Synthesis of novel isatin-type 5'-(4-Alkyl/Aryl-1H-1,2,3-triazoles) via 1,3-dipolar cycloaddition reactions

Article abstract of DOI:10.5935/0103-5053.20130023

Isatin and 1H-1,2,3-triazoles are two classes of compounds with great prominence in organic synthesis and medicinal chemistry as they are heterocycle nuclei with a high reactivity allowing to obtain several compounds with important biological properties. Herein, the synthesis of novel 5'-(4-alquil/aril-1H-1,2,3-triazole)-isatin via reaction of 1,3-dipolar cycloaddition catalyzed by acetic acid is reported.

Full text of DOI:10.5935/0103-5053.20130023

http://dx.doi.org/10.5935/0103-5053.20130023
J. Braz. Chem. Soc., Vol. 24, No. 2, 179-183, 2013.
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Communication
Synthesis of Novel Isatin-Type 5'-(4-Alkyl/Aryl-1H-1,2,3-triazoles) via
1,3-Dipolar Cycloaddition Reactions
Bianca N. M. Silva,*,a Bárbara V. Silva,a Fernando C. Silva,b Daniel T. G. Gonzaga,b
Vitor F. Ferreirab and Angelo C. Pintoa
aInstituto de Química, Universidade Federal do Rio de Janeiro, 21949-900 Rio de Janeiro-RJ, Brazil
bInstituto de Química, Universidade Federal Fluminense, 24020-141 Niterói-RJ, Brazil
As isatinas e os 1H-1,2,3-triazóis são duas classes de compostos com grande destaque na síntese
orgânica e na química medicinal uma vez que são núcleos heterociclos com elevada reatividade,
que permitem a obtenção de diversos compostos com importantes propriedades biológicas. Neste
artigo, a síntese de novos 5`-(4-alquil/aril-1H-1,2,3-triazóis)-isatina via reação de cicloadição
1,3-dipolar catalisada por ácido acético é descrita.
Isatin and 1H-1,2,3-triazoles are two classes of compounds with great prominence in organic
synthesis and medicinal chemistry as they are heterocycle nuclei with a high reactivity allowing
to obtain several compounds with important biological properties. Herein, the synthesis of novel
5’-(4-alquil/aril-1H-1,2,3-triazole)-isatin via reaction of 1,3-dipolar cycloaddition catalyzed by
acetic acid is reported.
Keywords: isatin, 1H-1,2,3-triazoles, 1,3-dipolar cycloaddition reactions
Introduction
preparation of new drugs with diverse biological activities
because these compounds can have different structures with
the same numbers of carbon and nitrogen atoms. 1H-1,2,3-
Triazoles (4, Figure 1b) are compounds of exclusively
synthetic origin,22 and there are several methods available
for the 1,4 regiospecific synthesis of 1H-1,2,3-triazoles.
The 1,3-dipolar cycloaddition of organic azides (2) with
terminal alkynes (3) catalyzed by Cu (I) is one of the most
versatile of these methods.23
Isatin (2,3-dihydro-2,3-dioxo-1H-indole 1, Figure 1a)
is a simple small molecule that is present in plants of the
genus Isatis1 and in some animals like, such as Bufo frogs.2
This compound is also distributed in different regions of the
brain and in various body fluids in humans.3-5 Its reactivity
has been explored by several research groups due to its
structure, which allows nucleophilic substitution reactions
involving the aromatic ring, especially at positions 5 and
7;6 acylation7 or alkylation8 at the N-H; and reduction9
or condensation10-12 at the amide [C-2] and ketone [C-3]
carbonyls, which have distinct reactivities.
Isatin and its derivatives have been reported to
exhibit a variety of biological properties, and are also
frequently employed as raw materials to produce bioactive
compounds.13 Isatin and its derivatives show sedative-
hypnotic,14 antitumor,15,16 antimicrobial,17 antibacterial,18
anticonvulsant,19 anticancer,20 and anti-HIV21 activities,
among others.
Triazoles represent a class of five-membered
heterocyclic compounds of great importance in the
Figure 1. (a) Structure of isatin and (b) scheme for obtaining 1,2,3-triazoles
(4) from organic azides (2) and terminal alkynes (3).
*e-mail: biancanascimento@iq.ufrj.br

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Synthesis of Novel Isatin-Type 5’-(4-alkyl/aryl-1H-1,2,3-triazoles) via 1,3-Dipolar Cycloaddition Reactions J. Braz. Chem. Soc.
Figure 2. Simplified mechanism of the 1,3-dipolar cycloaddition that yield 1,4-disubstituted 1,2,3-triazoles (4).
Although the reaction mechanism is not yet completely
understood, studies have indicated that the formation of
copper acetylide (5) is followed by the generation of an
unstable cyclic intermediate (6) that undergoes protonolysis
following successive steps, yielding 1,4-disubstituted
1,2,3-triazoles (4) (Figure 2).24-26
Currently, the most widespread reaction condition
employed for the 1,4- regiospecific method is the use of
an organic solvent, such as t-BuOH or CH2Cl2, water,
CuSO4.5H2O and sodium ascorbate.27,28
Hein and Folkin29 claim in their work that the presence of
water in the reaction medium is essential to maintain copper
acetylide (5) in its reactive state because the complexation
of Cu(I) with the alkyne in an aqueous system decreases the
pKa of hydrogen at 9.8 units, favoring its deprotonation.
However, Shao et al.30 observed that the use of protic
solvents in presence of base (N,N-diisopropylethylamine
or triethylenediamine), which are used to reduce Cu(II) to
Cu(I), promoted the formation of dimers as byproducts,
such as diacetylenes, bis-triazoles and 5-hydroxytriazoles.
Moreover, Straub and co-workers30 have described that
acetic acid more efficiently promoted the breaking of the
C-Cu bond to give C-H (4), leading to the desired product
in a shorter time.
In 2010, Sun and Wu32 proposed the use of an
azide:alkyne molar ratio of 1:1 based on the results
obtained using infrared spectroscopy. This ratio differs
from the ratios used in many other studies, which
employed excess azide. It is noteworthy that the unreacted
excess azide must be removed using a column, which
requires additional time and solvent and decreases the
reaction yield.
Triazoles have been attracting increasing attention from
the scientific community because of the wide variety of
pharmacological activities that this class exhibits.Although
their 1,2,4-regioisomers are present in many drugs,
1,2,3-triazoles are of great interest due to their excellent
synthetic accessibility. There are reports that the triazole
ring acts as a bioisostere of the amide functional group but
it is more stable because undergoes hydrolysis, oxidation
or reduction. Furthermore, 1,2,3-triazoles have large dipole
moments (ca. 5 D), and the nitrogens at positions 2 and 3
act as weak hydrogen bond acceptors.33
The literature describes a series of biological
properties34 for 1,2,3-triazoles and their derivatives,
such as antitubercular,35 fungicidal,36 anti-HSV,37 anti-
HIV,38 antitumor,39 anti-inflammatory40, tripanocidal,41
antimicrobial,42 antiplatelet43 and anticonvulsivant
activities.44
Results and Discussion
In this article, it is described the synthesis of novel isatin
derivatives, 5’-(4-alkyl/aryl-1H-1,2,3-triazoles) (11a-l),
using 5-azido-spiro[1,3-dioxolane-2,3’-indol]-2’(1’H)-
one (10) in the presence of various alkynes under acidic
conditions (Scheme 1). The products were characterized
by infrared spectroscopy (IR), nuclear magnetic resonance
(NMR) spectroscopy and electrospray mass spectrometry
(ESI-MS).
Initially, 5-nitro-spiro[1,3-dioxolane-2,3’-indol]-
2’(1’H)-one (8) was prepared from 5-nitro-isatin (7),
using ethylene glycol, p-toluenesulfonic acid and toluene
in a 67% yield. Then, the nitro group was reduced by

Vol. 24, No. 2, 2013
Silva et al.
181
Scheme 1. Yields and reaction conditions for novel isatin-type 5`-(4-alkyl/aryl-1H-1,2,3-triazoles) (11a-l).
catalytic hydrogenation to give 5-amino isatin (9), in an
87% yield. In the next step, the azido group was obtained
using a diazotization reaction with sodium nitrite in an
acidic medium, with subsequent addition of sodium azide,
producing 10 (Scheme 1).
Preliminary studies of the reaction of product 10 with
terminal alkynes were performed using CuSO4.5H2O,
sodium ascorbate and CH2Cl2 as the solvent. These reaction
conditions furnished triazoles in yields below 30%. Next,
to improve the yields, the dichloromethane was replaced
with a 1:1 mixture of tert-butanol, and 30 mol% (based on
10) of acetic acid was added, leading to products 11a-11l
in good yields (55-75%).
alkyne. Furthermore, although an acidic medium was used,
the dehydration of alkynes having hydroxyl group was not
observed (11b-11e).
1
The H NMR spectra showed that the structures of
the triazole compounds shared a common signal from the
amide hydrogen, which appeared at 10.7 ppm, whereas the
hydrogen attached to the triazole ring appeared in the range
of 8.5 to 9.2 ppm. The hydrogens H-8 and H-9 appeared
as a multiplet at 4.30 to 4.36 ppm (see Supplementary
Information section).
Conclusion
As shown in Scheme 1, in all cases, the reactions were
conducted over 24 h, and the nature of the substituent
did not have significant influence on the reactivity of the
In summary, we described herein the synthesis, in good
yields, of a series novel isatin-type 5’-(4-alkyl/aryl-1H-
1,2,3-triazoles) (11a-l) using the classical method for the

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Synthesis of Novel Isatin-Type 5’-(4-alkyl/aryl-1H-1,2,3-triazoles) via 1,3-Dipolar Cycloaddition Reactions J. Braz. Chem. Soc.
preparation of 1,4-disubstituted 1,2,3-triazoles from organic
azides and terminal alkynes. These novel isatin derivatives
are promising candidates for the treatment of different
illness, including cancer and neglected diseases, and these
compounds have the ability to act on the central nervous
system.
13. da Silva, J. F. M.; Garden, S. J.; Pinto, A. C.; J. Braz. Chem.
Soc. 2001, 12, 273.
14. Zudo, G.-S.; Pontes, L. B.; Gabriel, D.; Mendes, T. C. F.;
Ribeiro, N. M. Pinto, A. C.; Trachez, M. M.; Sudo, R. T.;
Pharmacol. Biochem. Behav. 2007, 86, 678.
15. Sun, S. Schiller, J. H.; Crit. Rev. Oncol. Hematol. 2007, 62, 93.
16. Vine, K. L.; Matesic, L.; Locke, J. M.; Ranson, M. Skropeta, D.;
Anti-Cancer Agents Med. Chem. 2009, 9, 397.
17. Pandeya, S. N.; Siriram, D.; Nath, C.; De Clercq, E.; Il Farmaco
1999, 54, 624.
Supplementary Information
Supplementary information associated with this work
contains NMR spectra (1H and 13C), infrared and the typical
procedure for preparation of the compounds (Experimental
section). These data are available free of charge at
http://jbcs.sbq.org.br as a PDF file.
18. Sridhar, S. K.; Saravanan, M.; Ramesh, A.; Eur. J. Med. Chem.
2001, 36, 615.
19. Küçükgüzel, I.; Küçükgüzel, S. G.; Rollas, S.; Sanis, G. Ö;
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Acknowledgment
20. Singh, P.; Sharma, P.;Anand,A.; Bidi, P. M. S.; Kaur, T.; Saxena,
A. K.; Kumar, V.; Eur. J. Med. Chem. 2012, 55, 455.
21. Pandeya, S. N.; Sriram, D.; Nath, G.; Declercg, E.; Eur. J.
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The authors thank the Brazilian agencies National
Counsel for Technological and Scientific Development
(CNPq) and State of Rio de Janeiro Research Foundation
(FAPERJ).
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M. C. B.V.; Ferreira, M. L. G.; Cunha,A. C.; Quim. Nova 2006,
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Submitted: December 2, 2012
Published online: February 7, 2013