An efficient synthetic approach for N-C bond formation from (S)-amino acids: An easy access to cis-2,5-disubstituted chiral piperazines

Article abstract of DOI:10.1039/c3ra42309c

An efficient synthetic strategy is described for the construction of amino acids derived enantiomerically pure cis-2,5-disubstituted chiral piperazines. Cu-catalyzed spontaneous regioselective ring opening and ring closing of non-activated N-tosyl aziridines as well as Pd-mediated N-C bond formation from N-tosyl halogenated amino-derivatives are the key steps for accessing disubstituted piperazines.

Full text of DOI:10.1039/c3ra42309c

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An efficient synthetic approach for N–C bond formation
from (S)-amino acids: an easy access to cis-2,5-
disubstituted chiral piperazines3
Cite this: RSC Advances, 2013, 3,
1
8332
Sudipta Kumar Manna and Gautam Panda*
Received 10th May 2013,
Accepted 24th July 2013
An efficient synthetic strategy is described for the construction of amino acids derived enantiomerically
pure cis-2,5-disubstituted chiral piperazines. Cu-catalyzed spontaneous regioselective ring opening and
ring closing of non-activated N-tosyl aziridines as well as Pd-mediated N–C bond formation from N-tosyl
halogenated amino-derivatives are the key steps for accessing disubstituted piperazines.
DOI: 10.1039/c3ra42309c
www.rsc.org/advances
prostatic hyperplasia. Also many compounds having the
piperazine scaffold find use in asymmetric catalysis as chiral
ligands. Traditionally, the asymmetric synthesis of chiral
Introduction
Piperazines, nitrogen-containing heterocycles and related
compounds are of major interest because of their wide
spectrum of pharmaceutical importance. They display a variety
21
piperazines involves the reduction of substituted mono- and
22,23
diketopiperazines
which are again obtained either from
1
,2
3
of biological activities including dopamine D
3
agents acting
chiral building blocks or via asymmetric synthesis using a
chiral auxiliary. However, this strategy suffers from many
drawbacks. Though Lewis acid mediated nucleophilic ring
4
5
1b
on CNS receptor, 5HT-anxiolytics, HIV protease inhibitors
such as indinavir, antimicrobial agents such as pefloxacin and
6
7
related quinolones, Bcl-2 inhibitors, cytochrome c inhibi-
22
opening of aziridines are well documented, copper acetate
8
9
10
tors, anti-proliferative agents, and antihypertensive agents.
catalyzed spontaneous regioselective ring opening and closing
of non-activated aziridines are new methods in this arena.
Our group is committed to developing new synthetic
methodology for the synthesis of chiral heterocycles and their
Furthermore, there are also a number of bioactive natural
products containing chiral piperazine spacer such as ectenais-
1
1
12
13
cidin 743,
Fig. 1).
piperazinomycin
and dragmacidins
(see
24
bioevaluation and in continuation of this project, we have
Piperazinomycin has been isolated from Streptoverticillium
developed an efficient synthetic methodology to synthesize
chirally pure cis-2,5-disubstituted piperazines utilizing cataly-
tic N–C bond formation.
1
2
olivoreticuli Neoenacticus and has antimicrobial and anti-
fungal activity. The group of dragmacidin alkaloids represent a
promising class of marine natural products obtained by an
exhaustive set of protocols from a number of deep water
sponges including Dragmacidon, Halicortex, Spongosorites,
1
3–15
Hexadella and the tunicate Didemnum candidum.
Although these compounds have been shown to hold a wide
array of biological activities, some of their metabolites
(
piperazine linking dragmacidins) exhibit potent and diverse
1
3,16,18
15a
15a
bioactivities such as cytotoxic,
antifungal,
antitumor, antiviral,
1
6,17
19
and anti-inflammatory activities. Bisindole
alkaloids, such as dragmacidins have been reported to inhibit
2
0
the ligand binding to a1a and a1b adrenergic receptors. The a
1
adrenergic antagonists may be considered as potential
candidates for the treatment of hypertension and benign
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute,
Lucknow-226001, UP, India. E-mail: gautam.panda@gmail.com;
gautam_panda@cdri.res.in; Fax: (+91)-522-2623405;
Tel: (+91)-522-2612411-18 (8 lines)
Fig. 1 Some important representative piperazine core containing natural
3
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3ra42309c
products.
1
8332 | RSC Adv., 2013, 3, 18332–18338
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Table 1 Optimization studies for the synthesis of 12b from halogenated amino
derivatives
Scheme 1 Retrosynthetic analysis of piperazine derivatives.
a
Entry Catalyst
Solvent
T/uC Base Yield (%)
c
1
2
3
4
5
6
7
Pd(OAc)
Pd(OAc)
2
5 mol (%)
10 mol (%)
10 mol (%)
DMF
Toluene
Acetonitrile 110 K
110 K
120 K
2
2
2
2
2
CO
CO
CO
CO
CO
3
3
3
3
3
55
Result and discussion
2
NR
NR
24
NR
Trace
NR
Pd(PPh
Pd(PPh
—
3
)
)
4
Retrosynthetic analysis
3
2
Cl
2
10 mol (%) DMSO
120 K
110 K
110 —
The retrosynthetic analysis of piperazines is illustrated in
Scheme 1. We envisioned that the chiral piperazine could be
constructed from intermediate B and D through intermole-
cular catalytic N–C bond formation via palladium acetate
mediated non-activated N-tosyl halogenated amino derivatives
DMF
DMF
Toluene
Pd(OAc)
Pd(MeCN)
0 mol (%)
Pd(PPh Cl
0 mol (%)
Pd(OAc)
0 mol (%)
Pd(OAc)2
2
10 mol (%)
Cl
2 2
110 K
2
CO
2
CO
2
CO
3
3
3
1
8
3
)
2
2
DMF
110 K
NR
NR
1
9
2
1,4-dioxane 100 K
(from B) and copper acetate mediated regioselective N-tosyl
1
b
aziridines ring opening (from D) and ring closing among
different amino acids counterparts by the synthetic sequences
mentioned above.
First, the synthesis of chiral halogenated amino alcohols
and aziridines was undertaken. All the compounds were
prepared with good yields from different naturally abundant
10
DMSO
DMF
2
110 K CO3 57(47 )
10 mol (%)
11
12
13
14
15
16
Pd(MeCN)
Cl
2 2
120 K
110 K
120 K
110 K
110 K
110 K
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
3
3
3
3
3
3
3
3
3
NR
NR
32
1
0 mol (%)
Pd(PPh
10 mol (%)
Pd(OAc)
0 mol (%)
3
)
4
Toluene
DMA
2
1
(S)-amino acids following four synthetic steps, involving
Pd(MeCN)
5 mol (%)
Cl
2 2
DMSO
DMF
NR
esterification of acids, tosylation of amines, LAH reduction
b
d
2
5
Pd(OAc)
10 mol (%)
Pd(PPh Cl
10 mol (%)
Pd(PPh Cl
0 mol (%)
Pd(OAc)
2
66(59 )(,55 )
of ester groups followed by Appel reaction (halogenations of
2
6
amino alcohols) and Mitsunobu cyclization (Scheme 2). Now
3
)
2
2
2
DMF
NR
NR
53
with chiral halogenated amino alcohols 10a–f and aziridines
11a–e in hand, the stage was set to implement the crucial
17
3
)
2
1,4-dioxane 110 K
1
catalytic N–C bond formation towards cis-2,5-disubstituted
chiral piperazines.
18
2
DMSO
DMF
110 K
110 K
5
mol (%)
e
In order to optimise the desired reaction conditions, at first
we used (S)-N-(1-bromo-3-methylbutan-2-yl)-4-methyl-benzene-
sulfonamide 10b as a model substrate with different Pd
19
Pd(OAc)
2
52
1
0 mol (%)
a
b
c
Isolated yield of 12b. 2 equiv. of Cs CO instead of K CO . 1.5
equiv. of K
replaced by -I, NR = no reaction.
2
3
2
3
d
e
2
CO
3
.
Reaction temperature (70–80 uC). When -Br is
sources, solvents, and bases at varied temperatures (Table 1).
The reaction occurred through oxidative addition, (cyclic five
membered stable transition state) and intra molecular
nucleophilic substitution followed by reductive elimination
to afford the desired (2S,5S)-2,5-diisopropyl-1,4-ditosylpiper-
azine 12b with 55% yield when the substrate was stirred with 5
mol% Pd(OAc)
Scheme 3.
2
in DMF at 110 uC under an argon atmosphere,
The catalytic activity of the Pd sources were compared, and
Pd(OAc)2 was found to be superior to Pd(PPh ) Cl ,
3 2
2
Pd(MeCN) Cl and Pd(PPh ) . Replacing the solvent DMF with
2
2
3 4
DMSO gave a 53% yield of 12b . The yield of 12b was further
increased to 66% when the substrate was stirred with 10 mol%
Pd(OAc)
2
in DMF. In contrast, solvents such as toluene,
acetonitrile, DMA, and 1,4-dioxane gave inferior results. The
2 3 2 3 2 3
reaction was effective with K CO , Cs CO , but K CO yielded
the best results.
