Synthesis of chiral vicinal C2 symmetric and unsymmetric bis(sulfonamide) ligands based on trans-1,2-cyclohexanediamine by aminolysis of N-tosylaziridines

Article abstract of DOI:10.1016/j.tetlet.2005.09.089

The ring opening of N-tosylaziridines with aliphatic amines can be efficiently catalyzed by lithium perchlorate to provide derivatives of the trans-1,2-diamine in high yields. The reaction was used in desymmetrization of several cyclic N-tosylaziridines using chiral amines. Using this strategy, an efficient synthesis of chiral vicinal C₂ symmetric bis(sulfonamide) and unsymmetrical bis(sulfonamide) ligands based on trans-1,2-cyclohexanediamine was developed.

Full text of DOI:10.1016/j.tetlet.2005.09.089

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7935–7939
Synthesis of chiral vicinal C2 symmetric and
unsymmetric bis(sulfonamide) ligands based on
trans-1,2-cyclohexanediamine by aminolysis of N-tosylaziridines
Alakesh Bisai, B. A. Bhanu Prasad and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology Kanpur, 208 016, India
Received 9 August 2005; revised 6 September 2005; accepted 15 September 2005
Available online 29 September 2005
Abstract—The ring opening of N-tosylaziridines with aliphatic amines can be efficiently catalyzed by lithium perchlorate to provide
derivatives of the trans-1,2-diamine in high yields. The reaction was used in desymmetrization of several cyclic N-tosylaziridines
using chiral amines. Using this strategy, an efficient synthesis of chiral vicinal C2 symmetric bis(sulfonamide) and unsymmetrical
bis(sulfonamide) ligands based on trans-1,2-cyclohexanediamine was developed.
Ó 2005 Elsevier Ltd. All rights reserved.
One of the most important factors in the advancement
of catalytic asymmetric synthesis is the design and devel-
opment of new chiral ligands. In catalytic asymmetric
systems, small changes in the donating ability of a ligand
or the size of its substituents can have a dramatic effect
on the catalyst efficiency and enantioselectivity.1–3 C2
symmetric bis(sulfonamide) ligands of the type 1
(Fig. 1) are electronically different from and bind well
to early transition metals4 and main group elements.5
This type of ligand has been used in the asymmetric
Diels–Alder reaction,5,6 the alkylation of aldehydes,7
the cyclopropanation of allylic alcohols8 and the amina-
tion of N-acyloxazolidones.9 The chemistry of these
ligands has been very well studied in the field of
asymmetric synthesis. However, no work has been done
using unsymmetrical bis(sulfonamide) ligands of type
2.10,11 This is mainly due to their non-availability and
difficulty in mono-sulfonylation of a 1,2-diamine such
as 3. Palladium catalyzed monoarylation of 1,2-diamine
3 has been developed, but yields were not high.12 Walsh
and co-workers have developed a very good method for
the synthesis of unsymmetrical bis(sulfonamides) via an
amino-sulfonamide 4 from the commercially available
corresponding diamine.13 In this letter, we report a
new approach to this type of chiral ligand based on ami-
nolysis of aziridines.
It was envisaged that if N-tosylcyclohexyl aziridine were
opened with a benzylamine in a diastereoselective man-
ner, the product could be converted into an amino-sul-
fonamide after debenzylation. With this idea in mind,
several N-tosyl aziridines were synthesized using known
procedures.14 Although ring opening of such N-acti-
vated aziridines with aromatic amines has been studied
extensively using Lewis acids,15 little has been published
on their opening with aliphatic amines.16 At the outset,
NHTs
NHTs
NH2
NH2
NHTs
NH2
NHSO2R
NHTs
(S,S)-1
S,S
(S,S)-3
S,S
Figure 1. Cyclohexane-based symmetrical and unsymmetrical chiral ligands.
Keywords: Chiral C2 symmetric and unsymmetric ligands; Sulfonamide ligands; Aminolysis; Aziridines.
*
Corresponding author. Tel.: +91 512 2597291; fax: +91 512 2597436; e-mail: vinodks@iitk.ac.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.089

7936
A. Bisai et al. / Tetrahedron Letters 46 (2005) 7935–7939
several Lewis acids such as Cu(OTf)2 (70%), Zn(OTf)2
(81%), Sn(OTf)2 (78%), YbCl3 (70%), ErCl3 (68%) and
LiClO4 (88%), were screened for opening of N-tosyl-
cyclohexyl aziridine with benzylamine in MeCN at
room temperature for more than 24 h. From this study,
it appeared that LiClO4 was more effective as indicated
by isolated yields. Long reaction times at room temper-
ature prompted us to try the same reaction at reflux
using LiClO4 as the catalyst. To our delight, the reaction
was complete in 4 h and the ring-opened product was
obtained in 94% yield (Table 1, entry 1). The trans ste-
reochemistry of the product was deduced from the cou-
pling constants (J = 10.48 and 3.92 Hz) of the signal at
The absolute stereochemistry was established by X-ray
analysis (vide infra). The ring-opening reaction pro-
ceeded well with (R)-3,3-dimethyl-2-butylamine also
and a separable mixture of diastereomers (1:1 ratio)
was obtained in 82% yield (Table 2, entry 2). The above
reaction was also extended to the tosylaziridine from
cyclopentene. Although good to excellent yields of the
ring-opened products were obtained, the diastereomers
could not be separated by column chromatography. An-
other chiral amine, (R)-1-(3-methoxy phenyl)ethylamine
was also tried, but also proved inseparable by column
chromotography (Table 2, entry 4). The mono-tosylazir-
idine of cyclohexa-1,4-diene gave a similar result to that
of cyclohexene, where diastereomers could be separated
(Table 2, entry 6).
1
2.29 ppm (–CH–NH–) in the H NMR spectrum. The
ring-opening reaction was also tried with other amines
such as phenethylamine, piperidine, morpholine and
N-ethoxycarbonyl piperazine. In all cases, high yields
of product were obtained (Table 1, entries 2–5). The
reaction was extended to a few other N-tosyl aziridines
and the results are summarized in Table 1.18 Aziridines
derived from cyclopentene and cyclohexa-1,4-diene gave
the ring-opened products in good to excellent yields
(Table 1, entries 6–9). An acyclic terminal aziridine gave
products resulting from terminal attack only (Table 1,
entries 10 and 11).
In order to prove the absolute stereochemistry of pro-
duct 9, the less polar diastereomer was methylated with
MeI to afford 15a whose crystal analysis (Fig. 2) proved
it to be (R,R,R)-9. In order to show the versatility, sev-
eral alkylated amines were synthesized (Scheme 1). Sur-
prisingly, alkylation of (R,R,R)-9 with 2-methoxybenzyl
bromide under identical conditions did not give the de-
sired product. Instead, the reaction took place on the
nitrogen to which tosyl group was attached, thus giving
16 in 72% yield (Scheme 1). The structure of 16 was con-
firmed by X-ray crystal structure (Fig. 2). This is
strange, especially having the fact that the same reaction
with benzyl bromide provided 15f where alkylation took
place on the other nitrogen. The reason for this anomaly
could be due to steric interaction between the methyl
group on the chiral centre and ortho-methoxy group
on the benzyl bromide.
Once the methodology for cleavage of N-tosylaziridines
with aliphatic amines,18 especially benzylamine was
established, it was extended to chiral amines. Initially,
(R)-a-methylbenzylamine was used for desymmetriza-
tion of N-tosylcyclohexyl aziridine in the presence of
LiClO4 in MeCN. The reaction was complete in 6 h at
reflux temperature and the product was obtained in
94% yield as a separable mixture of diastereomers in a
1:1 ratio (Table 2, entry 1). The reaction was scaled up
to 25 g scale without any problem. The (S,S,R)-9 diaste-
reomer is more polar (Rf 0.28) than (R,R,R)-9 (Rf 0.42).
After successful synthesis of enantiopure ring-opened
product 9, we planned to synthesize several chiral
ligands. Thus, the (S,S,R)-9 diastereomer was subjected
Table 1. Reaction of N-tosyl aziridines with chiral aliphatic amines catalyzed by LiClO4 in MeCN at reflux temperature
Entry
Aziridines
Products
% Yield (time, h)
1
2
3
4
5
5a;15a R1 = 4H, R2 = CH2Ph
5b;16b R1 = H, R2 = CH2CH2Ph
5c; NR1R2 = piperidino
94 (4)
87 (5)
88 (2)
95 (5)
96 (2)
NHTs
NTs
5d; NR1R2 = morpholino
NR1R2
5e; NR1R2 = N-ethoxycarbonyl piperazine
NHTs
6
7
6a;17 R1 = H, R2 = CH2Ph
6b; NR1R2 = morpholino
88 (6)
93 (5)
NTs
NR1R2
NHTs
8
9
7a; R1 = H, R2 = CH2Ph
7b; NR1R2 = morpholino
92 (6)
92 (6)
NTs
NTs
NR1R2
NTs
10
11
89 (4)
90 (4)
NHCH2Ph
8a
9
9
9
NTs
NTs
N
8b
9

