A microwave-assisted click chemistry synthesis of 1,4-disubstituted 1,2,3-triazoles via a copper(I)-catalyzed three-component reaction

Article abstract of DOI:10.1021/ol048341v

(Chemical Equation Presented) A microwave-assisted three-component reaction was used to prepare a series of 1,4-disubstituted-1,2,3-triazoles from corresponding alkyl halides, sodium azide, and alkynes. This procedure eliminates the need to handle organic azides, as they are generated in situ, making this already powerful click process even more user-friendly and safe.

Full text of DOI:10.1021/ol048341v

ORGANIC
LETTERS
2004
Vol. 6, No. 23
4223-4225
A Microwave-Assisted Click Chemistry
Synthesis of 1,4-Disubstituted
1,2,3-Triazoles via a Copper(I)-Catalyzed
Three-Component Reaction
Prasad Appukkuttan,† Wim Dehaen,† Valery V. Fokin,*,‡ and
Erik Van der Eycken*,†
Department of Chemistry, UniVersity of LeuVen, Celestijnenlaan 200F,
B-3001 LeuVen, Belgium, and Department of Chemistry, The Scripps Research
Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
erik.Vandereycken@chem.kuleuVen.ac.be; fokin@scripps.edu
Received August 20, 2004
ABSTRACT
A microwave-assisted three-component reaction was used to prepare a series of 1,4-disubstituted-1,2,3-triazoles from corresponding alkyl
halides, sodium azide, and alkynes. This procedure eliminates the need to handle organic azides, as they are generated in situ, making this
already powerful click process even more user-friendly and safe.
The ever increasing demand for novel medicinally active
compounds and the laborious process of lead discovery and
optimization have resulted in the continuous search for simple
and efficient methods for generation of libraries for biological
screening. “Click chemistry” has emerged as a fast and
efficient approach to synthesis of novel compounds with
desired function making use of selected “near perfect”
reactions.1 The Huisgen 1,3-dipolar cycloaddition2 of azides
and alkynes resulting in 1,2,3-triazoles is one of the most
powerful click reactions. Several members of the 1,2,3-
triazole family have indeed shown interesting biological
properties, such as anti-allergic,3 anti-bacterial,4 and anti-
HIV activity.5 Additionally, 1,2,3-triazoles are found in
herbicides, fungicides, and dyes.6 The recently discovered
copper(I) catalysis of this transformation,7 which accelerates
the reaction up to 107 times, has placed it in a class of its
own and has enabled many novel applications.8 To further
improve the utility and user-friendliness of this process, we
developed its practical multicomponent variant described
herein. The azides are generated in situ from corresponding
halides,9 whereupon they are captured by copper(I) acetyl-
(3) (a) Buckle, D. R.; Rockell, C. J. M. J. Chem. Soc., Perkin Trans. 1
1982, 627-630. (b) Buckle, D. R.; Outred, D. J.; Rockell, C. J. M.; Smith,
H.; Spicer, B. A. J. Med. Chem. 1983, 26, 251-254. (c) Buckle, D. R.;
Rockell, C. J. M.; Smith, H.; Spicer, B. A. J. Med. Chem. 1986, 29, 2269-
2267.
(4) Genin, M. J.; Allwine, D. A.; Anderson, D. J.; Barbachyn, M. R.;
Emmert, D. E.; Garmon, S. A.; Graber, D. R.; Grega, K. C.; Hester, J. B.;
Hutchinson, D. K.; Morris, J.; Reischer, R. J.; Ford, C. W.; Zurenko, G.
E.; Hamel, J. C.; Schaadt, R. D.; Stapert, D.; Yagi, B. H. J. Med. Chem.
2000, 43, 953-970.
(5) Alvarez, R.; Velazquez, S.; San-Felix, A.; Aquaro, S.; De Clercq,
E.; Perno, C.-F.; Karlsson, A.; Balzarini, J.; Camarasa, M. J. J. Med. Chem.
1994, 37, 4185-4194.
(6) Wamhoff, H. In ComprehensiVe Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 5, pp 669-732.
(7) (a) Rostovstev, 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, 3057-3064. (c) Himo,
F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. R.; Noodleman, L.; Sharpless,
K. B.; Fokin, V. V. J. Am. chem. Soc. 2004, in press.
† University of Leuven.
‡ The Scripps Research Institute.
(1) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004-2021. (b) Kolb, H. C.; Sharpless, K. B. Drug DiscoVery
Today 2003, 8, 1128-1137.
(2) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
Wiley: New York, 1984.
10.1021/ol048341v CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/21/2004

Scheme 1. Microwave-Assisted Three-Component Synthesis
of 1,4-Disubstituted 1,2,3-Triazoles 3a-m
Table 1. One-Pot Synthesis of 1,2,3-Triazoles from Alkyl
Halides, Sodium Azide, and Phenylacetylenea
ides, forming the corresponding 1,4-disubstituted-1,2,3-
triazoles (Scheme 1). Performing both steps of this process
under microwave irradiation10 significantly reduces the time
of the reaction. Products are easily isolated by simple
filtration. As the starting point of our exploration, we chose
the reaction between benzyl bromide 1a and phenylacetylene
2a. The alkyne, alkyl halide, and sodium azide were
suspended in a 1:1 mixture of t-BuOH and water, together
with the catalyst, in a 10-mL sealed glass vial. The Cu(I)
catalyst was prepared in situ by the comproportionation of
Cu(0) and Cu(II). After 10 min of irradiation and subsequent
cooling to room temperature, the triazole product crystallized
from the reaction mixture and was isolated by simple
filtration. Comparison with an authentic sample established
that the triazole was formed in a completely regioselective
manner, with no contamination by the 1,5-regioisomer. The
best conditions were found to be 100 W irradiation power
(8) (a) Punna, S.; Diaz, D. D.; Li, C.; Sharpless, K. B.; Fokin, V. V.;
Finn, M. G. Polym. Prepr. (Am. Chem. Soc., DiV. Polym. Chem.) 2004, 45,
778-779. (b) Lee, L. V.; Mitchell, M. L.; Huang, S.-J.; Fokin, V. V.;
Sharpless, K. B.; Wong, C.-H. J. Am. Chem. Soc. 2003, 125, 9588-9589.
(c) Seo, T. S.; Li, Z.; Ruparel, H.; Ju, J. J. Org. Chem. 2003, 68, 609-612.
(d) Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K. B.;
Finn, M. G. J. Am. Chem. Soc. 2003, 125, 3192-3193. (e) Lo¨ber, S.;
Rodriguez, P.-L.; Gmeiner, P. Org. Lett. 2003, 5, 1753-1755; Perez, F.-
B.; Ortega, M.-M.; Morales, J.-S.; Hera´ndez, F -M.; Calvo, F. G -F.; Calvo,
J. A.-A.; Isac, J.-G.; Santoyo, F.-G. Org. Lett. 2003, 5, 1951-1954.
(9) To the best of our knowledge, there is only one report describing an
in situ formation of 1,2,3-triazoles from alkyl halides, alkynes, and sodium
azide. The methodology reported therein requires heating at high temper-
atures for an extended period of time (up to 18 h), results in low yields of
the products, and prduces both 1,4- and 1,5-regioisomers. See: Maksikova,
A. V.; Serebryakova, E. S.; Tikhonova, L. G.; Vereshagin, L. I. Chem.
Heterocycl. Compd. 1980, 1284-1285.
(10) (a) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
2001, 57, 9225-9283. (b) Lidstro¨m, P.; Westman, J.; Lewis, A. Comb.
Chem. High Throughput Screening 2002, 6, 441-458. (c) Kappe, C. O.
Curr. Opin. Chem. Biol. 2002, 6, 314-320. (d) Larhed, M.; Moberg, C.;
Hallberg, A. Acc. Chem. Res. 2002, 35, 717-727. (e) Loupy, A. MicrowaVes
in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2002 and
references therein. (f) Perez-Balderas, F.; Ortega-Munoz, M.; Morales-
Sanfrutos, J.; Hernandez-Mateo, F.; Calvo-Flores, F. G.; Calvo-Asin, J. A.;
Isac-Garcia, J.; Santoyo-Gonzalez, F. Org. Lett. 2003, 5, 1951-1954. (g)
Sing, P. N. D.; Muthukrishnan, S.; Murthy, R. S.; Kilma, R. F.; Mandel, S.
M.; Hawk, M.; Yarbrough, N.; Gudmundsdo´ttir, A. D. Tetrahedron Lett.
2003, 44, 9169-9171.
(11) Typical Experimental Procedure. (ATTENTION: copper azides
are shock-sensitive when dry. Care should be taken to remove traces of
these compounds from the products by washing with basic ammonium citrate
or dilute HCl). Benzyl bromide (0.170 g, 1.0 mmol), phenylacetylene (0.107
g, 1.05 mmol), and sodium azide (0.068 g, 1.05 mmol) were suspended in
a 1:1 mixture of water and t-BuOH (1.5 mL each) in a 10-mL glass vial
equipped with a small magnetic stirring bar. To this was added copper
turnings (50 mg) and copper sulfate solution (1 M, 200 µL), and the vial
was tightly sealed with an aluminum/Teflon crimp top. The mixture was
then irradiated for 10 min at 125 °C, using an irradiation power of 100 W.
After completion of the reaction, the vial was cooled to 50 °C by air jet
cooling before it was opened. It was then diluted with water (20 mL), and
precipitated product was collected by filtration and washed with cold water
(20 mL), followed by 0.25 M HCl (10 mL), and finally with petroleum
ether (50 mL) to furnish 3a as a white solid (0.219 g, 93%).
a All reactions were carried out on a 1 mmol scale at 125 °C, using 100
W irradiation power; 1.05 equiv each of sodium azide and alkyne were
used with 1.0 equiv of halide in 3 mL of a 1:1 water/tBuOH mixture, with
50 mg of Cu turnings and 200 µL of 1 M CuSO4 solution.
and 125 °C. The product, 1-benzyl-4-phenyl-1H-1,2,3-
triazole11 (3a), has been isolated in 93% yield (Table 1,
entry 1). This prompted us to extend our studies toward
the incorporation of different alkyl halides (Table 1, entries
2-9).
As exemplified in Table 1, the reactions proceeded
smoothly to completion, and the products were isolated in
excellent yields and high purity. The o-nitro- and trimethoxy-
benzyl derivatives 1d and 1e were found to be less reactive
than other halides. However, the reactions were finished (as
analyzed by TLC and CI-MS) in 15 min, and products 3d
and 3e were isolated in 87% and 91% yields, respectively.
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Org. Lett., Vol. 6, No. 23, 2004

