Asymmetric trisubstituted aziridination of aldimines and ketimines using N-α-Diazoacyl camphorsultams

Article abstract of DOI:10.1002/asia.201000604

The acid-catalyzed reaction of diazoacetates and aldimines (Brookhart-Templeton aziridination) is now recognized as a reliable method to provide enantiomerically enriched disubstituted aziridines, thus owing to the development of asymmetric catalysis. However, the extension of this method to prepare trisubstituted aziridines has not been explored to date, even for racemic products. In this context, and considering their synthetic importance and lack of alternative direct synthetic methods, we recently launched a program to realize this unmet challenge. Herein, we report a detailed study, which led to the establishment of a highly stereoselective synthesis for various trisubstituted aziridines, building on the use of N-α-diazoacyl camphorsultams as a key component. SpringBoc reaction: An acid-catalyzed reaction of N-α-diazoacyl camphorsultams and N-Boc imines has been developed, as a facile means to provide trisubstituted aziridines in a highly stereoselective manner. The use of N-Boc α-ketimino esters and N-α-diazoacetyl camphorsultam as an alternative combination of substrates led to the construction of trisubstituted aziridines with two carbonyl functionalities (see scheme). Copyright

Full text of DOI:10.1002/asia.201000604

DOI: 10.1002/asia.201000604
Asymmetric Trisubstituted Aziridination of Aldimines and Ketimines using
N-a-Diazoacyl Camphorsultams
Takuya Hashimoto, Hiroki Nakatsu, Kumiko Yamamoto, Shogo Watanabe, and
Keiji Maruoka*[a]
Dedicated to Professor Eiichi Nakamura on the occasion of his 60th birthday
Abstract: The acid-catalyzed reaction
of diazoacetates and aldimines (Broo-
khart–Templeton aziridination) is now
recognized as a reliable method to pro-
vide enantiomerically enriched disub-
stituted aziridines, thus owing to the
development of asymmetric catalysis.
However, the extension of this method
to prepare trisubstituted aziridines has
not been explored to date, even for
racemic products. In this context, and
considering their synthetic importance
and lack of alternative direct synthetic
methods, we recently launched a pro-
gram to realize this unmet challenge.
Herein, we report a detailed study,
which led to the establishment of a
highly stereoselective synthesis for var-
ious trisubstituted aziridines, building
on the use of N-a-diazoacyl camphor-
sultams as a key component.
Keywords: asymmetric synthesis ·
aziridine · camphorsultam · chiral
auxiliaries · diazo compounds
Introduction
Among the various strategies available for the preparation
of aziridines,[1] the Brookhart–Templeton aziridination,
wherein aldimines and diazoacetates react under the influ-
ence of a catalytic amount of an acid, is considered to be
one of the most elaborated reaction systems; this allows
access to highly stereodefined cis-disubstituted aziridines
(Scheme 1, Eq. (1)).[2,3] Following the initial finding by
Brookhart and Templeton et al., Wulff and co-workers es-
tablished a catalytic asymmetric variant of this reaction by
use of chiral boron Lewis acid.[4–6] More recently, the up-
surge of chiral Brønsted acid catalysis has also contributed
to the development of this area, opening up ways for both
cis- and trans-disubstituted aziridines in a highly stereoselec-
tive manner.[7–9]
Scheme 1. The Brookhart–Templeton aziridination and its possible exten-
sion to trisubstituted aziridine synthesis.
In sharp contrast to these developments, as a means to
give disubstituted aziridines stereoselectively, the extension
of this attractive aziridination protocol to provide more con-
gested trisubstituted aziridines has not been reported to
date, even with regard to the preparation of racemic aziri-
dines. As a tactic to generate trisubstituted aziridines by
using Brookhart–Templeton aziridination, it can be envis-
aged that the combination of aldimines and a-substituted a-
diazocarbonyl compounds (Scheme 1, Eq. (2)), or ketimines
[a] Dr. T. Hashimoto, H. Nakatsu, K. Yamamoto, S. Watanabe,
Prof. Dr. K. Maruoka
Department of Chemistry
Graduate School of Science
Kyoto University
Sakyo, Kyoto, 606-8502 (Japan)
Fax : (+81)75-753-4041
E-mail: maruoka@kuchem.kyoto-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000604.
Chem. Asian J. 2011, 6, 607 – 613
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
607

FULL PAPERS
Table 1. Preliminary exploration of reaction conditions for aziridinations
between a-methyl-a-diazocarbonyl compounds and benzaldehyde-de-
rived imines.[a]
and a-unsubstituted a-diazocarbonyl compounds (Scheme 1,
Eq. (3)), would be applicable.
In this context, we recently reported our preliminary re-
sults on the asymmetric synthesis of trisubstituted aziridines
that uses N-a-diazoacyl camphorsultam (Scheme 1, Eq. (2),
X=camphorsultam), thereby offering a distinctive approach
for optically enriched trisubstituted aziridines.[10,11] We
report herein the detailed study on this asymmetric trisubsti-
tuted aziridination, including the derivatization of the as-ob-
tained trisubstituted aziridines by means of an acid-cata-
lyzed ring rearrangement, as a means to provide stereode-
fined a,a-disubstituted b-hydroxy-a-amino acid derivatives
in a straightforward fashion. In addition, the acid-catalyzed
reaction of N-a-diazoacetyl camphorsultam (with an a-hy-
drogen) and ketimines (Scheme 1, Eq. (3) X=camphorsul-
tam) was also established as an alternative approach to
afford stereodefined trisubstituted aziridines bearing two
carbonyl functionalities.
