C-S bond-forming reactions of barbiturylbromide with isothiocarbamides in aqueous media

Article abstract of DOI:10.1080/00397911.2013.804933

The C-S cross coupling of pharmaceutically active barbituric acid derivatives has been achieved by the interaction of selective monobromobarbituric acid with thioureas in an aqueous medium. This method is applicable for simple thiourea as well as monosubstituted thioureas, and corresponding products are obtained in good yield. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.804933

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C-S Bond-Forming Reactions
of Barbiturylbromide with
Isothiocarbamides in Aqueous Media
Madhuri M. Sontakke a , Atul A. Jichkar b , Madhukar G. Dhonde b ,
Chandrakant S. Bhaskar c & Baliram N. Berad a
a Department of Chemistry , RTM, Nagpur University , Nagpur , India
b Department of Chemistry , Shri Mathuradas Mohota College of
Science , Nagpur , India
c Department of Chemistry , Arts, Commerce, and Science College ,
Koradi , India
Published online: 20 Nov 2013.
To cite this article: Madhuri M. Sontakke , Atul A. Jichkar , Madhukar G. Dhonde , Chandrakant
S. Bhaskar & Baliram N. Berad (2014) C-S Bond-Forming Reactions of Barbiturylbromide with
Isothiocarbamides in Aqueous Media, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 44:3, 340-345, DOI: 10.1080/00397911.2013.804933
To link to this article: http://dx.doi.org/10.1080/00397911.2013.804933
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Synthetic Communications1, 44: 340–345, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.804933
C-S BOND-FORMING REACTIONS OF
BARBITURYLBROMIDE WITH ISOTHIOCARBAMIDES
IN AQUEOUS MEDIA
Madhuri M. Sontakke,1 Atul A. Jichkar,2
Madhukar G. Dhonde,2 Chandrakant S. Bhaskar,3 and
Baliram N. Berad1
1Department of Chemistry, RTM, Nagpur University, Nagpur, India
2Department of Chemistry, Shri Mathuradas Mohota College of Science,
Nagpur, India
3Department of Chemistry, Arts, Commerce, and Science College, Koradi,
India
GRAPHICAL ABSTRACT
Abstract The C-S cross coupling of pharmaceutically active barbituric acid derivatives has
been achieved by the interaction of selective monobromobarbituric acid with thioureas in an
aqueous medium. This method is applicable for simple thiourea as well as monosubstituted
thioureas, and corresponding products are obtained in good yield.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Aryl=H thiocarbamides; C-S cross coupling of barbituryl isothiocarbamides;
monobromobarbituric acid
INTRODUCTION
Barbiturates are biologically and pharmaceutically active drugs that depress
nerve activity in the brain and have been commonly used to treat anxiety, insomnia,
seizure disorder, and migraine headaches and used as general anesthetias in surgery.[1]
The C-S cross coupling of thiocyanates, isothiouronium salts,[2] 5-alkyl-5-(b-
mercapto ethyl), xanthate,[3] and barbituric acid derivatives in side chain was shown
Received March 22, 2013.
Address correspondence to Madhukar G. Dhonde, Department of Chemistry, Shri Mathuradas
Mohota College of Science, Nagpur, MS 440009, India. E-mail: madhudash2001@yahoo.co.in
340

BARBITURYL ISOTHIOCARBAMIDES
341
not to possess hypnotic and anesthetic activity. 5-Substituted barbiturates have been
predominantly used for their anticonvulsant[4] activity. 5-Monoalkylated barbituric
acids such as 5-(benzoxy)benzyl barbituric acids are used in the treatment of cancer
and AIDS via inhibition of human uridine phosphorylase,[5] and its derivatives are
proven to be valuable pharmaceuticals.[6] Thiobarbituric acid and barbituric acid
derivatives are well known to act as antibacterial,[7] herbicidal,[8] fungicidal,[9] and
antiviral[10] agents. Some barbiturates have been reportly used in antitumor,[11]
anticancer,[12] and osteoporosis[13] treatments and some of them have been studied
as nonlinear optical materials.[14] Literature survey revealed that 5-b-thiocyanates,
isothiourium, and 5-b-mercapto ethyl barbituric acid are synthesized by requiring
b-bromoethyl barbituric acid not to directly expose the active sites of barbituric acid
but to block the active methylene group. The reported procedure has some drawbacks
such as organic reaction medium, higher temperature, and longer reaction time.
Moreover, the prepared 5-b-ethylbarbituric acids are not suitable for anticonvulsant,
anesthetic, and hypnotic activity. To best of our knowledge, the C-S cross coupling in
barbituryl isothiocarbamides in aqueous medium is not reported earlier. Here, we
report our intensive studies on the C-S cross-coupling reaction of barbituryl isothio-
carbamides using selective monobromobarbituric acid with thioureas in aqueous
medium under catalyst-free conditions to form highly functionalized derivatives
(Fig. 1).
The reaction was initiated by the controlled bromination of barbituric acid
using molecular bromine, which gives selective monobromo product. Further
monobromo barbituric acid reacted with thioureas to furnish S-barbituryl isothiocar-
bamide in good yield. The product was characterized by elemental and spectral
=
analysis. Alkaline plumbite test of the products showed negative result for C S (free
Figure 1. Methods of C-S cross coupling of barbituryl isothiocarbamides. (Figure is provided in color
online.)

342
M. M. SONTAKKE ET AL.
Figure 2. R ¼ (a) H, (b) C6H5, (c) 2-(CH3-C6H4), (d) 3-(CH3-C6H4), (e) 4-(CH3-C6H4), (f) 2-(Cl-C6H4), (g)
3-(Cl-C6H4), (h) 4-(Cl-C6H4), (i) 2-(CH3O-C6H4), (j) 3-(CH3O-C6H4), (k) 4-(CH3O-C6H4), (l) a-C10H7),
and (m) CH2-C6H5. (Figure is provided in color online.)
sulfur), which indicated that C-S cross coupling was done. All the substituted thiour-
eas (3a–m) reacted with monobromo barbituric acid in optimized conditions to give
the expected products (4a–m) in good to excellent yield but N,N0-disubstituted thiour-
eas do not react with monobromo barbituric acid in the given conditions (Fig. 2).
RESULTS AND DISCUSSION
The optimum condition for every C-S cross-coupling reaction of barbituryl
isothiocarbamides were carried out in different solvents such as C2H5OH, tetrahy-
drofuran (THF), and H2O (Table 1). Initially every reaction carried out in THF gave
a poor yield of (4a–m) and longer reaction time. The same coupling reactions
Table 1. Optimization of reaction conditions
C2H5OH
THF
H2O
Entry Time (h) Yield 4 (%) Time (h) Yield 4 (%) Time (h) Yield 4 (%)
a
b
c
d
e
f
1.5
1.5
1.5
2.0
2.0
2.5
2.5
2.0
2.5
2.0
2.5
2.0
2.5
62
67
71
68
77
66
58
68
66
61
67
58
73
4.0
4.0
3.0
3.5
4.0
4.5
4.0
3.5
3.0
3.0
3.0
3.5
3.5
49
51
51
45
60
41
39
42
49
45
51
51
57
1.0
1.5
1.0
2.0
1.5
2.0
2.5
1.5
1.5
2.0
2.0
2.0
2.0
81
86
78
75
89
76
72
85
80
74
89
70
86
g
h
i
j
k
l
m

BARBITURYL ISOTHIOCARBAMIDES
343
observed in ethanol medium gave good yield with retardation in time. When the
same reactions were examined in a water medium, they gave very good yield and
comparatively less time for completion of reaction (Table 1, entries a–m). On the
basis of optimization data we investigated if the meta substituent on phenyl ring
suppressed the reaction rate while para substituent enhanced the rate of reaction
(Table 1, entries a–k).
The efficiency of the reaction is supported by the example of hindered isothio-
carbamide: for example, naphthyl thiocarbamide reacted with monobromo barbituric
acid to give corresponding product (Table 1, entry l). Similarly N-benzyl thiocarba-
mide reacted with monobromo barbituric acid in identical conditions to give good
yield (Table 1, entry m).
Table 2. C-S cross coupling of barbituryl isothiocarbamides in aqueous medium

344
M. M. SONTAKKE ET AL.
After optimization of reaction conditions the direct C-S cross coupling of
barbituryl isothiocarbmides are great synthetic challenge for C-S bond formation
due to the susceptibility of sulphur for coupling reaction in aqueous medium without
any catalysts. Therefore, we believe that present procedure provide the access for the
synthesis of selective and structurally diverse C-S cross coupling of barbituryl iso-
thiocarbamides in aqueous medium without any catalyst is very efficient, simple,
high yielding and general hence it is advantageous, eco-friendly and applicable for
synthesis of variety of isothiocarbamides (Table 2).
EXPERIMENTAL
Melting points were taken in open capillary tubes and are uncorrected. Unless
otherwise indicated, 1H (400 MHz) NMR spectra were recorded on a Bruker
DSX-300=AV-III 400L NMR spectrometer from dimethylsulfoxide (DMSO) sol-
ution with tetramethylsilane (TMS) as an internal reference. Chemical shifts are
recorded as parts per million (ppm) on the d scale and multiplicities are described
as s (singlet), d (doublet), and m (multiplet). The MS spectra were recorded using a
Quatro Micro API-WATER mass spectrometer. Infrared (IR) spectra were recorded
on a Bruker and Shimadzu (4000–450 cmꢀ1) FTIR spectrophotometer. Thin-layer
chromatography (TLC) was performed with E. Merck precoated TLC plates, alu-
minium silica gel60 F254, and spots were located with ultraviolet (UV) light or iodine
vapor and by charring with a suitable charring agent. All other commercial reagents
and solvents were used without further purification.
General Experimental Procedure for the Synthesis of 2-(2,4,6-Trioxo-
hexahydropyrimidin-5-yl)-isothiocarbamide (4a)
2-(2,4,6-Trioxo-hexahydropyri-midin-5-yl)-isothiocarbamide (4a) was prepared
by the interaction of of 5-bromo-pyrimidine-2,4,6-trione (2, 2.5 mmol) with thiourea
(3, 2.5 mmol) in water (25 ml) and stirring the reaction mixture at 50–60 ꢁC for 1.0 h to
afford a white solid. The progress of the reaction was monitored by TLC. After com-
pletion of the reaction, the crude product was basified using aqueous ammonium
hydroxide and then purified by column chromatography using silica gel (230–400
mesh) with ethyl acetate and n-hexane as eluent. The product was nondesulfurized
by alkaline plumbite solution, and its mp is 270 (d).
Spectral Data
1H NMR 400 MHz (DMSO): 9.55 (2H, s, 2H), 8.64 (s, 1H), 8.27 (s, 1H), 2.07
(s, 2H). MS (m=z), 202 (Mþ), 175 (C4H7O2N4Sþ), 159 (BA-Sþ). IR (cmꢀ1) 3328,
=
=
3127 (N-H), 2951, 2830 (C-H), 1704 (C O), 1584 (N-C N), 1250 (S-C-N), 765
(C-S). Anal. calcd. for C5H6O3N4S: C, 29.70; H, 2.97; N, 27.72; S, 15.84. Found:
C, 29.52; H, 2.75; N, 27.59; S, 15.90.
ACKNOWLEDGMENT
The authors are thankful to Shri Shivaji Science College, Akola, Indian Insti-
tute of Science, Bangalore, and Vishnu Chemical, Hyderabad, for recording the IR,

BARBITURYL ISOTHIOCARBAMIDES
345
NMR, and mass spectra. Thanks are also due to Dr. S. G. Charalwar, Principal, Shri
M. M. College of Science and Dr. L. J. Paliwal, Head, Department of Chemistry,
RTM Nagpur University, Nagpur, for encouragement and providing necessary
facilities.
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