An efficient ring-opening reaction of aziridines with alkynes catalyzed by CuOTf

Article abstract of DOI:10.1055/s-2004-829551

The alkynylation of activated aziridines in the presence of a catalytic amount of CuOTf provided the corresponding ring-opened products in high yields.

Full text of DOI:10.1055/s-2004-829551

LETTER
1691
An Efficient Ring-Opening Reaction of Aziridines with Alkynes Catalyzed by
CuOTf
b
a
a,b
A
C
n
Efficient Ring
h
-Opening
R
a
eaction of
A
n
ziridines wi
g
th
A
lkyne
s
-Hua Ding, Li-Xin Dai, Xue-Long Hou*
a
State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
b
354 Fenglin Road, Shanghai 200032, China
E-mail: xlhou@mail.sioc.ac.cn
Received 9 April 2004
Cu(OTf) , AgOAc or CuClO (entry 2–8) and correspond-
2
4
Abstract: The alkynylation of activated aziridines in the presence
of a catalytic amount of CuOTf provided the corresponding ring-
opened products in high yields.
ing homopropargyl amine was obtained in 96% yield (en-
try 2). Control experiment showed that the yield of the
product decreased to 20% in the absence of Lewis acid
Key words: aziridines, alkynylation, Lewis acids, copper(I) tri-
flate, ring-opening reaction
(
entry 10). The amount of n-BuLi was important for the
reaction and two equivalents of BuLi were necessary.
When the amount of n-BuLi was reduced to 1.0 equiva-
lent, the yield dropped sharply (entry 7 vs. 9). If more than
two equivalents of BuLi was used, the result was same as
that using two equivalents of BuLi. However, the reason
is unknown at the moment.
Aziridines are widely used as intermediates in organic
synthesis. Their synthetic utilities are mainly owing to
1
their ability to undergo regioselective ring-opening reac-
tions with various nucleophiles. However, the most often
2
3
4
used reagents are those O-, S- and N- nucleophiles and
a few examples were reported using carbon nucleophiles,
such as Grignard reagents, organolithiums, Wittig re-
agents, cuprates and malonates, in the ring-opening reac-
Table 1 Ring-Opening Reaction of Aziridine 1a with Phenylacety-
lene under Various Reaction Conditionsa
Entry
Solvent
THF
Lewis acid
Time (h)
46
Yield (%)b
5
tion of aziridines. In addition, there was structural
CuOTf c
1
2
3d
4
5
6
7
26
96
20
25
58
64
64
18
25
20
limitation when alkynyllithiums were the reagents, only
aziridines derived from acyclic alkenes gave good re-
Et O
CuOTf
45
2
6
sults. As a program aimed at the applications of aziri-
Et O
BF ·OEt
72
2
3
2
7
dines in organic synthesis, we explored the use of alkynes
as nucleophile in the ring-opening reaction of aziridines
and found that CuOTf is an effective catalyst in the alky-
nylation of aziridines. Herein, we would like to report our
preliminary results of Cu-catalyzed alkynylation of aziri-
dines.
Et
2
O
In(OTf)
3
72
Et O
Cu(OTf)2
AgOAc
CuClO4
46
2
Et O
46
2
Et O
45
2
Initially, phenylacetylene was added to a solution of n-
BuLi in n-hexane at –78 °C and the mixture was stirred for
8
Et O
Sc(OTf)3
24
2
3
0 minutes at the same temperature. Then aziridine 1a, 10
9e
Et O
CuClO4
43
2
mol% of Lewis acid in solvent were added (Equation 1).
1
0
Et O
–
45
As shown in Table 1, Et O was a better solvent than THF
2
2
(
entries 1 and 2). CuOTf was the best catalyst among the
a
Phenylacetylene:n-BuLi:aziridine:Lewis acid = 2:2:1:0.1.
Isolated yield based on aziridine.
b
c
d
e
tested Lewis acids such as Sc(OTf) , BF ·OEt , In(OTf) ,
3
3
2
3
CuOTf was used as (CuOTf) ·C H , as purchased.
2
6
6
1
.0 Equivalent of BF ·OEt was used.
3 2
Phenylacetylene:n-BuLi:aziridine:Lewis acid = 1.1:1.1:1:0.1.
NTs
NHTs
n-BuLi
1
a
To show the usefulness of this CuOTf-catalyzed ring-
opening reaction of aziridines, a variety of alkynes and
Ph
H
Solvent
Lewis acid
r.t.
–78 °C
various aziridines were tested (Equation 2) and the results
2a
Ph
are shown in Table 2.8
Equation 1
It can be seen from Table 2 that various aziridines with an
electro-withdrawing group at nitrogen atom and several
alkynes are suitable for this CuOTf-catalyzed reaction to
afford the corresponding ring-opening products in good to
excellent yields. The reactivity of aziridines derived from
SYNLETT 2004, No. 10, pp 1691–1694
0
9
.0
8
.2
0
0
4
Advanced online publication: 15.07.2004
DOI: 10.1055/s-2004-829551; Art ID: U10404ST
Georg Thieme Verlag Stuttgart · New York
©

1
692
C.-H. Ding et al.
LETTER
R1
constant of 2a (J = 9.9 Hz for two cyclic methine hydro-
gens at the trans-positions, entries 1–4). For aziridines de-
rived from terminal alkenes only terminal-attacked
products were obtained because of steric hindrance of the
alkyl substituent (entries 5–10) and for phenyl substituted
aziridine 1h, the reaction gave two products resulting
from internal as well as terminal attack of the nucleophile
NTs
n-BuLi (2.0 equiv)
R2
R
H
Et2O, –78 °C
CuOTf (0.1 equiv)
r.t.
30 min
R2
R1
NHTs
R1
NHTs
(
entry 11).
+
R2
In conclusion, a simple and convenient procedure using a
variety of alkynes as nucleophile in the ring-opening reac-
tion of aziridines was developed. Homopropargyl amines
were provided in high yields. The investigations on the
extension of the reaction to other substrates and on the
asymmetric version of the reaction are under progress in
our laboratory.
R
R
Equation 2
cycloalkenes was lower than that from acyclic alkenes but
good to excellent yields could be obtained with longer
reaction time (entry 1 vs. 5). Aromatic alkyne had higher
reactivity than aliphatic alkyne (entry 8 vs. 10). All of the
reactions with bicyclic aziridines gave products with anti-
stereochemistry, which were confirmed by the coupling
Table 2 Ring-Opening Reaction of Aziridines 1 with Alkynes Catalyzed by CuOTfa
Entry
1
Substrate
Alkyne
Product
Time (h)
45
Yield (%)b
96
NHTs
Ph
H
NTs
1
1
a
Ph
2
2
2
a
b
c
2
3
4
Ph
Ph
H
NHTs
72
30
72
71
88
72
NTs
b
Ph
H
NHSO Ph
2
NSO2Ph
1
c
Ph
Me Si
3
H
NHTs
NTs
1
1
a
SiMe3
2
2
aa
5
6
Ph
H
H
Ph
26
48
95
42
NTs
d
NHTs
Ph
d
Ph
NTs
NHTs
1e
2
e
Synlett 2004, No. 10, 1691–1694 © Thieme Stuttgart · New York

LETTER
An Efficient Ring-Opening Reaction of Aziridines with Alkynes
1693
a
Table 2 Ring-Opening Reaction of Aziridines 1 with Alkynes Catalyzed by CuOTf (continued)
Entry
7
Substrate
Alkyne
Product
Time (h)
20
Yield (%)b
93
Ph
H
Ph
NTs
n-C6H13
1f
n-C6H13
NHTs
2
f
8
9
Ph
H
Ph
20
45
80
36
91
80
81
69
NTs
NTs
NTs
n-C16H33
1g
n-C16H33
NHTs
2
g
Me Si
3
H
SiMe3
n-C6H13
1f
n-C6H13
NHTs
2
fa
1
1
0
n-C H9
H
nC H
4 9
4
n-C6H13
1f
n-C6H13
NHTs
Ph
2
fb
1c
Ph
H
NTs
Ph
1h
Ph
NHTs
2
h
Ph
Ph
NHTs
3
2
h
h/3h = 3/1
a
b
c
Alkyne:n-BuLi:aziridine:CuOTf = 2:2:1:0.1.
Isolated yield based on aziridine.
1
The ratio of 2h/3h was determined by H NMR.
Acknowledgment
(2) For examples of the reaction of aziridine with alcohols or
phenols see: (a) Jacques, B.; Josette, C. R.; Roger, V.
Synthesis 1992, 288. (b) Bellos, K.; Stamm, H. J. Org.
Chem. 1995, 60, 5661. (c) Wipf, P.; Uto, Y. Tetrahedron
Lett. 1999, 40, 5165. (d) Stamm, H.; Schneider, L. Chem.
Ber. 1974, 107, 2870.
This work was supported by National Natural Science Foundation
of China, the Major Basic Research Development Program (grant
No. G2000077506), National Outstanding Youth Fund and Chinese
Academy of Sciences. CHD gratefully acknowledged Hong Kong
Croucher Foundation for a Studentship.
(
3) For examples of the reaction of aziridine with thiols see:
a) Antolini, L.; Bucciarelli, M.; Caselli, E.; Davoli, P.;
Forni, A.; Moretti, I.; Prati, F.; Torre, G. J. Org. Chem. 1997,
2, 8784. (b) Maligres, P. E.; See, M. M.; Askin, D.; Reider,
(
References
6
P. J. Tetrahedron Lett. 1997, 38, 5253. (c) Bae, J. H.; Shin,
S. H.; Park, C. S.; Lee, W. K. Tetrahedron 1999, 55, 10041.
(
1) (a) McCoull, W.; Davis, F. A. Synthesis 2000, 1347.
(
(
b) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
c) Kump, J. E. G. In Comprehensive Organic Synthesis,
(
d) Katagiri, T.; Takahashi, M.; Fujiwara, Y.; Ihara, H.;
Uneyama, K. J. Org. Chem. 1999, 64, 7323. (e) Wu, J.;
Hou, X. L.; Dai, L. X. J. Chem. Soc., Perkin Trans. 1 2001,
Vol. 7; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford,
991, 467.
1
1314.
Synlett 2004, No. 10, 1691–1694 © Thieme Stuttgart · New York

1
694
C.-H. Ding et al.
LETTER
(
4) For examples of the reaction of aziridine with amines see:
a) Nakajima, K.; Tanaka, T.; Morita, K.; Okawa, K. Bull.
(s, 3 H), 2.41–2.49 (m, 1 H), 3.02–3.12 (m, 1 H), 4.81 (d,
J = 5.4 Hz, 1 H), 7.11 (d, J = 8.1 Hz, 2 H), 7.12–7.29 (m, 5
H), 7.75 (d, J = 8.4 Hz, 2 H).
(
Chem. Soc. Jpn. 1980, 53, 283. (b) Meguro, M.;
Yamamoto, Y. Heterocycles 1996, 43, 2473. (c) Lucet, D.;
Gallo, T. L.; Mioskowski, C. Angew. Chem. Int. Ed. 1998,
N-(2-phenyl-1-ynyl-cyclopentyl)-4-methyl-benzene-
sulfonamide (2b): H NMR: d = 1.45–1.53 (m, 1 H), 1.68–
1
3
6
7, 2580. (d) Sekar, G.; Singh, V. K. J. Org. Chem. 1999,
4, 2537.
1.75 (m, 3 H), 2.04–2.15 (m, 2 H), 2.32 (s, 3 H), 2.69–2.74
(m, 1 H), 3.52–3.56 (m, 1 H), 4.80 (d, J = 6.0 Hz, 1 H), 7.20
(d, J = 8.1 Hz, 2 H), 7.23–7.29 (m, 5 H), 7.78–7.82 (m, 2 H).
N-(2-phenyl-1-ynyl-cyclohexyl)-benzenesulfonamide
(
5) (a) Oppolzer, W.; Flaskamp, E. Helv. Chim. Acta 1977, 60,
204. (b) Osborn, H. M.; Sweeney, J. B.; Howson, B. Synlett
1
1993, 675. (c) Tanner, D.; He, H. M.; Somfai, P.
(2c): H NMR: d = 1.21–1.69 (m, 6 H), 1.99–2.05 (m, 1 H),
Tetrahedron 1992, 48, 6069. (d) Baldwin, J. E.; Adlington,
R. M.; Robinson, N. G. J. Chem. Soc., Chem. Commun.
2.23–2.27 (m, 1 H), 2.42–2.50 (m, 1 H), 3.07–3.13 (m, 1 H),
4.88 (d, J = 5.4 Hz, 1 H), 7.24–7.47 (m, 8 H), 7.87–7.89 (m,
2 H).
1
987, 153. (e) Lygo, B. Synlett 1993, 764. (f) Dubois, L.;
Mehta, A.; Tourette, E. J. Org. Chem. 1994, 59, 434.
g) Bouayed, Z.; Chanet-Ray, J.; Ducher, S.; Vessiere, R. J.
N-(2-trimethylsilanyl-1-ynyl-cyclohexyl)-4-methyl-
1
(
benzenesulfonamide (2aa): H NMR: d = 0.13 (s, 9 H),
Heterocycl. Chem. 1991, 28, 1757. (h) Müller, P.; Nury, P.
Org. Lett. 1999, 1, 439.
6) (a) Gronquist, M. R.; Meinwald, J. J. Org. Chem. 2001, 66,
1.48–1.64 (m, 6 H), 1.89–1.94 (m, 1 H), 2.21–2.33 (m, 2 H),
2.43 (s, 3 H), 2.89–2.94 (m, 1 H), 4.80 (d, J = 3.6 Hz, 1 H),
7.31 (d, J = 8.4 Hz, 2 H), 7.78 (d, J = 8.4 Hz, 2 H).
(
1
075. (b) Rainier, J. D.; Imbriglio, J. E. J. Org. Chem. 2000,
1-Phenyl-4-N-(p-toluenesulfonyl)aminooctyne-1 (2d):
H NMR: d = 0.82 (t, J = 6.6 Hz, 3 H), 1.19–1.25 (m, 4 H),
1
65, 7272. (c) Daub, G. W.; Heering, D. A.; Overman, L. A.
Tetrahedron 1988, 44, 3919. (d) Compain, P.; Goré, J.;
Vatèle, J. M. Tetrahedron 1996, 52, 10405. (e) Church, N.
J.; Young, D. W. Tetrahedron Lett. 1995, 36, 151. (f) Ooi,
T.; Kagoshima, N.; Ichikama, H.; Maruoka, K. J. Am. Chem.
Soc. 1999, 121, 3328. (g) Fuji, K.; Kawabata, T.; Kiryu, Y.;
Sugiura, Y. Heterocycle 1996, 42, 701.
1.56–1.62 (m, 2 H), 2.41 (s, 3 H), 2.48 (d, J = 5.1 Hz, 2 H),
3.36–3.46 (m, 1 H), 4.71 (d, J = 9.3 Hz, 1 H), 7.26–7.37 (m,
7 H), 7.78 (d, J = 8.1 Hz, 2 H).
1-Phenyl-5,5-dimethyl-4-N-(p-toluenesulfonyl)amino-
1
hexyne-1 (2e): H NMR: d = 0.98 (s, 9H), 2.28–2.36 (m,
1H), 2.39 (s, 3H), 2.49-2.56 (m, 1H), 3.16-3.23 (m, 1H), 4.89
(d, J = 10.5 Hz, 1H), 7.24-7.35 (m, 7H), 7.79 (d, J = 8.1 Hz,
2H).
(
7) (a) Li, A. H.; Dai, L. X.; Hou, X. L. Chem. Commun. 1996,
491. (b) Li, A. H.; Dai, L. X.; Hou, X. L.; Chen, M. B. J.
Org. Chem. 1996, 61, 4641. (c) Wang, D. K.; Dai, L. X.;
Hou, X. L. Chem. Commun. 1997, 1231. (d) Li, A. H.;
Zhou, Y. G.; Dai, L. X.; Hou, X. L.; Xia, L. J.; Lin, L.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1317. (e) Hou, X.
L.; Yang, X. F.; Dai, L. X.; Chen, X. F. Chem. Commun.
1-Phenyl-4-N-(p-toluenesulfonyl)aminodecyne-1 (2f):
H NMR: d = 0.85 (t, J = 6.9 Hz, 3 H), 1.17–1.29 (m, 8 H),
1.52–1.62 (m, 2 H), 2.41 (s, 3 H), 2.50 (d, J = 4.8 Hz, 2 H),
3.37–3.45 (m, 1 H), 4.67 (d, J = 9.0 Hz, 1 H), 7.26–7.38 (m,
7 H), 7.78 (d, J = 8.1 Hz, 2 H).
1
1
2
998, 747. (f) Wu, J.; Hou, X. L.; Dai, L. X. J. Org. Chem.
000, 65, 1344. (g) Hou, X. L.; Fan, R. H.; Dai, L. X. J. Org.
1-Phenyl-4-N-(p-toluenesulfonyl)aminoicosyne-1 (2g):
H NMR: d = 0.88 (t, J = 6.6 Hz, 3 H), 1.17–1.30 (m, 28 H),
1.57–1.64 (m, 2 H), 2.41 (s, 3 H), 2.49 (d, J = 4.8 Hz, 2 H),
3.36–3.44 (m, 1 H), 4.65 (d, J = 9.3 Hz, 1 H), 7.26–7.38 (m,
7 H), 7.77–7.79 (m, 2 H).
1
Chem. 2002, 67, 5295. (h) Fan, R. H.; Hou, X. L. J. Org.
Chem. 2003, 68, 726.
(
8) General Experimental Procedure: Alkyne (0.5 mmol) was
added to a mixture of n-BuLi in n-hexane (0.5 mmol) and
1-Trimethylsilanyl-4-N-(p-toluenesulfonyl)amino-
1
Et O (4.0 mL), which was precooled to –78 °C and the
decyne-1 (2fa): H NMR: d = 0.15 (s, 9 H), 0.85 (t, J = 6.9
2
mixture was stirred for 30 min at the same temperature. Then
CuOTf (10 mol%) and aziridine (0.25 mmol) were added.
The resulting mixture was stirred at r.t. until complete
consumption of substrate (monitored by TLC). The reaction
Hz, 3 H), 1.15–1.26 (m, 8 H), 1.88–2.04 (m, 2 H), 2.27–2.31
(m, 2 H), 2.43 (s, 3 H), 3.28–3.33 (m, 1 H), 4.61 (d, J = 9.0
Hz, 1 H), 7.30 (d, J = 7.5 Hz, 2 H), 7.76 (d, J = 8.4 Hz, 2 H).
1
8-N-(p-toluenesulfonyl)aminotetradecyne-5 (2fb): H
mixture was quenched with 5 mL of sat. NH Cl aq solution.
NMR: d = 0.85 (t, J = 6.6 Hz, 3 H), 0.91 (t, J = 7.2 Hz, 3 H),
1.16–1.25 (m, 8 H), 1.38–1.47 (m, 6 H), 2.12–2.16 (m, 2 H),
2.17–2.21 (m, 2 H), 2.43 (s, 3 H), 3.24–3.31 (m, 1 H), 4.63
(d, J = 9.6 Hz, 1 H), 7.29 (d, J = 7.5 Hz, 2 H), 7.75–7.78 (m,
2 H).
4
The aqueous layer was separated and extracted with CH Cl
2
2
(
3 × 10 mL). The combined organic layer was dried over
anhyd Na SO . The solvent was removed in vacuum and the
2
4
crude product was purified by flash column chromatography
on silica gel to provide corresponding homopropargyl
1,4-Diphenyl-4-N-(p-toluenesulfonyl)aminobutyne-1
(2h) and 1,3-Diphenyl-4-N-(p-toluenesulfonyl)amino-
1
amine. All products were fully characterized by H NMR,
1
mass spectrometry, infrared spectrometry and elemental
butyne-1 (3h): (2h/3h = 3:1) H NMR: 2h: d = 2.35 (s, 3 H),
1
analysis. The H NMR spectra of the products are as follows
2.85 (m, 2 H), 4.56 (dd, J = 6.3, 12.8 Hz, 1 H), 5.20 (d,
J = 6.6 Hz, 1 H), 7.12–7.41 (m, 12 H), 7.63 (d, J = 8.4 Hz, 2
H); 3h: d = 2.41 (s, 3 H), 3.21–3.41 (m, 2 H), 3.99 (dd,
J = 6.3, 8.1 Hz, 1 H), 4.72–4.76 (m, 1 H), 7.12–7.41 (m, 12
H), 7.73 (d, J = 8.4 Hz, 2 H).
(
300 MHz, CDCl , 25 °C, TMS):
3
N-(2-Phenyl-1-ynyl-cyclohexyl)-4-methyl-benzene-
1
sulfonamide (2a): H NMR: d = 1.24–1.27 (m, 4 H), 1.46–
1.69 (m, 2 H), 1.99–2.05 (m, 1 H), 2.24–2.28 (m, 1 H), 2.31
Synlett 2004, No. 10, 1691–1694 © Thieme Stuttgart · New York