A. Bisai et al. / Tetrahedron Letters 46 (2005) 7935–7939
7937
Table 2. Reaction of N-tosyl aziridines with chiral aliphatic amines catalyzed by LiClO4 in MeCN at reflux
Entry
Azirdines
Productsa
% Yield (time, h)
NHTs
N
NHTs
1
94 (6)
+
NTs
N
H
Ph
Ph
H
(R,R,R)-9
(S,S,R)-9
NHTs
NHTs
+
2
3
82 (6)
79 (6)
NTs
NTs
N
N
t-Bu
(R,R,R)-10
t-Bu
H
H
(S,S,R)-10
NHTs
N
Ph
11
12
H
NHTs
4
5
6
93 (6)
80 (6)
83 (8)
NTs
NTs
NTs
OMe
N
H
NHTs
N
t-Bu
13
H
NHTs
N
Ph
H
14
The diastereomers separated on TLC only for entries 1, 2 and 6.
a In all cases, the products were obtained in a 1:1 diastereomeric ratio.
important precursor for several chiral ligands. For
example, (S,S)-4 was tosylated to provide the C2 sym-
metric bis(sulfonamide) ligand (S,S)-1. Its treatment
with various sulfonyl chlorides provided a series of
enantiopure unsymmetrical vicinal bis(sulfonamide)
ligands (S,S)-2a–h in good to excellent yields. The
amino-sulfonamide (S,S)-4 compound was also converted
into an important chiral ligand 1710a in quantitative
yield (Scheme 2).13a
In conclusion, we have developed an efficient method for
the desymmetrization of N-tosyl aziridines in the pres-
ence of LiClO4. We have used the method to synthesize
a variety of chiral ligands. To the best of our knowledge,
this is the first straightforward method for the synthesis
of chiral unsymmetrical bis(sulfonamide) ligands based
on trans-1,2-diaminocyclohexane.
Figure 2. X-ray crystal structures of the sulfonamides.19
to debenzylation (Pd/C and HCOONH4) to provide the
amino-sulfonamide (S,S)-4 in 91% yield. This is an
MeO
o-MeOC6H4CH2Br,
15a, R = Me; X = I
RX, K2CO3,
Ts
NHTs
K2CO3, MeCN, reflux
15b, R = Et; X = Br
15c, R = n-Pr; X = Br
15d, R = n-Bu; X = Br
15e, R = allyl; X = Br
15f, R = benzyl; X = Br
MeCN, reflux
N
(R,R,R)-9
72%
72-96%
N
R
Ph
N
H
Ph
16
Scheme 1.

7938
A. Bisai et al. / Tetrahedron Letters 46 (2005) 7935–7939
10% Pd/C, HCOONH4,
MeOH, reflux, 8 h
p-TsCl, Et3N, DCM, 0 °C to rt
(S,S,R)-9
(S,S)-4
(S,S)-1
91%
80-
RSO2Cl, Et3N, DCM, 0 °C to rt
97%
99%
(S,S)-2a-h
a, R = p-Nos; b, R = p-BrC6H4;
c, R = p-MeOC6H4; d, R = o-Nos;
e, R = 8-Quin; f, R = m-Nos;
g, R = Ph; h, R = Me
N
NHTs
OH
(S,S)-17
Scheme 2.
J. J. Org. Chem. 2000, 65, 5005–5008; For asymmetric
transfer hydrogenation of ketones using chiral amino-
sulfonamide, see: (b) Ptintener, K.; Schwink, L.; Knochel,
P. Tetrahedron Lett. 1996, 37, 8165–8168; For the synthe-
sis and application of some other hybrid ligands of chiral
1,2-diaminocyclohexane, see: (c) Kim, Y. K.; Lee, S. J.;
Ahn, K. H. J. Org. Chem. 2000, 65, 7807–7813.
Acknowledgements
We thank the Department of Science and Technology,
Government of India for a research grant. A.B. thanks
the Council of Scientific and Industrial Research, New
Delhi, for a Senior Research Fellowship.
11. For application of other types of chiral amino-sulfon-
amide ligands in asymmetric synthesis, see: (a) Xue, D.;
Chen, Y.-C.; Cui, X.; Wang, Q.-W.; Zhu, J.; Deng, J.-G.
J. Org. Chem. 2005, 70, 3584–3591; (b) Duncan, A. P.;
Leighton, J. L. Org. Lett. 2004, 6, 4117–4119.
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18. General procedure for ring cleavage of N-tosylaziridine
with amine in the presence of LiClO4: The amine
(1.25 mmol) was added to a solution of N-tosyl aziri-
dine (1 mmol) and LiClO4 (0.1 mmol) in anhydrous
acetonitrile (6 mL) under an argon atmosphere at rt. The
reaction mixture was refluxed until completion of the reac-
tion (usually 4–8 h, monitoring by TLC). Most of the
acetonitrile was removed in vacuo and the crude reac-
tion mixture was partitioned between EtOAc and water.
The organic layer was washed with water, brine and
dried over anhydrous sodium sulfate. It was concen-
trated in vacuo to give a crude product, which was
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10. For asymmetric cyclopropanation using sulfonamide/
Schiff base chiral ligands, see: (a) Balsells, J.; Walsh, P.

A. Bisai et al. / Tetrahedron Letters 46 (2005) 7935–7939
7939
purified by silica gel column chromatography using
EtOAc and hexane to give the pure vicinal amino-
sulfonamide.
Data Centre as supplementary publications no. CCDC-
280469 and 280470, respectively. This data can be
obtained free of charge via the internet www.ccdc.cam.
ac.uk/conts/retrieving.html or by sending an email to
deposit@ccdc.cam.ac.uk.
19. Crystallographic data for (R,R,R)-15a and (R,R,R)-16
have been deposited with the Cambridge Crystallographic