Efficient ring opening of aziridines with carboxylic acids

Article abstract of DOI:10.1080/00397910801928723

An efficient ring cleavage of aziridines with acids has been studied in the absence of any catalyst. The hydrolysis of the products, amino esters, leads to the corresponding amino alcohols. The reaction has been extended to chiral cycloalkyl aziridines, leading to the formation of diastereomers. After separation, these diastereomers have been converted to optically pure amino alcohols in two steps. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910801928723

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Efficient Ring Opening of Aziridines with
Carboxylic Acids
Manoj Kumar a b , Shikha Gandhi a , Swinderjeet Singh Kalra b & Vinod K.
Singh a
a Department of Chemistry , Indian Institute of Technology , Kanpur, India
b Department of Chemistry , D. A. V. College , Kanpur, India
Published online: 24 Apr 2008.
To cite this article: Manoj Kumar , Shikha Gandhi , Swinderjeet Singh Kalra & Vinod K. Singh (2008) Efficient
Ring Opening of Aziridines with Carboxylic Acids, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 38:10, 1527-1532, DOI: 10.1080/00397910801928723
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Synthetic Communicationsw, 38: 1527–1532, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801928723
Efficient Ring Opening of Aziridines
with Carboxylic Acids
Manoj Kumar,1,2 Shikha Gandhi,1 Swinderjeet Singh Kalra,2
and Vinod K. Singh1
1Department of Chemistry, Indian Institute of Technology, Kanpur, India
2Department of Chemistry, D. A. V. College, Kanpur, India
Abstract: An efficient ring cleavage of aziridines with acids has been studied in the
absence of any catalyst. The hydrolysis of the products, amino esters, leads to the cor-
responding amino alcohols. The reaction has been extended to chiral cycloalkyl azir-
idines, leading to the formation of diastereomers. After separation, these
diastereomers have been converted to optically pure amino alcohols in two steps.
Keywords: Amino alcohols, amino esters, unactivated aziridines
Aziridines are the simplest class of nitrogen-containing heterocycles.[1] These
small ring heterocycles have invoked much interest among organic chemists
because of their capability to undergo facile ring-cleavage reactions. The
ring cleavage of aziridines leads to the formation of 1,3-dipoles, which can
either be trapped in cycloaddition reactions or, by the attack of nucleophiles,
which leads to ring-opening products. We have recently reported the cyclo-
addition reactions of aziridines with nitriles and carbonyls.[2] Ring-opening
reactions of aziridines have also been widely explored. Most of these reactions
utilize activated aziridines.[3] However, there are few reports on the ring
opening of unactivated aziridines.[4] There has been a report on the ring
cleavage of aziridines with acids.[5] However, the method is applicable only to
activated aziridines and requires the presence of a Lewis acid as catalyst. In
this article, we report the ring opening of unactivated aziridines with carboxylic
acids (Scheme 1). We have also extended the work to chiral aziridines and/or
Received November 26, 2007
Address correspondence to Vinod K. Singh, Department of Chemistry, Indian
Institute of Technology, Kanpur 208 016, India. E-mail: vinodks@iitk.ac.in
1527

1528
M. Kumar et al.
Scheme 1.
chiral carboxylic acids so as to prepare chiral products. The products formed are
convenient precursors for the synthesis of 1,2-amino alcohols.[6]
The reaction of N-substituted aziridines was studied with various aliphatic
and aromatic acids in acetonitrile (Table 1). The reaction of N-aryl substituted
Table 1. Reactions of N-substituted aziridines with various acids
Yield
(%)a
Entry
R1 R2
R
R0
CH3
Prodcut
Time
1
2
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
CH2Ph
CH2Ph
CH2Ph
CH2Ph
1a
1b
1c
1d
1e
1f
5 hb
2 hb
2 hb
2 hb
6 h
87
82
84
74
92
85
84
95
89
93
82
95
92
85
93
94
89
92
96
97
89
40c
50c
Ph
3
4-OMePh
4-NO2Ph
CH3
Ph
4
5
4-OMePh
4-OMePh
CH2Ph
6
6 h
7
CH3
Ph
1g
1h
1i
4 hb
2 hb
2 hb
2 hb
2 hb
6 h
8
CH2Ph
CH2Ph
9
4-OMePh
4-NO2Ph
CF3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CH2Ph
CH2Ph
1j
1k
11
1m
1n
1o
1p
1q
1r
1s
Ph
Ph
CH3
Ph
6 h
6 h
4-OMePh
4-OMePh
4-CIPh
CH3
Ph
6 h
6 h
CH3
Ph
4-CIPh
6 h
3,4-(OCH20)-Ph
3,4-(OCH20)-Ph
2-naphthyl
2-naphthyl
CH2Ph
CH3
Ph
6 h
2 hb
6 h
CH3
Ph
1t
1u
1v
1w
6 h
Ph
Ph
H
H
CH3
Ph
2 hb
2 hb
CH2Ph
aIsolated yield.
bReflux conditions.
cThe products 1v and 1w were isolated as a mixture of regioisomers in the ratios 93:7
and 84:16 respectively (only the major regioisomer is shown).

Ring Opening of Aziridines
1529
Scheme 2.
aziridines was complete in 6 h at room temperature. However, N-alkyl substi-
tuted aziridines required refluxing for 2 h. Most of the cyclic aziridines gave
high yields of the products. Although conversion of the ring-opened products
to amino alcohols is a trivial step, the process was shown by converting 1g into
2 by deesterification using K2CO3 in methanol (Scheme 2).
The reaction was then extended to N-((R)-1-phenylethyl)-cycloalkyl azir-
idines (Table 2). Both aliphatic and aromatic acids required refluxing for 2 h,
and the products were formed in high yields. The two diastereomers were
formed in the ratio of 70:30. In the case of the six-membered ring, these
two diastereomers 3d and 4d showed good separation on thin-layer chromato-
graphy (TLC), so they were separated, and the ester group was cleaved under
basic conditions to form the corresponding diastereomerically pure amino
alcohols 5 and 6 in high yields. The N-((R)-1-phenylethyl) substituted
amino alcohols were then debenzylated to yield optically pure amino
alcohols 7 and 8 in good yields (Scheme 3). The absolute configuration of
the products 5, 6, 7, and 8 was determined by comparison with the reported
data.[7] The configuration of compounds 3 and 4 was assigned according to
the configurations at 5 and 6.
Table 2. Ring cleavage of N-((R)-1-phenylethyl)-cycloalkyl aziridines with various
acids
Diastereomeric
ratio 3:4b
Entry
n
R0
Yield (%)a
1
2
3
4
1
1
2
2
CH3
Ph
90
97
93
97
70:30 (3a:4a)
70:30 (3b:4b)
69:31 (3c:4c)
71:29 (3d:4d)
CH3
Ph
aIsolated yield.
bDiastereomeric ratio determined by H NMR spectra.
1

1530
M. Kumar et al.
Scheme 3.
Table 3. Ring cleavage of N-benzyl cycloalkyl aziridines with chiral acid
Diastereomeric
ratio 9:10b
Entry
n
R0
Yield (%)a
1
2
1
2
72
84
54:46 (9a:10a)
57:43 (9b:10b)
alsolated yield.
1
bDiastereomeric ratio determined by H NMR spectra.
Scheme 4.
Further, the aziridine ring-cleavage reaction was studied by using chiral
acid as a nucleophile (Table 3). N-Benzyl substituted cycloalkyl aziridines
were reacted with O-acetyl-(S)-mandelic acid. The two diastereomers 9 and
10 were formed in high yields as an inseparable mixture. To determine the

Ring Opening of Aziridines
1531
absolute stereochemistry, the mixture of amino esters 9b and 10b was hydro-
lyzed to the corresponding amino alcohols. The stereochemistry at 11 and 12
was then assigned in comparison with the reported data (Scheme 4).[8] The
configuration of 9 and 10 was assigned according to the configuration at 11
and 12.
In conclusion, we have developed an efficient method for the ring opening
of aziridines with acids. The reaction proceeds without the use of any catalyst.
The products, amino esters, have been deesterified to the corresponding amino
alcohols. The diastereoselective cleavage of chiral aziridines with acids leads
to diastereomerically pure amino esters, which serve as precursors for the
synthesis of optically pure vicinal trans-1,2-amino alcohols.
ACKNOWLEDGMENT
V. K. S. thanks the Department of Science and Technology, Government of
India, for a research grant. S. G. thanks the Council of Scientific and Industrial
Research, New Delhi, for a senior research fellowship.
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