Synthesis of substituted-δ2-1,2,4-triazolin-5-ones and S-substituted isothiobiureas from 1-aryl/alkyl-6-phenyl-2-thiobiureas

Article abstract of DOI:10.1081/SCC-100104074

Reaction of 1-aryl/alkyl-6-phenyl-2-thiobiureas 1 with BnCl and BuI in neutral medium at reflux temperature resulted in the formation of the S-alkylated isothiobiureas 2 and 1,2,4-triazolin-5-one derivatives 3. A convenient route to 2 is also reported.

Full text of DOI:10.1081/SCC-100104074

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SYNTHESIS OF
SUBSTITUTED-Δ2-1,2,4-
TRIAZOLIN-5-ONES
AND S-SUBSTITUTED
ISOTHIOBIUREAS FROM 1-
ARYL/ALKYL-6-PHENYL-2-
THIOBIUREAS
M. M. Suni a , Vipin A. Nair a & C. P. Joshua a
a Department of Chemistry , University of Kerala ,
Trivandrum, Kerala, 695 581, India
Published online: 02 Aug 2010.
To cite this article: M. M. Suni , Vipin A. Nair & C. P. Joshua (2001) SYNTHESIS OF
SUBSTITUTED-Δ2-1,2,4-TRIAZOLIN-5-ONES AND S-SUBSTITUTED ISOTHIOBIUREAS
FROM 1-ARYL/ALKYL-6-PHENYL-2-THIOBIUREAS, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry,
31:10, 1599-1605, DOI: 10.1081/SCC-100104074
To link to this article: http://dx.doi.org/10.1081/SCC-100104074
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SYNTHETIC COMMUNICATIONS, 31(10), 1599–1605 (2001)
SYNTHESIS OF SUBSTITUTED-
D2-1,2,4-TRIAZOLIN-5-ONES AND
S-SUBSTITUTED ISOTHIOBIUREAS FROM
1-ARYL/ALKYL-6-PHENYL-2-THIOBIUREAS
M. M. Suni,* Vipin A. Nair, and C. P. Joshua
Department of Chemistry, University of Kerala,
Trivandrum 695 581, Kerala, India
ABSTRACT
Reaction of 1-aryl/alkyl-6-phenyl-2-thiobiureas 1 with BnCl
and BuI in neutral medium at reflux temperature resulted in
the formation of the S-alkylated isothiobiureas 2 and 1,2,4-
triazolin-5-one derivatives 3. A convenient route to 2 is also
reported.
Compounds containing twinned double bonds, such as carbodiimides
and iso (thio) cyanate esters, undergo rapid addition reactions with hydra-
zino1–3 and amidino groups.2,4 Reaction of 4-alkylthiosemicarbazides with
arylcyanamides afforded 4-alkyl-3-arylamino-1,2,4-triazoline-5-thiones.5
However, 1-phenylacetyl-4-substituted thiosemicarbazides undergo reaction
in alkaline and acidic media to yield 3-benzyl-Á2-1,2,4-triazoline-5-thiones
and 2-amino-5-benzyl-1,3,4-thiadiazoles, respectively.6 Quite interestingly,
it has been reported that 1-acyl-6-aryl/alkyl-2,5-dithiobiureas, on reaction
with p-toluenesulphonyl chloride in the presence of triethylamine,7,8 or
* Corresponding author.
1599
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1600
SUNI, NAIR, AND JOSHUA
a brominating agent,7 or with methyl iodide in the absence of a base,7
yielded 1,3,4-thiadiazole derivatives. On the other hand, 1-acyl-6-aryl/
alkyl-2,5-dithiobiurea derivative reacts with sodium ethanolate to afford a
1,2,4-triazoline-5-thione derivative only.9 Cyclization reactions of 1,6-disub-
stituted-2-thiobiureas with alkyl halides have not been reported to date.
Hence, our studies were mainly in that direction to understand the reaction
mechanism and its pathway.
The reaction of 1a with BnCl in ethanol at reflux temperature was
found to afford 1,6-diphenyl-2-S-benzyl isothiobiurea 2a and 4-phenyl-3-
benzylthio-Á2-1,2,4-triazolin-5-one 3a. Because of the high polarisability
of the SH bond, and also of the electropositive character of the sulfur
atom when compared to nitrogen, it is the SH group that undergoes pre-
ferential benzylation over the NH. The acid produced during the course of
S-benzylation favors the cyclization of 2a to yield 3a (Scheme 1).
Scheme 1.
During cyclization, the more basic nitrogen atom at position 1 makes a
nucleophilic attack on the carbonyl carbon, thereby expelling aniline, result-
ing in the formation of 3a. The presence of aniline in the reaction mixture
was detected by dye test (Scheme 2, mechanism).
Scheme 2.
The above reaction, carried out in neutral medium, afforded a 60%
yield of 2a and 30% yield of 3a, whereas a mere repetition of the same
reaction in hydrochloric acid afforded a complete conversion. This indicates
that the acid generated in situ or added is a must for the cyclization reaction.

D2-1,2,4-TRIAZOLIN-5-ONES
1601
The acid added protonates the N-6, thereby enhancing the elimination of
amine. The isolation of 2a and its acid-catalyzed cyclization to 3a confirms
the reaction pathway. Further proof for the structure 2a is arrived at from
its alternative synthesis by the reaction of 4-phenyl-3-S-benzylisothiosemi-
carbazide with phenyl isocyanate in dry acetonitrile. Compounds 1 (a–f)
undergo similar reaction with BuI (Tables 1, 2)
On similar lines, we found that reaction of 1-aryl/alkyl-2-thiobiureas
with alkyl halides in acidic and neutral media resulted in the exclusive
formation of 1,2,4-triazolin-5-one derivatives, which are identical to the
products formed in the case of 1,6-disubstituted-2-thiobiureas. The above
reaction once again highlights the mode of cyclization that occurs by the
attack of N-1 on C-5, resulting in the formation of five-membered hetero-
cycles. In conclusion, we have developed a simple and convenient method
for the synthesis of five-membered heterocycles from extended urea-like
chain compounds.
Table 1. 1-Aryl/alkyl-6-phenyl-2-S-substituted Isothiobiureas 2
Compounds
R
Substituent
M.p. (ꢀC)
a
b
cEt
d
e
f
g
h
C6H5
p-CH3C6H4
Bn
Bn
Bn
237–238
165
143
Pr
Bn
Bu
Bu
Bu
Bu
147
231–232
217
117–118
117
p-H3COC6H4
p-ClC6H4
Me
Et
Table 2. 4-Aryl/alkyl-3-substituted Thio-Á2-1,2,4-triazolin-5-ones 3
Compounds
R
Substituent
M.p. (ꢀC)
a
b
cEt
d
e
f
g
h
C6H5
p-CH3C6H4
Bn
Bn
Bn
157
186–187
93–94
Pr
Bn
Bu
Bu
Bu
Bu
91–92
122
109–110
84
70
p-H3COC6H4
p-ClC6H4
Me
Et

1602
SUNI, NAIR, AND JOSHUA
Figure 1. The ortex diagram of 4-ethyl-3-butylthio-Á2-1,2,4-triazolin-5-one.
EXPERIMENTAL
Melting points are uncorrected. Infrared spectra were taken on a
Perkin Elmer RX1 spectrophotometer using KBr pellets. 1H NMR and
13C NMR were recorded in CDCl3 and DMSO-d6 on a BRUCKER-300
spectrometer with tetramethylsilane as the internal standard. Mass spectra
were recorded at 70 eV ionizing voltage on a Jeol-D300 MS instrument. The
elemental analyses were performed by the National Chemical Laboratory,
Pune. The crystal structure of 3h was determined on an Enraf-Nonius
CAD4 diffractometer with Mo-Ka radiation. All the isothio cyanates
were prepared according to literature procedure.10
Preparation of 1-Aryl/alkyl-6-phenyl-2-thiobiureas 1 (a–f)
Phenyl isocyanate (1.19 mL, 0.01 mol) was added dropwise to a sus-
pension of 4-aryl/alkylthio semicarbazide (0.01 mol) in acetonitrile (15 mL)
with efficient stirring. The white product that separated after 10 min was
collected and triturated with 2N alkali. Neutralization of the alkaline filtrate
yielded 1 (a–f). It was crystallized from DMF: ethanol (1:1) as white needles.
All the required 4-aryl/alkylthiosemicarbazides were obtained by the reac-
tion of corresponding isothiocyanates with hydrazine hydrate at 0ꢀC in
ethanolicmedium.

