Ionic liquid as soluble support for synthesis of 1,2,3-thiadiazoles and 1,2,3-selenadiazoles

Article abstract of DOI:10.1021/jo301607a

A convenient synthesis of 1,2,3-thiadiazoles and 1,2,3-selenadiazoles was achieved using an ionic liquid as a novel soluble support. Ionic liquid-supported sulfonyl hydrazine was synthesized and reacted with a number of ketones to afford the corresponding ionic liquid-supported hydrazones that were converted to 1,2,3-thiadiazoles in the presence of thionyl chloride. The reaction of ionic liquid-supported hydrazones with selenium dioxide in acetonitrile afforded 1,2,3-selenadiazoles. The advantages of this methodology were the ease of workup, simple reaction conditions, and high purity.

Full text of DOI:10.1021/jo301607a

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Note
Ionic Liquid as Soluble Support for Synthesis
of 1,2,3-Thiadiazoles and 1,2,3-Selenadiazoles
Anil Kumar, Manoj Kumar Muthyala, Sunita Choudhary, Rakesh K. Tiwari, and Keykavous Parang
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 30 Sep 2012
Downloaded from http://pubs.acs.org on September 30, 2012
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Ionic Liquid as Soluble Support for Synthesis of 1,2,3-Thiadiazoles and
1,2,3-Selenadiazoles
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Anil Kumar,† * Manoj Kumar Muthyala,† Sunita Choudhary,† Rakesh K. Tiwari,‡ and
,
Keykavous Parang‡ *
†Department of Chemistry, Birla Institute of Technology and Science, Pilani 333031,
Rajasthan, India
‡Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of
Rhode Island, Kingston, 02881, USA
*Corresponding authors
A. Kumar: Department of Chemistry, Birla Institute of Technology and Science, Pilani,
Rajasthan, 333031, India; Tel.: +91ꢀ1596ꢀ515514; Fax: +91ꢀ1596ꢀ244183; Eꢀmail address:
anilkumar@bitsꢀpilani.ac.in
K. Parang: 7 Greenhouse Road, Department of Biomedical and Pharmaceutical Sciences,
College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, 02881, USA;
Tel.: +1ꢀ401ꢀ874ꢀ4471; Fax: +1ꢀ401ꢀ874ꢀ5787; Eꢀmail address: kparang@uri.edu.
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ABSTRACT. A convenient synthesis of 1,2,3ꢀthiadiazoles and 1,2,3ꢀselenadiazoles was
achieved using an ionic liquid as a novel soluble support. Ionic liquidꢀsupported sulfonyl
hydrazine was synthesized and reacted with a number of ketone and 1,2ꢀdiketones to afford
the corresponding ionic liquidꢀsupported hydrazones that were converted to 1,2,3ꢀ
thiadiazoles in the presence of thionyl chloride. The reaction of ionic liquidꢀsupported
hydrazones with selenium dioxide in acetonitrile afforded 1,2,3ꢀselenadiazoles. The
advantages of this methodology were the ease of workup, simple reaction conditions, and
high purity.
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1,2,3ꢀThiadiazoles are important heterocycles1 that possess broad pharmacological
properties such as anticancer, antibacterial, fungicidal,2 antiꢀhepatitis B virus,3 and antiꢀHIV4
activities. Figure 1 depicts chemical structures of selected bioactive 1,2,3ꢀthiadiazoles. 1,2,3ꢀ
Thiadiazoles are also useful intermediates in the synthesis of several organic compounds,
such as 2ꢀthioindole and 2ꢀalkoxybenzo[b]thiophenes,5 βꢀhydroxysulfides,6 and thioamides.7
1,2,3ꢀSelenadiazoles are bioisosteric heterocycle of 1,2,3ꢀthiadiazoles and have attracted
attention due to their diverse biological activities such as antibacterial,8,9 antifungal,10
anticancer,11,12 and antiꢀHIV13 activities. Furthermore, they have been utilized as
intermediates for the synthesis of organic compounds such as dihydroselenophenes14,15 and
2,3ꢀdihydroꢀ1Hꢀpyrroles16. Selenadiazoles are well known source for strained alkynes and
cycloalkynes.17,18
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Several synthetic routes have been developed for the synthesis of 1,2,3ꢀthiadiazoles and
1,2,3ꢀselenadiazoles.19 Hurd and Mori reported a practical synthesis of 1,2,3ꢀthiadiazoles by
the cyclization of the corresponding tosylhydrazones from αꢀmethylene ketones with thionyl
chloride.20 In analogous to synthesis of 1,2,3ꢀthiadiazoles, Yalpani group described the
synthesis of 1,2,3ꢀselenadiazoles by the oxidative cyclization of the tosylhydrazones with
selenium dioxide.21,22 Although the reported methods serve the synthetic requirements, but
they suffer from some disadvantages. For example, chromatographic separation is necessary
to remove the sulfonyl chloride, which is tedious in multiꢀgram scale. To overcome these
problems, several methodologies including “catch and release” have been developed for the
expedited workꢀup and purification of compounds synthesized in solution.23,24 However,
these methods are also associated with limitations. The need of excess reagents, longer times
to drive reactions to completion, and inability to use in pilot scale have made their
applicability narrow.
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Figure 1. Chemical structures of some bioactive 1,2,3ꢀthiadiazoles and biological activities.
Ionic liquidꢀsupported synthesis25 is a new strategy offering several advantages for
organic synthesis retaining the supremacy of product isolation and purification of solidꢀphase
synthesis along with solubility benefits of traditional solutionꢀphase chemistry. In this
approach, a desired molecule is attached to an ionic liquid by an appropriate linker and the
multistep synthesis of the target molecule is carried out without detaching the ionic liquid for
monitoring the reaction progress at every stage. Unreacted reagents and unwanted
compounds are easily separated out from the ionic liquid by simple washing with appropriate
solvents before the final cleavage. The main feature of ionic liquidꢀsupported synthesis
resembles the polymerꢀsupported synthesis, but highꢀloading efficiency, tuneable solubility,26
possibility to monitor the reaction progress by different analytical techniques, and minimal
use of solvents have made this method an attractive and favourable alternative to solidꢀphase
synthesis.
Ionic liquids with a different type of linkers and desired functional group or moiety (1-5,
Figure 2) have been synthesized and used for several organic transformations.33ꢀ42 Bazureau
et al.27 were the first to propose the use of ionic liquid as soluble support for the synthesis of
small organic molecules. Tao et al.28 described the advantages of ionic liquidꢀsupported
synthesis over polymerꢀsupported synthesis in combinatorial chemistry by synthesizing cisꢀβꢀ
lactam library. Recently, we reported ionic liquidꢀsupported synthesis of sulfonamides and
carboxamides29 using a novel ionic liquidꢀsupported linker. There are only a few reports on
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ionic liquidꢀsupported synthesis of heterocycles,30,31 possibly due to the fact that in most of
the ionic liquidꢀsupported synthesis, the substrate should have a functionality to anchor on
ionic liquid support that leads to containing an extra or unwanted functional group upon
cleavage.
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NH2
OH
N
N
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Cl
O
CHO
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COOH
N
N
N
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N
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2
1
n = 0, 1, 2
Figure 2. Some commonly used linkers in ionic liquidꢀsupported synthesis.
In continuation of our efforts on application of ionic liquids in organic synthesis,32ꢀ34
herein, we report a new, simple, and convenient approach for synthesis of 1,2,3ꢀthiadiazoles
and 1,2,3ꢀselenadiazoles using soluble ionic liquidꢀsupported sulfonyl hydrazine. To the best
of our knowledge this is first report on use of ionic liquidꢀsupported sulfonyl hydrazine as
catch and release linker.
Ionic liquidꢀsupported sulfonyl hydrazine was synthesized by simple reaction sequences
shown in Scheme 1. Initially, the reaction of 1ꢀmethylimidazole (6) with 1,4ꢀbutane sultone
(7) at 30 °C followed by reaction with trifluoromethane sulfonic acid (TfOH) at room
temperature for 2 h gave 8.35,36 Reaction of 8 with thionyl chloride under reflux conditions
gave ionic liquidꢀsupported sulfonyl chloride (9), which on reaction with hydrazine hydrate
1
afforded 10. Structure of 10 was confirmed by IR, H NMR, and mass spectrometry. A
singlet peak at =3.47 ppm corresponding to Nꢀmethyl group, triplet at 3.88 ppm for aliphatic
protons adjacent to the imidazole ring and two doublets at 7.58 and 7.56 ppm for imidazole
protons were observed in H NMR. In 13C NMR three peaks at 144, 122, and 121 ppm for
1
imidazole ring carbons along with other aliphatic carbons were observed. A peak at m/z
247.1208 [MꢀCF3SO3]+ was observed in ESIꢀTOF MS spectra, which confirmed the structure
of 10.
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Scheme 1. Synthesis of ionic liquidꢀsupported sulfonyl hydrazine
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Synthetic procedure for 1,2,3ꢀthiadiazole derivatives started from ionic liquidꢀsupported
sulfonyl hydrazone derivatives (12) that were obtained by reacting ionic liquidꢀsupported
sulfonyl hydrazine (10) with the corresponding carbonyl compounds (11). Different ketones
and 1,2ꢀdiketones were converted into corresponding ionic liquidꢀsupported hydrazones (12a-
j) in high to excellent yields (Table 1) at room temperature (Scheme 2). The structures of
ionic liquidꢀsupported sulfonyl hydrazones were confirmed by 1H NMR, 13C NMR and mass
1
analysis. A characteristic peak in the range of 10.2–10.7 ppm was observed in H NMR for
NH proton along with other protons and peak in the range of 150.2–156.5 ppm appeared for
C=NH carbon along with other carbons. In ESIꢀTOF MS, a peak appeared corresponding to
[MꢀCF3SO3]+ ion.
Scheme 2. Synthesis of ionic liquidꢀsupported sulfonyl hydrazones (12a-k).
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Table 1. Synthesis of ionic liquidꢀsupported hydrazones (12a-k).
