[3+2] Cycloaddition reactions in the solid-phase synthesis of 1,2,3-triazoles

Article abstract of DOI:10.1021/ol0611494

An efficient and regioselective procedure for the synthesis of 1,2,3-triazoles via a [3+2] cycloaddition of polymer-bound vinyl sulfone and sodium azide is described. Microwave irradiation provided significant rate enhancement in all steps of the three-st

Full text of DOI:10.1021/ol0611494

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3283-3285
[3+2] Cycloaddition Reactions in the
Solid-Phase Synthesis of 1,2,3-Triazoles
Yongnian Gao and Yulin Lam*
Department of Chemistry, National UniVersity of Singapore,
3 Science DriVe 3, Singapore 117543
chmlamyl@nus.edu.sg
Received May 11, 2006
ABSTRACT
An efficient and regioselective procedure for the synthesis of 1,2,3-triazoles via a [3+2] cycloaddition of polymer-bound vinyl sulfone and
sodium azide is described. Microwave irradiation provided significant rate enhancement in all steps of the three-step protocol. A representative
set of 23 compounds was prepared.
1,2,3-Triazoles are attractive targets as they are associated
with a wide range of applications in organic, materials, and
medicinal chemistry. Numerous synthetic approaches to this
class of compounds have been developed.1 Among them,
the 1,3-dipolar cycloaddition of azides and alkynes is the
traditional and extensively used method. However, the
efficiency of this process is dependent on the steric and
electronic properties of the alkyne, and until recently, the
regioselectivities of these reactions are generally low with
unsymmetrical alkynes giving regioisomeric mixtures of
triazoles.2 As a consequence of these problems, such cy-
cloaddition reactions have found limited use in the solid-
phase synthesis (SPS) of triazole libraries.
Alternative solid-phase routes for the synthesis of 1,2,3-
triazoles have rarely been explored.1e,k In particular, the [3+2]
cycloaddition of azides and electron-poor alkenes (Scheme
1) has received very little attention. This may be attributed
Scheme 1. Directed [3+2] Cycloaddition
(1) (a) Huisgen, R.; Knorr, R.; Moius, L.; Szeimies, G. Chem. Ber. 1965,
98, 4014-4021. (b) Maiorana, S.; Pocar, D.; Calla Croce, P. Tetrahedron
Lett. 1966, 7, 6043-6045. (c) Meek, J. S.; Fowler, J. J. Org. Chem. 1968,
33, 985-991. (d) Chakrasali, R. T.; Ila, H.; Junjappa, H. Synthesis 1988,
851-854. (e) Li, C. L.; Huang, W. Q.; Lu, Y.; He, B. L. Chin. Chem. Lett.
1991, 2, 773-774. (f) Dong, Z.; Hellmund, K. A.; Pyne, S. G. Aust. J.
Chem. 1993, 46, 1431-1436. (g) Gouault, N.; Cupif, J. F.; Sauleau, A.;
David, M. Tetrahedron Lett. 2000, 41, 7293-7297. (h) Rostovtsec, V. V.;
Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002,
41, 2596-2599. (i) Harju, K.; Vahermo, M.; Mutikainen, I.; Yli-Kau-
haluoma, J. J. Comb. Chem. 2003, 5, 826-833. (j) Batanero, D. B.; Barba,
F. Heterocycles 2004, 65, 1175-1180. (k) Raghavendra, M. S.; Lam, Y.
Tetrahedron Lett. 2004, 45, 6129-6132. (l) Krasin˜ski, A.; Fokin, V. V.;
Sharpless, K. B. Org. Lett. 2004, 6, 1237-1240. (m) Amantini, D.;
Fringuelli, F.; Piermatti, O.; Pizzo, F.; Zunino, E.; Vaccaro, L. J. Org. Chem.
2005, 70, 6426-6529. (n) Coats, S. J.; Link, J. S.; Gauthier, D.; Hlasta, D.
J. Org. Lett. 2005, 7, 1469-1472. (o) Roque, D. R.; Neill, J. L.; Antoon,
J. W.; Stevens, E. P. Synthesis 2005, 2497-2502.
to the poor reactivities of the reactants which require harsh
reaction conditions to facilitate the cycloaddition.1b,o Thus,
finding an easy method to facilitate the solid-phase cycloaddi-
tion would be essential. We herein report a convenient solid-
phase procedure for the regioselective and traceless synthesis
of trisubstituted and disubstituted 1,2,3-triazoles (Scheme 2).
Polystyrene/1% divinylbenzene sodium sulfinate resin 1
was chosen for our solid-phase studies because (i) the vinyl
sulfone dipolarophile can be efficiently generated and (ii)
the electronegative sulfone that is eliminated in the reaction
may serve as a means to direct the regiochemistry of the
cycloaddition as well as a traceless linker for the SPS.
To define the scope of this reaction, representative triazoles
were synthesized using 1 to survey the requisite reaction
(2) (a) Hlasta, D. J.; Ackerman, J. H. J. Org. Chem. 1994, 59, 6184-
6189. (b) Sasaki, T.; Eguchi, S.; Yamaguchi, M.; Esaki, T. J. Org. Chem.
1981, 46, 1800-1804. (c) Howell, S. J.; Spencer, N.; Philp, D. Tetrahedron
2001, 57, 4945-4954.
10.1021/ol0611494 CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/28/2006

set of compounds (4a-p) was prepared (Figure 1). Except
Scheme 2. Sulfinate SPS of 1,2,3-Triazoles
conditions required for SPS. Treatment of 1 with bromoac-
etonitrile, R-bromoketone, or R-bromoamide at 100 °C for
12 h gave 2 which was amenable to KBr FTIR monitoring
(disappearance of the sulfinate stretch at 959 cm-1 and
appearance of the sulfone stretch at 1320 and 1147 cm-1, of
the CdO stretch at 1746 cm-1, and of the CN stretch at 2258
cm-1). Subsequent Knoevanagel condensation of 2 with an
aldehyde in refluxing benzene and 1 equiv of piperidine as
a catalyst for 5 h1e gave the polymer-supported vinyl sulfone
3 which could not be reliably analyzed on the FTIR. Hence,
we proceeded with the cycloaddition of 3 with NaN3 in DMF
at 120 °C for 2 h (R1 ) CN), 5 h (R1 ) CO2CH3 or COCH3),
or 12 h (R1 ) CONH2) which concomitantly released the
target molecule from the solid support in trace amounts.
Attempts to carry out the condensation at higher temperatures
led to the formation of various decomposition products.
Further examination of the reaction indicated that the
condensation occurred most favorably in refluxing THF for
36 h with piperidine or piperidine acetate as the catalyst.
To facilitate combinatorial synthesis, we needed to estab-
lish a methodology to prepare the 1,2,3-triazoles more expe-
diently. Because microwave irradiation has been shown to
provide a striking reduction in reaction times and cleaner
reactions over conventional thermal procedures,3 we proceed-
ed to explore the SPS of our compounds under microwave
conditions. For the initial evaluation of the microwave-assist-
ed formation of 2, we carried out a systematic variation of the
reaction time and temperature with bromoacetonitrile as a
representative example. We discovered that the reaction was
completed within 20 min at a preselected temperature of 60
°C and 10 equiv of bromoacetonitrile. Microwave-assisted
Knoevanagel condensation of 2 (R1 ) CN) with benzalde-
hyde in THF at 82 °C for 20 min followed by sodium azide
cycloaddition at 120 °C for 20 min under microwave
activation, extraction, and purification gave 4a in 70% overall
yield (vs 55% yield obtained via conventional heating). To
illustrate the versatility of this methodology, a representative
Figure 1. Library of 4,5-disubstituted-1,2,3-triazoles. The values
in parentheses indicate the overall yields obtained via conventional
heating.4
for 4o and 4p (R1 ) CONH2), the microwave-assisted
procedure generally led to significantly higher conversion
and purity. The lower yields for the amide-substituted tria-
zoles may be attributed to the more sluggish Knoevanagel
condensation which did not proceed at 82 °C. Hence, forma-
tion of 3 (R1 ) CONH2) was carried out at 111 °C in DMF.
To address the regiochemistry of the cycloaddition reac-
tion, resin 3a was treated in a one-pot coupling procedure
with sodium azide and bromomethylcyclohexane (Table 1)
Table 1. Cycloaddition of Resin 3a To Form Triazole 5a
temperature (°C)
3a:A:B:C
yield (%)a
100
35
70
100
120
150
1:5:10:0
1:5:10:5
1:5:10:5
1:5:10:5
1:5:10:5
1:5:10:5
<5
41
45
45
50
55
a Overall yield of 5a.
(3) (a) Caddick, S. Tetrahedron 1995, 51, 10403-10432. (b) Varma, R.
S. Green Chem. 1999, 43-55. (c) Lew, A.; Krutzik, P. O.; Hart, M. E.;
Chamberlin, A. R. J. Comb. Chem. 2002, 4, 95-105.
to give two regioisomers in a 10:1 ratio.5 HMBC analysis
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Org. Lett., Vol. 8, No. 15, 2006

of the major regioisomer showed a proton-carbon correlation
between the methylene proton (CH2C6H11) and the nitrile
carbon indicating that the major isomer could possibly be
the N1 and N2 regioisomer. Further analysis by X-ray
crystallography confirmed that the major isomer is 2-cyclo-
hexylmethyl-5-phenyl-2H-[1,2,3]triazole-4-carbonitrile 5a
(Figure 2). Analogous cycloadditions with various resins 3
regioselectivity of each crude mixture was approximately
10:1 with only polymer-bound 3-benzenesulfonyl-6-chlorochro-
men-2-one and benzyl bromide providing a greater amount
of the second regioisomer. Regiochemical assignments based
on X-ray crystallography show that 5e1 and 5e2 are the major
and minor isomers, respectively (Figure 2).
We have also examined the synthesis of 3 (R1 ) H) via
the ionic addition of 1 to alkenes (Scheme 3). To our
Scheme 3. Sulfinate SPS of Monosubstituted 1,2,3-Triazoles 7
knowledge, this reaction has not been explored on the solid
phase. In our experiments, 1 was treated with styrene in the
presence of I2 to yield â-iodosulfone 6 which was subse-
quently reacted with TEA to give the desired vinyl sulfone
3b. Microwave-assisted cycloaddition with sodium azide in
DMF at 160 °C for 20 min gave 7a in 40% overall yield
(cycloaddition at 120 °C for 20 min gave 7a in 5% overall
yield). Similarly, treatment of 1 with 1-methyl-4-vinyl-
benzene gave 7b in 45% overall yield.
In summary, an efficient and regioselective traceless SPS
of trisubstituted and disubstituted 1,2,3-triazoles has been
devised. Using microwave irradiation, we have also shown
that the total reaction time could be shortened from over 1
day to 1 h. Because a variety of reagents can be used in
each step of the reaction, the overall strategy enables efficient
library generation.
Figure 2. Crystal structures of 5a, 5e1, and 5e2.
and alkyl halides were also performed (Figure 3). The
Acknowledgment. We thank the National University of
Singapore for financial support of this work.
Supporting Information Available: Experimental details
and characterization data of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0611494
(4) Triazoles are known to undergo tautomerism. From the X-ray crystal
studies of the compounds reported in this manuscript, it is clear that the
position of the NH is dependent on the substituents on the triazole ring.
Hence, for consistency in the drawings of our figures and schemes, we
have placed all the NH on position 2.
(5) Attempts to carry out the cycloaddition with organic azides did not
give the desired triazole, and the starting materials were recovered.
Figure 3. Trisubstituted-1,2,3-triazoles.
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