ORGANIC
LETTERS
2008
Vol. 10, No. 8
1617-1619
Intramolecular Azide−Alkyne
Cycloaddition for the Fast Assembly of
Structurally Diverse, Tricyclic
1,2,3-Triazoles
Ana I. Oliva,† Ute Christmann,† Daniel Font,† Fe´lix Cuevas,† Pablo Ballester,‡
Helmut Buschmann,# Antoni Torrens,# Susana Yenes,# and Miquel A. Perica`s*,§
Institute of Chemical Research of Catalonia (ICIQ), AV. Pa¨ısos Catalans, 16, 43007
Tarragona, Spain, Departament de Qu´ımica Orga`nica, UniVersitat de Barcelona (UB),
08028 Barcelona, Spain, ICREA and Laboratorios Dr. EsteVe, S.A., AV. Mare de Deu
de Montserrat, 221, 08041 Barcelona, Spain
Received February 8, 2008
ABSTRACT
The synthesis of novel tricyclic 1,2,3-triazoles starting from cyclic epoxides via the sequential azidolysis, propargylation and 1,3-dipolar
cycloaddition is described. Derivatization by N-arylation reaction and the synthesis of enantiomerically pure compounds is also reported.
Some of these compounds exhibit significant affinity for the sigma-1 receptor.
In recent years, the 1,3-dipolar cycloaddition between azides
and alkynes has witnessed a renewed interest since the
introduction by Sharpless of the Click Chemistry concept.1
In most cases, the 1,2,3-triazole system resulting from the
cycloaddition represents an almost universal ligation element
allowing the fast connection of properly functionalized
components of very diverse natures with quite different
functions/activities.2 In addition, the 1,2,3-triazole unit can
itself exhibit interesting properties, either catalytic or phar-
macological, among others.3
azide-alkyne cycloaddition appears as a most promising
alternative for the fast assembly of drug-like, tricyclic 1,2,3-
triazoles. However, either the fact that the involved dipolar
cycloaddition does not adjust to the structural requirements
of the click chemistry paradigm or the belief that the trans
arrangement in the cycloaddition substrate would play a
negative role on the cycloaddition process have hampered
the exploration of this possibility until now.
We report herein that cyclic epoxides, when submitted to
sequential azidolysis plus propargylation, lead to stereode-
fined azidoalkynes that readily undergo purely thermal 1,3-
dipolar cycloaddition leading to tricyclic [1,2,3]triazolo[1,5-
d][1,4]oxazines. The introduction of structural diversity at
two key points in these tricyclic structures is also demon-
The versatility of this cycloaddition has driven the
development of tandem processes involving it as the key step,
as a ready access to molecular diversity.4 Among these
multicomponent constructions, the combination of epoxide
ring-opening with azide, O-propargylation and intramolecular
(3) (a) Kolb, H. C.; Sharpless, K. B. Drug DiscoVery Today 2003, 8,
1128. (b) Whiting, M.; Mudoon, J.; Lin, Y. C.; Silverman, S. M.; Lindstrom,
W.; Olson, A. J.; Kolb, H. C.; Finn, M. G.; Sharpless, K. B.; Elder, J. H.;
Fokin, V. V. Angew. Chem., Int. Ed. 2006, 45, 1435. (c) Luo, S.; Xu, H.;
Mi, X.; Li, J.; Zheng, X.; Cheng, J. P. J. Org. Chem. 2006, 71, 9244. (d)
Detz, R. J.; Arevalo, S.; De Gelder, R.; van Leeuwen, P. W. N. M.; Hiemstra,
H.; Reek, J. N. H.; van Maarseven, J. H. Org. Lett. 2006, 8, 3227.
(4) (a) Thomas, A. W. Bioorg. Med. Chem. Lett. 2002, 12, 1881. (b)
Khanetskyy, B.; Dallinger, D.; Kappe, C. O. J. Comb. Chem. 2004, 6, 884.
(c) Akritopoulou-Zanze, I.; Gracias, V.; Djuric, S. W. Tetrahedron Lett.
2004, 45, 8439. (d) Gracias, V.; Darczak, D.; Gasiecki, A. F.; Djuric, S.
W. Tetrahedron Lett. 2005, 46, 9053.
† ICIQ.
‡ ICREA and ICIQ.
# Laboratorios Dr. Esteve, S. A.
§ ICIQ and UB.
(1) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004. (b) Rostovsev, V. V.; Gree, L. G.; Fokin, V. V.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596.
(2) (a) Moses, J. E.; Moorhouse, A. D. Chem. Soc. ReV. 2007, 36, 1249.
(b) Lutz, J. F. Angew. Chem., Int. Ed. 2007, 46, 1018.
10.1021/ol800291t CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/19/2008