Synthesis of Symmetrical Bis(5-substituted oxadiazolyl/thiadiazolyl/triazolylmethyl)sulfones

Article abstract of DOI:10.1002/jhet.2231

A new class of bis(oxadiazolyl/thiadiazolyl/triazolylmethyl)sulfones were prepared by the cyclocondensation of sulfonyldiacetic acid with aryl acid hydrazide and arylmethanesulfonylacetic acid hydrazide.

Full text of DOI:10.1002/jhet.2231

Month 2016
Synthesis of Symmetrical Bis(5-substituted oxadiazolyl/thiadiazolyl/
triazolylmethyl)sulfones
*
Padmaja Adivireddy, Pedamalakondaiah Devanaboina, Lavanya Gopala, and Rajasekhar Chittoor
Department of Chemistry, Sri Venkateswara University, Tirupati 517 502, Andhra Pradesh, India
*
E-mail: adivireddyp@yahoo.co.in
Received October 26, 2013
DOI 10.1002/jhet.2231
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
A new class of bis(oxadiazolyl/thiadiazolyl/triazolylmethyl)sulfones were prepared by the cyclocondensation
of sulfonyldiacetic acid with aryl acid hydrazide and arylmethanesulfonylacetic acid hydrazide.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
reported the synthesis of multifunctional 1,3,4-oxadiazoles,
1,3,4-thiadiazoles, and 1,2,4-triazoles via potassium salt of
different acid hyrazides [23]. We have also reported these het-
erocycles from various acids and acid hydrazides followed by
interconversion in the presence of appropriate nucleophiles
[24]. Encouraged by these results and our continued interest
in the development of a variety of heterocycles with different
pharmacophore unit, the present work has been taken up.
Aryl sulfones are widely used in medicinal chemistry and
found in several drugs including the recently developed se-
lective COX-2 inhibitor Vioxx [1]. The five-membered het-
erocycles particularly 1,3,4-oxadiazole, 1,3,4-thiadiazole,
and 1,2,4-triazoles are prominent compounds that possess
various pharmacological activities. Some 1,3,4-oxadiazole
sulfones exhibit antibacterial and antifungal activities
[2,3]. The important method for the synthesis of 1,3,4-
oxadiazoles involves cyclization of diacylhydrazines pre-
pared by the reaction of acyl chlorides and hydrazine. Sev-
eral cyclodehydrating agents Et2O·BF3 [4], triflic anhydride
[5], polyphosphoric acid [6], and so on, have been used.
One-pot synthesis of 1,3,4-oxadiazoles from hydrazine
and carboxylic acids has also been reported [7,8]. 1,3,4-
Thiadiazole nucleus constitutes the active part of several
compounds including antibacterial, antimycotic, and anti-
inflammatory agents [9,10]. Most frequently used methods
for the synthesis of thiadiazoles include the reaction
of acylthiosemicarbazides with acidic reagents such as
trifluoroacetic acid [11] and methanesulfonic acid [9]. Be-
sides, 1,2,4-triazole and their derivatives show insecticidal
[12], antifungal [13], antimicrobial [14], and anti-inflam-
matory [15] properties. One of the synthetic methods for
the preparation of triazoles involves the use of N,N′-
dimethyl formamide dimethyl acetals [16]. Replacement
of –O– by –S– or –NH– in some heterocycles was reported
viz., Bordner’s [17] preparation of pyrroles from furan
and the transformation of epoxides to episulfides by the
action of thiocyanates or thiourea [18–20]. However, re-
ports about the conversion of 1,3,4-oxadiazoles to 1,3,4-
thiadiazoles and 1,2,4-triazoles are relatively less [21,22].
Thus, there is a quest for the synthesis of a variety of azoles
linked by different pharmacophoric units. In fact, we have
RESULTS AND DISCUSSION
The synthetic routes adopted to prepare the target mole-
cules are outlined in Schemes 1 and 2. The cyclocondensation
of one mole of sulfonyldiacetic acid (2) with two moles aryl
acid hydrazide (5) in the presence of POCl3 led to the forma-
tion of bis(5-aryl-1,3,4-oxadiazolylmethyl)sulfone (9). Inter-
conversion of oxadiazole to thiadiazole was effected by
treating compound 9 with thiourea in tetrahydrofuran to ob-
tain bis(5-aryl-1,3,4-thiadiazolylmethyl)sulfone (10). On the
other hand, the reaction of compound 9 with hydrazine
hydrate in the presence of KOH in n-butanol furnished bis
(5-aryl(4-amino)-1,2,4-triazol-3-ylmethyl)sulfone(11)(Scheme1
and Table 1). The 1H NMR spectra of 9a and 10a exhibited
a singlet at δ 4.92 and 5.15 because of methylene protons
attached to C-2 while 11a at 5.01 ppm because of methy-
lene protons attached to C-3 in addition to aromatic protons.
Moreover, in compound 11a, a broad singlet appeared
at δ 5.62 ppm was attributed to NH2, which disappeared
on deuteration. The 70-eV mass spectra of 9a, 10a, and
11a displayed molecular ion peaks at 382.07, 414.03,
and 410.13 corresponding to their molecular formulae
C18H14N4O4S, C18H14N4O4S, and C18H18N8O2S.
Adopting similar methodology, the reaction of sulfonyldiacetic
acid (2) with two moles of arylmethanesulfonylacetic acid
© 2016 Wiley Periodicals, Inc.

P. Adivireddy, P. Devanaboina, L. Gopala, and R. Chittoor
Vol 000
Scheme 1
Scheme 2
Table 1
Physical and analytical data of compounds 9–14.
Analysis % calcd. (found)
Compound
Mp (°C)
Yield (%)
Molecular formula (mol. wt)
18H14N4O4S (382.39)
C
H
N
9a
9b
9c
141–143
134–136
155–157
150–152
146–148
162–164
159–161
143–145
171–173
188–190
167–169
203–205
210–212
191–193
218–220
207–209
197–199
216–218
75
72
80
77
74
82
78
76
81
84
79
87
83
78
86
84
80
88
C
56.66 (56.54)
58.60 (58.53)
48.07 (47.91)
52.25 (52.15)
54.24 (54.28)
44.79 (44.72)
52.43 (52.27)
54.87 (54.78)
45.21 (45.10)
44.78 (44.63)
48.53 (48.47)
41.66 (41.58)
44.08 (44.13)
46.10 (45.99)
39.67 (39.58)
44.54 (44.43)
46.36 (46.29)
39.87 (39.82)
3.74 (3.69)
4.45 (4.42)
2.74 (2.68)
3.48 (3.40)
4.12 (4.10)
2.49 (2.50)
4.47 (4.42)
5.10 (5.06)
3.34 (3.36)
3.96 (3.91)
4.44 (4.41)
3.13 (3.17)
3.72 (3.70)
4.16 (4.18)
3.03 (3.02)
4.45 (4.41)
4.88 (4.86)
3.64 (3.65)
14.79 (14.65)
13.75 (13.65)
12.60 (12.41)
13.68 (13.52)
12.76 (12.66)
11.72 (11.59)
27.51 (27.30)
25.57 (25.55)
23.53 (23.38)
10.06 (9.89)
9.31 (9.42)
8.96 (8.82)
9.48 (9.36)
9.12 (8.94)
8.53 (8.39)
19.02 (18.84)
18.11 (17.99)
16.98 (16.89)
C20H18N4O4S (410.45)
C18H12Cl2N4O4S (451.28)
C18H14N4O4S (414.52)
C20H18N4O2S3 (442.58)
C18H12Cl2N4O2S3 (483.41)
C18H18N8O2S (410.45)
C20H22N8O2S (438.51)
C18H16Cl2N8O2S (479.34)
C22H22N4O8S3 (566.63)
C24H26N4O8S3 (594.68)
C22H20Cl2N4O8S3 (655.52)
C22H22N4O6S5 (598.76)
C24H26N4O6S5 (626.81)
C22H20Cl2N4O6S5 (667.65)
C22H26N8O6S3 (594.69)
C24H30N8O6S3 (622.74)
C22H24Cl2N8O6S3 (663.58)
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
14a
14b
14c
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthetic Paper
Table 2
hydrazide (8) in the presence of POCl3 yielded bis(5-
IR data of compounds 9–14.
arylmethanesulfonylmethyl-1,3,4-oxadiazolylmethyl)sulfone
(12). The compound 12 on treatment with thiourea in tetra-
hydrofuran produced bis(5-arylmethanesulfonylmethyl-1,
3,4-thiadiazolylmethyl)sulfone (13). Furthermore, bis(5-
arylmethanesulfonylmethyl(4-amino)-1,2,4-triazol-3-ylmethyl)
sulfone (14) was prepared by the reaction of the compound
12 with hydrazine hydrate in the presence of KOH in
n-butanol (Scheme 2 and Table 1). The 1H NMR spectra of
12a displayed three singlets at δ 4.85, 5.49, 5.60ppm; 13a at
5.11, 5.58, 5.72 ppm; and 14a at 5.07, 5.51, 5.55ppm be-
cause of methylene protons attached to C-2/C-3, C-5, and
Ar-CH2, respectively. In addition to these, compound 14a
presented a broad singlet at 5.75 ppm for NH2. The signals
due to highly acidic protons disappeared when D2O was
added. The 70-eV mass spectra of 12a, 13a, and 14a showed
molecular ion peaks at 566.06, 598.01, and 594.11 corre-
sponding to their chemical composition C22H22N4O8S3,
C22H22N4O6S5, and C22H26N8O6S3. The structures of all
the new compounds were further established by IR (Table 2),
13C NMR (Table 3), and elemental analyses.
IR (KBr) cmÀ1
Compound
NH2
C=N
SO2
9a
9b
9c
—
—
—
—
—
—
—
—
—
—
1577
1576
1584
1582
1579
1585
1564
1560
1582
1568
1565
1574
1586
1583
1590
1578
1576
1582
1312
1310
1318
1331
1342
1322
1319
1314
1325
1341
1334
1345
1330
1339
1328
1338
1332
1326
1148
1142
1153
1145
1140
1147
1130
1132
1135
1139
1137
1143
1136
1131
1138
1136
1128
1150
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
14a
14b
14c
—
—
3480
3475
3486
—
—
—
—
—
—
3362
3360
3375
—
—
—
—
—
—
3488
3475
3492
3370
3365
3376
Table 3
1H and 13C NMR data of compounds 9–14.
Compound
9a
1H NMR (CDCl3/DMSO-d6)
13C NMR (CDCl3/DMSO-d6)
4.92 (s, 4H, CH2-(C-2)), 7.21–7.59 (m, 10H, Ar-H)
50.4 (CH2-(C-2)), 159.2 (C-5), 161.8 (C-2), 127.3, 128.9, 129.4,
130.1 (aromatic carbons)
9b
2.26 (s, 6H, Ar-CH3), 4.88 (s, 4H, CH2-(C-2)), 7.11-7.46
(m, 8H, Ar-H)
4.98 (s, 4H, CH2-(C-2)), 7.27–7.62 (m, 8H, Ar-H)
23.9 (Ar-CH3), 49.6 (CH2-(C-2)), 159.5 (C-5), 161.2 (C-2),
126.3, 128.6, 129.7, 131.2 (aromatic carbons)
51.2 (CH2-(C-2)), 161.2 (C-5), 163.5 (C-2), 127.8, 129.5, 132.7,
136.5 (aromatic carbons)
9c
10a
10b
10c
11a
11b
11c
5.15 (s, 4H, CH2-(C-2)), 7.24–7.58 (m, 10H, Ar-H)
51.3 (CH2-(C-2)), 174.2 (C-5), 175.6 (C-2), 128.2, 129.8, 13.5,
134.2 (aromatic carbons)
2.28 (s, 6H, Ar-CH3), 5.13 (s, 4H, CH2-(C-2)), 7.20-7.52 (m, 8H, Ar-H) 24.6 (Ar-CH3), 51.6 (CH2-(C-2)), 173.4 (C-5), 175.3 (C-2),
127.8, 129.6, 130.3, 136.2 (aromatic carbons)
5.16 (s, 4H, CH2-(C-2)), 7.29–7.70 (m, 8H, Ar-H)
52.7 (CH2-(C-2)), 176.6 (C-5), 178.2 (C-2), 128.4, 129.9, 131.4,
135.2 (aromatic carbons)
51.6 (CH2-(C-3)), 159.4 (C-5), 162.8 (C-3), 127.4, 129.5, 130.2,
131.3 (aromatic carbons)
24.1 (Ar-CH3), 50.9 (CH2-(C-3)), 157.9 (C-5), 161.4 (C-3),
126.8, 128.0, 131.2, 135.6 (aromatic carbons)
51.8 (CH2-(C-3)), 159.8 (C-5), 163.1 (C-3), 129.9, 131.8, 132.8,
134.5 (aromatic carbons)
5.01 (s, 4H, CH2-(C-3)), 5.62 (bs, 4H, NH2), 7.19-7.64
(m, 10H, Ar-H)
2.24 (s, 6H, Ar-CH3), 5.03 (s, 4H, CH2-(C-3)), 5.60 (bs, 4H,
NH2), 7.15–7.57 (m, 8H, Ar-H)
5.08 (s, 4H, CH2-(C-3)), 5.64 (bs, 4H, NH2), 7.25-7.75 (m, 8H, Ar-H)
12a
12b
12c
13a
13b
13c
14a
14b
14c
4.85 (s, 4H, CH2-(C-2)), 5.49 (s, 4H, CH2-(C-5)), 5.60
(s, 4H, Ar-CH2), 7.13–7.48 (m, 10H, Ar-H)
2.29 (s, 6H, Ar-CH3), 4.78 (s, 4H, CH2-(C-2)), 5.38 (s, 4H,
CH2-(C-5)), 5.58 (s, 4H, Ar-CH2), 7.03–7.35 (m, 8H, Ar-H)
5.03 (s, 4H, CH2-(C-2)), 5.52 (s, 4H, CH2-(C-5)), 5.63 (s, 4H,
Ar-CH2), 7.22–7.51 (m, 8H, Ar-H)
5.11 (s, 4H, CH2- (C-2)), 5.58 (s, 4H, CH2-(C-5)), 5.72 (s, 4H,
Ar-CH2), 7.16–7.49 (m, 10H, Ar-H)
2.31 (s, 6H, Ar-CH3), 5.09 (s, 4H, CH2-(C-2)), 5.47 (s, 4H, CH2- 26.7 (Ar-CH3), 55.7 (CH2-(C-2)), 59.8 (CH2-(C-5)), 62.7 (Ar-CH2), 175.3
(C-5)), 5.72 (s, 4H, Ar-CH2), 7.12–7.41 (m, 8H, Ar-H)
5.16 (s, 4H, CH2-(C-2)), 5.62 (s, 4H, CH2-(C-5)), 5.74 (s, 4H,
Ar-CH2), 7.23–7.53 (m, 8H, Ar-H)
5.07 (s, 4H, CH2-(C-3)), 5.51 (s, 4H, CH2-(C-5)), 5.55 (s, 4H,
Ar-CH2), 5.62 (bs, 4H, NH2), 7.10–7.47 (m, 10H, Ar-H)
54.8 (CH2-(C-2)), 58.5 (CH2-(C-5)), 60.3 (Ar-CH2), 161.4 (C-5),
163.4 (C-2), 124.5, 126.4, 128.7, 130.6 (aromatic carbons)
25.4 (Ar-CH3), 54.4 (CH2-(C-2)), 57.8 (CH2-(C-5)), 59.8 (Ar-CH2), 159.3
(C-5), 162.9 (C-2), 122.4, 129.8, 131.5, 136.4 (aromatic carbons)
55.8 (CH2-(C-2)), 59.2 (CH2-(C-5)), 61.5 (Ar-CH2), 162.8 (C-5),
163.7 (C-2), 123.4, 128.3, 132.9, 135.7 (aromatic carbons)
55.5 (CH2-(C-2)), 60.4 (CH2-(C-5)), 63.8 (Ar-CH2), 176.4 (C-5),
178.6 (C-2), 124.9, 126.9, 130.7, 131.9 (aromatic carbons)
(C-5), 177.9 (C-2), 124.2, 126.8, 132.9, 137.3 (aromatic carbons)
55.9 (CH2-(C-2)), 61.8 (CH2-(C-5)), 64.9 (Ar-CH2), 176.8 (C-5),
178.2 (C-2), 125.6, 127.9, 133.2, 136.8 (aromatic carbons)
53.8 (CH2-(C-3)), 59.5 (CH2-(C-5)), 62.5 (Ar-CH2), 153.8 (C-5),
164.2 (C-3), 124.6, 125.4, 131.6, 132.9 (aromatic carbons)
2.27 (s, 6H, Ar-CH3), 5.04 (s, 4H, CH2-(C-3)), 5.49 (s, 4H, CH2- (C-5)), 25.8 (Ar-CH3), 52.9 (CH2-(C-3)), 59.3 (CH2-(C-5)), 62.2 (Ar-CH2), 154.7
5.60 (s, 4H, Ar-CH2), 5.64 (bs, 4H, NH2), 7.06–7.39 (m, 8H, Ar-H)
5.14 (s, 4H, CH2-(C-3)), 5.54 (s, 4H, CH2-C-5), 5.62 (s, 4H,
Ar-CH2), 5.66 (bs, 4H, NH2), 7.17–7.52 (m, 8H, Ar-H)
(C-5), 163.9 (C-3), 123.2, 125.0, 131.0, 137.1 (aromatic carbons)
54.3 (CH2-(C-3)), 60.2 (CH2-(C-5)), 63.5 (Ar-CH2), 154.8 (C-5),
165.0 (C-3), 124.9, 125.7, 132.6, 135.7 (aromatic carbons)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. Adivireddy, P. Devanaboina, L. Gopala, and R. Chittoor
Vol 000
media, and the precipitate formed was filtered. The solid obtained
was acidified with conc. HCl to pH ≈3 and washed with water. It
was dried and recrystallized from ethanol.
CONCLUSION
A new class of bis(5-aryl-1,3,4-oxadiazolyl/thiadiazolyl/
1,2,4-triazolylmethyl)sulfones and bis(5-arylmethanesulfonyl
methyl-1,3,4-oxadiazolyl/thiadiazolyl/1,2,4-triazolyl methyl)
sulfones were synthesized by exploiting the ester functionali-
ties in aryl acid methyl ester and arylmethanesulfonylacetic
acid methyl ester adopting simple and well-versed methodol-
ogies. All the new compounds were characterized by spectral
parameters and elemental analyses.
Acknowledgement. One of the authors Dr. A. Padmaja is thankful
to Council of Scientific and Industrial Research (CSIR), New Delhi,
for financial assistance under a major research project.
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Bis(5-aryl(4-amino)-1,2,4-triazol-3-ylmethyl)sulfone (11)/bis
(5-arylmethane sulfonylmethyl(4-amino)-1,2,4-triazol-3-ylmethyl)
sulfone (14): general procedure. To a solution of 9/12 (1 mmol)
in n-butanol (10 mL), hydrazine hydrate (6 mmol) was added and
refluxed for 9–11 h. Then, KOH (4 mmol) was added to the reaction
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet