Grifantini, M.; Martelli, S.
Synthesis 1983, 47. (b) Amino, Y.; Eto, H.; Eguchi, C. Chem. Pharm. Bull.
(9) For oxidation of alkyl or aryl sulfide to sulfone by tungstic acid and
hydrogen peroxide, see: (a) Koyama, S. et al. JP 07053529, 1995. (b)
Miyauchi, H.; Nakamuara, T.; Ohashi, N. Bull. Chem. Soc. Jpn. 1996, 69(9),
2625. (c) Stec, Z.; Zawadiak, J.; Skibinski, A.; Pastuch, G. Pol. J. Chem.
1996, 70(9), 1121.
1
989, 37, 1481.
5) Kirchlechner, R.; Casutt, M.; Heywang, U.; Schwartz, M. W. Synthesis
994, 247.
(
1
(
(
6) Dickinson, R. E.; Cicerone, R. J. Nature 1986, 319, 109.
7) (a) Askin, D.; Cowen, J.; Maligres, P. E.; McWilliams, J. C.; Waters, M.
S. (Merck & CO., Inc.). WO 0001674.
(10) Sato, K.; Aoki, M.; Takagi, J.; Noyori, R. J. Am. Chem. Soc. 1997, 119,
12386.
(
8) Hydrogen peroxide in acidic medium was used for the desulfurization of
(11) Sato, K.; Aoki, M.; Ogawa, M.; Hashimoto, T.; Noyori, R. J. Org. Chem.
1996, 61, 8310.
2
-mercapto-thiazole derivatives, see: (a) Stewart, F. D.; Mathes, R. A. J.
Org. Chem. 1949, 14, 1111. (b) Buchman, E. R.; Reims, A. O.; Sargent,
H. J. Org. Chem. 1941, 6, 764. (c) D’Amico, J. J.; Bartram, T. J. J. Org.
Chem. 1960, 25, 1336.
(12) Francis, M. B.; Jacobsen, E. N. Angew. Chem., Int. Ed. 1999, 38, 937.
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(14) Yamazaki, S. Bull. Chem. Soc. Jpn. 1996, 69, 2955.
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Vol. 6, No. 5, 2002 / Organic Process Research & Development
10.1021/op020015c CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/25/2002