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Multi-Component Synthesis of Dihydropyrimidines by Iodine Catalyst at Ambient Temperature and in-vitro Antimycobacterial Activity.

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Arch. Pharm. Chem. Life Sci. 2009, 342, 469 – 475
P. Zalavadiya et al.
469
Full Paper
Multi-Component Synthesis of Dihydropyrimidines by Iodine
Catalyst at Ambient Temperature and in-vitro
Antimycobacterial Activity
Paresh Zalavadiya, Satish Tala, Jignesh Akbari, and Hitendra Joshi
Chemical Research Laboratory, Department of Chemistry, Saurashtra University, Rajkot Gujarat, India
An efficient and simple three-component domino synthesis of some new dihydropyrimidines
(DHPMs) from aromatic aldehydes, 1,3-dicarbonyl compounds and N-(3-chloro-4-fluorophenyl)urea using molecular iodine as catalyst is described. The 1-substituted dihydropyrimidines
were isolated in good to excellent yields (78-90%) within a short reaction time (4-6 h) at ambient
temperature. The biological evaluation revealed that the newly synthesized compounds (4a-i
and 5a-i) exhibited moderate antimycobacterial activity against Mycobacterium tuberculosis H37 RV.
Keywords: Ambient temperature / Antimycobacterial activity / Molecular iodine / 1-Substituted DHPMs / Three-component domino synthesis /
Received: December 8, 2008; accepted: January 16, 2009
DOI 10.1002/ardp.200800224
Introduction
Synthetic drugs for treating tuberculosis (TB) have been
available for over half a century, but incidences of the disease continue to rise worldwide. In 2007, the last year for
which statistics are available, according to World Health
Organization (WHO), TB is responsible for more than 1.6
million deaths per annum with 8.8 million new cases
being reported each year, out of them, 7.4 million from
Asia and sub-Saharan Africa. These numbers make TB one
of the leading infectious causes of death, eclipsed only by
AIDS. In addition, the number of multi-drug resistant
and extensively drug resistant TB cases is growing with
almost half a million new cases being reported each year.
Therefore, there is an urgent need to develop novel TB
chemotherapeutic agents [1].
Since the early 1980s, interest in dihydropyrimidines
(DHPMs) has increased significantly due to the structural
similarity of DHPMs to the well known dihydropyridines
(DHPs) calcium channel modulators of the Hantzsch type
Correspondence: Dr. Hitendra S. Joshi, Department of Chemistry, Saurashtra University, Rajkot-360005 (Gujarat) India.
E-mail: drhsjoshi49@gmail.com
Fax: +91 281 257-6802
Abbreviation: dihydropyrimidines (DHPMs)
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2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
[2, 3]. In recent years, properly functionalized DHPMs
have been developed as calcium channel modulators,
antihypertensive agents, a1a-adrenergic antagonists, neuropeptide Y (NPY) antagonists, and compounds that target the mammalian mitotic machinery [4 – 6] The synthesis of dihydropyrimidines using molecular iodine as catalyst and their in-vitro antitubercular activity is reported.
In 1893, Biginelli et. al. [7] reported the first synthesis
of DHPMs by a simple one-pot condensation reaction of
ethylacetoacetate, benzaldehyde, and urea under strong
acidic condition [8] (Scheme 1).
Multicomponent [9] and domino [10] reactions allow
the creation of several bonds in a single operation and
are attracting increasing attention as one of the most
powerful emerging synthetic tools for the creation of
molecular diversity and complexity [11]. They also have
considerable advantages in terms of user and environmental friendliness because of the step reduction and
atom economy associated to their use.
Several efficient methods have been developed for the
synthesis of 1,4-DHPMs, which comprise the use of silica
triflate [12], iodotrimethylsilane in acetonitrile [13],
strontium(II) nitrate [14], PEG-4000 [15], chloroacetic acid
[16], InBr3 [17], microwave irradiation [18, 19], and KSF
montmorillonite [20] as catalysts. The development of an
efficient and versatile method for the synthesis of 1,4-
470
P. Zalavadiya et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 469 – 475
Scheme 1. One-pot synthesis of Biginelli DHPMs.
Reagents and conditions: (a) 5 mol% I2, ethanol, rt.
Scheme 3. One-pot synthesis of 1-substituted 1,4-DHPMs.
Reagents and conditions: (a) NaOH, toluene, 1108C; (b) HCl, gl. CH3COOH, 1508C.
Scheme 2. Synthesis of intermediates 2 and 3.
DHPMs is an interesting research area and there is room
for further improvement towards mild reaction conditions to improve the yield of the reaction.
Molecular iodine [21] has attracted attention as an
inexpensive, readily available catalyst for various organic
transformations to afford the corresponding products in
excellent yield with high selectivity. There are only few
reports about its use for the synthesis of 1,4-DHPs [22]
and DHPMs [23]. Therefore, we decided to synthesize
some new 1-substituted 1,4-DHPMs from a three-components domino reaction catalyzed by molecular iodine
under mild reaction condition. Herein, we report the synthesis and antimycobacterial activity of some new 3,4dihydropyrimidin-2(1H)-ones.
Result and discussion
Chemistry
The synthesis of 3,4-dihydropyrimidin-2(1H)-ones 4a – i
and 5a – i is outlined in Schemes 2 and 3. The key intermediates 2 [24] and 3 [25] were prepared by following the
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2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Scheme 4. Role of I2 as a catalyst and probable reaction mechanism.
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Arch. Pharm. Chem. Life Sci. 2009, 342, 469 – 475
Dihydropyrimidines: Synthesis and in vitro Anti-TB Activity
Table 1. Synthesis of 1-substituted 1,4-DHPMs 4a – i and 5a – i.
Entry
1
2
3
4
5
6
7
8
9
10
11
R
-OC2H5
-OC2H5
-OC2H5
-OC2H5
-OC2H5
-OC2H5
-OC2H5
-OC2H5
-OC2H5
R1
Product
Time
(h)a)
Yield
(%)b)
H
2-Cl
3-Cl
2-NO2
3-NO2
4-F
4-OCH3
3,4-(OCH3)2
4-OH
4a
4b
4c
4d
4e
4f
4g
4h
4i
5
4.5
4.4
4.8
4
4.8
5
5
4.8
90
87
85
86
88
89
87
84
84
H
5a
5.5
86
2-Cl
5b
4.8
3-Cl
5c
5
82
13
2-NO2
5d
5.4
81
15
16
17
18
a)
b)
3-NO2
4-F
4-OCH3
5e
5f
5g
3,4-(OCH3)2 5h
4-OH
5i
5.2
5.4
5.5
5.8
6
Sr.
No.
R
R1
Assay
MIC
Growth
(lg/mL) Inhibition
(%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
-OC2H5
-OC2H5
-OC2H5
-OC2H5
-OC2H5
-OC2H5
-OC2H5
-OC2H5
-OC2H5
H
2-Cl
3-Cl
2-NO2
3-NO2
4-F
4-OCH3
3,4-(OCH3)2
4-OH
MABA
MABA
MABA
MABA
MABA
MABA
MABA
MABA
MABA
A6.25
A6.25
A6.25
A6.25
A6.25
A6.25
A6.25
A6.25
A6.25
63
35
20
19
25
74
65
44
69
5a
H
MABA
>6.25
33
5b
2-Cl
MABA
A6.25
00
5c
3-Cl
MABA
A6.25
18
5d
2-NO2
MABA
A6.25
11
5e
3-NO2
MABA
A6.25
07
5f
4-F
MABA
A6.25
20
5g
4-OCH3
MABA
A6.25
03
5h
3,4-(OCH3)2 MABA
A6.25
00
5i
4-OH
A6.25
46
83
86
81
78
80
MABA
Reaction time is monitored by TLC.
Isolated yield.
literature methods (Scheme 2). The one-pot three-components condensation reaction of substituted benzaldehydes 1 with 1,3-diketone 2 and N-(3-chloro-4-fluorophenyl)urea 3 proceeded smoothly in ethanol in the presence
of 5 mol% iodine [21] as a catalyst to give the corresponding 3,4-dihydropyrimidin-2(1H)-ones 4a – i and 5a – i in
good to excellent yields (Table 1). A possible role of the
molecular iodine in the formation of DHPMs is depicted
in Scheme 4. As described in the literature, iodine may
catalyze the reaction as a mild Lewis acid [28, 29]. Thus,
in the presence of iodine, the enol form I of 1,3-diketone
2 immediately attacks the iodine-activated N-acylinium
ion intermediate II to form intermediate III, which then
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Table 2. Antimycobacterial activity data for compounds 4a – i
and 5a – i.
84
12
14
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2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
undergoes an intramolecular cyclization to give IV. The
subsequent dehydration of IV results in dihydropyrimidine V (Scheme 4). All the newly synthesized derivatives
were characterized by m.p., IR, 1H-NMR, mass spectral
studies, and elemental analysis.
Biology
All the newly synthesized compounds 4a – i and 5a – i
were evaluated for their possible in-vitro antimycobacterial activity under the Tuberculosis Antimicrobial
Acquisition Coordinating Facility (TAACF), an antituberculosis drug discovery program, coordinated by the
Southern Research Institute (Birmingham, Alabama)
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472
P. Zalavadiya et al.
directed by the National Institute of Allergy and Infectious Diseases, USA. Initially, compounds 4a – i and 5a – i
were evaluated against Mycobacterium tuberculosis H37RV
(ATCC 27294) (American Type Culture Collection, Manassas, VA, USA.) at single concentration of 6.25 lg/mL in
BACTEC 12B medium using a broth micro dilution assay
and the micro plate Alamar blue assay (MABA) [26]. Compounds exhibiting fluorescence were tested in the BACTEC 460 radiometric system [27]. The results of antitubercular activities are shown in Table 2.
The structure-activity relationship studies revealed
that compounds containing 4-substituted phenyl at 4position of DHPMs were most active as compared to 2and 3- substituted phenyl ring derivatives. While compounds 5a – i are the weakest in activity as compared to
compounds 4a – i of these derivatives, compound 4f with
4-fluoro phenyl substitution at the 4-position of DHPMs
was the most active one. However, all the new derivatives
showed weak antimycobacterial activity compared to the
standard drug rifampin which exhibited 98% growth
inhibition at 6.25 lg/mL concentration (Table 2).
Conclusion
In connection with our ongoing work on multi-component domino synthesis and in view of our interest in the
molecular iodine catalyzed reactions at ambient temperature [23], we now wish to report on a convenient and
rapid one-pot three-component preparation of 1-substituted DHPMs derivatives with 5 mol% molecular iodine
as a catalyst involving aromatic aldehyde 1, 1,3-diketone
compound 2, and N-(3-chloro-4-fluoro-phenyl)urea 3.
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 – i and
5a – i have been substituted with a variety of groups. The
present methodology offers very attractive features such
as short reaction time, milder reaction condition and
good to excellent product yields, and commercially available iodine as a powerful catalyst for the synthesis for
one-pot multi-component condensation reactions. This is
further supported by spectral analysis. The newly synthesized 3,4-dihydropyrimidin-2(1H)-ones derivatives possess
moderate antimycobacterial activity. The structural modification to improve the potency of this class of compounds will be reported in due course.
Authors are thankful to Tuberculosis Antimicrobial Acquisition Coordinating Facility (TAACF), Alabama, USA for antitubercular activity and Department of Chemistry for providing
laboratory facilities. The authors are thankful for facilities &
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2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Arch. Pharm. Chem. Life Sci. 2009, 342, 469 – 475
grants given under UGC-SAP for Department Research Support
(DRS) and Department of Science & Technology (DST) New Delhi
from the Fund for Improvement of Science & Technology (FIST).
The authors have declared no conflict of interest.
Experimental
Chemistry
Melting points were determined on electrothermal apparatus
using open capillaries and are uncorrected. Thin-layer chromatography was accomplished on 0.2-mm precoated plates of silica
gel G60 F254 (Merck, St. Louis, MO, USA). Visualization was
achieved with UV light (254 and 365 nm) or with iodine vapor.
IR spectra were recorded on a FTIR-8400 spectrophotometer (Shimadzu, Kyoto, Japan), using DRS probe. 1H-NMR spectra were
recorded on a Bruker AVANCE II (400 MHz) spectrometer
(Bruker, Rheinstetten, Germany), in CDCl3. Chemical shifts are
expressed in ppm (d) downfield from 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, USA). Solvents were evaporated with
a Laborota 4000 efficient rotary evaporator (Heidolph, Germany). All reagents were purchased from Fluka (New Delhi,
India), Sigma Aldrich (New Delhi, India), Merck (St. Louis, MO,
USA), and Rankem (New Delhi, India) and were used without further purification.
Preparation of N-(4-methylphenyl)-3-oxobutanamide 2
A suspension of ethyl acetoacetate (1.30 g, 10 mmol) and p-toluidine (1.07 g, 10 mmol) in toluene (25 mL) containing catalytic
amount of NaOH (0.05 mL, 40%) was refluxed on oil bath for 8 h.
After completion of the reaction (TLC monitoring) the solvent
was removed under reduced pressure, separated solid was filtered and washed with petroleum ether and crystallized from
ethanol to give pure product. Yield: 74%; m.p.: 928C (lit. [30] m.p.:
92–948C).
Preparation of N-(3-chloro-4-fluorophenyl)urea 3
In a mixture of 3-chloro-4-fluoroaniline hydrochloride (18.1 g,
100 mmol) and urea (24.0 g, 400 mmol) in water (40 mL), concentrated HCl (1 mL) and glacial acetic acid (1 mL) were added. The
mixture was heated vigorously for 45 minutes. After cooling to
room temperature, the product was broken up and washed with
cold water. Yield: 58%; m.p.: 2288C.
General procedure for the preparation 3,4dihydropyrimidin-2(1H)-ones (DHPMs) 4a – i and 5a – i
A mixture of aromatic aldehydes 1 (10 mmol), 1,3-dicarbonyl
compounds 2 (10 mmol), N-(3-chloro-4-fluorophenyl)urea 3
(2.83 g, 15 mmol) and iodine (5 mol%) in ethanol (10 mL). The
reaction mixture was then stirred at room temperature until
the reaction was completed (4 – 6 h monitored by TLC). The reaction mixture was treated with 0.1 N Na2S2O3 solution, extracted
into ethyl acetate (3620 mL). The solvent was removed in vacuo
and the resulting crude product (78 – 90%) was crystallized from
ethanol to give the analytically pure compounds 4a – i and 5a – i.
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Arch. Pharm. Chem. Life Sci. 2009, 342, 469 – 475
Ethyl 1-(3-chloro-4-fluorophenyl)-6-methyl-4-phenyl-3,4dihydropyrimidin-2(1H)-one-5-carboxylate 4a
M.p.: 235 – 2378C; IR (KBr) cm – 1: 3465, 3250, 3086, 2961, 1721,
1662, 1541, 1469, 736; 1H-NMR d: 0.93 (t, J = 7.5 Hz, 3H, -CH2-CH3),
2.16 (s, 3H, Ar-CH3), 4.11 (q, J = 7.5 Hz, 2H, OCH2CH3), 5.42 (s, 1H,
CH), 7.30 – 8.64 (m, 8H, ArH), 9.96 (s(b), 1H, NH); EI-MS (m/z): 389
[M+]. Anal. Calcd. for C20H18ClFN2O3: C, 61.78; H, 4.67; N, 7.20.
Found: C, 61.69; H, 4.79; N, 6.08.
Ethyl 1-(3-chloro-4-fluorophenyl)-6-methyl-4-(2chlorophenyl)-3,4-dihydropyrimidin-2(1H)-one-5carboxylate 4b
M.p.: 213 – 2158C; IR (KBr) cm – 1: 3449, 3111, 3079, 2929, 1704,
1650, 1567, 1441, 723; 1H NMR d: 0.95 (t, J = 7.8 Hz, 3H, OCH2CH3),
2.15 (s, 3H, Ar-CH3), 4.10 (q, J = 7.7 Hz, 2H, OCH2CH3), 5.37 (s, 1H,
CH), 7.24 – 8.46 (m, 7H, ArH), 9.91 (s(b), 1H, NH); EI-MS (m/z): 425
[M+ +1]. Anal. Calcd. for C20H17Cl2FN2O3: C, 56.75; H, 4.05; N, 6.62.
Found: C, 56.67; H, 4.13; N, 6.48.
Ethyl 1-(3-chloro-4-fluorophenyl)-6-methyl-4-(3chlorophenyl)-3,4-dihydropyrimidin-2(1H)-one-5carboxylate 4c
M.p.: 235 – 2368C; IR (KBr) cm – 1: 3437, 3127, 3090, 2956, 1728,
1671, 1570, 1456, 739; 1H-NMR d: 0.92 (t, J = 7.6 Hz, 3H, OCH2CH3),
2.11 (s, 3H, Ar-CH3), 4.08 (q, J = 7.7 Hz, 2H, OCH2CH3), 5.31 (s, 1H,
CH), 7.17 – 8.34 (m, 7H, ArH), 9.82 (s(b), 1H, NH); EI-MS (m/z): 425
[M+ + 1]. Anal. Calcd. for C20H17Cl2FN2O3: C, 56.75; H, 4.05; N, 6.62.
Found: C, 56.70; H, 4.09; N, 6.53.
Ethyl 1-(3-chloro-4-fluorophenyl)-6-methyl-4-(2nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one-5carboxylate 4d
M.p.: 248 – 2508C; IR (KBr) cm – 1: 3450, 3241, 3052, 2934, 1756,
1715, 1630, 1451, 769; 1H-NMR d: 0.94 (t, J = 7.4 Hz, 3H, OCH2CH3),
2.08 (s, 3H, Ar-CH3), 4.03 (q, J = 7.3 Hz, 2H, OCH2CH3), 5.31 (s, 1H,
CH), 7.15 – 8.43 (m, 7H, ArH), 10.09 (s(b), 1H, NH); EI-MS (m/z) 434
[M+]. Anal. Calcd. for C20H17ClFN3O5: C, 55.37; H, 3.95; N, 9.69.
Found: C, 55.29; H, 4.02; N, 9.67.
Ethyl 1-(3-chloro-4-fluorophenyl)-6-methyl-4-(3nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one-5carboxylate 4e
–1
M.p.: 260 – 2628C; IR (KBr) cm : 3438, 3261, 3074, 2952, 1730,
1701, 1645, 1460, 742; 1H-NMR d: 0.91 (t, J = 7.9 Hz, 3H, OCH2CH3),
2.10 (s, 3H, Ar-CH3), 4.07 (q, J = 7.9 Hz, 2H, OCH2CH3), 5.36 (s, 1H,
CH), 7.21 – 8.51 (m, 7H, ArH), 10.04 (s(b), 1H, NH); EI-MS (m/z): 434
[M+]. Anal. Calcd. for C20H17ClFN3O5: C, 55.37; H, 3.95; N, 9.69.
Found: C, 55.24; H, 4.10; N, 9.60.
Ethyl 1-(3-chloro-4-fluorophenyl)-6-methyl-4-(4fluorophenyl)-3,4-dihydropyrimidin-2(1H)-one-5carboxylate 4f
M.p.: 187 – 1898C; IR (KBr) cm – 1: 3402, 3089, 2978, 2897, 1739,
1642, 1512, 1430, 704; 1H-NMR d: 0.89 (t, J = 7.2 Hz, 3H, OCH2CH3),
2.03 (s, 3H, Ar-CH3), 3.91 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.28 (s, 1H,
CH), 7.03 – 8.13 (m, 7H, ArH), 9.70 (s(b), 1H, NH); EI-MS (m/z) 407
[M+]. Anal. Calcd. for C20H17ClF2N2O3: C, 59.05; H, 4.21; N, 6.89.
Found: C, 58.97; H, 4.09; N, 6.73.
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2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Dihydropyrimidines: Synthesis and in vitro Anti-TB Activity
473
Ethyl 1-(3-chloro-4-fluorophenyl)-6-methyl-4-(4methoxyphenyl)-3,4-dihydropyrimidin-2(1H)-one-5carboxylate 4g
M.p.: 235 – 2368C; IR (KBr) cm – 1: 3437, 3127, 3090, 2956, 1728,
1671, 1570, 1456, 739; 1H-NMR d: 0.92 (t, J = 7.6 Hz, 3H, OCH2CH3),
2.11 (s, 3H, Ar-CH3), 3.75 (s, 3H, Ar-OCH3), 4.08 (q, J = 7.7 Hz, 2H,
OCH2CH3), 5.31 (s, 1H, CH), 7.17 – 8.34 (m, 7H, ArH), 9.82 (s(b), 1H,
NH); EI-MS (m/z): 419 [M+]. Anal. Calcd. for C21H20ClFN2O4: C,
60.22; H, 4.81; N, 6.69. Found: C, 60.17; H, 4.75; N, 6.73.
Ethyl 1-(3-chloro-4-fluorophenyl)-6-methyl-4-(3,4dimethoxyphenyl)-3,4-dihydropyrimidin-2(1H)-one-5carboxylate 4h
M.p.: 252 – 2538C; IR (KBr) cm – 1: 3410, 3156, 3125, 3018, 1745,
1672, 1568, 1449, 723; 1H NMR d: 0.96 (t, J = 7.9 Hz, 3H, OCH2CH3),
2.03 (s, 3H, Ar-CH3), 3.81 (s, 6H, Ar-OCH3), 4.15 (q, J = 7.8 Hz, 2H,
OCH2CH3), 5.28 (s, 1H, CH), 7.35 – 8.59 (m, 6H, ArH), 9.93 (s(b), 1H,
NH); EI-MS (m/z) 449 [M+]. Anal. Calcd. for C22H22ClFN2O5: C, 58.87;
H, 4.94; N, 6.24. Found: C, 58.80; H, 4.99; N, 6.18.
Ethyl 1-(3-chloro-4-fluorophenyl)-6-methyl-4-(4hydroxyphenyl)-3,4-dihydropyrimidin-2(1H)-one-5carboxylate 4i
M.p.: 189 – 1908C; IR (KBr) cm – 1: 3405, 3118, 3071, 2982, 1723,
1646, 1528, 1413, 708; 1H-NMR d: 0.89 (t, J = 7.7 Hz, 3H, OCH2CH3),
2.16 (s, 3H, Ar-CH3), 4.02 (q, J = 7.8 Hz, 2H, OCH2CH3), 5.22 (s, 1H,
CH), 7.10 – 8.21 (m, 7H, ArH), 9.89 (s(b), 1H, NH); EI-MS (m/z) 405
[M+ + 1]. Anal. Calcd. for C20H18ClFN2O4; C, 59.34; H, 4.48; N, 6.92.
Found: C, 59.21; H, 4.42; N, 6.82.
1-(3-Chloro-4-fluorophenyl)-6-methyl-N-(4methylphenyl)-4-phenyl-3,4-dihydropyrimidin-2(1H)-one5-carboxamide 5a
M.p.: 178 – 1808C; IR (KBr) cm – 1: 3410, 3259, 3092, 2958, 1736,
1642, 1530, 1418, 756; 1H-NMR d: 2.19 (s, 3H, Ar-CH3), 2.26 (s, 3H,
Ar-CH3), 5.46 (s, 1H, CH), 6.93 – 7.00 (d, J = 8.8 Hz, 2H, ArH), 7.137.43 (m, 8H, ArH), 7.59-7.62 (d, J = 8.9 Hz, 2H, ArH), 9.92 (s(b), 1H,
NH), 9.99 (s(b), 1H, NH); EI-MS (m/z): 450 [M+]. Anal. Calcd. for
C25H21ClFN3O2: C, 66.74; H, 4.70; N, 9.34. Found: C, 66.78; H, 4.62;
N, 9.39.
1-(3-Chloro-4-fluorophenyl)-6-methyl-N-(4methylphenyl)-4-(2-chlorophenyl)-3,4-dihydropyrimidin2(1H)-one-5-carboxamide 5b
M.p.: 258 – 2608C; IR (KBr) cm – 1: 3425, 3280, 3079, 2917, 1716,
1682, 1573, 1466, 720; 1H-NMR d: 2.21 (s, 3H, Ar-CH3), 2.32 (s, 3H,
Ar-CH3), 5.66 (s, 1H, CH), 6.98 – 7.03 (d, J = 8.7 Hz, 2H, ArH), 7.14 –
7.51 (m, 7H, ArH), 7.63 – 7.74 (d, J = 8.8 Hz, 2H, ArH), 9.96 (s(b), 1H,
NH), 10.08 (s(b), 1H, NH); EI-MS (m/z): 486 [M+ + 1]. Anal. Calcd. for
C25H20Cl2FN3O2: C, 61.99; H, 4.16; N, 8.68. Found: C, 61.86; H,
4.24; N, 8.59.
1-(3-Chloro-4-fluorophenyl)-6-methyl-N-(4methylphenyl)-4-(3-chlorophenyl)-3,4-dihydropyrimidin2(1H)-one-5-carboxamide 5c
M.p.: 189 – 1918C; IR (KBr) cm – 1: 3453, 3190, 3082, 2956, 1698,
1620, 1543, 1421, 746; 1H-NMR d: 2.23 (s, 3H, Ar-CH3), 2.31 (s, 3H,
Ar-CH3), 5.52 (s, 1H, CH), 7.08 – 7.15 (d, J = 9.2 Hz, 2H, ArH), 7.23 –
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7.38 (m, 7H, ArH), 7.50 – 7.57 (d, J = 9.2 Hz, 2H, ArH), 9.92 (s(b), 1H,
NH), 9.98 (s(b), 1H, NH); EI-MS (m/z): 486 [M+ + 1]. Anal. Calcd. for
C25H20Cl2FN3O2: C, 61.99; H, 4.16; N, 8.68. Found: C, 61.86; H,
4.24; N, 8.59.
1-(3-Chloro-4-fluorophenyl)-6-methyl-N-(4methylphenyl)-4-(2-nitrophenyl)-3,4-dihydropyrimidin2(1H)-one-5-carboxamide 5d
M.p.: 278 – 2798C; IR (KBr) cm – 1: 3478, 3205, 3073, 2968, 1714,
1628, 1530, 1481, 764; 1H-NMR d: 2.31 (s, 3H, Ar-CH3), 2.39 (s, 3H,
Ar-CH3), 5.68 (s, 1H, CH), 7.15 – 7.23 (d, J = 8.7 Hz, 2H, ArH), 7.32 –
7.46 (m, 7H, ArH), 7.63 – 7.72 (d, J = 8.6 Hz, 2H, ArH), 9.81 (s(b), 1H,
NH), 9.90 (s(b), 1H, NH); EI-MS (m/z): 495 [M+]. Anal. Calcd. for
C25H20ClFN4O4: C, 60.67; H, 4.07; N, 11.32. Found: C, 60.58; H,
4.14; N, 11.23.
Arch. Pharm. Chem. Life Sci. 2009, 342, 469 – 475
[M+]. Anal. Calcd. for C27H25ClFN3O4: C, 63.59; H, 4.94; N, 8.24.
Found: C, 63.48; H, 5.02; N, 8.29.
1-(3-Chloro-4-fluorophenyl)-6-methyl-N-(4methylphenyl)-4-(4-hydroxyphenyl)-3,4-dihydropyrimidin2(1H)-one-5-carboxamide 5i
M.p.: 283 – 2848C; IR (KBr) cm – 1: 3435, 3210, 3087, 2936, 1728,
1665, 1550, 1425, 720; 1H-NMR d: 1.83 (s, 3H, Ar-CH3), 2.03 (s, 3H,
Ar-CH3), 5.41 (s, 1H, CH), 6.82 – 6.98 (d, J = 8.3 Hz, 2H, ArH), 7.05 –
7.26 (m, 7H, ArH), 7.42 – 7.54 (d, J = 8.2 Hz, 2H, ArH), 9.82 (s(b), 1H,
NH), 9.95 (s(b), 1H, NH); EI-MS (m/z): 466 [M+]. Anal. Calcd. for
C25H21ClFN3O3: C, 64.45; H, 4.54; N, 9.02. Found: C, 64.35; H, 4.48;
N, 9.11.
References
1-(3-Chloro-4-fluorophenyl)-6-methyl-N-(4methylphenyl)-4-(3-nitrophenyl)-3,4-dihydropyrimidin2(1H)-one-5-carboxamide 5e
M.p.: 265 – 2678C; IR (KBr) cm – 1: 3419, 3284, 3062, 2923, 1706,
1676, 1566, 1471, 736; 1H-NMR d: 2.25 (s, 3H, Ar-CH3), 2.30 (s, 3H,
Ar-CH3), 5.59 (s, 1H, CH), 7.01 – 7.04 (d, J = 9.0 Hz, 2H, ArH), 7.08 –
7.35 (m, 7H, ArH), 7.55 – 7.58 (d, J = 9.0 Hz, 2H, ArH), 9.86 (s(b), 1H,
NH), 9.97 (s(b), 1H, NH); EI-MS (m/z): 495 [M+]. Anal. Calcd. for
C25H20ClFN4O4: C, 60.67; H, 4.07; N, 11.32. Found: C, 60.61; H,
4.19; N, 11.18.
1-(3-Chloro-4-fluorophenyl)-6-methyl-N-(4methylphenyl)-4-(4-fluorophenyl)-3,4-dihydropyrimidin2(1H)-one-5-carboxamide 5f
M.p.: 243 – 2448C; IR (KBr) cm – 1: 3439, 3183, 3019, 2945, 1725,
1640, 1509, 1451, 763; 1H-NMR d: 2.20 (s, 3H, Ar-CH3), 2.25 (s, 3H,
Ar-CH3), 5.42 (s, 1H, CH), 6.93 – 7.02 (d, J = 8.9 Hz, 2H, ArH), 7.12 –
7.29 (m, 7H, ArH), 7.48 – 7.54 (d, J = 8.9 Hz, 2H, ArH), 9.82 (s(b), 1H,
NH), 9.91 (s(b), 1H, NH); EI-MS (m/z): 468 [M+]. Anal. Calcd. for
C25H20ClF2N3O2: C, 64.17; H, 4.31; N, 8.98. Found: C, 64.08; H,
4.36; N, 8.89.
1-(3-Chloro-4-fluorophenyl)-6-methyl-N-(4methylphenyl)-4-(4-methoxyphenyl)-3,4dihydropyrimidin-2(1H)-one-5-carboxamide 5g
M.p.: 218 – 2208C; IR (KBr) cm – 1: 3422, 3241, 3026, 2953, 1700,
1683, 1542, 1425, 742; 1H-NMR d: 2.29 (s, 3H, Ar-CH3), 2.33 (s, 3H,
Ar-CH3), 3.72 (s, 3H, Ar-OCH3), 5.63 (s, 1H, CH), 7.18 – 7.29 (d, J =
9.1 Hz, 2H, ArH), 7.34 – 7.52 (m, 7H, ArH), 7.68 – 7.80 (d, J = 9.2 Hz,
2H, ArH), 9.92 (s(b), 1H, NH), 10.06 (s(b), 1H, NH); EI-MS (m/z): 480
[M+]. Anal. Calcd. for C26H23ClFN3O3: C, 65.07; H, 4.83; N, 8.76.
Found: C, 65.01; H, 4.75; N, 8.68.
1-(3-Chloro-4-fluorophenyl)-6-methyl-N-(4methylphenyl)-4-(3,4-dimethoxyphenyl)-3,4dihydropyrimidin-2(1H)-one-5-carboxamide 5h
M.p.: 229 – 2318C; IR (KBr) cm – 1: 3392, 3116, 3047, 2958, 1719,
1644, 1549, 1462, 768; 1H-NMR d: 1.89 (s, 3H, Ar-CH3), 2.12 (s, 3H,
Ar-CH3), 3.78 (s, 6H, Ar-OCH3), 5.73 (s, 1H, CH), 6.95 – 7.12 (d, J =
8.5 Hz, 2H, ArH), 7.23 – 7.47 (m, 6H, ArH), 7.63 – 7.80 (d, J = 8.5 Hz,
2H, ArH), 9.73 (s(b), 1H, NH), 9.86 (s(b), 1H, NH); EI-MS (m/z): 510
i
2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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