ORGANIC
LETTERS
2006
Vol. 8, No. 15
3283-3285
[3+2] Cycloaddition Reactions in the
Solid-Phase Synthesis of 1,2,3-Triazoles
Yongnian Gao and Yulin Lam*
Department of Chemistry, National UniVersity of Singapore,
3 Science DriVe 3, Singapore 117543
Received May 11, 2006
ABSTRACT
An efficient and regioselective procedure for the synthesis of 1,2,3-triazoles via a [3+2] cycloaddition of polymer-bound vinyl sulfone and
sodium azide is described. Microwave irradiation provided significant rate enhancement in all steps of the three-step protocol. A representative
set of 23 compounds was prepared.
1,2,3-Triazoles are attractive targets as they are associated
with a wide range of applications in organic, materials, and
medicinal chemistry. Numerous synthetic approaches to this
class of compounds have been developed.1 Among them,
the 1,3-dipolar cycloaddition of azides and alkynes is the
traditional and extensively used method. However, the
efficiency of this process is dependent on the steric and
electronic properties of the alkyne, and until recently, the
regioselectivities of these reactions are generally low with
unsymmetrical alkynes giving regioisomeric mixtures of
triazoles.2 As a consequence of these problems, such cy-
cloaddition reactions have found limited use in the solid-
phase synthesis (SPS) of triazole libraries.
Alternative solid-phase routes for the synthesis of 1,2,3-
triazoles have rarely been explored.1e,k In particular, the [3+2]
cycloaddition of azides and electron-poor alkenes (Scheme
1) has received very little attention. This may be attributed
Scheme 1. Directed [3+2] Cycloaddition
(1) (a) Huisgen, R.; Knorr, R.; Moius, L.; Szeimies, G. Chem. Ber. 1965,
98, 4014-4021. (b) Maiorana, S.; Pocar, D.; Calla Croce, P. Tetrahedron
Lett. 1966, 7, 6043-6045. (c) Meek, J. S.; Fowler, J. J. Org. Chem. 1968,
33, 985-991. (d) Chakrasali, R. T.; Ila, H.; Junjappa, H. Synthesis 1988,
851-854. (e) Li, C. L.; Huang, W. Q.; Lu, Y.; He, B. L. Chin. Chem. Lett.
1991, 2, 773-774. (f) Dong, Z.; Hellmund, K. A.; Pyne, S. G. Aust. J.
Chem. 1993, 46, 1431-1436. (g) Gouault, N.; Cupif, J. F.; Sauleau, A.;
David, M. Tetrahedron Lett. 2000, 41, 7293-7297. (h) Rostovtsec, V. V.;
Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002,
41, 2596-2599. (i) Harju, K.; Vahermo, M.; Mutikainen, I.; Yli-Kau-
haluoma, J. J. Comb. Chem. 2003, 5, 826-833. (j) Batanero, D. B.; Barba,
F. Heterocycles 2004, 65, 1175-1180. (k) Raghavendra, M. S.; Lam, Y.
Tetrahedron Lett. 2004, 45, 6129-6132. (l) Krasin˜ski, A.; Fokin, V. V.;
Sharpless, K. B. Org. Lett. 2004, 6, 1237-1240. (m) Amantini, D.;
Fringuelli, F.; Piermatti, O.; Pizzo, F.; Zunino, E.; Vaccaro, L. J. Org. Chem.
2005, 70, 6426-6529. (n) Coats, S. J.; Link, J. S.; Gauthier, D.; Hlasta, D.
J. Org. Lett. 2005, 7, 1469-1472. (o) Roque, D. R.; Neill, J. L.; Antoon,
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to the poor reactivities of the reactants which require harsh
reaction conditions to facilitate the cycloaddition.1b,o Thus,
finding an easy method to facilitate the solid-phase cycloaddi-
tion would be essential. We herein report a convenient solid-
phase procedure for the regioselective and traceless synthesis
of trisubstituted and disubstituted 1,2,3-triazoles (Scheme 2).
Polystyrene/1% divinylbenzene sodium sulfinate resin 1
was chosen for our solid-phase studies because (i) the vinyl
sulfone dipolarophile can be efficiently generated and (ii)
the electronegative sulfone that is eliminated in the reaction
may serve as a means to direct the regiochemistry of the
cycloaddition as well as a traceless linker for the SPS.
To define the scope of this reaction, representative triazoles
were synthesized using 1 to survey the requisite reaction
(2) (a) Hlasta, D. J.; Ackerman, J. H. J. Org. Chem. 1994, 59, 6184-
6189. (b) Sasaki, T.; Eguchi, S.; Yamaguchi, M.; Esaki, T. J. Org. Chem.
1981, 46, 1800-1804. (c) Howell, S. J.; Spencer, N.; Philp, D. Tetrahedron
2001, 57, 4945-4954.
10.1021/ol0611494 CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/28/2006