Metal-free aziridination of styrene derivatives with iminoiodinane catalyzed by a combination of iodine and ammonium iodide

Article abstract of DOI:10.1021/ol402276f

The metal-free catalytic aziridination of styrene derivatives with N-tosyliminophenyliodinane (PhI=NTs) in the presence of a combination of I ₂ and tetrabutylammonium iodide (TBAI) is reported. In situ generated TBAI₃ from I₂

Full text of DOI:10.1021/ol402276f

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Metal-Free Aziridination of Styrene
Derivatives with Iminoiodinane Catalyzed
by a Combination of Iodine and
Ammonium Iodide
Kensuke Kiyokawa, Tomoki Kosaka, and Satoshi Minakata*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University,
Yamadaoka 2-1, Suita, Osaka 565-0871, Japan
minakata@chem.eng.osaka-u.ac.jp
Received August 9, 2013
ABSTRACT
The metal-free catalytic aziridination of styrene derivatives with N-tosyliminophenyliodinane (PhI=NTs) in the presence of a combination of I2 and
tetrabutylammonium iodide (TBAI) is reported. In situ generated TBAI3 from I2 and TBAI dramatically promotes the reaction of alkenes with
N,N-diiodotosylamide, which is formed in situ.
Aziridines represent an important structural motif in
natural products and are also a useful building block in
organic synthesis.1 Therefore, numerous synthetic meth-
odologies for preparing aziridines have been reported in
the past decades. The direct aziridination of alkenes, the
transfer of a nitrogen atom to alkenes, are currently one
of the most practical and useful methods for the synthesis
of aziridines.1a,2,3 Significant progress has been achieved
to date in the transition-metal-catalyzed aziridination
of alkenes using several nitrogen sources such as organic
azides, N-sulfonyliminophenyliodinanes, and N-haloamine
salts. Among these reagents, iminoiodinanes have been
widely used for aziridination reactions including asym-
metric versions, since the discovery of a practical method
for the synthesis of N-tosyliminophenyliodinane (PhI=
NTs).4
Recently, the benign metal-free aziridination of al-
kenes has attracted considerable attention from practical,
(4) Yamada, Y.; Yamamoto, T.; Okawara, M. Chem. Lett. 1975, 361.
(5) For an example of metal-free aziridinations using an organic
azide, see: Mahoney, J. M.; Smith, C. R.; Johnston, J. N. J. Am. Chem.
Soc. 2005, 127, 1354.
(6) For selected examples of metal-free aziridinations using halo-
amine salts, see: (a) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1998, 120, 6844. (b) Ando, T.; Kano,
D.; Minakata, S.; Ryu, I.; Komatsu, M. Tetrahedron 1998, 54, 13485. (c)
Kano, D.; Minakata, S.; Komatsu, M. J. Chem. Soc., Perkin Trans. 1
2001, 3186. (d) Minakata, S.; Kano, D.; Oderaotoshi, Y.; Komatsu, M.
Angew. Chem., Int. Ed. 2004, 43, 79. (e) Minakata, S.; Murakami, Y.;
Tsuruoka, R.; Kitanaka, S.; Komatsu, M. Chem. Commun. 2008, 6363.
(f) Murakami, Y.; Takeda, Y.; Minakata, S. J. Org. Chem. 2011, 76,
6277. (g) Saikia, I.; Kashyap, B.; Phukan, P. Chem. Commun. 2011, 47,
2967.
(7) For selected examples of metal-free aziridinations using N-
aminophthalimide, see: (a) Siu, T.; Yudin, A. K. J. Am. Chem. Soc.
2002, 124, 530. (b) Li, J.; Liang, J.-L.; Hong Chan, P. W.; Che, C.-M.
Tetrahedron Lett. 2004, 45, 2685. (c) Li, J.; Chan, P. W. H.; Che,
C.-M. Org. Lett. 2005, 7, 5801. (d) Shen, Y.-M.; Zhao, M.-X.; Xu, J.;
Shi, Y. Angew. Chem., Int. Ed. 2006, 45, 8005. (e) Krasnova, L. B.;
Yudin, A. K. Org. Lett. 2006, 8, 2011. (f) Richardson, R. D.; Desaize,
M.; Wirth, T. Chem.;Eur. J. 2007, 13, 6745. (g) Yoshimura, A.;
Middleton, K. R.; Zhu, C.; Nemykin, V. N.; Zhdankin, V. V. Angew.
Chem., Int. Ed. 2012, 51, 8059.
(1) (a) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.;
Wiley-VCH: Weinheim, Germany, 2006. (b) McCoull, W.; Davis, F. A.
Synthesis 2000, 1347. (c) Cardillo, G.; Gentilucci, L.; Tolomelli, A.
Aldrichimica Acta 2003, 36, 39. (d) Shipman, M. Synlett 2006, 3205. (e)
Hou, X. L.; Wu, J.; Fan, R. H.; Ding, C. H.; Luo, Z. B.; Dai, L. X.
Synlett 2006, 181. (f) Hodgson, D. M.; Bray, C. D.; Humphreys, P. G.
Synlett 2006, 1. (g) Ismail, F. M. D.; Levitsky, D. O.; Dembitsky, V. M.
Eur. J. Med. Chem. 2009, 44, 3373.
(2) Minakata, S.; Takeda, Y.; Kiyokawa, K. In Methods and Applica-
tions of Cycloaddition Reactions in Organic Syntheses; Nishiwaki, N., Ed.;
Wiley-VCH: Weinheim, Germany, Chapter 2; ISBN 978-1-118-29988-3.
€
(3) For selected reviews, see: (a) Muller, P.; Fruit, C. Chem. Rev.
2003, 103, 2905. (b) Singh, G. S.; D’hooghe, M.; De Kimpe, N. Chem.
Rev. 2007, 107, 2080. (c) Driver, T. G. Org. Biomol. Chem. 2010, 8, 3831.
(d) Chang, J. W. W.; Ton, T. M. U.; Chan, P. W. H. Chem. Rec. 2011, 11,
331. (e) Jenkins, D. M. Synlett 2012, 1267.
r
10.1021/ol402276f
XXXX American Chemical Society

economical, and environmental points of view.5ꢀ9 How-
ever, to the best of our knowledge, aziridination using
iminoiodinanes under metal-free conditions, which would
be highly desirable, has not been developed, although the
direct amidation of a CꢀH bond in the presence of an I2
catalyst has been achieved.10 Herein, we report on the
metal-free catalytic aziridination of styrene derivatives
using an equimolar amount of PhI=NTs in the presence
of I2 and tetrabutylammonium iodide (TBAI). Although
the aziridination of alkenes generally requires an excess
amount of either the alkene or the nitrogen source to
produce a satisfactory yield, this is not needed in this
protocol.
Table 1. Screening of Additivesa
entry
additive
none
yield (%)b
1
55
2
Bu4NI
Bu4NI
BnEt3NI
Et4NI
94 (93)c
<5
3d
4
94
5
90
Previously, our group reported on the catalytic aziridi-
nation of alkenes withchloramine-T in the presence of I2.6b
On the basis of the conditions in that report, we first
examined the addition of 10 mol % of I2 in the reaction
of styrene (1 equiv) with PhI=NTs (1 equiv) in acetoni-
trile at room temperature, to produce the corresponding
aziridine 2a in moderate yield (Table 1, entry 1). During
further investigations of the catalytic system, we were
pleased to find that the use of TBAI (5 mol %) in com-
bination with I2 (10 mol %) resulted in a dramatically
increased yield of 2a up to 94% (Table 1, entry 2). Only a
trace amount of 2a was produced in the absence of I2
(Table 1, entry 3), suggesting that I2 plays a critical role in
the aziridination reaction. Other ammonium iodides, such
as BnEt3NI, Et4NI, and Me4NI in addition to TBAI, were
also highly effective (Table 1, entries 4ꢀ6). The use of
TBABr gave 2a in 85% yield, while TBACl, TBABF4, and
TBABPh4 inhibited the reactions (Table 1, entries 7ꢀ10).
Employing alkali metal iodides (LiI, NaI, and KI) instead
of ammonium salts resulted in slightly lower yields com-
pared to reactions using TBAI (Table 1, entries 11ꢀ13).
When the reaction was conducted in the presence of
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), a radical
inhibitor, the yield of the product was greatly depressed
(Table 1, entry 14). Furthermore, when the reaction was
run in the dark, it was suppressed (Table 1, entry 15). These
results indicate that the reaction involves a radical pathway
that is promoted by visible light (ambient laboratory light).
With the optimal conditions in hand, we next investi-
gated the scope of alkenes in metal-free aziridination
(Table 2). Styrene derivatives bearing various types of
functional groups at the para position were suitable
substrates (Table 2, entries 1ꢀ9).11 It is noteworthy that
electron-deficient styrenes as well as electron-rich deriva-
tives could also be used in the reaction. Substituents at
the ortho or meta position on the phenyl ring had a
6
Me4NI
Bu4NBr
Bu4NCl
Bu4NBF4
Bu4NBPh4
LiI
94
7
85
8
17
9
21
10
11
12
13
14e
15f
<5
85
NaI
89
KI
89
Bu4NI
Bu4NI
<5
61
a Reaction conditions: styrene (0.5 mmol), PhI=NTs (0.5 mmol), I2
(0.05 mmol), additive (0.025 mmol), MeCN (2 mL), rt, 3 h. b Yields of
crude products determined by 1H NMR analysis. c Isolated yield. d I2
was not added. e TEMPO (1 equiv) was added. f The reaction was carried
out in the dark.
negligible effect on reactivity (Table 2, entries 10 and 11).
R-Methylstyrene (1m) was also applicable (Table 2,
entry 12).11 Cyclic alkenes such as indene (1n) and 1,2-
dihydronaphthalene (1o) provided the corresponding azir-
idines selectively without amidation of the CꢀH bond
at the secondary benzylic position (Table 2, entries 13
and 14).10 Disappointingly, a very low yield was obtained
when an aliphatic alkene was used in the reaction (Table 2,
entry 15).
Interestingly, in the reaction of C60 with PhI=NTs in
o-dichlorobenzene (o-DCB), the azafulleroid 3 was the
major product, rather than the aziridinofullerene 4
(37% yield (combined isolated yield of 3 and 4), 69%
selectivity),12,13 which is contrary to the result when a
copper catalyst is used, in which 4 is produced selectively
(Scheme 1).14 Furthermore, the yield and selectivity were
similar, evenwhenTBAI was notemployed in the reaction.
The reactions of cis- and trans-disubstituted alkenes
1p and 1q gave insights into the stereochemistry of the
aziridination reaction (Table 3). The reaction of trans-
β-methylstyrene (trans-1p) provided the corresponding
aziridine 2p in 89% overall yield in a cis/trans ratio of
39:61 (Table 3, entry 1). No isomerization of either the
starting alkene (trans-1p) or the aziridine product (trans-2p)
was observed with the I2/TBAI catalyst in acetonitrile
(8) For selected examples of metal-free aziridinations using amides,
see: (a) Minakata, S.; Morino, Y.; Oderaotoshi, Y.; Komatsu, M. Chem.
Commun. 2006, 3337. (b) Fan, R.; Pu, D.; Gan, J.; Wang, B. Tetrahedron
Lett. 2008, 49, 4925. (c) Deiana, L.; Zhao, G.-L.; Lin, S.; Dziedzic, P.;
ꢀ
Zhang, Q.; Leijonmarck, H.; Cordova, A. Adv. Synth. Catal. 2010, 352,
3201.
(9) For an example of metal-free aziridination using ammonia, see:
Varszegi, C.; Ernst, M.; van Laar, F.; Sels, B. F.; Schwab, E.; De Vos,
D. E. Angew. Chem., Int. Ed. 2008, 47, 1477.
(10) Lamar, A. A.; Nicholas, K. M. J. Org. Chem. 2010, 75, 7644.
(11) Products 2b and 2m were unstable and partially decomposed
during their isolation by column chromatography using silica gel.
(12) The term “selectivity” is defined using the following equation:
selectivity = [yield of product]/[conversion of C60] ꢁ 100.
(13) Nagamachi, T.; Takeda, Y.; Nakayama, K.; Minakata, S.
Chem.;Eur. J. 2012, 18, 12035.
(14) Nambo, M.; Segawa, Y.; Itami, K. J. Am. Chem. Soc. 2011, 133,
2402.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Scope of Alkenesa
Table 3. Reactions of cis and trans-Disubstituted Alkenesa
a Reaction conditions: alkenes (0.5 mmol), PhI=NTs (0.5 mmol), I2
(0.05 mmol), TBAI (0.025 mmol), MeCN (2 mL), rt, 3 h. b Determined
by 1H NMR analysis of crude products. c Isolated yields.
To investigate the active species of the reaction, the
reaction was run using a mixture of PhI=NTs and an
equimolar amount of I2 in [D3]acetonitrile and was mon-
itored by NMR spectroscopy. In the 13C NMR spectrum
of the mixture, characteristic signals (δ(13C) = 145.6,
130.5, 130.4, 128.6, and 21.6 ppm), indicating the genera-
tion of N,N-diiodotosylamide 5 or its oligomeric species,10
were observed along with signals corresponding to iodo-
benzene (Scheme 2) (see the Supporting Information for
details). Amide 5, which acts as an amidyl radical pre-
cursor,10,12 is considered to be the active species in the
aziridination.
a Reaction conditions: alkene (0.5 mmol), PhI=NTs (0.5 mmol), I2
(0.05 mmol), TBAI (0.025 mmol), MeCN (2 mL), rt, 3 h. b Isolated
yields. c Yields of crude products determined by 1H NMR analysis. d I2
(20 mol %) and TBAI (10 mol %) were used.
Scheme 2. Reaction of PhI=NTs with I2 in Acetonitrile
Scheme 1. Reaction of C60 with PhI=NTs
It is known that ammonium tri-iodide (TBAI3) is in
equilibrium with I2 and TBAI in acetonitrile (eq 1), and tri-
iodide (I3ꢀ) is excited by a visible light togenerate an iodine
radical (I•) and an iodine radical anion (I2ꢀ•) (eq 2).16
However, to the best of our knowledge, the application
of such a system for organic synthesis has not been
reported.17 We speculated that TBAI3 would be generated
in situ from I2 and TBAI and then functions as a radical
promoter in the aziridination reaction. To confirm this
hypothesis, control experiments were conducted, as shown
in Scheme 3. Although the aziridine 2a was obtained in
94% yield under the standard conditions (Table 1, entry 2),
(see the Supporting Information for details). These results
strongly suggest that the aziridination proceeds via a
stepwise process, in which the stereochemistry of the
starting alkene is lost. Similarly, starting from the cis
isomer 1p, 2p was obtained in 92% yield as a mixture of
cis/trans isomers (Table 3, entry 2). Furthermore, in the
case of stilbene (trans-1q and cis-1q), the reactions also
proceeded in a nonstereospecific manner (Table 3, entries 3
and 4), consistent with a stepwise process.15
(16) (a) Gardner, J. M.; Abrahamsson, M.; Farnum, B. H.; Meyer,
G. J. J. Am. Chem. Soc. 2009, 131, 16206. (b) Boschloo, G.; Hagfeldt, A.
Acc. Chem. Res. 2009, 42, 1819.
(15) When the reaction of an aliphatic alkene, trans-3-hexene, was
conducted under optimized conditions (see, Table 1, entry 2), the
corresponding aziridine was obtained with a cis/trans ratio of 36:64 in
5% yield, as determined by 1H NMR analysis of the crude product.
(17) The reaction using tri-iodide (I3ꢀ) generated in situ from Cu-
(ClO4)2 and NaI as an electrophile has been reported; see: Brotherton,
W. S.; Clark, R. J.; Zhu, L. J. Org. Chem. 2012, 77, 6443.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Control Experiments Using TBAI or TBAI3
Scheme 4. Plausible Mechanism
where PhI=NTs and styrene (1a) were added to a mixture
of I2 and TBAI in acetonitrile, when PhI=NTs and I2 were
mixed in advance of the addition of TBAI and 1a, the
reaction was suppressed, and 2awas producedin only 29%
yield (Scheme 3, method a). In contrast, the use of TBAI3
instead of TBAI afforded 2a in 87% yield (Scheme 3,
method b), similar to the yield under the optimized condi-
tions describedabove, clearly showing thatTBAI3 played a
significant role in promoting the reaction. In the case of
method a, the rapid and complete consumption of I2 in the
initial reactionwithPhI=NTs, toprovide the diiodoamide
5, would inhibit the generation of TBAI3.
regeneration of I2. An alternative pathway is also possible,
in which I• participates in the NꢀI bond cleavage of 5 to
give 6 and I2, and I2ꢀ• reacts with 7 instead, affording 2 and
the tri-iodide (TBAI3).18 It is interesting to note that TBAI
appears to function as a precursor for TBAI3 rather than
as a phase-transfer catalyst.6c,e,f
In conclusion, the novel metal-free aziridination of sty-
rene derivatives with PhI=NTs has been developed by
employing a I2/TBAI catalyst system. Various functional
groups were compatible with this catalytic system. The
aziridination proceeds via a radical mechanism, where in
situ generated TBAI3 dramatically promotes the reaction
of alkenes with N,N-diiodotosylamide, which is formed in
situ. Further investigations of the mechanism and the
application of the procedure to organic synthesis including
enantioselective reactions are currently in progress.
Bu4NI þ I2 a Bu4NI3
ð1Þ
ð2Þ
visible light
ꢀ
•
ꢀ•
2
I3ꢀ
[I ] f I þ I
ꢂ
f
3
On the basis of the above experiments, a plausible
reaction mechanism for the radical aziridination is shown
in Scheme 4. Initially, PhI=NTs reacts with I2, providing
N,N-diiodotosylamide 5 (or its oligomeric species). Simul-
taneously, TBAI3, generated in situ from I2 and TBAI,ꢀis•
excited by visible light to provide I• and I2ꢀ•. When I2
promotes the homolytic cleavage of the NꢀI bond of 5
via the abstraction of an iodine atom, the amidyl radical
6 is generated along with the regeneration of tri-iodide
(TBAI3). The amidyl radical 6 is rapidly trapped by the
alkene 1, followed by the intramolecular cyclization of
7 assisted by I• to furnish the aziridine product 2 with
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research (Nos. 25288047 and 24850011)
from the Ministry of Education, Culture, Sports, Science,
and Technology (MEXT), Japan.
Supporting Information Available. Experimental de-
tails and spectra data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(18) A mechanism involving a single-electron transfer between I• (or
I2ꢀ•) and 5, leading to 6 with I2 (or I3ꢀ), cannot be ruled out, based on the
available data.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX