Silica gel-promoted tandem addition-cyclization reactions of 2-alkynylbenzenamines with isothiocyanates

Article abstract of DOI:10.1021/cc100012a

Tandem addition-cyclization reactions of 2-alkynylbenzenamines with isothiocyanates promoted by silica gel are described. This reaction proceeds smoothly at 80 °C under metal- and solvent-free conditions, which provides an efficient and practical route fo

Full text of DOI:10.1021/cc100012a

370
J. Comb. Chem. 2010, 12, 370–373
Silica Gel-Promoted Tandem Addition-Cyclization Reactions of
2-Alkynylbenzenamines with Isothiocyanates
Qiuping Ding,* Banpeng Cao, Zhenzhen Zong, and Yiyuan Peng
College of Chemistry and Chemical Engineering, Jiangxi Normal UniVersity, 99 Ziyang Road,
Nanchang 330022, China
ReceiVed January 24, 2010
Tandem addition-cyclization reactions of 2-alkynylbenzenamines with isothiocyanates promoted by silica
gel are described. This reaction proceeds smoothly at 80 °C under metal- and solvent-free conditions, which
provides an efficient and practical route for the generation of 2,4-dihydro-1H-benzo[d][1,3]thiazines. The
recovered silica gel could be reused for several times.
Introduction
from harsh reaction conditions, high temperature, and low
yields.12 Recently, two alternative approaches have been
developed: one was the use of Lawesson’s reagent,13 and
the other involved isothiocyanates.14 However, in these
systems the presence of metal is essential for reaction
development. It is well-known that metal-free conditions are
crucial in drug discovery process. In addition, from the
environmental point of view, design and implementation of
new organic-chemical synthetic methodologies is an impor-
tant process. An alternative potential process was devised
based on the adsorptive nature of silica gel.15 Herein, we
would like to report our preliminary results for the synthesis
of 2,4-dihydro-1H-benzo[d][1,3]thiazines starting from 2-alky-
nylbenzenamines with isothiocyanates in the presence of
silica gel under metal- and solvent-free conditions.
In the combinatorial chemistry field, tandem reactions have
been regarded as a powerful approach for construction of
small molecule libraries. Usually, tandem reactions involve
multiple chemical transformations in one synthetic operation,
and their importance stems from the intermediates not
needing to be stable enough for isolation and the tandem
processes with minimal work up and less waste generation.1
Meanwhile, the formation of C-S bond is one of the most
important processes in the synthesis of many molecules that
are of biological, pharmaceutical, and materials interest.2
Among the strategies utilized, transition-metal-catalyzed
cross-coupling reactions of thiols with aryl halides to achieve
aryl C-S bond formation are well developed.3 Tandem
reaction is another powerful method for the synthesis of
structurally complex molecules containing the C-S bonds
from relatively simple starting materials in a convergent way.
Synthesis of 3,1-benzothiazines is a continuing hot topic
because the 3,1-benzothiazines moieties are privileged phar-
macophores, as well as valuable reactive intermediates.4
While 3,1-benzothiazines are well studied and are known
for their biological activities, for example, anti-inflammatory
activity, the constitutional isomers 2,4-dihydro-1H-
benzo[d][1,3]thiazines have attracted much less attention. On
the other hand, transition metal- or Lewis acid-catalyzed
tandem addition-cyclization reactions of alkynes possessing
a nucleophile in proximity to the triple bond are important
processes in organic synthesis, which can construct various
heterocycles in an efficient and atom-economic way.5-10 As
part of a continuing effort in our laboratory toward the
development of new methods for the expeditious synthesis
of biologically relevant heterocyclic compounds,11 we be-
came interested in the possibility of developing a novel and
efficient method to construct the 2,4-dihydro-1H-benzo-
[d][1,3]thiazine scaffold.
Result and Discussion
Generally, the synthetic procedure involves impregnating
the mixture of silica gel, 2-alkynylbenzenamine, and isothio-
cyanate and heating the mixture in oil bath. When a mixture
of 2-alkynylbenzenamine 1a and the phenyl isothiocyanate
2a was adsorbed on silica gel at 80 °C, the reaction
completed overnight. The result was very excellent in terms
of yield (Table 1, entries 1). Blank experiment showed that
silica gel was necessary in the reaction to obtain the
respectable yield. Only 15% of the corresponding product
was generated in the absence of silica gel. The structure of
1
3a was verified by H and 13C NMR, mass spectroscopy,
and also by comparison with our previously result,14h which
was characterized, as well as with X-ray diffraction analysis.
The aryl isothiocyanates substituted with an electron-donating
(2b) or electron-withdrawing group (2c) were suitable
substrates in this process because of the high electrophilicity
of isothiocycanate, and they afforded the desired products,
3b or 3c, in high yields (Table 1, entries 2-3). In addition
to aryl isothiocycanates, the reactions of alkyl isothiocycan-
ates also proceeded smoothly. For example, the reaction of
alkyl isothiocyante 2d with 2-alkynylbenzenamine 1a gave
the corresponding 2,4-dihydro-1H-benzo[d][1,3]thiazines 3d
in good yield with prolonged reaction times (Table 1, entry 4).
Although several methods have been described for the
synthesis of benzo[d][1,3]thiazines, most of them suffered
* To whom correspondence should be addressed. E-mail: dqpjxnu@
gmail.com.
10.1021/cc100012a  2010 American Chemical Society
Published on Web 03/24/2010

Tandem Addition-Cyclization Reactions
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3 371
Table 1. Reactions of 2-Alkynylbenzenamine 1a with Various
Isothiocyanates 2 Promoted by Silica Gela
substituted 2-alkynylbenzenamines 1 and isothiocyanates 2.
The reactions proceeded efficiently with in mediate to
excellent yields at 80 °C under solvent free conditions. As
expected, both electron-rich and -poor aryl 2-alkynylbenze-
namines 1 are suitable partners in this process. For instance,
2-alkynylbenzenamine 1b reacted with phenyl isothiocycan-
ate 2a leading to the desired product 3e in 87% yield (Table
2, entry 1), and the reaction of 2-alkynylbenzenamine 1d
with 2c afforded the product 3k in 92% yield (Table 2, entry
7). Other 2-alkynylbenzenamines, 1e-g with substituents (F,
Cl, and Br) on aromatic ring were also tried, and similar
results were obtained (Table 2, entries 8-12). However, low
yields (27%) were obtained when 2-alkynylbenzenamine 1c
(R2 ) n-Bu) was reacted with phenyl isothiocycanate 2a
(Table 2, entries 4) because of the complicated reaction.
However, in the case of substrate 1h (R1 ) CF3, R2 )
4-(CH3)2NC6H4) only indole derivatives was generated. All
1
new products were characterized by H NMR, 13C NMR,
and elemental analysis. The advantage of the use of
heterogeneous system for this transformation is that ease of
promoter/substrate separation provided by a heterogeneous
system.
To check the recyclability of silica gel (Table 3), the silica
gel used in the conversion of 1a to 3a, and the remainder,
after leaching out of the products, was thoroughly washed
with ethyl acetate and dried in the air at 80 °C for 2 h. The
dried silica gel was then reused directly in the next reaction,
and the expected product 3a was obtained in excellent yield.
a Reaction conditions: 2-alkynylbenzenamine 1a (0.20 mmol),
phenyl isothiocyanate 2a (0.3 mmol, 1.5 equiv), silica gel 200 mg,
80 °C. b Isolated yield based on 2-alkynylbenzenamine 1a. c Stirred at
r.t. for 1 h, then at 80 °C for another 47 h.
In a similar fashion, various 2,4-dihydro-1H-benzo-
[d][1,3]thiazines 3 were prepared (Table 2) using different
Table 2. Reaction of 2-Alkynylbenzenamine 1 with Isothiocyanate 2 Promoted by Silica Gela
a Reaction conditions: 2-alkynylbenzenamine 1a (0.20 mmol), phenyl isothiocyanate 2a (0.3 mmol, 1.5 equiv), silica gel 200 mg, 80 °C. b Isolated
yield based on 2-alkynylbenzenamine 1a.

372 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3
Table 3. Efficiency of the Recovered Catalyst
Ding et al.
China (20962010), Natural Science Foundation of Jiangxi
Province of China (2009GQH0054), Jiangxi Educational
Committee (GJJ10387), and Startup Foundation for Doctors
of Jiangxi Normal University (200900266) is gratefully
acknowledged.
Supporting Information Available. Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
of compound 3. This information is available free of charge
via the Internet at http://pubs.acs.org.
no. of cycles
yield (%)
cycle I
98
cycle II
95
cycle III
92
cycle IV
89
The same procedure was repeated for all further cycles. The
recovered silica gel could be reused for several times with
just slight loss of catalytic activity.
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It is well-known that silica gel has mild Lewis acidity with
many reactive hydroxyl groups on the surface and has been
used as promoter in organic synthesis. We reasoned that silica
gel would be effective as promoter in the reaction process
because it may involve the formation of complex via
coordination of alkynyl moiety of 1 to hydrogen of silica
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In summary, we described herein the silica gel promoted
highly efficient, one-pot, tandem addition-cyclization
reactions of a series of 2-alkynylbenzenamines with
isothiocyanates for the synthesis of 2,4-dihydro-1H-
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Experimental Section
General Procedure for Preparation of 4-Benzylidene-
1H-benzo[d][1,3]thiazin-2(4H)-ylidene)benzenamine (3a).
A mixture of 2-alkynylbenzenamine 1a (0.20 mmol), isothio-
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surface area ) 200-300 m2/g, and pore size ) 50-75 µm)
was stirred at 80 °C. After completion of reaction as indicated
by TLC, the silica gel was filtered by EtOAc. Evaporation
of the solvent followed by purification on silica gel provided
1
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valuable advice during the course of this research. Financial
Supported from National Natural Science Foundation of

Tandem Addition-Cyclization Reactions
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3 373
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