aldehydes/ketones8,9 and nucleophiles.10 However, the gen-
eration of azomethine ylides via CꢀC heterolysis of azir-
idines has been rarely explored in previous literatures due to
the relatively high barrier (ca. 29 kcal molꢀ1).11 Very
recently, our group has successfully realized the CꢀC bond
cleavage12 of N-tosylarylaziridinyl dicarboxylate13 under
the catalysis of Lewis acid, leading to reactive N-tosylazo-
methine ylide, which can undergo 1,3-dipolar cycloaddition
with aldehydes and electron-rich alkenes. During this study,
we envisaged that electron-rich alkynes may be applied as
dipolarophiles to undergo 1,3-dipolar cycloaddition to af-
ford the corresponding highly substituted 3-pyrrolines.
Figure 1. Natural product and bioactive compounds containing
3-pyrroline scaffold.
Electronꢀdeficient alkynes are widely used for these
transformations,4 in contrast, only a few examples of using
electron-rich alkynes as the dipolarophile have been
explored.5 Herein, we wish to report a novel Sc(OTf)3-
catalyzed highly regioselective formal [3 þ 2] cycloaddition
of alkynes with azomethine ylides, which are obtained
from the selective CꢀC bond cleavage of N-tosylaziridines
under mild conditions, providing a facile, efficient route to
highly substituted 3-pyrroline.
Aziridines, highly ring strained but readily accessible
three membered cyclic amines, have been extensively studied
in past years.6 The chemistry of aziridines is contributed
largely by the reactivity of CꢀN bonds. For example, the
CꢀN bond cleavage of N-tosylaziridines under the catalysis
of Lewis acid would produce a masked 1,3-dipole, which
readily reacts with versatile dipolarophiles such as alkynes,7
Table 1. Screening Reaction Conditions of 4-Ethynylanisole 2a
and Aziridine 1aa
entry
catalyst
AgSbF6
solvent time (h) yieldb (%) 3a:4ac
1
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
24
8
9
42
71
53
41
54
84
24
10
22
83
43
70
61
2
Y(OTf)3
In(OTf)3
Yb(OTf)3
Cu(OTf)3
Fe(OTf)3
Sc(OTf)3
Mg(OTf)2
MgI2
7.7:1
3
3
4
7
20:1
>20:1
>20:1
5
8
6
10
3
7
8
10
8
2.2:1
1.6:1
5:1
(5) For the [3 þ 2] cycloaddition of azomethine ylides with electron-
rich alkynes, see: (a) Butler, R. N.; Coyne, A. G.; Macardle, P.;
Cunningham, D.; Burke, L. A. J. Chem. Soc., Perkin, Trans. 1 2001,
1391. (b) Friebolin, W.; Eberbach, W. Helv. Chim. Acta 2001, 84, 3822.
An alternative method for synthesis of 3-pyrrolines via cycloaddition of
azomethine ylides with nitroalkenes and subsequent elimination, see: (c)
Carrie, R. Bull. Soc. Chim. Fr. 1987, 325.
(6) (a) Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247. (b) Dahanukar,
V. H.; Zavialov, L. A. Curr. Opin. Drug Discovery Dev. 2002, 5, 918. (c)
Hu, X. E. Tetrahedron 2004, 60, 2701. (d) Ma, L. G.; Xu, J. X. Progress in
Chemistry 2004, 16, 220. (e) Watson, I. D. G.; Yu, L; Yudin, A. K. Acc.
Chem. Res. 2006, 39, 194.
9
10
11
12
13
14
Bi(OTf)3
Sn(OTf)2
8
3
Ni(ClO4)2 6H2O DCM
9
>20:1
3
Sc(OTf)3
Sc(OTf)3
DCE
7
toluene
10
a Reaction conditions: 1a (0.4 mmol), 2a (0.8 mmol), 5 mol % catalyst,
˚
and 200 mg of activated 4 A MS in 4 mL of solvent at room temperature.
b Isolated yield . c 1H NMR ratio. PMP = 4-methoxyphenyl.
(7) (a) Wender, P. A.; Strand, D. J. Am. Chem. Soc. 2009, 131, 7528.
(b) Wang, Z. Y. Chem. Commun. 2009, 5021. (c) Liu, R. S. Org. Lett.
2002, 4, 4150. (d) Ma, D. W. Org. Lett. 2005, 7, 5545. (e) Tu, Y. Q.; Zhao,
X.; Zhang, E. T. Org. Lett. 2009, 11, 4002. (f) Hayashi, Y; Kumamoto, T;
Kawahata, M; Yamaguchi, K; Ishikawa, T. Tetrahedron. 2010, 66, 3836.
(g) Pankova, A. S.; Voronin, V. V.; Kuznetso, M. A. Tetrahedron Lett.
2009, 50, 5990. (h) Khlebnikov, A. F.; Novikov, M. S.; Petrovkii, P. P.;
Konev, A. S.; Yufit, D. S.; Selivanov, S. I.; Frauenforf, H. J. Org. Chem.
2010, 75, 5211. (i) William, R.; Dolbier, J.; Zheng, Z. J. Org. Chem. 2009,
74, 5626. (j) Grzegorz, M.; Katarzyna, U.; Molgorzata, D. Helv. Chim.
Acta 2009, 92, 2631. (k) Alexander, V. U.; Mikhail, A. K.; Anthony, L.;
Heinz, H. Helv. Chim. Acta 2010, 93, 847. (l) Lopes, S. M.; Beja, A. M.;
Manuela, R. S.; Paixao, J. A.; Palacios, F; Teresa, M. V. Synthesis 2009,
2403. (m) Grigg, R.; Nimal, H. Q.; Tames, K. Tetrahedron. 1990, 46,
6467.
(8) (a) Kang, B.; Miller, W. A.; Goyal, S.; Nguyen, S. T. Chem.
Commun. 2009, 392. (b) Gandhi, S.; Bisai, A.; Prasad, B. A. B.; Singh,
V. K. J. Org. Chem. 2007, 72, 2133. (c) Ghorai, M. K.; Ghosh, K.
Tetrahedron Lett. 2007, 48, 3191. (d) Yadav, V. K.; Sriramurthy, V. J.
Am. Chem. Soc. 2005, 127, 16366.
(9) For other dipolarophiles, see: (a) Sudo, A.; Morioko, Y.; Koizumi,
E.; Sanda, F.; Endo, T. Tetrahedron Lett. 2003, 44, 7889. (b) Baeg, J. O.;
Bensimon, C.;Alper, H.J. Am. Chem. Soc. 1995, 117, 4700. (c)Baeg, J. O.;
Alper, H. J. Org. Chem. 1992, 57, 157. (d) Maas, H.; Bensimon, C.; Alper,
H. J. Org. Chem. 1998, 63, 17. (e) Munegumi, T.; Azumaya, I.; Kato, T.;
Masu, H.; Saito, S. Org. Lett. 2006, 8, 379.
We started to test our hypothesis by using N-tosylazir-
idine 1a14 and alkyne 2a as model substrates. Initially, 1a
and 2a were subjected to the solution of 5 mol % of
AgSbF6 in CH2Cl2 at room temperature, the reaction
yielded 3a as a single regioisomer in only 9% isolated yield
(Table 1, entry 1). Other commercially available and
common used Lewis acids such as Y(OTf)3, Yb(OTf)3,
Bi(OTf)3, Fe(OTf)3, Mg(OTf)2, MgI2 and Ni(ClO4)2 6H2O
3
were next investigated. The regiomer 4a was formed in some
cases. Finally, the best result is obtained by using 5 mol % of
Sc(OTf)3 in CH2Cl2, affording 3a in 84% isolated yield as a
single regiomer (Table 1, entry 7). Other tested solvents such
as 1, 2-dichloroethane, toluene cannot give better result. The
structure of 3a was confirmed by X-ray crystallography
analysis.15
With the optimal reaction conditions in hand, the scope
of this Lewis-acid catalyzed 1, 3-dipolar cycloaddition
Org. Lett., Vol. 13, No. 22, 2011
5941