One-pot synthesis of chiral aziridines by a domino reaction by using desulfonylative formation on the n-tosyl imine of chloroacetaldehyde with an asymmetric mannich reaction as a key step

Article abstract of DOI:10.1002/chem.201101668

Aziridines with ease: A one-pot synthesis of chiral aziridine derivatives with excellent diastereo- and enantioselectivities was developed through uninterrupted sequential reactions, including desulfonylative formation of the N-Ts imine derived from chloroacetaldehyde, a diarylprolinol silyl ether mediated asymmetric Mannich reaction, reduction, and aziridine formation (see scheme; Ts=tosyl).

Full text of DOI:10.1002/chem.201101668

COMMUNICATION
DOI: 10.1002/chem.201101668
One-Pot Synthesis of Chiral Aziridines by a Domino Reaction by Using
Desulfonylative Formation on the N-Tosyl Imine of Chloroacetaldehyde with
an Asymmetric Mannich Reaction as a Key Step
Yujiro Hayashi,* Tatsuya Urushima, Daisuke Sakamoto, Kou Torii, and
Hayato Ishikawa[a]
Aziridine is a versatile building block in organic synthesis
because of its facile transformation to other useful com-
pounds by ring-expansion and ring-opening reactions. Aziri-
dine is also found as a key structural unit in natural prod-
ucts. Thus, the development of an efficient method for the
preparation of chiral aziridines is synthetically important.[1]
There are several successful asymmetric, catalytic aziridina-
tions, such as nitrene addition to alkene and carbene addi-
tion to imine catalyzed by organometallic reagents. Organo-
catalysts[2] are known to catalyze aziridination, most of
which involve the reaction of a,b-enal or a,b-enone with hy-
droxyamine derivatives through an iminium ion intermedi-
ate.[3]
cause imines derived from chloroacetaldehyde possess a-hy-
drogens, their Mannich reaction is expected to be very diffi-
cult. Just recently, we have found that the asymmetric cata-
lytic Mannich reaction of imines derived from aliphatic alde-
hydes with a-hydrogens is catalyzed by diarylprolinol silyl
ether 1.[6,7] In this communication, we describe the successful
synthesis of chiral aziridine derivatives by an asymmetric
Mannich reaction catalyzed by 1, followed by intramolecular
cyclization in a one-pot operation.
Recently, we have reported the one-pot synthesis of chiral
b,g-epoxyaldehyde through uninterrupted sequential reac-
tions including an asymmetric aldol reaction of chloroacetal-
dehyde as a key step.[4] If the asymmetric Mannich reaction
of the imine derived from chloroacetaldehyde and unmodi-
fied aldehyde proceeds, followed by an intramolecular nu-
cleophilic substitution, a chiral aziridine derivative would be
generated (Scheme 1). The Mannich reaction of imines de-
rived from aliphatic aldehydes with a-hydrogens is thought
to be difficult because of the equilibrium between imine and
enamine,[5] and there are only four examples of the organo-
catalyst-mediated, asymmetric cross-Mannich reaction of an
unmodified aldehyde as the Mannich donor and imines de-
rived from aliphatic aldehydes with a-hydrogens.[5d,f,h] Be-
First, we chose N-(2-chloroethylidene)-p-toluenesulfona-
mide as the imine, which can be obtained from N-(2-chloro-
1-phenylsulfonylethyl)-p-toluenesulfonamide (7) by treat-
ment with a base. a-Amidosulfone 7 was prepared from an
aqueous solution of chloroacetaldehyde, p-toluenesulfona-
mide (TsNH2), and PhSO2Na·2H2O in aqueous formic acid
(Scheme 2).
Because all of the trials for the isolation of the desired
imine were unsuccessful as a result of its rapid degradation,
we investigated the domino reaction of the in situ desulfon-
AHCTUNGTREGyNNNU lative generation of N-Ts imine and the enantioselective
Mannich reaction.[8] The reaction was performed as follows:
organocatalyst, base, a-amidosulfone 7 and aldehyde were
all mixed together in the presence of solvent at 08C, and the
reaction mixture was stirred for 24 h. Because trifluorometh-
yl-substituted diarylprolinol silyl ether 1 gave good results in
Scheme 1.
[a] Prof. Dr. Y. Hayashi, T. Urushima, D. Sakamoto, K. Torii,
Dr. H. Ishikawa
Department of Industrial Chemistry, Faculty of Engineering
Tokyo University of Science, Kagurazaka, Shinjuku-ku
Tokyo 162-8601 (Japan)
Fax : (+81)3-5261-4631
E-mail: hayashi@ci.kagu.tus.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101668.
Scheme 2.
Chem. Eur. J. 2011, 17, 11715 – 11718
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11715

