4740
J . Org. Chem. 2000, 65, 4740-4742
Ch a r t 1
Regioselective Mon oben zoyla tion of
Un sym m etr ica l P ip er a zin es
Tao Wang,* Zhongxing Zhang, and
Nicholas A. Meanwell
Bristol-Myers Squibb Pharmaceutical Research Institute,
5 Research Parkway, P.O. Box 5100,
Wallingford, Connecticut 06492
wangta@bms.com
Received J anuary 4, 2000
Monoacylated piperazines are useful synthetic inter-
mediates1 that are also important structural elements2
present in a number of investigational and established
drugs,3 including the cardiac stimulant vesnarinone and
the antihypertensive agent prazosin (Chart 1). The direct
monoacylation of piperazines is a difficult process that
is complicated by the tendency for bis-acylation to occur.4
Moreover, with 2-alkyl or 2,6-dialkyl substitution, there
is an additional problem associated with the regioselec-
tivity of the acylation. While there are a limited number
of procedures that allow benzoylation of the less hindered
piperazine nitrogen,5 a process that specifically directs
benzoylation to the more hindered piperazine nitrogen
has not been reported.6 We describe herein two general
and experimentally convenient protocols that direct
mono-benzoylation regioselectively to the sterically less
hindered nitrogen atom or regiospecifically to the more
sterically encumbered nitrogen of unsymmetrically sub-
stituted piperazines.
We have previously demonstrated that symmetrical
piperazines 1 can be monobenzoylated via a kinetic
process in which the dilithio anions 2 react rapidly with
benzoyl chloride to afford the monoaroylated derivatives
3 in high yield, as summarized in Scheme 1.7
Conceptually, we anticipated that this approach could
be extended to the selective monobenzoylation of unsym-
metrically substituted piperazines 4 by taking advantage
of differences in the steric environments proximal to the
N atoms. As depicted in Scheme 2, route A, steric
interactions would be expected to direct the aroylation
of dianion 5 with benzoyl chloride to the less hindered
nitrogen, providing 7 as the predominant product. Al-
ternatively, to direct aroylation toward the more steri-
cally encumbered nitrogen atom, the sterically more
accessible N atom could be masked temporarily with a
silyl group, to afford intermediate 6 in situ. The subse-
quent addition of benzoyl chloride would lead to selective
aroylation of the more hindered nitrogen, producing
compound 8 after workup (Scheme 2, route B).
The direct benzoylation of unsymmetrically substituted
piperazines (Scheme 2, route A) was examined under the
conditions established earlier,7 and the results are sum-
marized in Table 1. Aroylation of 2-alkyl-substituted
piperazines occurred with only modest regiocontrol re-
gardless of the steric demand associated with the alkyl
moiety (Table 1, entries a-e), with the notable exception
of the tert-butyl derivative (Table 1, entry f). The ratio
of the two regioisomers 7 and 8 ranged from 2:1 to 2.5:1
(Table 1, entries a-e) for the smaller alkyl substituents,
although the less hindered nitrogen was preferentially
aroylated, but was >20:1 for the tert-butyl analogue.
However, when 2,6-dimethylpiperazine was used as the
substrate, only the desired regioisomer 7g was detected
and isolated in good yield (Table 1, entry g). This result
indicates that significant control over the regiochemistry
of aroylation of piperazines can only be obtained with the
steric encumberance provided by tert-butyl mono- and
2,6-disubstitution.
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To evaluate the procedure depicted in Scheme 2, route
B, the dilithio anion of 2-methylpiperazine, 4a , was
treated with an equimolar amount of TMSCl prior to the
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10.1021/jo000005e CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/06/2000