A concise and regioselective synthesis of 1-alkyl-4-imidazolecarboxylates

Article abstract of DOI:10.1021/ol026892k

(formula presented) Reaction between ethyl 3-N,N-(dimethylamino)-2-isocyanoacrylate (1) and a primary amine (2) regioselectively affords 1-alkyl-4-imidazolecarboxylates (3) in good yields (52-89%). The method is applicable to unhindered and hindered amine

Full text of DOI:10.1021/ol026892k

ORGANIC
LETTERS
2002
Vol. 4, No. 23
4133-4134
A Concise and Regioselective Synthesis
of 1-Alkyl-4-imidazolecarboxylates
Christopher J. Helal* and John C. Lucas
Neuroscience Medicinal Chemistry, Pfizer Global Research and DeVelopment,
Eastern Point Road, Groton, Connecticut 06340
chris_j_helal@groton.pfizer.com
Received September 12, 2002
ABSTRACT
Reaction between ethyl 3-N,N-(dimethylamino)-2-isocyanoacrylate (1) and a primary amine (2) regioselectively affords 1-alkyl-4-imidazolecar-
boxylates (3) in good yields (52−89%). The method is applicable to unhindered and hindered amine substrates, as well as those containing
reactive functionality such as alcohols and secondary and tertiary amines.
The imidazole nucleus is a common structural unit found in
compounds of biological interest. As a result, a number of
methods have been developed to prepare variously substituted
imidazoles.1 Despite the availability of such methods, the
ability to efficiently access certain specific substitution
patterns is limited and requires the design of new synthetic
strategies.
A particular example of this is 1-alkyl-4-imidazolecar-
boxylates. Stereoselective routes are known for the synthesis
of 1-aryl-4-imidazolecarboxylates,2 1-aryl-5-imidazolecar-
boxylates,3 1-alkyl-5-amino-4-imidazolecarboxylates,4 and
1,5-dialkyl-4-imidazolecarboxylates.5 Yet the only direct
route to 1-alkyl-4-imidazolecarboxylates is via the alkylation
of ethyl 4(5)-imidazolecarboxylate, which affords regio-
isomeric mixtures of alkylation products.6 To overcome these
issues, we have developed a simple and regioselective
synthesis of 1-alkyl-4-imidazolecarboxylates (3) from a
primary amine and readily prepared ethyl 3-N,N-(dimethyl-
amino)-2-isocyanoacrylate (1).7,8
Representative examples of substituted imidazoles that are
accessible via this chemistry and demonstrate the generality
of the process are shown in Table 1. A range of steric
substitution patterns about the primary amine is tolerated,
and all afford the expected products in good yield, exempli-
fied using n-alkylamines (2a, 2b) and more hindered sec-
(5) (a) Nunami, K.-i.; Yamada, M.; Fukui, T.; Matsumoto, K. J. Org.
Chem. 1994, 59, 7635-7642. (b) Hiramatsu, K.; Nunami, K.-i.; Hayashi,
K.; Matsumoto, K. Synthesis 1990, 781-782.
(6) Corelli, F.; Summa, V.; Brogi, A.; Monteagudo, E.; Botta, M. J. Org.
Chem. 1995, 60, 2008-2015.
(1) For a review of some general methods of imidazole synthesis, see:
(a) Gilchrist, T. L. Heterocyclic Chemistry; Longman: Essex, 1997; Chapter
8.1, pp 298-300. (b) Eicher, T.; Hauptmann, S. The Chemistry of
Heterocycles; Thieme: New York, 1995; Chapter 5.33, pp 170-172. (c)
Grimmett, M. R. In ComprehensiVe Heterocyclic Chemistry II; Shinkai, I.,
Ed.; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds. in Chief;
Elsevier: Tarrytown, 1996; Vol. 3, pp 185-209. (d) Grimmett, M. R. In
ComprehensiVe Heterocyclic Chemistry; Potts, K. T., Ed.; Katritzky, A.
R., Rees, C. W., Eds. in Chief; Pergamon: Elmsford, 1984; Vol 5, pp 457-
482.
(2) Combs, A. P.; Saubern, S.; Rafalski, M.; Lam, P. Y. S. Tetrahedron
Lett. 1999, 40, 1623-1626.
(3) Chen, B.-C.; Bednarz, M. S.; Zhao, R.; Sunden, J. E.; Chen, P.; Shen,
Z.; Skoumbourdis, A. P.; Barrish, J. C. Tetrahedron Lett. 2000, 41, 5453-
5456.
(7) For the first report of ethyl 3-N,N-(dimethylamino)-2-isocyanoacrylate
(1), see: Kantlehner, W.; Wagner, F.; Bredereck, H. Liebegs Ann. Chem.
1980, 344-357. General procedure for preparation of 1. Ethyl isocy-
anoacetate (5.4 mL, 49.5 mmol) and tert-butoxybis(dimethylamino)methane
(Bredereck’s reagent, 20.4 mL, 99 mmol) were stirred at 23 °C for 24 h.
Dimethylamine and tert-butyl alcohol were then removed in vacuo (90 °C,
1 Torr). The resulting residue could then be distilled following the literature
procedure (100-102 °C, 0.001 Torr) or purified via silica gel chromatog-
raphy (from 3:1 to 1:1 hexanes-ethyl acetate) to afford 4.7 g of 1 (57%
1
yield). H NMR (CDCl3, 400 MHz): δ 7.18 (s, 1H), 4.21 (q, J ) 7.1 Hz,
2H), 3.4-2.9 (brs, 6H), 1.30 (t, J ) 7.1 Hz, 3H).
(8) For other chemistry using ethyl 3-N,N-(dimethylamino)-2-iso-
cyanoacrylate (1) in heterocycle synthesis, see: (a) Lau, H.; Schollkopf,
U. Liebegs Ann. Chem. 1982, 2093-2095. (b) Heck, S.; Domling, A. Synlett
2000, 424-426.
(4) Hunt, J. T.; Bartlett, P. A. Synthesis 1978, 741-742.
10.1021/ol026892k CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/18/2002

Another salient feature of this chemistry is the chemo-
selectivity. Unprotected alcohols within the primary amine
substrate are tolerated (2e) as are tertiary and secondary
amine groups (2f, 2g), all providing the desired imidazoles
in good to high yields.
Table 1. Synthesis of 1-Alkyl-4-imidazolecarboxylates
Aniline can also be used to prepare ethyl 1-phenyl-4-
imidazolecarboxylate (3h), but a long reaction time is
required and the yield is modest (72 h, 31%; Table 1, h).9
The reactions proceed most rapidly when run neat in 3
equiv of the primary amine (method A). Alternatively,
n-butanol can be used as a solvent to improve amine
solubility or reduce amine equivalents (Method B).
In summary, we have developed an operationally simple,
regioselective, and efficient route for the synthesis of 1-alkyl-
4-imidazolecarboxylates (3) utilizing the readily available
starting material ethyl 3-N,N-(dimethylamino)-2-isocyanoacry-
late (1). The method works well with unhindered and
hindered amines as well as those containing alcohol and
secondary and tertiary amine functionality.10
OL026892K
(9) For an example of a related 1-heteroaryl-4-imidazolecarboxylate
synthesis, see: Selic, L.; Stanovnik, B. J. Heterocycl. Chem. 1998, 35,
1527-1529.
(10) Representative procedures. Method A: Ethyl-1-cyclopentyl-4-
imidazolecarboxylate (3c). Ethyl 3-N,N-(dimethylamino)-2-isocyanoacry-
late (1) (875 mg, 5.2 mmol) and cyclopentylamine (1.33 mL, 15.6 mmol)
were heated at 70 °C for 2 h. The excess amine was removed in vacuo,
and the resulting residue was purified by silica gel chromatography (30:1
CHCl3-MeOH) to afford 962 mg (89% yield) of 3c. 1H NMR (CDCl3,
400 MHz): δ 7.65 (s, 1H), 7.61 (s, 1H), 4.48 (m, 1H), 4.36 (q, J ) 7.0 Hz,
2H), 2.23 (m, 2H), 1.9-1.7 (m, 6H), 1.38 (t, J ) 7.2 Hz, 3H). 13C NMR
(CDCl3, 100 MHz): δ 163.1, 136.99, 133.96, 123.81, 60.48, 58.94, 33.81,
23.82, 14.55. IR (cm-1): 2960, 1721, 1543, 1378, 1214, 1187, 1117, 1025,
760, 665. MS (CI): (M + H)+ calcd, 209; (M + H)+ found, 209.2. Method
B: Ethyl 1-benzyl-4-imidazolecarboxylate (3b). A solution of ethyl 3-N,N-
(dimethylamino)-2-isocyanoacrylate (1) (552 mg, 3.3 mmol) and benzyl-
amine (432 uL, 4.0 mmol) in n-butanol (2.5 mL) was heated at reflux for
15 h. The solvent was removed in vacuo, and the residue was purified by
silica gel chromatography (CHCl3) to afford 515 mg (68% yield) of 3b. 1H
NMR (CDCl3, 400 MHz): δ 7.49 (s, 1H), 7.47 (s, 1H), 7.25 (m, 3H), 7.08
(m, 2H), 5.04 (s, 2H), 4.23 (q, J ) 7.05 Hz, 2H), 1.25 (t, J ) 7.05 Hz,
3H). 13C NMR (CDCl3, 400 MHz): δ 162.97, 138.31, 135.31, 134.45,
129.32, 128.80, 127.71, 125.53, 60.64, 51.54, 14.56. IR (cm-1): 2924, 1716,
1545, 1380, 1220, 1181, 1114, 1022, 971, 766, 711, 662. MS (CI): (M +
H)+ calcd, 231; (M + H)+ found, 231.1
alkyl (2c) and tert-alkylamines (2d). This is a key attribute
of the method, as imidazole alkylation generally proceeds
efficiently for unencumbered and/or activated alkylating
agents. It should be noted that reaction times are roughly
equivalent for the n-alkyl and sec-alkylamines (ca. 2 h, 70
°C), whereas the tert-alkylamine substrate necessitates a
considerably longer reaction time and higher temperature
(48 h, 140 °C).
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Org. Lett., Vol. 4, No. 23, 2002