One-pot synthesis of 1,4-disubstituted 1,2,3-triazoles from in situ generated azides

Article abstract of DOI:10.1021/ol048859z

(Chemical Equation Presented) 1,4-Disubstituted 1,2,3-triazoles are obtained in excellent yields by a convenient one-pot procedure from a variety of readily available aromatic and aliphatic halides without isolation of potentially unstable organic azide intermediates.

Full text of DOI:10.1021/ol048859z

ORGANIC
LETTERS
2
004
Vol. 6, No. 22
897-3899
One-Pot Synthesis of 1,4-Disubstituted
,2,3-Triazoles from In Situ Generated
3
1
Azides
Alina K. Feldman, Beno ˆı t Colasson, and Valery V. Fokin*
Department of Chemistry and the Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
fokin@scripps.edu
Received June 16, 2004
ABSTRACT
1,4-Disubstituted 1,2,3-triazoles are obtained in excellent yields by a convenient one-pot procedure from a variety of readily available aromatic
and aliphatic halides without isolation of potentially unstable organic azide intermediates.
Cu(I)-catalyzed ligation of organic azides and terminal
alkynes has enjoyed much use since its discovery. Exclusive
regioselectivity, wide substrate scope, mild reaction condi-
Aliphatic azides can be readily prepared from the corre-
sponding halides by nucleophilic displacement or, in cases
of aryl and vinyl azides, by a Cu(I)-catalyzed reaction (vide
infra) with sodium azide. The substitution is especially facile
when activated halides, such as allylic, propargylic, and
benzylic, are used. Herein, we report an efficient and safe
one-pot, two-step procedure for trapping thus generated
azides by alkynes to obtain the corresponding triazole
1
tions, and very high yields have made it the method of
choice for making permanent connections by means of 1,4-
disubstituted 1,2,3-triazoles. The methodology has found
applications in drug discovery, bioconjugations, and materials
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science.
4
Although organic azides are generally safe compounds,
those of low molecular weight can be unstable and, therefore,
products (Table 1).
The reagents were simply mixed in a vial (0.5 M) and
stirred overnight. In most cases, the pure products were
isolated by filtration. Furthermore, the efficiency of each
step is retained in this one-pot procedure (the formation
of tris-triazolyl derivative 3d, entry 4, requires six reac-
tions).
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difficult to handle. This is especially true for small molecules
with several azide functionalities that would be of much
interest for the generation of polyvalent structures. Thus, a
methodology that avoids isolation of organic azides is
desirable.
When the nucleophilic substitution of the halide is less
efficient, the competing formation of an N-H triazole is
observed. Inorganic azide adds to the alkyne, producing N-H
triazole byproducts. Further studies to eliminate this undes-
ired pathway are currently underway.
(
1) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596. (b) Tornœ, C. W.; Christensen, C.;
Meldal, M. J. Org. Chem. 2002, 67, 3057.
(2) For recent examples of the azide-acetylene ligation reaction, please
see: (a) Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K.
B.; Finn, M. G. J. Am. Chem. Soc. 2003, 125, 3192. (b) Speers, A. E.;
Adam, G. C.; Cravatt, B. F. J. Am. Chem. Soc. 2003, 125, 4686. (c)
Anderson, J. C.; Schultz, P. G. J. Am. Chem. Soc. 2003, 125, 11782. (d)
Link, A. J.; Tirrell, D. A. J. Am. Chem. Soc. 2003, 125, 11164. (e) Collman,
J. P.; Devaraj, N. K.; Chidsey, C. E. D. Langmuir 2004, 20, 1051. (f) Wu,
P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel, A.; Voit, B.;
Pyun, J.; Frechet, J. M. J.; Sharpless, K. B.; Fokin, V. V. Angew. Chem.
Int. Ed. 2004, 43, 3928-3932.
(4) 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. This method requires heating the reagents at high temperatures for
extended periods of time, resulting in a mixture of both regioisomers, and
gives low yields. Maksikova, A. V.; Serebryakova, E. S.; Tikhonova, L.
G.; Vereshagin, L. I. Chem. Heterocycl. Comp. 1980, 1284.
(3) Scriven, E. F. V.; Turnbull, K. Chem. ReV. 1988, 2, 351.
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0.1021/ol048859z CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/25/2004

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Table 1. One-Pot Synthesis of 1,2,3-Triazoles from Alkyl Halides, NaN , and Alkynes
a
Performed with 1.2 equiv of NaN3, 5 mol % CuSO4‚5H2O, and 10 mol % sodium ascorbate per halide functionality; all reactions were performed at
b
ambient temperature, except for reaction 4 (65 °C). Isolated yield.
3
Table 2. One-Pot Synthesis of 1,2,3-Triazoles from Aryl and Vinyl Halides, NaN , and Alkynes
a
Isolated yield. b Due to high water solubility, some product was lost during isolation.
3898
Org. Lett., Vol. 6, No. 22, 2004

