New method for the synthesis of diversely functionalized imidazoles from N-acylated α-aminonitriles

Article abstract of DOI:10.1021/ol036423y

(Equation presented) A new general method for the synthesis of medicinally important diversely functionalized imidazoles from N-acylated α-aminonitriles has been developed. N-Acylated α-aminonitriles were reacted with triphenylphosphine and carbon tetrahalide to afford 2,4-disubstituted 5-halo-1H-imidazoles in good yield. This new methodology was applied for the synthesis of 2-butyl-4-chloro-5-hydroxymethylimidazole. These halo-imidazoles can be directly converted to 2,4,5-trisubstituted imidazoles through palladium-catalyzed coupling reactions.

Full text of DOI:10.1021/ol036423y

ORGANIC
LETTERS
2004
Vol. 6, No. 6
929-931
New Method for the Synthesis of
Diversely Functionalized Imidazoles
from N-Acylated r-Aminonitriles
Yong-Li Zhong,* Jaemoon Lee, Robert A. Reamer, and David Askin
Department of Process Research, Merck Research Laboratories, P. O. Box 2000,
Rahway, New Jersey 07065
yongli_zhong@merck.com
Received December 12, 2003
ABSTRACT
A new general method for the synthesis of medicinally important diversely functionalized imidazoles from N-acylated r-aminonitriles has been
developed. N-Acylated r-aminonitriles were reacted with triphenylphosphine and carbon tetrahalide to afford 2,4-disubstituted 5-halo-1H-
imidazoles in good yield. This new methodology was applied for the synthesis of 2-butyl-4-chloro-5-hydroxymethylimidazole. These halo-
imidazoles can be directly converted to 2,4,5-trisubstituted imidazoles through palladium-catalyzed coupling reactions.
The synthesis of substituted imidazoles has received signifi-
cant attention due to their known biological activity and
diverse medicinal uses.1 Despite this high level of interest,
few general methods to assemble the functionalized imida-
zole ring have been reported.2 Merck’s Losartan (Cozaar)
1, a nonpeptide angiotensin II receptor antagonist for the
treatment of hypertension,3 contains a 2,4,5-trisubstituted
imidazole 2. In our search for enabling synthetic technologies
for a general synthesis of the imidazole system, we reasoned
that imidazole 2 could be prepared via activation of N-
acylated R-aminonitrile 3 followed by cyclization, chlorina-
tion, and tautomerization. Herein, we describe our efforts to
effect the described set of chemical transformations, which
provide the desired imidazole product in a one-pot protocol.
(1) (a) Claiborne, C. F.; Liverton, N. J.; Nguyen, K. T. Tetrahedron Lett.
1998, 39, 8939. (b) Laufer, S.; Wagner, G.; Kotschenreuther, D. Angew.
Chem., Int. Ed. 2002, 41, 2290. (c) Bilodeau, M. T.; Cunningham, A. M.
J. Org. Chem. 1998, 63, 2800. (d) Kang, U. G.; Shechter, H. J. Am. Chem.
Soc. 1978, 100, 651. (e) Sarshar, S.; Zhang, C.; Moran, E. J.; Krane, S.;
Rodarte, J. C.; Benbatoul, K. D.; Dixon, R.; Mjalli, A. M. M. Bioorg. Med.
Chem. 2000, 10, 2599. (f) Zhang, C.; Sarshar, S.; Moran, E. J.; Krane, S.;
Rodarte, J. C.; Benbatoul, K. D.; Dixon, R.; Mjalli, A. M. M. Bioorg. Med.
Chem. 2000, 10, 2603. (g) Shilcrat, S. C.; Mokhallalati, M. K.; Fortunak,
J. M. D.; Pridgen, L. N. J. Org. Chem. 1997, 62, 8449.
(2) Only the wide range of benzimidazoles can be prepared from 1,2-
diaminobenzene and related compounds. For reviews on the synthesis of
imidazoles, see: (a) Grimmett, M. R. In ComprehensiVe Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Potts, K. T., Eds.; Pergamon
Press: New York, 1984; Vol. 5, pp 457-497. (b) Grimmett, M. R. In
ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Shinkai, I., Eds.; Pergamon Press: New York, 1996;
Vol. 3, pp 77-220. (c) Grimmett, M. R. In Imidazole and Benzimidazole
Synthesis; Academic Press: New York, 1997. For recent imidazole
syntheses, see: (d) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125,
5274. (e) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2002, 124, 13964. (f) Sisko, J.; Kassick, A. J.; Mellinger, M.; Filan, J. J.;
Allen, A.; Olsen, M. A. J. Org. Chem. 2000, 65, 1516. (g) Sisko, J. J. Org.
Chem. 1998, 63, 4529. (h) Groarke, M.; McKervey, M. A.; Nieuwenhuyzen,
M. Tetrahedron Lett. 2000, 41, 1275. (i) Rolfs, A.; Liebscher, J. J. Org.
Chem. 1997, 62, 3480. (j) Matsumura, K.; Kuritani, M.; Shimadzu, H.;
Hashimoto, N. Chem. Pharm. Bull. 1976, 24, 960. (k) Roesler, P. P.; Kille,
G.; Fleury, J.-P. Bull. Soc. Chim. Fr. 1967, 545.
We initially explored the described process with N-
benzoylated 2-phenylglycinonitrile 4, which was prepared
via benzoylation of 2-phenylglycinonitrile with either benzoyl
chloride or benzoic anhydride. Treatment of the N-acylated
R-aminonitrile 4 under Vilsmeier conditions with oxalyl
chloride in the presence of a catalytic amount of DMF in
acetonitrile at ambient temperature (Scheme 1) resulted in
the formation of imidoyl chloride 5, which slowly decom-
10.1021/ol036423y CCC: $27.50 © 2004 American Chemical Society
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Scheme 1
Table 1. Synthesis of 2,4-Disubstituted 5-Haloimidazoles from
N-Acylated R-Aminonitrilesa
poses at 50 °C.4 Cyclized product 6 was not detected. The
same results were observed using thionyl chloride or
phosphorus oxychloride in place of oxalyl chloride. This
result implies that imidoyl chloride 5 is not a viable
intermediate for the cyclization to imidazole 6. In contrast,
it was found that treatment of compound 4 with 1.0 equiv
of triphenylphosphine and 1.0 equiv of carbon tetrachloride
at room temperature in acetonitrile gradually generated
5-chloro-2,4-diphenyl-1H-imidazole 6 as observed by NMR
and HPLC-MS. Further development led to the use of 2.5
equiv of triphenylphosphine and 2.5 equiv of carbon
tetrachloride at 45 °C. Under the optimized conditions, 6
was isolated in 76% yield after silica gel chromatography.
The scope of this new synthetic method for the efficient
construction of 2,4,5-trisubstituted imidazole was investigated
by employing these optimized conditions. The results are
summarized in Table 1. All substrates shown in the table
were prepared from appropriate 2-aminoacetonitrile, 2-phen-
yl-2-aminoacetonitrile, or 2-(2′-phenylethyl)-2-aminoaceto-
nitrile via acylation with commercially available carboxylic
acid or acid chloride. A variety of substrates, including both
functionalized aromatic (entries 2-8) and aliphatic (entries
9-12) N-acylated R-aminonitriles were effectively cyclized
to the chloroimidazoles. Reactions with a substrate containing
a quaternary center (entry 9) proceeded smoothly.
a Procedure: See Supporting Information for a detailed procedure. b PPh3
(2.5 equiv), CCl4 (2.5 equiv). c Isolated yield. d Assay yield by HPLC.
experiments,5 a possible mechanism for the new imidazole
synthesis via cyclization of N-acylated R-aminonitriles is
proposed (Scheme 2). The formation of the intermediate 20b
takes place by the reaction of dichlorotriphenylphosphorane
and (dichloromethylene)triphenylphosphorane or (chlorom-
ethylene)triphenylphosphorane with N-acylated R-amino-
nitrile 20a. This process could lead to the novel seven-
membered ring intermediate 20c, which could undergo ring-
opening, intramolecular addition, and then tautomerization
to generate imidazole 20f.
On the basis of the detailed studies performed by To-
moskozi et al. on the Ph3P-CCl4-mediated chlorination of
alcohol and some intermediates observed through NMR
(3) (a) Carini, D. J.; Duncia, J. V.; Aldrich, P. E.; Chiu, A. T.; Johnson,
A. L.; Pierce, M. E.; Price, W. A.; Santella, J. B., III; Wells, G. J.; Wexler,
R. R.; Wong, P. C.; Yoo, S.-E.; Timmermans, P. B. M. W. M. J. Med.
Chem. 1991, 34, 2525 and references therein. (b) Shi, Y.-J.; Frey, L. F.;
Tschaen, D. M.; Verhoeven, T. R. Synth. Commun. 1993, 23, 2623 and
references therein. (c) Larsen, R. D.; King, A. O.; Chen, C. Y.; Corley, E.
G.; Foster, B. S.; Roberts, F. E.; Yang, C.; Lieberman, D. R.; Reamer, R.
A.; Tschaen, D. M.; Verhoeven, T. R.; Reider, P. J.; Lo, Y. S.; Rossano, L.
T.; Brookes, A. S.; Meloni, D.; Moore, J. R.; Arnett, J. F. J. Org. Chem.
1994, 59, 6391. (d) Griffiths, G. J.; Hauck, M. B.; Imwinkelried, R.; Kohr,
J.; Roten, C. A.; Stucky, G. C. J. Org. Chem. 1999, 64, 8084 and references
therein.
(4) (a) Pure imidoyl chloride 5 is stable (mp 78-79 °C); see: Suvalova,
E. A.; Chudakova, T. I.; Onys’ko, P. P.; Sinitsa, A. D. Zh. Obshch. Khim.
1987, 57, 1514. (b) Imidoyl chloride 5 cannot be converted to imidazole 6
in the presence of various bases, e.g., pyridine, triethylamine, and DBU.
Under these conditions, imidoyl chloride 5 slowly decomposed. No
imidazole was detected. (c) We did not observe the formation of imidoyl
chloride 5 by HPLC under our optimized reaction conditions (PPh3/CCl4,
acetonitrile). However, treatment of N-benzoylated â-aminonitrile under
standard conditions (PPh3/CCl4, acetonitrile, 45 °C) afforded imidoyl
chloride in high yield. The cyclized product was not observed.
(5) (a) Tomoskozi, I.; Gruber, L.; Radics, L. Tetrahedron Lett. 1975,
1
2473. (b) The reaction of 4 to 6 in CD3CN was monitored by H NMR at
0 °C. It was observed that the intermediate 20e slowly tautomerized to 20f.
The byproduct (chloromethyl)triphenylphosphonium chloride was identified
by NMR studies.
(c) This reaction requires a free amide N-H bond. In our control experiment,
no reaction was observed when N-benzoylated N-methyl-R-aminonitrile was
subjected to the standard reaction conditions (PPh3/CCl4, acetonitrile, 45
°C) as determined by HPLC. (d) The reaction can be carried out at 0 °C.
Attempts to observe intermediate 20c by NMR (1H, 13C, and 31P NMR) at
0 °C and room temperature were unsuccessful.
930
Org. Lett., Vol. 6, No. 6, 2004

Scheme 2
Scheme 4
from the 5-chloroimidazole products. Employing the Suzuki
coupling conditions developed by Fu et al. (Pd2(dba)3,
tBu3P‚HBF4, K3PO4)8 allowed direct coupling of the unpro-
tected 2,4-disubstituted 5-chloro-1H-imidazole 19b with
various aryl/vinyl boronic acids in good yield without
optimization (Scheme 4 ). To the best of our knowledge,
this is the first example of a Suzuki coupling with an
unprotected 5-chloroimidazole as the substrate.
In conclusion, we have developed a mild and general
method for the efficient synthesis of pharmacologically
important diversely functionalized 2,4,5-trisubstituted imi-
dazoles from N-acylated R-aminonitriles. We have shown
that other functional groups could be easily introduced to
the resulting unprotected 5-chloroimidazoles by the Suzuki
cross-coupling reaction.
A demonstration of the utility of this new reaction was
showcased in the synthesis of 2-butyl-4(5)-chloro-5(4)-
hydroxymethyl-1H-imidazole 2, a key intermediate for the
synthesis of Cozaar 1 (Scheme 3). The imidazole precursor
Scheme 3
Acknowledgment. We thank Dr. Thomas J. Novak for
mass spectrometric assistance and Dr. Jingjun Yin and Dr.
Michael Palucki for helpful discussions.
Supporting Information Available: Full experimental
details and spectral data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
21 was simply prepared in 70% overall yield from the
reaction of benzyloxyacetaldehyde and sodium cyanide,6
followed by acylation with valeric acid. Treatment of 21 with
2.5 equiv of PPh3 and 2.5 equiv of CCl4 in acetonitrile at 45
°C gave imidazole 22 in 81% isolated yield. Deprotection
of 22 with methanesulfonic acid in chloroform7 furnished
the Cozaar intermediate 2 in 90% yield.
OL036423Y
(7) Matterson, D. S.; Man, H.-W., Ho, O. C. J. Am. Chem. Soc. 1996,
118, 4560.
(8) (a) For a review of palladium-catalyzed coupling reactions of aryl
chloride, see: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
4176. (b) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387.
(c) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020. (d)
Yin, J.; Rainka, M. P.; Zhang, X.-X.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 1162.
To further demonstrate the utility of this method, the
synthesis of 2,4,5-trisubstituted imidazoles was investigated
(6) Deng, S.-L.; Liu, D.-Z. Synthesis 2001, 2445 and references therein.
Org. Lett., Vol. 6, No. 6, 2004
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