Epimerization of trans-3-arylaziridine-2-carboxylates at the C3 position

Article abstract of DOI:10.3987/COM-08-S(N)74

We describe here effective epimerization of trans to cis isomer of 1-benzyl-3-arylaziridine-2-carboxylates. The combination of samarium metal, iodine and N,N-dimethylaminoethanol promoted the epimerization of trans isomer to a ca. 1 : 1 mixture of cis and trans ones. Investigating more effective catalyst, indium chloride was found to afford a ca. 2 : 1 mixture of cis and trans isomers. Epimerization at benzylic position in the aziridines is suggested from the result with optically active ones. Preparation of cis-2-indolylaziridine towards construction of aziridinomitosene skeleton was achieved in this epimerization reaction.

Full text of DOI:10.3987/COM-08-S(N)74

HETEROCYCLES, Vol. 76, No. 2, 2008
1155
HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1155 - 1170. © The Japan Institute of Heterocyclic Chemistry
Received, 30th March, 2008, Accepted, 19th May, 2008, Published online, 22nd May, 2008. COM-08-S(N)74
EPIMERIZATION OF TRANS-3-ARYLAZIRIDINE- 2-CARBOXYLATES
AT THE C3 POSITION †
Takuya Kumamoto,* Shin-ichiro Nagayama, Yukiko Hayashi, Hiroaki
Kojima, Lemin David, Waka Nakanishi, and Tsutomu Ishikawa
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho
Inage-ku, Chiba 263-8522 Japan
Abstract – We describe here effective epimerization of trans to cis isomer of
1-benzyl-3-arylaziridine-2-carboxylates. The combination of samarium metal,
iodine and N,N-dimethylaminoethanol promoted the epimerization of trans isomer
to a ca. 1 : 1 mixture of cis and trans ones. Investigating more effective catalyst,
indium chloride was found to afford a ca. 2 : 1 mixture of cis and trans isomers.
Epimerization at benzylic position in the aziridines is suggested from the result
with optically active ones. Preparation of cis-2-indolylaziridine towards
construction of aziridinomitosene skeleton was achieved in this epimerization
reaction.
INTRODUCTION
Aziridines are one of the versatile synthetic intermediates for the preparation of N-containing biologically
active compounds.1,2 Among them, synthesis and utilization of aziridine-2-carboxylates 1 are much
focused because they are convertible to α- 2 or β-amino acid derivatives 3 by regioselective ring-opening
reactions at C3-N and C2-N bond, respectively (Scheme 1).1,3,4 We have reported an atom-economical
synthesis of 3-arylaziridine-2-carboxylates 1 from guanidinium salt 4 (derived from ureas 5) and aromatic
aldehydes 6 mediated by a base such as 1,1,3,3-tetramethylguanidine (TMG).5 Synthesis of optically
active 1 was also achieved with employing chiral guanidinium salt 7 in high ee. In this process, trans
isomers mainly formed when electron-rich aromatic aldehydes such as piperonal and p-anisaldehyde were
used and were successfully applied to the synthesis of β-aminoalcohols.6,7 However, corresponding
cis-aziridines, applicable to the synthesis of natural products containing cis-aziridines such as mitomycin
C,8 were minor products in this process, whereas the ratio of cis isomer was increased up to 3 : 1 when
aromatic aldehydes with non-substituted or electron-withdrawing group are used.9 Epimerization of

1156
HETEROCYCLES, Vol. 76, No. 2, 2008
t
BnHN
CO2 Bu
NuH addition
at C3
Nu
Nu
Ar
2
3
Br-
t
CO2 Bu
Bn
t
NuH addition
at C2
N
CO2 Bu
Ar CHO
base
6
t
2
3
CO2 Bu
Me
Me
BnHN
Ar
Bn
N
N
N
*
*
Ar
t
epimerization
at C3
CO2 Bu
R
R
trans-1
Bn
N
4: R = H
O
7: R = Ph (2S,3S)
Ar
cis-1
Me
Me
N
N
t
epimerization
at C2
CO2 Bu
*
*
Bn
N
R
R
5
Ar
cis-1'
OR1
Ar =
OR1
a: 2 x R1 = CH2, b: R1 = Me
R2
d: R2 = H, e: R2 = Cl
N
Ts
c
Scheme 1 Synthesis of 3-arylaziridine-2-carboxylates trans-1 from guanidinium salts 4 or 7 and aromatic
aldehydes 6 and their transformations
trans-aziridines is one of the candidates for preparation of the corresponding cis isomers. During our
trials for reductive ring opening of trans-3-arylaziridine-2-carboxylates to amino acid derivatives, we
observed the epimerization of trans isomer to cis one. We describe here the new method for the
synthesis of cis-aziridinecarboxylates cis-1 by epimerization of the corresponding trans isomer trans-1
and its application for the synthesis of cis-indolylaziridine derivative, the useful synthetic intermediate for
the construction of aziridinomitosene skeleton.10
RESULTS
Synthesis of Aziridines
The trans isomers of aziridine substrates trans-1 employed in this study were synthesized according to
the reported procedure from guanidinium salt 4 or chiral one 7 and aldehydes 6 (Scheme 1).5,8 The
N-tosylindole-2-carboxyaldehyde (6c), the substrate for the synthesis of indolylaziridine 1c, was prepared
through LiAlH4 reduction and MnO2 oxidation of commercially available indole-2-carboxylate 8
followed by tosylation (Scheme 2).

HETEROCYCLES, Vol. 76, No. 2, 2008
1157
a)
c)
6c
EtO2C
R
N
H
N
H
8
9: R = CH2OH
10: R = CHO
b)
Scheme 2 Synthesis of N-tosylindole-2-carboxylaldehyde (6c) Conditions: a) LiAlH4, THF, 0 °C, 30
min; b) MnO2, CH2Cl2, rt, 14 h (77%, 2 steps); c) TsCl, NaH, DMF, 0 °C, 2 h (61%).
Trials for regioselective ring opening of trans-1a
Aziridines (11 in Figure 1) are classified into two groups, “activated” and “unactivated” (or nonactivated)
aziridines, dependent on their substituents on the nitrogen atom,1,3 in which the former category includes
electron-withdrawing substituents such as tosyl, tert-butoxycarbonyl or acyl functions, whereas a
hydrogen atom and alkyl substituents are typical for the latter one. Although the reactivity of
“activated” aziridines were well investigated, there are only limited reports on the utilization of
“unactivated” aziridines for organic synthesis.6,11
For example, β-aminoester synthesis via
regioselective reductive ring opening of aziridinecarboxylates by the reductions with magnesium metal in
methanol and with samarium (II) iodide (SmI2)12 had been reported. In the former condition, only
“activated” aziridines 12 gave the corresponding β-aminoester 13.13 On the other hand, the latter SmI2
afforded the corresponding β-aminoesters 13 and 15 from “activated” 1214 and even from “unactivated”
2-acylaziridine 14 (R = H in Figure 1),15 respectively, in the presence of N,N-dimethylaminoethanol
R'
R
N
"Activated" aziridines: R = Ts, Boc, Ac, etc.
"Unactivated" aziridines: R = H, alkyl, etc.
11
Figure 1 “Activated” and “unactivated” aziridines
O-
CO2Me
Ph
CO2Me
SmI2
2
2
R
N
OMe
DMEA, THF
R
N
RHN
Ph
Ph
12 : R = Ts
14 : R = H
13: R = Ts (87%)
15: R = H (28%) [+ α isomer (16%)]
16
Scheme 3 Reported synthesis of β-aminoesters 13 and 15 via reductive ring-opening of “activated” 12
and “unactivated” aziridines 14 by SmI2/DMEA system

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HETEROCYCLES, Vol. 76, No. 2, 2008
(DMEA) as a proton source and a Lewis acid scavenger (Scheme 3). The selective formation of
β-aminoesters 13 and 15 could be explained by the regioselective C2-N bond cleavage of ketyl radicals
16.
Thus, we attempted reductive ring opening of “unactivated” aziridinecarboxylate (±)-trans-1a (R =
benzyl in Figure 1) with SmI2 for the synthesis of β-aminoester 17. However, most of the starting
material was recovered and only small amount of desired β-aminoester 17 was obtained on the reaction
with SmI2, prepared from samarium metal (Sm) and diiodomethane (CH2I2), in the presence of DMEA at
-78 °C (run 1, Table 1). The reaction was sluggish even at -40 °C to give α- 18 and β-aminoesters 17 in
low yields (run 2). Therefore, we turned to utilize molecular iodine (I2) for the activation of Sm.16
This reaction system has the following advantages towards conventional Sm/CH2I2 system for the
preparation of SmI2: 1) Sm has higher reductive potential compared to SmI2 (Sm2+/Sm = -2.68 V,
Sm3+/Sm2+ = -1.55 V);17 2) iodide anion could be reusable in Sm(0)-Sm(II) and Sm(II)-Sm(III)
conversions. Two procedures for the preparation of SmI2 from Sm and I2 reported by Yanada et al. were
Table 1 Trials for ring-opening reaction of aziridine (±)-trans-1a with “SmI2”
t
t
t
t
CO2 Bu
CO2 Bu
BnHN
CO2 Bu
CO2 Bu
"SmI2"
Bn
N
+
+
DMEA, THF
Ar
BnHN
Ar
Ar
Ar
(±)-trans-1a
17
18
19
t
t
CO2 Bu
CO2 Bu
(Ar = 3,4-methylenedioxyphenyl)
Bn
N
+
+
Ar
Ar
(±)-cis-1a
20
run method
I2
(eq)
-
conditions
crude
product ratio a
(%)
57
trans-1a
17
12
8
-
18
-
19
20 cis-1a
1 b
2 b
3
-
-78 °C, 30 min
-40 °C, 30 min
50 °C, 30 min
rt, 30 min
88
70
50
7
-
-
-
-
-
-
-
-
77
22
-
A
A
B
B
B
0.4
4.0
0.4
0.4
4.0
quant.
80
-
-
50
13
-
4
-
26
trace
-
29
8
18
-
5
50 °C, 30 min
rt, 30 min
77
91
91
-
-
6 c
91
9
-
-
-
-
7
50 °C, 30 min
63
38
62
-
-
c
a The ratio was determined by the 1H-NMR analysis. b SmI2 (4 equivalents), prepared from Sm metal and CH2I2, was used.
HMPA (2 equivalents) was added.

HETEROCYCLES, Vol. 76, No. 2, 2008
1159
tested: THF was added to a mixture of Sm, I2 and aziridine substrate followed by addition of DMEA as
described in the literature (method A);18a,b a mixture of Sm and I2 in THF was roughly degassed and
sonicated. Confirmed the blue color in the reaction mixture, a solution of aziridine and DMEA in THF
was added (method B).18c At first, the effect of the equivalency of I2 was examined in method A.
When 0.4 equivalent of I2 was used, the epimerization product (±)-cis-1a was obtained instead of the
desired β-aminoester 17 (run 3). In this case, the ratio of cis and trans isomers in crude product was ca.
1 : 1. Increment of I2 to 4.0 equivalents lead to the non-selective formation of α-aminoester 18,
dihydrocinnamate 19, cinnamate 20,19 and (±)-cis-1a (run 4). The indicative blue color of SmI2 was not
observed in each trials in method A. On the other hand, the reaction was retarded in method B with 0.4
equivalent of I2, even in the presence of HMPA (runs 5, 6). Dihydrocinnamate 19 and α-aminoester 18
were mainly generated with excess amount of I2 (run 7). In these trials, desired β-aminoester 17 was not
obtained as a major product, however, the epimerization of trans-aziridine to cis-one was observed with
0.4 equivalent of I2 in method A. To our knowledge, only the epimerization reaction of aziridines in
basic,20 thermal21,22 and photochemical conditions22 and that of vinyl aziridines with palladium catalysts23
were reported.24 Thus, we explored the epimerization reactions of trans-1a.25
Table 2 Effects of reagents on the epimerization of aziridine (±)-trans-1a
t
t
CO2 Bu
COR
Ar
BnHN
HO
CO2 Bu
Sm, I2
Bn
N
Bn
N
+
DMEA, THF
50 °C, 30 min
Ar
Ar
(±)-cis-1a: R = OtBu
cis-21: R = NHBn
(±)-trans-1a
(Ar = 3,4-methylenedioxyphenyl)
22
run
Sm
I2
DMEA
product ratio a
(4 eq)
(0.4 eq)
(4.0 eq)
trans-1a cis-1a
50 50
cis-21
22
-
1 b
2
+
+
-
+
+
+
+
-
+
-
-
24 (13) 60 (30) 16 (19)
-
3
+
-
45 c
54 c
-
-
-
4
-
40 (24) 40 (32)
20 (13) d
5
+
+
no reaction
a
The ratio was determined by the 1H-NMR analysis. The value in parenthesis shows isolated yield after column
b
c
chromatography (hexane - AcOEt = 20 : 1 to 5 : 1). Run 3 in Table 1. Small amount of unidentified byproducts was
contaminated. d Anti : syn = 1.0 : 0.2.

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HETEROCYCLES, Vol. 76, No. 2, 2008
Epimerization reaction of trans- to cis-aziridinecarboxylates
We next examined the role of reagents in method A (Table 2). Epimerization is predominant in the
absence of DMEA, however, amide cis-21 was isolated as a byproduct, which would be derived from
(±)-cis-1a and benzylamine, presumably generated on decomposition of 1a (run 2). Corresponding
trans-isomer of 21 was not observed in this experiment. Surprisingly, even in lacking Sm and both of
Sm and DMEA, 1 : 1 mixtures of (±)-cis- and (±)-trans-1a were obtained (runs 3, 4). A small amount of
unidentified byproducts was contaminated in the former, and ring-opening product 22 was generated as a
mixture of diastereoisomers in the latter condition. No reaction was observed in the absence of I2 (run 5).
These results showed that I2 is crucial for this epimerization.
To identify the epimerized chiral center of trans-1a, optically active aziridine trans-1a was subjected to
the reaction in method A (Scheme 4). Treatment of (2R,3S)-trans-1a (71% ee) with Sm/I2 system
afforded a 1 : 1 mixture of cis- and trans-1a. After the separation, absolute configuration of each
diastereoisomer was determined as (2R,3S) for trans and (2R,3R) for cis isomer by chiral HPLC
analysis,26 respectively, which shows that the epimerization occurs at benzylic C3 position of trans-1a.
Next, the effect of the aryl groups at C3 of aziridines was investigated (Table 3). Reactions of
trans-aziridines with electron-rich aromatics such as 3,4-methylenedioxy- trans-1a and
3,4-dimethoxyphenyl derivatives trans-1b gave a 1 : 1 mixture of diastereoisomers (runs 1, 2).
Disappointingly, epimerization of 2-indolyl derivative trans-1c to cis-one, a synthon for the
aziridinomitosene skeleton, was sluggish (run 3) and phenyl trans-1d and 4-chlorophenyl derivatives
trans-1e gave no isomerization product (runs 4, 5). These results clearly showed that the
electron-donating character of aryl group is important in this epimerization reaction.
Thus, more powerful catalysts were explored with using several Lewis acids (Table 4). Epimerization of
(±)-trans-1a with boron trifluoride etherate (BF3·OEt2) at -60 °C produced a trans-major mixture (cis :
trans = ca. 1 : 2.3) (run 2). Stronger Lewis acid, such as tin (IV) chloride (SnCl4) was not so effective to
give a mixture in the same ratio as the reaction with BF3·OEt2 (run 3). Milder Lewis acid such as zinc
iodide (ZnI2) gave cis-major mixture, however, ring opening product 22 was contaminated as a major
t
t
t
CO2 Bu
CO2 Bu
CO2 Bu
Sm, I2
Bn
N
Bn
N
+
Bn
N
DMEA, THF
50 °C, 30 min
3
Ar
Ar
Ar
(2R,3S)-trans-1a
(71% ee)
(2R,3S)-trans-1a
(38%, 71% ee)
(2R,3R)-cis-1a
(41%, 73% ee)
(Ar = 3,4-methylenedioxyphenyl)
Scheme 4 Epimerization reaction of optically active aziridine (2R,3S)-trans-1a with Sm/I2 system

HETEROCYCLES, Vol. 76, No. 2, 2008
1161
Table 3 Effects of aryl group at C3 on the epimerization of aziridine (±)-trans-1
t
t
CO2 Bu
CO2 Bu
Sm, I2
Bn
N
Bn
N
DMEA, THF
50 °C, 30 min
3
Ar
Ar
(±)-trans-1
(±)-cis-1
run aziridine a product ratio b
run aziridine a product ratio b
trans : cis
trans : cis
1 c
2
1a
1b
1c
50 : 50
52 : 48
83 : 17
4
5
1d
1e
100 : 0
100 : 0
3
a Ar in aziridines 1 correspond to those in Scheme 1. b The ratio was determined by the 1H-NMR analysis. c Run 3 in Table 1.
Table 4 Effects of reagents on the epimerization of aziridine trans-1
t
t
t
CO2 Bu
CO2 Bu
BnHN
HO
CO2 Bu
reagents
Bn
N
Bn
N
+
solvent
O
O
Ar
Ar
conditions
(±)-trans-1
(±)-cis-1
22
run aziridine a
reagents
(eq)
solvent
THF
condition
crude
yield (%) trans-1
product ratio b
cis-1
22
Sm (4), I2 (0.4),
DMEA (4)
BF3·OEt2 (1.0)
SnCl4 (1.0)
ZnI2 (0.8)
50 °C,
30 min
1 c
1a
quant.
50
50
-
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a e
1c
CH2Cl2 -60 °C, 3.5 h
quant.
95
70 (60) 30 (25)
-
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
-60 °C, 1 h
0 °C, 2 h
rt, 30 min
rt, 30 min
rt, 1 d
70
29
30
14
64
70
70
70 f
-
97
57 d
InCl3 (0.7)
InCl3 (0.2)
InCl3 (0.2)
InCl3 (0.3)
InCl3 (0.2)
98
36
-
-
-
quant.
quant.
quant.
quant.
30
30
30 e
rt, 20 min
rt, 1 h
48 (44) 52 (43)
-
a
b
1
Ar in aziridines 1 correspond to those in Scheme 1. The ratio was determined by the H-NMR analysis. The value in
parenthesis shows isolated yields after column chromatography. c Run 3 in Table 1. d Anti : syn = 1.0 : 0.1. e (2R,3S)-isomer
(76% ee). f (2R,3R)-isomer (76% ee).

1162
HETEROCYCLES, Vol. 76, No. 2, 2008
product (cis-1a : trans-1a : 22 = ca. 2 : 1 : 4) (run 4). Next, indium chloride (InCl3), effective catalyst
for the ring opening of “activated”27 and “unactivated”6 aziridines, was applied. As a result, cis-major
mixture (cis : trans = ca. 1.8 : 1) of 1a was obtained without any formation of byproduct (run 5). The
ratio of the epimeric products was not affected by the decrease of the reagent from 0.7 to 0.2 equivalent
(run 6) or longer reaction period to 1 day (run 7). Epimerization at C-3 position of 1a was confirmed by
conversion of (2R,3S)-trans to (2R,3R)-cis isomer (run 8). The epimerization of trans-indolylaziridine
1c with InCl3 gave a ca. 1 : 1 mixture of cis- and trans-1c (run 9).
DISCUSSION
The epimerization of trans-1a with Sm/I2 system could be proceeded in mainly two steps: 1) ring opening,
2) re-cyclization, and via four pathways (Scheme 5): cationic cleavage of aziridine trans-1a at C2-N (to
23, path A) and C3-N bonds (to 24, path B), and single-electron reduction on the carbonyl group to ketyl
radical 27 and cleavage at C2-N (to 25, path C) and C2-C3 bonds (to 26, path D). The result with
optically active trans-aziridine (2R,3S)-trans-1a to cis-one (2R,3R)-1a (Scheme 4) supports path B.
The results of runs 2-4 in Table 2 showed the important role of I2. Furthermore, the epimerization was
not observed when I2 was completely consumed for the preparation of SmI2 in method B (run 5 in Table
t
t
CO2 Bu
CO2 Bu
path A
2) re-cyclization
(2R,3S)-
trans-1a
Bn
N
+
1) C2-N
cleavage
"Sm"
N
Ar
Ar
t
2
3
CO2 Bu
23
(2S,3S)-cis-1a
Bn
Bn
N
"Sm"
N
Ar
t
t
CO2 Bu
CO2 Bu
path B
2) re-cyclization
2) re-cyclization
Bn
(2R,3S)-trans-1a
(2R,3S)-
trans-1a
Bn
Bn
N
+
+
1) C3-N
24
Ar
Ar
cleavage
(2R,3R)-cis-1a
SmI2
OSmI2
OtBu
t
CO2 Bu
path C
(2R,3S)-
trans-1a
N
1) C2-N
cleavage
OSmI2
N
Ar
Ar
26
(2S,3S)-cis-1a
OtBu
Bn
Bn
N
I2SmO
OtBu
Ar
t
CO2 Bu
path D
25
2) re-cyclization
Bn
N
Bn
N
1) C2-C3
cleavage
Ar
27
Ar
a mixture of racemic
(Ar = 3,4-methylenedioxyphenyl)
trans- and cis-1a
Scheme 5 Possible pathways of the epimerization of trans- to cis-aziridine 1a

HETEROCYCLES, Vol. 76, No. 2, 2008
1163
X
t
N
CO2 Bu
Bn
path E
I2
SN1
I
Ar
28 (X = H or I)
"Sm"
N
t
t
2
CO2 Bu
t
t
CO2 Bu
CO2 Bu
CO2 Bu
"Sm"
path F
Bn
N
Bn
N
Bn
N
Bn
"Sm"
I2
3
SN1
3
I
I
Ar
Ar
I
Ar
30
Ar
29
(±)-trans-1a
(±)-cis-1a
+ (±)-trans-1a
InCl2
t
N
CO2 Bu
SN1
Bn
path G
InCl3
("Sm" = Sm0 or SmI2)
Ar
31
(Ar = 3,4-methylenedioxyphenyl)
Scheme 6 Proposed mechanisms of epimerization of trans-1a via C3-N bond cleavage
1). From these results, the selective cleavage of benzylic C3-N bond mediated by I2 (path E in Scheme
6) to iodide 28 and SN1-type re-cyclization were proposed as a reaction mechanism. Sm species could
act as Lewis acid towards 1a to promote the ring-opening step via aziridinium 29 to iodide 30 (path F).
Reaction with other Lewis acids such as InCl3 is considered to proceed through C3-N bond cleavage of
trans-1a to cationic intermediate 31 followed by re-cyclization (path G). For the moment, the reason
why InCl3 gave the best result is not clear.
X
N
H
N
t
t
CO2 Bu
CO2 Bu
2 SmI2
H+
I2
Bn
Bn
(±)-trans-1a
28 (X = H or I)
I2Sm
Ar
Ar
(Ar = 3,4-methylenedioxyphenyl)
32
18
X
33
N
Bn
SmI2
t
t
CO2 Bu
CO2 Bu
2 SmI2
Ar
Ar
20
19
Scheme 7 Proposed mechanism for the generation of hydrogenated products 18 and 19

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HETEROCYCLES, Vol. 76, No. 2, 2008
On the other hand, the main products of the reaction with excess mount of I2 are hydrogenated products
such as 18 and 19 (runs 4 and 7 in Table 1). Selective C3-N bond cleavage of aziridine trans-1a with I2
and reduction of corresponding iodide 28 with SmI2 would furnish organosamarium species 32, which
would be protonated to α-aminoester 18. Elimination of samarium amide 33 from 32 to cinnamate 20
followed by reduction with SmI2 would give dihydrocinnamate 19 (Scheme 7).
CONCLUSION
In conclusion, we found the epimerization conditions of trans to cis isomer of
3-arylaziridine-2-carboxylates. In the preliminary trials, a combination of Sm, I2, and DMEA was found
to be effective, in which I2 is crucial in this epimerization. The reaction with optically active aziridine
suggested the epimerization at benzylic C3 position. InCl3 was found to be the most effective Lewis
acid for the epimerization of aziridines with electron-rich aromatics as well as indolyl group.28
Application of this system to the synthesis of cis-aziridine-containing natural products such as
mitomycins is under investigation.
EXPERIMENTAL
General: All melting points were measured on Yanagimoto MPSI melting point apparatus and are
uncorrected. IR spectra were recorded in neat or with Attenuated Total Reflectance (ATR) system on a
JASCO FT / IR-300E spectrophotometer. 1H and 13C NMR spectra were recorded in CDCl3 on a JEOL
JNM-GSX-400α, JNM-ECP-400, JNM-GSX-500α, JNM-ECP-600 unless otherwise stated. MS spectra
were measured on JEOL JNM MS-GCMATE for EIMS, and JEOL JMS-HX110 or JEOL JMS-AX505
for FABMS. Ultrasonic stirrer, a Nihonseiki Youkai-kun, USS-1, was used for sonication. For column
chromatography was used Kanto Chemical silica gel 60 spherical. For TLC were used Merck Art 5715
DC-Fertigplatten Kieselgel 60 F254. Anhydrous CH2Cl2 and THF were purchased from Kanto Chemical
and Wako Chemical, respectively. Samarium metal (Sm) was purchased from Nippon Yttrium Co. Ltd.
as ingot and was used after grind and washing with hexane and methanol, successively, and dried.
1H-Indole-2-carboxyaldehyde (10)
A solution of ethyl indole-2-carboxylate (3.00 g, 15.9 mmol) in THF (18 mL) was added to a suspension
of LiAlH4 (3.03 g, 79.8 mmol) in THF (18 mL) at 0 °C and the whole was stirred at 0 °C for 30 min.
H2O (5 mL), 20% NaOH (5 mL), and H2O (20 mL) was added successively at 0 °C. The whole was
diluted with CH2Cl2-CH3OH (8 : 1, 50 mL) and was stirred at rt for 1 h. The mixture was filtered off
through a pad of Celite pad and the filtrate was washed with brine (3 x 40 mL) and dried over MgSO4.
The solvent was evaporated in vacuo to leave alcohol 9 as pale yellow solids (2.32 g, 99%). The crude 9

HETEROCYCLES, Vol. 76, No. 2, 2008
1165
was dissolved in CH2Cl2 (75 mL) and MnO2 (13.2 g, 152 mmol) was added. After stirring at rt for 14 h,
the whole was filtered off through a pad of Celite® and the precipitate was washed with CH2Cl2. The
filtrate and the washing was combined and evaporated in vacuo to give aldehyde 10 as brown solid (1.77
g, 79%), which was used for next step without further purification.
1-(p-Toluenesulfonyl)-1H-indole-2-carboxyaldehyde
A solution of aldehyde 10 (2.35 g, 16.2 mmol) in DMF (9 mL) was added to a suspension of NaH (60%,
976 mg, 24.4 mmol) in DMF (15 mL) at 0 °C and the whole was stirred at rt for 30 min. A solution of
p-toluenesulfonyl chloride (4.32 g, 22.7 mmol) in DMF (7 mL) was added at 0 °C and the whole was
stirred at 0 °C for 2 h. H2O (25 mL) was added at 0 °C and the whole was extracted with AcOEt (5 x 40
mL). The combined organic layer was washed with H2O (10 x 1.5 mL) and brine (5 x 1.5 mL) and was
dried over MgSO4. The solvent was evaporated in vacuo and the residue was purified by silica gel
(SiO2) column chromatography (CC) (hexane : benzene = 1 : 2) to give pale yellow solids (2.95 g, 61%).
mp 136.5 - 137.5 °C. IR (ATR, cm-1) 1674 (C=O). 1H-NMR (400 MHz) δ (ppm): 2.33 (3H, s, CH3),
7.20 (2H, d, J = 8.3 Hz, Ts-meta-H2), 7.32 (1H, t, J = 7.6 Hz, H-6), 7.47 (1H, s, H-3), 7.53 (1H, t, J = 7.3
Hz, H-5), 7.63 (1H, d, J = 8.1 Hz, H-7), 7.66 (2H, d, J = 8.3 Hz, Ts-ortho-H2), 8.24 (1H, d, J = 8.6 Hz,
H-4), 10.54 (1H, s, CHO). 13C-NMR (100 MHz) δ (ppm): 21.5, 115.3, 118.8, 123.6, 124.8, 126.6, 128.1,
128.89, 129.9, 134.6, 137.7, 138.4, 145.6, 183.3. HREIMS m/z 299.0641 (Calcd for C16H13NO3S:
299.0616).
Synthesis of indolylaziridinecarboxylates 1c
A mixture of aldehyde 6c (150 mg, 0.50 mmol) and guanidinium salt 4 (240 mg. 0.60 mmol) in THF (0.5
mL) was sonicated until complete dissolution of 6a and 4. Freshly distilled TMG (0.08 mL, 0.64 mmol)
was added at rt and the whole was stirred at rt for 23 h. The whole was dissolved in MeCN (10 mL) and
SiO2 (Fuji silicia, FL100D, 3.0 g) was added. The mixture was stirred at rt for 1 day. After the suction
filtration of the SiO2, the residue was washed with CHCl3. The filtrate and the washings were combined
and the whole was evaporated in vacuo. The residue was purified br CC (hexane - AcOEt = 15 : 1) to
give trans-1c as a yellow oil (169 mg, 67%) and cis-1c as a yellow oil (13 mg, 5%)
(2RS,3RS)-tert-Butyl
(trans-1c)
[1-benzyl-3-(1-p-toluenesulfonyl-1H-indol-2-yl)aziridine-2-carboxylate
IR (ATR, cm-1) 1722 (C=O). 1H-NMR (400 MHz) δ (ppm): 1.46 [9H, s, C(CH3)3], 2.32 (3H, s, CH3),
2.76 (1H, br s, C2H), 3.83 (1H, br s, C3H), 4.16, 4.40 (each 1H, d, J = 13.9 Hz, PhCH2), 6.54 (1H, s,
indole C3H), 7.14-7.44 (total 10H, m, Ar), 7.76 (2H, d, J = 8.1 Hz, Ts-ortho-H2), 8.11 (1H, d, J = 8.2 Hz,
indole C4H). 13C-NMR (100 MHz) δ (ppm): 21.5, 28.0, 42.9, 44.1, 54.6, 82.0, 109.5, 114.3, 120.9,

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HETEROCYCLES, Vol. 76, No. 2, 2008
123.6, 124.5, 126.6, 126.9, 128.21, 128.25, 129.1, 129.8, 135.8, 136.9, 138.6, 139.2, 144.8, 167.4.
HREIMS m/z 502.1923 (Calcd for C29H30N2O4S: 502.1926).
(2RS,3SR)-tert-Butyl [1-benzyl-3-(1-p-toluenesulfonyl-1H-indol-2-yl)aziridine-2-carboxylate (cis-1c)
IR (ATR, cm-1) 1738 (C=O). 1H-NMR (400 MHz) δ (ppm): 1.19 [9H, s, C(CH3)3], 2.31 (3H, s, CH3),
2.69 (1H, d, J = 6.4 Hz, C2H), 3.58 (1H, d, J = 6.4 Hz, C3H), 3.82, 3.90 (each 1H, d, J = 13.9 Hz,
PhCH2), 6.74 (1H, s, indole C3H), 7.14-7.36 (total 7H, m, Ar), 7.42 (2H, diffused t, J = 7.6 Hz, Ar), 7.74
(2H, d, J = 8.4 Hz, Ts-ortho-H2), 8.00 (1H, d, J = 8.2 Hz, indole C4H). 13C-NMR (100 MHz) δ (ppm):
21.5, 27.7, 42.1, 47.2, 63.3, 81.3, 111.7, 114.1, 120.9, 123.4, 12435, 126.7, 127.2, 127.9, 128.4, 129.1,
129.8, 135.5, 135.8, 136.7, 137.9, 144.7, 167.2. HREIMS m/z 502.1934 (Calcd for C29H30N2O4S:
502.1926).
General procedure for the trials towards reductive ring opening of trans-1a with Sm/I2 system
(method A, run 3 in Table 1)
To a mixture of Sm (92 mg, 0.61 mmol), I2 (16 mg, 0.06 mmol) and trans-1a (53 mg, 0.15 mmol) under
Ar atmosphere, THF (1 mL) and DMEA (0.06 mL, 0.60 mmol) were added at rt and the whole was
stirred vigorously at 50 °C for 30 min. After cooling, 10% aq. Na2S2O3 (5 mL) was added and the whole
was filtered through a pad of Celite. The filtrate was extracted with AcOEt (2 x 20 mL). The
combined organic layers were combined and was washed with saturated aq. NaHCO3 (2 x 5 mL), H2O (2
x 5 mL), and brine (2 x 5 mL), successively, and dried over MgSO4. The solvent was evaporated in
vacuo and the residue was analyzed by 1H-NMR to be a 1 : 1 mixture of trans- and cis-1a.
General procedure for the trials towards reductive ring opening of trans-1a with Sm/I2 system
(method B, run 6 in Table 1)
To a mixture of Sm (92 mg, 0.61 mmol), I2 (16 mg, 0.06 mmol), THF (1.0 mL) was added and the whole
was roughly vacuumed with stirring and sonication at rt. After 20 min, color of the mixture changed to
dark blue. HMPA (0.05 mL, 0.29 mmol) was added and the color of the mixture changed to purple.
After stirring for 15 min, a solution of trans-1a (50 mg, 0.14 mmol) and DMEA (0.06 mL, 0.60 mmol) in
THF (1.0 mL) was added at rt and the whole was stirred at rt for 30 min. 10% aq. Na2S2O3 (5 mL) was
added and the whole was filtered through a pad of Celite. The filtrate was extracted with AcOEt (2 x 20
mL). The combined organic layers were combined and was washed with saturated aq. NaHCO3 (2 x 5
mL), H2O (2 x 5 mL), and brine (2 x 5 mL), successively, and dried over MgSO4. The solvent was
1
evaporated in vacuo and the residue was analyzed by H-NMR to be a mixture of trans-1a and 17 (91 :
9).

HETEROCYCLES, Vol. 76, No. 2, 2008
1167
(±)-tert-Butyl 3-benzylamino-3-(3,4-methylenedioxyphenyl)propionate (17)
A colorless oil. IR (neat, cm-1) 3332 (N-H), 1719 (C=O). 1H-NMR (400 MHz) δ (ppm): 1.38 [9H, s,
C(CH3)3], 2.48 (1H, dd, J = 15.3, 5.2 Hz, one of CH2CO), 2.58 (1H, dd, J = 15.3, 8.7 Hz, one of CH2CO),
3.53, 3.64 (each 1H, d, J = 13.2 Hz, PhCH2), 4.00 (1H, dd, J = 8.7, 5.2 Hz, CH), 5.95 (2H, s, OCH2O),
6.75-6.81 (2H, m, Ar), 6.91 [1H, d, J = 1.5 Hz, Ar(2)-H], 7.21-7.32 (5H, m, Ar). 13C-NMR (100 MHz)
δ (ppm): 28.0, 44.4, 51.3, 58.9, 80.7, 100.9, 107.2, 108.0, 120.6, 126.8, 128.1, 128.3, 136.8, 140.3, 146.7,
147.8, 171.0. HRFABMS m/z 356.1829 (Calcd for C21H26NO4: 356.1862).
(±)-tert-Butyl 2-benzylamino-3-(3,4-methylenedioxyphenyl)propionate (18)
A colorless oil. IR (neat, cm-1) 3334 (N-H), 1722 (C=O). 1H-NMR (400 MHz) δ (ppm): 1.40 [9H, s,
C(CH3)3], 2.82 (1H, dd, J = 13.7, 7.1 Hz, one of CH2Ar), 2.86 (1H, dd, J = 13.7, 6.6 Hz, one of CH2Ar),
3.35 (1H, dd, J = 7.1, 6.6 Hz, CH), 3.64, 3.81 (each 1H, d, J = 12.9 Hz, PhCH2), 5.92 (2H, s, OCH2O),
6.64 [1H, dd, J = 7.8, 1.7 Hz, Ar(6)-H], 6.70 [1H, d, J = 1.7 Hz, Ar(2)-H], 6.71 [1H, d, J = 7.8 Hz,
Ar(6)-H], 7.21-7.32 (5H, m, Ar). 13C-NMR (100 MHz) δ (ppm): 28.1, 39.5, 52.0, 62.7, 81.2, 100.8,
108.0, 109.8, 122.4, 127.0, 128.2, 128.4, 131.3, 146.2, 147.4, 173.9. HRFABMS m/z 356.1886 (Calcd
for C21H26NO4: 356.1862).
tert-Butyl 3-(3,4-methylenedioxyphenyl)propionate (19)
A colorless oil. IR (neat, cm-1) 1724 (C=O). 1H-NMR (400 MHz) δ (ppm): 1.43 [9H, s, C(CH3)3],
2.49 (2H, t, J = 8.0 Hz, CH2CO), 2.82 (2H, t, J = 8.0 Hz, CH2Ar), 5.92 (2H, s, OCH2O), 6.65 [1H, dd, J =
8.0, 2.0 Hz, Ar(6)-H], 6.69 [1H, d, J = 2.0 Hz, Ar(2)-H], 6.72 [1H, d, J = 8.0 Hz, Ar(5)-H]. 13C-NMR
(100 MHz, CDCl3) δ (ppm): 28.2, 30.9, 37.4, 80.4, 100.8, 108.1, 108.8, 121.1, 134.6, 145.8, 147.6, 172.2.
HREIMS m/z 250.1199 (Calcd for C14H18O4: 250.1205).
(E)-tert-Butyl 3-(3,4-methylenedioxyphenyl)acrylate (20)
Colorless needles. mp 79-81 °C (lit.,19 79-80 °C). IR (neat, cm-1) 1739 (C=O). 1H-NMR (400 MHz)
δ (ppm): 1.53 [9H, s, C(CH3)3], 6.00 (2H, d like, J = ,1.1 Hz, OCH2O), 6.19 (1H, d, J = 15.9 Hz, C2-H),
6.80 [1H, d, J = 8.1 Hz, Ar(5)-H], 6.67 [1H, diffused dd, J = 8.1, 1.5 Hz, Ar(6)-H], 6.99 [1H, diffused d, J
= 1.5 Hz, Ar(2)-H], 7.49 (1H, d, J = 15.9 Hz, C3-H).
(2RS,3RS)-N,N’-Dibenzyl-3-(3,4-methylenedioxyphenyl)aziridine-2-caroboxamide (cis-21)
A yellow oil. IR (ATR, cm-1) 3376 (N-H), 1664 (C=O). 1H-NMR (400 MHz) δ (ppm): 2.26 (1H, d, J
= 7.0 Hz, C2H), 3.11 (1H, d, J = 7.0 Hz, C3H), 3.61, 3.81 (each 1H, d, J = 13.0 Hz, PhCH2), 4.00 (1H, dd,
J = 15.0, 7.3 Hz, one of PhCH2), 4.38 (1H, dd, J = 15.0, 4.9 Hz, one of PhCH2), 5.90, 5.91 (each 1H, d, J

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HETEROCYCLES, Vol. 76, No. 2, 2008
= 1.5 Hz, one of OCH2O), 6.53 (1H, brt, J = 5.8 Hz, NH), 6.64 [1H, d, J = 8.1 Hz, Ar(5)-H], 6.69 [1H, d,
J = 1.5 Hz, Ar(2)-H], 6.72-6.74 (3H, m, Ar), 7.15-7.18 (3H, m, Ar), 7.31-7.36 (5H, m, Ar). 13C-NMR
(100 MHz) δ (ppm): 42.6, 46.6, 47.5, 63.3, 101.0, 108.2, 108.3, 121.1, 127.0, 127.2, 127.7, 128.3, 128.4,
128.7, 128.9, 137.7, 137.8, 147.0, 147.5, 167.6. HRFABMS m/z 387.1729 (Calcd for C24H23N2O3:
387.1709).
General procedure for the isomerization of aziridine trans-1a with InCl3 (run 7 in Table 4)
To a mixture of trans-1a (41 mg, 0.12 mmol) and InCl3 (6 mg, 0.027 mmol), CH2Cl2 (1.5 mL) was added
and the whole was stirred at rt for 25 min. Sat. aq. NaHCO3 (5 mL) was added and the whole was
extracted with CH2Cl2 (4 x 6 mL). The organic layers were combined and the whole was washed with
H2O (2 x 6 mL) and brine (2 x 6 mL), successively, and dried over K2CO3. The solvent was evaporated
in vacuo and the residue was analyzed by 1H-NMR to be a mixture of trans- and cis-1a (30 : 70).
ACKNOWLEDGEMENTS
This work was supported by Grants-in Aid for Scientific Research (18790007) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan. Japan Society of Promotion of Science was
acknowledged by D.L. for the post-doctoral fellowship. Prof. Reiko Yanada, Faculty of Pharmaceutical
Sciences, Hiroshima International University was acknowledged for the helpful discussion for the
procedure of preparation of SmI2 from Sm and I2.
REFERENCES AND NOTES
† This article was dedicated to Prof. Ryoji Noyori on the occasion of his 70th birthday.
1. 'Aziridines and Epoxides in Organic Synthesis', ed. by A. K. Yudin, Wiley-VCH, Weinheim, 2006.
2. (a) G. Cardillo, L. Gentilucci, and A. Tolomelli, Aldrichim. Acta, 2003, 36, 35. (b) W. K. Lee and
H. Ha, Aldrichim. Acta, 2003, 36, 57.
3. W. McCoull and F. A. Davis, Synthesis, 2000, 1347.
4. X. E. Hu, Tetrahedron, 2004, 60, 2701.
5. K. Hada, T. Watanabe, T. Isobe, and T. Ishikawa, J. Am. Chem. Soc., 2001, 123, 7705.
6. T. Manaka, S. Nagayama, W. Disadee, N. Yajima, T. Kumamoto, T. Watanabe, T. Ishikawa, M.
Kawahata, and K. Yamaguchi, Helv. Chim. Acta, 2007, 90, 128.
7. Synthesis of vinylaziridines from α,β-unsaturated aldehydes and the application towards synthesis of
sphingosine were also reported: W. Disadee and T. Ishikawa, J. Org. Chem., 2005, 70, 9399.
8. Y. Kishi, J. Nat. Prod., 1979, 42, 549. T. Fukuyama and L. Yang, J. Am. Chem. Soc., 1989, 111,
8303.

HETEROCYCLES, Vol. 76, No. 2, 2008
1169
9. T. Haga and T. Ishikawa, Tetrahedron, 2005, 61, 2857.
10. For the examples of construction of aziridinomitosene skeletons: (a) D. R. Bobeck, D. L. Warner,
and E. Vedejs, J. Org. Chem., 2007, 72, 8506; D. L. Warner, A. M. Hibberd, M. Kalman, A. Klapars,
and E. Vedejs, J. Org. Chem., 2007, 72, 8519. (b) K. Tsuboike, D. J. Guerin, S. M. Mennen, and S.
J. Miller, Tetrahedron, 2004, 60, 7367. (c) S. Lee, W.-M. Lee, and G. A. Sulikowski, J. Org.
Chem., 1999, 64, 4224. (d) W. Dong and L. S. Jimenez, J. Org. Chem., 1999, 64, 2520. (e) F. E.
Ziegler and M. Belema, J. Org. Chem., 1997, 62, 1083. (f) Y. Ban, S. Nakajima, K. Yoshida, M.
Mori, M. Shibasaki, and T. Date, Heterocycles, 1994, 39, 657.
11. (a) L. Legters, L. Thijs, and B. Zwanenburg, Recl. Trav. Chim. Pays-Bas, 1992, 111, 16. (b) C.
Xiong, W. Wang, C. Cai, and V. J. Hruby, J. Org. Chem., 2002, 67, 1399. (c) C. Loncaric and W.
D. Wulff, Org. Lett., 2001, 3, 3675. (d) G. Cardillo, L. Gentilucci, and A. Tolomelli, Tetrahedron
Lett., 1999, 40, 8261.
12. P. Girard, J. L. Namy, and H. B. Kagan, J. Am. Chem. Soc., 1980, 102, 2693.
13. C. S. Pak, T. H. Kim, and S. J. Ha, J. Org. Chem., 1998, 63, 10006.
14. G. A. Molander and P. J. Stengel, J. Org. Chem., 1995, 60, 6660.
15. G. A. Molander and P. J. Stengel, Tetrahedron, 1997, 53, 8887.
16. T. Imamoto and M. Ono, Chem. Lett., 1987, 501.
17. D. R. Lide, In CRC Handbook of Chemistry and Physics; CRC Press: Boca Raton, 2001, 8-33.
18. (a) R. Yanada, K. Bessho, and K. Yanada, Synlett, 1995, 443. (b) R. Yanada, N. Negoro, K.
Bessho, and K. Yanada, Synlett, 1995, 1261. (c) R. Yanada, personal communication.
19. S. G. Davies, A. W. Mulvaney, A. J. Russell, and A. D. Smith, Tetrahedron: Asymmetry, 2007, 18,
1554.
20. R. E. Lutz and A. B. Turner, J. Org. Chem., 1968, 33, 516.
21. A. Padwa and H. Ku, J. Org. Chem., 1979, 44, 255.
22. R. Huisgen, W. Scheer and H. Huber, J. Am. Chem. Soc., 1967, 89, 1753.
23. (a) H. Ohno, Yakugaku Zasshi, 2001, 121, 733. (b) K. Ishii, H. Ohno, Y. Takemoto, and T. Ibuka,
Synlett, 1999, 228. (c) A. Honda, H. Ohno, N. Mimura, and T. Ibuka, Synlett, 1998, 969. (d) T.
Ibuka, N. Mimura, H. Aoyama, M. Akaji, H. Ohno, Y. Miwa, T. Taga, K. Nakai, H. Tamamura, N.
Fujii, and Y. Yamamoto, J. Org. Chem., 1997, 62, 999. (e) T. Ibuka, N. Mimura, H. Ohno, K.
Nakai, M. Akaji, H. Habashita, H. Tamamura, Y. Miwa, T. Taga, N. Fujii, and Y. Yamamoto, J. Org.
Chem., 1997, 62, 2982. (f) T. Ibuka, M. Akaji, N. Mimura, H. Habashita, K. Nakai, H. Tamamura,
N. Fujii, and Y. Yamamoto, Tetrahedron Lett., 1996, 37, 2849. (g) N. Mimura, T. Ibuka, M. Akaji,
Y. Miwa, T. Taga, K. Nakai, H. Tamamura, N. Fujii, and Y. Yamamoto, Chem. Commun., 1996,
351.

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24. For examples of epimerization during the reaction course of aziridination: (a) D. A. Evans, M. M.
Faul, and M. T. Bilodeau, J. Am. Chem. Soc., 1994, 116, 2742. (b) D. Kühnau, I. Thomsen, and K.
A. Jørgensen, J. Chem. Soc., Perkin Trans. 1, 1996, 1167.
25. 2,3-Cis isomer bearing tetrahedral structure on the aziridine nitrogen were reported to be preferable
rather than 2,3-trans isomer: N. Miura, Y. Miwa, T. Ibuka, and Y. Yamamoto, J. Org. Chem., 2002,
67 5796.
26. The absolute configuration of the product cis-1a was tentatively determined by the comparison on
chiral HPLC analysis of known (2R,3R)-cis-1d.5 Conditions: column: DAICEL CHIRALCEL
AD-H, solvent: hexane : 2-propanol = 50 : 1, rate: 1.0 mL/min, detection: 254 nm. Retention time:
(2R,3R)-cis-1d: 6.5 min (major), 11.6 min (minor); cis-1a in this experiment: 11.4 min (major), 15.2
min (minor).
27. J. S. Yadav, B. V. S. Reddy, S. Abraham, and G. Sabitha, Tetrahedron Lett., 2002, 43, 1565.
28. Preliminary trial for the treatment of (±)-trans-1a in basic condition (LDA, THF, -15 °C, 1 h then
H2O or acetic acid at -78 °C) showed no epimerization.