NH4Cl mediated new protocol for the synthesis of 5-arylidene barbiturates

Article abstract of DOI:10.2174/157017811794557778

Eco-benign method for synthesizing arylidene barbiturates has been developed by using ammonium chloride (NH₄Cl) in stoichiometric amount, as an enolization activator, in water. Execution of methodology is simple, products obtained in high yield

Full text of DOI:10.2174/157017811794557778

28
Letters in Organic Chemistry, 2011, 8, 28-32
NH4Cl Mediated New Protocol for the Synthesis of 5-Arylidene
Barbiturates
Khalid Mohammed Khan*,a, Muhammad Alia, Momin Khana, Muhammad Tahaa and
Shahnaz Perveenb
aH. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of
Karachi, Karachi-75270, Pakistan
bPCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman, Karachi-75280, Pakistan
Received July 17, 2009: Revised December 08, 2010: Accepted December 08, 2010
Abstract: Eco-benign method for synthesizing arylidene barbiturates has been developed by using ammonium chloride
(NH4Cl) in stoichiometric amount, as an enolization activator, in water. Execution of methodology is simple, products
obtained in high yields and the reactions are completed within 30 min. The new methodology does not involve any
solvent/solvent extraction while solid products were yielded in all cases which were filtered and washed.
Keywords: Barbituric acid, ammonium chloride, enolization activator, eco-friendly.
Dedicated to Professor Dr. Muhammad Iqbal Choudhary, Director, International Center for Chemical and Biological
Sciences, University of Karachi, Pakistan, on the occasion of his 50th birthday.
INTRODUCTION
various catalysts like NH4OAc/AcOH, montmorillonite K-
10, silica gel, basic alumina, NaCl, montmorillonite KSF,
and KSF/NaCl for the synthesis of 5-arylidene barbiturates
[16]. Grinding method has also been employed for the
synthesis of arylidene barbiturates [17]. These condensation
reactions have also been reported in water only or without
solvents using BiCl3 [18, 19].
Medicinal chemists have paid attention towards
barbituric acids and their analogs for over 100 years due to
their therapeutic values [1]. The first scientific data on
barbiturates were published in 1903 [2]. One of the
important members of pyrimidine family is 5-arylidene
barbiturates. The major importance of this class of
compounds has been focusing on their application as useful
precursors in the preparation of new heterocyclic compounds
[3] and as selective oxidizing agents [4-6]. 5-Benzylidene
barbiturate derivatives show inhibitory effects on mushroom
tyrosinase and their antibacterial activities [7]. Medicinal use
of barbiturates in neurological disorders has also been
investigated [8]. Barbiturate may be synthesized by
Knovenagel reaction of barbituric acid with different
aldehydes [9]. We very recently reported an improved
version of Knovenagel reaction of barbituric acid with
different aldehydes in the presence of bismuth chloride [10].
Condensation between N-alkyl-Nꢀ-aryl carbodiimides and
malonic acid monoesters leads to barbiturate in the presence
of base [11]. Optically active N-alkylated barbiturates were
synthesized from disubstituted cyanoacetates [12] and 5-
(cyclohexylmethyl) barbituric acid derivatives [13].
Synthesis of eco-benign version of biologically active
compounds is well known [20]. At the beginning of the 21st
century, green chemistry approaches held out noteworthy
potential not only to diminish the byproducts, a marked
reduction in waste production and lowering of energy costs
but also in the advancement of new methodologies towards
previously unfeasible materials using existing technologies
[21].
Previously reported methods using water without any
catalyst were unfortunately not working in our hands,
therefore we had used NH4Cl as a catalyst [22, 23]. In any
case this will be one of the new methods for synthesizing
these types of compounds. In this communication, we wish
to report a convenient method for the synthesis of 5-
arylidene barbiturates in water using ammonium chloride
(NH4Cl) as catalyst.
5-Arylidene barbiturates are generally prepared by
condensation of barbituric/thiobarbituric acid with various
aldehydes on refluxing in water by using acetic acid as
catalyst [14]. Villemein et al. reported the synthesis of
barbiturates in the presence of montmorillonite KSF clay
under microwave irradiation [15]. Dewan has reported
RESULTS AND DISCUSSION
During the drug design and discovery program of our
research group, we investigated a variety of heterocyclic
compounds to disclose their biological potential [24]. In the
present study, fifteen (15) arylidine barbiturates 1-15 have
been synthesized from commercially available barbituric
acid by condensing with different aldehydes using
ammonium chloride (NH4Cl) in stoichiometric amount, as an
enolization activator, in water. In all cases, solid products
were formed which were filtered, washed with cold water
*Address correspondence to this author at the H. E. J. Research Institute of
Chemistry, International Center for Chemical and Biological Sciences,
University of Karachi, Karachi-75270, Pakistan; Tel: 00922134824910;
Fax: 00922134819018; E-mails: hassaan2@super.net.pk,
khalid.khan@iccs.edu
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

NH4Cl Mediated New Protocol for the Synthesis
Letters in Organic Chemistry, 2011, Vol. 8, No. 1
29
R
HO
O
O
O
-H2O
O
OH2
NH2
NH4Cl
H2O
-NH3
NH3
HN
NH
HN
NH
R
H
R
H
R
H
O
O
Fig. (1). Proposed mechanism of arylidene barbiturates via iminium ion formation.
and ether followed by drying under vacuum. Mechanism
involved a net dehydration via aldol intermediate obtained
by nucleophilic attack of active methylene at aldehyde
carbonyl. The acidic nature of ammonium chloride helps to
dissociate barbituric acid to generate nucleophilic specie
which is capable of attacking on electrophilic carbon of
aldehydes. Therefore, ammonium chloride (NH4Cl), a mildly
acidic in aqueous media acts as an enolization activator,
R
O
O
O
NH4Cl
30 min, r.t
O
O
HN
NH
R
H
HN
NH
O
O
1-15
R-
R-
S. No.
Yield (%)
S. No.
Yield (%)
OCH3
H3CO
H3CO
1
98
9
95
F
2
3
4
5
91
94
96
89
10
11
12
13
85
82
81
89
O2N
Ph
HO
(H3C)2N
HO
H3CO
O2N
H3CO
F
H3CS
HO
HO
6
7
8
85
95
92
14
15
-
93
94
-
Cl
OH
F
Cl
HO
-
OMe
Scheme 1. Synthesis of arylidene barbiturates 1-15 by using NH4Cl.

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Letters in Organic Chemistry, 2011, Vol. 8, No. 1
Khan et al.
which not only speeds up the reaction but also the reaction
proceeded at room temperature. There is another plausible
mechanism which may be predicted by assuming the
formation of iminium ion through the reaction of aldehyde
and ammonia (Fig. 1). In the next step, the intermediate
iminium ion is attacked by enol barbituric acid to form
transitory aldol specie, which is later on converted to final
adduct by dehydration. All the reactions were completed
within 30 min in excellent yields (Scheme 1).
95 (7.2); Anal. calcd. for C11H7FN2O3 (234.18): C, 56.42; H,
3.01; F, 8.11; N, 11.96; O, 20.50; Found: C, 56.35; H, 3.06;
N, 11.89.
5-(4-Nitrobenzylidene)-2,4,6(1H,3H,5H)-pyrimidinetrione 2
Yield: 0.95 g (91%); 1H-NMR (400 MHz, DMSO-d6): ꢀ
11.48 (s, 1H, NH), 11.31 (s, 1H, N-H), 8.31 (s, 1H, Vin.-H),
8.14 (d, 2H, J = 8.7 Hz, Ar-H), 8.01 (d, 2H, J = 8.7 Hz, Ar-
H); EIMS m/z (% rel. abund.): 261 (M+, 92), 260 (40), 244
(93), 214 (70), 172 (25.7), 132 (12), 101 (51.4), 89 (100);
Anal. calcd. for C11H7N3O5 (261.19): C, 50.58; H, 2.70; N,
16.09; O, 30.63; Found: C, 50.51; H, 2.78; N, 16.14.
To generalize our method, we have used a variety of
aldehydes with different functional groups for this
condensation and found that the method is valid for all types
of species and obtained high yields. The immiscibility of
aldehydes in water does not affect the progress of reaction
and yields of products in all cases.
5-(3,4-Dihydroxybenzylidene)-2,4,6(1H,3H,5H)-pyrimidin-
etrione 3
Yield: 1.5 g (94%); 1H-NMR (400 MHz, DMSO-d6): ꢀ
11.19 (s, 1H, NH), 11.06 (s, 1H, NH), 10.36 (br. S, 1H, -
OH), 9.44 (br. s, 1H, -OH), 8.17 (d, 1H, J = 2.1 Hz, Ar-H),
8.1 (s, 1H, Vin.-H), 7.6 (dd, 1H, J = 8.6, 2.1 Hz, Ar-H), 6.84
(d, 1H, J = 8.6 Hz, Ar-H); EIMS m/z (% rel. abund.): 248
(M+, 100), 247 (40), 231 (11.8), 203 (31), 187 (14.3), 134
(21), 109 (5.5); Anal. calcd. for C11H8N2O5 (248.19): C,
53.23; H, 3.25; N, 11.29; O, 32.23; Found: C, 53.30; H, 3.18;
N, 11.24.
Hence, ammonium chloride (NH4Cl) is environmentally
benign and its use in organic reactions with water enhances
its compatibility. Low cost is another advantage which
makes the methodology extremely useful for the synthetic
chemist for the synthesis of such an important class of
compounds in excellent yields. Product isolation is easy and
clean, no solvent/solvent extraction is required while
products are obtained in pure forms.
5-(3-Nitrobenzylidene)-2,4,6(1H,3H,5H)-pyrimidinetrione 4
Yield: 1.3 g (96%); 1H-NMR (400 MHz, DMSO-d6): ꢀ
11.47 (s, 1H, NH), 11.33 (s, 1H, NH), 8.9 (br. s, 1H, Ar-H),
8.52 (dd, 1H, J = 8.1, 2.3 Hz, Ar-H), 8.32 (s, 1H, Vin.-H),
7.9 (t, 2H, J = 8.0 Hz, Ar-H); EIMS m/z (% rel. abund.): 261
(M+, 48.7), 260 (37.7), 216 (16.8), 214 (63.3), 172 (30.1),
116 (53), 101 (59.8), 89 (83.6); Anal. calcd. for C11H7N3O5
(261.19): C, 50.58; H, 2.70; N, 16.09; O, 30.63; Found: C,
50.65; H, 2.63; N, 16.04.
EXPERIMENTAL GENERAL
EI mass spectra were recorded with various MAT 711
(70 eV) spectrometers and data are tabulated as m/z. H-
1
NMR spectra were recorded in DMSO-d6 using Bruker
Avance AC400 (400 MHz) spectrometer, respectively.
Splitting patterns were as follows; s, singlet; d, doublet; dd,
double doublets; t, triplet; m, multiplet. Chemical shifts are
reported in ꢀ (ppm) and coupling constants are given in Hz.
Elemental analysis was performed on a Carlo Erba 1106
elemental analyzer. The progress of all reactions was
monitored by TLC, which was performed on 2.0 X 5.0 cm
aluminum sheets pre-coated with silica gel 60F254 to a
thickness of 0.25 mm (Merck). The chromatograms were
visualized under ultraviolet light (254-366 nm) or by iodine
vapors. The compounds 1-15 were synthesized and
characterized satisfactorily.
5-[4-(Methylsulfanyl)benzylidene]-2,4,6(1H,3H,5H)-pyrim-
idinetrione 5
Yield: 0.93 g (89%); 1H-NMR (400 MHz, DMSO-d6): ꢀ
11.32 (s, 1H, NH), 11.2 (s, 1H, NH), 8.21 (s, 1H, Vin.-H),
8.18 (d, 2H, J = 8.6, Ar-H), 7.33 (d, 2H, J = 8.6, Ar-H), 2.3
(s, 3H, -SCH3); EIMS m/z (% rel. abund.): 262 (M+, 100),
261 (21.3), 215 (8.6), 172 (38), 148 (14.2), 133 (21.13), 89
(46.7); Anal. calcd. for C12H10N2O3S (262.28): C, 54.95; H,
3.84; N, 10.68; O, 18.30; S, 12.23; Found: C, 54.85; H, 3.89;
N, 10.72.
General Procedure for the Synthesis of 5-Arylidene
Barbiturates 1-15
5-(4-Chlorobenzylidene)-2,4,6(1H,3H,5H)-pyrimidinetri-
one 6
Ammonium chloride (1.56 mmol, 1 eq) was dissolved in
cold distilled water (10 mL) followed by the addition of
barbituric acid (1.56 mmol) and corresponding aldehyde
(1.56 mmol, 1 eq). Reaction mixture was stirred at room
temperature for 30 min as the TLC showed complete
disappearance of starting aldehyde. In all cases, solid product
was formed which was filtered and solid was washed with
cold water and ether followed by drying under vacuum.
Yield: 1.3 g (85%); 1H-NMR (400 MHz, DMSO-d6): ꢀ
11.38 (s, 1H, NH), 11.23 (s, 1H, NH), 8.23 (s, 1H, Vin.-H),
8.06 (d, 2H, J = 8.55, Ar-H), 7.52 (d, 2H, J = 8.55, Ar-H);
EIMS m/z (% rel. abund.): 250 (M+, 70.8), 249 (100), 206
(58.6), 172 (35.2), 136 (52.5), 101 (38.7), 75 (42.7); Anal.
calcd. for C11H7ClN2O3 (250.64): C, 52.71; H, 2.82; Cl,
14.15; N, 11.18; O, 19.15; Found: C, 52.64; H, 2.91; N,
11.19.
5-(4-Fluorobenzylidene)-2,4,6(1H,3H,5H)-pyrimidinetri-
one 1
5-(3-Chlorobenzylidene)-2,4,6(1H,3H,5H)-pyrimidinetri-
one 7
Yield: 1.37 g (95%); 1H-NMR (400 MHz, DMSO-d6): ꢀ
11.41 (s, 1H, NH), 11.25 (s, 1H, NH), 8.22 (s, 1H, Vin.-H),
8.16 (br. s, 1H, Ar-H), 7.84 (d, 1H, J = 7.7 Hz, Ar-H), 7.55
Yield: 1.15 g (98%); 1H-NMR (400 MHz, DMSO-d6): ꢀ
11.39 (s, 1H, NH), 11.25 (s, 1H, NH), 8.25 (s, 1H, Vin.-H),
8.2 (dd, 2H, J = 8.8, 5.8 Hz, Ar-H), 7.31 (br. t, 2H, J = 8.8
Hz, Ar-H); EIMS m/z (% rel. abund.): 234 (M+, 70), 233
(100), 215 (3.2), 190 (63.47), 162 (2.5), 147 (42), 120 (85.9),

NH4Cl Mediated New Protocol for the Synthesis
Letters in Organic Chemistry, 2011, Vol. 8, No. 1
31
(d, 1H, J = 8.27 Hz, Ar-H), 7.47 (br. t, 1H, J = 8.0 Hz, Ar-
H); EIMS m/z (% rel. abund.): 250 (M+, 99.7), 249 (100),
206 (67.6), 172 (60.2), 136 (70.7), 101 (61.7), 75 (77.2);
Anal. calcd. for C11H7ClN2O3 (250.64): C, 52.71; H, 2.82;
Cl, 14.15; N, 11.18; O, 19.15; Found: C, 52.73; H, 2.80; N,
11.16.
56.52; H, 4.38; N, 10.14; O, 28.96; Found: C, 56.49; H, 4.40;
N, 10.11.
5-(3-Fluorobenzylidene)-2,4,6(1H,3H,5H)-pyrimidinetri-
one 13
Yield: 0.91 g (89%); 1H-NMR (400 MHz, DMSO-d6): ꢀ
11.43 (s, 1H, NH), 11.28 (s, 1H, NH), 8.23 (s, 1H, Vin.-H),
8.16 (br. s, 1H, Ar-H), 7.84 (d, 1H, J = 7.7 Hz, Ar-H), 7.55
(d, 1H, J = 8.2 Hz, Ar-H), 7.47 (br. t, 1H, J = 8.14 Hz, Ar-
H); EIMS m/z (% rel. abund.): 234 (M+, 90.8), 233 (99.1),
215 (8.6), 190 (69), 147 (44), 120 (100), 94 (30.7); Anal.
calcd. for C11H7FN2O3 (234.18): C, 56.42; H, 3.01; F, 8.11;
N, 11.96; O, 20.50; Found: C, 56.39; H, 2.99; N, 11.98.
5-(3-Hydroxy-5-methoxybenzylidene)-2,4,6(1H,3H,5H)-
pyrimidinetrione 8
Yield: 1.1 g (92%); 1H-NMR (400 MHz, DMSO-d6): ꢀ
11.21 (s, 1H, NH), 11.1 (s, 1H, NH), 8.47 (br. s, 1H, Ar-H),
8.22 (s, 1H, Vin.-H), 7.74 (d, 1H, J = 1.8 Hz, Ar-H), 7.72 (d,
1H, J = 1.8 Hz, Ar-H), 4.07 (q, 2H, J = 14.0, 6.9 Hz, -
OCH2CH3), 1.35 (t, 3H, J = 6.9 Hz, -OCH2CH3); EIMS m/z
(% rel. abund.): 276 (M+, 100), 275 (2.5), 247 (67.1), 204
(25.6), 188 (18.6), 161 (15.6), 134 (21.3), 105 (17); Anal.
calcd. for C12H10N2O5 (262.22): C, 54.97; H, 3.84; N, 10.68;
O, 30.51; Found: C, 54.95; H, 3.86; N, 10.63.
5-(3,4,5-Trihydroxybenzylidene)-2,4,6(1H,3H,5H)-pyrimi-
dinetrione 14
Yield: 0.91 g (93%); 1H-NMR (400 MHz, DMSO-d6): ꢀ
11.19 (s, 1H, NH), 11.06 (s, 1H, NH), 10.36 (br. s, 1H, -
OH), 9.44 (br. s, 1H, -OH), 9.35 (br. s, 1H, -OH), 8.17 (d,
1H, J = 2.1 Hz, Ar-H), 8.1 (s, 1H, Vin.-H), 7.91 (d, 1H, J =
2.1 Hz, Ar-H); EIMS m/z (% rel. abund.): 265 (M+, 100),
264 (40), 248 (11.8), 220 (31), 187 (14.3), 134 (21), 109
(5.5); Anal. calcd. for C11H8N2O6 (264.19): C, 50.01; H,
3.05; N, 10.60; O, 36.34; Found: C, 49.97; H, 2.98; N, 10.65.
5-(2,3,4-Trimethoxybenzylidene)-2,4,6(1H,3H,5H)-pyrimi-
dinetrione 9
Yield: 1.15 g (95%); 1H-NMR (400 MHz, DMSO-d6): ꢀ
11.29 (s, 1H, NH), 11.13 (s, 1H, NH), 8.47 (s, 1H, Vin.-H),
8.3 (d, 1H, J = 9.1 Hz, Ar-H), 6.91 (d, 1H, J = 9.2 Hz, Ar-
H), 3.89 (s, 3H, -OCH3), 3.87 (s, 3H, -OCH3), 3.75 (s, 3H, -
OCH3); EIMS m/z (% rel. abund.): 306 (M+, 20.4), 275
(100), 232 (47.5), 189 (3), 162 (8.5), 134 (9.3), 106 (6.1);
Anal. calcd. for C14H14N2O6 (306.27): C, 54.90; H, 4.61; N,
9.15; O, 31.34; Found: C, 54.88; H, 4.63; N, 9.13.
5-(2-Fluorobenzylidene)-2,4,6(1H.3H,5H)-pyrimidinetri-
one 15
Yield: 1.15 g (94%); 1H-NMR (400 MHz, DMSO-d6): ꢀ
11.39 (s, 1H, N-H), 11.25 (s, 1H, NH), 8.25 (s, 1H, Vin.-H),
8.2 (dd, 2H, J = 8.8, 5.85 Hz, Ar-H), 7.31 (br. t, 2H, J = 8.8
Hz, Ar-H); EIMS m/z (% rel. abund.): 234 (M+, 70), 233
(100), 215 (3.2), 190 (63.47), 162 (2.5), 147 (42), 120 (85.9),
95 (7.2); Anal. calcd. for C11H7FN2O3 (234.18): C, 56.42; H,
3.01; F, 8.11; N, 11.96; O, 20.50; Found: C, 56.43; H, 2.99;
N, 11.97.
5-([1,1ꢀ-Biphenyl]-4-ylmethylene)-2,4,6(1H,3H,5H)-pyrimi-
dinetrione 10
Yield: 0.95 g (85%); 1H-NMR (400 MHz, DMSO-d6): ꢀ
11.39 (s, 1H, NH), 11.25 (s, 1H, NH), 8.31 (s, 1H, Vin.-H),
8.23 (d, 2H, J = 8.4 Hz, Ar-H), 7.8 (d, 2H, J = 8.4 Hz, Ar-
H), 7.7 (d, 2H, J = 7.2 Hz, Ar-H), 7.5 (br. t, 1H, J = 7.2 Hz,
Ar-H), 7.43 (d, 2H, J = 7.2 Hz, Ar-H); EIMS m/z (% rel.
abund.): 292 (M+, 100), 291 (53.2), 248 (48.5), 215 (40.8),
165 (30), 139 (8.3), 102 (10.7), 76 (28.5); Anal. calcd. for
C17H12N2O3 (292.29): C, 69.86; H, 4.14; N, 9.58; O, 16.42;
Found: C, 69.83; H, 4.17; N, 9.55.
ACKNOWLEDGEMENT
Higher Education Commission of Pakistan (Pakistan) is
greatly acknowledged for providing financial support under,
National Research Program for Universities.
5-[4-(Dimethylamino)benzylidene]-2,4,6(1H,3H,5H)-pyri-
midinetrione 11
REFERENCES
Yield: 0.97 g (82%); 1H-NMR (400 MHz, DMSO-d6): ꢀ
11.04 (s, 1H, NH), 10.9 (s, 1H, NH), 8.42 (d, 2H, J = 9.24
Hz, Ar. H), 8.14 (s, 1H, Vin.-H), 6.78 (d, 2H, J = 9.2 Hz, Ar-
H), 3.11 (s, 6H, -N(CH3)2); EIMS m/z (% rel. abund.): 259
(M+, 100), 258 (57), 215 (15), 172 (13.2), 144 (23), 101
(8.6), 77 (6.5); Anal. calcd. for C13H13N3O3 (259.26): C,
60.22; H, 5.05; N, 16.21; O, 18.51; Found: C, 60.23; H, 5.09;
N, 16.17.
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5-(3,4-Dimethoxybenzylidene)-2,4,6(1H,3H,5H)-pyrimidin-
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Yield: 0.85 g (81%); 1H-NMR (400 MHz, DMSO-d6): ꢀ
11.3 (s, 1H, NH), 11.2 (s, 1H, NH), 8.39 (d, 1H, J = 1.9 Hz,
Ar-H), 8.24 (s, 1H, Vin.-H), 7.89 (dd, 1H, J = 8.6, 1.9 Hz,
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100), 275 (13.2), 232 (6.1), 190 (23.2), 147 (13.2), 119
(23.5), 76 (38); Anal. calcd. for C13H12N2O5 (276.24): C,
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