Short synthesis of enantiopure trans-3-arylpiperazine-2-carboxylic acid derivatives via diaza-cope rearrangement

Article abstract of DOI:10.1021/ol301506b

An efficient synthetic method was developed for the construction of enantiomerically pure trans-3-arylpiperazine-2-carboxylic acid derivatives using diaza-Cope rearrangement (DCR) as a key step starting from (R,R)/(S,S)-1,2- bis(2-hydroxyphenyl)-1,2-diaminoethane (HPEN). A complete transfer of stereochemical integrity was observed for the transformation. Piperazine ring formation from the chiral 1,2-ethylenediamine derivatives using diphenylvinylsulfonium triflate followed by oxidation using ruthenium(III) chloride monohydrate in the presence of sodium periodate provided the desired enantiopure trans-3-arylpiperazine-2-carboxylic acid derivatives.

Full text of DOI:10.1021/ol301506b

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3664–3667
Short Synthesis of Enantiopure
trans-3-Arylpiperazine-2-carboxylic Acid
Derivatives via Diaza-Cope
Rearrangement
Soon Ho Kwon,† Sang Min Lee,† Sang Moon Byun,† Jik Chin,*,‡ and B. Moon Kim*,†
Department of Chemistry, College of Natural Sciences, Seoul National University,
Seoul 151-747, South Korea, and Department of Chemistry, University of Toronto,
Toronto, Ontario M5S 3H6, Canada
kimbm@snu.ac.kr; jchin@chem.utoronto.ca
Received June 1, 2012
ABSTRACT
An efficient synthetic method was developed for the construction of enantiomerically pure trans-3-arylpiperazine-2-carboxylic acid derivatives
using diaza-Cope rearrangement (DCR) as a key step starting from (R,R)/(S,S)-1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (HPEN). A complete
transfer of stereochemical integrity was observed for the transformation. Piperazine ring formation from the chiral 1,2-ethylenediamine
derivatives using diphenylvinylsulfonium triflate followed by oxidation using ruthenium(III) chloride monohydrate in the presence of sodium
periodate provided the desired enantiopure trans-3-arylpiperazine-2-carboxylic acid derivatives.
Piperazine is a useful building block often employed in
the design of physiologically active molecules.1 Among
various substituted piperazine structures, piperazine-
2-carboxylic acid derivatives can be regarded as novel amino
acid analogues and therefore have been utilized in many
peptidomimetic structures for therapeutically important
compounds. Examples of chiral piperazine-2-carboxylic
acid derivatives embedded in drug candidates include a
human immunodeficiency virus (HIV) protease inhibitor,2
cholecystokinin-1 receptor (CCK1R) agonists,3 κ-receptor
agonists,4 substance P (SP) receptor antagonists,5N-
methyl-D-aspartic acid (NMDA) antagonists,6 and MMP-
13 and TNF-R converting enzyme inhibitors (Figure 1).7
Although many reports exist for the synthesis of
optically active piperazine-2-carboxylic acid derivatives,
preparation of stereodefined 3-, 5-, or 6-substituted piper-
azine-2-carboxylic acid derivatives in an enantiomeri-
cally pure form is still a challenging synthetic pro-
blem. Previously, chiral piperazine-2-carboxylic acid
derivatives have been synthesized through cyclizations,8
multicomponent synthesis,9 amino-acid-based synthesis,10
enzymatic resolution,11 asymmetric hydrogenation of
pyrazine derivatives,12 R-lithiation of piperazine using
† Seoul National University.
‡ University of Toronto.
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10.1021/ol301506b
Published on Web 07/06/2012
2012 American Chemical Society

