Syn th esis of C-Ca r ba m oyl-1,2,3-tr ia zoles by
Micr ow a ve-In d u ced 1,3-Dip ola r
Cycloa d d ition of Or ga n ic Azid es to
Acetylen ic Am id es
Only rare examples of 1,3-dipolar cycloaddition of
azides to acetylenic amides have been reported, and
reaction times of 24 h to 1 week are reported.6 The low
reactivity of acetylenic amides toward 1,3-dipolar cy-
cloaddition with azides has remained a problem for direct
access to biologically active 1,2,3-triazoles with an amide
substituent; the preparation of these compounds has
generally involved the use of easily available 1,2,3-tri-
azole esters,11 acids, or imines as intermediates, fol-
lowed by a functional group transformation to the amide.
Microwave heating has emerged as a powerful tech-
i,10
Alan R. Katritzky* and Sandeep K. Singh
Center for Heterocyclic Compounds,
Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
12
1
3
nique to promote a variety of chemical reactions.
Microwave reactions under solvent-free conditions are
attractive in offering reduced pollution and low cost
Received September 4, 2002
1
4
together with simplicity in processing and handling.
A
recent report from Palacios et al. on microwave synthesis
of 1,2,3-triazoles shows a substantial decrease in reaction
times down to 5-30 min as compared to 30-40 h
refluxing under thermal conditions for the 1,3-dipolar
cycloaddition between phosphonate azides and acetylenic
esters.15 In continuation of an ongoing program in our
laboratories to synthesize a variety of 1,2,3-triazoles
under mild conditions, we now report the first examples
of 1,3-dipolar cycloadditions of organic azides to acety-
lenic amides under solvent-free microwave irradiation.
Reactions of benzyl chloride, γ-phenylpropyl chloride,
or R,R′-dichloro-p-xylene with sodium azide in ethanol/
water (4:1) at reflux gave the corresponding azides 1, 2,
or 6 in 85-97% yields.16 N-Benzyl-2-propynamide (4) was
obtained in 59% yield by the reaction of propiolic acid
and benzylamine following the mixed anhydride method
of Coppola et al.17 1-Piperidino-2-propyn-1-one (5) was
similarly prepared from propiolic acid and piperidine in
Abstr a ct: 1,3-Dipolar cycloaddition of organic azides 1, 2,
or 3 to acetylenic amides 4 or 5 under solvent-free microwave
irradiation produced the corresponding N-substituted C-car-
bamoyl-1,2,3-triazoles 7a -12a in good to excellent yields.
Under similar reaction conditions, 1,3-dipolar cycloaddition
of diazide 6 and acetylenic amide 4 gave the azido-triazole
1
3a .
1
,3-Dipolar cycloaddition of azides to alkynes is a
1
versatile route to 1,2,3-triazole, and the progress in this
2
area has been reviewed periodically. Combinations of
substituents on the azide3 and the alkyne allow the
,4
5
preparation of diverse N-substituted 1,2,3-triazoles.
Substituents on the alkyne include importantly esters6a-d
and also carboxyl, hydroxy, keto, aryl, haloalkyl, tri-
methylsilyl, phenylsulfonyl, or phosphonate groups.4,6e-j
Classical 1,3-dipolar cycloadditions also include azides
7
8
with metal acetylides, alkynic Grignard reagents, and
6
8% yield.
phosphonium salts.9
(
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0.1021/jo026398u CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/09/2002
J . Org. Chem. 2002, 67, 9077-9079
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