Copper iodide-catalyzed aziridination of alkenes with sulfonamides and sulfamate esters

Article abstract of DOI:10.1016/j.tetlet.2008.10.105

An efficient copper iodide-catalyzed aziridination of a variety of alkenes with sulfonamides and sulfamate esters as the nitrogen source and iodosylbenzene (PhI{double bond, long}O) as the oxidant is reported herein. The reaction is operationally straight

Full text of DOI:10.1016/j.tetlet.2008.10.105

Tetrahedron Letters 50 (2009) 161–164
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Tetrahedron Letters
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Copper iodide-catalyzed aziridination of alkenes with sulfonamides and
sulfamate esters
*
Joyce Wei Wei Chang, Thi My Uyen Ton, Zhengyang Zhang, Yanjun Xu, Philip Wai Hong Chan
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient copper iodide-catalyzed aziridination of a variety of alkenes with sulfonamides and sulfa-
mate esters as the nitrogen source and iodosylbenzene (PhI@O) as the oxidant is reported herein. The
reaction is operationally straightforward, applicable to a variety of alkenes containing electron-with-
drawing, electron-donating, and sterically encumbered substrate combinations, and proceeds under mild
conditions at room temperature in good to excellent yields.
Received 8 September 2008
Revised 13 October 2008
Accepted 22 October 2008
Available online 25 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Aziridines are found in a myriad of bioactive natural products,
and are compounds of current therapeutic interest exhibiting a
variety of biological properties, such as antibiotic and antitumor
activities.1–11 The ability of aziridines to undergo regio- and stere-
oselective ring opening reactions also renders this class of com-
pounds as invaluable building blocks in organic synthesis. For
this reason, the development of novel synthetic routes for the
preparation of aziridines has received significant attention. Among
the various strategies developed for preparing aziridines, transition
metal-catalyzed aziridination of C@C bonds has been reported to
be a mild and efficient approach. In recent years, these methods
have relied heavily on the use of metal catalysts such as Fe,5
Mn,6 Ru,7 Rh2,8 Ag,9 Au,10 and Co11 with preformed iminoiodinanes
(PhI@NSO2R, typically R = Ar) or sulfonamide, sulfamate and carba-
mate esters in combination with a hypervalent iodine(III) oxidant12
as the nitrogen source. However, a drawback of many of these
methodologies has been the need to prepare the metal catalyst,
which can be expensive, arduous and time-consuming. In addition,
a competitive CꢀH insertion process and, in many instances, the
need for an excess of the alkene substrate, which are often invalu-
able intermediates in natural product synthesis, to achieve high
conversions and yields have been reported. In this regard, attempts
to overcome such limitations have led to a resurgence in interest
toward exploring catalytic systems that employ copper salts.13–16
In a recent notable advance, Lebel and co-workers demonstrated
that the aziridination of alkenes with N-tosyloxycarbamates pro-
ceeds smoothly in the presence of a pyridylcopper(II) complex as
catalyst.14 At about the same time, Fleming and co-workers de-
scribed the intramolecular aziridination of carbamates catalyzed
by (CF3SO3Cu)2ꢁC6H6.15 More recently, Appella and co-workers re-
ported that N-heterocyclic carbene copper complexes could facili-
tate alkene aziridination with 2,2,2-trichloroethyl sulfamate and
iodosylbenzene (PhI@O) as oxidant.16 In contrast, a synthetic ap-
proach that relies on the exceptional activity offered by copper
catalysis, but makes use of CuI as the source of the metal catalyst
is not known. In general, such nitrogen-transfer reactions across
a C@C bond have often relied upon making use of copper com-
plexes derived from more expensive and moisture-sensitive cop-
per triflate salts. As part of an ongoing program on CꢀN bond
formation in our group,17 we present herein a CuI-catalyzed meth-
od for the aziridination of a wide variety of alkenes with sulfona-
mides and sulfamate esters and PhI@O as oxidant (Scheme 1).
The reaction proceeds under mild conditions at room temperature
in good to excellent yields of up to 99%.
Initially, we examined the effect of various oxidizing agents and
solvents on the aziridination of styrene 1a in the presence of
10 mol % CuI as catalyst and p-toluenesulfonamide 2a as the nit-
rene source to establish the reaction conditions (Table 1). Our stud-
ies showed that the best yields were obtained when 1.5 equiv of
PhI@O was employed as the oxidant in the presence of powdered
4 Å molecular sieves in MeCN at room temperature for 18 h.18 Un-
der these conditions, aziridine 3a was obtained in 99% yield (entry
1). Further investigations revealed that reducing the loading of
PhI@O to 1.25 equiv gave the desired aziridine product in a lower
yield of 79% (entry 4). A further reduction in oxidant loading to
1 equiv resulted in a respective decrease in product yield to 56%
SO2R5
R1
R2
R3
R4
CuI (10 mol%)
N
NH2SO2R5
R1
R2
R3
R4
+
PhI=O, 4Å MS
MeCN, 18 h
1
2
3
R1-R5 = H, alkyl, aryl
* Corresponding author. Tel.: +65 6316 8760; fax: +65 6791 1961.
E-mail address: waihong@ntu.edu.sg (P. W. H. Chan).
Scheme 1. CuI-catalyzed aziridination of alkenes.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.105

162
J. W. W. Chang et al. / Tetrahedron Letters 50 (2009) 161–164
Table 1
MeCN resulted in a drastic drop in product yield to 19%, the anal-
Optimization of the reaction conditionsa
ogous reaction repeated at the same catalyst loading in CH2Cl2
afforded 3a in 99% yield (entries 3 and 12). On the other hand,
replacing PhI@O with other hypervalent iodine reagents, such as
2-iodobenzoic acid, hydroxyl(tosyloxy)iodobenzene (HTIB), iodo-
benzene diacetate [PhI(OAc)2], bis(tbutylcarbonyloxy)iodobenzene
[PhI(OCOtBu)2], and 2-iodoxybenzoic acid (IBX), resulted in no
reaction and near quantitative recovery of the starting materials.
Under similar conditions, the use of inorganic oxidants such as Ox-
oneÒ, K3Fe(CN)6, K2Cr2O7, KIO4, and K2S2O8 in place of PhI@O was
also found to give no reaction. With an oxidant loading of 2 equiv,
an examination of solvent effects showed that reactions carried out
in CHCl3 and CH2Cl2 gave the desired aziridine 3a in near quantita-
tive yields (entries 10 and 11). In contrast, lower product yields of
21–66% were obtained when C6H6, MeNO2 1,4-dioxane, and 1,2-
dichloroethane were employed as solvents (entries 6–9).
CuI (10 mol%)
NTs
+
TsNH2
Ph
1a
Ph
PhI=O, 4Å MS
2a
3a
solvent
Entry
PhI@O (equiv)
Solvent
Yieldb (%)
1
2c
3d
4
5
6
7
8
9
1.5
1.5
1.5
1.25
1
2
2
2
2
MeCN
MeCN
MeCN
MeCN
MeCN
C6H6
CH3NO2
1,4-Dioxane
ClCH2CH2Cl
CHCl3
CH2Cl2
99
81
19
79
56
21
66
54
29
99
99
99
10
11
12d
2
2
1.5
To define the scope of the present procedure, we applied this
process to a variety of internal and terminal alkenes 1a–k and
nitrogen sources 2a–f (Table 2). These reactions gave the corre-
sponding aziridines in good to excellent yields (entries 2–19). This
included near quantitative product yields obtained for the reac-
tions of 1f with 2a and 1a with 2b, which was found to be consis-
tent with our earlier findings on the aziridination of 1a with 2a (cf.
entry 1 with entries 6 and 12). More notably, the electronic nature
of either the C@C bond or aryl sulfonamide was found to have no
effect on the reaction yield. A competitive rate study of a number
CH2Cl2
a
Unless otherwise stated, all reactions were carried out with 0.5 mmol of 1a and
2 equiv of 2a for 18 h at room temperature.
b
Isolated yield.
c
Reaction conducted with 1.5 equiv of 2a.
Reaction conducted with 5 mol % of CuI.
d
(entry 5). The use of 2 equiv of TsNH2 was also found to be neces-
sary for the aziridination to proceed smoothly, when TsNH2 was
reduced to 1.5 equiv, a slightly lower product yield of 81% was
afforded (entry 2). A decrease of catalyst loading to 5 mol % in
t
of para-substituted styrenes [X = Me (1b), Bu (1c), F (1d), Cl (1e),
and Br (1f)] gave logKX/KH values of 0.057 (1b), 0.026 (1c),
Table 2
CuI-catalyzed aziridination of alkenes 1a–k with sulfonamides 2a–c and sulfamate ester 2da
R
R
1a, R = H
1b, R = Me
1c, R = tBu
1d, R = F
1e, R = Cl
1f, R = Br
1g, R = Me
1h, R = Br
1i
1j
O
Me
O
O
NH2
R
S NH2
S
Cl3C
O
RO
NH2
O
O
2e, R = tBu
2f, R = Bn
1k
2a, R = Me
2b, R = OMe
2c, R = Cl
2d
Entry
Substrates
Product
Yieldb (%)
1
2
3
4
5
6
1a + 2a
1b + 2a
1c + 2a
1d + 2a
1e + 2a
1f + 2a
3a, R = H
3b, R = Me
3c, R = tBu
3d, R = F
3e, R = Cl
3f, R = Br
99
68
93
79
83
99
Ts
N
R
Ts
N
7
8
1g + 2a
1h + 2a
3g, R = Me
3h, R = Br
63
40
R
Ts
N
9
1i + 2a
3i
92

J. W. W. Chang et al. / Tetrahedron Letters 50 (2009) 161–164
163
Table 2 (continued)
Entry
Substrates
Product
Yieldb (%)
NTs
10
11
1j + 2a
3j
25 (56)c
— (90)c
Ts
N
Me
1k + 2a
3k
Ph
O
N
Ph
S
12
13
14
1a + 2b
1a + 2c
1a + 2d
3l, R = OMe
3m, R = Cl
3n, R = H
99
84
69
O
R
O
15
16
17
18
19
1b + 2d
1c + 2d
1d + 2d
1e + 2d
1f + 2d
3o, R = Me
3p, R = tBu
3q, R = F
3r, R = Cl
3s, R = Br
41
50
67
60
68
N
S
O
CCl3
O
R
O
N
d
20
21
1a + 2e
1a + 2f
3t, R = tBu
3v, R = Bn
—
—
OR
d
Ph
a
All reactions were carried out at room temperature in MeCN for 18 h with CuI:1:2:PhI@O molar ratio = 1:10:20:15.
Isolated yields.
b
c
Values in parentheses denote yields from reactions conducted in CH2Cl2.
d
No reaction was observed based on TLC and 1H NMR analysis of the crude reaction mixture.
ꢀ0.034 (1d), ꢀ0.079 (1e) and ꢀ0.061 (1f), which implied that elec-
would like to thank the Singapore Millennium Foundation (SMF)
for a SMF PhD scholarship award. T.M.U.T. and Z.Z. would like to
acknowledge funding support for this project from Nanyang Tech-
nological University under the Undergraduate Research Experience
on CAmpus (URECA) program.
tron-deficient alkenes accelerated aziridination more rapidly than
electron-rich alkenes.19 Steric effects of the alkene substrate may
also play a role since increasingly bulky groups, such as an o-meth-
ylphenyl or o-bromophenyl, were found to provide 3g and 3h in
lower yields of 63% and 40%, respectively (entries 7 and 8). In addi-
tion, both 1j and 1k were found to be poor substrates under the
standard conditions. In our hands, reaction of 1j was found to af-
ford 3j in a low yield of 25% while no reaction was observed when
we examined 1k. However, in both cases, good to excellent product
yields were obtained on changing the solvent from MeCN to
CH2Cl2, although the reasons for this stark difference in reactivity
remain unclear (entries 10 and 11). On the other hand, the present
procedure was shown to work well for the aziridinations of alkenes
1a–f with the sulfamate ester 2d as the nitrogen source (entries
14–19). In these reactions, the corresponding aziridines 3n–s were
furnished in 41–69% yields. However, the analogous reactions of 1a
with carbamates, such as t-butyl carbamate 2e and benzyl carba-
mate 2f, were found to be ineffective. Under our standard condi-
tions, TLC and 1H NMR analysis of the crude mixtures only
detected the presence of the starting materials, which were subse-
quently recovered in near quantitative yields (entries 20 and 21).
In summary, we have demonstrated a CuI-catalyzed process for
the aziridination of alkenes in good to excellent yields. The present
protocol was shown to be applicable to a variety of alkenes and
sulfonamide and sulfamate ester nitrogen sources. Further exami-
nation of the scope and applications of this reaction is currently
underway, and will be reported in due course.
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This work is supported by a University Research Committee
Grant (RG55/06) and Supplementary Equipment Purchase Grant
(RG134/06) from Nanyang Technological University. J.W.W.C.

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18. General experimental procedure: To
RSO2NH2 2 (1 mmol), CuI (0.05 mmol), and powdered 4 ÅA molecular sieves in
dry MeCN (2 mL) was added the alkene (0.5 mmol) under nitrogen
a suspension of PhI@O (0.75 mmol),
0
1
a
atmosphere. The reaction mixture was stirred at room temperature for 18 h,
after which the suspension was filtered through CeliteÒ, washed with EtOAc,
and evaporated to dryness. The residue was purified via silica gel flash column
chromatography to afford the title compound 3.
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