Entry
X
R2
Catalyst
t [8C]
Yield [%][b]
1
2
3
4
5
EtO (1a)
EtO
EtO
EtO
EtO
Bn
Ph
BF3·Et2O RT, 2.5 h
BF3·Et2O RT, 20 min
–
<9
Boc BF3·Et2O ꢀ78, 30 min <17
Boc TiCl4
ꢀ50, 1.5 h
<16
19
Boc CF3SO3H ꢀ78, 10 min
6
7
Boc BF3·Et2O ꢀ78, 10 min
52
56
Boc BF3·Et2O ꢀ78, 1 h
Results and Discussion
8
9
10
Boc BF3·Et2O ꢀ78, 1 h
Boc CF3SO3H ꢀ78, 10 min
Boc CH3SO3H ꢀ78, 4 h
43 (>20/1)[c]
74 (>20/1)[c]
68 (>20/1)[c]
Asymmetric Trisubstituted Aziridination of N-Boc
Aldimines and a-Substituted a-Diazocarbonyl Compounds
In the preliminary experiments aimed at finding a suitable
conditions for trisubstituted aziridination, we set out to in-
vestigate the combination of several a-diazocarbonyl com-
pounds bearing a different functionality at the carbonyl
carbon and benzaldehyde-derived imines bearing a different
protecting group by using a catalytic amount of an acid cata-
lyst (Table 1). This study clearly indicated the ineffectiveness
of ethyl ester 1a, which is commonly used in the Brookhart–
Templeton aziridination, in this trisubstituted aziridine syn-
thesis, regardless of the N-protecting groups of benzalde-
hyde-derived imines and acid catalysts (Table 1, entries 1–5).
Subsequently, we moved our attention to the use of other a-
diazocarbonyl compounds that bear other templates at the
carbonyl carbon, as we were aware of the importance of this
part to control the course of acid-catalyzed reactions of a-
diazocarbonyl compounds, based on our analysis of previous
studies.[7,11d] The attachment of the oxazolidinone (1b) or
the sultam (1c) led to a significant improvement in the reac-
[a] Reactions were performed with 1 or 2a (0.10 mmol) and benzalde-
hyde-derived imine (0.15 mmol) in the presence of 20 mol% catalyst in
CH2Cl2. [b] Isolated yield. [c] The diastereoselectivity of the trans isomer,
1
as determined by H NMR analysis of the crude mixture.
tion efficiency, and this afforded the desired aziridines in 52
and 56% yield, respectively (Table 1, entries 6 and 7). Fur-
thermore, only trans-aziridines were observed in both cases.
The promising reactivity of 1b and 1c prompted us to in-
vestigate the application of the chiral auxiliary to provide
enantiomerically enriched trisubstituted aziridines. Although
the use of Evansꢁ chiral oxazolidinone afforded the trisubsti-
tuted aziridine with low diastereoselectivity (data not
shown), the aziridination of N-a-diazoacyl camphorsultam
2a and N-Boc imine provided the desired trans-aziridine in
43% yield with rigorous control of the stereoselectivity
(Table 1, entry 8). Further optimization of the acid catalysts
led to the discovery of the superiority of strong Brønsted
acids like CF3SO3H and CH3SO3H in this reaction system
(Table 1, entries 9 and 10).
Abstract in Japanese:
With these optimized conditions in hand, we set out to ex-
amine the scope of this asymmetric trisubstituted aziridina-
tion, as summarized in Table 2. Aziridinations of N-a-diazo-
acyl camphorsultam 2a with various aryl aldehyde-derived
N-Boc imines proceeded in good yields, irrespective of the
substituent pattern and electronic properties (Table 2, en-
tries 1–8). In all cases, the trans-aziridine was obtained as a
sole product with high stereoselectivity (>20/1). In contrast
to the high tolerance for aryl aldehyde-derived N-Boc
imines, the aliphatic aldehyde-derived N-Boc imine was
found to be completely unreactive (Table 2, entry 9). As for
608
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 607 – 613

Aziridination of Aldimines and Ketimines
Table 2. Scope of asymmetric trisubstituted aziridination between N-a-
diazoacyl camphorsultams and N-Boc imines.[a]
a,a-Disubstituted b-Hydroxy-a-Amino Acid Synthesis via
One-pot Trisubstituted Aziridination/Ring Rearrangement
In the literature there is precedent for N-Boc-protected cis-
or trans-disubstituted aziridines to rearrange to their corre-
sponding oxazolidinones under acidic conditions.[4e,12] With
optically enriched trisubstituted aziridines in hand, we com-
menced a study to apply this ring rearrangement to these
aziridines, as a facile means to provide a,a-disubstituted b-
hydroxy-a-amino acids.[13] As shown in Scheme 2, this ring
Entry R1
R2
Me (2a) Boc Ph
2-tolyl
R3
Yield [%][b]
dr (trans)[c]
1
2
3
74
60
63
59
54
62
56
62
–
3a
3b
3c
3d
3e
3 f
3g
3h
–
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
–
3-tolyl
4-tolyl
2-Np
4-ClC6H4
4-PivOC6H4
3-MeOC6H4
Cy
4[d]
5
6
7
8
9
10
Et (2b)
Me (2a) Cbz Ph
2-tolyl
Ph
50
61
64
66
56
55
3i
3j
3k
3l
3m
3n
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
11[e]
12[e]
13[e]
14[e]
15
3-tolyl
3-MeOC6H4
4-BrC6H4
[a] Reactions were performed with 2 (0.10 mmol) and imine (0.15 mmol)
in the presence of 20 mol% CF3SO3H in CH2Cl2 for 5–20 min. [b] Isolat-
ed yield. [c] Determined by 1H NMR analysis of the crude material.