Compd
12a
R
Yield (%)a
Compd
12g
R
Yield (%)a
C6H5
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81
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90
4ꢀClC6H4
4ꢀBrC6H4
4ꢀNO2C6H4
C5H4N
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88
86
92
94
4ꢀOCH3C6H4
4ꢀCH3C6H4
1ꢀC10H7
12b
12c
12h
12i
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12d
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12j
2ꢀC10H7
C4H3S
12k
4ꢀFC6H4
12f
aIsolated yield
For optimizing reaction conditions to synthesize 1,2,3ꢀthiadiazoles, 12a (1.0 eq.) was first
reacted with SOCl2 (5.0 equiv) in dichloroethane (DCE) at room temperature. The reaction
was very sluggish and took 10 h to be completed. However, with heating the reaction at 60
°C, it took only 4 h for completion of the reaction. Next, we tried the reaction without
solvent, and it was found that there was not much difference in the yield of 13a as well as in
time of reaction in the absence of solvent. In fact, ionic liquidꢀsupported hydrazones 12a was
readily reacted under solventꢀfree conditions with thionyl chloride producing 13 in excellent
yield at 60 °C (Scheme 3, Table 2). The reaction mixture was neutralized by sodium
bicarbonate solution and the compound was removed from ionic liquid layer by extracting in
ethyl acetate/hexane layer. The compounds were pure and the chromatographic purification
was not required. The formation of the thiadiazole 13a was confirmed by spectroscopy
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techniques. A characteristic singlet peak in the range of 8.5–8.8 ppm was observed in H
NMR for C5ꢀproton of 1,2,3ꢀthiadiazole ring and the corresponding carbon was observed in
the range of 130.3–136.4 ppm in 13C NMR. To investigate the generality of the method, we
synthesized library of 1,2,3ꢀthiadiazoles from the corresponding ionic liquidꢀsupported
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sulfonyl hydrazones (12a-k) and thionyl chloride (Table 2). Both aliphatic and aromatic
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ketones were found to be excellent substrates for the synthesis of 1,2,3ꢀthiadiazoles.
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Scheme 3. Synthesis of 1,2,3ꢀthiadiazoles.
Table 2. Synthesis of 1,2,3ꢀthiadiazoles 13a-k.
Yield
(%)b
Yield
(%)b
Compd
R
Product
Compd
R
Product
C6H5
91
86
87
4ꢀClC6H4
88
90
83
13a
13g
4ꢀOCH3C6H4
4ꢀCH3C6H4
4ꢀBrC6H4
13b
13c
13h
13i
4ꢀNO2C6H4
C10H7
C10H7
84
88
89
C5H4N
C4H3S
80
88
13d
13e
13f
13j
13k
4ꢀFC6H4
aReaction conditions: Ionic liquidꢀsupported sulfonyl hydrazone (12) (1 mmol), thionyl chloride (5
mmol), 60 °C, 4 h; bIsolated yield.
Considering our success with 1,2,3ꢀthiadiazoles, we employed similar strategy for the
synthesis of 1,2,3ꢀselenadiazoles. The reaction of ionic liquidꢀsupported sulfonyl hydrazones
(12a-f) with selenium dioxide for the synthesis of 1,2,3ꢀselenadiazoles (14a-f) was
challenging. Initially, reaction of 12a with selenium dioxide in the presence of acetic acid in
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the expectation of 4ꢀphenylꢀ1,2,3ꢀselenadiazole (14a) did not result in the formation of
desired heterocycle; instead it got hydrolyzed to generate the starting acetophenone (11a).
Thus, the reaction was carried out under different reaction conditions and in different
solvents. Using selenium dioxide in acetonitrile without acetic acid led to the conversion of
12a into 14a in modest yield and purity. We then applied this methodology to different ionic
liquidꢀsupported hydrazones 12b-f to generate the corresponding selenadiazoles 14b-f
(Scheme 4) in moderate yield (Table 3). There was a slight increase in the yield after using
dry sodium sulphate as it absorbs the water released in the reaction. The yield were
comparable with the reported solution phase yield of 1,2,3ꢀselenadiazoles and purity was over
90% as shown by HPLC analysis.
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Scheme 4. Synthesis of selenadiazoles (14a-f).
Table 3. Synthesis of selenadiazoles (14a-f).a
Yield
(%)a
Yield
(%)b
Compd
14a
R
Product
Compd
14d
R
Product
C6H5
30
22
30
C4H3S
C10H7
32
25
40
4ꢀCH3OC6H4
4ꢀClC6H4
14b
14e
4ꢀBrC6H4
14c
14f
aReaction conditions: Ionic liquidꢀsupported hydrazone (1 mmol), selenium dioxide (1.05 mmol),
sodium sulphate (1.5 mmol), acetonitrile (6 ml), 24 h; bIsolated yield.
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The chemical structures of 1,2,3ꢀselenadiazoles were confirmed using 1H, 13C NMR and
mass spectroscopy. In 1H NMR, the proton attached to C5 gives a strong singlet around 9.00–
9.50 ppm along with other protons, while C5ꢀcarbon appeared in the range of 135.0ꢀ146.0
ppm along with other carbons in 13C NMR.
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In summary, we have demonstrated a simple and convenient approach for ionic liquidꢀ
supported synthesis of 1,2,3ꢀthiadiazoles and 1,2,3ꢀselenadiazoles. The advantage of this
methodology is the ease of workup, simple reaction conditions, and high purity. Indeed,
1,2,3ꢀthiadiazoles were obtained pure by neutralizing with sodium hydrogen carbonate,
isolating with organic solvents, and subsequent evaporation of the organic solvent. Thus, this
methodology provides access towards the synthesis of diverse 1,2,3ꢀthiadiazole and 1,2,3ꢀ
selenadiazole derivatives under simple reaction conditions. This study provides insights for
using ionic liquidꢀsupported reagents for the synthesis of other heterocyclic compounds.
EXPERIMENTAL SECTION
Synthesis of ionic liquid-supported sulfonic acid (8). Ionic liquidꢀsupported sulfonic acid
was prepared according to earlier procedures with slight modifications.35,36 1,4ꢀButanesultone
(1 equiv) was added dropwise to 1,2ꢀdimethylimidazole (1 equiv) at 30 °C. The resulting
solution was stirred till solid was obtained at room temperature. After completion of reaction,
the product was washed with toluene (3 × 15 mL) and finally with diethyl ether (3 × 15 mL)
to remove unreacted starting materials. The compound was dried under reduced pressure to
get zwitterionic form. Trifluoromethane sulfonic acid (1.1 mmol) was added dropwise to
zwitter ion at 0 °C. After completion of the addition, the solution was stirred at 40 °C until a
thick liquid was obtained. The resulting liquid was washed with diethyl ether to remove
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excess of triflic acid. The compound was dried under reduced pressure to give pale yellow
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thick liquid 8 (7 g, 98%).
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Synthesis of ionic liquid-supported sulfonyl chloride (9). Thionyl chloride (SOCl2, 3
equiv) was added dropwise by an additional funnel to the ionicꢀliquid sulfonic acid (8, 1
equiv) at 0 °C. The resulting mixture was stirred at room temperature for 8 h and finally
heated up to 80 °C for 2 h. Excess of thionyl chloride was removed by a rotatory evaporator
under reduced pressure with nitrogen atmosphere to get yellow thick liquid ionic liquidꢀ
supported sulfonyl chloride 9 (7.08 g, 96%).
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Synthesis of ionic liquid-supported sulfonyl hydrazide (10). Hydrazine hydrate (2 eq) was
added slowly to 9 at 0 °C in THF. After completion of addition, the reaction mixture was
slowly heated up to 40 °C for 4 h. After completion of the reaction, THF was evaporated
under reduced pressure. Resulting mixture was washed with ethyl acetate (3 × 15 mL) to
1
remove hydrazine in order to get pure white solid 10 (6.73 g, 96%); Mp: 94ꢀ97 °C. H NMR
(500 MHz, DMSOꢀd6) δ 7.90 (s, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.19 (bs, 2H), 4.15 (t, J = 7.3
Hz, 2H), 3.75 (s, 3H), 3.13 (t, J = 7.7 Hz, 2H), 2.59 (S, 3H), 1.85 – 1.80 (m, 2H), 1.65 – 1.61
(m, 2H); 13C NMR (126 MHz, DMSOꢀd6) δ 144.8, 122.8, 121.3, 47.4, 46.7, 35.2, 28.1, 20.2,
9.7; HRMS (ESIꢀTOF) (m/z): Calcd for C9H19N4O2S+ 247.1229, Found 247.1208 [M –
CF3SO3]+.
Synthesis of ionic liquid-supported hydrazones (12a-k). Acetophenone (1.05 equiv) and
liquidꢀsupported sulfonyl hydrazide (1 equiv) were taken in ethanol (10 ml) and vigorously
stirred at room temperature until solid precipitates out. The reaction mixture was filtered and
washed with cold ethanol (2 × 5 ml) and dried under reduced pressure to get the pure product.
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Compound 12a. White solid (34 mg, 86%); Mp: 145−150 °C; 1H NMR (500 MHz, DMSOꢀd6)
δ 10.34 (s, 1H), 7.73 – 7.71 (m, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 4.15 (t, J =
7.0 Hz, 2H), 3.71 (s, 3H), 3.36 – 3.27 (m, 2H), 2.56 (s, 3H), 2.23 (s, 3H), 1.86 – 1.82 (m, 2H), 1.75 –
1.69 (m, 2H); 13C NMR (126 MHz, DMSOꢀd6) δ 153.7, 144.8, 138.0, 129.8, 128.8, 126.6,
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122.7, 121.3, 49.7, 47.3, 35.1, 28.1, 20.1, 15.0, 9.6; HRMS (ESIꢀTOF) (m/z): Calcd for
C17H25N4O2S+ 349.1698, Found 349.1719 [M – CF3SO3]+.
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Compound 12b. Light yellow (310 mg, 81%); Mp: 126ꢀ130 °C; H NMR (500 MHz,
DMSOꢀd6) δ 10.21 (s, 1H), 7.75 (d, J = 9 Hz, 2H), 7.69 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 2.0
Hz, 1H), 7.02 (d, J = 9 Hz, 2H), 4.22 (t, J = 7.0 Hz, 2H), 3.85 (s, 3H), 3.79 (s, 3H), 3.41 –
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3.33 (m, 2H), 2.63 (s, 3H), 2.26 (s, 3H), 1.97 – 1.89 (m, 2H), 1.82 – 1.77 (m, 2H); C NMR
(126 MHz, DMSOꢀd6) δ 160.7, 153.7, 144.8, 130.4, 128.1, 122.7, 121.3, 114.1, 55.7, 49.3,
47.3, 35.1, 28.1, 20.1, 14.8, 9.6; HRMS (ESIꢀTOF) (m/z): Calcd for C18H27N4O3S+ 379.1804,
Found 379.1779 [M – CF3SO3]+.
