Facile one-pot synthesis of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines and 3,7-dimethyl-4H-[1,2,4]triazino[3,4-b][1,3,4]thiadiazin-6-one using heteropolyacid catalysts

Article abstract of DOI:10.1002/jhet.407

[1,2,4]Triazolo[3,4-b][1,3,4]thiadiazines 2a-f and 3,7-dimethyl-4H-[1,2,4] triazino[3,4-b][1,3,4]thiadiazin-6-one 4 were synthesized by one-pot cyclocondensation reaction with α-chloroacetonitrile and α-haloketones in the presence of catalytic amounts of

Full text of DOI:10.1002/jhet.407

604
Facile One-Pot Synthesis of [1,2,4]Triazolo
[3,4-b][1,3,4]thiadiazines and 3,7-Dimethyl-4H-[1,2,4]triazino
[3,4-b][1,3,4]thiadiazin-6-one Using Heteropolyacid Catalysts
Vol 48
Radineh Motamedi,a* Aazam Monfared,a Zohre Ghahghai Nezamabadi,a and
Fatemeh F. Bamoharramb
aDepartment of Chemistry, School of Sciences, Payam Noor University (PNU), Tehran, Iran
bDepartment of Chemistry, Islamic Azad University, Mashhad, Iran
*E-mail: radineh2005@yahoo.com
Received September 24, 2009
DOI 10.1002/jhet.407
Published online 15 March 2011 in Wiley Online Library (wileyonlinelibrary.com).
[1,2,4]Triazolo[3,4-b][1,3,4]thiadiazines 2a–f and 3,7-dimethyl-4H-[1,2,4]triazino[3,4-b][1,3,4]thiadia-
zin-6-one 4 were synthesized by one-pot cyclocondensation reaction with a-chloroacetonitrile and a-hal-
oketones in the presence of catalytic amounts of heteropolyacids in very high yields and rates.
J. Heterocyclic Chem., 48, 604 (2011).
INTRODUCTION
these compounds in high yields by two-step reactions
involving addition of propargyl bromide to 4-amino-5-
substituted-1,2,4-triazole-3-thiones 1aꢀc and 4-amino-6-
methyl-1,2,4-triazine-3(2H)-thion-5-one 3 in the presence
of sodium methoxide, followed by cyclization in the pres-
ence of heteropolyacids (HPAs), such as H14[NaP5W29-
MoO110] or H6P2W18O60 [17].
[1,2,4]Triazolo[3,4-b][1,3,4]thiadiazines and [1,2,4]
triazino[3,4-b][1,3,4]thiadiazines display a broad spec-
trum of pharmacological properties and chemical reac-
tivities [1ꢀ5]. Certain derivatives have been reported
to possess antibacterial [6ꢀ8], anti-inflammatory [9],
antiviral [10,11], antitumor [12,13], and antifungal [14]
activities, as well as interesting CNS depressing activ-
ity [15].
Because of the environmental restrictions on using
harmful mineral acids, solid acid catalysts are becoming
popular in the chemical industry [18ꢀ23]. Among solid
acid catalysts, HPAs have attracted considerable interest
by virtue of their favorable properties, such as low tox-
icity, safety, low quantity of waste, and ease of
A series of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines
has been synthesized by one-pot cyclocondensation of
triazoles 1aꢀc with a-chloroacetonitrile and a-haloke-
tones [16]. We have recently reported the synthesis of
C
V
2011 HeteroCorporation

May 2011 Facile One-Pot Synthesis of [1,2,4]Triazolo[3,4-b][1,3,4]thiadiazines and 3,7-Dimethyl-4H-
[1,2,4]triazino[3,4-b][1,3,4]thiadiazin-6-one Using Heteropolyacid Catalysts
605
Scheme 1
ketones could be carried out by refluxing in ethanol for
5 h over sulfuric acid adsorbed on silica gel to give the
desired 6-phenyl-, methyl-, and amino-7H-[1,2,4]tria-
zolo[3,4-b][1,3,4]thiadiazines in 60ꢀ82% yields [16].
The structure assigned to these compounds was as
shown for 2aꢀf (Scheme 1), with a double bond linking
the 5- and 6-positions, based on analytical and spectral
data.
In the work described herein, we have used triazoles
1aꢀc and a-chloroacetonitrile or a-chloroacetone as
reagents, which were reacted in refluxing acetic acid in
the presence of a catalytic amount of HPA for reaction
times of 20 min to 3 h. When the reaction was carried
out in the absence of HPA, reaction products are not
produced. As expected, 5H-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazines 2aꢀc were prepared by using a-chloroace-
tone and HPA. The HPA was separated by filtration and
the products were purified by crystallization from etha-
nol; the yields are shown in Table 1.
separation, in addition to possessing higher acidity
[23ꢀ25]. HPAs are widely used in a variety of acid-cat-
alyzed reactions, such as esterification [26], etherifica-
tion [27], hydration of olefins [28], de-esterification
[29], dehydration of alcohols [30], and the polymeriza-
tion of tetrahydrofuran [31] in homogeneous and hetero-
geneous systems.
The reactions were monitored by TLC and subsequent
work-up afforded a single compound by TLC in each
1
case. The products were subjected to H NMR and mass
spectrometric analyses, and were also compared with
authentic samples [16]. The presence of the 5H-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine moiety in 2aꢀc
1
was confirmed by H NMR signals at d ¼ 4.51ꢀ4.55
In continuation of our recent studies [32] on reactions
catalyzed by HPAs leading to heterocyclic compounds
of biological significance, we wish to report a one-pot,
rapid, and green method for the synthesis of [1,2,4]tria-
zolo[3,4-b][1,3,4]thiadiazines and [1,2,4]triazino[3,4-
b][1,3,4]thiadiazines with the aid of HPAs.
and d ¼ 5.60ꢀ5.64, attributable to one vinyl proton and
an NH group, respectively. The mechanism must
involve two steps, namely nucleophilic substitution of
sulfur by chlorine and cyclization through direct attack
of the amino group on the carbonyl group. From eluci-
dation of the structure, it can be assumed that HPA cata-
lyzes the second step by activating the carbonyl group
to direct attack of the amino group, which is followed
by isomerization to convert the methylene moiety to a
methyl group. Such a cyclization and isomerization
has been reported for the two-step synthetic route to
RESULTS AND DISCUSSION
Heravi et al. found that the one-pot cyclocondensation
of triazoles 1aꢀc with a-chloroacetonitrile and a-halo-
Table 1
Catalytic synthesis of triazolothiadiazine 2a–f and triazinothiadiazin 4 by heteropolyacids.
Compd.
2a
2b
2c
2d
2e
2f
4
R
R0
H
Me
Me
Me
Et
Me
H
NH2
Me
NH2
Et
NH2
mp(ꢁC)
Lit.
204
205 [17]
98%, 20 min
215
215–217 [17]
91%, 3 h
242–244
242–244 [17]
83%, 1 h
271–273
270–271 [16]
95%, 20 min
255
255–256 [16]
90%, 3 h
223–225
197–198
198 [17]
98%, 10 min
Yield (%) and time using
H14[NaP5W29MoO110
Yield (%) and time using
K3PW9Mo3O40
Yield (%) and time using
92%, 1 h
80%, 1 h
45%, 1 h
60%, 1 h
65%, 3 h
]
85%, 30 min
67%, 30 min
65%, 30 min
72%, 30 min
70%, 3 h
40%, 3 h
67%, 1 h
50%, 1 h
62%, 1 h
68%, 3 h
80%, 30 min
67%, 30 min
60%, 30 min
70%, 30 min
70%, 3 h
42%, 3 h
45%, 3 h
53%, 3 h
98%, 10 min
98%, 4 h
K7PW Mo2O39
9
Yield (%) and time using
H6P2Mo18O62
65%, 3.5 h
72%, 3.5 h
98%, 4 h
Yield (%) and time using
H6P2W18O62
98%, 2 h
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

606
R. Motamedi, A. Monfared, Z. G. Nezamabadi, and F. F. Bamoharram
Vol 48
Scheme 2
these compounds [17]. 6-Amino-7H-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazines 2dꢀf were prepared by using a-
chloroacetonitrile and HPA as the catalyst. The 1H
NMR spectra of the products featured signals at d ¼
3.1ꢀ3.7 for the methylene group and d ¼ 7.0ꢀ7.1 for
the NH2 group. The structure of these compounds may
have been preferred in the presence of the amino group
due to hydrogen-bonding interactions. The results
showed the best catalyst for this reaction to be the
Pryssler catalyst, H14[NaP5W29MoO110] (Table 1).
In acid-catalyzed reactions, several types of acid sites
are present [27,33ꢀ35]. These include proton sites in
bulk HPAs, Lewis acid sites in their salt form (metal
counterions), proton sites in acidic form, and proton
sites generated by partial hydrolysis of polyanions. Gen-
erally, reactions catalyzed by HPAs may be represented
by the conventional mechanisms of Brønsted acid catal-
ysis. The mechanism may involve protonation of the
substrate by conversion of the ionic intermediate to
yield the reaction product [33ꢀ35].
This function of the HPA catalysts as a result of their
acidity was expected [32]. Having established HPAs as
effective catalysts for the synthesis of [1,2,4]tria-
zolo[3,4-b][1,3,4]thiadiazines 2aꢀf, we were persuaded
to study the use of these catalysts for the synthesis of
similar systems, such as 3,7-dimethyl-4H-[1,2,4]tria-
zino[3,4-b][1,3,4]thiadiazin-6-one 4. 4-Amino-3-mer-
capto-6-methyl-4H-[1,2,4]triazin-5-one 3 and a-chloroa-
cetone were refluxed in acetic acid using HPA as the
catalyst (Scheme 2). The reaction was monitored by
TLC and work-up was carried out as described in the
Experimental Section. The yield is shown in Table 1.
EXPERIMENTAL
Chemicals and all solvents used in this study were pur-
chased from Merck AG and Alderich Chemical. Melting points
were determined on a Kofler hot stage apparatus and are
uncorrected. The IR spectra were obtained on a Shimatdzu 470
spectrophotometer (potassium bromide disks).1H NMR spectra
Table 2
1H NMR and mass spectral data for triazolothiadiazine 2a–f and
triazinothiadiazin 4.
1
The product was identified by its H NMR, mass, and
IR spectra, which were compared to those reported pre-
Compd.
m/z
1H NMR d (ppm)
1
2a
154 (Mþ) (CDCl3), 2.65 (3H, s, CH3), 4.5 (1H, s,
CH), 5.6 (s, 1H, NH, exchanged with
D2O), 8.42 (1H, s, CH)
168 (Mþ) (CDCl3), 2.6 (3H, s, CH3), 2.7 (3H, s,
CH3), 4.5 (1H, s, CH), 5.6 (s, 1H,
NH, exchanged with D2O)
182 (Mþ) (CDCl3), 1.39 (3H, t, CH3), 2.93 (2H,
q, CH2), 2.6 (3H, s, CH3), 4.5 (1H, s,
CH), 5.64 (s, 1H, NH, exchanged
with D2O)
196 (Mþ) (d6-DMSO), 2.2 (3H, s, CH3), 2.65
(3H, s, CH3) 4.66 (1H, s, CH), 5.8
(s, 1H, NH, exchanged with D2O)
155 (Mþ) (CDCl3), 3.19 (2H, s, CH2), 7.10 (s,
2H, NH2, exchanged with D2O), 9.80
(1H, s, CH)
169 (Mþ) (CDCl3), 2.28 (3H, s, CH3), 3.78 (2H,
s, CH2), 7.02 (s, 2H, NH2, exchanged
with D2O)
183 (Mþ) (CDCl3), 1.21 (3H, t, J ¼7.0 Hz, CH3),
2.40 (2H, q, J ¼ 7.0 Hz, CH2), 3.72
(2H, s, CH2), 7.04 (s, 2H, NH2,
viously [26c]. In the H NMR spectrum of compound 4,
the signals of the methyl protons of the 1,3,4-thiadiazine
moiety and the vinyl proton appeared at d ¼ 2.65 and d
¼ 4.66, respectively, which confirmed the proposed
structure. The mechanism must be the same as that
outlined earlier for the syntheses of 2aꢀf. An attempt to
2b
2c
synthesize
7-amino-3-methyl-4H-[1,2,4]triazino[3,4-
b][1,3,4]thiadiazin-6-one by using a-chloroacetonitrile
as a reagent was unsuccessful.
4
Comparison of the results shows that HPA not only
catalyzed this kind of reaction but also showed more
advantages compared with using mineral acidic media,
such as H2SO4. In studying the progress of the reactions
by TLC, we found that conversion rate and yield were
affected by catalyst structure. Among the various HPAs
used, the yields were higher with the Pryssler catalyst,
H14[NaP5W29MoO110] systems as a result of their high
acid strengths. This result is in agreement with the find-
ings of earlier work [32].
2d
2e
2f
exchanged with D2O)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2011 Facile One-Pot Synthesis of [1,2,4]Triazolo[3,4-b][1,3,4]thiadiazines and 3,7-Dimethyl-4H-
[1,2,4]triazino[3,4-b][1,3,4]thiadiazin-6-one Using Heteropolyacid Catalysts
607
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chemical shifts are expressed as d (ppm) with tetramethylsi-
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F254 plates were used for analytical TLC; column chromatog-
raphy was performed on Merck silica gel (70-230 mesh).
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[3,4-b][1,3,4]thiadiazines and [1,2,4]triazino[3,4-b][1,3,4]
thiadiazine. The appropriate HPA (0.04 mmol) was suspended
in a solution of 1aꢀc or 3 (0.9 mmol) in acetic acid (10 mL)
and the mixture was refluxed for the indicated time (Table 1).
The catalyst was removed by filtration and washed with warm
acetic acid (the catalyst is not soluble in acetic acid). The cata-
lyst was further washed with diethyl ether after filtration. It
could be reused for a second run of the reaction. The yields of
product were almost identical to those obtained using fresh
catalyst. The filtrate was cooled and the precipitated solid was
collected by filtration, washed with water, dried, and recrystal-
lized from ethanol to give pure product 2aꢀf or 4 (Table 1).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet