Synthesis of some new dihydropyrimidines by iodine as a catalyst at ambient temperature and evaluation of their biological activity

Article abstract of DOI:10.1002/jhet.728

An improved method for the synthesis of some new dihydropyrimidines from aromatic aldehydes, 1,3-dicarbonyl compounds, and thiourea with significant enhancement in reaction rates, short reaction time (4-6 h), good to excellent yields (70-93%), and ambient temperature using molecular iodine as catalyst is described. The biological evaluation revealed that the newly synthesized compounds 4a-j and 7a-j exhibited good antimicrobial activity and moderate antimycobacterial activity against Mycobacterium tuberculosis H₃₇RV.

Full text of DOI:10.1002/jhet.728

July 2013
Synthesis of Some New Dihydropyrimidines by Iodine as a
Catalyst at Ambient Temperature and Evaluation of Their
Biological Activity
973
P. D. Zalavadiya, R. M. Ghetiya, B. L. Dodiya,
*
P. B. Vekariya, and H. S. Joshi
Chemical Research Laboratory, Department of Chemistry, Saurashtra University,
Rajkot, Gujarat 360005, India
*
E-mail: drhsjoshi49@gmail.com
Received June 10, 2010
DOI 10.1002/jhet.728
Published online 2 July 2013 in Wiley Online Library (wileyonlinelibrary.com).
An improved method for the synthesis of some new dihydropyrimidines from aromatic aldehydes, 1,3-
dicarbonyl compounds, and thiourea with significant enhancement in reaction rates, short reaction time
(4–6 h), good to excellent yields (70–93%), and ambient temperature using molecular iodine as catalyst is
described. The biological evaluation revealed that the newly synthesized compounds 4a–j and 7a–j
exhibited good antimicrobial activity and moderate antimycobacterial activity against Mycobacterium tuber-
culosis H37RV.
J. Heterocyclic Chem., 50, 973 (2013).
INTRODUCTION
transformations to afford the corresponding products in
excellent yield with high selectivity. There are only few
reports about its use for the synthesis of DHPMs [12] and
1,4-DHPs [13].
In continuation of our work on the development of
useful synthetic methodologies by using molecular iodine
catalysts [14], we observed that molecular iodine is an
efficient catalyst for the synthesis of DHPMs via
Biginelli condensation. Herein, we report the synthesis,
antimycobacterial and antimicrobial activity of some new
3,4-dihydropyrimidin-2(1H)-ones.
3,4-Dihydropyrimidinones denoted as Biginelli com-
pounds, and their derivatives are highly important heterocy-
clic units in the realm of natural and synthetic organic
chemistry that possess diverse therapeutic and pharmacolog-
ical properties [1],[2] so the synthesis of these compounds
has become an important target in current years. The diver-
sity, efficiency, and rapid access to small and highly
functionalized organic molecules makes this approach of
central current interest in the construction of compounds
library and optimization in drug discovery process [3].
The dihydropyrimidine (DHPM) nucleus exhibits a
broad spectrum of biological effects such as antitumor
[4], antibacterial [5], anti-inflammatory [2], and anti-viral
[2],[5],[6] activities. Furthermore, appropriately function-
alized DHPMs have emerged as calcium channel blockers,
antihypertensive, α1a-adrenrgic antagonists, and neuropep-
tide Y 7 antagonists, antimitotic [7], anticarcinogenic [8],
and antihypertensive [9] agents, and additionally, their par-
ticular structure has been found in natural marine alkaloid
batzelladine which are the first low molecular weight natu-
ral products reported in the literature to inhibit the binding
of HIV gp-120 to CD4 cells, so disclosing a new field
toward the development of AIDS therapy [10].
RESULTS AND DISCUSSION
The synthesis of 3,4-dihydropyrimidin-2(1H)-ones
4a–j and 7a–j were performed in the following steps shown
in reaction (Scheme 1) and (Scheme 2). The required
intermediates 3 [15] and 6 [16] have been prepared by the
literature methods (Scheme 3). The compounds 4a–j were
synthesized by The one-pot three-components condensation
reaction of substituted arylaldehydes 1a–j with thiourea
2
and N-(2,4-dichlorophenyl)-3-4-methoxyphenyl)-3-
oxopropanamide 3 proceeded smoothly in ethanol in
the presence of 5 mol % iodine [12] as a catalyst. Com-
pounds 7a–j was synthesized by the use of substituted
arylaldehydes 1a–j, N-(3-chloro-4-fluorophenyl) thiourea 6
Molecular iodine [11] has attracted attention as an
inexpensive, readily available catalyst for various organic
© 2013 HeteroCorporation

974
P. D. Zalavadiya, R. M. Ghetiya, B. L. Dodiya, P. B. Vekariya, and H. S. Joshi
Vol 50
Scheme 1
Scheme 3
purity of all the synthesized compounds was checked by
thin layer chromatography (TLC). The structures of the
synthesized compounds were assigned on the basis
1
of spectral data like IR, H-NMR, mass spectral analysis,
and elemental analysis. All the newly synthesized
compounds were in full agreement with the proposed
structures.
