Eco-efficient, regioselective and rapid access to 4,5-disubstituted 1,2,3-thiadiazoles via [3 + 2] cycloaddition of α-enolicdithioesters with tosyl azide under solvent-free conditions

Article abstract of DOI:10.1039/c3gc37047j

An efficient, sustainable, and regioselective one-pot synthesis of hitherto unreported 4-aroyl/hetaroyl/alkanoyl-5-alkyl/allyl/benzylsulfanyl-1,2,3- thiadiazoles has been achieved by [3 + 2] cycloaddition of α- enolicdithioesters with tosyl azide through cascade 1-2 (S-N) and 3-4 (C-N) bond connections involving Wolff-type heterocyclization. Optimally, the reactions are very fast and completed within 2-15 minutes, when a mixture of α-enolicdithioester and tosyl azide was stirred at 0°C in the presence of Et₃N under solvent-free conditions. Furthermore, no co-catalyst or activator is necessary. The eco-compatibility, mild conditions, excellent yields, easy purification, and avoidance of expensive/toxic reagents are advantages of this protocol to access this medicinally privileged substructure.

Full text of DOI:10.1039/c3gc37047j

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Eco-efficient, regioselective and rapid access to
4,5-disubstituted 1,2,3-thiadiazoles via [3 + 2]
cycloaddition of α-enolicdithioesters with tosyl azide
under solvent-free conditions†
Cite this: DOI: 10.1039/c3gc37047j
Maya Shankar Singh,*a Anugula Nagaraju,a Girijesh Kumar Verma,a Gaurav Shukla,a
Rajiv Kumar Verma,a Abhijeet Srivastavaa and Keshav Raghuvanshib
An efficient, sustainable, and regioselective one-pot synthesis of hitherto unreported 4-aroyl/hetaroyl/
alkanoyl-5-alkyl/allyl/benzylsulfanyl-1,2,3-thiadiazoles has been achieved by [3 + 2] cycloaddition of
α-enolicdithioesters with tosyl azide through cascade 1–2 (S–N) and 3–4 (C–N) bond connections invol-
ving Wolff-type heterocyclization. Optimally, the reactions are very fast and completed within
2–15 minutes, when a mixture of α-enolicdithioester and tosyl azide was stirred at 0 °C in the presence of
Et3N under solvent-free conditions. Furthermore, no co-catalyst or activator is necessary. The eco-compat-
ibility, mild conditions, excellent yields, easy purification, and avoidance of expensive/toxic reagents are
advantages of this protocol to access this medicinally privileged substructure.
Received 17th December 2012,
Accepted 28th January 2013
DOI: 10.1039/c3gc37047j
www.rsc.org/greenchem
nucleoside reverse transcriptase inhibitors),7a acrylamide
derivatives (antihepatitis B virus),7b benzylamides (inhibitors
Introduction
Synthetic organic chemistry occupies a central role in every of non-regulated cell death),7c and 1,2,3-thiadiazole-containing
area of our increasingly technological society, retains its pyrazolones as substituents (potent KDR/VEGFR-2 kinase inhi-
importance as it is an integral part of new drug discovery, and bitors).7d Furthermore, 1,2,3-thiadiazoles undergo cleavage in
is the basis of the bulk of the chemical industry. Synthesis of the presence of strong base to form alkynethiolates,8a which
heterocycles is key in organic synthesis, since heterocycles are were further utilized as synthons for the synthesis of dendri-
indispensable materials in the functioning of any developed mers,8b,c tetrathiafulvalenes,8d,e 2-benzofuran thiolates,8f
society.1 Among the four isomeric forms of thiadiazoles, 1,2,3- amides of 1-adamantylthioacetic acids,8g and 1,1-dialkylindo-
thiadiazoles2 are versatile privileged scaffolds present in many lium-2-thiolates.8h Moreover, the properties of easy breakdown
bioactive natural products and pharmaceuticals, and exhibit of the 1,2,3-thiadiazole ring through release of N2 into low
diverse applications in medicine3 and agriculture.4 Among the molecular weight compounds favor the use of its derivatives as
various pharmacological profiles of 1,2,3-thiadiazoles, their eco-friendly pesticide candidates with low toxicity.9 In
antibacterial,5a,b antiamoebic,5c anticancer,5d anti-HIV,5e,f anti- addition, thiadiazole can act as the bio-isosteric replacement
fungal,6a–c and antiviral6d–f properties seem to be the best of the thiazole moiety, so it acts like third and fourth gener-
documented. Additionally, 1,2,3-thiadiazoles are also useful ation cephalosporins.
intermediates to construct several important bioactive com-
Among many strategies towards substituted 1,2,3-thiadia-
pounds such as thioacetanilides (as potent HIV-1 non- zoles,10 cyclization of hydrazones with thionyl chloride (Hurd–
Mori synthesis),10a cycloaddition of diazoalkanes onto a CvS
bond (Pechmann synthesis),10b,c and heterocyclization of
α-diazo thiocarbonyl compounds (Wolff synthesis)10d are the
aDepartment of Chemistry, Faculty of Science, Banaras Hindu University,
most favourite protocols. A number of interesting applications
Varanasi-221005, India. E-mail: mssinghbhu@yahoo.co.in; Fax: +91-542-2368127;
of the Hurd–Mori reaction11 and the Wolff synthesis12 are
Tel: +91-542-6702502
bInstitut für Organische und Biomolekulare Chemie, Georg-August-Universität,
Tammannstrasse 2, 37077 Göttingen, Germany
reported. Recently, Kumar et al.13 have synthesized 1,2,3-thia-
diazoles using ionic liquid-supported sulfonyl hydrazine.
Although the reported methods are useful tools and serve the
synthetic requirements, most of them suffer from significant
limitations such as harsh reaction conditions, expensive
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of all compounds. CCDC reference numbers 889622 (3aa) and 914821 (3ad). For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3gc37047j
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catalysts/reagents, prolonged reaction times, multistep synth- from the normal β-ketoester due to the unique array of three
eses, and poor availability of starting materials. In view of nucleophilic (O, C and S) and two electrophilic (CvO and
these limitations, there is still a need for exploration of mild, CvS) centres. Due to the presence of these active centres,
efficient, rapid, and widely applicable eco-compatible routes enolic and dithioester moieties, the reactions of α-enolic-
for the synthesis of 1,2,3-thiadiazole derivatives owing to their dithioesters with various electrophilic and nucleophilic
great synthetic and medicinal relevance. In the present investi- reagents have been exploited to construct five-/six-membered
gation, the application of Wolff synthesis has been adopted and fused heterocycles, depending on the reaction conditions,
utilizing tosyl azide,14a which is a good substrate for the intro- during the past few years.16
duction of a diazo functional group. In most recent times,
In continuation of our research interests regarding the syn-
organic azides have become widely used in organic synthesis thetic utility of β-oxodithioesters,17 and as a part of our
as valuable intermediates and building blocks,14b,c particularly ongoing programme aimed at exploring one-pot solvent-free
in the synthesis of nitrogen-containing heterocycles, peptide synthetic protocols,18 we report herein a simple, convenient,
chemistry, materials science, polymer chemistry, and drug dis- and solvent-free synthesis of 4,5-disubstituted 1,2,3-thiadia-
covery.14d Thus, organic azides have assumed an important zoles involving Wolff-type heterocyclization from [3 + 2] atom
position at the interface of chemistry, biology, medicine, and fragments. As an interesting alternative, this two-component
materials science.
one-pot domino process led to the concomitant creation of
Synthetic strategies regarding how to construct and cleave two new bonds (C–N and S–N) and one ring. So far, to the best
carbon–carbon (C–C) and carbon–heteroatom (C–X) bond(s) of our knowledge, this is first report on the use of α-enolic-
represent the central theme in organic synthesis, and are also dithioesters and tosyl azide for the straightforward synthesis
cutting-edge methodology. The drive to environmentally sus- of 4,5-disubstituted 1,2,3-thiadiazoles.
tainable or so-called ‘green technologies’ looks for alternative
α-Enolicdithioesters, pivotal three-carbon synthons, are not
ways to reduce drastic prerequisites for reactions. Because of commercially accessible, and have been easily synthesized in
the increasing public concern for the harmful effects of good yields by stirring methyl ketones with (S,S)-dialkyltrithio-
organic solvents on the environment and the human body, carbonate in the presence of NaH in DMF–hexane (1 : 4)
solvent-free reactions15 have aroused the attention of organic mixture according to a reported procedure.16d Tosyl azide has
chemists due to their more efficient and less labour-intensive been synthesized by the literature method.14a Thus, treatment
methodologies. So, it is now often claimed that ‘the best of α-enolicdithioesters 1 with tosyl azide 2 in the presence of
solvent is no solvent’. Furthermore, solvent-free reactions offer Et3N (TEA) at 0 °C under solvent-free conditions resulted the
several advantages such as faster reaction rates, reduced reac- corresponding 4,5-disubstituted-1,2,3-thiadiazoles
3 within
tion time, less energy consumption, easy separation, and pro- 2–15 minutes in good to excellent yields with tosyl amide only
ducts with high yields and better purity. Due to the above as the waste, which was removed by simple washing
considerations, in recent years it has become an important (Scheme 1).
green protocol to perform reactions under solvent-free
conditions.15
Initially, to optimize the reaction conditions for the syn-
thesis of substituted 1,2,3-thiadiazoles, methyl 3-hydroxy-3-
phenyl-prop-2-enedithioate 1a and tosyl azide 2 were taken as
model substrates. The effects of different bases, solvents, and
temperatures were examined on the model reaction and the
results are listed in Table 1. Generally, base plays an important
role in the formation of 1,2,3-thiadiazoles. Obviously, without
any base, the reaction did not take place in dichloromethane
(DCM) as well as under solvent-free conditions at room temp-
erature even after 24 h of stirring, and the starting materials
remain entirely unconsumed (Table 1, entries 1 and 2). With
this failure, we next carried out the above model reaction in
the presence of Et3N (1.0 equiv.) at room temperature under
solvent-free conditions. Surprisingly, the reaction proceeded
rapidly in exothermic fashion to give the corresponding
Results and discussion
Simple polyfunctional molecules are ideal starting materials in
diversity-oriented synthesis, which aims at providing quick
access to libraries of molecules. Synthons containing both
electrophilic and nucleophilic sites have great potential in
developing new reaction pathways. One such synthon is β-oxo-
dithioester, a thio-analogue of the normal β-ketoester with
general formula 1 (Fig. 1). Notably, its reactivity is far different
Fig. 1 Reactive sites of α-enolicdithioesters 1.
Scheme 1 Synthesis of 4,5-disubstituted 1,2,3-thiadiazoles 3.
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Table 1 Optimization of reaction conditions for the synthesis of 3aaa
Table 2 α-Enolicdithioesters scope for the synthesis of 3
Entry Base (equiv.)
Solvent
Temp. (°C) Time
Yieldb (%)
c
1
2
3
4
5
6
7
8
None
None
DCM
None
None
None
None
None
None
None
25
25
25
15
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
24 h
24 h
2 min
2 min
3 min
—
c
—
TEA (1.0)
TEA (1.0)
TEA (1.0)
DABCO (1.0)
DMAP (1.0)
DBU (1.0)
55d
68d
92
10 min 81
8 min 80
10 min 82
12 min 85
10 min 82
10 min 84
9
Pyrrolidine (1.0) None
Piperidine (1.0) None
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
DIPA (1.0)
Pyridine (1.0)
ButOK (1.0)
K2CO3 (1.0)
NaOH (1.0)
TEA (1.0)
TEA (1.0)
TEA (1.0)
TEA (1.0)
TEA (1.0)
TEA (1.0)
TEA (1.0)
TEA (1.0)
TEA (0.5)
TEA (1.3)
None
None
None
None
None
DCM
CH3CN
DMF
DMSO
MeOH
EtOH
H2O
4 h
55
15 min 75
20 min 78
15 min 70
8 h
8 h
8 h
6 h
6 h
7 h
65
60
65
69
70
70
0
0
0
0
0
0
30 min 80
9 h 40
10 min 82
3 min 88
Toluene
None
None
a Reactions were carried out using 1a (1.0 mmol) and 2 (1.0 mmol).
b Isolated pure yield. c No reaction. d Highly exothermic reaction.
product 3aa in 55% yield within 2 minutes (Table 1, entry 3).
Since at room temperature, the reaction is highly exothermic,
so we performed the reaction at lower temperatures (Table 1,
entries 4 and 5). To our delight, the desired product 3aa was
obtained exclusively in 92% yield at 0 °C within 3 minutes
(Table 1, bold entry 5).
Encouraged by the above results, other readily available
organic bases such as DABCO, DMAP, DBU, pyrrolidine, piper-
idine, diisopropyl amine (DIPA), pyridine and ButOK, and in-
organic bases like K2CO3 and NaOH, were also examined
separately at 0 °C under solvent-free conditions. All the above
bases afforded the desired product in good yield. However,
compared to Et3N, they gave relatively lower yield in longer
time (Table 1, entries 6–15). Triethylamine promoted this
transformation more efficiently than other organic and in-
organic bases. Next, the utility of different solvents such as
DCM, CH3CN, DMF, DMSO, MeOH, EtOH, H2O, and toluene
was also investigated, but no superior results were obtained
Experiments probing the scope and generality of this
(Table 1, entries 16–23). Finally, the amount of Et3N was inves- process under optimized conditions are summarized in
tigated, and the results showed that increasing or decreasing Table 2. A broad spectrum of α-enolicdithioesters 1, bearing R1
the amount of Et3N resulted in slightly lower yields (Table 1, as aryl, hetaryl, extended aromatics and alkyl groups, and R2
entries 24 and 25). Thus, the best reaction condition for the as saturated and unsaturated alkyl groups, could be employed
synthesis of 3aa was found to be 1.0 equiv. of Et3N at 0 °C to afford thiadiazoles 3 in good to excellent yields. As can be
under solvent-free conditions (entry 5, bold in Table 1).
seen from Table 2, all reactions proceeded very fast and
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afforded the corresponding products 3 in high yields within
2–15 minutes.
To probe electronic and steric influences on the annulation
strategy, a wide range of dithioesters derived from acetophe-
none containing both electron-donating and electron-with-
drawing groups were employed. α-Enolicdithioesters bearing
R1 as aryl group with electron-donating substituents gave con-
siderably higher yields than those with electron-withdrawing
groups (Table 2, entries 3ab, 3ad, 3aj vs. 3ac). After successful
utilization of aromatic dithioesters, we next extended our study
to various heteroaromatic dithioesters obtained from 2/3-sub-
stituted heteroaromatic compounds such as 2-acetylthiophene,
2-acetylfuran, 3-acetylpyridine, and N-methyl-3-acetylpyrrole,
which was also demonstrated to be effective substrates and
afforded the desired compounds 3 in 78–85% yields (Table 2,
entries 3af, 3ae, 3ah, 3ak and 3ff). We were pleased to find
that extended aromatics such as 1-naphthyl, 2-naphthyl, and
biphenyl as R1 substituents were also tolerated well resulting
in high yields of the products 3 (Table 2, entries 3ag, 3al, 3fg
and 3gp).
Fig. 2 ORTEP diagrams of 3aa and 3ad.
Scheme 2 Plausible mechanism for the formation of 1,2,3-thiadiazole 3.
Notably, alkyl-substituted dithioesters derived from ali-
phatic ketones such as acetone and iso-propyl methyl ketone
also went smoothly to give desired compounds 3 in good
yields (Table 2, entries 3am, 3fo and 3go). However, when the
more bulky tert-butyl group was installed, the reaction became
sluggish and yield decreased significantly, yet it remained
good (≥65%, Table 2, entries 3an and 3dn). In order to extend
the reaction scope further, we turned our attention to modifi-
cation of the thioalkyl moiety R2 at position 5 of thiadiazole
ring. Therefore, we next tuned the dithioesters by introducing
at R2 different alkyl groups such as ethyl, n-propyl, n-butyl,
n-pentyl, allyl, and benzyl moieties. Gratifyingly, α-enolicdithio-
esters bearing the above alkyl groups at R2 were also tolerated
well and the desired thiadiazoles 3 were isolated in good yields
(Table 2). Altering the methyl group at R2 to an allyl group in
α-enolicdithioesters resulted the desired 1,2,3-thiadiazoles 3
almost in comparable yields.
Noteworthy features of the conversion include the follow-
ing: (1) elegant efficiency of the process has been demon-
strated in bond formation (two new bonds created) and ring
construction (one new ring); (2) the reaction proceeds through
a three-step sequence, abstraction of enolic proton of α-enolic-
dithioester, nucleophilic attack of α-carbon of α-enolicdithio-
ester on the sp-hybridized nitrogen of tosyl azide, and
intramolecular S-cyclization; (3) the overall yields of this con-
version are excellent; (4) the steric effect of ortho-substituent is
minimal (Table 2, 3ai); (5) electron-withdrawing group on the
aromatic ring exhibit comparable reduced reactivity in the
preparation of thiadiazloes (Table 2, 3ac); (6) an electron-
the single crystal X-ray diffraction analysis (see the ESI†)19 of
two representative compounds 3aa and 3ad (Fig. 2). The mass
spectra of these compounds displayed molecular ion peaks at
the appropriate m/z values.
Taking into consideration the entire outcome, a plausible
mechanistic pathway for the domino one-pot two-component
heteroannulation is outlined in Scheme 2. The first step in the
mechanism is believed to be the abstraction of enolic proton
from α-enolicdithioesters 1 by Et3N followed by nucleophilic
attack of α-carbon on the sp-hybridized electrophilic nitrogen
of tosylazide 2, forming C–N bond to generate the intermedi-
ate A1, which is believed to be the key rate-determining step.
The intermediate A1 is likely to cyclize via its two possible rota-
mers A1 and A2 through pathways I and II to furnish 1,2,3-thia-
diazole
3 and 1,2,3-oxadiazole 4, respectively, with the
extrusion of p-tosyl amide. The intermediate A1 undergoes
intramolecular cyclization by regioselective attack through
sulfur via route I to give the desired 1,2,3-thiadiazole 3 exclu-
sively in accordance with our previous results.17d The alterna-
tive intramolecular O-cyclization of A2 via route II could lead to
1,2,3-oxadiazole 4, which was not observed even in trace
amounts during our investigations, making the protocol
highly selective.
Conclusions
donating group gives a better result in the synthesis of thiadia- In summary, we have developed an experimentally rapid,
zloes (Table 2, 3ab, 3ad, 3aj); (7) the extended aromatic rings straightforward and regioselective protocol for the synthesis of
also afforded thiadiazloes in good yields (Table 2, 3ag, 3al, 3fg, 4,5-disubstituted 1,2,3-thiadiazoles by [3 + 2] cycloaddition of
3gp).
α-enolicdithioesters with tosyl azide in the presence of Et3N at
The structures of all the newly synthesized 1,2,3-thiadiazole 0 °C under solvent-free conditions for the first time. Tosyl
derivatives 3 were deduced by their satisfactory spectral (IR, azide transfers the diazo-functional group to α-enolicdithio-
1H, 13C NMR, and mass) studies and explicitly established by esters followed by Wolff cyclization to give the desired 1,2,3-
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thiadiazoles. This transformation avoids the use of transition-
4-(4-Methylbenzoyl)-5-methylsulfanyl-1,2,3-thiadiazole (3ab).
metal catalyst and constructs two new bonds and one ring White solid; mp 168–169 °C. 1H NMR (300 MHz, CDCl3): δ
with both reactants efficiently being utilized. Importantly, the 8.30 (d, J = 8.1 Hz, 2H, ArH), 7.32 (d, J = 8.1 Hz, 2H, ArH), 2.71
presence of keto- and alkylthio- groups at 4- and 5-positions of (s, 3H, SCH3), 2.44 (s, 3H, ArCH3). 13C NMR (75 MHz, CDCl3):
1,2,3-thiadiazoles makes these compounds excellent entrants δ 185.3, 170.0, 144.1, 134.4, 130.8, 129.0, 100.5, 21.8, 21.7. IR
as precursors for further synthetic renovations to meet the (KBr, cm−1): 3070, 2950, 1620, 1602, 1563, 1414, 1394, 1183,
need for diverse useful purposes. The removal of tosyl amide 1076.
by simply washing makes the process very simple and no chro-
5-Methylsulfanyl-4(4-trifluoromethylbenzoyl)-1,2,3-thiadiazole
matographic separation is required except in the case of liquid (3ac). White solid; mp 130–131 °C. 1H NMR (300 MHz,
products and compounds containing basic moieties. We hope CDCl3): δ 8.47 (d, J = 8.1 Hz, 2H, ArH), 7.78 (d, J = 8.1 Hz, 2H,
this clean and green protocol may be of value for both syn- ArH), 2.74 (s, 3H, SCH3). 13C NMR (75 MHz, CDCl3): δ 184.6,
thetic and medicinal chemists for academic research and prac- 171.2, 152.6, 139.8, 134.2 (q, J = 33.3 Hz, 1C), 130.8, 125.2,
tical applications.
121.8, 21.8. IR (KBr, cm−1): 3063, 2948, 1631, 1609, 1544, 1424,
1386, 1165, 1079.
4-(4-Methoxybenzoyl)-5-methylsulfanyl-1,2,3-thiadiazole (3ad).
White solid; mp 169–170 °C. 1H NMR (300 MHz, CDCl3): δ
8.47 (d, J = 8.7 Hz, 2H, ArH), 7.00 (d, J = 8.7 Hz, 2H, ArH), 3.90
(s, 3H, OCH3), 2.70 (s, 3H, SCH3). 13C NMR (75 MHz, CDCl3): δ
183.9, 169.7, 163.7, 153.4, 133.1, 129.7, 113.6, 55.4, 21.7. IR
(KBr, cm−1): 3075, 2984, 2916, 1619, 1596, 1565, 1426, 1393,
1255, 1173, 1085. Elemental analysis for C11H10N2O2S2: calc.
C, 49.61; H, 3.78; N 10.52%. Found: C, 49.93; H, 4.12; N,
10.24%.
4-(2-Furoyl)-5-methylsulfanyl-1,2,3-thiadiazole (3ae). White
solid; mp 198–199 °C. 1H NMR (300 MHz, CDCl3): δ 8.07 (d, J =
3.3 Hz, 1H, ArH), 7.70 (s, 1H, ArH), 6.57 (d, J = 1.8 Hz, 1H,
ArH), 2.63 (s, 3H, SCH3). 13C NMR (75 MHz, CDCl3): δ 172.0,
169.3, 151.6, 151.0, 148.0, 122.9, 112.5, 21.6. IR (KBr, cm−1):
3089, 2979, 1666, 1587, 1516, 1418, 1268, 1049.
Experimental section
General information
The commercially available starting materials were used as
received without further purification. α-Enolicdithioesters16d
1
and tosyl azide14a 2 were prepared by the reported procedures.
Infrared (IR) spectra are recorded in KBr, and wavenumbers (ν)
1
are reported in cm−1. H and 13C NMR spectra were recorded
on NMR spectrometers operating at 300 and 75 MHz, respecti-
vely. Chemical shifts (δ) are given in parts per million (ppm)
using the residue solvent peaks as reference relative to TMS.
J values are given in Hz. Mass spectra were recorded using
electrospray ionization (ESI) mass spectrometry. The C, H, and
N analyses were performed by microanalytical laboratory ana-
lysis. The melting points are uncorrected.
5-Methylsulfanyl-4-(2-thienoyl)-1,2,3-thiadiazole (3af). Yellow
solid; mp 176–177 °C. 1H NMR (300 MHz, CDCl3): δ 8.65 (d, J =
3.6 Hz, 1H, ArH), 7.78 (d, J = 4.8 Hz, 1H, ArH), 7.24 (dd, J = 5.7
Hz, J = 4.2 Hz, 1H, ArH), 2.72 (s, 3H, SCH3). 13C NMR
General procedure for synthesis of 4-alkanoyl/aroyl/hetaroyl-5-
alkyl/allyl/benzylsulfanyl-1,2,3-thiadiazoles 3
An oven-dried round bottom flask was charged with the appro- (100 MHz, CDCl3): δ 177.0, 169.6, 152.2, 142.2, 136.2, 135.6,
priate α-enolicdithioesters (1.0 mmol), tosyl azide
128.4, 21.8. IR (KBr, cm−1): 3087, 2980, 1656, 1599, 1507, 1420,
(1.0 mmol), and Et3N (1.0 mmol), and the reaction mixture 1270, 1057, 838.
1
2
was stirred in an ice bath at 0 °C for the stipulated period of
5-Methylsulfanyl-4-(1-naphthoyl)-1,2,3-thiadiazole (3ag).
time till the completion of the reaction (monitored by TLC). White solid; mp 117–118 °C. 1H NMR (300 MHz, CDCl3): δ
Methanol (1 ml) was added to the reaction mixture, followed 8.31 (d, J = 9.3 Hz, 1H, ArH), 8.04 (d, J = 3 Hz, 2H, ArH), 7.91
by 1 ml of conc. HCl and 3 ml of water. The solid product (d, J = 9.3 Hz, 1H, ArH), 7.58–7.52 (m, 3H, ArH), 2.73 (s, 3H,
obtained was filtered, washed with water, and finally recrystal- SCH3). 13C NMR (75 MHz, CDCl3): δ 188.6, 169.9, 154.1, 135.0,
lized from MeOH–CHCl3 mixture (1 : 1) to give the analytically 133.6, 132.4, 130.7, 129.7, 128.4, 127.5, 126.3, 125.2, 124.2,
pure sample. The liquid compounds and products 3ah and 21.8. IR (KBr, cm−1): 3049, 2909, 1629, 1505, 1436, 1409, 1274,
3ak were purified by rapid filtration through a short column 1058. HRMS (ESI) m/z calcd for C14H10N2OS2 [M + Na+],
filled with silica gel using EtOAc–hexane as eluent. 309.0127; Found 309.0003. Elemental analysis for
The spectral and analytical data of all the compounds are C14H10N2OS2: calc. C, 58.72; H, 3.52; N, 9.78%. Found:
given as follows.
C 58.79, H 3.74, N 9.93%.
4-Benzoyl-5-methylsulfanyl-1,2,3-thiadiazole
(3aa). White
5-Methylsulfanyl-4-(3-pyridoyl)-1,2,3-thiadiazole (3ah). White
solid; mp 106–107 °C. 1H NMR (300 MHz, CDCl3): δ 8.37 (d, J = solid; mp 100–101 °C. 1H NMR (300 MHz, CDCl3): δ 9.51
7.2 Hz, 2H, ArH), 7.61–7.50 (m, 3H, ArH), 2.71 (s, 3H, SCH3). (s, 1H, ArH), 8.80–8.66 (m, 2H, ArH), 7.49–7.45 (m, 1H, ArH),
13C NMR (75 MHz, CDCl3): δ 185.7, 170.3, 153.0, 136.9, 133.1, 2.71 (s, 3H, SCH3). 13C NMR (75 MHz, CDCl3): δ 183.9, 171.2,
130.5, 128.2, 21.7. IR (KBr, cm−1): 3072, 2916, 1624, 1568, 152.7, 152.5, 151.1, 138.3, 132.7, 123.3, 21.8. IR (KBr, cm−1):
1592, 1447, 1392, 1218, 1087. HRMS (ESI) m/z calcd for 3047, 2923, 2853, 1625, 1579, 1428, 1397, 1274, 1012, 879.
C10H8N2OS2 [M + Na+], 258.9970; Found 258.9866. Elemental
4-(2-Chlorobenzoyl)-5-methylsulfanyl-1,2,3-thiadiazole (3ai).
analysis for C10H8N2OS2: calc. C, 50.83; H, 3.41; N, 11.85%. Yellow solid; mp 101–102 °C. 1H NMR (300 MHz, CDCl3):
Found: C, 50.64; H, 3.24; N, 11.49%.
δ 7.62–7.39 (m, 4H, ArH), 2.74 (s, 3H, SCH3). 13C NMR
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(75 MHz, CDCl3): δ 186.9, 169.5, 153.0, 138.2, 131.8, 131.7, 130.5, 128.2, 41.0, 21.5, 13.4. IR (KBr, cm−1): 3051, 2921, 1631,
130.1, 129.6, 126.5, 21.7. IR (KBr, cm−1): 3075, 2907, 1646, 1532, 1545, 1432, 1381, 1221, 1054.
1588, 1432, 1398, 1275, 1014, 878. HRMS (ESI) m/z calcd for
4-Benzoyl-5-(1-butylsulfanyl)-1,2,3-thiadiazole (3da). Yellow
C10H7ClN2OS2 [M + Na+], 292.9580; Found 292.9460. Elemental viscous liquid. 1H NMR (300 MHz, CDCl3): δ 8.35 (d, J = 7.2
analysis for C10H7ClN2OS2: calc. C, 44.36; H, 2.61; N, 10.35%. Hz, 2H, ArH), 7.63–7.49 (m, 3H, ArH), 3.09–3.04 (t, J = 6.9 Hz,
Found: C, 44.61; H, 2.94; N, 10.41%.
2H, SCH2), 1.89–1.67 (m, 2H, CH2), 1.60–1.43 (m, 2H, CH2),
4-(3,4-Methylenedioxybenzoyl)-5-methylsulfanyl-1,2,3-thia- 0.98–0.94 (m, 3H, CH3). 13C NMR (75 MHz, CDCl3): δ 185.6,
1
diazole (3aj). White solid; mp 190–191 °C. H NMR (300 Hz, 168.7, 153.2, 137.0, 133.0, 130.5, 128.2, 38.8, 29.9, 21.9, 13.3.
CDCl3): δ 8.19 (dd, J = 8.1 Hz, J = 1.2 Hz, 1H, ArH), 7.89 (d, J = IR (KBr, cm−1): 3148, 2903, 1629, 1521, 1548, 1427, 1359, 1218,
1.5 Hz, 1H, ArH), 6.92 (d, J = 8.1 Hz, 1H, ArH), 6.07 (s, 2H, 1061.
CH2), 2.70 (s, 3H, SCH3). 13C NMR (75 MHz, CDCl3): δ 183.4,
5-(1-Butylsulfanyl)-4-(2,2-dimethylpropan-1-oyl)-1,2,3-thiadia-
1
169.8, 152.1, 147.9, 131.4, 127.8, 127.6, 110.4, 107.9, 101.8, zole (3dn). Yellow viscous liquid. H NMR (300 MHz, CDCl3):
21.7. IR (KBr, cm−1): 3054, 2924, 2890, 1641, 1608, 1499, 1439, δ 3.01 (t, J = 7.2 Hz, 2H, SCH2), 1.84–1.79 (m, 2H, CH2);
1398, 1266, 1075, 856. HRMS (ESI) m/z calcd for C11H8N2O3S2 1.57–1.45 (m, 11H, 1 × CH2 and 3 × CH3), 0.97 (t, J = 7.3 Hz,
[M + Na+], 302.9869; Found 302.9744.
3H, CH3). 13C NMR (75 MHz, CDCl3): δ 199.9, 168.0, 151.9,
4-(N-Methylpyrrol-3-oyl)-5-methylsulfanyl-1,2,3-thiadiazole 44.8, 38.8, 30.0, 26.8, 21.9, 13.4. IR (KBr, cm−1): 2931, 1641,
(3ak). White crystalline solid; mp 148–149 °C. 1H NMR 1447, 1389, 1239, 1087.
(300 MHz, CDCl3): δ 8.06 (s, 1H, ArH), 6.92 (s, 1H, ArH), 6.56
4-Benzoyl-5-(1-pentylsulfanyl)-1,2,3-thiadiazole (3ea). White
(s, 1H, ArH), 3.66 (s, 3H, NCH3), 2.59 (s, 3H, SCH3). 13C NMR solid; mp 65–66 °C. H NMR (300 MHz, CDCl3): δ 8.35 (d, J =
(75 MHz, CDCl3): δ 178.8, 167.6, 153.5, 130.6, 123.8, 123.1, 7.2 Hz, 2H, ArH), 7.63–7.49 (m, 3H, ArH), 3.06 (t, J = 7.2 Hz,
111.1, 36.6, 21.6. IR (KBr, cm−1): 3069, 2923, 2918, 1641, 1624, 2H, SCH2), 1.91–1.81 (m, 2H, CH2), 1.55–1.32 (m, 4H, 2 × CH2),
1568, 1592, 1447, 1392, 1218, 1087. HRMS (ESI) m/z calcd for 0.93 (t, J = 7.5 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3): δ
1
C9H9N3OS2 [M + Na+], 262.0079; Found 261.9980.
5-Methylsulfanyl-4-(4-phenylbenzoyl)-1,2,3-thiadiazole (3al). 22.0, 13.8. IR (KBr, cm−1): 2921, 1632, 1449, 1397, 1237, 1031.
White solid; mp 180–181 °C. 1H NMR (300 MHz, CDCl3):
5-Allylsulfanyl-4-benzoyl-1,2,3-thiadiazole (3fa). Yellow solid;
185.7, 168.7, 153.3, 137.1, 133.1, 130.5, 128.2, 39.1, 30.8, 27.7,
δ 8.39 (d, J = 8.1 Hz, 2H, ArH), 7.66 (d, J = 8.4 Hz, 2H, ArH), mp 52–53 °C. 1H NMR (300 MHz, CDCl3): δ 8.33 (d, J = 7.2, 2H,
7.58 (d, J = 7.2 Hz, 2H, ArH), 7.42–7.29 (m, 3H, ArH), 2.63 (s, ArH), 7.61–7.47 (m, 3H, ArH), 5.95–5.86 (m, 1H, CH), 5.48 (d,
3H, SCH3). 13C NMR (75 MHz, CDCl3): δ 185.1, 170.3, 153.2, J = 16.2 Hz, 1H, CH), 5.36 (d, J = 10.2 Hz, 1H, CH), 3.70 (d, J =
145.8, 139.8, 135.6, 131.2, 128.9, 128.1, 127.2, 126.9, 21.8. IR 6.3 Hz, 2H, SCH2). 13C NMR (75 MHz, CDCl3): δ 185.7, 166.9,
(KBr, cm−1): 3071, 2921, 1638, 1559, 1583, 1439, 1386, 1223, 153.8, 136.9, 133.1, 130.5, 129.8, 128.2, 121.5, 41.0. IR (KBr,
1076. HRMS (ESI) m/z calcd for C16H12N2OS2 [M + Na+], cm−1): 3122, 3089, 3010, 2929, 2903, 1625, 1516, 1408, 1361,
335.0283; Found 335.0150. Elemental analysis for 1229, 1069, 1048, 827.
C16H12N2OS2: calc. C, 61.51; H, 3.87; N, 8.97%. Found:
C 61.42, H 3.93, N 8.76%.
5-Allylsulfanyl-4-(4-methylbenzoyl)-1,2,3-thiadiazole (3fb).
Yellow solid; mp 70–71 °C. H NMR (300 MHz, CDCl3): δ 8.21
1
4-Acetyl-5-methylsulfanyl-1,2,3-thiadiazole (3am). White (d, J = 8.1 Hz, 2H ArH), 7.24 (d, J = 8.1 Hz, 2H, ArH), 5.89–5.78
solid; mp 118–119 °C. 1H NMR (300 MHz, CDCl3): δ 2.84 (m, 1H, CH), 5.42 (d, J = 16.8 Hz, 1H, CH), 5.30 (d, J = 10.2 Hz,
(s, 3H, CH3), 2.68 (s, 3H, SCH3). 13C NMR (75 MHz, CDCl3): 1H, CH), 3.64 (d, J = 6.6 Hz, 2H, SCH2), 2.36 (s, 3H, CH3). 13C
δ 192.1, 167.0, 153.2, 28.5, 21.4. IR (KBr, cm−1): 2974, 1638, NMR (75 MHz, CDCl3): δ 185.3, 166.6, 154.0, 144.1, 134.4,
1386, 1211, 1017.
130.8, 129.9, 129.0, 121.5, 41.05, 21.7. IR (KBr, cm−1): 3118,
4-(2,2-Dimethylpropan-1-oyl)-5-methylsulfanyl-1,2,3-thiadia- 3059, 3015, 2929, 2903, 1624, 1536, 1429, 1345, 1241, 1061,
1
zole (3an). Yellow viscous liquid. H NMR (300 MHz, CDCl3): 1002, 865. Elemental analysis for C13H12N2OS2: calc. C, 56.49;
δ 2.65 (s, 3H, SCH3), 1.49 (s, 9H, CH3). 13C NMR (75 MHz, H, 4.38; N, 10.14%. Found: C, 56.28; H, 4.91; N, 9.83.
CDCl3): δ 199.9, 169.5, 151.7, 44.8, 26.8, 21.8. IR (KBr, cm−1):
2967, 1634, 1592, 1392, 1218, 1007.
5-Allylsulfanyl-4-(4-methoxybenzoyl)-1,2,3-thiadiazole (3fd).
White solid; mp 78–79 °C. H NMR (300 MHz, CDCl3): δ 8.45
1
4-Benzoyl-5-ethylsulfanyl-1,2,3-thiadiazole (3ba). White (d, J = 9.0 Hz, 2H, ArH), 7.00 (d, J = 9.0 Hz, 2H, ArH), 5.97–5.86
solid; mp 102–103 °C. 1H NMR (300 MHz, CDCl3): δ 8.35 (d, J = (m, 1H, CH), 5.50 (d, J = 16.5 Hz, 1H, CH), 5.38 (d, J = 10.2 Hz,
7.2 Hz, 2H, ArH), 7.61–7.51 (m, 3H, ArH), 3.09 (q, J = 7.4 Hz, 1H, CH), 3.90 (s, 3H, OCH3), 3.72 (d, J = 6.6 Hz, 2H, SCH2). 13
C
2H, CH2), 1.52 (t, J = 6.9 Hz, 3H, CH3). 13C NMR (75 MHz, NMR (75 MHz, CDCl3): δ 184.0, 166.3, 163.7, 133.2, 130.0,
CDCl3): δ 185.7, 168.3, 153.3, 137.0, 133.0, 130.5, 128.2, 33.1, 129.7, 121.5, 113.6, 84.3, 55.5, 41.0. IR (KBr, cm−1): 3029, 3073,
13.1. IR (KBr, cm−1): 3030, 2908, 2898, 1619, 1543, 1419, 1323, 2919, 2901, 1624, 1515, 1409, 1335, 1215, 1089.
1231, 1051, 853.
5-Allylsulfanyl-4-(1-naphthoyl)-1,2,3-thiadiazole (3fg). Yellow
4-Benzoyl-5-(1-propylsulfanyl)-1,2,3-thiadiazole (3ca). Yellow solid; mp 135–136 °C. 1H NMR (300 MHz, CDCl3): δ 8.31 (d, J =
viscous liquid. 1H NMR (300 MHz, CDCl3): δ 8.27 (d, J = 7.2 5.7 Hz, 1H, ArH), 8.03–7.88 (m, 3H, ArH), 7.57–7.51 (m, 3H,
Hz, 2H, ArH), 7.52–7.40 (m, 3H, ArH), 2.97 (t, J = 7.2, 2H, ArH), 5.98–5.89 (m, 1H, CH), 5.51 (d, J = 17.1 Hz, 1H, CH2),
SCH2), 1.85–1.65 (m, 2H, CH2), 1.05 (t, J = 7.2 Hz, 3H, CH3). 5.39 (d, J = 10.2 Hz, 1H, CH2), 3.73 (d, J = 6.3 Hz, 2H, SCH2).
13C NMR (75 MHz, CDCl3): δ 185.6, 168.6, 153.3, 137.0, 133.0, 13C NMR (75 MHz, CDCl3): δ 188.6, 166.6, 154.9, 135.1, 133.7,
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132.4, 130.7, 129.7, 128.4, 127.5, 126.3, 125.3, 124.2, 121.6,
5-Benzylsulfanyl-4-(2-methyl-propan-1-oyl)-1,2,3-thiadiazole
41.1. IR (KBr, cm−1): 3125, 3079, 3010, 2956, 2905, 1631, 1606, (3go). Yellow viscous liquid. 1H NMR (300 MHz, CDCl3): δ
1516, 1419, 1349, 1237, 1081, 1001. Elemental analysis for 7.43–7.33 (m, 5H, ArH), 4.22 (s, 2H, SCH2), 3.95–3.90 (m, 1H,
C16H12N2OS2: calc. C, 61.51; H 3.87; N 8.97%. Found: C, 61.68; CH), 1.28 (d, J = 6.9 Hz, 6H, CH3). 13C NMR (75 MHz, CDCl3): δ
H, 4.24; N, 8.64%.
198.7, 164.5, 152.7, 133.6, 129.0, 128.9, 128.4, 42.6, 38.5, 18.5.
5-Allylsulfanyl-4-(2-furoyl)-1,2,3-thiadiazole (3fe). White IR (KBr, cm−1.): 3069, 2924, 1633, 1552, 1501, 1465, 1382,
solid; mp 101–102 °C. 1H NMR (300 MHz, CDCl3): δ 8.10 (d, 1227, 1039.
J = 3.6 Hz, 1H, ArH), 7.74 (s, 1H, ArH), 6.61 (d, J = 1.5 Hz, 1H,
ArH), 5.95–5.82 (m, 1H, CH), 5.47 (d, J = 16.8 Hz, 1H, CH2),
5.35 (d, J = 9.9 Hz, 1H, CH2), 3.69 (d, J = 6.3 Hz, 2H, SCH2).
Acknowledgements
13C NMR (75 MHz, CDCl3): δ 172.0, 166.0, 152.3, 151.0, 148.0,
129.8, 122.9, 121.5, 112.5, 40.9. IR (KBr, cm−1): 3126, 3074, We gratefully acknowledge the generous financial support
3015, 2958, 2903, 1623, 1507, 1407, 1356, 1235, 1071, 1053. from the Council of Scientific and Industrial Research (CSIR)
HRMS (ESI) m/z calcd for C10H8N2O2S2 [M + H+], 253.0100; and the Department of Science and Technology (DST), New
Found 253.0108. Elemental analysis for
calc. C, 47.60; H, 3.20; N, 11.10%. Found: C, 47.51; H, 3.16; N, A. S. are thankful to CSIR, New Delhi, for a research
11.40%. fellowship. K. R. is highly grateful to DAAD and George-
C10H8N2O2S2: Delhi. A. N. and G. K. V. are thankful to UGC, and G. S. and
5-Allylsulfanyl-4-(2-thienoyl)-1,2,3-thiadiazole (3ff). White August-Universität-Göttingen for financial support of a DAAD
solid; mp 119–120 °C. 1H NMR (300 MHz, CDCl3): δ 8.64 (d, J = fellowship.
3.6 Hz, 1H, ArH), 7.79 (d, J = 4.5 Hz, 1H, ArH), 7.28–7.22 (m,
1H, ArH), 6.00–5.87 (m, 1H, CH), 5.52 (d, J = 16.8 Hz, 1H,
CH2), 5.40 (d, J = 9.9 Hz, 1H, CH2), 3.74 (d, J = 6.9 Hz, 2H,
Notes and references
SCH2). 13C NMR (75 MHz, CDCl3): δ 176.8, 166.2, 152.8, 142.1,
136.0, 135.5, 129.8, 128.2, 121.5, 40.9. IR (KBr, cm−1): 3121,
3084, 3005, 2948, 2913, 1604, 1503, 1418, 1352, 1231, 1072,
1031. Elemental analysis for C10H8N2OS3: calc. C, 44.75; H,
3.00; N, 10.44%. Found: C, 45.13; H, 3.39; N, 10.07%.
5-Allylsulfanyl-4-(2-methyl-propan-1-oyl)-1,2,3-thiadiazole
(3fo). Yellow viscous liquid. 1H NMR (300 MHz, CDCl3): δ
6.49–6.42 (m, 1H, vCH), 6.32–6.17 (m, 2H, CH2), 3.99–3.91
(m, 1H, CH), 1.94 (d, J = 6.9 Hz, 2H, SCH2), 1.30 (d, J = 6.6 Hz,
6H, CH3). 13C NMR (75 MHz, CDCl3): δ 198.9, 166.8, 151.6,
141.2, 120.6, 38.5, 38.4, 18.5. IR (KBr, cm−1): 3061, 2927, 1639,
1586, 1382, 1221, 1078.
4-Benzoyl-5-benzylsulfanyl-1,2,3-thiadiazole (3ga). White
solid; mp 135–136 °C. 1H NMR (300 MHz, CDCl3) δ 8.34 (d, J =
7.2 Hz, 2H, ArH), 7.57 (d, J = 7.2 Hz, 1H, ArH), 7.51–7.41 (m,
4H, ArH), 7.33 (d, J = 6.6 Hz, 3H, ArH), 4.24 (s, 2H, CH2). 13C
NMR (75 MHz, CDCl3): δ 185.5, 167.0, 153.4, 136.8, 133.6,
133.1, 130.5, 129.0, 128.9, 128.4, 128.2, 42.7. IR (KBr, cm−1):
3148, 2903, 1629, 1521, 1548, 1427, 1359, 1218, 1061.
5-Benzylsulfanyl-4-(2-naphthoyl)-1,2,3-thiadiazole (3gp). Yellow
solid; mp 176–177 °C. 1H NMR (300 MHz, CDCl3): δ 8.64 (d, J =
3.6 Hz, 1H, ArH), 7.78 (d, J = 4.8 Hz, 1H, ArH), 7.48–7.37 (m,
9H, ArH), 7.28–7.22 (m, 1H, ArH), 4.29 (s, 2H, CH2). 13C NMR
(75 MHz, CDCl3): δ 186.8, 176.8, 166.3, 166.1, 156.2, 152.5,
146.9, 142.1, 136.0, 135.5, 133.6, 133.4, 129.3, 129.1, 128.9,
128.4, 128.2, 42.7. IR (KBr, cm−1): 3101, 2921, 1631, 1519,
1537, 1461, 1356, 1221, 1058.
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1H, ArH), 7.76 (d, J = 4.5 Hz, 1H, ArH), 7.43–7.35 (m, 5H, ArH),
7.21 (s, 1H, ArH), 4.27 (s, 2H, CH2). 13C NMR (75 MHz, CDCl3):
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128.5, 128.3, 42.7. IR (KBr, cm−1): 3121, 2983, 1629, 1507,
1581, 1478, 1362, 1218, 1056.
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