A new facile method for the synthesis of 1-arylimidazole-5-carboxylates

Article abstract of DOI:10.1016/S0040-4039(00)00910-2

A new facile method for the preparation of 1-arylimidazole-5- carboxylates was developed. The new method involved reaction of anilines and ethyl glyoxylate in methanol to give α-anilino-α-methoxyacetates followed by cyclization with TosMIC, affording 1-ar

Full text of DOI:10.1016/S0040-4039(00)00910-2

Tetrahedron Letters 41 (2000) 5453±5456
A new facile method for the synthesis of
1-arylimidazole-5-carboxylates
Bang-Chi Chen,* Mark S. Bednarz, Rulin Zhao, Joseph E. Sundeen, Ping Chen,
Zhongqi Shen, Amanda P. Skoumbourdis and Joel C. Barrish
Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA
Received 19 April 2000; accepted 1 June 2000
Abstract
A new facile method for the preparation of 1-arylimidazole-5-carboxylates was developed. The new
method involved reaction of anilines and ethyl glyoxylate in methanol to give a-anilino-a-methoxyacetates
followed by cyclization with TosMIC, a€ording 1-arylimidazole-5-carboxylates in two steps in 40±94%
overall yields. # 2000 Elsevier Science Ltd. All rights reserved.
1-Arylimidazole-5-carboxylic esters are a class of important intermediates in organic synthesis.
For example, they were used in the synthesis of biologically active compounds such as fungicides,1 3
herbicides,1 3 and plant growth regulators,1,2,4 6 in the synthesis of analogs of histidine and hist-
amine,7 and in the synthesis of phenylimidazoles for treatment of cerebral disorders, amnesia, and
senile dementia.8 More recently, 1-arylimidazole-5-carboxylic esters found applications in the
synthesis of Factor Xa inhibitors.9 11
1-Arylimidazole-5-carboxylic esters were originally prepared via a six-step sequence involving
b-hydroxy-a-(N-formyl-N-aryl)amino acrylates.12 Reaction of aniline hydrochloride with formalin
and potassium cyanide followed by treatment of the resulting anilinoacetonitrile 1 with alcohol in
the presence of HCl gave N-arylglycine ester 2. N-Formylation of 2 with mixed formic acetic
anhydride a€orded N-formyl-N-arylglycine ester 3. Condensation of 3 with formate and sodium
alkoxide gave rise to b-hydroxy-a-(N-formyl-N-aryl)amino acrylate 4. Cyclization of 4 with
KSCN resulted in formation of 2-mercapto-1-arylimidazole-5-carboxylic ester 5 which, after
oxidative desulfurization using nitric acid, gave 1-arylimidazole-5-carboxylic ester 6. While the
overall yields for this method were usually satisfactory, the number of steps involved in the
synthesis and the use of potassium cyanide made it unpractical especially for large-scale synthesis.
As a consequence, a number of improvements were made to the original synthesis which include
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00910-2

5454
the direct formation of N-arylglycine esters 2 from anilines and a-haloacetates,13 direct preparation
of N-formyl-N-arylglycine esters 3 from N-formyl anilines and a-haloacetates,14 direct prepara-
tion of b-hydroxy-a-(N-formyl-N-phenyl)amino acrylates 4 from N-arylglycine esters,14 and
direct imidazole ring formation using formamide at high temperature to eliminate the oxidative
desulfurization step.1 4 In a program of our drug discovery, we required easy access to large
amounts of 1-arylimidazole-5-carboxylic esters. Herein, we describe a facile method for the pre-
paration of the title compounds.
Base-promoted cyclization of N-arylimines with (p-tolylsulfonyl)methyl isocyanide (TosMIC)
is an ecient method for the preparation of 1,5-disubstituted imidazoles.15 Our initial idea was to
prepare imino-glyoxylates from anilines and glyoxylates and subject them to reaction with Tos-
MIC. Thus, treatment of 2-nitro-4,5-dimethoxyaniline 7a with ethyl glyoxylate 8 in methanol at
re¯ux overnight a€orded a crystalline compound after cooling and ®ltration. It was interesting to
note that the desired imino proton was not observed in the proton NMR. Instead, an extra
methoxy singlet peak appeared at 3.34 ppm in addition to two sets of doublets at 5.35 and 9.13
ppm corresponding to the a-methine proton and NH proton, respectively. These, in addition to
the LC/MS results (M+H=315), indicated that the resulting product is a-anilino-a-methoxy-
acetate 9a rather than the expected imino-glyoxylate 10a. We envisioned, however, that this
a-anilino-a-methoxyacetate 9a could still be a useful substrate for imidazole ring formation.
Under the reaction conditions, 9a may undergo elimination to give imino-glyoxylate 10a in situ
which would, as expected, react with TosMIC reagent resulting in formation of 1-arylimidazole-
5-carboxylate 11a (Scheme 1).16 Indeed, treatment of 9a with TosMIC in re¯uxing ethanol in the
presence of potassium carbonate a€orded 11a in 68% yield.
Scheme 1.

5455
The formation of a-anilino-a-methoxyacetates from anilines and glyoxylates in methanol and
subsequent cyclization with TosMIC reagent to yield 1-arylimidazole-5-carboxylates appeared
to be general (Table 1). The new method is applicable to electron-rich anilines (Table 1, entry 2)
as well as electron-de®cient anilines (Table 1, entry 4). In addition, this method also worked with
heterocyclic anilines (Table 1, entries 5 and 6).
Table 1
Preparation of a-anilino-a-methoxyacetates 9 and 1-arylimidazole-5-carboxylates 1118
In summary, a new facile method for the preparation of 1-arylimidazole-5-carboxylates was
developed. The new method involves condensation of anilines and a glyoxylate in methanol to
give a-anilino-a-methoxyacetates followed by cyclization with TosMIC, a€ording 1-arylimidazole-
5-carboxylates in two steps in 40±94% overall yields. The application of 1-arylimidazole-5-
carboxylates to the synthesis of other biologically active agents will be reported in due course.
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18. 1H NMR spectroscopic data for: compound 11a (CDCl3) ꢀ 7.87 (s, 1H), 7.78 (s, 1H), 7.67 (s, 1H), 6.80 (s, 1H),
4.18 (q, J=7.1 Hz, 2H), 4.03 (s, 3H), 3.97 (s, 3H), 1.25 (t, J=7.1 Hz, 3H); compound 11b (DMSO-d6) ꢀ 8.10 (s,
1H), 7.80 (s, 1H), 7.42±7.52 (m, 5H), 4.12 (q, J=7.1 Hz, 2H), 1.14 (t, J=7.1 Hz, 3H); compound 11c (DMSO-d6) ꢀ
8.35 (d, J=8.7 Hz, 2H), 8.24 (s, 1H), 7.86 (s, 1H), 7.79 (d, J=8.7 Hz, 2H), 4.16 (q, J=7.1 Hz, 2H), 1.17 (t, J=7.1
Hz, 3H); compound 11d (CDCl3) ꢀ 8.35 (s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 6.22 (br s, 1H), 4.24 (q,
J=7.1 Hz, 2H), 1.49 (s, 9H), 1.25 (t, J=7.1 Hz, 3H); compound 11e (CDCl3) ꢀ 8.41 (S, 1H), 7.90 (s, 1H), 7.70 (d,
J=8.6 Hz, 1H), 7.69 (s, 1H), 7.48 (d, J=9.6 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H).