Scheme 2
Antimycobacterial activity. All the newly synthesized
compounds were evaluated for their possible in vitro
antimycobacterial activity under the Tuberculosis
Antimicrobial Acquisition Coordinating Facility, an anti-
tuberculosis drug discovery program, coordinated by the
Southern Research Institute (Birmingham, AL) directed
by the National Institute of Allergy and Infectious
Diseases, U.S.A. Initially, compounds 4a–j and 7a–j
were evaluated against Mycobacterium tuberculosis
H37RV [American type culture collection (ATCC)
27294] (American Type Culture Collection, Manassas,
VA) at single concentration of 6.25 μg/mL in BACTEC
12B medium using both micro dilution assay and the
micro plate Alamar blue assay [18]. Compounds
exhibiting fluorescence were tested in the BACTEC 460
radiometric system [19] The antitubercular activity
data were compared with standard drug rifampin at
0.25 μg/mL concentrations, which showed 98%
inhibition (Table 2). The structure–activity relationship
studies revealed that compounds containing 4-substituted
phenyl at 4- and 4,2-position of DHPMs were most
active as compared with 2- and 3-substituted phenyl ring
derivatives. Although compounds 7a–j are the weakest
in activity as compared with compounds 4a–j of these
derivatives, compound 4d (—3-OCH3), 4f (—4-F), 4h
(—2-OH, 4-OCH3) of DHPMs was the most active as
compared with other compounds. However, all the new
derivatives showed weak antimycobacterial activity
compared with the standard drug rifampin, which
exhibited 98% growth inhibition at 6.25 lg/mL
concentrations (Table 2).
and ethyl acetoacetate 5 as per same procedure, to give the
excellent yields. Synthesis of compounds 4a–j and 7a–j
was carried out by the use of acid catalyst to give poor yield
and longer reaction time as compare with iodine catalyst,
shown in (Table 1).
A possible role of the molecular iodine in the formation
of DHPMs as described in the literature, iodine may
catalyze the reaction as a mild Lewis acid [5],[17]. The
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2013
Synthesis of Some New Dihydropyrimidines by Iodine as a Catalyst at Ambient
Temperature and Evaluation of Their Biological Activity
975
Table 1
Synthesis of 4a–j and 7a–j using iodine and acid catalyst.
Iodine catalyst
Time (h)
Acid catalyst (HCl)
Sr. No.
Entry
R
Yield (%)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
2-NO2
3-NO2
3-OCH3
4-OCH3
4-F
4.4
4.3
5.0
5.4
7.0
5.2
5.5
6.0
5.2
6.1
4.5
5.3
6.0
6.3
7.0
4.5
5.0
6.3
5.5
6.1
83
87
78
73
84
93
88
79
74
75
87
81
73
90
77
89
82
85
76
78
12.3
15.0
17.0
18.3
13.3
15.3
16.0
14.0
15.3
13.0
18.0
12.0
15.0
18.3
16.3
15.0
17.0
12.0
16.0
13.0
63
57
61
66
45
75
67
59
62
53
71
64
49
54
66
70
55
47
58
60
2-Cl
2-OH,4-OCH3
4-N(CH3)2
C10H7
H
2-NO2
3-NO2
3-OCH3
4-OCH3
4-F
4j
7a
7b
7c
7d
7e
7f
7g
7h
7i
2-Cl
2-OH,4-OCH3
4-N(CH3)2
C10H7
7j
Table 2
Antimicrobial screening results of compounds 4a–j and 7a–j.
Zones of inhibition (mm)
Antimicrobial activity
Antifungal activity
% Inhibition
Entry
antitubercular activity
B. megaterium
P. aeruginosa
E. coli
S. aureus
A. niger
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
7a
7b
7c
7d
7e
7f
45
00
33
51
41
49
05
52
34
24
40
10
37
33
48
43
06
47
00
00
–
11
17
00
21
11
20
18
19
15
12
14
13
11
20
18
14
12
15
17
10
21
20
20
18
00
15
12
13
18
11
18
17
16
18
13
10
18
14
16
18
11
12
18
20
13
24
18
24
17
00
20
14
15
19
13
17
17
10
12
18
18
15
13
13
17
14
11
20
15
14
25
18
22
24
00
17
10
12
17
11
16
14
17
14
11
18
17
16
17
19
15
12
11
13
18
25
15
21
25
00
12
13
15
11
12
21
23
17
16
17
18
18
17
17
19
13
15
16
15
14
00
00
00
00
24
7g
7h
7i
7j
Amoxicillin
Benzyl–Penicillin
Ampicillin
Norfloxacin
Greseofulvin
–
–
–
–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

976
P. D. Zalavadiya, R. M. Ghetiya, B. L. Dodiya, P. B. Vekariya, and H. S. Joshi
Vol 50
Antimicrobial activity. The antimicrobial activity was
hydrochloric acid was removed with hot water, and crude
product was isolated and crystallized from methanol. Yield
89%, mp 236°C.
General procedure for the preparation of N-(2,4-
dichlorophenyl)-1,2,3,4-tetrahydro-6-(4-methoxyphenyl)-4-aryl-
assayed by using the cup-plate agar diffusion method
[20] by measuring the zone of inhibition in mm. Newly
synthesized compounds were screened in vitro for their
antimicrobial activity against varieties of bacterial strains
such Bacillus megaterium ATCC 14518, Pseudomonas
aeruginosa ATCC 27853, Escherichia coli ATCC 25922,
Staphylococcus aureus ATCC 25923, and fungi Aspergillus
niger ATCC 9029 at 40 μg/mL concentration. Standard
drugs like ampicillin, amoxicillin, norfloxacin, benzyl
penicillin, and greseofulvin were used for the comparison
purpose. The results are given in Table 2.
From the result of antimicrobial data, compounds 4d,
4g, 4h, 7d, and 7e were active and compounds 7b, 7i,
7h, and 7i were moderately active against B. megaterium.
Same as compounds 4d, 4f, 4i, 7b, 7e, 7h, and 7i were
active, whereas compounds 4a, 4g, 4h, 7c, and 7d were
moderately active against P. aeruginosa. Further compounds
4a, 4d, 4j, 7a, and 7h were active and compounds 4c, 4f, 4g,
7b, and 7i show moderate activity against E. coli. In case
of S. aureus, compounds 4a, 7e, and 7j were active and
compounds 4d, 4f, 4h, 7b, and 7c were moderately active.
Against A. niger compounds 4d, 4f, 4g, 7a, 7b, and 7e were
active, whereas compounds 4h, 4i, 4j, 7c, 7d, and 7h
moderately active. Remaining compounds did not show
any promising activity against tested bacteria and fungi.
2-thioxopyrimidine-5-carboxamides (4a–j).
A mixture of
thiourea 2 (0.76 g, 10 mmol), N-(2,4-dichlorophenyl)-3-(4-
methoxyphenyl)-3-oxopropanamide 3 (3.38 g, 10 mmol), different
substituted aryl aldehydes 1a–j (10 mmol) and iodine (5 mol%) in
ethanol (15 mL) was stirred at room temperature until the reaction
was completed (4–6 h monitored by TLC). The reaction mixture
was treated with 0.1N Na2S2O3 solution and extracted into ethyl
acetate. The solvent was removed in vacuo, and the resulting
crude product was crystallized from ethanol to give the analytical
pure compounds 4a–j.
N-(2,4-Dichlorophenyl)-1,2,3,4-tetrahydro-6-(4-methoxyphenyl)-
4-phenyl-2-thioxopyrimidine-5-carboxamide (4a). Yield 83%;
mp 257–259°C; IR (KBr): 3432, 3064, 2923, 1683, 1542, 1452,
1
1406, 765 cm—1; H-NMR (400 MHz, CDCl3): δ 10.17 (s, 1H,
NH), 9.95 (s, 1H, NH), 8.87 (s, 1H, NH), 7.56 (d, 2H, Ar—H),
7.37–7.25 (m, 8H, Ar—H), 6.97 (d, 2H, Ar—H), 5.56 (s, 1H,
CH), 3.91 (s, 3H, OCH3); MS: m/z = 484 [M+]; Anal. Calcd. for
C24H19Cl2N3O2S: C, 59.51; H, 3.95; N, 8.67%. Found: C, 59.54;
H, 3.96; N, 8.66%.
N-(2,4-Dichlorophenyl)-1,2,3,4-tetrahydro-6-(4-methoxyphenyl)-
4-(2-nitrophenyl)-2-thioxopyrimidine-5-carboxamide (4b). Yield
87%; mp 209–211°C; IR (KBr): 3425, 3079, 2917, 1716, 1682,
1
1573, 1466, 746 cmÀ1; H-NMR (400 MHz, CDCl3): δ 9.98 (s,
1H, NH), 9.79 (s, 1H, NH), 8.73 (s, 1H, NH), 7.61 (d, 2H, ArÀH),
7.47–7.39 (m, 7H, ArÀH), 6.91 (d, 2H, ArÀH), 5.42 (s, 1H, CH),
3.81 (s, 3H, OCH3); MS: m/z = 529 [M+]; Anal. Calcd. for
C24H18Cl2N4O4S: C, 54.45; H, 3.43; N, 10.58%. Found: C, 54.47;
H, 3.41; N, 10.57%.
EXPERIMENTAL
N-(2,4-Dichlorophenyl)-1,2,3,4-tetrahydro-6-(4-methoxyphenyl)-
4-(3-nitrophenyl)-2-thioxopyrimidine-5-carboxamide (4c). Yield
78%; mp 226–228°C; IR (KBr): 3453, 3082, 2956, 1698, 1620,
Melting points were determined on electro thermal apparatus
using open capillaries and are uncorrected. Thin-layer chromatog-
raphy was accomplished on 0.2-mm precoated plates of silica gel
G60 F254 (Merck, St. Louis, MO). Visualization was made with
UV light (254 and 365 nm) or with an iodine vapor. IR spectra
were recorded on a FTIR-8400 spectrophotometer (Shimadzu,
1543, 1421, 720 cmÀ1 1H-NMR (400 MHz, CDCl3): δ 10.21
;
(s, 1H, NH), 9.91 (s, 1H, NH), 8.81 (s, 1H, NH), 7.67 (d, 2H,
ArÀH), 7.43–7.28 (m, 7H, ArÀH), 6.83 (d, 2H, ArÀH), 5.63
(s, 1H, CH), 3.88 (s, 3H, OCH3); MS: m/z = 529 [M+]; Anal. Calcd.
for C24H18Cl2N4O4S: C, 54.45; H, 3.43; N, 10.58%. Found: C,
54.49; H, 3.42; N, 10.56%.