[d] Performed with 3 equivalents of the imine. [e] Performed with
20 mol% CH3SO3H for 1–4 h under otherwise identical conditions.
Scheme 2. Acid-catalyzed ring rearrangement of the aziridine to the oxa-
zolidinone.
rearrangement was found to be feasible under the influence
of both Lewis acid and Brønsted-acid catalysts. Compared
to the low reactivity of BF3·Et2O, which required 2 h of stir-
ring at room temperature until completion of the reaction,
the CF3SO3H-catalyzed ring rearrangement proceeded rap-
idly even at ꢀ408C, and this afforded oxazolidinone 5a in
76% yield. This ring rearrangement furnished the trans-oxa-
zolidinone exclusively with retention of the configuration at
the b-carbon.
N-a-diazoacyl camphorsultam, a-ethyl substituted diazo
compound 2b could be utilized to give the trisubstituted
trans-azridine 3i in 50% yield, as an essentially single
isomer (Table 2, entry 10).
The close similarity of the reaction conditions for aziridi-
nation and ring rearrangement further prompted us to im-
plement a one-pot sequential aziridination/ring rearrange-
ment, which could provide a straightforward method for the
synthesis of b-hydroxy-a-amino acid derivatives. The appli-
cation of triflic-acid catalysis to this sequential reaction by
gradually warming the reaction temperature from ꢀ78 to
ꢀ408C gave the desired product only in low yield, whereas
the use of BF3·Et2O in CH2Cl2 at room temperature was
able to achieve this goal. As showcased in Table 3, this se-
quential process afforded the stereodefined oxazolidinones
in moderate yields regardless of the imines employed.
Detachment of the chiral auxiliary from this oxazolidi-
none could be accomplished under very mild conditions.
Treatment of the crude material 5a, obtained by the reac-
tion of 2a and benzaldehyde derived N-Boc imine, with trie-
thylamine in methanol, smoothly gave rise to the methyl
ester 6 in 45% yield (2 steps). The enantiomeric excess of
this compound was determined to be 95% by using chiral
HPLC analysis, thus confirming the high stereoselectivity in-
duced by camphorsultam (Scheme 3).
In consideration of the synthetic utility of the benzyloxy-
carbonyl (Cbz) moiety, as a N-protecting group, we then fo-
cused on the use of N-Cbz imines instead of N-Boc imines.
Under the above reaction conditions, using CF3SO3H as cat-
alyst, the reaction of benzaldehyde N-Cbz imine led to the
formation of the ring rearranged product 4, which is consid-
ered to be generated by means of an initial aziridination
and then successive ring rearrangements (see below). To
prevent this undesired ring rearrangement, we opted for the
use of CH3SO3H, a milder Brønsted acid, in expectation of
stopping the reaction at the initial aziridination. Under this
tuned reaction condition, Cbz-protected trans-aziridines
could be obtained as the major product with high stereose-
lectivity (Table 2, entries 11–14). One exception in this
regard is the reaction with 4-bromobenzaldehyde-derived N-
Cbz imine wherein the aziridination did not proceed well
with CH3SO3H, presumably as a result of the attenuated in-
teraction of the less basic imine and the acid catalyst. In this
case, use of CF3SO3H was reactive enough to give the trans-
aziridine in 55% yield (Table 2, entry 15).
Chem. Asian J. 2011, 6, 607 – 613
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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609

K. Maruoka et al.
FULL PAPERS
Table 3. One-pot sequential aziridination/ring rearrangement.[a]
Table 4. Scope of asymmetric trisubstituted aziridination between N-a-
diazoacetyl camphorsultam and N-Boc a-ketimino esters.[a]
Entry
R3
Yield [%][b]
dr (trans)[c]
1
2
3
4
5
6
7
8
Ph
2-tolyl
3-tolyl
4-tolyl
46
46
50
42
41
50
56
47
5a
5b
5c
5d
5e
5 f
5g
5h
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
Entry
R4
9:10[b]
Yield (9) [%][c]
dr (trans)[b]
2-Np
1
2
3
4
5
6
Ph
74:26
82:18
78:22
74:26
73:27
71:29
65
66
59
51
60
56
9a
9b
9c
9d
9e
9 f
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
4-ClC6H4
4-PivOC6H4
3-MeOC6H4
3-tolyl
4-tolyl
2-Np
4-ClC6H4
3-MeOC6H4
[a] Reactions were performed with 2a (0.10 mmol) and imine
(0.15 mmol) in the presence of 20 mol% BF3·Et2O in CH2Cl2 for 5–11 h.
[b] Isolated yield. [c] Determined by H NMR analysis of the crude mate-
1
[a] Reactions were performed with 7 (0.20 mmol) and a-ketoimino ester
8 (0.24 mmol) in the presence of 20 mol% Tf2NH in toluene for 15~
20 min. [b] Determined by 1H NMR analysis of the crude material.
[c] Isolated yield.
rial.
(trans/cis, >20/1) by use of toluene as solvent (Table 4,
entry 1).[16] This aziridination was tolerant to various aro-
matic functionalities attached to the a-ketimino esters to
give trisubstituted aziridines in yields ranging from 51 to
66% with high diastereoselectivities (Table 4, entries 2–6).
At present, we have been unable to expand this method to
the synthesis of tetrasubstituted aziridines by the use of a-
substituted N-a-diazoacyl camphorsultams and ketimines as
a route for highly encumbered vicinal quaternary stereogen-
ic centers.