Table 1. Effect of solvent and catalyst in the domino desulfonylation/
Mannich reaction.[a]
the Mannich reaction of imines derived from aliphatic alde-
hydes with an a-hydrogen,[6] compound 1 was employed as
the organocatalyst in this transformation. Propanal and
NaHCO3 were chosen as the Mannich donor and base, re-
spectively. When CH2Cl2 was employed as the solvent, the
reaction proceeded and afforded the Mannich product 8a in
59% yield with predominant formation of the anti isomer.
When 8a was treated with NaBH4, not only reduction but
also aziridination reaction proceeded to afford the desired
2-aziridinylpropanol 9a in 85% yield, and the enantiomeric
excess (ee), which was found to be excellent (92% ee), was
determined by HPLC using a chiral phase (Scheme 3).
Entry
Catalyst
Solvent
t
Yield
[%][b]
anti/syn[c]
ee
[h]
[%][d]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
2
3
4
5
6
CH2Cl2
CH3CN
toluene
1,4-dioxane
brine
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
24
24
24
24
24
72
6
6
24
24
59
70
81
82
61
27
93
95
12
23
15:1
4:1
16:1
16:1
5:1
1:10
4:1
2.3:1
1.6:1
2.3:1
92
88
97
96
90
nd
74
92
nd
22
First, the domino desulfonylation/Mannich reaction was
investigated and the effect of the solvent was examined; the
results are summarized in Table 1. The reaction proceeds in
10
[a] Reactions were performed employing a-amidosulfone 7 (0.4 mmol),
propanal (2.0 mmol), catalyst (0.04 mmol), NaHCO3 (1.2 mmol), and sol-
vent (0.8 mL) at 08C. nd=not determined. [b] Isolated product yield.
[c] Diastereomer ratio was determined by 1H NMR spectroscopy.
[d] Enantiomeric excess of anti isomer was determined by HPLC analysis
on chiral column material after conversion to 9a by the reduction and
aziridination with NaBH4.
Scheme 3.
most of the solvents under investigation. Even in the pres-
ence of brine without organic solvent, the desired product
was obtained in 61% yield (Table 1, entry 5). The yield and
diastereoselectivity are dependent on the solvent; a good
yield and excellent diastereo- and enantioselectivities were
obtained when toluene or 1,4-dioxane was employed
(Table 1, entries 3 and 4). Next, the catalyst was examined.
Diphenylprolinol silyl ethers 3 and 4 are more reactive, pro-
moting the reaction in much shorter time (6 h) than 1. In
particular, tert-butyldimethylsilyl ether 4 gave the product in
excellent yield (95%) and enantioselectivity (92% ee) in a
short reaction time (6 h), although the diastereoselectivity
(d.r.) was modest (d.r.=2.3:1; Table 1, entry 8). It should be
noted that the corresponding alcohol 2 gave the other syn
diastereomer predominantly, although the yield is insuffi-
cient (Table 1, entry 6). Low yield and enantioselectivity
were obtained in the presence of proline (Table 1, entry 10).
Next, the one-pot synthesis of 2-aziridinylpropanol 9a was
investigated (Scheme 4). After the domino reaction of desul-
fonylative formation of imine and Mannich reaction, addi-
tion of NaBH4 and MeOH in the same pot gave 9a in 69%
yield with excellent enantioselectivity (95% ee). In the reac-
tion with NaBH4, first reduction of aldehyde occurs and
then the aziridine is formed.
Because aziridinylaldehyde is also a useful chiral building
block, its generation was investigated. When three equiva-
lents of NaHCO3 were employed in the desulfonylative gen-
eration of imine and the addition of MeOH to the reaction
mixture of Mannich product 8a, which was gradually con-
verted into aziridinylaldehyde 10a (40 h) as detected by
1H NMR spectroscopy. Because 10a is difficult to purify, it
was reduced to alcohol 9a, which was isolated in 68% yield
from 7 with excellent enantioselectivity (95% ee, Scheme 5).
Scheme 4.
Scheme 5.
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Chem. Eur. J. 2011, 17, 11715 – 11718