1
Kyoto, Japan), using DRS prob. H-NMR spectra were recorded
on a Bruker AVANCE II (400 MHz) spectrometer (Bruker,
Rheinstetten, Germany), in CDCl3. Chemical shifts are expressed
in δ ppm downfield from Tetra methyl silane (TMS) as an internal
standard. Mass spectra were determined using direct inlet probe
on a GCMS-QP 2010 mass spectrometer (Shimadzu, Kyoto,
Japan). Elemental analysis was performed on a Carlo-Erba
EA 1108 elemental analyzer (Waltham, MA). Solvents were
evaporated with a Laborota 4000 efficient rotary evaporator
(Heidolph, Germany).
N-(2,4-Dichlorophenyl)-1,2,3,4-tetrahydro-4-(3-methoxyphenyl)-
6-(4-methoxyphenyl)-2-thioxopyrimidine-5-carboxamide (4d).
Yield 73%; mp 222–224°C; IR (KBr): 3478, 3073, 2968,
1714, 1628, 1530, 1481, 768 cmÀ1 1H-NMR (400 MHz,
;
CDCl3): δ 9.96 (s, 1H, NH), 9.54 (s, 1H, NH), 8.59 (s, 1H,
NH), 7.54 (d, 2H, ArÀH), 7.47–7.34 (m, 7H, ArÀH), 6.87
(d, 2H, Ar—H), 5.37 (s, 1H, CH), 3.73 (s, 6H, OCH3);
MS: m/z = 514 [M+]; Anal. Calcd. for C25H21Cl2N3O3S:
C, 58.37; H, 4.11; N, 8.17%. Found: C, 58.29; H, 4.13;
N, 8.19%.
Preparation of N-(2,4-dichlorophenyl)-3-(4-methoxyphenyl)-
3-oxopropanamide (3).
A mixture of ethyl-3-(4-methoxyphenyl)
-3-oxopropanoate (2.22 g, 10 mmol) and 2,4-dichloro aniline (1.62 g,
10 mmol) in ethanol was refluxed for 10 h. The resulting solution
was poured over crushed ice. The separated solid was filtered and
crystallized from ethanol, Yield 71%, mp 267°C.
Preparation of N-(3-chloro-4-fluorophenyl) thiourea (6).
To a mixture of 3-chloro-4-fluoroaniline hydrochloride (18.1 g,
100 mmol) and thiourea (24.0 g, 400 mmol) in water (40 mL),
concentrated HCl (1 mL) and glacial acetic acid (1 mL) were
added. The content was refluxed for 12 h. After completion of
the reaction, content was poured in to ice water. Excess of
N-(2,4-Dichlorophenyl)-1,2,3,4-tetrahydro-4,6-bis-(4-
methoxyphenyl)-2-thioxopyrimidine-5-carboxamide (4e).
Yield 84%; mp 286–288°C; IR (KBr): 3439, 3019, 2945, 1725,
1640, 1509, 1451, 742 cmÀ1 1H-NMR (400 MHz, CDCl3): δ
;
10.15 (s, 1H, NH), 9.76 (s, 1H, NH), 8.63 (s, 1H, NH), 7.63 (d,
2H, ArÀH), 7.49–7.38 (m, 7H, ArÀH), 6.74 (d, 2H, ArÀH),
5.48 (s, 1H, CH), 3.91 (s, 6H, OCH3); MS: m/z = 514 [M+];
Anal. Calcd. for C25H21Cl2N3O3S: C, 58.37; H, 4.11; N, 8.17%.
Found: C, 58.32; H, 4.12; N, 8.17%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2013
Synthesis of Some New Dihydropyrimidines by Iodine as a Catalyst at Ambient
Temperature and Evaluation of Their Biological Activity
977
N-(2,4-Dichlorophenyl)-4-(4-fluorophenyl)-1,2,3,4-tetrahydro-
6-(4-methoxyphenyl)-2-thioxopyrimidine-5-carboxamide (4f).
Ethyl-1-(3-chloro-4-flurophenyl)-1,2,3,4-tetrahydro-6-methyl-
4-phenyl-2-thioxopyrimidine-5-carboxylate (7a). Yield 87%;
mp 219–222°C; IR (KBr): 3384, 258, 3027, 2934, 1709, 1543,
1435, 748 cmÀ1 1H-NMR (400 MHz, CDCl3): δ 9.98 (s, 1H,
Yield 93%; mp 285–287°C; IR (KBr): 3410, 3092, 2958,
1736, 1642, 1530, 1418, 756 cmÀ1 1H-NMR (400 MHz,
;
;
NH), 8.49–7.23 (m, 8H, ArÀH), 5.49 (s, 1H, CH), 4.68 (q, 2H,
CH2), 2.14 (s, 3H, CH3), 1.04 (t, 3H, CH3); MS: m/z = 405 [M+];
Anal. Calcd. for C20H18ClFN2O2S: C, 59.33; H, 4.48; N, 6.92%.