Scheme 2 Synthesis of chiral halogenated amino derivatives (10a–f) and
aziridines (11a–e).
Lowering the reaction temperature (below 100 uC) or the
base (1.5 equiv.) gave ,55% yield of 12b. Control experiments
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Scheme 3 Proposed mechanistic pathway for the synthesis of symmetrical and unsymmetrical piperazine derivatives.
confirmed that no product was obtained in the absence of the
palladium source. In summary, the optimal conditions in DMF
include Pd(OAc) (10 mol%) and K CO (2 equiv.) at 110 uC for
marily occurs at the benzylic position presumably due to the
stabilisation of the incipient carbocation by the phenyl ring.
3
0
2
2
3
Similarly nucleophilic attack on the non-activated 2-phenyla-
ziridines occurs almost exclusively at the benzylic position,
while reactivity as a formal 1,3-dipole obtained by a C–N bond
cleavage, to the best of our knowledge, has never been
24 h under an argon atmosphere. However, this reaction was
performed two times on the gram scale (10b: 3.840 mmol,
yield: 64% and 4.746 mmol, yield: 63%).
Next, we decided to vary the protecting groups in the final
products, so that they could be easily deprotected. But when
we subjected tert-butyl (2S,3R)-1-bromo-3-methylpentan-2-
3
1
reported.
While surveying the literature we found that the formation
of piperazinium halides from N-alkylaziridines and the
formation of C-unsubstituted piperazines from b-chloro- or
b-tosyloxyethylamines have been respectively reported by
ylcarbamate 10c
of getting the desired piperazine, we obtained (S)-4-sec-
butyloxazolidin-2-one 12c (Scheme 4) as the sole product.
1
to the above optimised condition instead
3
2
33
1
Dick et al. and De Kimpe et al. Further He et al. observed
the formation of N,N9-diethyl piperazines as a minor side
So, we considered other protecting groups such as tosyl
chloride, nosyl chloride, mesyl chloride. Finally we detected
tosyl chloride as an optimised protecting group on the basis of
variation of yields (Table 2).
product when N-alkyl C -substituted aziridines were reacted
2
3
4
with CO2. Recently it was found that in the presence of
metal, some non-activated aziridines underwent dimerization
to the corresponding piperazines depending on the reaction
After successful synthesis of piperazine derivatives from
halogenated amino derivatives, we turned our attention to
access the chiral piperazine scaffold through copper acetate
mediated regioselective ring opening and ring closing of
N-tosyl aziridines 11a–e. For ring opening reactions (both
nucleophilic as well as pericyclic) of aziridines, it is well
documented that the substituents attached to the nitrogen
atom play a decisive role. For example, electron withdrawing
groups on the nitrogen atom activate the aziridine ring
towards the ring opening reaction while the electron releasing
3
5
conditions.
For the said purpose, we performed a model study on one of
the previously prepared piperazines 12b, the reaction condi-
tions were optimized using (S)-2-isopropyl-1-tosylaziridine 11b
as a model substrate with different Cu sources, solvents, and
bases at various temperatures (Table 3). To find the most
2
7
Table 2 Variation of protecting groups for the synthesis of 12b
group deactivates it. Moreover aziridines can act as marked
,3 dipoles and thereby take part in Lewis acid (LA) mediated
or thermal 1,3 dipolar cycloaddition with alkenes, nitriles and
1
2
8,29
ketones.
However LA mediated nucleophilic attack pri-
a
Entry
R
PG
Yield (%)
1
2
3
–CH(CH
–CH(CH
–CH(CH
3
3
3
)
)
)
2
2
2
-Ts(10b)
66
58
51
-Ns(10b
1
)
-Ms(10b
2
)
a
Scheme 4 Synthesis of (S)-4-sec-butyloxazolidin-2-one.
Isolated yield of 12b after silica gel column chromatography.
1
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Table 3 Catalytic scanning of 12b from aziridines
Table 4 Synthesis of piperazine derivatives from halogenated amino derivatives
and aziridines
a
Entry
Catalyst
Solvent
Base
T/uC
Yield (%)
a
Entry
R
1
R
2
Yield (%)
1
2
3
4
5
6
7
8
9
Cu(OAc)
Cu(OAc)
2
DMF
DMF
DMF
DMF
DMSO
DMF
DMF
DMSO
DMF
Toluene
1,4-dioxane
K
—
2
CO
CO
CO
3
3
3
80
80
80
80
47
2
NR
b
c
b
1(12a)
-methyl
-methyl
57 (52 )
b c
Cu(OTf)
Cu(OTf)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
K
2
43
2
3
(12b)
(12c)
-iso-propyl
-sec-butyl
-iso-butyl
-iso-propyl
-sec-butyl
-iso-butyl
-benzyl
O-Tos-benzyl
-iso-butyl
-benzyl
66 (76 )
b c
2
—
NR
32
76(54)
76 (68 )
2
2
2
2
K
2
80
b
c
c
4(12d)
69 (71 )
Cs
—
Cs
Cs
Cs
Cs
2
CO
3
100
100
100
100
100
100
b c
5
6
(12e)
(12f)
-benzyl
62 (56 )
NR
44
b
O-Tos-benzyl
-sec-butyl
-sec-butyl
O-Tos-benzyl
O-Tos-benzyl
70
2
2
2
2
CO
CO
CO
CO
3
3
3
3
d
b
7(12g)
52
Cu(OTf)
Cu(OAc)
Cu(OAc)
2
72
d
8
9
1
(12h)
(12i)
0(12j)
48
1
1
0
1
2
2
NR
NR
d
-benzyl
-iso-butyl
51
d
47
a
b
Isolated yield of 12b after silica gel column chromatography.
Mixture of diastereoisomers. 5 mol% Cu(OAc) , NR = no reaction.
2
a
c
Isolated yield of piperazine derivatives after silica gel column
b
chromatography. Isolated yield from chiral halogenated amino
c
d
derivatives. Isolated yield from chiral aziridines. Trace amount of
symmetrical piperazines.
advantageous reaction condition for the dimerization of
aziridines 11a–e, we tested two LAs Cu(OAc) and Cu(OTf) at
2
2
different reaction conditions (solvent, temperature and LA
amount). It was found that, when the substrate was stirred
with 10 mol% Cu(OAc)2 and Cs CO (1.2 equiv.) in DMF
2
3
preheated at 100 uC under an argon atmosphere, appreciable
yields were obtained of the corresponding diastereoselective
piperazine 12b (Table 3). The Cu(OAc)
2
was tested in both
Scheme 5 Deprotection of the tosyl group of 12b.
stoichiometric and catalytic (10 mol%) amounts, only the use
of a catalytic amount of the LA gave faster reactions and higher
yields. When Cu(OAc)
same conditions, we got a mixture of diastereomers because in
the presence of Cu(OTf) , non-activated aziridine could be
highly activated and opening of the ring occurs through
nucleophilic attack from both sides. Replacing the solvent
DMF with DMSO gave a 44% yield of 12b. In contrast, solvents
such as toluene and 1,4-dioxane gave negative results. The
2 2
was replaced by Cu(OTf) under the
ing to the halogenated amino alcohols were always obtained
(Table 4).
2
As a representative example, the tosyl group of the cis-2,5-
disubstituted chiral piperazine 12b was selectively deprotected
24l
by using sodium naphthalenide
as a reducing agent
providing 13b with 64% yield, which gives scope for further
structural diversification (Scheme 5).
reaction was effective with K
the best results. Lowering of the reaction temperature (below
0 uC), Cu(OAc) (5 mol%) or the base (0.5 equiv.) gave a lower
yield of 12b. The role of Cs CO is very important, it may react
2 3 2 3 2 3
CO , Cs CO , but Cs CO yielded
5
2
Conclusion
2
3
with Cu(OAc)2 to generate ionic CsOAc which takes part in
spontaneous regioselective aziridine ring opening and finally
Cs CO abstracts the NH-proton and is cyclised through the
SN2 pathway (Scheme 3). In this process we frequently
monitored the reaction and also isolated the intermediate
In summary, we have developed a scalable synthetic route for
piperazine derivatives from readily available (S)-amino acids
involving catalytic N–C bond formation. Although both routes
are effective, the Pd-catalyzed process is more favourable than
the Cu-catalyzed process, which furnished both symmetrical as
well as unsymmetrical piperazines. Further investigations are
underway in order to increase the yield as well as to expand the
applicability of this process with controlled stereoselectivity.
2
3
(R)-2-(4-methylphenylsulfonamido)-3-phenylpropyl
acetate
(
12e , see ESI ) thereby indicating the proposed mechanistic
3
1
path. Control experiments confirmed that no product was
obtained in the absence of the copper source. In summary, the
optimal conditions in DMF include Cu(OAc)
2
(10 mol%) and
Cs CO (1.2 equiv.) preheated at 100 uC for 5–15 min under an
2
3
argon atmosphere. Moreover, this reaction was also performed
on a large scale (11b: 3.133 mmol, yield: 74%).
By using the same procedure as in the case of symmetrical
piperazines we achieved the synthesis of unsymmetrical ones
though trace amounts of symmetrical piperazines correspond-
Experimental section
General
All the dry reactions were carried out under argon in oven-
dried glassware using standard gas-light syringes, cannulas
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and septa. All reagents and solvents were dried prior to use
according to standard methods. Commercial reagents were
used without further purification unless otherwise stated.
Amino acids, tosyl chloride, nosyl chloride, mesyl chloride,
palladium acetate, copper acetate and LAH were purchased
from Aldrich Milwaukee, WI. Organic solvents were dried by
standard methods. All the final products were characterized by
chromatography using 1 : 9 ethyl acetate and hexane as the
eluent to obtain 12a–e.
(2S,5S)-2,5-diisopropyl-1,4-ditosylpiperazine (12b). A color-
less oily liquid, yield = 66% (from 10b), 76% (from 11b). This
reaction was performed two times at the gram scale (from 10b:
3.840 mmol, yield: 64% and 4.746 mmol, yield: 63%) and the
yield varied from 63–64% (from 11b: 3.133 mmol, yield: 74%).
1
13
25
H, C, IR, ESI-MS, HRMS. Analytical TLC was performed
[ a´ ]D = +78.231 (c = 0.110, CH OH). HPLC analysis: ee . 99 (tR
3
using 2.5 6 5 cm plates coated with a 0.25 mm thickness of
silica gel (60F-254), visualization was accomplished with
= 5.268 min, iso-propanol/acetonitrile). R 0.62 (20% EtOAc/
f
1
hexane). H NMR (300 MHz, CDCl , 25 uC): a¨ 7.66 (d, J = 8.28
3
H
iodine under a UV lamp. Column chromatography was
Hz, 4H), 7.28 (d, J = 8.04 Hz, 4H), 3.62–3.54 (m, 4H), 3.09–3.00
(m, 2H), 2.42 (s, 6H), 2.21–2.10 (m, 2H), 0.82 (dd, J = 7.05, J =
1
performed using silica gel (60–120 and 100–200 mesh).
H
1
1
1
3
13
NMR and C NMR spectra were recorded with a Brucker DPX-
14.7 Hz, 12H) ppm. C NMR (75 MHz, CDCl , 25 uC): a¨ 143.4,
3 C
1
13
2
3
00 (operating at 200 MHz for H and 50 MHz for C) or DPX-
137.5, 129.7, 127.0, 58.4, 40.8, 30.7, 21.5, 18.6, 15.6 ppm. IR
1
13
21
00 (operating at 300 MHz for H and 75 MHz for C)
spectrometer. H NMR splitting patterns were designated as
singlet (s), doublet (d), double dublet (dd), triplet (t), quartet
(Neat, cm ): 3460, 3241, 2964, 1637, 1460, 1339, 1158, 1094,
1
929, 761. Mass (ESI-MS): m/z 479.1 (80, [M + 1]+), 501.1 (30, [M
+ Na]+), 323.1 (35, [M-Ts]+), 168.1 (50, [M-2Ts]+). ESI-HRMS: m/
z [M + H]+ calcd for C H N O S 479.2038, found 479.2040.
(
q) or multiplet (m). Experiments were recorded in CDCl at 25
3
24 35 2 4 2
uC. Chemical shifts were given in the d scale and were
Synthesis of cis-2,5-disubstituted chiral piperazines (unsym-
metrical) (12g–j) from N-tosyl halogenated amino alcohols.
Pd(OAc) (10 mol%), K CO (2 mmol) and N-tosyl halogenated
referenced to TMS at 0.00 expressed in parts per million (ppm)
1
3
for protons. For the C NMR reference CDCl3 appeared at
7.00 ppm. IR spectra were recorded with Perkin–Elmer 881
2
2
3
7
amino alcohols 10c–f (1 mmol) (1 mmol of each N-tosyl
halogenated amino alcohol) were stirred at 110 uC in DMF (10
mL) for 24 h under an argon atmosphere. The progress of the
reaction was monitored by TLC using ethyl acetate and
hexane. The reaction mixture was cooled to room temperature
and diluted with ethyl acetate (20 mL). The usual work-up was
carried out (as described above), the residue obtained was
purified by silica gel column chromatography using 1 : 9 ethyl
acetate and hexane as the eluent to obtain 12g–j.
and FTIR-8210 PC Shimadzu Spectrophotometers. Mass
spectra were recorded with a JEOL JMS-600H high resolution
spectrometer using the EI mode at 70 eV. Optical rotations
were determined with Autopol III polarimeters using a 1 dm
cell at 25 uC in chloroform and methanol as the solvents, the
concentrations mentioned are in g/100 mL. The enantiomeric
excess was determined using a Lichro CART Chiradex column
(250 6 4 mm) and an R,R-Whelk-01 column with an eluent of
5
% iso-propanol and 95% acetonitrile and a flow rate of 0.50
Experimental procedure for the synthesis of (2S,5S)-2,5-
diisopropylpiperazine (13b). Finely chopped sodium metal (87
mg, 3.760 mmol) and naphthalene (531 mg, 4.136 mmol) were
dissolved in 10 mL dry THF and stirred for 2 h, until a dark
green colour appeared. The desired THF solution of 12b (90
mg, 0.188 mmol) was cooled to 278 uC and then Na-
napthalenide solution was added dropwise to the reaction
mixture via a syringe, until a dark green colour persisted
followed by stirring for 15 min at 278 uC. The reaction was
quenched by adding 1–2 drops water to discharge the green
colour and the usual work-up was carried out followed by
column chromatography. A light brown oily liquid was
2
1
mL min at 25 uC. The retention time range was 0 to 30 min.
Experimental procedures and characterization data
Procedure for the synthesis of chiral aziridines (11a–e). The
chiral aziridines were prepared using our previously reported
procedure.
Synthesis of cis-2,5-disubstituted chiral piperazines (sym-
metrical) (12a–f) from N-tosyl halogenated amino alcohols.
3
6
Pd(OAc)
amino alcohols 10a–f (1 mmol) were stirred at 110 uC in DMF
10 mL) for 24 h under an argon atmosphere. The progress of
2 2 3
(10 mol%), K CO (2 mmol) and N-tosyl halogenated
(
the reaction was monitored by TLC using ethyl acetate and
hexane. The reaction mixture was cooled to room temperature
and diluted with ethyl acetate (20 mL). The organic layer was
washed successively with brine (1 6 3 mL) and water (3 6 5
mL). Drying (Na SO ) and vaporation of the solvent gave a
2 4
residue that was purified by silica gel column chromatography
using 1 : 9 ethyl acetate and hexane as the eluent.
obtained, yield = 64%. R
f
0.46 (15% methanol/chloroform).
25
D
[a] = +18.243 (c = 0.030, CH OH). HPLC analysis: ee . 99 (t =
3
R
1
5
.549 min, iso-propanol/acetonitrile). H NMR (300 MHz,
): d 4.76 (s, 2H), 3.21 (d, J = 12.12 Hz, 2H), 3.02–2.96
m, 2H), 2.85 (s, 2H), 2.03 (s, 2H), 0.98 (d, J = 6.48, 6H), 0.95 (d,
CDCl
(
3
H
1
3
J = 6.27, 6H) ppm. C NMR (50 MHz, CDCl
3
C
): d 58.5, 43.3,
2
1
27.4, 19.0, 18.7 ppm. IR (Neat, cm ): 3298, 3024, 2964, 1463,
Synthesis of cis-2,5-disubstituted chiral piperazines (sym-
merical) (12a–e) from aziridines. Cu(OAc) (10 mol%), Cs CO
1321, 1158, 758. Mass (ESI-MS): m/z 171.2 (90, [M + H]+). ESI-
HRMS: m/z [M + H]+ calcd for C H N 171.1861, found
2
2
3
10 23 2
(1.2 mmol) and aziredines 10a–e (1 mmol) were preheated to
171.1860.
100 uC and stirred for 5–15 min in DMF (10 mL) under an
argon atmosphere. The progress of the reaction was monitored
by TLC using ethyl acetate and hexane. The reaction mixture
was cooled to room temperature and diluted with ethyl acetate
Acknowledgements
(
20 mL). The usual work-up was carried out (as described
This research project was partly supported by DST, New Delhi,
India. Sudipta thanks CSIR, India for a research fellowship.
above), the residue obtained was purified by silica gel column
1
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Instrumental facilities from SAIF, CDRI is acknowledged. We
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