final compounds, and low yields resulting from compli-
cated multistep syntheses. In the course of our medicinal
chemistry programs, we were in search of an efficient
method for the preparation of trans-3-arylpiperazine-
2-carboxylic acid derivatives and have found that there
are scarce reports on them.8g To obtain 3-substituted
piperazine-2-carboxylic acids, SN2-type cyclization and
the reduction of 2,3-disubstituted ketopiperazines derived
from chiral 1,2-diamines have been previously used.7,8g
For the latter method, synthesis of suitably substituted
enantiopure chiral vicinal diamines is essential. We have
recently developed a stereospecific synthesis of symmetric
chiral vicinal diaminesthrough the rearrangement ofchiral
diimines prepared from the reaction of (R,R)/(S,S)-1,
2-bis(2-hydroxyphenyl)-1,2-diaminoethane (HPEN) and
2 equiv of aldehydes.15 The rearrangement reaction was
nicely extended to a stereospecific “one pot” route to R-
substituted syn-R,β-diamino esters.16 We envisioned that
the chiral nonsymmetrical 1,2-disubstituted vicinal dia-
mines synthesized by diaza-Cope rearrangement (DCR)
could serve as suitable intermediates for the preparation
of chiral nonsymmetrical 2,3-substituted piperazines.
Herein, we report on the development of an efficient route
to enantiopure trans-3-arylpiperazine-2-carboxylic acids
starting from optically pure HPEN via DCR using various
aryl aldehydes and trans-cinnamaldehyde.
Figure 1. Compounds containing chiral piperazine-2-carboxylic
acid derivatives.
Toward the construction of structurally diverse trans-3-
arylpiperazine-2-carboxylic acids, formation of the un-
symmetrically substituted diimines was studied from the
reaction of HPEN, benzaldehyde, and trans-cinnamalde-
hyde. To find optimal reaction conditions, factors such as
solvent and stoichiometry of aldehydes were investigated.
From solvent screening experiments using DMSO, THF,
and toluene, DMSO was quickly identified as the solvent
of choice. As for the reaction stoichiometry, 1 equiv of aryl
aldehyde and 1 equiv of trans-cinnamaldehyde were found
to be optimal for the reaction. The reactions proceeded
smoothly at room temperature, and reactions at higher
temperatures did not improve the yield. Since two different
aldehydes are involved in the reaction to form heterodi-
meric diimine product, the hetero- versus homodimer
selectivity is critical. It was found that the best heterodimer
s-BuLi/(ꢀ)-sparteine,13 and Pd-catalyzed asymmetric
allylic allylation.14 However, some of these methods suffer
from shortcomings such as the problem of catalyst traces
remaining in final product(s), low enantiomeric purities of
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Org. Lett., Vol. 14, No. 14, 2012
3665

selectivity was obtained when an aminal 2 was first for-
med and then was subjected to the reaction with trans-
cinnamaldehyde, as outlined in Scheme 1. The formation
of the aminal 2 was accomplished through slow addition of
an aryl aldehyde to the solution of HPEN. This aminal 2
was then subjected to the reaction with cinnamaldehyde
without isolation. Addition ofcinnamaldehyde to aminal2
then allowed for the formation of diimine 3, which was
converted to the desired diimine 4 facilitated by the
resonance-assisted hydrogen bonding (RAHB).15b The
formation of diimine 4 was observed as a major product
along with small amounts of homodimeric diimine pro-
ducts of each aldehyde.
Table 2. Synthesis of N-Ns-Protected Vicinal Diaminesa
entry
product
Ar
yield (%)b
ee (%)e
1
2
8a
8b
8c
8d
8e
8f
Ph
79
86
84
84
83
91
76
74c,d
76
59
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99f
4-FC6H4
3
4-ClC6H4
4
2-BrC6H4
5
3-BrC6H4
Scheme 1. Stereospecific Synthesis of Diimine via Diaza-Cope
Rearrangement
6
4-BrC6H4
7
8g
8h
8i
1-naphthyl
2-pyridyl
8
9
4-OMeC6H4
4-acetamidophenyl
10
8j
a Reagents and conditions: (a) 2.5 equiv of concd HCl in THF (0.1 M);
(b) 4 equiv of 4-NsCl, 6 equiv of TEA in THF (0.1 M). b Yields of isolated
products after column chromatography. c Excess (3.5 equiv) concd HCl
was used. d In this reaction, 8 equiv of TEA was used in dichloro-
methane. e Values of ee were determined through chiral HPLC analysis
using Chiralpak IA column. f Value of ee was determined at the chiral
diimine 4j stage.
diimines and slightly higher ratios of unwanted homodi-
meric diimines (entries 9 and 10, respectively).
Formation of the homodimeric product 6 of trans-
cinnamaldehyde is believed to come from the very nature
of the reaction, which involves an equilibrium from HPEN
and two aldehydes to the very end product, thus allowing
for disproportionation after addition of trans-cinnamalde-
hyde. Attempts to purify the heterodimeric diimine pro-
ducts from the homodimeric diimines on a silica gel
column were accompanied by some decomposition of the
diimine species. Therefore, we decided to purify the hetero-
dimeric product at a later stage.
Hydrolysis ofdiimine4 and subsequent protection of the
resulting diamine 7 was carried out, and the data are shown
in Table 2. Upon hydrolysis of diimines 4aꢀj using con-
centrated HCl, diamine HCl salts 7aꢀj were obtained as
precipitates. HCl salts 7aꢀj underwent smooth reaction
with 4-nitrobenzenesulfonyl chloride (NsCl) and triethy-
lamine in THF to give N,N0-bisNs-protected vicinal dia-
mines 8aꢀj in good overall yields (59ꢀ91% for the two
steps). Enantiomeric purities of the product diamines were
determined at this stage through chiral HPLC analyses,
and all of them were uniformly high (>99% ee).
With the optimized reaction conditions in hand, various
aryl aldehydes were investigated in the formation of com-
pound 2 to ensure structural diversity of the chiral piper-
azine derivatives. Excellent yields (mostly >90%) of
aminal intermediates 2 were observed as determined by
NMR analysis (see Table 1).17 In this step, slow addition of
the aryl aldehyde was found to be critical to minimize the
formation of homodimeric diimine product 5 or 6. Subse-
quently, the formation of heterodimeric diimine 4 as a
major product was confirmed 12 h after addition of 1 equiv
of trans-cinnamaldehyde.
As can be seen in Table 1, the yields of heterodimeric
diimine 4 were dependent upon the substituents on aryl
aldehydes. Diimines formed from an aryl aldehyde con-
taining electron-withdrawing or halide substituents were
obtained in good to excellent yields (entries 2ꢀ6) with
good hetero/homo product ratios, which were deter-
mined through 1H NMR analysis.17 Diimines formed
from 1-naphthyl and heteroaromatic aldehydes were also
obtained in satisfactory yields (entries 7 and 8). On
the other hand, reactions of p-methoxybenzaldehyde and
4-acetamidobenzaldehydegavemoderateyields ofproduct
In 2008, Aggarwal et al. reported an annulation reaction
for the synthesis of piperazines from ethylenediamine
derivatives using diphenylvinylsulfonium triflate.18 We
took compound 7a to study optimal reaction condi-
tions for the construction of piperazine structures using
Aggarwal’s protocol. First, reactions using Aggarwal’s
(18) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Angew. Chem.,
Int. Ed. 2008, 47, 3784–3786.
(17) Mesitylene was used as an internal standard in NMR analysis.
3666
Org. Lett., Vol. 14, No. 14, 2012

Table 1. Stereospecific Synthesis of Chiral Nonsymmetrical
Disubstituted Diiminesa
Scheme 2. Synthesis of Enantiopure 3-Arylpiperazine-2-car-
boxylic Acids
entry product
Ar
yield (%)b 4/5/6 ratiob,c
1
2
4a
4b
4c
4d
4e
4f
Ph
89
91
91
86
91
83
90
82
71
74
88/7/5
88/7/5
91/4/5
97/2/1
91/6/3
91/4/5
89/7/4
94/4/2
79/13/8
80/11/9
4-FC6H4
3
4-ClC6H4
4
2-BrC6H4
5
3-BrC6H4
6
4-BrC6H4
removal of the N,N0-diTs group. The N,N0-diNs protec-
tion provided another advantage where, at this stage, the
heterodimeric amines were easily separable from the
homodimeric diamine derivatives through silica gel col-
umn chromatography.
7
4g
4h
4i
1-naphthyl
2-pyridyl
8
9
4-OMeC6H4
4-acetamidophenyl
10
4j
a Reagents and conditions: (a) ArCHO, DMSO, rt, 1 h; (b) trans-
cinnamaldehyde, rt, 12 h. b Determined by 1H NMR analysis of the
crude mixture. c The relative Rf values of the homodimeric side products
compared to the desired heterodimeric product vary depending upon
their structures.
With the optimal protecting group selected, another sub-
strate having a 4-bromophenyl substituent (compound 8f)
was tested for the ring forming reaction with diphenylvi-
nylsulfonium triflate 11, and the reaction proceeded in
89% yield, showing the generality of this cyclization. Even-
tually, the double bond moieties of 9a and 9f were effi-
ciently oxidized into carboxylic acids via oxidation using
ruthenium(III) chloride monohydrate with sodium perio-
date21 in 74 and 72% yields, respectively (Scheme 2).
In conclusion, we have developed a simple, yet highly
efficient synthetic route for enantiopure trans-3-arylpiper-
azine-2-carboxylic acids as exemplified in 10a and 10f
starting from HPEN as a chiral starting material with
various aryl aldehydes and trans-cinnamaldehyde. Use of
the chiral 3-arylpiperazine-2-carboxylic acids as an artifi-
cial amino acid analogue in the construction of physiolo-
gically activecompoundsisinprogressandwillbereported
in due course.
vinylsulfonium salt were attempted on the free diamine 7a;
however, the reaction was very sluggish, yielding only
11% of the desired piperazine product. Diamines having
various N,N0-protecting groups such as Boc, CBz, CF3CO,
Ts, and Ns groups, which are associated with diffe-
rent pKa values,19 were screened for the construction
of piperazine ring (the results are reported in the Support-
ing Information, Table S1). The reaction from N,N0-
diBz-protected diamines gave almost no desired pro-
duct at all. However, 47% yield of the desired piperazine
ring was obtained in the reaction of the N,N0-
di-Boc-protected diamine. When more acidic N,N0-diNs
or diTs groups, which allow lower pKa values on the
nitrogen atoms compared to other protecting groups, were
employed as protecting groups, the reactions proceeded
in good yields (82 and 84%, respectively). Even though
both N,N0-diTs- and N,N0-diNs-protected diamines pro-
vided good yields of the desired product, N,N0-diNs pro-
tection, which can be deprotected via treatment with PhSH
and K2CO3 in dimethylforamide,20 was preferred since
harsh reaction conditions would be required for the
Acknowledgment. This research was supported by Ba-
sic Science Research Program through the National Re-
search Foundation of Korea (NRF) funded by the
Ministry of Education, Science and Technology (2009-
0073645). J.C. thanks the Natural Sciences and Engineer-
ing Research Council of Canada for financial support.
Supporting Information Available. Experimental de-
tails and compound characterizations. This material is
available free of charge via the Internet at http://pubs.acs.
org.
(19) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463.
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36, 6373–6374.
(21) (a) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J. Org. Chem. 1981, 46, 3936–3938. (b) Davies, H. M. L.; Bruzinski,
P. R.; Lake, D. H.; Kong, N.; Fall, M. J. J. Am. Chem. Soc. 1996, 118,
6897–6907.
The authors declare no competing financial interest.
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