Vol. 27, No. 12, 2016
Silva et al.
2381
consumption of 1, and flash column chromatography was
used to isolate the resulting byproduct.
believed that the propagation of ultrasound can facilitate
the interaction at various stages and the migration of the
nucleophile into the organic phase, making it easier to
attack.21,22
Few investigations have focused on the effects of the
substituents on the reactivity of the substrates involved in
the reaction of 1,3-dipolar cycloaddition, especially using
the click reaction. However, generally speaking, alkynes23
and azides24 containing electron-withdrawing groups
(EWG) are less bulky and more reactive. Thus, Feldman
et al.25 reported that primary and secondary azides react
selectively with phenyl acetylene, and no product was
observed when tertiary azides were used.
Even though the byproduct of the structure has not
been fully identified in our investigation, it is noteworthy
that Sharpless and co-authors16 observed the formation of
dimers (bis-triazoles, 5-hydroxytriazoles and diacetylenes)
as undesired byproducts in the click reaction. The triazole
derivatives were obtained in yields below 30% (Table 1).
In addition to low yields, the use of a chromatography
column is not considered environmentally friendly because
of the large amount of solvent used (approximately 4 L of
ethyl acetate and 4 L hexane for each substance). Notably,
in these conditions the reagents were not completely soluble
in the reaction medium. Some researchers emphasize that
there is no need for the species involved in the reaction to
fully dissolve in the medium provided that the samples are
kept under strong agitation.17
Aiming at improving the product yields in the first
method, the CH2Cl2 was replaced with tert-butanol, and
excess alkyne was added with a catalytic amount ofAcOH,
leading to a good yield in the 2a-2l products (method ii,
Scheme 1 and Table 1) without requiring further purification
using column chromatography.
As shown in Table 1, we have observed that the reaction
time for the synthesis of triazoles was influenced by the
presence ofAcOH. In this condition, the reaction time was
reduced from 48 to 24 hours.18
In general, reactions performed under ultrasound
irradiation have higher yields and better selectivities than
those carried out under classical conditions (shaking, heating,
cooling). Furthermore, the reaction time is greatly reduced.
Indeed, the use of ultrasound produced 5’-(4-alkyl/aryl-
1H-1,2,3-triazoles) in higher yields than the observed for
methods i and ii, and the reaction time was only 5 minutes.
How the ultrasound irradiation affects the reaction is still
a subject of much debate in the scientific community.
There are two phenomena involved in ultrasound-mediated
reactions that can be analyzed separately to gain a better
understanding: the physical phenomenon and the chemical
phenomenon.19,20 The physical phenomenon can be divided
into three types: the first refers to the sonic pressure,
which subjects the liquid compression and rarefaction; the
second is cavitation, which is the collapse of microbubbles
of a liquid formed by ultrasonic energy; and the third is
a phenomenon related to mass transport resulting from
turbulent mixing and acoustic agitation.
Conclusions
In summary, we investigated three methods for the
synthesis of a series of isatin-type 5’-(4-alkyl/aryl-1H-
1,2,3-triazoles) from organic azides and terminal alkynes.
Acetic acid combined with ultrasonic irradiation was
shown to play a key role in the click reaction, providing
triazoles-isatins quickly and efficiently.All the products are
obtained in just 5 min without purification step, saving time,
reducing energy and wastes, featuring an environmentally
friendly method.
The ultrasound effects influencing the reaction are not
well understood; however, using ultrasound, triazoles were
obtained approximately 300 times faster than by other
methods. The nature of the substituent had no significant
influence on the reactivity of the alkyne.Although an acidic
medium was used, the dehydration of the alkynes with a
hydroxyl group was not observed.
Supplementary Information
Supplementary information associated with this work
(NMR spectra (1H and 13C), infrared and EMAR-ESI(+):
[M + H]+) is available in reference 12.
Acknowledgments
The authors thank the Brazilian agencies National
Counsel for Technological and Scientific Development
(CNPq), State of Rio de Janeiro Research Foundation
(FAPERJ) and Coordination for the Improvement of Higher
Education Personnel (CAPES).
A chemical phenomenon bound to a physical
phenomenon primarily is a result of the cavitation effect
of changes in the temperature and pressure of the reaction
medium, and in this case, the reactivities of the substances
involved in the reaction are increased. However, it is
References
1. Garden, S. J.; Torres, J. C.; Ferreira, A. A.; Silva, R. B.; Pinto,
A. C.; Tetrahedron Lett. 1997, 38, 1501.