Synthesis of substituted 1H-imidazol-1-ylmethylpiperidines. Facile separation of 1,4- and 1,5-disubstituted imidazoles

Article abstract of DOI:10.1016/S0040-4039(02)02157-3

The synthesis of several 1H-imidazol-1-ylmethylpiperidines is described. A method for the regioselective isolation of 1,4-disubstituted imidazoles utilizing the selective quaternization of the 1,5-disubstituted regioisomer was developed.

Full text of DOI:10.1016/S0040-4039(02)02157-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8917–8919
Synthesis of substituted 1H-imidazol-1-ylmethylpiperidines.
Facile separation of 1,4- and 1,5-disubstituted imidazoles
Jocelyn Rivera, Nilukshi Jayasuriya, Dinanath Rane, K. Keertikar, J. Albert Ferreira,
Jianping Chao, Keith Minor and Timothy Guzi*
Chemical Research, Infectious Diseases and Tumor Biology, Schering–Plough Research Institute, 2015 Galloping Hill Road,
Kenilworth, NJ, 07033, USA
Received 26 August 2002; revised 26 September 2002; accepted 30 September 2002
Abstract—The synthesis of several 1H-imidazol-1-ylmethylpiperidines is described. A method for the regioselective isolation of
1,4-disubstituted imidazoles utilizing the selective quaternization of the 1,5-disubstituted regioisomer was developed. © 2002
Elsevier Science Ltd. All rights reserved.
As farnesyl transferase has emerged as a leading target
for the development of novel cancer chemotherapeutic
agents many of the most potent inhibitors have been
found to contain functionalized imidazoles.1 As part of
a continuing research program to identify novel farne-
syl transferase inhibitors, we were interested in prepar-
nitrogen protection gave aminoalcohol 3. Treatment of
3 with tosyl chloride, displacement with sodium imida-
zole, and deprotection gave the desired product 5a. The
corresponding 2-methyl derivative was prepared in a
similar fashion by substituting imidazole for 2-
methylimidazole gave the corresponding derivative 5b.
ing
a
series of compounds containing the
1H-imidazol-1-ylmethylpiperidine moiety with varying
substitution on the imidazole ring.
While the preparation of N-substituted and 1,2-disub-
stituted imidazoles is straightforward, the regioselective
preparation and separation of the 1,4- and 1,5-disubsti-
tuted imidazoles presents a more difficult problem.
Direct alkylation generally gives limited enrichment of
one regioisomer over the other. In rare instances, the
1,4-disubstituted analogs can be prepared by direct
alkylation, but the relative efficiency is dependent on
the presence of directing substitution.3c,4 Limited exam-
ples for the preparation of the 1,4-disubstituted cases
through the construction of the imidazole ring have
been developed but these preparations are generally
limited in scope and yield.5
The general synthetic route to this class of compound is
illustrated in Scheme 1. Resolution of ethyl nipecotate
using tartaric acid,2 followed by LAH reduction and
Substantial precedent exists for the preparation of 1,5-
disubstituted imidazoles.3 Quaternization of the N4-
protected triphenylmethyl imidazole with the desired
electrophile and cleavage of the more labile triphenyl-
methyl group readily yields the 1,5-disubstituted imida-
zole. Successful quaternization is dependent on the use
of highly electrophilic alkylating agents which is some-
what limiting to the overall breadth of the sequence.
Scheme 1. Reagents and conditions: (a) Ref. 1; (b) LiAlH4; (c)
ditertbutyldicarbonate; (d) p-tosyl chloride; (e) R=H, sodium
imidazole; R=CH3, NaH, 2-methyl imidazole.
By exploiting the propensity of the imidazole ring to
undergo quaternization, we discovered an efficient
method for the separation and isolation of mixtures of
* Corresponding author. Tel.: +0-908-740-2883; fax: +0-908-740-7152;
e-mail: timothy.guzi@spcorp.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02157-3

8918
J. Ri6era et al. / Tetrahedron Letters 43 (2002) 8917–8919
Scheme 2. Reagents and conditions: (a) NaH, 4(5)-methylimidazole; (b) TrCl; (c) MeOH, reflux.
General procedure for isolation of 1,4-disubstituted imi-
1,4- and 1,5-disubstituted imidazoles. Thus, quaterniza-
tion utilizing sterically encumbered yet reactive
triphenylmethyl chloride, regioselectively occurs on the
least hindered nitrogen and, therefore, predominates on
the 1,5-disubstituted regioisomer.
dazoles: To a solution of 6 (0.295 mol, 60% 1,4-disubsti-
tuted regioisomer) in CH2Cl2 (1000 mL) at 0°C was
added triphenylmethyl chloride (37.6 g, 1.15 equiv.
based on 1,4-disubstituted) in one portion. The result-
ing solution was stirred at 0°C for 2 h and concentrated
under reduced pressure. The residue was redissolved in
CH2Cl2 and loaded onto a plug of silica gel (100×140
mm) and eluted using a 50:50 EtOAc:acetone mix as
eluent to give 7 as a clear oil (37.5 g, 75% yield, based
In practice, direct alkylation of the intermediate tosyl-
ate 4 gave 6 as a ꢀ60:40 mix of 1,4- and 1,5-disubsti-
tuted imidazoles, respectively, as determined by NMR
(Scheme 2). Regioselective coordination of the 1,5-di-
substituted imidazole with triphenylmethylchloride led
to an easily separable mixture of 7 and quaternized
1,5-disubstituted imidazole 8 in good yield based on the
initial composition of the mixture. While the prepara-
tion of the 1,4-disubstituted isomers were of greater
interest for our program, the 1,5-disubstituted isomer 9
can be easily isolated by liberating the quaternized
product by heating in methanol at reflux. Because
quaternization of the 1,4-isomer does occur to some
extent in the presence of excess triphenylmethylchloride
adjustment of equivalents of triphenylmethyl chloride
relative to the 1,4-isomer is essential for isolation of the
desired regioisomer, i. e. 1.05 and 0.95 equiv. for the
mixture of the 1,4- and 1,5-isomer, respectively.
1
on 1,4-disubstituted regioisomer). H NMR (CDCl3):
7.32 (s, 1H), 6.61 (s, 1H), 3.79 (m, 4H), 2.7 (m, 1H),
2.22 (s, 3H), 1.89 (m, 2H), 1.69 (m, 2H), 1.45 (m, 10H),
1.20 (m, 1H); 13C NMR (CDCl3): 154.4, 137.3, 136.2,
115.5, 79.6, 49.7, 46.9, 44.1, 37.0, 28.3, 28.1, 24.0, 13.4;
FABMS: 280 (M+H). [h]2D0=−10° (c 2.5, CH3OH).
Anal. (C15, H25, N3, O2.0.05 CH2Cl2) C, H, N.
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In conclusion, we have developed a method for the
efficient synthesis of 1H-imidazol-1-ylmethylpiperidi-
nes. The development of an efficient method for the
separation of 1,4- and 1,5-disubstituted mixtures
allowed for the facile preparation of a variety of pure 1,
4-disubstituted imidazole analogs.

J. Ri6era et al. / Tetrahedron Letters 43 (2002) 8917–8919
Table 1. Isolation of 1,4-disubstituted imidazoles
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