Ruthenium-catalyzed cycloaddition of aryl azides and alkynes

Article abstract of DOI:10.1021/ol701912s

The formation of 1,5-disubstituted 1,2,3-triazoles from aryl azides and alkynes was readily accomplished using [Cp*RuCl]₄ catalyst in dimethylformamide. It was also demonstrated that the reaction provided higher yields, cleaner product, and sho

Full text of DOI:10.1021/ol701912s

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5337-5339
Ruthenium-Catalyzed Cycloaddition of
Aryl Azides and Alkynes
Lars Kyhn Rasmussen, Brant C. Boren, and Valery V. Fokin*
Department of Chemistry, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037
fokin@scripps.edu
Received August 6, 2007
ABSTRACT
The formation of 1,5-disubstituted 1,2,3-triazoles from aryl azides and alkynes was readily accomplished using [Cp*RuCl]4 catalyst in
dimethylformamide. It was also demonstrated that the reaction provided higher yields, cleaner product, and shorter reaction times when
carried out under microwave irradiation.
Since the discovery of the Cu(I)-catalyzed azide-alkyne
cycloaddition (CuAAC),1 the number of its applications in
different fields of chemistry has exploded. The reaction has
enabled discovery of novel bioactive compounds, ligands for
transition metals, new materials, and bioconjugates, under-
scoring its exceptionally broad scope and fidelity.2 Neverthe-
less, the CuAAC process works only with terminal alkynes
and produces 1,4-disubstituted 1,2,3-triazoles. The recent
addition to the family of catalytic azide-alkyne cycloaddi-
tions, the ruthenium-catalyzed process (RuAAC),3 provides
ready access to the complementary 1,5-regioisomers of 1,2,3-
triazole. Furthermore, internal alkynes also participate in the
RuAAC, thus significantly expanding the scope of this
cycloaddition process. Bis(triphenylphosphine) pentameth-
ylcyclopentadienyl ruthenium(II) chloride, Cp*RuCl(PPh3)2
(1),4 was identified early on as an efficient catalyst in the
original study.3a
Although RuAAC exhibits good scope with respect to both
components, the reaction of alkynes with aryl azides is often
plagued by low yields and formation of byproducts. De-
scribed herein are the results of our study aimed at the
development of an improved catalytic system which engages
aryl azides in the catalysis and allows facile access to 1-aryl-
substituted 1,2,3-triazoles.
During our investigation of the catalytic activity of
different ruthenium complexes in the reaction of aliphatic
azides and alkynes, we found that pentamethylcyclopenta-
dienyl ruthenium(II) chloride tetramer5 [Cp*RuCl]4 (2) in
dimethylformamide performed significantly better than
Cp*RuCl(PPh3)2 (1) in most other solvents. For example,
the reaction of benzyl azide and phenylacetylene catalyzed
by Cp*RuCl(PPh3)2 in tetrahydrofuran required 30 min at
65 °C to reach 90% conversion, whereas it proceeded to
completion in only 15 min and at room temperature when
catalyst 2 in dimethylformamide was used.
(1) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596-2599. (b) Tornøe, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057-3062.
(2) (a) Breinbauer, R.; Ko¨hn, M. ChemBioChem 2003, 4, 1147-1149.
(b) Kolb, H. C.; Sharpless, K. B. Drug DiscoVery Today 2003, 8, 1128-
1137. (c) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org.
Chem. 2005, 51-68. (d) Wu, P.; Fokin, V. V. Aldrichimica Acta 2007, 40,
7-17. (e) Lutz, J.-F. Angew. Chem., Int. Ed. 2007, 46, 1018. (f) Hawker,
C. J.; Fokin, V. V.; Finn, M. G.; Sharpless, K. B. Aust. J. Chem. 2007, 60,
381.
(3) (a) Zhang, L.; Chen, X. G.; Xue, P.; Sun, H. H. Y.; Williams, I. D.;
Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127, 15998-
15999. (b) Majireck, M. M.; Weinreb, S. M. J. Org. Chem. 2006, 71, 8680-
8683. (c) Boren, B. C.; Narayan, S; Rasmussen, L. K.; Zhang, L.; Zhao,
H.; Lin, Z.; Jia, G.; Fokin, V. V. J. Am. Chem. Soc. 2007, in press.
Catalyst 2 is easily prepared from [Cp*RuCl2]n by treating
the THF solution of the latter with LiBHEt3, without
(4) Oshima, N.; Suzuki, H.; Morooka, Y. Chem. Lett. 1984, 1161-1164.
(5) Fagan, P. J.; Ward, M. D.; Calabrese, J. C. J. Am. Chem. Soc. 1989,
111, 1698-1719.
10.1021/ol701912s CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/01/2007

Scheme 1. RuAAC of Benzyl Azide and Phenylacetylene
Table 2. RuAAC: Azide Scope
rigorously excluding air and moisture (Scheme 1). Although
it can be handled in air without a significant loss of activity,
highest yields were obtained when freshly prepared (within
24 h) catalyst was used.
The finding of increased catalytic activity of 2 prompted
us to investigate its performance in reactions that proved
difficult when Cp*RuCl(PPh3)2 was used as a catalyst. To
facilitate the optimization process, the reactions were per-
formed under microwave irradiation.
Among different solvents tested in the reaction between
4-iodophenylazide and phenylacetylene (Table 1), dimethyl-
Table 1. Variation of Amount of Catalyst, Temperature, and
Reaction Time
entry
[Ru], mol %
temp, °C
time, min
yield,a %
1
2
3
4
5
6
7
0
5
110
110
110
100
110
90
20
20
10
40
20
20
20
69
66
73
73
69
33
10
10
10
10
2
110
a Yield determined by quantitative GC analysis.
a Isolated yield after flash chromatography. b Oil bath 65 °C. c Oil bath
110 °C.
formamide clearly stood out, producing the 1,5-disubstituted
triazole product with highest conversion (ca. 70%), with
acetonitrile in a distant second place (ca. 40% conversion).
1,4-Dioxane, tetrahydrofuran, toluene, and dimethylsulfoxide
resulted in significantly lower efficiency of the reaction
(Scheme 2).
Although catalyst 2 is a cluster compound, the labile
Ru-Cl-Ru bonds are easily broken by donor ligands, and
both organic azides and alkynes are evidently sufficiently
potent to activate the tetramer. Furthermore, dimethyl-
formamide is known to form complexes with ruthenium, thus
acting as an activating and also stabilizing ligand in its own
right.6
Scheme 2. Effect of Solvents on the Efficiency of the
Reaction
The efficiency of the reaction was improved when the
amount of catalyst was increased to 10 mol % (entry 5, Table
1), while reducing the catalyst loading to 2 mol % was
detrimental (entry 7). Slight variations of the reaction
(6) Trost, B. M.; Frederiksen, M. U.; Rudd, M. T. Angew. Chem., Int.
Ed. 2005, 44, 6630-6666.
5338
Org. Lett., Vol. 9, No. 26, 2007

temperature (90-110 °C) had little effect on the outcome
(entries 4 and 6). Likewise, increasing the reaction time did
not improve the conversion, suggesting that catalyst de-
activation is a competing process.
Table 3. RuAAC: Alkyne Scope
With the optimized conditions in hand, we probed the
scope of the reaction with respect to both the azide and the
alkyne components. As evidenced by the results in Table 2,
aryl azides with different substituents smoothly reacted with
phenylacetylene, producing triazole products in generally
good yield. Both electron-rich (entries 3 and 4) and mod-
erately electron-poor (entry 7) aryl azides readily participated
in the reaction. However, those containing sterically demand-
ing substituents, diortho substituents, or strongly electron-
withdrawing groups, such as (4-nitro)azidobenzene, failed
to participate in the reaction, likely due to catalyst
deactivation3c and/or decomposition of the azide at the
elevated temperature. It is noteworthy that, although the
reaction proceeded under conventional heating (oil bath) at
65 and 110 °C, the formation of byproducts was evident,
and isolated yields were markedly lower.
The scope of the reaction with respect to alkyne was next
investigated and found to be excellent. As Table 3 illustrates,
a broad range of functional groups could be employed
without significantly affecting the yield of the product
triazole. Thus, alkynes containing an amine, alcohol, nitrile,
and heterocyclic amine functionality readily participated in
the reaction.
In summary, a highly active catalytic system for ruthenium-
catalyzed cycloaddition of azides and alkynes is now
available. Aryl azides, a troublesome class of sub-
strates that failed to react cleanly using the original
Cp*RuCl(PPh3)2 catalyst can now be readily and regio-
selectively converted to the corresponding triazoles upon a
reaction with [Cp*RuCl]4 catalyst in DMF at 90-110 °C
under microwave irradiation.
Acknowledgment. This work was supported by the
Skaggs Institute for Chemical Biology and Pfizer, Inc. We
are grateful to Prof. K. Barry Sharpless for stimulating
discussions and advice.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data are available. This
material is available free of charge via the Internet at
http://pubs.acs.org.
a Isolated yield after flash chromatography.
OL701912S
Org. Lett., Vol. 9, No. 26, 2007
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