we wish to report the application of this process using solid-
phase methods toward the generation of 1,5-disubstituted 1H-
1,2,3-triazole libraries bearing four diversity centers.7 During
the course of our work, Sharpless and Meldal reported the
use of copper(I) catalysis to control the regioselective
synthesis of 1,4-disubstituted 1H-1,2,3-triazoles from ter-
minal acetylenes and azides.8,9 More recently, 1-bromomag-
nesium acetylenes were shown to react selectively with
organoazides in good yield to form 1,5-disubstituted triazoles;
however, reactive functional groups such as carbonyl are not
compatible.10 These methods complement our method de-
scribed herein, since our work selectively provides 1,5-
disubstituted 1H-1,2,3-triazoles and is compatible with
1-trimethylsilylacetylenes bearing aliphatic, aryl, or carbonyl
groups in the 2-position.
Electron-withdrawing groups on acetylenes are well-known
to increase the cycloaddition reaction rate with azides. The
electron-neutral -CH2OH example (entry 9) as expected
required extended reaction time to obtain a reasonable yield.
The 4-trimethylsilyl group was stable in all examples, except
for entry 8 where 15% of the desilylated triazole 11 was
obtained as a byproduct.
Wang resin was chosen for our initial solid-phase studies
due to its rapid and efficient cleavage protocol. Acylation
of the resin with chloromethylbenzoyl chloride yielded the
resin-bound benzyl chloride that was converted with tri-
methylsilyl azide to the resin-bound benzyl azide 14 (Scheme
2). We found that resin 14 was stable for more than seven
To define the scope of this reaction, representative triazoles
were synthesized in solution and characterized to determine
the extent of regioselectivity observed in each case. As shown
in Table 1, complete regioselectivity was obtained with
Scheme 2. Wang Resin Chemistrya
Table 1. 1,3-Dipolar Cycloaddition of Acetylenes 3 to Form
Triazoles 4-13
a Conditions: (a) 4-(chloromethyl)benzoyl chloride (5 equiv),
DIEA (6 equiv), rt, DCM, 23 h; (b) TBAF (10 equiv), trimethylsilyl
azide (10 equiv), rt, THF, 24 h; (c) ethyl trimethylsilyl-propynoate
(5 equiv), 110 °C, toluene, 14 h; (d) trimethylsilyl-propynoic acid
(2.5 equiv), 110 °C, toluene, 22 h; (e) TFA:DCM (1:1), 1 h.
months when stored at 4 °C on the basis of FT-IR analysis
and subsequent chemical yields. The cycloaddition of 14 with
ethyl trimethylsilyl-propynoate provided complete conversion
to the resin-bound triazole after refluxing in toluene for 16
h. The progress of the cycloaddition reactions with 14 was
monitored by FT-IR spectroscopy (azide stretch 2095 cm-1
relative to the carbonyl stretch at 1717 cm-1). However, we
a Product obtained was desilylated 6 (R3 ) H). b Minor amount (15%)
of desilylated 11 (R1 ) H) was isolated. c Minor amount (∼20%) of the
deprotected piperazinyl triazole 13 was isolated.
(7) This work was presented in a preliminary form: Link, J. S.; Coats,
S. J.; Hlasta, D. J. Metal Directed 1,3-Dipolar Cycloadditions in Solution
and Solid-Phase Synthesis; Abstract at the 223rd National Meeting of the
American Chemical Society, Orlando, FL, April 7-11, 2002; ORGN 228.
(8) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057-3064.
1-trimethylsilyl acetylenes.11 Conversely, when nonsilylated
acetylenes (entries 6 and 7) were used, regiomeric mixtures
of triazoles were observed. The cycloadditions were run in
refluxing toluene with reaction times ranging between 12
and 46 h.
(9) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596-2599. Feldman, A. K.; Colasson,
B.; Fokin, V. V. Org. Lett. 2004, 6, 3897-3899. Kolb, H. C.; Sharpless,
K. B. Drug DiscoVery Today 2003, 8, 1128-1137 and references therein.
(10) Krasinski, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett. 2004, 6,
1237-1240.
Entries 1, 2, 5, 8, and 9 show a range of examples where
the electron-withdrawing ability of the R2 group is varied.
(11) Regiochemical assignments were made in accordance with 1H, 13C,
and two-dimensional NMR studies. For example, triazole 8 in an HMBC
experiment shows a three-bond proton-carbon correlation between the
benzylic protons and the carbon of the triazole ring with the carbonyl
attached, whereas no correlation is seen to the carbon with the trimethylsilyl
group attached.
(3) Birkhofer, L.; Franz, M. Chem. Ber. 1972, 105, 1759-1767.
(4) Guillerm, G.; L’Honore, A.; Veniard, L.; Pourcelot, G.; Benaim, J.
Bull. Soc. Chim. Fr. 1973, 105, 2739-2746.
(5) Padwa, A.; Wannamaker, M. W. Tetrahedron 1990, 46, 1145-1162.
(6) Hlasta, D. J.; Ackerman, J. H. J. Org. Chem. 1994, 59, 6184-6189.
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