NBS-mediated aziridination between styrenes and amides under transition metal-free conditions

Article abstract of DOI:10.1002/jhet.1555

An efficient and simple protocol for N-bromosuccinimide (NBS)-mediated styrenes aziridination using amides as the nitrenoid source has been developed. This aziridination affords desired products in moderate to good yields without using transition metal catalyst under very mild reaction condition.

Full text of DOI:10.1002/jhet.1555

July 2014
NBS-Mediated Aziridination between Styrenes and Amides under
Transition Metal-Free Conditions
937
*
Xu Meng, Wenlin Chen, Yuanqing Zhang, Yongxin Chen, and Baohua Chen
Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, State Key Laboratory of
Applied Organic Chemistry Lanzhou University, Lanzhou University, Lanzhou 730000, People’s Republic of China
*
E-mail: chbh@lzu.edu.cn
Additional Supporting Information may be found in the online version of this article.
Received August 14, 2011
DOI 10.1002/jhet.1555
Published online 10 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
CO
R1
N
NBS (1.0 equiv)
CHCl3, 40 oC, 3h
Transition Metal Free
+
CONH2
R2
R2
R1
3
1
2
R1= Cl, Br, F, Me, OMe, CF3
R2= Cl, Me, tert-butyl
23 examples
35-86%
An efficient and simple protocol for N-bromosuccinimide (NBS)-mediated styrenes aziridination using
amides as the nitrenoid source has been developed. This aziridination affords desired products in moderate
to good yields without using transition metal catalyst under very mild reaction condition.
J. Heterocyclic Chem., 51, 937 (2014).
INTRODUCTION
alternative nitrenoid sources in some N-transfer aziriditions
[8]. For example, Komatsu and co-workers developed a
novel and eco-friendly silica water-mediated olefin aziridina-
tion that uses chloramine-T as the nitrenoid source and I2 as
the catalyst [9]. More recently, De Vos and co-workers
developed a direct, novel, and highly selective route to
the synthesis of unprotected aziridines from NH3 and simple
olefins in the presence of stoichiometric amounts of I2
[10]. In 2008, Chang’s group reported an efficient
protocol for Cu-catalyzed aziridination using 5-methyl-2-
pyridinesulfonamide or 2-pyridinesulfonyl azide as the
simple nitrenoid source [11]. Despite the great advantages
of these cases, there are still certain limitations remained, such
as a metal catalysts is required for the reactions (metal
catalysts are sometimes undesirable) and some reaction
reagents are not eco-friendly (for example, I2, and ammonia).
Consequently, the simple and highly selective olefin
aziridination using easily available nitrenoid source under
mild and eco-friendly reaction conditions remains to be
exploited. Herein, we describe a transition-metal-free aziridition
of stryenes in the presence of N-bromosuccinimide (NBS)
under very mild reaction condition as a complement to the
previous methods.
The aziridine structure is ubiquitous in a number
of important natural molecules, such as ficellomycin,
porfiromycin, mitomycin, miraziridine, azinomycine,
FR-66979, FR-900482, and maduropeptin [1]. And the
antitumor, antibiotic activity, and other biological prop-
erties of several of these compounds are well-known
[2]. In addition, as synthetic targets, aziridines are also
essential building blocks in organic synthesis [3].
Therefore, a wide range of preparative procedures
of aziridines that via either traditional syntheses or
catalytic routes have been developed. Synthetic method-
ologies for the preparation of aziridines include nitrene
addition to olefins, carbene and ylid addition to imines,
and cyclization of 1,2-amino alcohols, 1,2-aminohalides, and
1,2-azido alcohols [4]. More importantly, a range of catalytic
aziridinations have been profited from the utilization of tran-
sition metal catalyst, including Cu, Ag, Au, Ru, Rh, Mn, Fe,
Co, Pd, Ni, Re, or In in combination with suitable oxidants
and coordinating ligands [5]. Although catalyst options have
been expended in recent years, known nitrenoid sources
remain limited. Because of the significant pioneering work
of Mansuy [6], PhI = NTs has been employed as an efficient
nitrenoid source in aziridination of olefins widely. However,
some drawbacks are also obvious, for example, sensitivity
to air and moisture, generation of a vast number of side
products, and difficulty in scaling up [7]. Recently, several
research groups discovered the N-halogenated sulfonamide
salts such as chloramine-T and bromamine-T could be
RESULTS AND DISCUSSION
Initially, we tried to synthesize a hydroaminated product
4 in a Markovnikov fashion using styrene and amide as the
substrates (Scheme 1) [12]. To our surprise, when styrene
© 2013 HeteroCorporation

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X. Meng, W. Chen, Y. Zhang, Y. Chen, and B. Chen
Vol 51
Scheme 1. Aziridination of amide and styrene.
O
NH2
NHCOPh
reaction
1a
+
COPh
condition
N
X
air, heat
Ph
4
3a 25%
not formed
2a
(2a) was reacted with benzamide (1a) in the presence of
NBS in CH2Cl2, phenyl(2-phenylaziridin-1-yl)methanone
(3a) was obtained as the single product, albeit in low yield.
In contrast, no hydroaminated product 4 was observed
under the initial reaction condition (Scheme 1).
Encouraged by this unexpected and preliminary result,
we tried to optimize the aziridiantion conditions using sty-
rene (2a) and benzamide (1a) in the presence of NBS
(Table 1). As shown in Table 1, 25% of the desired product
3a and 28% of the side product 5 were obtained by using
Table 1
Optimization of reaction conditions.a
Entry
NXS (equiv)
Solvent
Yield of 3a (%)b
Yield of 5 (%)b
1
2
3
4
5
6
7
8
NBS (0.1)
None
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CHCl3
CHCl3
CCl4
MeCN
MeCN/CCl4 = 1/1
DCE
DME
Et-O-Et
THF
Acetone
EtOAc
MeNO2
EtOH
Benzene
PhMe
DMF
DMSO
none
25
0
38
45
70
0
56
8
16
18
24
Trace
Trace
0
Trace
10
28
0
25
24
11
0
35
42
36
28
23
14
16
Trace
Trace
20
NBS(0.5)
NBS(1.0)
NBS(1.0)
NCS(1.0)
NBS(2.0)
NBS(1.0)
NBS(1.0)
NBS(1.0)
NBS(1.0)
NBS(1.0)
NBS(1.0)
NBS(1.0)
NBS(1.0)
NBS(1.0)
NBS(1.0)
NBS(1.0)
NBS(1.0)
NBS(1.0)
NBS(1.0)
NBS(1.0)
NBS(1.0)
NBS(1.0)
NBS(1.0)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
20
Trace
21
14
10
14
45
48
0
0
0
0
15
Trace
CHCl3
CHCl3
Tracec, 46d
41e, 30f, 55g
Tracec, 60d
55e,10f, 10g
aReaction conditions: 1a (1.0 mmol), 2a (1.2 mmol), NXS (1.0 equiv, X = B, C), 1 mL of solvent at 40 ꢀC for 3 h under air.
bIsolated yields.
cAt room temperature.
dAt 60 ꢀC.
eFor 8 h.
fFor 1 h.
gUnder N2.
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NBS-Mediated Aziridination between Styrenes and Amides under
Transition Metal-Free Conditions
939
catalytic amount of NBS (0.1 eq) in CH2Cl2, whereas
the aziridination was failed without NBS (Table 1, Entries
1–2). When the amount of NBS increased to 1.0 equiv
from 0.1 equiv relative to benzamide, the yield of 3a
boosted to 45% (Table 1, Entries 3–4). To our delight,
CHCl3 was found as the best solvent in the optimized
condition, which led to 70% yield of 3a and reduced the
yield of side product 5 (11%) by using 1.0 equiv NBS
(Table 1, Entry 5). However, better results of the aziridina-
tion were not observed by using NCS or other related
reagents to replace NBS (see the supporting information)
or increasing the load of NBS up to 2.0 equiv (Table 1,
Entries 6–7). Moreover, adding transition metal catalyst
(such as Cu, Fe, and Pd salt) could not enhance the yield
of the aziridination as well [5,13]. Secondly, the effect of
solvents (CCl4, MeCN, Et-O-Et, MeNO2, Benzene, DMF,
etc.) was also investigated (Table 1, Entries 4, 8–23); the
results demonstrated that the CHCl3 afforded the highest
yield (Table 1, Entry 5). Then, the effect of the temperature
was also examined, thereby enhancing yield of the desired
product (Table 1, Entry 24). The olefin aziridination could
not perform at room temperature, whereas lower yield
Table 2
NBS-mediated aziridination of amides and styrene.a
Entry
Amide (R= )
2
Product
Yield (%)b
1
2
3
4
5
6
7
H
4-Me
3-Me
3,4-diMe
4-MeO
2-MeO
2a
2a
2a
2a
2a
2a
2a
3a
3b
3c
3d
3e
3f
70
78
76
80
84
Trace
86
3g
8
9
4-Cl
3-Cl
2-Cl
2,4-diCl
4-Br
3-Br
2-Br
3-F
4-CF3
4-NO2
4-N3
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
3h
3i
3j
59
51
38
55
62
51
36
55
35
10
11
12
13
14
15
16
17
18
19
3k
3 l
3m
3n
3o
3p
3q
3r
3s
Trace
Trace
75
20
2a
-
0
21
22
23
24
25
H
4-Me
4-Cl
H
2b
2b
2b
2c
2d
3 t
3u
3v
-
72
79
57
0
H
-
0
aReaction condition: 1 (1.0 mmol), 2 (1.2 mmol), NBS(1.0 equiv), 1 mL of CHCl3 at 40 ꢀC for 3 h under air.
bIsolated yields.
Journal of Heterocyclic Chemistry
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X. Meng, W. Chen, Y. Zhang, Y. Chen, and B. Chen
Vol 51
Table 3
NBS-mediated aziridination of amide and olefins.a
Entry
Substrate
Product
Yield (%)b
58
1
2
3w
3r
64
3
4
3y
3z
75
65
aReaction condition: amide (1.0 mmol), 2 (1.2 mmol), NBS(1.0 equiv), 1 mL of CHCl3 at 40 ꢀC for 3 h under air.
bIsolated yields.
Scheme 2. Possible mechanism of NBS-mediated aziridination of amides and olefins.
O
O
Br
NBS
+
HBr
N
H
NH2
Br
COPh
N
COPh
N
H
A
of 3a could be obtained and the higher yield of 1-(1,2-
dibromoethyl)benzene (60%) was obtained at higher
temperature (Table 1, Entry 24). Furthermore, the exami-
nation of the reaction time demostrated that 3 h was the
best time frame (Table 1, Entry 25). Similarly, the shorter
reaction time led to lower yield of 3a and the longer reac-
tion time brought about a host of side product 5 (55%)
rather than improving the reaction (Table 1, Entry 25).
Finally, other simple nitrenoid sources (such as TsNH2,
CbzNH2, MeOCONH2, etc.) were also investigated for
the purpose of the scope of the aziridination (see the
supporting information). The results demonstrated that
the carboxamides is the only suitable substrates for the
reaction [11]. After the optimization process of reaction
condition, the following aziridination was conducted under
our standard condition: 1.0 equiv of NBS relative to
amides, CHCl3 as solvent at 40ꢀC without exclusion of
air (Table 1, Entry 25).
Under the optimized condition, a variety of amides and
a-substituted or b-substituted styrenes were investigated,
and the results were shown in Table 2. Generally, the
olefins aziridination could be carried out smoothly, and the
corresponding products were obtained in moderate to good
yields. More importantly, the aziridination was influenced
by electronic properties to some extent (Table 2, Entries
1–5, 7–25). Specifically, electron-rich amides could lead
to higher yield of desired products than electron-poor
ones (Table 2, Entries 1–5, 7–23) and 4-nitrobenzamide, 4-
azidobenzamide as well as isonicotinamide even rendered
the amidation failed (Table 2, Entries 17–18, 20). Likewise,
when electron-withdrawing groups are on the b-position on
styrenes, the reaction was found not working (Table 2,
Entries 24–25). On the other hand, steric hindrance could
affect the reaction obviously. It was evident that ortho-
substituted amides afforded lower yield of products than
para-substituted ones (Table 2, Entries 8–10, 12–14), and
Journal of Heterocyclic Chemistry
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July 2014
NBS-Mediated Aziridination between Styrenes and Amides under
Transition Metal-Free Conditions
941
highly hindered amides could make the reaction failed, such
as ortho-substituted methoxy benzamide (Table 2, Entry 6).
Subsequently, para-substituted or ortho-substituted sty-
renes and 4-methylamide were used as substrates to examine
the yield of the aziridination (Table 3). Not surprisingly, the
desired products were obtained in 58 and 64% isolated yield,
respectively, when electron-poor 1-chloro-4-vinylbenzene
and 1-chloro-2-vinylbenzene were used as the substrates
(Table 3, Entries 1–2). And the aziridines could be obtained
when using para-substituted electron-rich styrenes as the sub-
strates (Table 3, Entries 3–4). Exactly, 1-methyl-4-vinylbenzene
afforded aziridine 3y in 75% yield, whereas 1-tert-butyl-4-
vinylbenzene afforded 3z in 65% yield.
Although the exact reaction mechanism remains unclear,
the most plausible pathway would involve the appearance
of the species ArCONHBr [12,14] firstly when ArCONH2
was reacted with NBS (Scheme 2). After that, the interaction
between ArCONHBr and styrene leads to the protonation of
a styrenic double bond to reach the intermediate A [12].
Finally, the intermediate A might undergo ring closure to
give the aziridine [15].
(m, 5H), 6.93 (d, J = 7 Hz, 2H), 5.63 (dd, J=8, 2Hz, 1H),
4.45 (dd, J= 11, 4 Hz, 1H), 3.96 (dd, J=8, 6Hz, 1H), 3.84
(s, 3H); 13C NMR (75 MHz, CDCl3): d = 163.8, 162.1, 141.0,
129.9, 128.7, 128.1, 125.6, 119.9, 113.6, 80.8, 63.0, 55.3.
Supporting Information. Experimental procedures, more attempted
experiments, and characterization data and copies of NMR spectra
for products.
Acknowledgments. We are grateful to the project sponsored
by the Scientific Research Foundation for the State
Education Ministry (No. 107108) and the Project of National
Science Foundation of the People’s Republic of China
(No. J0730425).
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CONCLUSION
In summary, we have demonstrated an NBS-mediated
olefin aziridination using carboxamides as the nitrenoid source
under transition metal catalyst-free condition. The simple
procedure for synthesis of aziridines appears to afford high
selectivity, mild reaction condition, and a wide substrate
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EXPERIMENTAL
General procedure for NBS-mediated reaction. Amide
(1.0 mmol), styrene (1.2 mmol), NBS (1.0 mmol), and
CHCl3 (1 ml) were added to a flask with a bar. The flask
was stirred at 40ꢀC for 3 h. After cooling at room
temperature, the mixture was diluted with ethyl acetate and
filtered. The filtrate was removed under reduced pressure to
obtain the crude product, which was further purified by
silica gel chromatography (petroleum/ethyl acetate = 10/1 as
eluent) to yield corresponding product. The identity and
purity of the products was confirmed by 1 H and 13 C NMR
spectroscopic analysis.
Compound 3a.
Colorless oil. 1H NMR (400 MHz,
CDCl3): d = 8.03 (d, J = 11 Hz, 2H), 7.53–7.31 (m, 8H),
5.67 (dd, J = 8, 2 Hz, 1H), 4.48 (dd, J = 10, 4 Hz, 1H), 4.00
(dd, J = 8, 7 Hz, 1H); 13 C NMR (75 MHz, CDCl3):
d = 163.8, 140.9, 131.3, 128.8, 12.8.2, 128.1, 127.5, 125.5,
80.8, 63.1. MS: m/z (%) = 223 (M+, 6), 117 (100), 105 (57),
77 (85.6), 51 (70).
Compound 3e.
1
White solid, mp 58–60ꢀC; H NMR
(300 MHz, CDCl3): d =7.95 (d, J= 2 Hz, 2H), 7.35–7.31
Journal of Heterocyclic Chemistry
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X. Meng, W. Chen, Y. Zhang, Y. Chen, and B. Chen
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Journal of Heterocyclic Chemistry
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