Synthesis and antibacterial activity of a new series of 2,3,5,7-substituted-pyrido[2,3-d/]pyrimidin-4(3H)-one derivatives

Article abstract of DOI:10.1248/cpb.56.1342

A new series of 2,3,5,7-substituted-pyrido[2,3-d]pyrimidin-4(3H)-one derivatives were prepared from 2-amino-N,6-substituted phenyl-4-(trifluoromethyl or methyl)nicotinamides. The key intermediate 2-amino-N,6-substituted phenyl-4-(trifluoromethyl or methyl)nicotinamides were synthesized from 2-bromo-N,6-disubstituted phenyl-4-(trifluoromethyl or methyl)nicotinamides as well as fromethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) coupling of 2-amino-4,6-substituted nicotinic acid and substituted arylamines. All the synthesized compounds were screened for antibacterial activity against Gram +ve and Gram -ve bacteria. Compound 7c showed better antibacterial activity against Gram +ve and Gram -ve bacteria.

Full text of DOI:10.1248/cpb.56.1342

1342
Notes
Chem. Pharm. Bull. 56(9) 1342—1348 (2008)
Vol. 56, No. 9
Synthesis and Antibacterial Activity of a New Series of 2,3,5,7-
Substituted-pyrido[2,3-d]pyrimidin-4(3H)-one Derivatives
a
Lakshmi Narayana BHEEMANAPALLI, Raghuram Rao AKKINEPALLY, ,a and
Shanthan Rao PAMULAPARTHY
*
b
a Department of Pharmaceutical Chemistry, University Institute of Pharmaceutical Sciences, Panjab University;
Chandigarh–160014, India: and b Fluoroorganics Division, Indian Institute of Chemical Technology; Hyderabad–500 007,
Andhra Pradesh, India. Received April 29, 2008; accepted June 11, 2008; published online June 23, 2008
A new series of 2,3,5,7-substituted-pyrido[2,3-d]pyrimidin-4(3H)-one derivatives were prepared from 2-
amino-N,6-substituted phenyl-4-(trifluoromethyl or methyl)nicotinamides. The key intermediate 2-amino-N,6-
substituted phenyl-4-(trifluoromethyl or methyl)nicotinamides were synthesized from 2-bromo-N,6-disubstituted
phenyl-4-(trifluoromethyl or methyl)nicotinamides as well as from ethyl-3-(3-dimethylaminopropyl)-carbodi-
imide (EDC) coupling of 2-amino-4,6-substituted nicotinic acid and substituted arylamines. All the synthesized
compounds were screened for antibacterial activity against Gram ꢀve and Gram ꢁve bacteria. Compound 7c
showed better antibacterial activity against Gram ꢀve and Gram ꢁve bacteria.
Key words pyrido[2,3]pyrimidin-4(3H)-one; N-substituted nicotinamide; antibacterial activity; 1-ethyl-3-(3-dimethylamino-
propyl)-carbodiimide; triethylorthopropionate
Pyrido[2,3-d]pyrimidine ring system is present in a num- analyses. The IR spectra of the compounds showed disap-
ber of biologically active compounds which includes, anti- pearance of cyano (–CN–) peak in the range of 2225—
bacterial,1—3) antitumor,4) antipyretic,5) analgesic,6) antihista- 2218 cmꢀ1 and disappearance of ketone (CꢁO) peak in the
minic,7—9) phosphodiesterase-4 (PDE4) inhibitor,10) adeno- range of 1730—1715 cmꢀ1 indicate the cyclization of ketone
1
sine kinase inhibitor,11) tyrosine kinase inhibitor12) and di- and cyano group to form compound 4. H-NMR spectra
uretic13,14) activities. More specifically pyrido[2,3-d]pyrim- showed the disappearance of the signals at the range of d
idines were considered as inhibitors of Pneumocystis carinii, 4.92 to 3.64 ppm due to aliphatic protons and it showed the
Toxoplasma gondii of tumor cells in culture this activity is signal around d 8.80 ppm due to pyridine (C-5) proton. The
mainly due to inhibition of dihydrofolate reductase (DHFR) mass spectra exhibited the molecular ion peaks correspond-
enzyme.15—19)
ing to the molecular weight of the compounds which further
The synthesis of pyrido[2,3-d]pyrimidines is mainly by confirmed the formation of compound 4.
two ways i.e., annulation of pyrimidine ring over pyridine or
vice versa.20) The wide range of activity profile of pyrido[2,3- romethyl or methyl)nicotinamides 4a—j with aromatic
d]pyrimidines given insight to probe into synthesis of novel amine (aniline) in pyridine gave two products 5 and 6 (Chart
analogues and to study their antibacterial activity. Moreover
trifluoromethyl substituted compounds are supposed to have
enhanced activity due to high lipid solubility. Thus in contin-
uation of our efforts to synthesize novel heterocycles,21—24)
we report here a convenient synthesis of 2-substituted-3-
(4-substituted phenyl)-7-(substituted phenyl)-5-(trifluoro-
methyl or methyl)pyrido[2,3-d]pyrimidin-4(3H)-ones 7 from
2-bromo-N,6-substituted phenyl-4-(trifluoromethyl or meth-
yl)nicotinamide 4 via 2-amino-N,6-substituted phenyl-4-(tri-
fluoromethyl or methyl)nicotinamides 5 and their in vitro an-
tibacterial activity.
Reaction of 2-bromo-N,6-substituted phenyl-4-(trifluo-
Chemistry 2-Cyano-N-substituted phenyl-5-oxo-5-sub-
stituted phenyl-3-(trifluoromethyl or methyl)pentanamide
analogues 3 were synthesized from condensation of 1,4-
disubstituted but-2-en-1-ones 1 with 2-cyano-N-(substituted
phenyl)acetamides 2a—j in the presence of a catalytic
amounts of morpholine as a basic catalyst, afforded the cor-
responding compounds 3a—j in good yields. The structure
1
of the latter was established through spectroscopic (IR, H-
NMR and MS) as well as elemental analyses data. Addition
of bromine to pentamides 3a—j in glacial acetic acid at 70—
80 °C gave directly the 2-bromo-N,6-substituted phenyl-4-
(trifluoromethyl or methyl)nicotinamides 4a—j in good
yields (Chart 1). The structure of 4a—j was determined
through spectroscopic (IR, 1H-NMR, and MS) and elemental
Chart 1
∗ To whom correspondence should be addressed. e-mail: raghumedpu@gmail.com
© 2008 Pharmaceutical Society of Japan

September 2008
1343
Chart 3
the yielding of 2-amino-3-pyridinecarbonitrile derivatives
through the reaction of 2-bromo analogues with primary
amino acid (glycine or alanine) in pyridine.27) It was assumed
in the latter reaction that, the mechanistic pathway proceeded
analogously to the famous ninhydrin reaction with a-amino
acids where the amino acids isomerized to the corresponding
imino-acid forms under the effect of applied reaction condi-
Chart 2
2) which were separated and purified by column chromatog- tions.28) Then, upon hydrolysis, due to unavoidable moisture,
raphy using silica gel (60—120 mesh) and the desired prod- ammonia was liberated which in turn interacted with 2-
uct was eluted with ethyl acetate–n-hexane as mobile phase. bromo-3-pyridinecarbonitriles giving the 2-amino deriva-
The structures of which were characterized as 2-amino-N,6- tives. Another observation was also reported about the for-
substituted phenyl-4-(trifluoromethyl or methyl)nicotinamide mation of 2-aminonicotinate esters through the reaction of 2-
5 and 2-(substituted amino)-N,6-substituted phenyl-4-(triflu- bromonicotinates with primary aromatic amines under simi-
oromethyl or methyl)nicotinamide 6 based on spectroscopic lar reaction conditions.29)
(IR, 1H-NMR, and MS) and elemental analyses data.
Pyrido[2,3-d]pyrimidines were prepared by reaction of 2-
Formation of 5 probably took place through iminoform aminonicotinamide and triethylorthoformate.30—33) In this
isomerization originated from the primary aromatic amines note we are reporting facile synthesis and antibacterial activ-
under the basic reaction conditions (pyridine reflux), which ity of N-substituted pyrido[2,3-d]pyrimidines. The reaction
via hydrolysis ‘due to unavoidable moisture’ liberated am- of 2-amino-N,6-substituted phenyl-4-(trifluoromethyl or
monia. The latter due to aromatic nucleophilic substitution methyl)nicotinamides 5 with triethylorthoacetate or triethy-
with the used starting compound 2-bromo-N,6-substituted lorthopropionate in the presence of catalytic amounts of gla-
phenyl-4-(trifluoromethyl or methyl)nicotinamides 4 gave fi- cial acetic acid gave 2,3,7-substituted-5-(trifluromethyl or
nally, the 2-amino-N,6-substituted phenyl-4-(trifluoromethyl methyl)pyrido[2,3-d]pyrimidin-4(3H)-ones 7a—p in good
or methyl)nicotinamides 5. Simultaneously compounds 5 yields (Chart 3). The structure of compounds 7 was deter-
1
were synthesized from the 2-amino-4,6-substituted nicotinic mined through spectroscopic (IR, H-NMR and MS) as well
acid and substituted arylamines through EDC (1-ethyl-3-(3- as elemental analyses. IR spectra of the compounds were
dimethylaminopropyl)-carbodiimide) coupling.25,26) It has showed the disappearance of the peaks pertaining to primary
been noticed that, the yields of 5a—j (39—25%) were and secondary amine groups in the range of 3400—
1
greater in case of aromatic amine substituted with deactivat- 3250 cmꢀ1. Disappearance of H-NMR amino signals (pri-
ing moiety compared with the cases, when the amines were mary and secondary) around d 6.18 ppm and d 10.32 ppm
substituted with electron-donating or activating functions. and mass spectra exhibited molecular ion peaks correspon-
This observation supports the role of substituent attached ding to the molecular weight of the compounds which further
with the used aromatic amine in deriving the reaction mecha- confirmed the formation of compounds 7. The elemental
nistic route toward the product 5 formation, which coincides analyses showed that all the newly synthesized compounds
with the role of substitution favoring the imino-form process were having the purity within ꢂ0.4% of the theoretical val-
isomerization during the reaction course. Eventually, it could ues.
be concluded that, the opportunity of 5 formation under
Antibacterial Activity (in Vitro) Six bacterial test or-
the described basic reaction conditions appeared greater ganisms such as Bacillus subtilis (MTCC 441), Staphylococ-
when the used primary aromatic amine substituted with cus aureus (MTCC 96), Bacillus sphaericus (MTCC 511),
deactivating moieties. Formation of 5 during the reaction Escherichia coli (MTCC 722), Chromobacterium violaceum
course seems similar to what was previously reported about (MTCC 2656) and Klebsiella pneumoniae (MTCC 109) were

1344
Vol. 56, No. 9
Table 1. MIC (in mg/ml) Values of 2,3,5,7-Substituted-pyrido[2,3-d]pyrimidin-4(3H)-ones (7a—p)
Microorganigms
Compounds
Gram positive
Gram negative
B. subtilis
S. aureus
B. sphaericus
E. coli
C. violaceum
K. pneumoniae
7a
7b
7c
7d
7e
7f
7g
7h
3.25
12.50
1.25
1.25
1.25
1.25
6.25
25.00
3.25
3.25
25.00
1.25
6.25
3.25
1.25
50.00
3.25
3.25
6.25
12.50
1.25
50.00
3.25
6.25
6.25
3.25
12.50
12.50
12.50
25.00
1.50
25.00
—
12.50
12.50
1.25
12.50
3.25
50.00
1.25
12.50
3.25
1.25
25.00
25.00
50.00
—
6.25
12.50
25.00
6.25
—
—
7i
1.25
7j
7k
7l
7m
7n
7o
7p
25.00
1.25
12.5
12.50
25.00
6.25
25.00
0.78
25.00
3.25
12.25
12.50
12.50
6.25
12.50
3.25
12.25
25.00
50.00
3.25
3.25
1.25
12.50
25.00
1.25
6.25
6.25
0.39
—
25.00
—
3.25
6.25
50.00
50.00
12.50
1.25
—
25.00
3.25
6.25
0.39
25.00
0.39
12.50
0.78
6.25
0.78
Ciprofloxacin
selected and obtained from the Institute of Microbial Tech- activity. As all the compounds exhibited antibacterial activity
nology, Chandigarh. Cultures of test organisms were main- against both Gram ꢃve and Gram ꢀve bacteria under study,
tained on nutrient agar slants and were sub cultured in petri it indicates that this basic moiety can be a potential scaffold
dishes prior to testing. The media used was nutrient agar, nu- for the antibacterial agents.
trient broth procured from Himedia Laboratories, Mumbai.
Experimental
Melting points were recorded on Casiaa siamea (VMP-AM) melting point
apparatus and are uncorrected. IR spectra were recorded on a Perkin-Elmer
Results and Discussions
FT-IR 240-C spectrophotometer using KBr optics. 1H-NMR spectra were
recorded on Gemini Varian 400 MHz spectrometer in DMSO-d6 using TMS
as an internal standard. Electron impact and chemical ionization mass spec-
tra were recorded on a VG 7070 H instrument at 70 eV. CHN analyses were
recorded on a Vario EL analyzer and were within ꢂ0.4% of the theoretical
values. All the reactions were monitored by thin layer chromatography
(TLC) on precoated silica gel 60 F254 (mesh), spots were visualized with UV
light. Merck silicagel (100—200 mesh) was used for chromatography. The
starting compounds 1a—j34) and 2a—j35) were prepared according to the
previously reported procedures. All solvents were dried and freshly distilled
prior to use according to standard procedures. All the chemicals used were
of analytical grade and commercially available.
All the synthesized compounds were evaluated for the an-
timicrobial activity against various Gram ꢃve (Bacillus sub-
tilis, Staphylococcus aureus and Bacillus sphaericus) and
Gram ꢀve (Escherichia coli, Chromobacterium violaceum
and Klebsiella pneumoniae). Among all the compounds,
compounds having the chloro and fluoro substitutions exhib-
ited better activity compared to other compounds. Compound
7c, 7e, and 7k showed better activity against both Gram ꢃve
and Gram ꢀve bacteria. Antibacterial activity of compounds
7c, d, e, f and k were comparable with standard
(ciprofloxacine) against B. subtilis. Compounds 7a and 7g
Synthesis of 2-Cyano-N-subsituted phenyl-5-oxo-5-substituted phen-
exhibited better activity against Gram ꢃve (B. sphaericus) yl-3-(trifluoromethyl or methyl)pentanamides (3a—j) A mixture of
equimolar amounts of 1-(4-chlorophenyl)-4,4,4-trifluorobut-2-en-1-one
(10 mmol) [4,4,4-trifluoro-1-phenyl-2-en-1-one (in case of 3a, e and g) or
1-phenyl-but-2-en-1-one (in case of 3b, h and j) and the corresponding
2-cyano-N-(substituted phenyl)acetamides 2a—j (10 mmol) in absolute
than Gram ꢀve bacteria which are comparable with stan-
dard. Compounds 7d and 7f showed better activity against B.
subtilis. Compounds 7b, 7l, 7m and 7p exhibited moderate
activity against both Gram ꢃve and Gram ꢀve bacteria.
Compounds 7c, g and o were exhibited comparable activity
that of standard against K. pneumonia. Compounds 7b, 7g,
7h, 7i, 7j, 7l and 7m were inactive against Gram ꢀve bacte-
ria (C. violaceum) at the concentration of 100 mg/ml, only 7c
showed better activity against C. violaceum. Compound 7o
showed comparable activity to that of standard against K.
pneumoniae. Compounds 7h and 7n exhibited better activity
against Escherichia coli. Introduction of chlorosubstitution at
7th position of pyridopyrimidine ring found to be increased
antibacterial activity. Replacement of methyl group with tri-
fluoromethyl group at 5th position showed better antibacter-
ial activity. Exchange of electron-releasing substitution with
electron-withdrawing substitution at N-phenyl leads to the
better antibacterial activity. Replacement of ethyl group with
ethanol (20 ml) containing morpholine (3—5 drops) as a basic catalyst was
boiled under reflux for 24 h. The reaction mixture was evaporated until dry-
ness under reduced pressure and the remaining residue was triturated with
methanol (5 ml). So, the separated solid was collected and crystallized from
ethyl acetate–n-hexane mixture.
N-(4-Chlorophenyl)-2-cyano-5-oxo-5-phenyl-3-(trifluoromethyl)pen-
tanamide (3a): Yield: 79 %, mp 203 °C; IR (KBr) cmꢀ1: 3302, 2220, 1720,
1
1685, 1600, 1542. H-NMR (400 MHz, DMSO-d6) d: 3.64 (1H, dd, upfield
H of CH2CH, Jꢁ5.3, 17.5 Hz), 3.76 (1H, dd, downfield H of CH2CH, Jꢁ8.5,
17.5 Hz), 4.33 (1H, d, CH), 4.92 (1H, m, CF3CH), 7.23—7.99 (9H, m, Ar-
H), 10.43 (1H, s, br, NH). EI-MS m/z: 396 (Mꢃꢃ2), 394 (Mꢃ). Anal. Calcd
for C19H14ClF3N2O2 (394.77): C, 57.81; H, 3.57; N, 7.10. Found: C, 57.53;
H, 3.54; N, 7.17.
2-Cyano-N-(4-iodophenyl)-3-methyl-5-oxo-5-phenylpentanamide (3b):
Yield: 83%, mp 224 °C; IR (KBr) cmꢀ1: 3300, 2222, 1722, 1680, 1600,
1
1532. H-NMR (400 MHz, DMSO-d6) d: 1.12 (3H, d, CH3), 3.25 (1H, dd,
upfield H of CH2CH, Jꢁ5.6, 17.8 Hz), 3.52 (1H, dd, downfield H of CH2CH,
Jꢁ8.8, 17.2 Hz), 4.23—4.29 (2H, m, CH2CHꢃCH2CHCH), 7.23—7.99
methyl group at 2nd-position showed decreased antibacterial (9H, m, Ar-H), 10.22 (1H, s, br, NH). EI-MS m/z: 434 (Mꢃꢃ2), 432 (Mꢃ).

September 2008
1345
Anal. Calcd for C19H17IN2O2 (432.25): C, 52.79; H, 3.96; N, 6.48. Found: C,
53.04; H, 4.13; N, 6.72.