Found: C, 59.31; H, 4.47; N, 6.90%.
CDCl3): δ 10.13 (s, 1H, NH), 9.98 (s, 1H, NH), 8.91 (s, 1H,
NH), 7.65 (d, 2H, ArÀH), 7.55–7.40 (m, 7H, ArÀH), 6.73
(d, 2H, ArÀH), 5.66 (s, 1H, CH), 3.79 (s, 3H, OCH3); MS:
m/z = 502 [M+]; Anal. Calcd. for C24H18Cl2FN3O2S: C,
57.38; H, 3.61; N, 8.36%. Found: C, 57.39; H, 3.67; N,
8.33%.
Ethyl-1-(3-chloro-4-flurophenyl)-1,2,3,4-tetrahydro-6-methyl-
4-(2-nitrophenyl)-2-thioxopyrimidine-5-carboxylate (7b). Yield
81%; mp 211–213°C; IR (KBr): 3394, 3261, 3031, 2931,
N-(2,4-Dichlorophenyl)-4-(2-chlorophenyl)-1,2,3,4-tetrahydro-
6-(4-methoxyphenyl)-2-thioxopyrimidine-5-carboxamide (4g).
Yield 88%; mp 153–155°C; IR (KBr): 3435, 3087, 2936,
1
1705, 1546, 1430, 750 cmÀ1; H-NMR (400 MHz, CDCl3): δ
10.04 (s, 1H, NH), 8.33–7.21 (m, 7H, ArÀH), 5.56 (s, 1H,
1700, 1665, 1550, 1425, 720 cmÀ1 1H-NMR (400 MHz,
;
CH), 4.76 (q, 2H, CH2), 2.20 (s, 3H, CH3), 1.22 (t,
=
450 [M+]; Anal. Calcd. for
CDCl3): δ 10.07 (s, 1H, NH), 9.73 (s, 1H, NH), 8.54 (s, 1H,
NH), 7.58 (d, 2H, ArÀH), 7.43–7.30 (m, 7H, ArÀH), 6.94
(d, 2H, ArÀH), 5.47 (s, 1H, CH), 3.83 (s, 3H, OCH3);
MS: m/z = 519 [M+]; Anal. Calcd. for C24H18Cl3N3O2S:
C, 55.56; H, 3.50; N, 8.10%. Found: C, 55.60; H, 3.53;
N, 8.08%.
3H, CH3); MS: m/z
C20H17ClFN3O4S: C, 53.39; H, 3.81; N, 9.34%. Found: C,
53.42; H, 3.86; N, 9.32%.
Ethyl-1-(3-chloro-4-flurophenyl)-1,2,3,4-tetrahydro-6-methyl-
4-(3-nitrophenyl)-2-thioxopyrimidine-5-carboxylate (7c). Yield
73%; mp 268–270°C; IR (KBr): 3378, 3265, 3033, 2927, 1711,
1540, 1460, 753 cmÀ1 1H-NMR (400 MHz, CDCl3): δ 10.02
;
N-(2,4-Dichlorophenyl)-1,2,3,4-tetrahydro-4-(2-hydroxy-4-
methoxyphenyl)-6-(4-methoxyphenyl)-2-thioxopyrimidine-5-
carboxamide (4h). Yield 79%; mp 326–328°C; IR (KBr): 3422,
(s, 1H, NH), 8.56–8.47 (m, 7H, ArÀH), 5.53 (s, 1H, CH), 4.71
(q, 2H, CH2), 2.23 (s, 3H, CH3), 1.19 (t, 3H, CH3); MS: m/z = 450
[M+]; Anal. Calcd. for C20H17ClFN3O4S: C, 53.39; H, 3.81; N,
9.34%. Found: C, 53.41; H, 3.84; N, 9.33%.
1
3047, 2923, 1719, 1644, 1549, 1462, 748 cmÀ1; H-NMR (400
MHz, CDCl3): δ 10.03 (s, 1H, NH), 9.81 (s, 1H, NH), 8.85
(s, 1H, NH), 7.39 (d, 2H, ArÀH), 7.23–7.18 (m, 6H, Ar), 6.79
(d, 2H, ArÀH), 5.44 (s, 1H, CH), 4.91 (s,1H, OH), 3.76
(s, 6H, OCH3); MS: m/z = 530 [M+]; Anal. Calcd. for
C25H21Cl2N3O4S: C, 56.61; H, 3.99; N, 7.92%. Found: C,
56.67; H, 3.91; N, 7.90%.
Ethyl-1-(3-chloro-4-flurophenyl)-1,2,3,4-tetrahydro-4-(3-
methoxyphenyl)-6-methyl-2-thioxopyrimidine-5-carboxylate(7d).
Yield 90%; mp 250–251°C; IR (KBr): 3397, 3269, 3026, 2939,
1714, 1547, 1450, 743 cmÀ1 1H-NMR (400 MHz, CDCl3): δ
;
10.05 (s, 1H, NH), 8.27–7.19 (m, 7H, ArÀH), 5.51 (s, 1H, CH),
4.72 (q, 2H, CH2), 3.91 (s, 3H, OCH3), 2.17 (s, 3H, CH3), 1.09
N-(2,4-Dichlorophenyl)-4-(4-(dimethylamino)phenyl)-1,2,3,4-
tetrahydro-6-(4-methoxyphenyl)-2-thioxopyrimidine-5-carboxamide
(4i). Yield 74%; mp 222–224°C; IR (KBr): 3392, 3117, 2933,
(t, 3H, CH3); MS: m/z
=
435 [M+]; Anal. Calcd. for
C21H20ClFN2O3S: C, 57.99; H, 4.64; N, 6.44%. Found: C, 57.94;
H, 4.69; N, 6.47%.
1693, 1666, 1522, 1442, 773 cmÀ1 1H-NMR (400 MHz,
;
CDCl3): δ 9.84 (s, 1H, NH), 9.37 (s, 1H, NH), 8.48 (s, 1H,
NH), 7.59 (d, 2H, ArÀH), 7.17–7.08 (m, 7H, ArÀH), 6.93
(d, 2H, ArÀH), 5.51 (s, 1H, CH), 3.86 (s, 3H, OH), 2.81
(s, 6H, OCH3); MS: m/z = 527 [M+]; Anal. Calcd. for
C26H24Cl2N4O2S: C, 59.26; H, 4.63; N, 10.60%. Found: C,
59.21; H, 4.67; N, 10.53%.
Ethyl-1-(3-chloro-4-flurophenyl)-1,2,3,4-tetrahydro-4-(4-
methoxyphenyl)-6-methyl-2-thioxopyrimidine-5-carboxylate (7e).
Yield 77%; mp 286–288°C; IR (KBr): 3393, 3273, 3029, 2941,
1712, 1542, 1456, 739 cmÀ1 1H-NMR (400 MHz, CDCl3): δ
;
9.98 (s, 1H, NH), 8.22–7.17 (m, 7H, ArÀH), 5.61 (s, 1H, CH),
4.78 (q, 2H, CH2), 3.79 (s, 3H, OCH3), 2.21 (s, 3H, CH3), 1.13
(t, 3H, CH3); MS: m/z
=
435 [M+]; Anal. Calcd. for
N-(2,4-Dichlorophenyl)-1,2,3,4-tetrahydro-6-(4-methoxyphenyl)-
4-(naphthalen-1-yl)-2-thioxopyrimidine-5-carboxamide (4j). Yield
75%; mp 305–307°C; IR (KBr): 3419, 3062, 2925, 1706, 1676,
C21H20ClFN2O3S: C, 57.99; H, 4.64; N, 6.44%. Found: C, 57.91;
H, 4.67; N, 6.44%.
1566, 1471, 736 cmÀ1 1H-NMR (400 MHz, CDCl3): δ 10.09
;
Ethyl-1-(3-chloro-4-flurophenyl)-4-(4-fluorophenyl)-1,2,3,4-
tetrahydro-6-methyl-2-thioxopyrimidine-5-carboxylate (7f).
Yield 89%; mp 253–254°C; IR (KBr): 3407, 3168, 3081,
(s, 1H, NH), 9.78 (s, 1H, NH), 8.68 (s, 1H, NH), 7.59–7.19
(m, 10H, ArÀH), 7.14 (d, 2H, ArÀH), 6.77 (s, 2H, CH), 5.31
(s, 1H, OH), 3.71 (s, 3H, OCH3); MS: m/z = 534 [M+]; Anal. Calcd.
for C28H21Cl2N3O2S: C, 62.92; H, 3.96; N, 7.86%. Found: C,
62.98; H, 3.93; N, 7.89%.
General procedure for the preparation of ethyl 1-(3-
chloro-4-flurophenyl)-1,2,3,4-tetrahydro-6-methyl-4-aryl-2-
thioxopyrimidine-5-carboxylates (7a–j). A mixture of ethyl
acetoacetate 5 (1.30 g, 10 mmol), N-(3-chloro-4-fluoropheny)
thiourea (6) (2.04 g, 10 mmol), different substituted aryl
aldehydes 1a–j (10 mmol), and iodine (5 mol%) in ethanol (15
mL) was stirred at room temperature till the reaction completed
(4–6 h monitored by TLC). The reaction mixture was treated
with 0.1 N Na2S2O3 solution and extracted into ethyl acetate.
The solvent was removed in vacuo; the resulting crude product
was crystallized from ethanol to give the analytical pure
compounds 7a–j.
2975, 1742, 1537, 1428, 717 cmÀ1 1H-NMR (400 MHz,
;
CDCl3): δ 10.01 (s, 1H, NH), 8.23–7.13 (m, 7H, ArÀH), 5.57
(s, 1H, CH), 4.69 (q, 2H, CH2), 2.11 (s, 3H, CH3), 1.16 (t, 3H,
CH3); MS: m/z
=
423 [M+]; Anal. Calcd. for
C20H17ClF2N2O2S: C, 56.80; H, 4.05; N, 6.62%. Found: C,
56.77; H, 4.06; N, 6.61%.
Ethyl-1-(3-chloro-4-flurophenyl)-4-(2-chlorophenyl)-1,2,3,4-
tetrahydro-6-methyl-2-thioxopyrimidine-5-carboxylate (7g).
Yield 82%; mp 144–146°C; IR (KBr): 3403, 3111, 3076, 2926,
1704, 1568, 1440, 723 cmÀ1 1H-NMR (400 MHz, CDCl3):
;
δ 10.07 (s, 1H, NH), 8.46–7.25 (m, 7H, ArÀH), 5.47 (s,
1H, CH), 4.82 (q, 2H, CH2), 2.15 (s, 3H, CH3), 1.26 (t, 3H,
CH3); MS: m/z
=
439 [M+]; Anal. Calcd. for
C20H17Cl2FN2O2S: C, 54.68; H, 3.90; N, 6.38%. Found: C,
54.73; H, 3.87; N, 6.35%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

978
P. D. Zalavadiya, R. M. Ghetiya, B. L. Dodiya, P. B. Vekariya, and H. S. Joshi
Vol 50
Ethyl-1-(3-chloro-4-flurophenyl)-1,2,3,4-tetrahydro-4-(2-hydroxy-
4-methoxyphenyl)-6-methyl-2-thioxopyrimidine-5-carboxylate (7h).
Acknowledgments. The authors thank the Tuberculosis
Antimicrobial Acquisition Coordinating Facility (TAACF), Alabama,
USA, for antitubercular activity and Department of Chemistry for
providing laboratory facilities. They also thank for facilities and
grants given under UGC-SAP for Department Research Support
(DRS) and Department of Science and Technology (DST), New
Delhi for Fund for Improvement of Science and Technology
(FIST). They also thank the RSIC Chandigarh for providing
1H-NMR spectral analysis of the compounds.
Yield 85%; mp 246–248°C; IR (KBr): 3423, 3187, 3054,
2947, 1733, 1574, 1470, 741 cmÀ1 1H-NMR (400 MHz,
;
CDCl3): δ 9.93 (s, 1H, ÀNH), 8.17–7.09 (m, 7H, ArÀH),
5.37 (s, 1H, CH), 4.83 (s, 1H, OH), 4.53 (q, 2H, CH2), 3.67
(s, 3H, OCH3), 1.97 (s, 3H, CH3), 1.24 (t, 3H, CH3); MS:
m/z = 451 [M+]; Anal. Calcd. for C21H20ClFN2O4S: C,
55.94; H, 4.47; N, 6.21%. Found: C, 55.97; H, 4.53; N,
6.19%.
Ethyl-1-(3-chloro-4-flurophenyl)-4-(4-(dimethylamino)phenyl)-
1,2,3,4-tetrahydro-6-methyl-2-thioxopyrimidine-5-carboxylate (7i).
Yield 76%; mp 264–266°C; IR (KBr): 3387, 3218, 3090, 2956,
REFERENCES AND NOTES
[1] (a) Weber, L. Drug Discov Today 2002, 7, 143; (b) Domling,
A. Curr Opin Chem Biol 2002, 6, 306.
[2] For an interesting review see: Kappe, C. O. Eur J Med Chem
2000, 35, 1043.
[3] (a) Dolle, R. E.; Nelson, K. H. J Comb Chem 1999, 1, 235; (b)
Thompson, L. A.; Ellman, J. A. Chem Rev 1996, 96, 555; (c) Gordon, E.
M.; Gallop, M. A.; Patel, D. V. Acc Chem Res 1996, 29, 144.
[4] Kappe, C. O. Tetrahedron 1993, 43, 6937.
1
1708, 1568, 1437, 739 cmÀ1; H-NMR (400 MHz, CDCl3): δ
9.97 (s, 1H, NH), 8.09–7.04 (m, 7H, ArÀH), 5.35 (s, 1H, CH),
4.61 (q, 2H, CH2), 2.85 (s, 6H, NCH3), 2.09 (s, 3H, CH3), 1.29
(t, 3H, CH3); MS: m/z = 448 [M+]; Anal. Calcd. for
C22H23ClFN3O2S: C, 58.99; H, 5.18; N, 9.38%. Found: C,
59.03; H, 5.22; N, 9.36%.
Ethyl-1-(3-chloro-4-flurophenyl)-1,2,3,4-tetrahydro-6-methyl-
4-(naphthalene-1-yl)-2-thioxopyrimidine-5-carboxylate (7j).
Yield 78%; mp 257–259°C; IR (KBr): 3405, 3261, 3083,
[5] Kappe, C. O. Acc Chem Res 2000, 33, 879.
[6] Kappe, C. O. Tetrahedron 1993, 49, 6937.
[7] Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.;
Schreiber, S. L.; Mitchison, T. J. Science 1999, 286, 971.
[8] Kato, T. Jpn Kokay Tokkyo Koho 59,190,974 (1984); Kato, T.
Chem Abstr 102, 132067.
[9] (a) Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.;
Moreland, S.; Hedberg, A.; Reilly, B. C. O. J Med Chem 1991, 34, 806;
(b) Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S. D.; Moreland,
S.; Gougoutas, J. Z.; O'Reilley, B. C.; Schwartz, J.; Malley, M. F. J Med
Chem 1992, 35, 3254.
