Notable coordination effects of 2-pyridinesulfonamides leading to efficient aziridination and selective aziridine ring opening

Article abstract of DOI:10.1021/ol0481784

(Chemical Equation Presented) We have developed, on the basis of a chelation-strategy, an efficient copper-catalyzed aziridination protocol with the use of 5-methyl-2-pyridinesulfonamide and Phl(OAc)₂. The reaction proceeds smoothly under mild conditions to give aziridines in moderate to good yields in the absence of external ligands or bases. The coordination-assisted approach offers the additional benefits that efficient deprotection of the N-substituent and selective aziridine ring-opening are effectively achieved.

Full text of DOI:10.1021/ol0481784

ORGANIC
LETTERS
2004
Vol. 6, No. 22
4109-4112
Notable Coordination Effects of
2-Pyridinesulfonamides Leading to
Efficient Aziridination and Selective
Aziridine Ring Opening
Hoon Han, Imhyuck Bae, Eun Jeong Yoo, Junseong Lee, Youngkyu Do, and
Sukbok Chang*
Center for Molecular Design and Synthesis, Department of Chemistry and School of
Molecular Science (BK21), Korea AdVanced Institute of Science and Technology
(KAIST), Daejon 305-701, Republic of Korea
sbchang@kaist.ac.kr
Received September 9, 2004
ABSTRACT
We have developed, on the basis of a chelation-strategy, an efficient copper-catalyzed aziridination protocol with the use of 5-methyl-2-
pyridinesulfonamide and PhI(OAc)2. The reaction proceeds smoothly under mild conditions to give aziridines in moderate to good yields in the
absence of external ligands or bases. The coordination-assisted approach offers the additional benefits that efficient deprotection of the
N-substituent and selective aziridine ring-opening are effectively achieved.
Setting a properly chosen directing group in an appropriate
position influences reaction pathways significantly leading
to noticeable changes in efficiency and selectivity.1 Recently,
the 2-pyridyl group has drawn much attention as an efficient
directing group, and intensive research has been undertaken
to utilize the coordination-assisted approach with the moiety,
making a large number of synthetically useful organic
transformations possible.2 Aziridines are important building
blocks in organic synthesis, and they are also responsible
for diverse biological activities in natural products. This has
stimulated the development of numerous preparative proce-
dures of aziridines either by conventional synthesis or by
catalytic routes.3 Despite remarkable advances in the metal-
catalyzed addition of nitrene derivatives to alkenes, which
would be one of the most attractive aziridination routes,4,5
some challenges still remain. For example, available nitrene
sources in the catalytic reactions are rather limited, and
N-tosyliminophenyliodinane (TsNdIPh) has been employed
in most cases, which is an unstable and capricious compound
being prepared via two steps. Efficient deprotection and
selective ring-opening of N-tosyl aziridines consist of ad-
ditional formidable tasks to be improved. Changes in the
steric and electronic properties of nitrene source have been
proposed as one of the feasible breakthrough of these
limitations.6 Described herein are our recent findings that a
practical protocol of aziridination, efficient deprotection, and
(4) For selected examples of Cu-catalyzed aziridination, see: (a) Evans,
D. A.; Faul, M. M.; Bilodeau, M. T. J. Org. Chem. 1991, 56, 6744. (b) Li,
Z.; Conser, K. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1993, 115, 5326. (c)
Dauban, P.; Sanie`re, L.; Tarrade, A.; Dodd, R. H. J. Am. Chem. Soc. 2001,
123, 7707.
(5) For some examples of aziridination methods catalyzed by other metals
than copper: (a) Au, S.-M.; Huang, J.-S.; Yu, W.-Y.; Fung, W.-H.; Che,
C. M. J. Am. Chem. Soc. 1999, 121, 9120. (b) Guthikonda, K.; Du Bois, J.
J. Am. Chem. Soc. 2002, 124, 13672. (c) Liang, J.-L.; Yuan, S.-X.; Chan,
P. W. H.; Che, C.-M. Org. Lett. 2002, 4, 4507. (d) Cui, Y.; He, C. J. Am.
Chem. Soc. 2003, 125, 16202.
(1) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.
(2) (a) Jun, C.-H.; Hong, J.-B.; Lee, D.-Y. Synlett 1999, 1. (b) Itami,
K.; Mitsudo, K.; Nokami, T.; Kamei, T.; Koike, T.; Yoshida, J. J.
Organomet. Chem. 2002, 653, 105. (c) Kakiuchi, F.; Chanati, N. AdV. Synth.
Catal. 2003, 345, 1077.
(3) For recent reviews, see: (a) Sweeney, J. B. Chem. Soc. ReV. 2002,
31, 247. (b) Mu¨ller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905. (c) Dauban,
P.; Dodd, R. H. Synlett 2003, 1571-1586.
10.1021/ol0481784 CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/30/2004

Table 1. Aziridination of Styrene with Various Sulfonamides
Table 2. Aziridination of Styrene with Various Metal Catalysts
entry
R
X
Y
yielda (%)
entry
catalyst
Cu(OTf)2
Cu(OTf)‚PhH
CuBr‚(CH3)2S
Cu(CH3CN)4PF6
CuCl2
CuBr
CuI
Cu(acac)2
Cu(tfac)2
yielda (%)
1
2
3
4
5
6
7
H
N
N
N
CH
CH
CH
N
SO2
SO2
SO2
SO2
SO2
CO
76
84
1
2
3
4
5
6
7
8
9
71
66
8
58
10
6
trace
78
84
5-Me
6-Me
4-Me
H
73b
NRc
15
NRc
NRc
H
H
CO
a NMR yield. b 3.0 equiv of styrene was used. c NR ) no reaction.
10
11
12
13
14
15
16
17
18
Cu((hfac)2‚H2O
Cu(OAc)
Cu(OAc)2
48
10
5
63b
NRc
NRc
NRc
NRc
NRc
selective aziridine ring-opening were achieved on the basis
of a chelation strategy.7
[Rh(OAc)2]2
RuCl2(CO)2(PPh3)2
d
At the outset of our studies, we intended to develop a
practical aziridination system by using readily available
sulfonamides or amides as a nitrogen source in combination
with an easily handled oxidant such as PhI(OAc)2 for the
generation of nitrene precursor that is catalytically transferred
to alkenes (Table 1). In initial experiments with styrene, it
was found that certain copper complexes effectively cata-
lyzed the aziridination when 2-pyridinesulfonamides (X )
N, Y ) SO2) were employed in combination with PhI(OAc)2
alone in the absence of any external ligands or bases (entry
1). Introduction of a methyl group at the C5 position slightly
improved reaction efficiency to afford the corresponding
aziridine in the highest yield (entry 2). Interestingly, use of
6-methyl-2-pyridinesulfonamide gave less satisfactory results
even under more forcing conditions (3.0 equiv of styrene,
entry 3). On the other hand, aziridination reaction of styrene
with p-toluenesulfonamide (R ) 4-Me, X ) CH, Y ) SO2)
or benzenesulfonamide (R ) H, X ) CH, Y ) SO2) turned
out to be sluggish under the employed conditions (entry 4
and 5, respectively), thus strongly implying that a driVing
force for the reaction is the coordination of Cu to the pyridyl
N atom of 2-pyridinesulfonamides. During preparation of this
manuscript, Che et al. reported that addition of external
ligands is highly important for giving high efficiency and
enantioselectivity in Cu(CH3CN)4ClO4-catalyzed aziridina-
tion of olefins using sulfonamides and PhI(OAc)2 systems.8
In the meantime, carboxamides turned out to be poor nitrene
donors under the present catalyst systems (entries 6 and 7).
Efficiency of catalysts was next investigated in the
aziridination of styrene with the use of 5-methyl-2-pyridine-
sulfonamide (1) and PhI(OAc)2 system (Table 2, R: 5-meth-
d
Ru(acac)3
CpRu(PPh3)2Cld
d
RuCl3
RuCl2(C10H8N2)2‚2H2Od
a NMR yield. b 10 equiv of styrene was used. c NR ) no reaction. d 10
mol % of catalyst was employed.
yl-2-pyridinesulfonyl). It was immediately found that certain
Cu complexes showed higher catalytic activities compared
to other transition-metal species which exhibited either lower
or almost no reactivities. Among Cu catalysts tested, copper-
(II) trifluoroacetylacetonate yielded the best results (entry
9).
Table 3 shows results of the coordination-assisted aziri-
dination of a range of olefins with sulfonamide 1 under the
optimized conditions (R: 5-methyl-2-pyridinesulfonyl). Aro-
matic olefins were smoothly reacted irrespective of their
electronic and steric properties to afford the corresponding
aziridines in good yields (entries 1-8). Interestingly, a ring-
opened compound was isolated from the reaction with O-silyl
styrene (entry 9), which was presumably derived by a
subsequent reaction of aziridine with acetate released from
the oxidant, PhI(OAc)2. While a reaction of trans-â-
methylstyrene afforded only E-aziridine, that of cis-olefin
took place nonstereoselectively so that a mixture of cis/trans-
isomeric products were generated (entries 11 and 12). This
strongly suggests that the nitrene-transfer process in our
system proceeds stepwise via a radical pathway.9
Aliphatic olefins were rather less reactive so the corre-
sponding aziridines were obtained in moderate yields under
more forcing conditions (entries 13 and 14). In the case of
norbornene, only exo-aziridine was produced, confirmed by
a single-crystal X-ray diffraction study (Figure 1).10 Intrigu-
(6) (a) So¨dergren, M. J.; Alonso, D. A.; Bedekar, A. V.; Andersson, P.
G. Tetrahedron Lett. 1997, 38, 6897. (b) Dauban, P.; Dodd, R. H. J. Org.
Chem. 1999, 64, 5304.
(7) Recent reports from this laboratory regarding on the chelation
approach: (a) Ko, S.; Na, Y.; Chang, S. J. Am. Chem. Soc. 2002, 124, 750.
(b) Ko, S.; Lee, C.; Choi, M.-G.; Na, Y.; Chang, S. J. Org. Chem. 2003,
68, 1607. (c) Ko, S.; Han, H.; Chang, S. Org. Lett. 2003, 5, 2687. (d) Na,
Y.; Ko, S.; Hwang, L. K. Tetrahedron Lett. 2003, 44, 4475.
(8) Kwong, H.-L.; Liu, D.; Chan, K.-Y.; Lee, C.-S.; Huang, K.-H.; Che,
C.-M. Tetrahedron Lett. 2004, 45, 3965.
(9) For mechanistic studies in Cu-catalyzed aziridination, see: (a) Evans,
D. A.; Faul, M. M.; Bilodeau, M. T. J. Am. Chem. Soc. 1994, 116, 2742.
(b) Li, Z.; Quan, R. W.; Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117,
5889. (b) Brandt, P.; So¨dergren, M. J.; Andersson, P. G.; Norrby, P.-O. J.
Am. Chem. Soc. 2000, 122, 8013.
4110
Org. Lett., Vol. 6, No. 22, 2004

Scheme 1. Proposed Pathway for the Aziridination Using 1
Table 3. Coordination-Assisted Aziridination of Various
Olefins
and PhI(OAc)2
mentioned that the aziridination procedure developed herein
is highly flexible and practical so that a large-scale process
is readily operational. For example, reaction of styrene in
gram scale (12 mmol, 1.2 equiv to sulfonamide 1) proceeded
smoothly, giving the aziridine (2.2 g, 81%) using 3.0 mol
% of Cu(tfac)2.10
Although the involvement of a metallonitrene intermediate
is now well accepted in the catalytic aziridination,9 the direct
experimental evidence for active species is limited. On the
basis of the results obtained from Table 1, it might be
anticipated that the presence of 2-pyridyl group coordinated
to copper would stabilize the speculative nitrene intermedi-
ates represented as 2 (Scheme 1).
Nucleophilic ring opening of aziridines is of great interest
in that it furnishes a broad range of amine functionalities.11
While reaction of N-tosylphenylaziridine 3 with in situ
generated methyl cuprate exhibited poor selectivity favoring
at less hindered 3-position (5a/5b, 1:2), consistent with the
literature (Scheme 2),12 a completely reVersed regioselectiVity
Scheme 2. Stereoselective Ring Opening and Deprotection
a Isolated yield. b 5.0 equiv of olefin was used. c Run at 40 °C.
d Cu(CH3CN)4PF6 was employed as a catalyst.
ingly, Cu(I) catalyst was found to be marginally superior to
Cu(II) catalyst in the reaction of cyclooctene. It should be
was obserVed from the reaction of aziridine 4 bearing the
N-pyridine sulfonyl group. The preferential opening at C2
(6a/6b, 5:1) of 4 could be attributed to a pre-coordination
of cuprate complex to the pyridyl nitrogen atom followed
by the transfer of a methyl group into more electrophilic
benzylic position via intramolecular manner. At the present
stage, however, other possibilities than chelation effects that
govern the observed regioselectivity in the aziridine ring-
opening reaction still remain to be elucidated.
(10) For details, see the Supporting Information.
(11) For a review, see: Hu, X. E. Tetrahedron 2004, 60, 2701.
(12) Kozikowski, A. P.; Ishida, H.; Isobe, K. J. Org. Chem. 1979, 44,
2788.
Figure 1. X-ray structure of N-(5-methyl-2-pyridinesulfonyl)-
norbonylaziridine.
Org. Lett., Vol. 6, No. 22, 2004
4111

Deprotection of the N-pyridinesulfonyl group from both
aziridine 4 and ring-opened moieties 6a/6b were readily
achieved using magnesium in methanol.13 This mild and
efficient reductive deprotection is likely related to its lower
LUMO energy level of the pyridinesulfonyl group compared
to toluenesulfonyl group.14 It should be addressed that
removal of the N-toluenesulfonyl group from N-tosylaziri-
dines is not so easy up to date that it is regarded as a major
drawback with these most frequently studied aziridines.15
Therefore, the observed rather mild and facile deprotection
procedure from the N-pyridinesulfonyl adducts demonstrates
an additional significant advantage of pyridinesulfonyl
moiety facilitated herein.
based on the chelation-approach for the first time, which also
allows mild and selective deprotection as well as aziridine
ring-opening.
Acknowledgment. This research was supported by KO-
SEF (R02-2003-000-10075-0) through the Basic Research
Program.
Supporting Information Available: Spectral data and
copies of 1H and 13C NMR spectra for new compounds and
crystallographic data for compound N-(5-methyl-2-pyridine-
sulfonyl)norbonyl aziridine (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have developed an efficient, practical,
and external ligand-free Cu-catalyzed aziridination protocol
OL0481784
(15) In fact, the desulfonylation from 3 and 5a/5b was incomplete and
nonselective under the same conditions as for 4 and 6a/6b. For a relevant
method of deprotection of N-tosyl group from aziridines, see: Alonso, D.
A.; Andersson, P. G. J. Org. Chem. 1998, 63, 9455.
(13) Pak, C. S.; Lim, D. S. Synth. Commun. 2001, 31, 2209.
(14) Maze´as, D.; Skrydstrup, T.; Doumeix, O.; Beau, J. M. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1383 and references therein.
4112
Org. Lett., Vol. 6, No. 22, 2004