5-(4-Chlorophenyl)-2-cyano-N-(4-fluorophenyl)-5-oxo-3-(trifluoro-
2-Bromo-N-(4-chlorophenyl)-6-phenyl-4-(trifluoromethyl)nicotinamide
(4a): Yield: 81%, mp 220 °C; IR (KBr) cmꢀ1: 3272, 3246, 1658, 1600,
1542. 1H-NMR (400 MHz, DMSO-d6) d: 7.12—7.52 (7H, m, Ar-H), 8.16—
methyl)pentanamide (3c): Yield: 88%, mp 184 °C; IR (KBr) cmꢀ1: 3308, 8.18 (2H, m, Ar-H), 8.84 (1H, s, pyr. H-5), 10.62 (1H, s, br, NH). EI-MS
2220, 1728, 1680, 1658, 1610, 1522. 1H-NMR (400 MHz, DMSO-d6) d: m/z: 458 (Mꢃꢃ4), 456 (Mꢃꢃ2), 454 (Mꢃ). Anal. Calcd for
3.52 (1H, dd, upfield H of CH2CH, Jꢁ5.5, 17.5 Hz), 3.78 (1H, dd, downfield C19H11BrClF3N2O (455.65): C, 50.08; H, 2.43; N, 6.15. Found: C, 50.23; H,
H of CH2CH, Jꢁ8.8, 17.5 Hz), 4.34 (1H, d, CH), 4.94 (1H, m, CF3CH), 2.21; N, 6.22.
7.23—7.99 (8H, m, Ar-H), 10.06 (1H, s, br, NH). EI-MS m/z: 414 (Mꢃꢃ2),
2-Bromo-N-(4-iodophenyl)-4-methyl-6-phenylnicotinamide (4b): Yield:
412 (Mꢃ). Anal. Calcd for C19H13ClF4N2O2 (412.76): C, 55.29; H, 3.17; N, 88%, mp 205 °C; IR (KBr) cmꢀ1: 3278, 1660, 1602, 1539. 1H-NMR
6.79. Found: C, 55.48; H, 3.22; N, 6.99.
(400 MHz, DMSO-d6) d: 2.23 (3H, s, CH3), 7.13—7.54 (7H, m, Ar-H), 7.74
5-(4-Chlorophenyl)-2-cyano-5-oxo-N-p-tolyl-3-(trifluoromethyl)pen-
(1H, s, pyr. H-5), 8.14—8.19 (2H, m, Ar-H), 10.43 (1H, s, br, NH). EI-MS
tanamide (3d): Yield: 73%, mp 194 °C; IR (KBr) cmꢀ1: 3302, 2220, 1718, m/z: 494(Mꢃꢃ2), 492 (Mꢃ). Anal. Calcd for C19H14BrIN2O (493.13): C,
1678, 1610, 1522. 1H-NMR (400 MHz, DMSO-d6) d: 1.23 (3H, s, CH3), 50.08; H, 2.43; N, 6.15. Found: C, 50.21; H, 2.24; N, 6.22.
3.54 (1H, dd, upfield H of CH2CH, Jꢁ5.6, 17.4 Hz), 3.81 (1H, dd, downfield
2-Bromo-6-(4-chlorophenyl)-N-(4-fluorophenyl)-4-(trifluoromethyl)-
H of CH2CH, Jꢁ8.5, 17.4 Hz), 4.33 (1H, d, CH), 5.01 (1H, m, CF3CH), nicotinamide (4c): Yield; 82%, mp 212 °C; IR (KBr) cmꢀ1: 3280, 1662,
7.23—7.86 (8H, m, Ar-H), 10.14 (1H, s, br, NH). EI-MS m/z: 410 (Mꢃꢃ2), 1602, 1540. 1H-NMR (400 MHz, DMSO-d6) d: 6.96 (2H, d, Jꢁ8.4 Hz,
408 (Mꢃ). Anal. Calcd for C20H16ClF3N2O2 (408.80): C, 58.76; H, 3.94; N, Ar-H), 7.43 (2H, d, Jꢁ8.4 Hz, Ar-H), 7.76 (2H, d, Jꢁ8.4 Hz, Ar-H), 8.02
6.85. Found: C, 58.42; H, 3.83; N, 6.98.
(2H, d, Jꢁ8.3 Hz, Ar-H), 8.79 (1H, s, pyr. H-5), 10.41 (1H, s, br, NH).
2-Cyano-5-oxo-5-phenyl-3-(trifluoromethyl)-N-[4-(trifluoromethyl)-
EI-MS m/z: 476 (Mꢃꢃ4), 474 (Mꢃꢃ2), 472 (Mꢃ). Anal. Calcd for
phenyl]pentanamide (3e): Yield: 88%, mp 204 °C; IR (KBr) cmꢀ1: 3300, C19H10BrClF4N2O (473.64): C, 48.18; H, 2.13; N, 5.91. Found: C, 48.23; H,
2224, 1730, 1689, 1604, 1548. 1H-NMR (400 MHz, DMSO-d6) d: 3.44 (1H, 2.21; N, 5.74.
dd, upfield H of CH2CH, Jꢁ5.4, 17.7 Hz), 3.78 (1H, dd, downfield H of
2-Bromo-6-(4-chlorophenyl)-N-p-tolyl-4-(trifluoromethyl)nicotinamide
CH2CH, Jꢁ8.6, 17.7 Hz), 4.33 (1H, d, CH), 4.92 (1H, m, CF3CH), 7.23— (4d): Yield: 78%, mp 194 °C; IR (KBr) cmꢀ1: 3284, 1660, 1612, 1540. H-
7.99 (9H, m, Ar-H), 10.41 (1H, s, br, NH). EI-MS m/z: 430 (Mꢃꢃ2), 428 NMR (400 MHz, DMSO-d6) d: 2.14 (3H, s, CH3), 7.21—7.37 (4H, m, Ar-
(Mꢃ); Anal. Calcd for C20H14F6N2O2 (428.32): C, 56.08; H, 3.29; N, 6.54. H), 7.54 (2H, d, Jꢁ8.3 Hz, Ar-H), 7.96 (2H, d, Jꢁ8.5 Hz, Ar-H), 8.81 (1H,
1
Found: C, 56.22; H, 3.24; N, 6.61.
s, pyr. H-5), 10.41 (1H, s, br, NH). EI-MS m/z: 472 (Mꢃꢃ+4), 470 (Mꢃꢃ2),
468 (Mꢃ). Anal. Calcd for C20H13BrClF3N2O (469.68): C, 51.14; H, 2.79; N,
5-(4-Chlorophenyl)-2-cyano-N-(2-methoxyphenyl)-5-oxo-3-(trifluo-
romethyl)pentanamide (3f): Yield: 93%, mp 179 °C; IR (KBr) cmꢀ1: 3302, 5.96. Found: C, 50.96; H, 2.83; N, 5.84.
2222, 1723, 1685, 1601, 1542. 1H-NMR (400 MHz, DMSO-d6) d: 3.64 (1H,
2-Bromo-6-phenyl-4-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]-
dd, upfield H of CH2CH, Jꢁ5.3, 17.5 Hz), 3.76 (1H, dd, downfield H of nicotinamide (4e): Yield: 91%, mp 199 °C; IR (KBr) cmꢀ1: 3270, 3240,
CH2CH, Jꢁ8.5, 17.5 Hz), 3.84 (3H, s, OCH3), 4.33 (1H, d, CH), 4.92 (1H, 1660, 1600, 1542. 1H-NMR (400 MHz, DMSO-d6) d: 7.22—7.46 (7H, m,
m, CF3CH), 7.23—7.99 (8H, m, Ar-H), 10.43 (1H, s, br, NH). EI-MS m/z: Ar-H), 8.26—8.29 (2H, m, Ar-H), 8.83 (1H, s, pyr. H-5), 10.54 (1H, s, br,
426 (Mꢃꢃ2), 424 (Mꢃ). Anal. Calcd for C20H16ClF3N2O3 (424.80): C,
56.55; H, 3.80; N, 6.59. Found: C, 56.62; H, 3.87; N, 6.65.
NH). EI-MS m/z: 490 (Mꢃꢃ2), 488 (Mꢃ). Anal. Calcd for C20H11BrF6N2O
(489.21): C, 49.10; H, 2.27; N, 5.73. Found: C, 49.23; H, 1.98; N, 5.82.
2-Bromo-6-(4-chlorophenyl)-N-(2-methoxyphenyl)-4-(trifluoromethyl)-
2-Cyano-N-[(4-methylthio)phenyl]-5-oxo-5-phenyl-3-(trifluoromethyl)-
pentanamide (3g): Yield: 86%, mp 221 °C; IR (KBr) cmꢀ1: 3306, 2218, nicotinamide (4f): Yield: 73%, mp 224 °C; IR (KBr) cmꢀ1: 3272, 3242,
1728, 1685, 1601, 1542. 1H-NMR (400 MHz, DMSO-d6) d: 3.62 (1H, dd, 1662, 1600, 1544. H-NMR (400 MHz, DMSO-d6) d: 3.26 (3H, s, OCH3),
1
upfield H of CH2CH, Jꢁ5.3, 17.5 Hz), 3.72 (1H, dd, downfield H of CH2CH, 7.16 (2H, m, Ar-H), 7.24 (1H, dd, Jꢁ1.8, 7.9 Hz, Ar-H), 7.42 (1H, dd,
Jꢁ8.5, 17.5 Hz), 3.76 (3H, s, SCH3), 4.32 (1H, d, CH), 4.94 (1H, m, Jꢁ4.5, 7.8 Hz, Ar-H), 7.53 (2H, d, Jꢁ8.4 Hz, Ar-H), 7.96 (2H, d, Jꢁ8.4 Hz,
CF3CH), 7.23—7.99 (9H, m, Ar-H), 10.39 (1H, s, br, NH). EI-MS m/z: 408
Ar-H), 8.81 (1H, s, pyr. H-5), 10.46 (1H, s, br, NH). EI-MS m/z: 488
(Mꢃꢃ2), 406 (Mꢃ). Anal. Calcd for C20H17F3N2O2S (406.42): C, 59.10; H, (Mꢃꢃ4), 486 (Mꢃꢃ2), 484 (Mꢃ). Anal. Calcd for C20H13BrClF3N2O2
4.22; N, 6.89. Found: C, 59.18; H, 4.14; N, 7.04.
(485.68): C, 49.46; H, 2.70; N, 5.77. Found: C, 49.55; H, 2.79; N, 5.82.
2-Cyano-3-methyl-5-oxo-5-phenyl-N-o-tolylpentanamide (3h): Yield:
2-Bromo-N-[4-(methylthio)phenyl]-6-phenyl-4-(trifluoromethyl)nicoti-
1
92%, mp 175 °C; IR (KBr) cmꢀ1: 3302, 2220, 1721, 1678, 1610, 1522. H-
namide (4g): Yield: 86%, mp 206 °C; IR (KBr) cmꢀ1: 3270, 3240, 1660,
1
NMR (400 MHz, DMSO-d6) d: 1.24 (3H, d, CH3), 3.54 (1H, dd, upfield H of 1600, 1542. H-NMR (400 MHz, DMSO-d6) d: 3.42 (3H, s, SCH3), 7.23—
CH2CH, Jꢁ5.6, 17.4 Hz), 3.81 (1H, dd, downfield H of CH2CH, Jꢁ8.5, 7.45 (7H, m, Ar-H), 8.26—8.29 (2H, m, Ar-H), 8.81 (1H, s, pyr. H-5), 10.52
17.4 Hz), 4.23 (1H, m, CH), 4.31 (1H, d, CH), 7.23—7.86 (9H, m, Ar-H), (1H, s, br, NH). EI-MS m/z: 470 (Mꢃꢃ4), 468 (Mꢃꢃ2), 466 (Mꢃ). Anal.
10.10 (1H, s, br, NH). EI-MS m/z: 320 (Mꢃ). Anal. Calcd for C20H20N2O2 Calcd for C20H14BrF3N2OS (467.30): C, 51.40; H, 3.02; N, 5.99. Found: C,
(320.38): C, 74.98; H, 6.29; N, 8.74. Found: C, 74.82; H, 6.37; N, 8.88.
51.23; H, 3.06; N, 6.34.
5-(4-Chlorophenyl)-2-cyano-N-(3,5-dimethylphenyl)-5-oxo-3-(trifluo-
2-Bromo-4-methyl-6-phenyl-N-o-tolylnicotinamide (4h): Yield: 83%, mp
romethyl)pentanamide (3i): Yield: 81%, mp 184 °C; IR (KBr) cmꢀ1: 3302, 224 °C; IR (KBr) cmꢀ1: 3274, 1662, 1602, 1540. 1H-NMR (400 MHz,
2220, 1712, 1678, 1610, 1522. 1H-NMR (400 MHz, DMSO-d6) d: 1.28 (6H, DMSO-d6) d: 2.13 (3H, s, CH3), 2.22 (3H, s, CH3), 7.13—7.54 (9H, m, Ar-
s, CH3), 3.54 (1H, dd, upfield H of CH2CH, Jꢁ5.6, 17.4 Hz), 3.81 (1H, dd, H), 7.74 (1H, s, pyr. H-5), 10.43 (1H, s, br, NH). EI-MS m/z: 384 (Mꢃꢃ4),
downfield H of CH2CH, Jꢁ8.5, 17.4 Hz), 4.33 (1H, d, CH), 5.01 (1H, m, 382 (Mꢃꢃ2), 380 (Mꢃ). Anal. Calcd for C20H17BrN2O (381.26): C, 63.00;
CF3CH), 7.23—7.86 (7H, m, Ar-H), 10.14 (1H, s, br, NH). EI-MS m/z: 424 H, 4.49; N, 7.35. Found: C, 63.33; H, 4.25; N, 7.69.
(Mꢃꢃ2), 422 (Mꢃ). Anal. Calcd for C21H18ClF3N2O2 (422.82): C, 59.65; H,
2-Bromo-6-(4-chlorophenyl)-N-(3,5-dimethylphenyl)-4-(trifluoromethyl)-
4.29; N, 6.63. Found: C, 59.83; H, 4.57; N, 6.52.
nicotinamide (4i): Yield: 79%, mp 194 °C; IR (KBr) cmꢀ1: 3280, 1664,
2-Cyano-N-(3,4-dimethoxyphenyl)-3-methyl-5-oxo-5-phenylpentanamide 1610, 1540. 1H-NMR (400 MHz, DMSO-d6) d: 2.24 (6H, s, CH3), 7.22—
(3j): Yield: 83%, mp 224 °C; IR (KBr) cmꢀ1: 3302, 2220, 1720, 1678, 1610, 7.39 (3H, m, Ar-H), 7.54 (2H, d, Jꢁ8.3 Hz, Ar-H), 7.96 (2H, d, Jꢁ8.5 Hz,
1
1522. H-NMR (400 MHz, DMSO-d6) d: 1.22 (3H, d, CH3), 3.52 (1H, dd, Ar-H), 8.81 (1H, s, pyr. H-5), 10.41 (1H, s, NH). EI-MS m/z: 486 (Mꢃꢃ4),
upfield H of CH2CH, Jꢁ5.6, 17.4 Hz), 3.79 (1H, dd, downfield H of CH2CH,
484 (Mꢃꢃ2), 482 (Mꢃ). Anal. Calcd for C21H15BrClF3N2O (483.71): C,
Jꢁ8.5, 17.4 Hz), 3.89 (6H, s, OCH3), 4.23 (1H, m, CH), 4.31 (1H, d, CH), 52.14; H, 3.13; N, 5.79. Found: C, 52.36; H, 3.23; N, 5.66.
7.23—7.86 (8H, m, Ar-H), 10.12 (1H, s, br, NH). EI-MS m/z: 366 (Mꢃ).
2-Bromo-N-(3,4-dimethoxyphenyl)-4-methyl-6-phenylnicotinamide (4j):
Anal. Calcd for C21H22N2O4 (366.41): C, 68.84; H, 6.05; N, 7.65. Found: C, Yield: 85%, mp 214 °C; IR (KBr) cmꢀ1: 3274, 1662, 1602, 1540. H-NMR
68.62; H, 6.17; N, 7.73.
1
(400 MHz, DMSO-d6) d: 2.14 (3H, s, CH3), 3.82 (6H, s, OCH3),6.98—7.02
Synthesis of 2-Bromo-N,6-substituted phenyl-4-(trifluoromethyl or (3H, m, Ar-H), 7.39—7.44 (5H, m, Ar-H), 7.72 (1H, s, pyr. H-5), 10.40 (1H,
methyl)nicotinamide (4a—j) To a solution of the appropriate 3a—j s, br, NH). EI-MS m/z: 430 (Mꢃꢃ4), 428 (Mꢃꢃ2), 426 (Mꢃ). Anal. Calcd
(10 mmol) in glacial acetic acid (30 ml), heated at 70—80 °C, a solution of
for C21H19BrN2O3 (427.29): C, 57.98; H, 4.38; N, 6.76. Found: C, 57.84; H,
bromine (11 mmol) in glacial acetic acid (10 ml) was added dropwise while 4.25; N, 6.83.
stirring, at such a rate maintaining the same temperature for 30 min. After
complete addition, stirring was continued for 4 h at the same temperature.
Synthesis of 2-Amino-N,6-substituted phenyl-4-(trifluoromethyl or
methyl)nicotinamide 5a—j and N,6-substituted phenyl-2-(phenyl-
The separated solid was collected and purified by column chromatography amino)-4-(trifluoromethyl or methyl)nicotinamide 6a—j. Method A
using silica gel (60—120 mesh) and the desired product was eluted with
Solution of 4a—j (10 mmol) and primary aromatic amine (aniline)
ethyl acetate–n-hexane as mobile phase.
(20 mmol) in pyridine (40 ml) was boiled under reflux for 3 d. The solid sep-

1346
Vol. 56, No. 9
arated upon pouring the reaction mixture into water (400 ml) and acidifica- nicotinamide (5i): Yield: method A: 30% and method B: 50%, mp 218 °C;
1
tion with dil HCl (5%), was collected and washed with water. Then, it was IR (KBr) cmꢀ1: 3498, 3382, 3256, 1648, 1602, 1546. H-NMR (400 MHz,
purified by column chromatography using silica gel (60—120 mesh) and the DMSO-d6) d: 2.21 (6H, s, CH3), 6.16 (2H, s, br, NH2), 7.22—7.41 (3H, m,
desired product was eluted with ethyl acetate–n-hexane as mobile phase. Ar-H), 7.53 (2H, d, Jꢁ8.3 Hz, Ar-H), 7.94 (2H, d, Jꢁ8.5 Hz, Ar-H), 8.80
The resulted products were characterized as 5a—j and 6a—j.
Method mixture of 2-amino-4,6-substituted nicotinic acid
(1H, s, pyr. H-5), 10.32 (1H, s, br, NH). EI-MS m/z: 421 (Mꢃꢃ2), 419(Mꢃ).
Anal. Calcd for C21H17ClF3N3O (419.82): C, 60.08; H, 4.08; N, 10.01.
B
A
(10 mmol), substituted arylamine (10 mmol), N-hydroxybenzotriazole Found: C, 60.21; H, 4.28; N, 10.06.
(HOBt, 4 mmol) and EDC (12 mmol) in freshly distilled DCM (80 ml) was
2-Amino-N-(3,4-dimethoxyphenyl)-4-methyl-6-phenylnicotinamide (5j):
allowed to stir at room temperature for 24 h. The reaction mixture was suc- Yield: method A: 38% and method B: 70%, mp 172 °C; IR (KBr) cmꢀ1
:
cessively washed with water (20 ml), 10% NaOH (20 ml), water (20 ml), 3498, 3382, 3256, 1648, 1602, 1546. 1H-NMR (400 MHz, DMSO-d6) d:
brine (20 ml) and dried over anhydrous Na2SO4. The solvent was evaporated 2.12 (3H, s, CH3), 3.84 (6H, s, OCH3), 6.19 (2H, s, br, NH2), 6.98—7.27
under reduced pressure to get dryness and the product was purified by col-
umn chromatography using ethyl acetate–n-hexane as mobile phase.
(3H, m, Ar-H), 7.39—7.44 (5H, m, Ar-H), 7.72 (1H, s, pyr. H-5), 10.40 (1H,
s, br, NH). EI-MS m/z: 363 (Mꢃ). Anal. Calcd for C21H21N3O3 (363.41): C,
2-Amino-N-(4-chlorophenyl)-6-phenyl-4-(trifluoromethyl) nicotinamide 69.41; H, 5.82; N,11.56. Found: C, 69.64; H, 5.75; N, 11.43.
(5a): Yield: method A: 28% and method B: 65%, mp 189 °C; IR (KBr)
N-(4-Chlorophenyl)-6-phenyl-2-(phenylamino)-4-(trifluoromethyl)nico-
cmꢀ1: 3490, 3393, 3249, 1650, 1600, 1542. 1H-NMR (400 MHz, DMSO-d6) tinamide (6a): Yield: 68%, mp 198 °C; IR (KBr) cmꢀ1: 3390, 1662, 1610,
d: 6.18 (2H, s, br, NH2), 7.23—7.56 (7H, m, Ar-H), 8.10—8.16 (2H, m, Ar- 1551, 1270, 710. 1H-NMR (400 MHz, DMSO-d6) d: 7.18—7.52 (12H, m,
H), 8.81 (1H, s, pyr. H-5), 10.32 (1H s, br, NH). EI-MS m/z: 393 (Mꢃꢃ2), Ar-H), 8.12—8.18 (2H, m, Ar-H), 8.83 (1H, s, pyr. H-5), 9. 43 (2H, s, NH).
391 (Mꢃ). Anal. Calcd for C19H13ClF3N3O (391.77): C, 58.25; H, 3.34; N, EI-MS m/z: 469 (Mꢃꢃ2), 467 (Mꢃ). Anal. Calcd for C25H17ClF3N3O
10.73. Found: C, 58.32; H, 3.28; N, 10.89.
(467.87): C, 64.18; H, 3.66; N, 8.98. Found: C, 64.42; H, 3.58; N, 8.84.
2-Amino-N-(4-iodophenyl)-4-methyl-6-phenylnicotinamide (5b): Yield:
N-(4-Iodophenyl)-4-methyl-6-phenyl-2-(phenylamino)nicotinamide (6b):
method A: 25% and method B: 57%, mp 176 °C; IR (KBr) cmꢀ1: 3486, Yield: 74%, mp 194 °C; IR (KBr) cmꢀ1: 3384, 1653, 1614, 1555, 1265, 705.
3390, 3250, 1653, 1603, 1542. 1H-NMR (400 MHz, DMSO-d6) d: 2.19 (3H, 1H-NMR (400 MHz, DMSO-d6) d: 2.22 (3H, s, CH3), 7.19—7.94 (12H, m,
s, CH3), 6.20 (2H, s, br, NH2), 7.15—7.94 (7H, m, Ar-H), 7.72 (1H, s, pyr. Ar-H), 7.74 (1H, s, pyr. H-5), 8.15—8.21 (2H, m, Ar-H), 9.42 (2H, s, NH).
H-5), 8.15—8.21 (2H, m, Ar-H), 10.38 (1H, s, br, NH). EI-MS m/z: 431 EI-MS m/z: 505 (Mꢃ). Anal. Calcd for C25H20IN3O (505.35): C, 59.42; H,
(Mꢃꢃ2), 429 (Mꢃ). Anal. Calcd for C19H16IN3O (429.25): C, 53.16; H, 3.99; N, 8.32. Found: C, 59.24; H, 3.82; N, 8.29.
3.76; N, 9.79. Found: C, 53.27; H, 3.92; N, 9.91.
6-(4-Chlorophenyl)-N-(4-fluorophenyl)-2-(phenylamino)-4-(trifluoro-
2-Amino-6-(4-chlorophenyl)-N-(4-fluorophenyl)-4-(trifluoromethyl)nico-
tinamide (5c): Yield: method A: 39% and method B: 68%, mp 212 °C; IR
(KBr) cmꢀ1: 3491, 3386, 3252, 1646, 1599, 1538. 1H-NMR (400 MHz,
DMSO-d6) d: 6.22 (2H, s, br, NH2), 6.89 (2H, d, Jꢁ8.5 Hz, Ar-H), 7.40 (2H,
d, Jꢁ8.3 Hz, Ar-H), 7.73 (2H, d, Jꢁ8.3 Hz, Ar-H), 8.08 (2H, d, Jꢁ8.3 Hz,
methyl)nicotinamide (6c): Yield: 50%, mp 230 °C; IR (KBr) cmꢀ1: 3384,
1
1653, 1614, 1555, 1265, 705. H-NMR (400 MHz, DMSO-d6) d: 6.86 (2H,
d, Jꢁ8.5 Hz, Ar-H), 7.21—7.24 (5H, m, Ar-H), 7.40 (2H, d, Jꢁ8.3 Hz, Ar-
H), 7.73 (2H, d, Jꢁ8.3 Hz, Ar-H), 8.09 (2H, d, Jꢁ8.3 Hz, Ar-H), 8.82 (1H,
s, pyr. H-5), 9.46 (2H, s, NH). EI-MS m/z: 487 (Mꢃꢃ2), 485 (Mꢃ). Anal.
Ar-H), 8.81 (1H, s, pyr. H-5), 10.38 (1H, s, br, NH). EI-MS m/z: 411 Calcd for C25H16ClF4N3O (485.86): C, 61.80; H, 3.32; N, 8.65. Found: C,
(Mꢃꢃ2), 409 (Mꢃ). Anal. Calcd for C19H12ClF4N3O (409.76): C, 55.69; H, 61.96; H, 3.21; N, 8.52.
2.95; N, 10.25. Found: C, 55.86; H, 2.98; N, 10.58.
2-Amino-6-(4-chlorophenyl)-N-p-tolyl-4-(trifluoromethyl)nicotinamide
(5d): Yield: method A: 36% and method B: 65%, mp 220 °C; IR (KBr)
6-(4-Chlorophenyl)-2-(phenylamino)-N-p-tolyl-4-(trifluoromethyl)nico-
tinamide (6d): Yield: 62%, mp 236 °C; IR (KBr) cmꢀ1: 3360, 1663, 1614,
1555, 1254, 712. 1H-NMR (400 MHz, DMSO-d6) d: 2.14 (3H, s, CH3),
cmꢀ1: 3494, 3381, 3262, 1649, 1597, 1541. 1H-NMR (400 MHz, DMSO-d6) 7.19—7.42 (9H, m, Ar-H), 7.51 (2H, d, Jꢁ8.4 Hz, Ar-H), 7.94 (2H, d,
d: 2.12 (3H, s, CH3), 6.24 (2H, s, br, NH2), 7.19—7.42 (4H, m, Ar-H), 7.51 Jꢁ8.5 Hz, Ar-H), 8.80 (1H, s, pyr. H-5), 9.43 (2H, s, NH). EI-MS m/z: 483
(2H, d, Jꢁ8.4 Hz, Ar-H), 7.94 (2H, d, Jꢁ8.5 Hz, Ar-H), 8.80 (1H, s, pyr. H- (Mꢃꢃ2), 481 (Mꢃ). Anal. Calcd for C26H19ClF3N3O (481.89): C, 64.80; H,
5), 10.31 (1H, s, br, NH). EI-MS m/z: 407 (Mꢃꢃ2), 405 (Mꢃ). Anal. Calcd 3.97; N, 8.72. Found: C, 64.82; H, 4.13; N, 8.62.
for C20H15ClF3N3O (405.80): C, 59.20; H, 3.73; N, 10.35. Found: C, 59.43;
H, 3.64; N, 10.59.
6-Phenyl-2-(phenylamino)-4-(trifluoromethyl)-N-[4-(trifluoromethyl)-
phenyl]nicotinamide (6e): Yield: 62%, mp 224 °C; IR (KBr) cmꢀ1 : 3362,
1672, 1621, 1552, 1250, 710. 1H-NMR (400 MHz, DMSO-d6) d: 7.19—7.49
(12H, m, Ar-H), 8.21—8.28 (2H, m, Ar-H), 8.79 (1H, s, pyr. H-5), 9.45 (2H,
s, NH). EI-MS m/z: 501 (Mꢃ). Anal. Calcd for C26H17F6N3O (501.42): C,
2-Amino-6-phenyl-4-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]-
nicotinamide (5e): Yield: method A: 32% and method B: 72%, mp 208 °C;
1
IR (KBr) cmꢀ1: 3490, 3378, 3260, 1653, 1599, 1544. H-NMR (400 MHz,
DMSO-d6) d: 6.21 (2H, s, br, NH2), 7.21—7.49 (7H, m, Ar-H), 8.23—8.26 62.28; H, 3.42; N, 8.38 Found: C, 62.41; H, 3.54; N, 8.18.
(2H, m, Ar-H), 8.81 (1H, s, pyr. H-5), 10.31 (1H, s, br, NH). EI-MS m/z: 425
6-(4-Chlorophenyl)-N-(2-methoxyphenyl)-2-(phenylamino)-4-(trifluo-
(Mꢃ). Anal. Calcd for C20H13F6N3O (425.32): C, 56.43; H, 3.08; N, 9.88. romethyl)nicotinamide (6f): Yield: 60%, mp 218 °C; IR (KBr) cmꢀ1: 3352,
1
Found: C, 56.29; H, 2.94; N, 9.98.
1668, 1612, 1552, 1258, 706. H-NMR (400 MHz, DMSO-d6) d: 3.27 (3H,
s, OCH3), 7.14—7.19 (7H, m, Ar-H), 7.25 (1H, dd, Jꢁ1.6, 7.8 Hz, Ar-H),
7.40 (1H, dd, Jꢁ4.6, 7.6 Hz, Ar-H), 7.54 (2H, d, Jꢁ8.5 Hz, Ar-H), 7.91 (2H,
d, Jꢁ8.3Hz, Ar-H), 8.79 (1H, s, pyr. H-5), 9.59 (2H, s, NH). EI-MS m/z: 499
2-Amino-6-(4-chlorophenyl)-N-(2-methoxyphenyl)-4-(trifluoromethyl)-
nicotinamide (5f): Yield: method A: 36% and method B: 69%, mp 202 °C;
1
IR (KBr) cmꢀ1: 3494, 3382, 3262, 1646, 1602, 1542. H-NMR (400 MHz,
DMSO-d6) d: 3.26 (3H, s, OCH3), 6.23 (2H, s, br, NH2), 7.14 (2H, m, Ar- (Mꢃꢃ2), 497 (Mꢃ). Anal. Calcd for C26H19ClF3N3O2 (497.89): C, 62.72; H,
H), 7.26 (1H, dd, Jꢁ1.6, 7.8 Hz, Ar-H), 7.41 (1H, dd, Jꢁ4.6, 7.6 Hz, Ar-H), 3.85; N, 8.44. Found: C, 62.62; H, 3.72; N, 8.26.
7.55 (2H, d, Jꢁ8.5 Hz, Ar-H), 7.93 (2H, d, Jꢁ8.3Hz, Ar-H), 8.80 (1H, s,
N-[4-(Methylthio)phenyl]-6-phenyl-2-(phenylamino)-4-(trifluoromethyl)-
pyr. H-5), 10.31 (1H, s, br, NH); EI-MS m/z: 423 (Mꢃꢃ2), 421 (Mꢃ). Anal.
nicotinamide (6g): Yield: 71%, mp 210 °C; IR (KBr) cmꢀ1: 3352, 2254,
Calcd for C20H15ClF3N3O2 (421.8): C, 56.95; H, 3.58; N, 9.96. Found: C, 1668, 1612, 1552, 1258. 1H-NMR (400 MHz, DMSO-d6) d: 3.37 (3H, s,
57.15; H, 3.72; N, 9.88.
SCH3), 7.19—7.45 (12H, m, Ar-H), 8.22—8.28 (2H, m, Ar-H), 8.76 (1H, s,
pyr. H-5), 9.46 (2H, s, NH ). EI-MS m/z: 481 (Mꢃꢃ2), 479 (Mꢃ). Anal.
Calcd for C26H20F3N3OS (479.51): C, 65.12; H, 4.20; N, 8.76. Found: C,
65.33; H, 4.51; N, 8.81.
2-Amino-N-[4-(methylthio)phenyl]-6-phenyl-4-(trifluoromethyl)nico-
tinamide (5g): Yield: method A: 27% and method B: 69%, mp 181 °C; IR
(KBr) cmꢀ1: 3492, 3378, 3260, 2250,1650, 1602, 1541. 1H-NMR (400 MHz,
DMSO-d6) d: 3.39 (3H, s, SCH3), 6.15 (2H, s, br, NH2), 7.22—7.45 (7H m,
2-Amino-4-methyl-6-phenyl-N-o-tolyl nicotinamide (6h): Yield: 61%, mp
Ar-H), 8.22—8.28 (2H, m, Ar-H), 8.78 (1H, s, pyr. H-5), 10.30 (1H, s, br, 184 °C; IR (KBr) cmꢀ1: 3364, 1671, 1622, 1555. 1H-NMR (400 MHz,
NH). EI-MS m/z: 405 (Mꢃꢃ2), 403 (Mꢃ). Anal. Calcd for C20H16F3N3OS
DMSO-d6) d: 1.24 (3H, s, CH3), 2.22 (3H, s, CH3), 7.15—7.54 (14H, m, Ar-
(403.42): C, 59.54; H, 4.00; N, 10.42. Found: C, 59.24; H, 4.26; N, 10.22.
H), 7.65 (1H, s, pyr. H-5), 9.49 (2H, s, NH). EI-MS m/z: 393 (Mꢃ). Anal.
2-Amino-4-methyl-6-phenyl-N-o-tolyl nicotinamide (5h): Yield: method Calcd for C26H23N3O (393.48): C, 79.36; H, 5.89; N, 10.68. Found: C,
A: 37% and method B: 52%, mp 172 °C; IR (KBr) cmꢀ1: 3498, 3382, 3256, 79.49; H, 6.01; N, 10.41.
1648, 1602, 1546. 1H-NMR (400 MHz, DMSO-d6) d: 1.96 (3H, s, CH3),
2-Amino-6-(4-chlorophenyl)-N-(3,5-dimethylphenyl)-4-(trifluoromethyl)-
2.19 (3H, s, CH3), 6.18 (2H, s, br, NH2), 7.15—7.54 (9H, m, Ar-H), 7.69 nicotinamide (6i): Yield: 69%, mp 221 °C; IR (KBr) cmꢀ1: 3362, 1659,
(1H, s, pyr. H-5), 10.29 (1H, s, br, NH). EI-MS m/z: 317 (Mꢃ). Anal. Calcd 1625, 1555, 1268, 752. 1H-NMR (400 MHz, DMSO-d6) d: 2.19 (6H, s,
for C20H19N3O (317.38): C, 75.69; H, 6.03; N, 13.24. Found: C, 75.61; H, CH3), 7.24—7.41 (8H, m, Ar-H), 7.53 (2H, d, Jꢁ8.3 Hz, Ar-H), 7.93 (2H, d,
6.29; N, 13.12.
Jꢁ8.5 Hz, Ar-H), 8.79 (1H, s, pyr. H-5), 9.41 (2H, s, NH). EI-MS m/z: 497
2-Amino-6-(4-chlorophenyl)-N-(3,5-dimethylphenyl)-4-(trifluoromethyl)- (Mꢃꢃ2), 495(Mꢃ). Anal. Calcd for C27H21ClF3N3O (495.92): C, 65.39; H,

September 2008
1347
4.27; N, 8.47. Found: C, 65.54; H, 4.58; N, 8.69.
2-Ethyl-5-methyl-7-phenyl-3-o-tolyl pyrido[2,3-d]pyrimidin-4(3H)-one
2-Amino-N-(3,4-dimethoxyphenyl)-4-methyl-6-phenylnicotinamide (6j): (7h): Yield: 82%, mp 280 °C; IR (KBr) cmꢀ1: 3054, 2978, 1681, 1586,
Yield: 60%, mp 202 °C; IR (KBr) : 3352, 1675, 1622, 1555 cmꢀ1. 1H-NMR 1492, 1248, 788. H-NMR (400 MHz, DMSO-d6) d: 1.19 (3H, t, Jꢁ7.4 Hz,
1
(400 MHz, DMSO-d6) d: 2.14 (3H, s, CH3), 3.85 (6H, s, OCH3), 6.98—7.27 CH3), 2.16 (3H, s, CH3), 2.22 (2H, q, Jꢁ8.4 Hz, CH2), 2.49 (3H, s, CH3),
(3H, m, Ar-H), 7.39—7.44 (10H, m, Ar-H), 7.72 (1H, s, pyr. H-5), 9.42 (2H, 7.24—7.44 (9H, m, Ar-H), 7.82 (1H, s, H-6). EI-MS m/z: 355 (Mꢃ). Anal.
s, NH). EI-MS m/z: 439 (Mꢃ). Anal. Calcd for C27H25N3O3 (439.50): C,
73.78; H, 5.73; N, 9.56. Found: C, 73.52; H, 5.83; N, 9.67.
Calcd for C23H21N3O (355.17): C, 77.77; H, 5.96; N, 11.82. Found: C,
77.94; H, 5.84; N, 12.02.
2,3,7-Substituted-5-(trifluoromethyl or mrthyl)pyrido[2,3-d]pyrimi-
din-4(3H)-one. General Procedure To a solution or slurry of the substi-
7-(4-Chlorophenyl)-3-(3,5-dimethylphenyl)-2-ethyl-5-(trifluoromethyl)-
pyrido[2,3-d]pyrimidin-4(3H)-one (7i): Yield: 92%, mp 288 °C; IR (KBr)
tuted 2-aminonicotinamide (10 mmol) in triethylorthopropionate (80 mmol) cmꢀ1: 3068, 2988, 1683, 1603, 1422, 1270, 708. 1H-NMR (400 MHz,
[or triethyl orthoacetaqte (80 mmol) in case of k—p] was added glacial DMSO-d6) d: 1.21 (3H, t, Jꢁ7.3 Hz, CH3), 2.15 (6H, s, CH3), 2.32 (2H, q,
acetic acid (20 mmol). The mixture was heated to 90 °C for 7 h at which time Jꢁ8.4 Hz, CH2), 7.07 (2H, s, Ar-H), 7.18 (1H, s, Ar-H), 7.42 (2H, d,
the HPLC analysis revealed full consumption of starting material. The mix- Jꢁ8.5 Hz, Ar-H), 7.98 (2H, d, Jꢁ8.5 Hz, Ar-H), 8.82 (1H, s, H-6). EI-MS
ture was diluted with aq 1 M HCl (10 ml) and stirred for 20 min. The reaction
mixture was made basic by the addition of concd NH4OH and extracted with 62.96; H, 4.18; N, 9.18. Found: C, 63.25; H, 3.94; N, 8.92.
m/z: 459(Mꢃꢃ2), 457 (Mꢃ). Anal. Calcd for C24H19ClF3N3O (457.88): C,
dichloromethane (5ꢄ15 ml). The organic layers were combined, dried,
3-(3,4-Dimethoxyphenyl)-2-ethyl-5-methyl-7-phenylpyrido[2,3-d]pyrim-
filtered and concentrated in vacuo. Silica gel chromatography of the crude idin-4(3H)-one (7j): Yield: 84%, mp 296 °C; IR (KBr) cmꢀ1: 2978, 2844,
material (hexane–ethylacetate, 30 : 70) afforded the desired substituted 1681, 1586, 1492. 1H-NMR (400 MHz, DMSO-d6) d: 1.21 (3H, t, Jꢁ7.5 Hz,
pyrido[2,3-d]pyrimidines.
CH3), 1.99 (3H, s, CH3), 2.20 (2H, q, Jꢁ8.3 Hz, CH2), 3.86 (6H, s, OCH3),
3-[4-Chlorophenyl]-2-ethyl-7-phenyl-5-(trifluoromethyl)pyrido[2,3-
6.98—7.02 (3H, m, Ar-H), 7.39—7.44 (5H, m, Ar-H), 7.80 (1H, s, H-6). EI-
d]pyrimidin-4(3H)-one (7a): Yield: 80%, mp 331 °C; IR (KBr) cmꢀ1: 3070, MS m/z: 401 (Mꢃ). Anal. Calcd for C24H23N3O3 (401.17): C, 71.80; H, 5.77;
2996, 1678, 1600, 1425, 1270, 750. 1H-NMR (400 MHz, DMSO-d6) d: 1.24 N, 10.47. Found: C, 71.94; H, 5.54; N, 10.39.
(3H, t, Jꢁ7.6 Hz, CH3), 2.42 (2H, q, Jꢁ8.5 Hz, CH2), 7.24 (5H, m, Ar-H),
7.44 (2H, d, Jꢁ8.6 Hz, Ar-H), 7.98 (2H, d, Jꢁ8.6 Hz, Ar-H), 8.92 (1H, s, H-
7-(4-Chlorophenyl)-3-(4-fluorophenyl)-2-methyl-5-(trifluoromethyl)-
pyrido[2,3-d]pyrimidin-4(3H)-one (7k): Yield: 90%, mp 300 °C; IR (KBr)
6). EI-MS m/z: 431 (Mꢃꢃ2), 429 (Mꢃ). Anal. Calcd for C22H15ClF3N3O cmꢀ1: 3068, 2998, 1675, 1603, 1422, 1270, 768. 1H-NMR (400 MHz,
(429.82): C, 61.48; H, 3.52; N, 9.78. Found: C, 61.72; H, 3.22; N, 9.94.
DMSO-d6) d: 2.19 (3H, s, CH3), 6.98 (2H, d, Jꢁ8.5 Hz, Ar-H), 7.42 (2H, d,
Jꢁ8.3 Hz, Ar-H), 7.78 (2H, d, Jꢁ8.5 Hz, Ar-H), 8.02 (2H, d, Jꢁ8.3 Hz, Ar-
2-Ethyl-3-[4-iodophenyl]-5-methyl-7-phenyl pyrido[2,3-d]pyrimidin-4(3H)-
one (7b): Yield: 78%, mp 315 °C; IR (KBr) cmꢀ1: 3062, 2986, 1674, 1606, H), 8.82 (1H, s, H-6). EI-MS m/z: 435 (Mꢃꢃ2), 433 (Mꢃ). Anal. Calcd for
1
1432. H-NMR (400 MHz, DMSO-d6) d: 1.26 (3H, t, Jꢁ7.4 Hz, CH3), 1.92 C21H12ClF4N3O (433.06): C, 58.14; H, 2.79; N, 9.69. Found: C, 58.28; H,
(3H, s, CH3), 2.88 (2H, q, Jꢁ8.2 Hz, CH2), 7.26 (5H, m, Ar-H), 7.42 (2H, d, 2.83; N, 9.56.
Jꢁ8.4 Hz, Ar-H), 7.81 (1H, s, H-6), 7.98 (2H, d, Jꢁ8.2 Hz, Ar-H). EI-MS
7-(4-Chlorophenyl)-2-methyl-3-p-tolyl-5-(trifluoromethyl)pyrido[2,3-
m/z: 467 (Mꢃ). Anal. Calcd for C22H18IN3O (467.05): C, 56.54; H, 3.88; N, d]pyrimidin-4(3H)-one (7l): Yield: 96%, mp 310 °C; IR (KBr) cmꢀ1: 3068,
8.99. Found: C, 56.72; H, 3.84; N, 9.06.
7-(4-Chlorophenyl)-2-ethyl-3-(4-fluorophenyl)-5-(trifluoromethyl)-
2988, 1678, 1603, 1422, 1270, 778. 1H-NMR (400 MHz, DMSO-d6) d: 2.12
(3H, s, CH3), 2.26 (3H, s, CH3), 7.24—7.36 (4H, m, Ar-H), 7.52 (2H, d,
pyrido[2,3-d]pyrimidin-4(3H)-one (7c): Yield: 92%, mp 306 °C; IR (KBr) Jꢁ8.3 Hz, Ar-H), 7.98 (2H, d, Jꢁ8.5 Hz, Ar-H), 8.79 (1H, s, H-6). EI-MS
cmꢀ1: 3068, 2998, 1675, 1603, 1422, 1268, 768. 1H-NMR (400 MHz, m/z: 431 (Mꢃꢃ2), 429 (Mꢃ). Anal. Calcd for C22H15ClF3N3O (429.09): C,
DMSO-d6) d: 1.19 (3H, t, Jꢁ7.8 Hz, CH3), 2.52 (2H, q, Jꢁ8.3 Hz, CH2), 61.48; H, 3.52; N, 9.78. Found: C, 61.66; H, 3.44; N, 9.62.
6.98 (2H, d, Jꢁ8.5 Hz, Ar-H), 7.42 (2H, d, Jꢁ8.3 Hz, Ar-H), 7.78 (2H, d,
Jꢁ8.5 Hz, Ar-H), 8.02 (2H, d, Jꢁ8.3 Hz, Ar-H), 8.82 (1H, s, H-6). EI-MS
m/z: 449 (Mꢃꢃ2), 447 (Mꢃ). Anal. Calcd for C22H14ClF4N3O (447.08): C,
59.01; H, 3.15; N, 9.38. Found: C, 59.08; H, 3.22; N, 9.56.
7-(4-Chlorophenyl)-3-(2-methoxyphenyl)-2-methyl-5-(trifluoromethyl)-
pyrido[2,3-d]pyrimidin-4(3H)-one (7m): Yield: 81%, mp 282 °C; IR (KBr)
cmꢀ1: 2978, 2844, 1678, 1586, 1492, 1248, 788. 1H-NMR (400 MHz,
DMSO-d6) d: 2.23 (3H, s, CH3), 3.76 (3H, s, OCH3), 7.14 (2H, m, Ar-H),
7.22 (1H, dd, Jꢁ1.8, 7.9 Hz, Ar-H), 7.44 (1H, dd, Jꢁ4.5, 7.8 Hz, Ar-H),
7-(4-Chlorophenyl)-2-ethyl-3-p-tolyl-5-(trifluoromethyl)pyrido[2,3-
d]pyrimidin-4(3H)-one (7d): Yield: 94%, mp 312 °C; IR (KBr) cmꢀ1: 3068, 7.52 (2H, d, Jꢁ8.4 Hz, Ar-H), 7.98 (2H, d, Jꢁ8.4 Hz, Ar-H), 8.82 (1H, s, H-
2988, 1678, 1603, 1422, 1269, 778. 1H-NMR (400 MHz, DMSO-d6) d: 1.22
6). EI-MS m/z: 447 (Mꢃꢃ2), 445 (Mꢃ). Anal. Calcd for C22H15ClF3N3O2
(3H, t, Jꢁ7.6 Hz, CH3), 1.56 (3H, s, CH3), 2.42 (2H, q, Jꢁ8.5 Hz, CH2), (445.08): C, 59.27; H, 3.39; N, 9.43. Found: C, 58.98; H, 3.48; N, 9.63.
7.24—7.36 (4H, m, Ar-H), 7.52 (2H, d, Jꢁ8.3 Hz, Ar-H), 7.98 (2H, d,
2,5-Dimethyl-7-phenyl-3-o-tolyl pyrido[2,3-d]pyrimidin-4(3H)-one (7n):
Jꢁ8.5 Hz, Ar-H), 8.79 (1H, s, H-6). EI-MS m/z: 445 (Mꢃꢃ2), 443 (Mꢃ). Yield: 84%, mp 272 °C; IR (KBr) cmꢀ1: 3054, 2978, 1681, 1586, 1492. 1H-
Anal. Calcd for C23H17ClF3N3O (443.1): C, 62.24; H, 3.86; N, 9.47. Found: NMR (400 MHz, DMSO-d6) d: 2.13 (3H, s, CH3), 2.26 (3H, s, CH3), 2.29
C, 62.48; H, 4.04; N, 9.56.
2-Ethyl-7-phenyl-5-(trifluoromethyl)-3-[4-(trifluoromethyl)phenyl]-
(3H, s, CH3), 7.24—7.44 (9H, m, Ar-H), 7.82 (1H, s, H-6). EI-MS m/z: 341
(Mꢃ). Anal. Calcd for C22H19N3O (341.15): C, 77.40; H, 5.61; N, 12.31.
pyrido[2,3-d]pyrimidin-4[3H]-one (7e): Yield: 86%, mp 321 °C; IR (KBr) Found: C, 77.54; H, 5.84; N, 12.63.
cmꢀ1: 3068, 2990, 1676, 1603, 1422, 1270, 778. 1H-NMR (400 MHz,
7-(4-Chlorophenyl)-3-(3,5-dimethylphenyl)-2-methyl-5-(trifluoromethyl)-
DMSO-d6) d: 1.22 (3H, t, Jꢁ7.6 Hz, CH3), 2.42 (2H, q, Jꢁ8.5 Hz, CH2), pyrido[2,3-d]pyrimidin-4(3H)-one (7o): Yield: 90%, mp 272 °C; IR (KBr)
7.24—7.28 (3H, m, Ar-H), 7.52 (2H, d, Jꢁ8.6 Hz, Ar-H), 7.72 (2H, d, cmꢀ1: 3068, 2988, 1683, 1603, 1422, 1270, 708. 1H-NMR (400 MHz,
Jꢁ8.6 Hz, Ar-H), 7.98 (2H, d, Jꢁ8.5 Hz, Ar-H), 8.81 (1H, s, H-6). EI-MS
m/z: 465 (Mꢃꢃ2), 463 (Mꢃ). Anal. Calcd for C23H15ClF6N3O (463.11): C,
59.62; H, 3.26; N, 9.07. Found: C, 59.83; H, 3.24; N, 9.26.
DMSO-d6) d: 2.16 (6H, s, CH3), 2.22 (3H, s, CH3), 7.07(2H, s, Ar-H), 7.18
(1H, s, Ar-H), 7.42 (2H, d, Jꢁ8.5 Hz, Ar-H), 7.98 (2H, d, Jꢁ8.5 Hz, Ar-H),
8.82 (1H, s, H-6). EI-MS m/z: 445 (Mꢃꢃ2), 443 (Mꢃ). Anal. Calcd for
C23H17ClF3N3O (443.1): C, 62.24; H, 3.86; N, 10.78. Found: C, 61.93; H,
3.62; N, 10.65.
7-(4-Chlorophenyl)-2-ethyl-3-(2-methoxyphenyl)-5-(trifluoromethyl)-
pyrido[2,3-d]pyrimidin-4(3H)-one (7f): Yield: 75%, mp 290 °C; IR (KBr)
cmꢀ1: 2978, 2844, 1678, 1586, 1492, 1248, 788. 1H-NMR (400 MHz,
DMSO-d6) d: 1.30 (3H, t, Jꢁ7.3 Hz, CH3), 2.45 (2H, q, Jꢁ8.4 Hz, CH2),
3-(3,4-Dimethoxyphenyl)-2,5-dimethyl-7-phenylpyrido[2,3-d]pyrimidin-
4(3H)-one (7p): Yield: 88%, mp 288 °C; IR (KBr) cmꢀ1: 2978, 2844, 1681,
3.76 (3H, s, OCH3), 7.14 (2H, m, Ar-H), 7.22 (1H, dd, Jꢁ1.8, 7.9 Hz, Ar-H), 1586, 1492. 1H-NMR (400 MHz, DMSO-d6) d: 2.20 (3H, s, CH3), 2.29 (3H,
7.44 (1H, dd, Jꢁ4.5, 7.8 Hz, Ar-H), 7.52 (2H, d, Jꢁ8.4 Hz, Ar-H), 7.98 (2H, s, CH3), 3.86 (6H, s, OCH3), 6.98—7.02 (3H, m, Ar-H), 7.39—7.44 (5H, m,
d, Jꢁ8.4 Hz, Ar-H), 8.82 (1H, s, H-6). EI-MS m/z: 461 (Mꢃꢃ2), 459 (Mꢃ). Ar-H), 7.80 (1H, s, H-6). EI-MS m/z: 387 (Mꢃ). Anal. Calcd for C23H21N3O3
Anal. Calcd for C23H17ClF3N3O2 (459.1): C, 60.07; H, 3.73; N, 9.14. Found: (387.16): C, 71.30; H, 5.46; N, 10.85. Found: C, 71.53; H, 5.54; N, 10.67.
C, 59.88; H, 4.04; N, 9.22.
Antibacterial Activity (in Vitro) All the test compounds was assayed in
vitro for antibacterial activity against different strains of Gram-negative [Es-
2-Ethyl-3[4-(methylthio)phenyl]-7-phenyl-5-(trifluoromethyl)pyrido[2,3-
d]pyrimidin-4[3H]-one (7g): Yield: 79%, mp 318 °C; IR (KBr) cmꢀ1: 3060, cherichia coli (MTCC 722), Chromobacterium violaceum (MTCC 2656)
1
2990, 2254, 1686, 1574, 1422, 1270, 708. H-NMR (400 MHz, DMSO-d6) and Klebsiella pneumoniae (MTCC 109)], Gram-positive [Bacillus subtilis
d: 1.22 (3H, t, Jꢁ7.6 Hz, CH3), 2.22 (2H, q, Jꢁ8.5 Hz, CH2), 2.56 (3H, s, (MTCC 441), Staphylococcus aureus (MTCC 96) and Bacillus sphaericus
SCH3), 7.12 (2H, d, Jꢁ8.4 Hz, Ar-H), 7.24—7.31 (3H, m, Ar-H), 7.52 (2H,
d, Jꢁ8.5 Hz, Ar-H), 7.98 (2H, d, Jꢁ8.5 Hz, Ar-H), 8.82 (1H, s, H-6). EI-MS
m/z: 442 (Mꢃꢃ2), 441 (Mꢃ). Anal. Calcd for C23H18ClF3N3O S (441.11): C,
62.57; H, 4.11; N, 9.52. Found: C, 62.42; H, 3.92; N, 9.68.
(MTCC 511)] bacteria using standard protocol.36) The minimum inhibitory
concentration (MIC) was determined by the test tube dilution technique
using ciprofloxacin as standard. The stock solution (1 mg/ml) of test com-
pounds was prepared in DMSO. The stock solution was sterilised by passing

1348
Vol. 56, No. 9
through a 0.2 mm polycarbonate sterile membrane (Nuclepore) filters. Fur-
ther the serial dilution of test compounds was carried out and the following
216 (1989).
14) Harlie A. P., Jr., Richard D. G., J. Med. Chem., 25, 98—102 (1982).
concentration was used: 100, 50, 25, 12.5, 6.25, 3.25, 1.25 mg/ml. Test com- 15) Aleem G., Ona O. A., Sherry F. Q., J. Med. Chem., 46, 5074—5082
pounds at various concentrations were added to culture medium in a ster- (2003).
ilised borosilicate test tube and different bacterial strains were inoculated at 16) Andre R., Han C., Hongning F., Sherry F. Q., Bioorg. Med. Chem., 11,
106 bacilli/ml concentration. The tubes were incubated at 37 °C for 24 h and 59—67 (2003).
then examined for the presence or absence of growth of the test organisms. 17) Aleem G., Ona O. A., Sherry F. Q., Bioorg. Med. Chem., 9, 2929—
All experiments were performed in triplicate. The MIC values were obtained 2935 (2001).
from the lowest concentration of the test compound where the tubes re- 18) Aleem G., Ona O. A., Sherry F. Q., J. Med. Chem., 42, 2447—2455
mained clear, indicated that the bacterial growth was completely inhibited at (1999).
this concentration. The MIC values were expressed in mg/ml and the results 19) Aleem G., Anil V., Sherry F. Q., J. Med. Chem., 39, 1438—1446
were tabulated (Table 1).
(1996).
20) Kataritzky A. R., Charles S., Comprehensive Heterocyclic Chem-
istry—II, 7, 591—603 (1996).
Acknowledgments One of the authors (BLN) is thankful to All India
Council for Technical Education (AICTE) for financial support. We are very 21) Ravikanth S., Venkat Reddy G., Shanthan Rao P., Synthetic Commun.,
grateful to the Chairperson, University Institute of Pharmaceutical Sciences, 34, 4463—4469 (2004).
Panjab University, Chandigarh and Director, Indian Institute of Chemical 22) Maitraie D., Venkat Reddy G., Shanthan Rao P., J. F. Chem., 118, 73—
Technology, Hyderabad for providing necessary facilities to carry out this
work.
79 (2002).
23) Venkat Reddy G., Maitraie D., Shanthan Rao P., J. F. Chem., 124,
203—209 (2003).
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