Aziridination of alkenes with N-substituted hydrazines mediated by iodobenzene diacetate

Article abstract of DOI:10.1016/j.tetlet.2004.01.127

Aziridination of a variety of alkenes with N-substituted hydrazines mediated by iodobenzene diacetate under mild conditions (K₂CO ₃, CH₂Cl₂) and ambient temperature were achieved in good to excellent yields (up to 99%), and conversions. The practicality and simplicity of this C-N bond formation protocol was exemplified by its application to the aziridination of cholesteryl acetate in a stereoselective manner.

Full text of DOI:10.1016/j.tetlet.2004.01.127

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2685–2688
Aziridination of alkenes with N-substituted hydrazines mediated by
iodobenzene diacetate
Jiayin Li,a Jiang-Lin Liang,b Philip Wai Hong Chanb and Chi-Ming Chea,b,
*
aShanghai-Hong Kong Joint Laboratory on Chemical Synthesis, Shanghai Institute of Organic Synthesis,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, PR China
bDepartment of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and
Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong, PR China
Received 12 November 2003; revised 15 January 2004; accepted 18 January 2004
Abstract—Aziridination of a variety of alkenes with N-substituted hydrazines mediated by iodobenzene diacetate under mild
conditions (K2CO3, CH2Cl2) and ambient temperature were achieved in good to excellent yields (up to 99%), and conversions. The
practicality and simplicity of this C–N bond formation protocol was exemplified by its application to the aziridination of cholesteryl
acetate in a stereoselective manner.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The ability of aziridines to undergo regio- and stereo-
selective ring opening reactions renders them invaluable
building blocks in organic synthesis.1 The aziridine
structural unit itself is found in a number of bioactive
products such as mitomycins and azinomycins.1;2
Despite this, studies on C–N bond formations, particularly
those involving amidation of saturated C–H bonds and
aziridination of C@C bonds remain sparse. Recent
studies by us3 and others4 demonstrated the simplicity
and versatility of transition-metal catalysts for nitrene
transfer reactions. Work in our laboratory found that
iodobenzene diacetate {PhI(OAc)2} and RNH2 (R ¼
p-MeC6H6SO2, p-NO2C6H6SO2) could be used directly
as a nitrogen source in ruthenium(II) porphyrin-cata-
lyzed inter- and intramolecular amidation processes.3a;e
More recently, we reported extension of the
ÔPhI(OAc)2 + RNH2Õ amidation protocol to the intra-
molecular aziridination of acyclic sulfonamides cata-
lyzed by rhodium(II,II) dimers.5
phthalimide as a nitrogen source.9 In light of this work,
we wondered whether the same nitrogen source and
related N-amino compounds could be applied to a
ÔPhI(OAc)2 + RNH2Õ mediated C@C bond aziridination
procedure. Padwa et al. described that the iodosylben-
zene mediated intramolecular aziridination of cyclic
carbamates gave the corresponding products in good
yields and selectivities.4d Herein, we describe the reali-
zation of a metal catalyst-free ÔPhI(OAc)2 + RNH2Õ
(R ¼ phthalimide, benzooxazolone) protocol for effect-
ing intermolecular aziridination of a series of alkenes
under mild conditions (Scheme 1).
The intermolecular aziridination of styrene was initially
chosen as the substrate to establish the reaction condi-
tions (Table 1). Treatment of styrene (1 equiv) with
1.5 equiv of PhI(OAc)2, 1.4 equiv of N-aminophthal-
imide (PthNH2) and 2.8 equiv of K2CO3, in CH2Cl2 at rt
furnished aziridine 1a in 85% yield (entry 1). Similar
Atkinson et al. showed that reactions of alkenes in the
presence of lead(IV) acetate (LTA) and chiral N-am-
inoquinazolinones gave the desired aziridines with high
diastereoselectivity.1d;6 More recent works by Vederas7
and Chen8 demonstrated that similar high product dia-
stereo- and enantioselectivities could be accomplished
by employing the same metal catalyst with N-amino-
R3
N
R3 NH2
R2
R1
PhI(OAc)2
R1
R2
R1, R2 = H, alkyl, aryl
O
O
R3 =
,
N
O
N
O
Scheme 1. PhI(OAc)2-mediated aziridination of a series of alkenes
with N-substituted hydrazines.
* Corresponding author. Tel.: +852-2859-2154; fax: +852-2857-1586;
e-mail: cmche@hku.hk
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.127

2686
J. Li et al. / Tetrahedron Letters 45 (2004) 2685–2688
Table 1. Optimization of reaction conditionsa
Table 2 (continued)
Entry Substrate
Product 1
Conversion Yield
(%)b
O
O
Ph
(%)
PhI(OAc)2
NPth
N
NH2
N N
+
Ph
base, solvent
6
7
87
63
O
O
1a
1f
Me
Me
Entry
Solvent
Base
Temperature (ꢁC) Yield (%)b
79
94
45
73
79
99
N
Pth
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
C6H6
K2CO3
K2CO3
K2CO3
2,6-Cl2py
Al2O3
KOH
––
rt
85
85
79
54
13
50
71
76
50
59
1g
0 fi rt
40
rt
NPth
3
8
4
Me
Me
5
rt
1h
6
rt
NPth
7
rt
OH
OH
8
––
––
rt
9
40
9
10
THF
MeCN
rt
1i
––
rt
NPth
a All reactions were performed for 12 h with styrene:PhI(OAc)2:N-
aminophthalimide:base molar ratio of 1:1.5:1.4:2.8.
b Isolated yield.
CO2Me
CO2Me
10
100
1j
O
O
Me
11
12
13
14
99
94
46
71
98
99
90
99
Me
N
yields were obtained when the reaction was conducted at
either 0 ꢁC or at reflux (entries 2 and 3). In contrast,
reactions employing either 2,6-dichloropyridine (2,6-
Cl2py), Al2O3 or KOH as the base gave significantly
lower yields (entries 4–6). When base was removed from
the reaction conditions, aziridine 1a was afforded in a
slightly lower yield (entry 7). An examination of solvent
effects under these latter conditions revealed that a
similar product yield was obtained when C6H6 was
employed as the solvent (entry 8). The analogous reac-
tions conducted in THF and acetonitrile, however, were
found to give 1a with markedly lower yields (entries 9
and 10).
Pth
1k
O
O
N
Pth
1l
NPth
1m
NPth
Me
Me
Me
Me
O
O
1n
NPth
15
16
17
81
74
38
71
80
93c
In turning attention to exploring the generality of the
present procedure, we examined the PhI(OAc)2 medi-
ated aziridination of a series of terminal and internal
alkenes (Table 2). These reactions afforded the corre-
1o
PthN
1p
Table 2. Intermolecular PhI(OAc)2-mediated aziridination with
N-aminophthalimidea
O
O
AcO
AcO
AcO
N
Pth
Entry Substrate
Product 1
Conversion Yield
(%)b
AcO
OAc
1q
OAc
(%)
NPth
Me(CH2)5
1
97
87
Me(CH2)5
18
NPth
29
77
1a
1r
NPth
a All reactions were performed for 12 h with alkene:PhI(OAc)2:N-am-
inophthalimide:K2CO3 molar ratio of 1:1.5:1.4:2.8 in CH2Cl2 at rt.
b Isolated yield.
c Combined yield with a a:b ratio of ¼ 1.5:1.
2
64
64
97
87
F3C
F3C
1b
NPth
3
F
F
1c
1d
1e
sponding aziridines 1b–r in good to excellent yields (up
to 99%) and conversions (entries 2–18). In a number of
cases product yields and conversions obtained were near
quantitative (entries 1, 4, 5 and 10–12). More notably,
the electron-rich and electron-deficient nature of the
C@C bond was found to have no effect on reaction
yield. A competitive rate study of a number of para-
NPth
4
96
94
76
74
Cl
Me
Cl
NPth
5
Me

J. Li et al. / Tetrahedron Letters 45 (2004) 2685–2688
2687
substituted styrenes (Y-C6H4CH@CH2 where Y ¼ Me,
OMe, F, CF3) did imply electron-deficient alkenes
accelerated aziridination more quickly than electron-
rich alkenes.10 Furthermore, reaction of cis- and trans-b-
methylstyrene giving 1g and 1h with exclusive cis- and
trans-selectivity, respectively, suggests the present pro-
tocol to be diastereoselective (entries 7 and 8). In
instances where it was initially envisaged that the pres-
ence of other functional groups would lead to compet-
itive side reactions, the exclusive formation of the
aziridine product implies the present procedure to be
chemoselective. No other products that could be
attributed to side reactions of the functional groups
present in the alkenes examined were detected (entries 9–
12). Conformationally restricted alkenes were found to
undergo intermolecular aziridination. Aziridines 1m–q
were afforded in 80–99% yields based on conversions of
38–81% (entries 13–17). Reaction of 1-heptene is the
only example where conversion was found to be mod-
erate (entry 18). Nevertheless, in every instance lower
product yields were reported for the analogous reactions
catalyzed by LTA.10;11 For example, the LTA-catalyzed
aziridination of styrene with N-aminophthalimide gave
1a in 42% yield in contrast to the 87% yield using the
present procedure (Table 2, entry 1).10 Furthermore, the
present protocol realized aziridination of a broad spec-
trum of alkenes with PhI(OAc)2 which is less toxic and
more environmentally friendly than LTA.12 This is
exemplified by the aziridination of tri-O-acetyl-D-glucal
in 93% yield based on 38% conversion and with an a:b
ratio of 1.5:1 (entry 17). The analogous reaction with
LTA is not known.
With 3-amino-3H-benzooxazol-2-one (BoNH2) as a
nitrogen source, the aziridination of a variety of alkenes
proceeded in good to excellent yields and moderate to
good conversions (Table 3). Treatment of styrene
(1 equiv) with 1.5 equiv of PhI(OAc)2, 1.4 equiv of 1-
amino-1,3-dihydro-indol-2-one and 2.8 equiv of K2CO3,
in CH2Cl2 at rt furnished aziridine 2a in 53% yield (entry
1). Under similar conditions, yields up to 94% were ob-
tained for the aziridination of both electron-deficient and
-rich alkenes (entries 2–4). Likewise, reaction of 2,2-di-
methyl-2H-chromene gave the corresponding aziridine
product 2e in 68% yield based on 31% conversion (entry 5).
Amino steroids have been shown to exhibit noteworthy
pharmacological activity.13 Previous work by Dauban
and Dodd reported a copper catalyzed aziridination of
11-pregnene-3,20-dione in 53% yield.14 Breslow dem-
onstrated manganese porphyrin catalyzed amidation of
equilenin acetate in 47% yield.15 Work previously
undertaken in our laboratory had shown that the
amidation of cholesteryl acetate catalyzed by ruthenium
porphyrin occurred with a-selectivity (a:b ratio up to
4.2:1),3b but the same reaction catalyzed by ruthenium–
salen complexes resulted in b-selectivity (b:a ratio up to
2.3:1).3c It therefore intrigued us to explore the present
PhI(OAc)2-mediated aziridination protocol as an alter-
native route to these biologically interesting compounds.
Thus, when cholesteryl acetate was treated in the pres-
ence of 1.5 equiv of PhI(OAc)2, 1.4 equiv N-aminoph-
thalimide and 2.8 equiv K2CO3 in CH2Cl2, aziridine 1t
was obtained in 95% isolated yield based on 29% con-
Table 3. Intermolecular PhI(OAc)2-mediated aziridination with
3-amino-3H-benzooxazol-2-one as the nitrogen sourcea
Entry Substrate
Product 2
Conversion Yield
(%)
53
(%)b
NBo
1
80
2a
NBo
NBo
2
54
55
84
82
Cl
Cl
2b
3
Me
Me
1
2c
version. By comparing the H NMR spectrum obtained
for 1t with known literature data,16 reaction was ob-
served to occur with exclusive a-selectivity (Scheme 2). It
is noteworthy that this is comparable to the product
yield of 40% reported for the analogous reaction using
LTA as the catalyst.16
O
O
Me
4
42
31
94
68
Me
N
Bo
2d
NBo
5c
Me
Me
Me
Me
O
O
2e
In this Letter, we describe a practical and simple
PhI(OAc)2 mediated aziridination reaction that is both
general and high yielding. Effects are currently under-
way to develop an asymmetric polyvalent iodine-medi-
ated version of the present reaction and its application
to the total synthesis of a variety of natural products.
a All reactions were performed for 12 h with alkene:PhI(OAc)2:3-am-
ino-3H-benzooxazol-2-one:K2CO3 molar ratio of 1:1.5:1.4:2.8 in
CH2Cl2 at rt.
b Isolated yield.
c Reaction conducted with 3 equiv of PhI(OAc)2.
O
Me
Me
Me
N NH
2,PhI(OAc)2
O
Me
CH2Cl2, RT
AcO
AcO
PthN
29% conversion, 95% yield
1t
Scheme 2. PhI(OAc)2-mediated aziridination of cholesteryl acetate.

2688
J. Li et al. / Tetrahedron Letters 45 (2004) 2685–2688
J. Am. Chem. Soc. 1994, 116, 2742; (i) Li, Z.; Conser, K.
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