D2-1,2,4-TRIAZOLIN-5-ONES
1603
Preparation of 4-Aryl/alkyl-3-benzyl/butylthio-
D2-1,2,4-triazolin-5-ones 3 (a–h)
A suspension of 1 (a–f) (0.01 mol) in ethanol containing 2 mL concen-
trated HCl/HI was refluxed with BnCl/BuI (0.01 mol). The solid obtained
after 4 h was dissolved in alkali. Neutralization of the alkaline filtrate
yielded 3 (a–h). Purification was done either by column chromatography
on silica or by crystallization from aqueous ethanol (1:1). The triazoles
obtained are listed below. The reaction was repeated in neutral medium
for 4 h and the residue obtained on TLC examination indicated the presence
of two compounds. It was triturated with 2N alkali and acidified to obtain
compounds 3 (a–h). The alkali-insoluble products were identified as the
open-chain S-alkylated isothiobiureas 2 (a–h).
3a: IR (KBr)ꢀ: 3450, 3050, 2900, 1690, 1590, 1510, 760 cmꢁ1. 1H NMR
d: 4.21 (s, 2H, SCH2), 7.29–7.51 (m, 10H, Ar), 9.95 (s, 1H, NH). 13C NMR
d: 35.91, 124.29, 126.78, 127.84, 128.68, 129.10, 129.49, 132.15, 135.89,
144.24, 155.64. MS, m/z: 283 (Mþ, 20), 240 (M-43, 25), 135 (6), 91 (100).
Anal. calc. for C15H13N3OS: C, 63.60; H, 4.59; N, 14.84; S, 11.31. Found: C,
63.46; H, 4.19; N, 15.01; S, 11.81.
3b: IR (KBr)ꢀ: 3400, 3050, 2950, 1700, 1510, 815, 725 cmꢁ1. 1H NMR
d: 2.4 (s, 3H), 4.18 (s, 2H, SCH2), 7.28–7.50 (m, 9H, Ar), 10.1 (s, 1H, NH).
MS, m/z: 297 (Mþ, 20), 254 (7), 149 (31), 91(100).
1
3c: IR (KBr)ꢀ: 3450, 3050, 2900, 1710, 1515, 720 cmꢁ1. H NMR d:
1.19 (t, 3H, J ¼ 7.24 Hz), 3.58 (q, 2H, J ¼ 7.24 Hz, NCH2), 4.26 (s, 2H,
SCH2), 7.28–7.35 (m, 5H, Ar), 9.99 (s, 1H, NH).13C NMR d: 14.12,
36.57, 36.80, 127.94, 128.77, 128.99, 136.09, 143.79, 155.75.
3d: IR (KBr)ꢀ: 3400, 3050, 2900, 1700, 1510, 710 cmꢁ1. 1H NMR d: 0.88
(t, 3H, J ¼ 7.3 Hz),1.64 (m, 2H), 3.46 (t, 2H, J ¼ 7.2, 7.5 Hz, NCH2), 4.26 (s,
2H, SCH2), 7.26–7.35 (m, 5H, Ar), 10.28 (s, 1H, NH). 13C NMR d: 10.95,
22.09, 36.66, 43.09, 127.88, 128.71, 128.96, 136.03, 144.12, 155.95. MS, m/z:
249 (Mþ, 22), 149 (3), 91 (100). Anal. calc. for C12H15N3OS: C, 57.83; H,
6.02; N, 16.87. Found: C, 57.79; H, 6.16; N, 16.83.
3e: IR (KBr)ꢀ: 3250, 3100, 2950, 1720, 1520, 1260, 840 cmꢁ1. 1H NMR
d: 0.91 (t, 3H), 1.41 (m, 2H), 1.7 (m, 2H), 2.98 (t, 2H, SCH2), 3.89 (s, 3H,
OMe), 7.01 (d, 2H, Ar), 7.31 (d, 2H, Ar), 11.01 (s, 1H, NH). 13C NMR d:
13.46, 21.79, 30.86, 31.06, 55.56, 114.79, 124.79, 128.24, 145.26, 155.89,
160.05. MS, m/z: 279 (Mþ, 52), 223 (100), 149 (32).
3f: IR (KBr)ꢀ: 3250, 3100, 2900, 1690, 1520, 1220, 790 cmꢁ1. 1H NMR
d: 0.9 (t, 3H), 1.42 (m, 2H), 1.7 (m, 2H), 3.10 (t, 2H, SCH2), 7.37 (d, 2 H,
Ar), 7.5 (d, 2H, Ar), 10 (s, 1H, NH).
3g: IR (KBr)ꢀ: 3200, 2900, 2800, 1700, 1510, 760 cmꢁ1. 1H NMR d: 0.9
(t, 3H), 1.43 (m, 2H), 1.7 (m, 2H), 2.89 (t, 2H, SCH2), 3.19 (s, 3H, NCH3),

1604
SUNI, NAIR, AND JOSHUA
9.21 (s, 1H, NH). 13C NMR d: 13.48, 21.74, 27.42, 31.26, 31.49, 144.79,
156.28. MS, m/z: 187 (Mþ, 16), 149 (5), 131 (100), 74 (16).
Preparation of 1,6-Disubstituted-2-S-benzyl/butyl-
isothiobiureas 2 (a–h)
To an etherial solution (dry) of 4-phenyl-3-S-benzyl/butylisothiosemi-
carbazide (0.01 mol) prepared by the condensation of 4-aryl/alkylthiosemi-
carbazide with BnCl/BuI, phenyl isocyanate (0.01 mol) was added with
efficient stirring. The solid obtained was collected and washed with 2N
alkali, and finally crystallized from ethanol as white needles.
2a: IR (KBr)ꢀ: 3450, 3400, 3390, 3150, 2950, 1670, 1510, 720 cmꢁ1
.
1H NMR d: 4.24 (s, 2H, SCH2), 6.63, 7.12, 7.14 (three NH protons),
7.26–7.42 (m, 15H, Ar) MS, m/z: (Mþ, absent), 253 (M-123, 4), 149 (2),
121 (C6H5CONH2þ, 8), 91 (100). Anal. calc. for C21H20N4OS: C, 67.02;
H, 5.32, N, 14.89. Found: C, 68.01; H, 5.52; N, 13.79.
2b: IR (KBr)ꢀ: 3500, 3450, 3390, 3050, 2900, 1690, 1520, 820 cmꢁ1
.
1H NMR d: 2.5 (s, 3H), 4.38 (s, 2H, SCH2), 7.97, 8.18, 9.77 (three NH
protons), 7.18–7.42 (m, 14H, Ar). MS. m/z (Mþ, absent), 267 (5), 149
(10), 106 (8), 91(100).
2c: IR (KBr)ꢀ: 3450, 3400, 3350, 3150, 2950, 1690, 1515, 715 cmꢁ1
.
1H NMR d: 1.2 (t, 3H), 3.61 (q, 2H), 4.2 (s, 2H, SCH2), 7.87, 8.3, 9.21 (three
NH protons), 7.25–7.48 (m, 10H, Ar). MS. m/z: (Mþ, absent), 194 (5), 150
(13), 93 (100), 91 (80).
2d: IR (KBr)ꢀ: 3450, 3430, 3400, 3250, 3000, 1700, 1510, 720 cmꢁ1
.
1H NMR d: 0.89 (t, 3H), 1.65 (m, 2H), 3.5 (t, 2H, NCH2), 4.30 (s, 2H,
SCH2), 8.4, 8.48, 9.21 (three NH protons), 7.26–7.43 (m, 10H, Ar). MS,
m/z: (Mþ, absent), 218 (100), 91 (22). Anal. calc. for C18H22N4OS: C, 63.16;
H, 6.43; N, 16.37. Found: C, 62.98; H, 6.13; N, 16.21.
2e: IR (KBr)ꢀ: 3400, 3200, 3150, 3050, 2910, 1590, 1510, 810 cmꢁ1
.
1H NMR d: 0.99 (t, 3H), 1.41 (m, 2H), 1.59 (m, 2H), 2.79 (t, 2H, SCH2), 3.82
(s, 3H, OMe), 6.55, 6.98, 8.27 (three NH protons), 7.13–7.24 (m, 5H, Ar),
7.26 (d, 2H, Ar), 7.34 (d, 2H, Ar). MS. m/z: (Mþ, absent), 212 (83), 135 (3),
121 (4), 93 (100).
2f: IR (KBr)ꢀ: 3450, 3200, 3150, 3050, 2900, 1590, 1490, 820 cmꢁ1
.
1H NMR d: 0.92 (t, 3H), 1.44 (m, 2H), 1.72 (m, 2H), 2.93 (t, 2H, SCH2),
6.95, 6.97, 8.29 (three NH protons), 7.25–7.31 (m, 5H, Ar), 7.45 (d, 2H, Ar),
7.48 (d, 2H, Ar). 13C NMR d:13.57, 21.66, 30.06, 31.07, 119.19, 119.93,
122.21, 122.94, 128.39, 128.77, 128.89, 138.41, 139.52, 153.25. Anal. calc.
for C18H21N4OSCl: C, 57.37; H, 5.58; N, 14.87. Found: C, 57.42; H, 5.54;
N, 14.92.

D2-1,2,4-TRIAZOLIN-5-ONES
1605
1
2g: IR (KBr)ꢀ: 3410, 3300, 3150, 2850, 1590, 1220 cmꢁ1. H NMR
d: 0.94 (t, 3H), 1.44 (m, 2H), 1.71 (m, 2H), 2.96 (t, 2H, SCH2), 3.01
(s, 3H, NCH3), 6.05, 8.09, 9.53 (three NH protons), 7.29–7.71 (m, 5H,
Ar). 13C NMR d: 13.61, 21.61, 30.44, 31.14, 32.14, 119.29, 122.94, 128.75,
138.3, 153.71, 155.44. MS, m/z: 280 (Mþ, 9), 224 (8), 212 (10), 135 (46), 91
(100). Anal. calc. for C13H20N4OS: C, 55.71; H, 7.4; N, 20.0. Found: C,
55.85; H, 7.18; N, 19.06.
1
2h: IR (KBr)ꢀ: 3450, 3400, 3350, 2850, 1600, 1310 cmꢁ1. H NMR
d: 0.93 (t, 3H), 1.29 (t, 3H), 1.43 (m, 2H), 1.7 (m, 2H), 3.07 (t, 2H,
SCH2), 3.69 (q, 2H, NCH2), 6.08, 8.1, 9.41 (three NH protons), 7.29–7.72
(m, 5H, Ar). MS. m/z: 294 (Mþ, 7), 239 (13), 136 (42), 93 (100).
ACKNOWLEDGMENTS
The authors acknowledge the instrumental services rendered by the
National Single Crystal Diffractometer Facility (established by DST) at the
School of Chemistry, University of Hyderabad, for crystal structure,
National Chemical Laboratory, Pune, for elemental analysis, and Central
Drug Research Institute, Lucknow, for EIMS spectra.
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Received in Japan May 26, 2000