Removal of the camphorsultam moiety from this product
could be accomplished by treatment with hydrolytic condi-
tions by using a combination of excess LiOH and LiCl
(Scheme 4). Reprotection of this crude acid with TMSCHN2
furnished the corresponding aziridine dicarboxylate 11 in
93% yield with 95% ee.
Scheme 3. Removal of chiral auxiliary from 5a.
Asymmetric Trisubstituted Aziridination of N-Boc a-
Ketimino Esters and a-Unsubstituted a-Diazocarbonyl
Compound
Successful implementation of asymmetric trisubstituted azir-
idinations by using N-a-diazoacyl camphorsultams prompted
us to investigate the possibility of employing the combina-
tion of a-unsubstituted a-diazocarbonyl compounds and ke-
timines (Scheme 1, Eq. (3)). Because the high stereofidelity
of camphorsultam as a chiral auxiliary had been demonstrat-
ed by the above examples, we decided to examine the reac-
tion using N-a-diazoacetyl (ꢀ)-camphorsultam 7.[14] As for
the corresponding ketimines, Boc-protected a-ketimino
ester 8 was selected because the Boc protecting group is
necessary for the required ring-closure. These ketimines
were easily accessed by use of a procedure developed re-
cently in our laboratory.[15]
The initial experiment using 7 and 8 (R4 =Ph), under the
reaction conditions described above (20 mol% CF3SO3H,
CH2Cl2, ꢀ788C), led to a low yield, concomitant with the
formation of a considerable amount of byproduct 10, which
is considered to be derived from the migration of the R4
group via a diazonium intermediate (Scheme 1). Additional-
ly, use of the milder Brønsted acid CH3SO3H exhibited ap-
parently low reactivity in this reaction system. Accordingly,
we employed a different strong Brønsted acid Tf2NH as the
catalyst, wherefore the trisubstituted aziridine could be ob-
tained in 65% yield as an essentially single trans isomer
Scheme 4. Removal of chiral auxiliary from 9a.
Conclusions
In summary, we demonstrated herein two approaches for
the acid-catalyzed asymmetric synthesis of trisubstituted
aziridines. The key finding to realize these aziridinations
was the importance of choosing the proper template embed-
ded in a-diazocarbonyl compounds and the N-protecting
group of imines. By using N-a-diazoacyl camphorsultams
610
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Chem. Asian J. 2011, 6, 607 – 613

Aziridination of Aldimines and Ketimines
The combined organic layers were dried over anhydrous Na2SO4 and
concentrated. The residue was purified by using column chromatography
on silica gel to give the corresponding oxazolidinone. Spectral data for
5a were reported previously.[10]
with N-Boc imines, we succeeded to establish a practical
method for the stereoselective synthesis of trisubstituted
aziridines. To extend the synthetic utility of the so-obtained
aziridines, acid-catalyzed ring rearrangement was conducted
to give a,a-disubstituted b-hydroxy-a-amino acid deriva-
tives. The acidic reaction conditions used for both aziridina-
tion and ring rearrangement further prompted us to proceed
with a one-pot sequential aziridination/ring rearrangement,
as a straightforward method to access these amino acid de-
rivatives. As an alternative approach, we also investigated
the combination of a-unsubstituted N-a-diazoacetyl cam-
phorsultam and N-Boc a-ketimino esters, which made avail-
able trisubstituted aziridines bearing two carbonyl moieties.
Research is currently underway to elaborate these synthetic
methods to catalytic asymmetric trisubstituted aziridina-
tions.
Data for 5b: 1H NMR (400 MHz, CDCl3): d=7.26–7.28 (3H, m), 7.20
(1H, m), 6.67 (1H, s), 6.41 (1H, s), 4.02 (1H, dd, J=7.7, 4.4 Hz), 3.56
(1H, d, J=13.5 Hz), 3.49 (1H, d, J=13.8 Hz), 2.41 (3H, s), 1.26–2.14
(7H, m), 1.18 (3H, s), 1.13 (3H, s), 0.98 ppm (3H, s); 13C NMR
(100 MHz, CDCl3): d=176.1, 157.1, 135.9, 133.4, 131.0, 129.1, 126.6,
126.2, 81.9, 67.5, 67.0, 53.3, 49.3, 48.2, 44.3, 38.6, 32.7, 26.8, 20.7, 20.0,
19.6, 19.2 ppm; IR (neat): n˜ =1769, 1688, 1327, 1215, 1200, 1144, 1101,
1055 cmꢀ1
; HRMS (ESI) exact mass: m/z: calcd for C22H28N2O5S:
455.1611 ([M+Na]+); found: (455.1614 [M+Na]+); ½aꢁ2D4 =ꢀ62.8 (c=1.1,
CHCl3).
Data for 5c: 1H NMR (400 MHz, CDCl3): d=7.16–7.30 (4H, m), 6.60
(1H, s), 6.01 (1H, s), 4.00 (1H, dd, J=7.7, 4.4 Hz), 3.55 (1H, d, J=
13.5 Hz), 3.49 (1H, d, J=13.8 Hz), 2.37 (3H, s), 1.26–2.15 (7H, m), 1.17
(3H, s), 1.15 (3H, s), 0.98 ppm (3H, s); 13C NMR (100 MHz, CDCl3): d=
174.8, 156.9, 138.4, 134.5, 129.8, 128.5, 127.4, 124.1, 84.0, 67.2, 66.8, 53.3,
49.2, 48.2, 44.3, 38.5, 32.7, 26.7, 21.6, 20.7, 20.5, 20.0 ppm; IR (neat): n˜ =
1770, 1688, 1329, 1238, 1167, 1105, 1059 cmꢀ1; HRMS (ESI) exact mass:
m/z: calcd for C22H28N2O5S: 455.1611 ([M+Na]+); found: (455.1603
[M+Na]+); ½aꢁ2D0 =ꢀ64.8 (c=1.0, CHCl3).
