Desymmetrization of aziridine with malononitrile using cinchona alkaloid amide/zinc(ii) catalysts

Article abstract of DOI:10.1039/c6cc09457k

The catalytic enantioselective desymmetrization of aziridines with malononitrile has been developed. Good yield and enantioselectivity were obtained by using cinchona alkaloid amide/Zn(ii) catalysts. The obtained product can be converted to β-aminoester,

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Desymmetrization of Aziridine with Malononitrile
using Cinchona Alkaloid Amide/Zinc(II) Catalysts
Cite this: DOI: 10.1039/x0xx00000x
Noriyuki Shiomi,ab Mami Kuroda,a Shuichi Nakamuraab
*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
chiral catalyst
The catalytic enantioselective desymmetrization of aziridines
with malononitrile has been developed. Good yield and
enantioselectivity were obtained by using cinchona alkaloid
amide/Zn(II) and base catalysts. The obtained product can
be converted to βꢀaminoester, βꢀaminoamide and triamide
compounds.
COAr
COAr
HN
CN
NCOAr
R
HN
NC
CN
R
CO2R'
*
*
R *
CN
R
*
R
R
COAr
CH2NH2
COAr
HN
HN
Desymmetrization of aziridines with various nucleophiles is an
effective strategy for the preparation of useful chiral 2ꢀ
substituted amine compounds.1 Therefore there are many
reports on the catalytic desymmetrization of aziridines with
various nucleophiles, such as nitrogen,2 sulfur,3 halogen,4 and
other nucleophiles.5 In spite of these impressive advances, the
desymmetrization of aziridines for carbon nucleophiles has not
been too fruitful, except for the reaction with cyanides.6 Müller
and coꢀworkers reported the first enantioselective ringꢀopening
reaction with Grignard reagents as carbon nucleophiles using
copper(II)ꢀSchiff base catalysts to give products with high
*
*
*
*
R
CH2NH2
R
CO2R'
R
R
Fig. 1. Catalytic desymmetrization of aziridines with malononitrile
using our original chiral catalysts derived from cinchona alkaloids
We first examined the asymmetric desymmetrization of
aziridines
1
with malononitrile using a catalytic amount of
in various reaction conditions
diethylzinc and picolinamides
3
(Table 1). Although the ringꢀopening reaction of 1a with
malononitrile using 3a derived from cinchonidine in toluene
afforded product 2a in moderate yield with low
enantioselectivity, the reaction in THF afforded 2a in 62% yield
with 87% ee (entries 1 and 2). The reaction in other solvents
such as CH2Cl2 or 1,2ꢀdichloroethane gave 2a in better yield
but with slightly lower enantioselectivity than the reaction in
THF (entries 3 and 4). The reaction using 5.0 equiv. of
malononitrile improved the yield of product 2a (entry 5). Next,
we investigated the effect of protecting group of aziridines in
order to improve enantioselectivity. We found that the reaction
of aziridines 1bꢀd having an imidazolecarbonyl group afforded
products 2bꢀd in good yield with high enantioselectivity (82ꢀ
93% yield, 92ꢀ96% ee, entries 6ꢀ8). The reaction using
aziridine 1b showed higher reactivity than other aziridines, and
enantioselectivity.7
Recently, the desymmetrization of
aziridines with malonates using chiral heteroꢀdinuclear rare
earth metal catalysts have been reported by Shibasaki and
Matsunaga.8
enantioselective
Since these milestone achievements,
ringꢀopening reactions with carbon
nucleophiles have attracted considerable attention in organic
chemistry, leading some research groups to report on the
desymmetrization of aziridines with enolates and arene
compounds as carbon nucleophiles.9 However, there are no
reports on the desymmetrization of aziridines with
malononitriles as nucleophiles, in which the reaction gives
highly functionalized chiral amines.10 As a part of our ongoing
studies on our original cinchona alkaloid catalysts, we recently
reported the first highly enantioselective ringꢀopening reaction
of aziridines with phosphorous nucleophiles11 and nitro
compounds12 using chiral catalysts derived from cinchona
o
the reaction of 1b at lower temperature (0 C) gave product 2b
in 89% yield with 97% ee (entry 9). The reaction using
picolinamide 3b derived from cinchonine gave 2b having
opposite stereochemistry in 74% yield with 94% ee (entry 10).
alkaloids.13
enantioselective reactions of the αꢀcarbanion of nitrile
compounds.14
Herein, we report the first catalytic
Furthermore, we recently reported various
desymmetrization of aziridines with malononitrile using
cinchona alkaloid picolinamide catalysts (Figure 1).
This journal is © The Royal Society of Chemistry 2012
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DOI: 10.1039/C6CC09457K
Table 1 Optimization of reaction conditions
Time
(h)
Yield
(%)
Ee
(%)b
3a
(x mol%)
Entry
2
1 c
10
20
20
36
89
71
97
94
2
3c,d,e
20
20
48
48
21
61
73
95
Yield
(%)
Ee
Entry
Solvent Time (h)
1
3
(%)b
4
1
2
Toluene
THF
48
24
24
24
6
51
62
75
76
74
84
88
82
89
74
15
87
73
79
88
92
95
96
97
94e
1a 3a
1a 3a
1a 3a
1a 3a
1a 3a
1b 3a
1c 3a
1d 3a
1b 3a
1b 3b
5e
6e
7e
20
20
20
10
14
20
64
75
69
90
94
94
3
CH2Cl2
DCE
THF
4
5c
6c
7c
8c
9c,d
10c,d
THF
3
THF
6
THF
12
20
20
THF
THF
a) Reaction conditions: aziridine
(10 equiv.), Et2Zn (10ꢀ20 mol %),
M) were used. b) Ee was determined by HPLC analysis using a
chiral column. c) Malononitrile (5 equiv.) was used. d) 1,2ꢀ
Dichloroethane was used as the solvent. e) At r.t.
1
4
(0.1 mmol), malononitrile
(12 mol %) in solvent (0.2
DCE: 1,2ꢀdichloroethane. a) Reaction conditions: aziridine 1 (0.1
mmol), malononitrile (1.5 equiv.), Et2Zn (10 mol %), and 3 (12
mol %) in solvent (0.2 M) were used. b) Ee was determined by
HPLC analysis using a chiral column. c) Malononitrile (5.0 equiv.)
was used. d) At 0 oC. e) Opposite enantiomer was obtained.
Next, the transformation of product 2b to an ester or amides,
and deprotection of the imidazole carbonyl group were
examined (Scheme 1).
Having established the optimized reaction conditions for the
desymmetrization of aziridines, the reaction of various
aziridines 1b
The reaction of aziridines 1b
structure afforded products 2b
,
eꢀ
i
with malononitrile was carried out (Table 2).
having sixꢀmembered ring
with high enantioselectivities,
,
e
Scheme 1 Transformation of 2b to βꢀaminoester 5, βꢀaminoamide 6
and triamine 7
,
e
but aziridine 1f having a bulky substituent showed low
reactivity with moderate enantioselectivity. (entries 1ꢀ3). The
reaction of aziridine 1g bearing a fiveꢀmembered ring afforded
product 2g in moderate yield (61%) with high enantioselectivity
(95% ee, entry 4). Interestingly, the reaction of acyclic
aziridines 1hꢀj with malononitrile using the 3aꢀZn catalyst gave
2,3ꢀdihydroꢀ1Hꢀpyrrole compounds 2hꢀj which were formed by
the intramolecular nucleophilic addition of amide nitrogen to
the cyano group, in moderate yield with good enantioselectivity
(entries 5ꢀ7).15,16
Table 2 Catalytic enantioselective desymmetrization of various
aziridines with malononitrilea
The reaction of 2b with
βꢀaminoester
in 67% yield.17 Deprotection of the Boc group
on the amide group of was carried out using sodium
methoxide in methanol to give ꢀBocꢀβꢀaminoester in 73%
yield (two steps). The absolute configuration of was
mꢀCPBA and Cs2CO3 in methanol gave
4
4
N
5
5
determined as (1R,2S), based on the value of the specific
rotation for previous paper (see supporting information).18 We
2 | J. Name., 2012, 00, 1-3
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DOI: 1C0.O10M39M/CU6CNCI0C9A4T57IOK N
also succeeded to prepare βꢀaminoamide
2b with benzylamine, and potassium carbonate under an the catalyst forms
oxygen atmosphere in 91% yield with 99% ee.19 Furthermore, Malononitrile then attacks aziridine on the zinc cation.
2b could be transformed to triamide in 59% yield with 98%
ee by the reduction of the cyano group in 2b using NaBH4 and
NiCl2 6H2O followed by Boc protection. These derivatives
6
from the reaction of the zinc cation in a tetrahedral form, and the quinuclidine moiety in
a
hydrogen bond with malononitrile.
7
Conclusions
•
We developed the enantioselective desymmetrization of
aziridines with malononitrile using cinchona alkaloid
amide/zinc(II) catalysts. The reaction was screened for various
could be synthesized without the loss of enantiopurity.
The assumed catalytic cycle for the reaction of aziridine 1b
with malononitrile is shown in Figure 2. First, Et2Zn reacts
aziridines.
Both enantiomers of the product could be
with picolinamide ligand 3a to give complex
then reacts with complex to afford complex
coordinates to aziridine 1b to give complex , and the ringꢀ
opening reaction between aziridine 1b and activated
malononitrile gives complex . Finally, the ligand exchange
reaction of complex with malononitrile proceeds to give
product 2b and complex . In order to clarify the proposed
reaction cycle, we conducted an ESIꢀmass spectroscopic
analysis. We observed complex for the reaction mixture of Notes and references
1b, malononitrile, Et2Zn, and 3a (cation mode, calcd for
C36H40N7O2Zn+ as complex ꢀ(CN)2CHꢀ: 666.2, found: 666.2).
A
. Malononitrile
synthesized by using pseudoenantiomeric chiral catalysts.
Additional studies are in progress to investigate the potential of
these chiral catalysts for other synthetic processes.
A
B
, which
C
This work was partially supported by GrantsꢀinꢀAid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts” from MEXT (26105727)
and the Uehara Memorial Foundation.
E
E
B
C
aDepartment of Life Science and Applied Chemistry, Graduate School of
Engineering, Nagoya Institute of Technology, Gokiso, Showaꢀku, Nagoya
466ꢀ8555 (Japan). Eꢀmail: snakamur@nitech.ac.jp
C
This signal supports our proposed reaction mechanism.
bFrontier Research Institute for Material Science, Nagoya Institute of
Technology, Gokiso, Showaꢀku, Nagoya 466ꢀ8555 (Japan)
Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/c000000x/
R
R
N
R
R
N
∗
Et2Zn
N
N
N
∗
Et Zn
NH
N
HN
N
O
Et-H
N
complex A
1
For reviews of enantioselective desymmetrization of aziridines, see:
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CN
3a
NC
Me
N
O
Et-H
N
R
N
R
NH
9
, 1677.
For selected examples with TMSN3, see: (a) Z. Li, M. Fernández, E.
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2b
O
∗
CH(CN)2
C
N
Zn
N
N
2
N
NC
N
1
N
Me
complex B
1b
,
NC
CN
CH(CN)2
R
R
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R
N
R
N
N
O
N
∗
Zn
N
∗
N
O
N
Me
N
N
Zn
(CN)2CH-
N
N
N
Me
complex E
complex C
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C
R
N
R
N
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N
N
Me
(CN)2CH-
complex D
Fig. 2 Proposed reaction cycle for the desymmetrization of
with malononitrile using 3a and Et2Zn.
1
N
N
O
N
N
H
Me
Zn
N
N
3
For selected examples with sulfur nucleophiles, see: (a) M. Hayashi,
K. Ohno, H. Hoshimi, N. Oguni, Tetrahedron, 1996, 52, 7817; (b)
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N
Zn
N
N
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CN
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CH(CN)2
(1R,2S)-isomer
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H3C
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Fig. 3 Assumed transition state for the reaction of malononitrile
with aziridine 1b using 3a
.
From the absolute stereochemistry of products and the assumed
reaction cycle, the proposed transition state for the desymmetrization
of aziridine 1b with malononitrile is shown in Figure 3. Pyridine
nitrogen and carbonyl oxygen in the imidazolyl group coordinates to
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