The scope of the reaction regarding the alkyne component
was then examined and was found to be excellent. Benzyl
azide was formed in situ from benzyl bromide 1a and sodium
azide. Alkynes containing various functionalities participated
in the three-component process, as Table 2 shows. The yields
remained good to excellent, and regioselectivity was exclu-
sive: only 1,4-regioisomeric products were formed.
Table 2. One-Pot Synthesis of 1,2,3-Triazoles from Benzyl
Bromide, NaN3, and Alkynesa
Most reactions easily tolerated the 125 °C temperature and
the 100 W power that was applied (Table 2, entries 1-4).
However, in case of ethyl propiolate 2l (Table 2, entry 5)
and trimethylsilyl acetylene 2m (Table 2, entry 6), the high
temperature resulted in diminished yields. Reducing the
temperature to 75 °C circumvented this problem, and
products 3l and 3m were isolated in good yields (83% and
88%, respectively).
In conclusion, a microwave-enhanced, fast, and efficient
three-component reaction for generation of 1,4-disubstituted-
1,2,3-triazoles in a completely regioselective manner has been
developed. The method avoids isolation and handling of
potentially unstable small organic azides and provides triazole
products in pure form. Microwave irradiation dramatically
decreases reaction time from hours to minutes. 1,2,3-Triazole
products often crystallize from the reaction mixture and do
not require any purification, rendering the process an ideal
multicomponent click reaction.
Acknowledgment. We are grateful to Prof. K. Barry
Sharpless for his advice. We thank the F.W.O. (Fund for
Scientific Research-Flanders (Belgium)) and the Research
Fund of the University of Leuven for financial support to
the laboratory. P.A. is grateful to the University of Leuven
for obtaining a scholarship. V.V.F. thanks Biotage AB for
providing a Microwave Synthesizer under the Scientific
Partnership Program. We also wish to thank Mr. K. Duer-
inckx for his valuable help with NMR experiments.
a All reactions were carried out on 1 mmol scale; 1.05 equiv each of
azide and alkyne were used with 1.0 equiv of halide in 1.5 mL each of
water and tBuOH, 50 mg of Cu turnings, and 200 µL of 1 M CuSO4
solution.
When methyl iodide 1h was used as the halide, the reaction
proceeded smoothly in 10 min, and the product 3h was
isolated in 89% yield (entry 9). This example clearly
demonstrates the power of the new strategy, as the synthesis
of 3h is otherwise difficult owing to the hazardous nature
of methyl azide.
Supporting Information Available: Characterization
data (1H, 13C, and DEPT NMR, EI-MS) of all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL048341V
Org. Lett., Vol. 6, No. 23, 2004
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