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Compound 12c. Light yellow (320 mg, 82%); Mp: 139ꢀ142 °C; H NMR (500 MHz,
DMSOꢀd6) δ 10.22 (s, 1H), 7.63 – 7.59 (m, 4H), 7.21 (d, J = 7.7 Hz, 2H), 4.15 (t, J = 7.0 Hz,
2H), 3.72 (s, 3H), 3.45–3.09 (m, 2H), 2.56 (s, 3H), 2.32 (s, 3H), 2.20 (s, 3H), 1.91–1.79 (m,
2H), 1.79–1.61 (m, 2H); 13C NMR (126 MHz, DMSOꢀd6) δ 153.7, 144.8, 139.5, 135.2, 129.4,
126.5, 122.7, 121.3, 49.4, 47.3, 35.1, 28.1, 21.3, 20.1, 14.9, 9.6; HRMS (ESIꢀTOF) (m/z):
Calcd for C18H27N4O2S+ 363.1855, Found 363.1874 [M – CF3SO3]+.
Compound 12d. White solid (360 mg, 88%); Mp: 126ꢀ132 °C; 1H NMR (500 MHz, DMSOꢀ
d6) δ 10.44 (s, 1H), 8.11–8.05 (m, 1H), 7.96 (d, J = 7.8 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H),
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7.57–7.48 (m, 4H), 4.14 (t, J = 6.9 Hz, 2H), 3.71 (s, 3H), 3.30–3.23 (m, 2H), 2.54 (s, 3H),
2.39 (d, J = 17.9 Hz, 3H), 1.89–1.80 (m, 2H), 1.79–1.70 (m, 2H); 13C NMR (126 MHz,
DMSOꢀd6) δ 156.1, 144.8, 137.4, 133.8, 130.4, 129.4, 128.9, 127.1, 126.5, 126.3, 125.7,
125.6, 122.8, 121.3, 49.5, 47.3, 35.1, 28.2, 20.1, 19.8, 9.6; HRMS (ESIꢀTOF) (m/z): Calcd for
C21H27N4O2S+ 399.1855, Found 399.1830 [M – CF3SO3]+.
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Compound 12e. Light yellow solid (360 mg, 86%); Mp: 146ꢀ150 °C; H NMR (500 MHz,
DMSOꢀd6) δ 10.40 (s, 1H), 8.24 (s, 1H), 7.99 (d, J = 7.6 Hz, 2H), 7.91 (d, J = 7.1 Hz, 2H),
7.66–7.48 (m, 4H), 4.17 (t, J = 7.2 Hz, 2H), 3.70 (s, 3H), 3.38 (t, J = 7.2 Hz, 2H), 2.56 (s,
3H), 2.35 (s, 3H), 1.94–1.81 (m, 2H), 1.80–1.66 (m, 2H); 13C NMR (126 MHz, DMSOꢀd6) δ
153.2, 144.8, 135.3, 133.7, 133.1, 129.0, 128.2, 128.0, 127.4, 127.0, 126.6, 123.8, 122.8,
121.3, 49.6, 47.3, 35.1, 28.1, 20.1, 14.7, 9.6; HRMS (ESIꢀTOF) (m/z): Calcd for
C21H27N4O2S+ 399.1855, Found 399.1844 [M – CF3SO3]+.
Compound 12f. White solid (350 mg, 91%); Mp: 138ꢀ142 °C; 1H NMR (500 MHz, DMSOꢀ
d6) δ 10.33 (s, 1H), 7.78 (dd, J = 8.5, 4.8 Hz, 2H), 7.62 (d, J = 3.0 Hz, 1H), 7.60 (d, J = 3.0
Hz, 1H), 7.24 (td, J = 9.0, 2.5 Hz, 2H), 4.15 (t, J = 7.5 Hz, 2H), 3.72 (s, 3H), 3.35 – 3.26 (m,
2H), 2.57 (s, 3H), 2.22 (s, 3H), 1.88 – 1.82 (m, 2H), 1.75 – 1.69 (m, 2H); 13C NMR (126
MHz, DMSOꢀd6) δ 152.6, 144.8, 134.5, 134.4, 128.8, 122.7, 121.3, 115.8, 49.5, 47.3, 35.1,
28.1, 20.1, 15.0, 9.6; HRMS (ESIꢀTOF) (m/z): Calcd for C17H24FN4O2S+ 367.1604, Found
367.1635 [M – CF3SO3]+.
Compound 12g. White solid (340 mg, 88%); Mp: 155ꢀ157 °C; 1H NMR (500 MHz, DMSOꢀ
d6) δ 10.47 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.65 (brs, 1H), 7.62 (brs, 1H), 7.46 (d, J = 9.0
Hz, 2H), 4.16 (t, J = 7.0 Hz, 2H), 3.74 (s, 3H), 3.36 – 3.29 (m, 2H), 2.58 (s, 3H), 2.23 (s, 3H),
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1.92 – 1.84 (m, 2H), 1.80 – 1.70 (m, 2H); 13C NMR (126 MHz, DMSOꢀd6) δ 152.5, 144.8,
136.8, 134.5, 128.8, 128.4, 122.7, 121.3, 49.5, 47.3, 35.1, 28.1, 20.0, 14.9, 9.6; HRMS (ESIꢀ
TOF) (m/z): Calcd for C17H24ClN4O2S+ 383.1308, Found 383.1332 [M – CF3SO3]+.
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Compound 12h. White solid (380 mg, 88%); Mp: 159ꢀ163 °C; 1H NMR (500 MHz, DMSOꢀ
d6) δ 10.44 (s, 1H), 7.74 – 7.51 (m, 6H), 4.15 (t, J = 7.0 Hz, 2H), 3.72 (s, 3H), 3.37 – 3.22
(m, 2H), 2.57 (s, 3H), 2.22 (s, 3H), 1.90 – 1.78 (m, 2H), 1.78 – 1.65 (m, 2H); 13C NMR (126
MHz, DMSOꢀd6) δ 152.4, 144.8, 137.2, 131.8, 128.6, 123.3, 122.6, 121.3, 49.5, 47.3, 35.1,
28.1, 20.1, 14.8, 9.6; HRMS (ESIꢀTOF) (m/z): Calcd for C17H24BrN4O2S+ 427.0803, Found
427.0800 [M – CF3SO3]+.
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Compound 12i: Light pink color solid (350 mg, 86%); Mp: 167ꢀ171 °C. H NMR (500
MHz, DMSO) δ 10.73 (s, 1H), 8.26 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 8.5 Hz, 2H), 7.64 (d, J =
1.6 Hz, 1H), 7.62 (d, J = 1.7 Hz, 1H), 4.19 (t, J = 6.9 Hz, 2H), 3.76 (s, 3H), 3.44–3.32 (m,
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2H), 2.60 (s, 2H), 2.31 (s, 3H), 1.94–1.83 (m, 2H), 1.82–1.75 (m, 2H); C NMR (126 MHz,
DMSO) δ 150.8, 148.0, 144.8, 144.0, 127.7, 124.0, 122.7, 121.3, 49.8, 47.3, 35.1, 28.1, 20.1,
14.8, 9.6; HRMS (ESIꢀTOF) (m/z): Calcd for C17H24N5O4S+ 394.1549, Found 394.1528 [M –
CF3SO3]+.
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Compound 12j. Black color solid (350 mg, 92 %); Mp: 105ꢀ111 °C; H NMR (500 MHz
DMSOꢀd6) δ 10.66 (s, 1H), 8.63 (d, J = 4.5 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.90 (td, J = 9,
2.5 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.47 (dd, J = 7.0, 5.0 Hz, 1H),
4.17 (t, J = 7.1 Hz, 2H), 3.74 (s, 3H), 3.51 – 3.30 (m, 2H), 2.58 (s, 3H), 2.33 (s, 3H), 1.96 –
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1.83 (m, 2H), 1.78ꢀ1.73 (m, 2H).; C NMR (126 MHz, DMSOꢀd6) δ 154.5, 153.0, 148.7,
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144.8, 137.8, 124.8, 122.7, 121.3, 120.9, 49.8, 47.3, 35.1, 28.1, 20.1, 13.3, 9.6; HRMS (ESIꢀ
TOF) (m/z): Calcd for C16H24N5O2S+ 350.1651, Found 350.1637 [M – CF3SO3]+.
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Compound 12k. Yellow color solid (360 mg, 94%); Mp: 121ꢀ134 °C; 1H NMR (500 MHz,
DMSOꢀd6) δ 10.33 (s, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.55 (dd, J =
5.0, 1.0 Hz, 1H), 7.46 – 7.42 (m, 1H), 7.08 – 7.04 (m, 1H), 4.14 (t, J = 7.5 Hz, 2H), 3.71 (s,
3H), 3.26 (td, J = 7.5, 2.1 Hz, 2H), 2.56 (s, 3H), 2.25 (s, 3H), 1.91 – 1.79 (m, 2H), 1.79 –
1.66 (m, 2H); 13C NMR (126 MHz, DMSOꢀd6) δ 150.3, 144.8, 142.8, 129.1, 128.3, 128.1,
122.8, 121.3, 49.6, 47.3, 35.1, 28.2, 20.1, 15.2, 9.6; HRMS (ESIꢀTOF) (m/z): Calcd for
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C15H23N4O2S2 355.1262, Found 355.1251 [M – CF3SO3]+.
Synthesis of 1,2,3-thiadiazoles (13a-k). To ionic liquidꢀsupported hydrazone (1 mmol),
thionyl chloride (5 mmol) was added dropwise at room temperature, and the reaction mixture
was heated slowly up to 60 °C for 4 h. Progress of the reaction was monitored by thin layer
chromatography (TLC). After completion of the reaction, the reaction mixture was
neutralized by sodium bicarbonate solution. The compound was extracted using ethyl
acetate/hexane (3: 2 v/v, 3 × 5 mL), dried over sodium sulphate, and evaporated under
reduced pressure to get pure compound.
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Compound 13a. White solid (58 mg, 91%); Mp: 77ꢀ78 °C (Lit.37 mp 75ꢀ77 °C); H NMR
(500 MHz, CDCl3) δ 8.65 (s, 1H), 8.05 (d, J = 7.8 Hz, 2H), 7.51 (t, J = 7.7 Hz, 2H), 7.45 (t, J
= 7.1 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 159.6, 147.5, 136.6, 136.3, 128.1, 124.4;
HRMS (ESIꢀTOF) (m/z): Calcd for C8H7N2S+ 163.0330, Found 163.0321 [M + H]+.
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Compound 13b. White solid (62 mg, 86%); Mp: 87ꢀ91°C (Lit.37 mp: 91ꢀ93.5 °C); H NMR
(500 MHz, CDCl3) δ 8.52 (s, 1H), 7.99 (d, J = 7.9 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 3.88 (s,
3H); 13C NMR (126 MHz, CDCl3) δ 162.7, 160.5, 128.8, 128.4, 123.6, 114.6, 55.5; HRMS
(ESIꢀTOF) (m/z): Calcd for C9H9N2OS+ 193.0436, Found 193.0423 [M + H]+.
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Compound 13c. White solid (55 mg, 87%); Mp: 73ꢀ76 °C (Lit.37 mp: 74ꢀ76 °C); 1H NMR
(500 MHz, CDCl3) δ 8.59 (s, 1H), 7.94 (d, J = 7.7 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 2.43 (s,
3H); 13C NMR (126 MHz, CDCl3) δ 163.0, 139.5, 129.8, 129.2, 128.0, 127.3, 21.3; HRMS
(ESIꢀTOF) (m/z): Calcd for C9H9N2S+ 177.0486, Found 177.0458 [M + H]+.
Compound 13d. White solid (64 mg, 84%); Mp: 197ꢀ201 °C; 1H NMR (500 MHz, CDCl3) δ
8.68 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 7.4 Hz, 1H), 7.77
(dd, J = 7.1, 1.0 Hz, 1H), 7.63–7.49 (m, 3H); 13C NMR (126 MHz, CDCl3) δ 160.9, 133.2,
133.1, 132.8, 130.4, 129.0, 127.5, 127.4, 126.0, 125.2, 124.2, 124.1; HRMS (ESIꢀTOF) (m/z):
Calcd for C12H9N2S+ 213.0486, Found 213.0474 [M + H]+.
Compound 13e. White solid (67 mg, 88%), Mp: 203ꢀ207 °C; 1H NMR (500 MHz, CDCl3) δ
8.76 (s, 1H), 8.61 (s, 1H), 8.11 (dd, J = 8.4, 1.3 Hz, 1H), 8.01–7.93 (m, 2H), 7.91–7.88 (m,
1H), 7.67–7.54 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 162.9, 133.7, 133.5, 130.1, 130.0,
129.0, 128.5, 128.1, 127.8, 126.9, 126.9, 124.7; HRMS (ESIꢀTOF) (m/z): Calcd for
C12H9N2S+ 213.0486, Found 213.0455 [M + H]+.
Compound 13f. White solid (67 mg, 89%); Mp: 185ꢀ189 °C; 1H NMR (500 MHz, CDCl3) δ
8.61 (s, 1H), 8.11–7.97 (m, 2H), 7.26–7.17 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 164.4,
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162.4, 129.7, 129.3, 127.0, 116.4; HRMS (ESIꢀTOF) (m/z): Calcd for C8H6FN2S+ 181.0236,
Found 181.0220 [M + H]+.
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Compound 13g. White solid (64 mg, 88%); Mp: 138ꢀ140 °C (Lit.37 Mp: 136ꢀ137.5 °C); H
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NMR (500 MHz, CDCl3) δ 8.65 (s, 1H), 7.99 (d, J = 7.8 Hz, 2H), 7.48 (d, J = 7.9 Hz, 2H);
13C NMR (126 MHz, CDCl3) δ 161.7, 135.4, 130.2, 129.4, 129.37, 128.6; HRMS (ESIꢀTOF)
(m/z):Calcd for C8H6ClN2S+ 196.9935, Found 196.9905 [M + H]+.
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Compound 13h. White solid (74 mg, 90 %); Mp: 150ꢀ154°C (Lit.23 Mp: 150ꢀ152°C); H
NMR (500 MHz, CDCl3) δ 9.40 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H);
13C NMR (126 MHz, CDCl3) δ 162.0, 133.9, 131.4, 130.0, 128.6, 125.1; HRMS (ESIꢀTOF)
(m/z): Calcd for C8H6BrN2S+ 240.9435, Found 240.9434 [M + H]+ and 242.9587 [M + H +
2]+.
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Compound 13i: White solid (74 mg, 83%); Mp: 207ꢀ211°C (Lit.37 Mp: 183°C); H NMR
(500 MHz, DMSO) δ 9.92 (s, 1H), 8.53–8.25 (m, 4H); 13C NMR (126 MHz, DMSO) δ 159.6,
147.5, 136.6, 136.3, 128.1, 124.4; HRMS (ESIꢀTOF) (m/z): Calcd for C8H6N3O2S+ 208.0181,
found 208.0166 [M + H]+.
Compound 13j. White solid (51 mg, 80%); Mp: 158ꢀ161 °C (Lit.46 2010, 45, 6127
) Mp: 163
°C); 1H NMR (500 MHz, CDCl3) δ 9.24 (s, 1H), 8.69 (d, J = 4.7 Hz, 1H), 8.48 (d, J = 7.9 Hz,
1H), 7.92–7.85 (m, 1H), 7.35 (t, J = 6.2 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 163.3,
149.9, 149.8, 137.4, 133.9, 123.9, 122.4; HRMS (ESIꢀTOF) (m/z): Calcd for C7H6N3S+
164.0282, Found 164.0269 [M + H]+.
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Compound 13k. White solid (58 mg, 88%); Mp: 72ꢀ74 °C (Lit.47 Mp: 70ꢀ71 °C); H NMR
(400 MHz, CDCl3) δ 8.74 (s, 1H), 7.64 (dd, J = 3.6, 1.2 Hz, 1H), 7.43 (m, 2H), 7.14 (dd, J =
4.8, 1.4 Hz, 1H); 13C NMR (126 MHz, DMSOꢀd6) δ 163.2, 139.0, 135.8, 128.6, 127.5, 126.8,
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HRMS (ESIꢀTOF) (m/z): Calcd for C6H5N2S2 168.9889, Found 168.9875 [M + H]+.
+
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Synthesis of selenadiazoles (14). Ionic liquidꢀsupported hydrazone (1 mmol), selenium
dioxide (1.05 mmol), and sodium sulphate (1.50 mmol) were mixed in acetonitrile (6 ml) and
vigorously stirred at room temperature for 24 h. Progress of reaction was monitored by TLC.
After completion of the reaction, the residue was purifed using toluene as a mobile phase to
get pure product.
Compound 14a. Yellow solid (29 mg, 30%); Mp. 70ꢀ71 °C (Lit.48 Mp: 76 °C); 1H NMR (500
MHz, CDCl3) δ 9.40 (s, 1H), 8.06 (d, J = 7.8 Hz, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.43 (t, J = 7.3
Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 162.9, 137.0, 132.1, 129.1, 127.7; HRMS (ESIꢀ
TOF) (m/z): Calcd for C8H7N2Se+ 210.9774, Found 210.9753 [M + H]+.
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Compound 14b. Yellow solid (20 mg, 22%); Mp: 85ꢀ89 °C; H NMR (500 MHz, CDCl3) δ
9.26 (s, 1H), 8.00 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 162.8, 160.1, 135.1, 129.1, 124.9, 114.6, 55.3; HRMS (ESIꢀTOF) (m/z):
Calcd for C9H9N2OSe+ 240.9875, found 240.9843 [M + H]+.
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Compound 14c. Black solid (26 mg, 30%); Mp: 118ꢀ125 °C (Lit.46 Mp: 154 °C); H NMR
(500 MHz, CDCl3) δ 9.39 (s, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H); 13C
NMR (126 MHz, CDCl3) δ 160.7, 136.2, 133.8, 129.5, 128.4, 127.9; HRMS (ESIꢀTOF)
(m/z):Calcd for C8H6ClN2Se+ 244.9385, Found 244.9386 [M + H]+.
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Compound 14d. Viscous liquid (27 mg, 32%); Mp: 162ꢀ167 °C (Lit.46 Mp: 164 °C); H
NMR (500 MHz, DMSOꢀd6) δ 10.03 (s, 1H), 7.80–7.75 (m, 1H), 7.66 (dd, J = 5.1, 1.2 Hz,
1H), 7.20 (ddd, J = 5.2, 3.6, 1.6 Hz, 1H); 13C NMR (126 MHz, DMSOꢀd6) δ 138.9, 136.5,
134.8, 128.6, 127.5, 126.8; HRMS (ESIꢀTOF) (m/z): Calcd for C6H5N2SSe+ 216.9333, Found
216.9302 [M + H]+.
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Compound 14e. Solid (23 mg, 25%); Mp: 134ꢀ136 °C; H NMR (500 MHz, CDCl3) δ 9.52
(s, 1H), 8.63 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.02–7.94 (m, 2H), 7.89 (d, J = 8.2 Hz, 1H),
7.58–7.48 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 158.5, 137.1, 133.6, 133.4, 129.3, 128.94,
128.5, 127.8, 127.2, 126.8, 126.7, 125.1; HRMS (ESIꢀTOF) (m/z): Calcd for C12H9N2Se+
260.9931, Found 260.9902 [M + H]+.
Compound 14f. Solid (39 mg, 40%); Mp: 128ꢀ133 °C (Lit.46 Mp: 177 °C); H NMR (500
1
MHz, CDCl3) δ 9.40 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H); 13C NMR
(126 MHz, CDCl3) δ 161.8, 137.3, 132.4, 131.0, 129.2, 123.0; HRMS (ESIꢀTOF) (m/z):
Calcd for C8H6BrN2Se+ 288.8880, found 288.8876 [M + H]+ and 290.8872 [M + H + 2]+.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support of this work by the Council of Scientific and
Industrial Research, New Delhi, India and U. S. A. National Science Foundation, Grant
Number CHE 0748555.
Supporting Information. Copies of H NMR and 13C NMR spectra for compounds 10, 12,
1
and 14. This material is available free of charge via the Internet at http://pubs.acs.org.
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