An efficient method for opening nonactivated aziridines with TMS azide: Application in the synthesis of chiral 1,2-diaminocyclohexane

Article abstract of DOI:10.1016/S0040-4039(00)01793-7

A variety of N-substituted aziridines have been opened with TMS azide in MeCN at rt in the absence of any Lewis acid. The reaction was extended to the synthesis of (R,R)- and (S,S)-1,2-diaminocyclohexane. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01793-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10079–10083
An efficient method for opening nonactivated aziridines with
TMS azide: application in the synthesis of chiral
1,2-diaminocyclohexane†
M. Chandrasekhar, G. Sekar and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
Received 30 August 2000; revised 27 September 2000; accepted 11 October 2000
Abstract
A variety of N-substituted aziridines have been opened with TMS azide in MeCN at rt in the absence
of any Lewis acid. The reaction was extended to the synthesis of (R,R)- and (S,S)-1,2-diaminocyclohex-
ane. © 2000 Elsevier Science Ltd. All rights reserved.
Aziridines are versatile intermediates for the synthesis of nitrogen containing biologically
active compounds.1 Although these are nitrogen analogues of epoxides, reactivity of this
strained heterocyclic ring system is less than that of epoxides and dependent upon the
substitution on the nitrogen atom. Electron withdrawing groups on nitrogen enhance the
reactivity of the ring and these compounds are termed as activated aziridines. A number of
nucleophilic ring-opening reactions have been studied on activated aziridines with various
nucleophiles, but studies on nonactivated aziridines (N-alkyl or aryl) have been restricted mainly
due to their lack of reactivity and nonavailability of easy methods of synthesis. The ring-opening
reaction of aziridines with nitrogen nucleophiles has special significance because the products are
vicinal diamines which have varied applications in organic synthesis.2 Recently, we have shown
that nonactivated aziridines can be opened effectively with aromatic amines in the presence of
a catalytic amount of Sn(OTf)2 or Cu(OTf)2 in a very short period of time and high yield.3 We
have also shown that activated aziridines can be opened with hydroxyl compounds in the
presence of a catalytic amount of Sn(OTf)2 or BF3·OEt2.4 These results encouraged us to use
trimethylsilyl (TMS) azide for the nucleophilic ring opening of aziridines and apply the method
in synthesis of chiral ligands.
* Corresponding author. E-mail: vinodks@iitk.ac.in
†
We dedicate this paper with great respect to Professor K. K. Balasubramanian (I.I.T. Madras) on the occasion of
his 60th birthday.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01793-7

10080
There are only a few reports on the ring opening of aziridines with TMSN3. Yeung and
co-workers reported the azidolysis of N-tosylaziridines with TMSN3 in the presence of an
imidochromium complex.5,6 In this method, the reaction was too slow and the yields and
regioselectivities were moderate. Later, Lectka et al. reported that certain transition metal and
rare earth metal complexes catalyzed the azidolysis of N-benzoylaziridines.7 It has recently been
published that ring opening of activated aziridines by TMS azide can be triggered by the fluoride
ion.8 The above reported methods are compatible only with activated aziridines. Nonactivated
aziridines are inert to these conditions. For example, Hou et al.8 found that there is no reaction
when the substituent on nitrogen is not strongly electron withdrawing (hydrogen or benzyl or
even a Boc group).9 This prompted us to look into the ring-opening reaction of nonactivated
aziridines. In this paper we report our results of aziridine opening with TMSN3 and its
application in the synthesis of a useful chiral diamine.
At the outset, we carried out ring opening of N-benzylcyclohexyl aziridine with TMSN3 in
CH2Cl2 using 5 mol% of Sn(OTf)2. The reaction was very effective as the ring-opened product
was obtained in 98% yield. Under the same conditions Cu(OTf)2 gave only 75% yield. The
reaction was carried out in several solvents (Table 1) and it was observed that CH2Cl2 and
MeCN both gave high yields of the ring-opened product except that the reaction was faster in
MeCN. It was further observed that the reaction proceeded equally well in the absence of
Sn(OTf)2. In view of the above surprising results, the reaction was carried out on a variety of
N-substituted aziridines in the presence and absence of the catalyst. In most of the cases, the
absence of catalyst gave better results (Table 2). It was also observed that nonactivated
aziridines reacted much faster than activated ones under the present experimental conditions
(entry 9). In the case of cyclic aziridines, the stereochemistry of the ring-opened product was
found to be trans from coupling constants of ring protons (entries 1–9). Phenyl substituted
aziridines underwent reaction in a regiospecific manner, whereby azide ion attacked the benzylic
position (entries 11 and 12). This is in contrast to the literature results where both regioisomers
Table 1
H
N
Condition A or B
CH2Ph
N CH2Ph + TMSN3
N3
A = Sn(OTf)2, Solvent, rt.
B = Solvent, rt.
Solvent
Isolated yield (time)
Condition A
Condition B
CH2Cl2
Et2Oa
Benzene
Hexanea
MeCN
98% (6 h)
99% (12 h)
40%b
90% (24 h)
85% (10 h)
90% (16 h)
98% (2.5 h)
90% (24 h)a
25% (30%)
99% (2.5 h)
a Large excess of TMSN3 needed for completion of the reaction.
b Reaction was not complete even after addition of excess TMSN3.

10081
Table 2
Cleavage of N-substituted aziridines with TMS azide in MeCN at room temperature
Isolated Yield ( Time )
Entry
Azidoamine
Aziridine
5 mol % Sn(OTf)2
No catalyst
H
N
Ph
98% (2.5 h)
99% (2.5 h)
98% (4 h)
N
Ph
1
N3
NHAr
98% (2 h)
Ar = Ph
2
3
N - Ar
N3
Ar = C6H4-p -OMe
Ar = C6H4-m-Cl
Ar = C6H4-o-Me
Ar = 2-naphth
75% (1.5 h)
75% (1.5 h)
82% (3 h)
56% (2 h)
92% (6 h)
90% (1.5 h)
94% (6 h)
91% (6 h)
90% (4 h)
90% (7 h)
4
5
6
7
Ar = C6H4-p-Cl
H
N
n-Bu
58% (45 min)
70% (45 min)
70% (20 d)
70% (3.5 h)
8
N n-Bu
N Ts
N3
H
N
Ts
9
30% (10 d)
71% (3 h)
N3
H
N
Me
Me
Ph
Me
Me
N
Ph
10
11
N3
N3
CH2Ph
N
NHCH2Ph
NHn - Bu
60% (45 min)
83% (2 h)
n - Bu
N3
N
12
13
62% (1 h)
88% (1 h)
92% (1 h)
93% (1 h)
82% (1 h)
93% (1 h)
CH2Ph
CH2Ph
N
HN
( )6
N3
( )6
t - Bu
N3
t - Bu
HN
( )9
N
N
78% (1 h)
88% (1 h)
14
15
( )9
n - Bu
N3
n - Bu
HN
( )9
( )9

10082
were reported to be formed.5,8 Acyclic terminal aziridines gave products resulting from terminal
attack only, as has been observed in most of the azirdine-opening reactions by others.
In order to show the scope and utility of the above reaction, it was applied to the synthesis
of a C2 symmetric chiral diamine 3, which is a very important ligand in asymmetric synthesis.10
Cyclohexene oxide was converted into a chiral aziridine 1 by opening it with (R)-1-phenylethy-
lamine and ring closure of the resulting amino alcohol by using diisopropyl azodicarboxylate
and triphenylphosphine. The reaction of chiral aziridine 1 with TMS azide in MeCN at rt gave
90% yield of two distinctly separable (on TLC) diastereomers in a ratio of 4:1. The hydrogena-
tion (20% Pd(OH)2/C, H2, 40 psi, rt) of the major diastereomer 2a11 (Rf 0.45; 10% EtOAc in
hexanes) gave a diamine (R,R)-3 {[h]D of its HCl salt −9.7 (c 1.5, MeOH); lit.12 [h]D −9.4 (c 1.05,
MeOH)} in 95% yield. Similarly, the minor diastereomer 2b (Rf 0.29; 10% EtOAc in hexanes)
provided the other enantiomer (S,S)-3 (Scheme 1).
N3
N3
b
a
N
+
O
N
H
N
H
1
2b (Rf 0.29)
2a (Rf 0.45)
c
c
NH2
NH2
NH2
(R,R)-3
NH2
(S,S)-3
Scheme 1. (a) (i) R-(+)-1-Phenylethylamine, LiClO4, MeCN, rt, 48 h, 95% yield; (ii) DIAD, Ph3P, DCM, 0°C to rt,
7 h, 75% yield. (b) TMSN3, MeCN, rt, 7 h, 90% yield (ratio of 2a and 2b=4:1). (c) 20% Pd(OH)2/C, MeOH, H2, 40
psi, rt, 48 h, 95% yield
In conclusion, we have shown that nonactivated aziridines can be opened with TMS azide in
high yield in MeCN in the absence of any Lewis acid. We have successfully used the method in
the synthesis of an important chiral ligand in high yield.
Acknowledgements
V.K.S. thanks DST (Government of India) for the Swarnajayanti Fellowship award (1998).
M.C. thanks UGC for a research fellowship.
References
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10083
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7.27 (m, 5H). 13C NMR (CDCl3, 100 MHz) l 24.2, 24.32, 24.33, 30.5, 32.5, 56.6, 59.3, 66.3, 126.4, 126.7, 128.3,
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