Transition-metal-free catalytic synthesis of 1,5-diaryl-1,2,3-triazoles

Article abstract of DOI:10.1021/ol101568d

Figure Presented. 1,5-Diarylsubstituted 1,2,3-triazoles are formed in high yield from aryl azides and terminal alkynes in DMSO in the presence of catalytic tetraalkylammonium hydroxide. The reaction is experimentally simple, does not require a transition-

Full text of DOI:10.1021/ol101568d

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4217-4219
Transition-Metal-Free Catalytic Synthesis
of 1,5-Diaryl-1,2,3-triazoles
Sen W. Kwok, Joseph R. Fotsing, Rebecca J. Fraser, Valentin O. Rodionov, and
Valery V. Fokin*
The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
fokin@scripps.edu
Received July 7, 2010
ABSTRACT
1,5-Diarylsubstituted 1,2,3-triazoles are formed in high yield from aryl azides and terminal alkynes in DMSO in the presence of catalytic
tetraalkylammonium hydroxide. The reaction is experimentally simple, does not require a transition-metal catalyst, and is not sensitive to
atmospheric oxygen and moisture.
The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC)
is a reliable means for the synthesis of 1,4-disubstituted-
1H-1,2,3-triazoles.1 The exceptional stability of 1,2,3-tria-
zoles and the availability of a reliable synthesis leading to
these heterocycles have enabled widespread applications of
this previously underutilized class of azoles in medicinal
chemistry, chemical biology, and materials science.2
electrophilic terminal nitrogen of the azide are known,9 the
requirement for the stoichiometric lithium or magnesium
acetylide reagent imposes obvious limitations on the range
of functional groups that are compatible with these processes.
Reported here is a mild and experimentally simple catalytic
method for the generation of the reactive acetylides which
readily react with organic azides resulting in the exclusive
formation of 1,5-disubstituted triazoles.
In contrast to the 1,4-disubstituted-1H-1,2,3-triazoles,
general and regioselective routes leading to the 1,5-regioi-
somers are not as well developed.3-8 Although syntheses
relying on the nucleophilic attack by the acetylide at the
We envisioned that the high acidity of aryl acetylenes in
dimethylsulfoxide10-12 should allow formation of the reac-
(7) (a) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams, I. D.;
Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127, 15998.
(b) Rasmuseen, L. K.; Boren, B. C.; Fokin, V. V. Org. Lett. 2007, 9, 5337.
(c) Boren, B. C.; Narayan, S.; Rasmuseen, L. K.; Zhang, L.; Zhao, H.; Lin,
Z.; Jia, G.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 8923.
(8) Krasinski, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett. 2004, 6,
1237.
(1) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
67, 3057. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 2596.
(2) For recent reviews, see: (a) Wu, P.; Fokin, V. V. Aldrichimica Acta
2007, 40, 7. (b) Fournier, D.; Hoogenboom, R.; Schubert, U. S. Chem. Soc.
ReV. 2007, 36, 1369. (c) Moses, J. E.; Moorhouse, A. D. Chem. Soc. ReV.
2007, 36, 1249. (d) Johnson, J. A.; Koberstein, J. T.; Finn, M. G.; Turro,
N. J. Macromol. Rapid Commun. 2008, 29, 1052.
(9) (a) Akimova, G. S.; Chistokletov, V. N.; Petrov, A. A. Zh. Obsh.
Khim. 1965, 1, 2077. (b) Akimova, G. S.; Chistokletov, V. N.; Petrov, A. A.
Zh. Org. Khim. 1967, 3, 2241. (c) Akimova, G. S.; Chistokletov, V. N.;
Petrov, A. A. Zh. Org. Khim. 1967, 3, 968. (d) Akimova, G. S.; Chistokletov,
V. N.; Petrov, A. A. Zh. Org. Khim. 1968, 4, 389.
(3) Brunner, M.; Maas, G.; Klaerner, F.-G. HelV. Chim. Acta 2005, 88,
1813
.
(4) Coats, S. J.; Link, J. S.; Gauthier, D.; Hlasta, D. J. Org. Lett. 2005,
7, 1469
(10) Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.;
Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.; McCollum,
.
(5) Holzer, W.; Ruso, K. J. Heterocycl. Chem. 1992, 29, 1203
.
G. J.; Vanier, N. R. J. Am. Chem. Soc. 1975, 97, 7006
(11) Olmstead, W. N.; Margolin, Z.; Bordwell, F. G. J. Org. Chem.
1980, 45, 3295
.
(6) Uhlmann, P.; Felding, J.; Vedso, P.; Begtrup, M. J. Org. Chem. 1997,
62, 9177
.
.
10.1021/ol101568d  2010 American Chemical Society
Published on Web 09/08/2010

tive acetylide species by treatment of the alkyne with a
hydroxide or alkoxide base in this solvent. In fact, formation
of acetylide intermediates has been proposed by Ishikawa
and co-workers in their studies of the alkynylation of
ketones.13 Screening of various hydroxides and alkoxides
confirmed this hypothesis, revealing that anhydrous sodium,
potassium, cesium hydroxides, and aqueous tetramethylam-
monium and benzyl-trimethylammonium hydroxides catalyze
formation of 1,5-diaryl-substituted-1H-1,2,3-triazoles in DMSO
at room temperature (Table 1).
Scheme 1. Proposed Intermediates in the Base-Catalyzed
Synthesis of 1,5-Disubstituted-1,2,3-Triazoles
Table 1. Performance of Selected Hydroxide Bases in Catalytic
Synthesis of 1,2,3-Triazoles
KOHc BnNMe3OH NMe4OH
base
KOH (powder)
(aq)
(aq)
(aq)
under the reaction conditions is evidenced by the incor-
poration of deuterium into the product when the reaction
is performed in d6-DMSO with potassium tert-butoxide
(0.2 equiv). This finding suggests that in addition to
stabilizing the anionic intermediates (II and III) DMSO
participates in the various necessary proton-relay events.
Observation of a trace amount of 4-triazenyl triazole
byproduct, the formation of which can be rationalized by
the nucleophilic attack of triazolyl anion III on another
molecule of aryl azide, lends further support to the
involvement of triazolyl anion III.
The scope of this process was examined as illustrated
by the examples in Table 2. Most aryl and heteroaryl
azides and terminal alkynes readily participate in this 1,5-
diaryl-substituted-1,2,3-triazole synthesis. It is noteworthy
that base-labile functionalities (entries 6 and 9) were
tolerated. Aryl azides with sterically demanding ortho-
substituents gave slightly lower yields, possibly due to
interference with the ring closure of the triazenide
intermediate (Table 2, entries 2, 4, and 15). Electronic
properties of both reactants significantly influence the
outcome of the reaction. For example, very electron-
deficient 4-nitrophenyl azide produced the triazole in
moderate 62% yield (entry 3), likely due to the less
efficient triazenide cyclization step. Similarly, 4-nitro-
phenyl acetylene produced the desired triazole product in
only 37% yield (entry 12), which could be a consequence
of the reduced nucleophilicity of the acetylide anion. Alkyl
acetylenes failed to react under the current conditions,
probably due to their lower acidity.14
yield (%)a
time (h)b
91
>10
86
>10
81
5
86
5
a Base (0.42 mmol) was added to a solution of phenylacetylene (461
µL, 4.2 mmol) and azidobenzene (500 mg, 4.2 mmol) in DMSO (16.8 mL)
at room temperature and stirred under a CO2-free atmosphere. Product was
isolated by vacuum filtration after addition of water. b Reaction progress
was monitored by LC-MS. c 2.6 M aqueous solution of KOH (160 µL,
0.42 mmol) was added to the reaction mixture.
Dry DMSO and less nucleophilic bases such as potassium
tert-butoxide can also be used to minimize hydrolysis of
substrates which contain base-sensitive functionalities. In
many cases, the desired products precipitated upon addition
of 5-20× volume of ice-cold water and were isolated by
simple filtration. Reactions in DMSO afforded higher isolated
yields than in DMF on larger scale and at higher concentra-
tion. Although tetraalkylammonium hydroxides resulted in
the slightly diminished yields of the products compared to
powdered KOH, the shorter reaction times and the experi-
mental convenience of using aqueous base solutions make
tetraalkylammonium hydroxides advantageous catalysts for
practical reasons.
While our mechanistic studies of this hydroxide-catalyzed
synthesis of triazoles in DMSO are not complete, we offer
in Scheme 1 a general proposal for 1,5-triazole formation
from acetylides and organic azides. Reversible deprotonation
of the terminal alkyne 1 generates an aryl acetylide I, which
acts as a nucleophile to attack the terminal nitrogen of aryl
azide a. The triazenide intermediate II then undergoes either
6π-electrocyclization or 5-endo-dig cyclization to form 1,5-
disubstituted-1,2,3-triazolyl anion III which completes the
catalytic cycle by deprotonation of a molecule of DMSO,
terminal alkyne, or water. That DMSO is likely deprotonated
The results described above demonstrate that sufficiently
nucleophilic and reactive acetylides can be prepared from
terminal alkynes without involving aggressive lithium or
magnesium reagents. Such acetylides react selectively with
even modestly electrophilic organic azides, producing 1,5-
(12) Bordwell, F. G.; Algrim, D.; Fried, H. E. J. Chem. Soc., Perkin
Trans. 2 1979, 726.
(13) Ishikawa, T.; Mizuta, T.; Hagiwara, K.; Aikawa, T.; Kudo, T.; Saito,
S. J. Org. Chem. 2003, 68, 3702. and the references cited therein.
(14) Chrisment, J.; Delpuech, J. J. J. Chem. Soc., Perkin Trans. 2 1977,
407.
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Org. Lett., Vol. 12, No. 19, 2010

Table 2. Scope of the Base-Catalyzed Synthesis of 1,2,3-Triazoles
a Unless stated otherwise, method A (base ) aq NMe4OH) was used, and the product was isolated by filtration. b Method B (base ) t-BuOK) was used.
c Isolated yield after flash column chromatography.
disubstituted triazoles under mild, transition-metal-free con-
ditions. Experimental simplicity, ease of product isolation,
low cost, and ready availability of reagents should make this
method immediately useful for the synthesis of these
heterocycles.
Biology, and Pfizer, Inc. is gratefully acknowledged. The
authors thank Profs. M. G. Finn and K. B. Sharpless (The
Scripps Research Institute) for helpful discussions.
Supporting Information Available: Experimental pro-
1
cedures, characterization data, and copies of H NMR and
13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support from the National
Institute of General Medical Sciences, National Institutes of
Health (GM087620), the Skaggs Institute for Chemical
OL101568D
Org. Lett., Vol. 12, No. 19, 2010
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