2934, 1728, 1570, 1450, 736 cmÀ1 1H-NMR (400 MHz,
;
CDCl3): δ 9.94 (s, 1H, NH), 7.89–6.97 (m, 9H, ArÀH), 5.41
(s, 1H, CH), 4.58 (q, 2H, CH2), 2.29 (s, 3H, CH3), 1.32
(t, 3H, CH3); MS: m/z
=
455 [M+]; Anal. Calcd. for
C24H20ClFN2O2S: C, 63.36; H, 4.43; N, 6.16%. Found: C, 63.34;
H, 4.41; N, 6.13%.
[10] Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.; Freyer,
A. J.; Debrossi, C.; Mai, S.; Truneh, A.; Faulkner, D. J.; Carte, B.; Breen,
A. L.; Hertzberg, R. P.; Johnson, R. K.; Westley, J. W.; Potts, B. C. J Org
Chem 1995, 60, 1182.
CONCLUSIONS
[11] Some selected publications for molecular iodine as catalyst,
see: (a) Bhosale, R. S.; Bhosale, S. V.; Wang, T.; Zubaidha, P. K. Tetra-
hedron Lett 2004, 45, 9111; (b) Kidwai, M.; Mothsra, P. Tetrahedron Lett
2006, 47, 5029; (c) Kidwai, M.; Mothsra, P.; Bansal, V.; Somvanshi, R.
K.; Ethayathulla, A. S.; Dey S.; Singh T. P. J Mol Catal A 2007, 265,
177; (d) Kidwai, M.; Bansal, V.; Mothsra, P. J Mol Catal A 2007, 266,
43; (e) Kidwai, M.; Bansal, V.; Mothsra, P.; Saxena, S.; Somvanshi R.
K.; Dey S.; Singh T. P. J Mol Catal A 2007, 268, 76.
[12] (a) Ko, S.; Sastry, M. N. V.; Lin, C.; Yao, C. F. Tetrahedron
Lett 2005, 46, 5771; (b) Zolfigol, M. A.; Saleh, P.; Khorramabadi, Z.
A.; Shayegh, M. J Mol Catal A 2007, 261, 88.
[13] Akbari, J. D.; Tala, S. D.; Dhaduk, M. F.; Joshi, H. S.
ARKIVOC 2008, 12, 126.
[14] Zalavadiya, P. Z.; Tala, S. D.; Akbari, J. D.; Joshi, H. S. Arch
Pharm Chem Life Sci 2009, 342, 469.
[15] Kaminski, J.; Jean, Z.; Glinska, E.; Rusek, D.; Eckstein, Z. Pol
J Chem 1978, 52, 1583.
[16] Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A.
R. In Vogel's Textbook of Practical Organic Chemistry, 5th ed.; Wiley:
New York, 1989; p965.
[17] Some selected publications concerning the role of molecular
iodine as catalyst, see: (a) Liu, B.; Ji, S. J. Synth Commun 2008, 38,
1201; (b) Wang, X. S.; Li, Q.; Wu, J. R.; Li, Y. L.; Yao C. S.; Tu S. J.
Synthesis 2008, 12, 1902; (c) Wang, J.; Xu, F. X.; Lin, X. F.; Wang, Y.
G. Tetrahedron Lett 2008, 49, 5208; (d) Wang, X. S.; Li, Q.; Yao, C.
S.; Tu, S. J. Eur J Org Chem 2008, 20, 3513.
In connection with our ongoing work on multicomponent
domino synthesis and in view of our interest in the mo-
lecular iodine catalyzed reactions at ambient tempera-
ture, we now wish to report on a convenient and rapid
one-pot three-component preparation of DHPMs deriva-
tives with 5 mol % molecular iodine as a catalyst involv-
ing aromatic aldehydes 1a–j, 1,3-diketone compound 3,
5, and thiourea 2, 6. Iodine may play a crucial role in
accelerating the dehydrative steps and enolization of
1,3-diketone compounds, in which the 4- and 5-positions
of the DHPMs 4a–j and 7a–j have been substituted with
a variety of groups. We have demonstrated a simple
route for the synthesis of 1-substituted DHPMs. This
methodology offers very attractive features such as short
reaction time, mild reaction condition, good to excellent
product yields, minimum environmental effects, and
commercially available iodine as a powerful catalyst;
the use of iodine was well tolerated with a range of
aldehydes. This protocol is general and provides DHPMs
in good to excellent yields depending on the reactivity of
arylaldehydes.
[18] Franzblau, S. G.; Witzig, R. S.; McLaughlin, J. C.; Torres, P.;
Madico, G.; Hernandez, A.; Degnan, M. T.; Cook, M. B.; Quenzer, V. K.;
Freguson, R. M.; Gilman, R. H. J Clin Microbiol 1998, 36, 362.
[19] Collins, L. A.; Franzblau, S. G. Antimicrob Agents Chemother
1997, 41, 1004.
[20] Barry, A. L. The Antimicrobial Susceptibility Test: Principle
and Practices; Illus lea and Febiger: Philadelphia, P.A., USA, 1976;
p180; Barry, A. L. Biol Abstr 1976, 64, 25183.
Some of the newly synthesized compounds 4d (3-OCH3),
4f (4-F), and 7e (4-OCH3) exhibited good antimyco-
bacterial and antibacterial activities against E. coli, S.
aureus, and P. aeruginosa as well as antifungal activity
against C. albicans.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet