C O M M U N I C A T I O N S
Table 1. Ru-Catalyzed Reactions of Azides with Terminal
acetylides is unlikely (and not even possible for the latter). Of
course, cyclotrimerization of alkynes is well-known and, for the
specific case of the Cp*RuCl(COD) catalyst, has been shown to
proceed via ruthenacyclopentadienes.10 Therefore, we suggest that
the newly discovered Ru-catalyzed triazole annulations represent
a simple, and early, shunt off the usual alkyne oligomerization
sequence. That is, oxidative coupling of an alkyne and an azide on
ruthenium may initially give a six-membered ruthenacycle (Scheme
3; A is more likely than B), which then undergoes reductive
elimination releasing the aromatic triazole product.
In summary, an experimentally convenient catalytic process for
regioselective synthesis of 1,5-disubstituted and 1,4,5-trisubstituted
1,2,3-triazoles from organic azides and terminal and internal alkynes
is now available. Together with the CuAAC, these transformations
allow selective preparation of both regioisomers of 1,2,3-triazoles,
heterocycles that have recently become popular as a means for
establishing reliable and stable connections in organic synthesis,
medicinal chemistry, and materials science.
Acknowledgment. This work was supported by the Hong Kong
Research Grant Council, the National Institute of General Medical
Sciences, National Institutes of Health (GM-28384), and Pfizer,
Inc. The authors are grateful to Drs. B.C. Boren, J. Loren, S.
Narayan, and Prof. M. G. Finn for experimental assistance and
valuable advice.
Supporting Information Available: Experimental procedures and
characterization data (PDF). X-ray crystallographic files (CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
a
Benzene, 1-2 mmol scale, 80 °C, 1 mol % of Cp*RuCl(PPh3)2.
b
c
Dioxane, 60 °C. Dioxane, 60 °C, 2 mol % of the catalyst.
References
Scheme 2. Ru-Catalyzed Synthesis of Triazoles from Internal
Alkynes
(
1) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
Wiley: New York, 1984.
(
2) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2596. (b) Tornoe, C. W.; Christensen, C.; Meldal,
M. J. Org. Chem. 2002, 67, 3057.
(
3) Kolb, H. C.; Sharpless, K. B. Drug DiscoVery Today 2003, 8, 1128.
4) Recent examples: (a) Horne, W. S.; Yadav, M. K.; Stout, C. D.; Ghadiri,
M. R. J. Am. Chem. Soc. 2004, 126, 15366. (b) Manetsch, R.; Krasinski,
A.; Radic, Z.; Raushel, J.; Taylor, P.; Sharpless, K. B.; Kolb, H. C. J.
Am. Chem. Soc. 2004, 126, 12809. (c) Link, A. J.; Vink, M. K. S.; Tirrel,
D. A. J. Am. Chem. Soc. 2004, 126, 10598. (d) Zhou, Z.; Fahrni, C. J. J.
Am. Chem. Soc. 2004, 126, 8862. (e) Lewis, W. G.; Magallon, F. G.;
Fokin, V. V.; Finn, M. G. J. Am. Chem. Soc. 2004, 126, 9152. (f) Wu, P.;
Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel, A.; Voit, B.; Pyun,
J.; Fr e´ chet, J. M. J.; Sharpless, K. B.; Fokin, V. V. Angew. Chem., Int.
Ed. 2004, 43, 3928. (g) Meng, J. C.; Averbuj, C.; Lewis, W. G.; Siuzdak,
G.; Finn, M. G. Angew. Chem., Int. Ed. 2004, 43, 1255. (h) Opsteen, J.
A.; van Hest, J. C. M. Chem. Commun. 2005, 57. (i) Punna, S.; Kuzelka,
J.; Wang, Q.; Finn, M. G. Angew. Chem., Int. Ed. 2005, 44, 2215.
(
Likewise, reactions can be carried out at temperatures ranging from
ambient to 80 °C. For example, benzyl azide was almost quanti-
tatively converted to the corresponding triazoles when it was
allowed to react with a slight excess of Ph
PhCtCH in benzene at room temperature for 24 h in the presence
of 5% mol of Cp*RuCl(PPh
2
C(OH)CtCH or
3 2
) .
The structures of new triazoles are fully consistent with their
1H, 13C NMR, and MS data.8 In addition, structures of 1a, 6a, and
7a have also been confirmed by X-ray diffraction studies.
(5) (a) Mocharla, V. P.; Colasson, B.; Lee, L. V.; Roper, S.; Sharpless, K.
B.; Wong, C. W.; Kolb, H. C. Angew. Chem., Int. Ed. 2005, 44, 116. (b)
Dondoni, A.; Giovannini, P. P.; Massi, A. Org. Lett. 2004, 6, 2929. (c)
Wroblewski, A. E.; Glowacka, I. E. Tetrahedron: Asymmetry 2004, 15,
Since Cu(I) acetylides seem to be the bona fide intermediates in
9
the CuAAC, this transformation is limited to terminal alkynes. The
1
457. (d) Liu, J.; Numa, M. M. D.; Liu, H.; Huang, S. J.; Sears, P.;
[Cp*RuCl] system, in fortunate contrast, is active with internal
Shikhman, A. R.; Wong, C. H. J. Org. Chem. 2004, 69, 6273.
alkynes as well. Thus, when a mixture of diphenylacetylene and
benzyl azide (1.1:1 equiv, 0.15 M) was refluxed in benzene in the
presence of ca. 1 % mol of Cp*RuCl(PPh ) for 2 h, the azide was
3 2
completely converted to the triazole 12 (Scheme 2). The uncatalyzed
reaction was very sluggish, and only a trace amount of triazole
was detected even after 24 h at reflux.
The mechanistic underpinnings for this ruthenium(II)-catalyzed
synthesis of triazoles need much more studies, but we offer the
following tentative hypothesis. Since both terminal and internal
alkynes participate in catalysis, the involvement of ruthenium
(
6) Krasinski, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett. 2004, 6, 1237.
(7) (a) Naota, T.; Takaya, H.; Murahashi, S. I. Chem. ReV. 1998, 98, 2599.
(
b) Bruneau, C.; Dixneuf, P. H. Acc. Chem. Res. 1999, 32, 311. (c) Trost,
B. M.; Toste, F. D.; Pinkerton, A. B. Chem. ReV. 2001, 101, 2067.
(8) See Supporting Information for the details.
(
9) (a) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.;
Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210. (b)
Rodionov, V. O.; Fokin, V. V.; Finn, M. G. Angew. Chem., Int. Ed. 2005,
44, 2210.
(
10) (a) Kirchner, K.; Calhorda, M. J.; Schmid, R.; Veiros, L. F. J. Am. Chem.
Soc. 2003, 125, 11721. (b) Yamamoto, Y.; Arakawa, T.; Ogawa, R.; Itoh,
K. J. Am. Chem. Soc. 2003, 125, 12143.
JA054114S
J. AM. CHEM. SOC.
9
VOL. 127, NO. 46, 2005 15999