One-Pot Synthesis of Chiral Aziridines
COMMUNICATION
Table 2. The domino reaction of desulfonylative formation of imine and
This result indicates that aziridinylaldehyde can be synthe-
sized in moderate yield with excellent enantioselectivity in a
one-pot reaction.
Mannich reaction catalyzed by organocatalyst 1.[a]
The generality of both the desulfonylative Mannich reac-
tion and the one-pot synthesis of 2-hydroxyethylaziridine 9,
using the method in Scheme 5, was investigated and the re-
sults are summarized in Tables 2 and 3, respectively.
Entry
1
Product
Time
[h]
Yield
[%][b]
anti/syn[c]
ee
In both the domino reaction and the one-pot reaction for
the synthesis of 2-hydroxyethylaziridine 9, there is a wide
generality: the domino reaction product 8 and 2-hydroxye-
thylaziridine derivative 9 are obtained with excellent diaster-
eo- and enantioselectivities. In most of the reactions, moder-
ate to good yields were obtained. In the reaction of isovaler-
aldehyde, the reaction is slow because of the steric bulkiness
of the aldehyde. Double and triple bonds do not interfere
with the reaction, affording the products 8 and 9 in good
yield. It is noteworthy that the (2-hydroxy-1-methylethyl)a-
ziridine derivative, which was prepared in good yield with
excellent diastereo- and enantioselectivities in a single-pot
reaction (Table 3, entry 1), is an enantiomer of the key inter-
mediate of (À)-deoxynupharidine, previously synthesized in
five steps from (R)-aspartic acid.[9]
Other synthetically useful chiral compounds can also be
prepared with excellent enantioselectivity based on the pres-
ent reaction, as follows. The ethyl 4-aziridinyl-2-pentenoate
derivative was prepared in a one-pot reaction in good yield
with excellent enantioselectivity with the domino reaction,
followed by the successive Wittig reaction and aziridine for-
mation (Scheme 6).
[%][d]
24
24
24
72
24
83
89
90
65
62
9:1
96
99
99
99
99
2
3
4
5
>20:1
>20:1
>20:1
>20:1
6
24
90
>20:1
99
The aziridine dimethylacetal derivative was also prepared
in a one-pot reaction by using the domino reaction, followed
by acetalization and aziridine formation (Scheme 7).
In conclusion, we have developed a one-pot synthesis of
1-substituted-2-hydroxyethylaziridine derivatives through
uninterrupted sequential reactions including desulfonylative
formation of N-Ts imine, an asymmetric, direct Mannich re-
action catalyzed by diarylprolinol silyl ether 1, reduction,
and aziridine formation. Synthetically useful chiral aziridines
with a hydroxyethyl moiety can be prepared in a single flask
with good anti selectivity and excellent enantioselectivity.
Aziridines with an a,b-unsaturated ester moiety or acetal
moiety were also synthesized in a one-pot procedure. Be-
7
24
24
67
70
>20:1
99
80
8[e]
–
[a] Unless otherwise shown, the reaction was performed employing a-
amidosulfone 7 (0.4 mmol), aldehyde (1.2 mmol), catalyst 1 (0.04 mmol),
NaHCO3 (1.2 mmol), and 1,4-dioxane (0.8 mL) at 08C for the indicated
time. [b] Isolated product yield. [c] Diastereomer ratio was determined
1
by H NMR spectroscopy. [d] The enantiomeric excess of anti isomer was
determined by HPLC analysis on chiral column material after reduction
and aziridination with NaBH4. [e] Acetaldehyde (2.0 mmol) was em-
ployed.
Scheme 6.
cause the generated product
possesses several functional
groups, with excellent diaste-
reoselectivity and enantioselec-
tivity and the synthetic proce-
Scheme 7.
Chem. Eur. J. 2011, 17, 11715 – 11718
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11717

Y. Hayashi et al.
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Entry
Product
Time
[h]
Yield
[%][b]
anti/syn[c]
ee
[%][d]
1
2
3
4
5
24
24
24
72
24
69
90
88
69
60
8:1
>20:1
>20:1
>20:1
>20:1
96
99
99
99
99
6
7
24
24
65
60
>20:1
>20:1
99
99
8[e]
9[f]
24
24
69
48
–
80
94
7:1
[a] Reactions were performed employing a-amidosulfone 7 (0.4 mmol),
aldehyde (1.2 mmol), catalyst 1 (0.04 mmol), NaHCO3 (1.2 mmol) and
1,4-dioxane (0.8 mL) for the indicated time. [b] Isolated product yield.
1
[c] Diastereomer ratio was determined by H NMR spectroscopy. [d] The
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enantiomeric excess of anti isomer was determined by HPLC analysis on
chiral column material after reduction and aziridination with NaBH4.
[e] Acetaldehyde (2.0 mmol) was employed. [f] Catalyst 3 (0.04 mmol)
was employed.
dure is simple, this method offers an efficient route for the
preparation of chiral aziridine derivatives.
Keywords: asymmetric reaction
·
domino reactions
·
enantioselectivity · Mannich reaction · one-pot reaction ·
organocatalysis
[1] a) Aziridines and Epoxides in Organic Synthesis (Ed.: A. K. Yudi),
Wiley-VCH, Weinheim, 2006; b) C. Mobner, C. Bolm, Catalyzed
Asymmetric Aziridinations in Transition Metals for Organic Synthesis,
Vol. 2, 2nd ed. (Ed.: M. Beller, C. Bolm), Wiley-VCH, Weinheim,
Received: June 1, 2011
Published online: September 2, 2011
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Chem. Eur. J. 2011, 17, 11715 – 11718