The methods for generation of aryl and vinyl azides that
would be compatible with the copper catalysis have not been
available until now. We were, therefore, pleased to find that
a recently published report describing preparation of aryl and
vinyl azides from the corresponding halides via a Cu(I)-
As is the case with the parent reaction,1a the one-pot
process exhibits excellent scope with regards to both the
halide and the alkyne components.
Since aryl iodides are generally more reactive than the
corresponding bromides, the p-bromo iodobenzene 1f was
successfully converted to the mono-triazole product 3n
without affecting the aryl bromide functionality, thus making
it available for further transformations. Heteroaryl halides
such as 3-iodopyridine 1h also readily participate in this
process.
5
catalyzed proline-promoted reaction provided a convenient
route to the azide intermediates used in a one-pot method.
The results are summarized in Table 2. After screening a
variety of copper sources, ligands, and solvent combinations,
we arrived at the experimentally simple and safe general
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procedure for this one-pot two-step process. Under the
Even though reactivity of alkenes with azides is generally
higher than of alkynes, we successfully converted vinyl
iodides to the corresponding allylic triazole derivatives
optimized conditions, the triazole products are obtained in
good yields, and formation of the undesired N-H triazole
byproducts is suppressed. The regioselectivity of the reaction
is maintained even at the elevated temperatures.
(entries 13 and 14).
In conclusion, a safe and efficient method for the synthesis
of 1,4-disubstituted 1,2,3-triazoles directly from a variety of
alkyl and aryl halides, sodium azide, and terminal alkynes
has been developed. The procedure does not require isolation
of the azide intermediates and should prove to be especially
useful when unstable low-molecular weight and polyvalent
azides are needed.
(
5) Zhu, W.; Ma, D. Chem. Commun. 2004, 7, 888.
(6) Typical Experimental Procedure A. Products precipitate from the
reaction mixture. Iodobenzene 1e (102 mg, 0.5 mmol, 1 equiv) was mixed
with 1-chloro-4-prop-2-ynyloxy-benzene 2g (84 mg, 0.5 mmol, 1 equiv) in
a 20 mL scintillation vial. To the mixture were added L-proline (12 mg,
.1 mmol, 0.2 equiv), Na2CO3 (12 mg, 0.1 mmol, 0.2 equiv), NaN3 (39
mg, 0.6 mmol, 1.2 equiv), sodium ascorbate (20 mg, 0.05 mmol, 0.1 equiv),
:1 DMSO/H2O (1 mL), and CuSO4‚5H2O (13 mg, 0.025 mmol, 0.05 equiv).
0
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The mixture was stirred overnight at 65 °C. Upon completion (monitored
by TLC or LC-MS), the crude mixture was poured into 30 mL of ice-cold
water. The off-white precipitate was isolated by filtration and washed with
dilute NH4OH (ATTENTION: this step is important, as copper azides are
explosive when dry, and their traces should be removed before the product
is dried) to yield 3k as an off-white solid (211 mg, 83%). Typical
Experimental Procedure B. Products do not precipitate from the reaction
mixture. 3-Iodopyridine 1h (103 mg, 0.5 mmol, 1 equiv) is mixed with
Acknowledgment. We thank Prof. K. Barry Sharpless
for his scientific advice. We thank the National Institute of
General Medical Sciences, the National Institutes of Health
(
GM-28384), and Pfizer, Inc., for financial support. B.C.
thanks the French Minist e` re des Affaires Etrang e` res for the
Lavoisier fellowship. A.K.F. thanks the Skaggs Foundation
for a graduate fellowship.
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-diethylamino-1-propyne (56 mg, 0.5 mmol, 1 equiv) in a 20 mL
scintillation vial. To the mixture were added L-proline (12 mg, 0.1 mmol,
0
1
.2 equiv), Na2CO3 (12 mg, 0.1 mmol, 0.2 equiv), NaN3 (39 mg, 0.6 mmol,
.2 equiv), sodium ascorbate (20 mg, 0.05 mmol, 0.1 equiv), 9:1 DMSO/
H2O (1 mL), and CuSO4‚5H2O (13 mg, 0.025 mmol, 0.05 equiv). The
mixture was heated overnight at 65 °C. Upon completion (monitored by
TLC or LC-MS), the crude mixture was poured into dilute NH4OH (30
mL; ATTENTION: this step is important, as copper azides are explosive
when dry, and their traces should be removed before the product is dried)
and extracted with ethyl acetate (3 × 20 mL). The organic layer was washed
with brine (2 × 20 mL), dried over MgSO4, and evaporated to yield 3p as
a pale yellow oil (112 mg, 94%).
Supporting Information Available: Spectral character-
ization of all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL048859Z
Org. Lett., Vol. 6, No. 22, 2004
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