Experimental Section
Data for 5d: 1H NMR (400 MHz, CDCl3): d=7.31 (2H, d, J=8.0 Hz),
7.20 (2H, d, J=8.2 Hz), 6.57 (1H, s), 6.00 (1H, s), 4.00 (1H, dd, J=7.7,
4.4 Hz), 3.55 (1H, d, J=13.8 Hz), 3.48 (1H, d, J=13.8 Hz), 2.36 (3H, s),
1.26–2.14 (7H, m), 1.17 (3H, s), 1.14 (3H, s), 0.98 ppm (3H, s); 13C NMR
(100 MHz, CDCl3): d=174.8, 157.0, 139.0, 131.5, 129.3, 126.9, 84.0, 67.2,
66.8, 53.3, 49.2, 48.2, 44.3, 38.6, 32.8, 26.7, 21.3, 20.7, 20.5, 20.0 ppm; IR
(neat): n˜ =1771, 1686, 1329, 1167, 1146, 1103, 1059 cmꢀ1; HRMS (ESI)
exact mass: m/z: calcd for C22H28N2O5S: 455.1611 ([M+Na]+); found:
(455.1606 [M+Na]+); ½aꢁD23 =ꢀ76.1 (c=1.2, HCl3).
General Information
The 1H NMR spectra were measured by using a JEOL JNM-FX400
(400 MHz) spectrometer. Data were reported as follows: chemical shifts
in ppm from tetramethylsilane as an internal standard, integration, multi-
plicity (s=singlet, d=doublet, t=triplet, q=quartet, dd=double dou-
blet, dq=double quartet, ddd=double double doublet, sept=septet, m=
multiplet, br=broad, and app=apparent), coupling constants (Hz), and
assignment. Infrared (IR) spectra were recorded by using a Shimadzu IR-
Prestige-21 spectrometer. High-resolution mass spectra (HRMS) were
performed on a Brucker microTOF. Optical rotations were measured on
a JASCO DIP-1000 digital polarimeter. High-performance liquid chro-
matography (HPLC) was performed on a Shimadzu 10 A instrument at
l=206 nm using 4.6 nmꢂ25 cm Daicel Chiralcel OD-H and Daicel Chir-
alpak AD-H columns. For thin layer chromatography (TLC) analysis
Data for 5e: 1H NMR (400 MHz, CDCl3): d=7.94 (1H, s), 7.84–7.88
(3H, m), 7.51–7.55 (3H, m), 6.66 (1H, s), 6.22 (1H, s), 4.03 (1H, dd, J=
7.7, 4.8 Hz), 3.56 (1H, d, J=13.5 Hz), 3.50 (1H, d, J=13.8 Hz), 1.25–2.19
(7H, m), 1.20 (3H, s), 1.18 (3H, s), 1.00 ppm (3H, s); 13C NMR
(100 MHz, CDCl3): d=174.8, 157.0, 133.6 ,133.1, 131.9, 128.5, 128.4,
127.8, 126.8, 126.7, 126.4, 124.2, 84.1, 67.3, 66.9, 53.3, 49.2, 48.2, 44.3, 38.6,
32.8, 26.7, 20.73, 20.71, 20.0 ppm; IR (neat): n˜ =1769, 1688, 1329, 1271,
throughout this work, Merck precoated TLC plates (silica gel 60 GF254
,
0.25 mm) were used. The products were purified by using flash column
chromatography on silica gel 60 (Merck, 230–400 mesh) or neutral silica
gel (KANTO CHEMICAL CO., INC., 40–50 mm), and Merck precoated
1144, 1125, 1105, 1059 cmꢀ1; HRMS (ESI) exact mass: m/z: calcd for
22
C25H28N2O5S: 491.1611 ([M+Na]+); found: (491.1612 [M+Na]+); ½aꢁD
=
ꢀ97.1 (c=1.0, CHCl3).
preparative thin layer chromatography (PLC) plate (silica gel 60 GF254
,
Data for 5 f: 1H NMR (400 MHz, CDCl3): d=7.37–7.42 (4H, m), 6.61
(1H, s), 6.00 (1H, s), 3.99 (1H, m), 3.55 (1H, d, J=13.8 Hz), 3.49 (1H, d,
J=13.8 Hz), 1.26–2.15 (7H, m), 1.17 (3H, s), 1.15 (3H, s), 0.99 ppm (3H,
s); 13C NMR (100 MHz, CDCl3): d=174.3, 156.5, 135.1, 133.0, 128.9,
128.4, 83.1, 67.1, 66.8, 53.3, 49.2, 48.2, 44.3, 38.5, 32.7, 26.7, 20.7, 20.6,
20.0 ppm; IR (neat): n˜ =1770, 1686, 1493, 1327, 1167, 1103, 1092,
1059 cmꢀ1; HRMS (ESI) exact mass: m/z: calcd for C21H25ClN2O5S:
475.1065 ([M+Na]+); found: (491.1052 [M+Na]+); ½aꢁ2D3 =ꢀ71.5 (c=1.2,
CHCl3).
Data for 5g: 1H NMR (400 MHz, CDCl3): d=7.46 (2H, d, J=8.5 Hz),
7.11 (2H, d, J=8.7 Hz), 6.60 (1H, s), 6.03 (1H, s), 4.00 (1H, dd, J=7.7,
4.4 Hz), 3.55 (1H, d, J=13.8 Hz), 3.49 (1H, d, J=13.8 Hz), 1.26–2.15
(7H, m), 1.36 (9H, s), 1.17 (3H, s), 1.16 (3H, s), 0.98 ppm (3H, s);
13C NMR (100 MHz, CDCl3): d=177.0, 174.5, 156.6, 151.7, 131.7, 128.1,
121.8, 83.4, 67.2, 66.8, 53.3, 49.2, 48.2, 44.3, 39.3, 38.5, 32.7, 27.2, 26.7,
20.7, 20.6, 20.0 ppm; IR (neat): n˜ =1771, 1757, 1688, 1329, 1207, 1167,
1109, 1059 cmꢀ1; HRMS (ESI) exact mass: m/z: calcd for C26H34N2O7S:
541.1979 ([M+Na]+); found: (541.1977 [M+Na]+); ½aꢁ2D2 =ꢀ71.1 (c=1.0,
CHCl3).
0.5 mm). In experiments requiring dry solvent, dichloromethane and tolu-
ene were purchased from Kanto Chemical Co. Inc. as “dehydrated” and
were further purified by passing through neutral alumina under a nitro-
gen atmosphere. N-Boc imines,[17] N-Cbz imines,[18] and N-a-diazoacyl
(ꢀ)-camphorsultams[11d,14] were prepared according to the literature.
General Procedure for Asymmetric Trisubstituted Aziridination between
N-a-Diazoacyl Camphorsultams and N-Boc Imines (Table 2)
CF3SO3H (1.8 mL, 0.020 mmol) was added to a stirred solution of N-a-di-
azoacyl (ꢀ)-camphorsultam 2 (0.10 mmol) and imine (0.15 mmol) in
CH2Cl2 (1.0 mL) at ꢀ788C under argon atmosphere. The reaction mix-
ture was stirred at the same temperature until completion of the reaction
and was then treated with Et3N (20 mL). The mixture was poured into
aqueous NaHCO3 and extracted with ethyl acetate. The combined organ-
ic layers were dried over anhydrous Na2SO4 and concentrated. The resi-
due was purified by using column chromatography on silica gel to give
the corresponding aziridine. Spectral data for 3a–n have been previously
reported.[10]
General procedure for one-pot sequential aziridination/ring rearrangement
(Table 3)
Data for 5h: 1H NMR (400 MHz, CDCl3): d=7.31 (1H, app t, J=
8.0 Hz), 7.02 (1H, m), 6.98 (1H, m), 6.90 (1H, m), 6.59 (1H, s), 6.01
(1H, s), 4.00 (1H, dd, J=7.7, 4.4 Hz), 3.82 (3H, s), 3.55 (1H, d, J=
13.8 Hz), 3.49 (1H, d, J=13.8 Hz), 1.26–2.15 (7H, m), 1.18 (3H, s), 1.17
(3H, s), 0.98 ppm (3H, s); 13C NMR (100 MHz, CDCl3): d=174.6, 159.9,
156.7, 136.1, 129.7, 119.2, 114.7, 112.4, 83.8, 67.2, 66.8, 55.5, 53.3, 49.2,
48.2, 44.3, 38.5, 32.7, 26.7, 20.7, 20.4, 20.0 ppm; IR (neat): n˜ =1771, 1688,
BF3·OEt2 (2.5 mL, 0.020 mmol) was added to a stirred solution of N-a-di-
azoacyl (ꢀ)-camphorsultam 2a (0.10 mmol) and N-Boc imine
(0.15 mmol) in CH2Cl2 (1.0 mL) at room temperature under an argon at-
mosphere. The reaction mixture was stirred until completion of the reac-
tion. The mixture was poured into water and extracted with ethyl acetate.
Chem. Asian J. 2011, 6, 607 – 613
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
611

K. Maruoka et al.
FULL PAPERS
1327, 1267, 1238, 1105, 1057 cmꢀ1; HRMS (ESI) exact mass: m/z: calcd
for C22H28N2O6S: 471.1560 ([M+Na]+); found: (471.1559 [M+Na]+);
½aꢁ2D2 =ꢀ80.9 (c=1.0, CHCl3).
Data for 9d: 1H NMR (400 MHz, CDCl3): d=8.07 (1H, s), 7.87–7.78
(2H, m), 7.76–7.64 (2H, m), 7.46–7.43 (2H, m), 4.60 (1H, s), 3.55–3.42
(3H, m), 2.03–1.21 (7H, m), 1.54 (9H, s), 1.44 (9H, s), 1.16 (3H, s),
0.94 ppm (3H, s); 13C NMR (100 MHz, CDCl3): d=180.0, 165.5, 162.7,
133.2, 132.8, 129.4, 129.2, 128.5, 127.6, 127.2, 126.9, 126.1, 125.7, 84.0,
82.6, 65.3, 54.6, 53.1, 49.0, 47.8, 47.4, 44.6, 37.9, 32.9, 28.1, 27.8, 26.2, 21.0,
19.9 ppm; IR (neat): n˜ =2978, 2357, 1740, 1713, 1331, 1153 cmꢀ1; HRMS
(ESI) exact mass: m/z: calcd for C33H42N2O7S: 633.2605 ([M+Na]+);
found: 633.2615 [M+Na]+); ½aꢁD28 =ꢀ13.5 (c=0.50, CHCl3).
Removal of chiral auxiliary from 5a (Scheme 3)
BF3·OEt2 (2.5 mL, 0.020 mmol) was added to a stirred solution of N-a-di-
azoacyl (ꢀ)-camphorsultam 2a (0.10 mmol, 29.7 mg) and benzaldehyde
N-Boc imine (0.15 mmol, 30.7 mg) in CH2Cl2 (1.0 mL) at room tempera-
ture under an argon atmosphere. The reaction mixture was stirred for
7 h. The mixture was quenched with H2O and extracted with ethyl ace-
tate. The combined organic layers were dried over anhydrous Na2SO4
and concentrated. Triethylamine (0.20 mmol, 28 mL) was added to a
stirred solution of the crude material of 5a in MeOH at room tempera-
ture. The reaction mixture was stirred for 3 h. The mixture was concen-
trated and purified by using column chromatography on silica gel (eluting
with hexane/EtOAc, 3:1) to give the corresponding oxazolidione 6 as a
colorless oil [45%, 10.5 mg, dr=>20/1]. The enantiomeric purity of the
product was determined by HPLC analysis (Daicel CHIRALPAK AD-
Data for 9e: 1H NMR (400 MHz, CDCl3): d=7.50 (2H, d, J=8.5 Hz),
7.27 (2H, d, J=7.7 Hz), 4.53 (1H, s), 3.60 (1H, dd, J=7.7, 4.8 Hz), 3.53
(1H, d, J=13.8 Hz), 3.42 (1H, d, J=13.8 Hz), 2.06–1.22 (7H, m), 1.50
(9H, s), 1.45 (9H, s), 1.17 (3H, s), 0.96 ppm (3H, s); 13C NMR
(100 MHz, CDCl3): d=165.0, 162.6, 157.1, 134.0, 131.2, 130.3, 127.7, 84.2,
82.7, 65.3, 53.6, 53.0, 49.0, 47.8, 47.2, 44.6, 37.9, 32.8, 27.9, 27.7, 26.2, 20.9,
19.8 ppm; IR (neat): n˜ =2978, 2357, 2255, 1738, 1707, 1331, 1150 cmꢀ1
;
HRMS (ESI) exact mass: m/z: calcd for C29H39ClN2O7S: 617.2059
([M+Na]+); found: 617.2038 [M+Na]+); ½aꢁD22 =ꢀ29.8 (c=1.0, CHCl3).
Data for 9 f: 1H NMR (400 MHz, CDCl3): d=7.21 (1H, app t, J=
8.1 Hz), 7.14–7.12 (2H, m), 6.82 (1H, m), 4.51 (1H, s), 3.79 (3H, s), 3.64
(1H, dd, J=7.7, 4.8 Hz), 3.52 (1H, d, J=13.8 Hz), 3.42 (1H, d, J=
13.8 Hz), 2.06–1.21 (7H, m), 1.51 (9H, s), 1.44 (9H, s), 1.17 (3H, s),
0.95 ppm (3H, s); 13C NMR (100 MHz, CDCl3): d=165.4, 162.7, 158.8,
157.3, 133.2, 128.5, 122.1, 115.0, 114.2, 83.8, 82.4, 65.3, 55.1, 54.3, 53.0,
48.9, 47.8, 47.1, 44.6, 38.0, 32.9, 28.0, 27.7, 26.2, 20.9, 19.8 ppm; IR (neat):
n˜ =2978, 2253, 1736, 1709, 1604, 1585, 1331, 1150 cmꢀ1; HRMS (ESI)
exact mass: m/z: calcd for C30H42N2O8S: 613.2554 ([M+Na]+); found:
613.2541 [M+Na]+); ½aꢁD28 =ꢀ39.8 (c=1.0, CHCl3).
H, hexane/2-propanol, 5:1, flow rate=0.5 mLminꢀ1
, retention time;
17.0 min (minor) and 19.4 min (major)).
Data for 6: 1H NMR (400 MHz, CDCl3): d=7.36–7.44 (5H, m), 5.88
(1H, s), 5.65 (1H, s), 3.88 (3H, s), 1.05 ppm (3H, s); 13C NMR
(100 MHz, CDCl3): d=134.4, 129.2, 128.7, 126.6, 82.4, 64.4, 53.5,
22.1 ppm; IR (neat): n˜ =1759, 1739, 1257, 1118, 1040 cmꢀ1; HRMS (ESI)
exact mass: m/z: calcd for C12H13NO4S: 258.0737 ([M+Na]+); found:
(258.0734 [M+Na]+); ½aꢁD22 =ꢀ17.3 (c=0.83, CHCl3; 95% ee).
General procedure for asymmetric trisubstituted aziridination between N-
a-diazoacetyl camphorsultam and N-Boc a-ketimino esters (Table 4)
Removal of chiral auxiliary from 9a (Scheme 4)
A solution of the aziridine 9a (0.070 mmol, 39.3 mg), LiCl (1.4 mmol,
59.4 mg) and LiOH·H2O (1.4 mmol, 58.7 mg) in C2H5CN (2.0 mL) was
stirred vigorously at room temperature for 24 h. The reaction mixture
was then poured into 1N HCl and extracted with ethyl acetate. The com-
bined organic layers were dried over anhydrous Na2SO4 and concentrat-
ed. After dissolving the crude residue in methanol/benzene (0.5 mL/
0.5 mL), this solution was then treated with a 2.0m Et2O solution of
TMSCHN2 (0.14 mmol, 70 mL), and stirred at room temperature for
40 min. After removing the volatile compounds under reduced pressure,
the residue was purified by using column chromatography on silica gel
(eluting with hexane/ethyl acetate, 3:1) to give 11, as a white solid (93%,
24.5 mg). The enantiomeric purity of the product was determined by
using HPLC analysis (Daicel CHIRALPAK AD-H, hexane/2-propanol,
A 0.5m CH2Cl2 solution of Tf2NH (0.040 mmol, 80 mL) was added to a
stirred solution of N-a-diazoacetyl (ꢀ)-camphorsultam 7 (0.20 mmol) and
N-Boc a-ketimino ester 8 (0.24 mmol) in toluene (2.0 mL) at ꢀ788C
under an argon atmosphere. The reaction mixture was stirred at the same
temperature until completion of the reaction and then treated with Et3N
(30 mL). The mixture was poured into aqueous NaHCO3 and extracted
with ethyl acetate. The combined organic layers were dried over anhy-
drous Na2SO4 and concentrated. The residue was purified by using
column chromatography on silica gel to give 9.
Data for 9a: M.p. 1158C; 1H NMR (400 MHz, CDCl3): d=7.56–7.54
(2H, m), 7.33–7.29 (3H, m), 4.53 (1H, s), 3.60 (1H, dd, J=7.7, 5.1 Hz),
3.52 (1H, d, J=13.8 Hz), 3.43 (1H, d, J=13.8 Hz), 2.05–1.21 (7H, m),
1.51 (9H, s), 1.44 (9H, s), 1.17 (3H, s), 0.95 ppm (3H, s); 13C NMR
(100 MHz, CDCl3): d=165.4, 162.7, 157.4, 131.7, 129.7, 128.0, 127.4, 83.8,
82.4, 65.3, 54.3, 53.0, 48.9, 47.8, 47.1, 44.6, 38.0, 32.8, 28.0, 27.7, 26.2, 21.0,
10:1, flow rate=0.5 mLminꢀ1
, retention time; 10.7 min (major) and
20.3 min (minor)).
Data for 11: 1H NMR (400 MHz, CDCl3) 7.38–7.29 (5H, m), 3.93 (1H, s),
3.44 (3H, s), 1.51 (9H, s), 1.39 ppm (9H, s); 13C NMR (100 MHz,
CDCl3): d=166.1, 165.9, 157.4, 132.4, 128.5, 128.1, 127.7, 83.9, 82.6, 52.9,
52.2, 46.5, 28.0, 27.8 ppm; IR (neat): n˜ =2980, 2934, 2359, 1765, 1740,
19.8 ppm; IR (neat): n˜ =2980, 2941, 2253, 1736, 1709, 1333, 1150 cmꢀ1
;
HRMS (ESI) exact mass: m/z: calcd for C29H40N2O7S: 583.2448
([M+Na]+); found: 583.2471 [M+Na]+); ½aꢁD22 =ꢀ39.4 (c=0.50, CHCl3).
Data for 9b: 1H NMR (400 MHz, CDCl3): d=7.38 (1H, s), 7.31 (1H, d,
J=7.7 Hz), 7.17 (1H, t, J=7.6 Hz), 7.08 (1H, d, J=7.5 Hz), 4.51 (1H, s),
3.62 (1H, dd, J=7.9, 5.0 Hz), 3.52 (1H, d, J=13.8 Hz), 3.43 (1H, d, J=
13.8 Hz), 2.34 (3H, s), 2.04–1.21 (7H, m), 1.51 (9H, s), 1.44 (9H, s), 1.17
(3H, s), 0.95 ppm (3H, s); 13C NMR (100 MHz, CDCl3): d=165.5, 162.8,
157.4, 136.9, 131.5, 130.3, 128.9, 127.3, 126.7, 83.7, 82.4, 65.3, 54.4, 53.0,
48.9, 47.8, 47.0, 44.6, 37.9, 32.9, 28.0, 27.7, 26.2, 21.4, 20.9, 19.8 ppm; IR
(neat): n˜ =2978, 2251, 1736, 1709, 1369, 1331, 1150 cmꢀ1; HRMS (ESI)
exact mass: m/z: calcd for C30H42N2O7S: 597.2605 ([M+Na]+); found:
597.2603 [M+Na]+); ½aꢁD28 =ꢀ38.1 (c=1.0, CHCl3).
1300, 1254, 1152 cmꢀ1
; HRMS (ESI) exact mass: m/z: calcd for
26
C20H27NO6: 400.1731 ([M+Na]+); found: 400.1719 [M+Na]+); ½aꢁD
=
ꢀ79.7 (c=0.41, CHCl3; 95% ee).
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science and
Technology, Japan. T.H. thanks a Grant-in-Aid for Young Scientists (B).
Data for 9c: 1H NMR (400 MHz, CDCl3): d=7.43 (2H, d, J=8.2 Hz),
7.10 (2H, d, J=8.0 Hz), 4.51 (1H, s), 3.61 (1H, dd, J=8.0, 4.8 Hz), 3.52
(1H, d, J=13.8 Hz), 3.42 (1H, d, J=13.8 Hz), 2.32 (3H, s), 2.06–1.21
(7H, m), 1.50 (9H, s), 1.45 (9H, s), 1.17 (3H, s), 0.95 ppm (3H, s);
13C NMR (100 MHz, CDCl3): d=165.6, 162.9, 157.5, 137.7, 129.6, 128.6,
128.3, 83.8, 82.4, 65.3, 54.3, 53.1, 49.0, 47.8, 47.2, 44.7, 38.0, 32.9, 28.0,
27.8, 26.3, 21.3, 21.0, 19.9 ppm; IR (neat): n˜ =2978, 2941, 2253, 1738,
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1709, 1333, 1152 cmꢀ1
; HRMS (ESI) exact mass: m/z: calcd for
22
C30H42N2O7S: 597.2605 ([M+Na]+); found: 597.2602 [M+Na]+); ½aꢁD
=
ꢀ35.1 (c=0.50, CHCl3).
612
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 607 – 613

Aziridination of Aldimines and Ketimines
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Received: August 25, 2010
Published online: November 10, 2010
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Chem. Asian J. 2011, 6, 607 – 613
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