Synthesis and biological study of novel methylene-bis-chalcones and substituted methylene-bis-pyrimidines/pyrimidinones

Article abstract of DOI:10.1002/jhet.5570440534

(Chemical Equation Presented) A series of novel methylene-bis-chalcones was prepared by the reaction of 5,5′-methylene-bis-salicylaldehyde with different acetophenones, subsequent treatment of methylene-bis-chalcones with urea/thiourea gave the correspond

Full text of DOI:10.1002/jhet.5570440534

Sep-Oct 2007
1181
Synthesis and Biological Study of Novel Methylene-bis-chalcones
and Substituted Methylene-bis-pyrimidines/pyrimidinones
Adki Nagaraj and Cherkupally Sanjeeva Reddy*
Department of Chemistry, Kakatiya University, Warangal 506 009, India,
E-mail: chsrkuc@yahoo.co.in
Received October 26, 2006
OH
OH
HO
HO
R
R
R
O
N
O
R
N
NH
HN
O
O
HO
OH
R
R
N
N
N
N
SH
SH
A series of novel methylene-bis-chalcones was prepared by the reaction of 5,5'-methylene-bis-salicyl-
aldehyde with different acetophenones, subsequent treatment of methylene-bis-chalcones with urea/
thiourea gave the corresponding methylene-bis-pyrimidinones/ methylene-bis-mercaptopyrimidines in
1
good yields. Characterization of the new compounds has been done by means of IR, H NMR, MS and
elemental analysis. The antibacterial, antitubercular and antifungal activity of the compounds has also
been evaluated.
J. Heterocyclic Chem., 44, 1181 (2007).
INTRODUCTION
Inspired with the biological profile of pyrimidine
derivatives and their increasing importance in pharma-
ceutical and biological fields, and in continuation of our
work on biologically active heterocycles [13] it was
considered worthwhile to synthesize certain new chemical
entities incorporating two active pyrimidine/pyrimidinone
nuclei in a single molecular frame work and to get them
evaluated for their antibacterial, antitubercular and
antifungal activity.
Heterocycles are abundant in nature and are of great
significance to life [1], hence have attracted considerable
attention in the design of biologically active molecules [2]
and advanced organic materials [3]. Pyrimidine ring
systems containing substituted six membered ring exhibit
anticancer and herbicidal activities [4,5]. In recent years
pyrimidine derivatives have received significant attention
owing to their diverse range of biological properties,
particularly being antitubercular [6] and calcium channel
blockers [7]. Many classes of chemotherapeutic agents
containing pyrimidine nucleus are in clinical use such as
antibacterial, anticancer, antiviral, antifungal, antimalarial
and antihypertensive agents. Apart from this, chalcones
and their derivatives have been reported to possess
various biological activities such as antibacterial [8],
antifungal [8b] anti-inflammatory [9], antitumor [10],
anticancer [11] and prostaglandin binding [11b].
The most general and widely employed synthetic route
to pyrimidine [12] involves the combination of a reagent
containing the N-C-N skeleton with C-C-C unit. There
are typical examples of bis nucleophile with bis electro-
phile method of constructing heterocycles. Both the
nitrogen atoms of the N-C-N reagent act as necleophiles
and both the terminal carbon atoms of C-C-C reagent are
electrophiles. Urea and thiourea are the most commonly
used N-C-N reagents and chalcones are typically C-C-C
reagents.
RESULTS AND DISCUSSION
The 5,5'-methylene-bis-salicylaldehyde
2
was
prepared by the reaction of salicylaldehyde 1 with
trioxane in the presence of a mixture of acetic acid and
concentrated sulfuric acid [14]. The methylene-bis-
chalcones 3a-f were synthesized by the Claisen
condensation of substituted acetophenones and 5,5'-
methylene-bis-salicylaldehyde 2 in ethanol in the
presence of 60% aqueous KOH at room temperature
[15] (Scheme 1). The reaction times as well as the
yields vary depending on the corresponding reagents.
The crude product contaminated by some starting
materials was purified by extracting with ether. The
methylene-bis-chalcones 3 were reacted with urea [16]
or thiourea [17] in presence of aqueous NaOH to get the
corresponding methylene-bis-pyrimidinones 4a-f and
methylene-bis-mercaptopyrimidines 5a-f (Scheme 2).
These compounds have low solubility in the most

1182
A. Nagaraj and C. Sanjeeva Reddy
Vol 44
Scheme 1
R
OH
OH
HO
OH
HO
Trioxane
H2SO4
O
KOH/EtOH
CHO
CHO
OHC
R
R
1
O
O
3
2
Compound 3, R=
-NO
a) H
b) 4-OMe e) 4-Br
c) 4-Cl f) 2-Cl
d) 4
2
common solvents hence purified in small quantities by
crystallizing the solid products in appropriate amounts
of ethanol/benzene. The structures of the synthesized
compounds were confirmed by ir, 1H nmr, ms and
elemental analysis. The compounds were subject to
antibacterial, antitubercular and antifungal activity
testing.
Antimicrobial Activity. The compounds 4a-f and
5a-f were screened for their antibacterial activity
against human pathogenic bacteria Escherichia coli,
Staphylococcus aureus and Bacillus subtilis. The
minimum inhibition concentration (MIC) was determined
using the tube dilution method [18]. DMF was used as a
blank and streptomycin/neomycin was used as anti-
bacterial standard. An examination of the data reveals
that all the compounds showed antibacterial activity
ranging from 25 to 100 μg/mL. The antibacterial activity
was compared with the known antibiotic streptomycin/
neomycin and the results are given in Table 1.
E.coli and S.subtilis and the compound 5c was highly
active against S.aureus and B.subtilis. The compound
4a did not show any promising results. From the
screened results, it is evident that the presence of
methoxy/chloro group at the phenyl ring enhances the
antibacterial activity.
Antitubercular screening of the compounds 4a-f and
5a–f were carried out using Almar blue assay procedure
[19], INH was used as a standard drug. Antitubercular
screening revealed that the compounds 4b, 4d, and 4f
exhibited equipotent activity with the standard at both the
tested conc. 1.0 μg/mL and 0.1 μg/mL. The compounds
5b, 5d and 5f exhibited moderate activity.
Antifungal Activity. The compounds 4a-f and 5a-f
were also screened for their antifungal activity against
Candida albicans at 160, 320, 480 and 640 μg/mL
concentration using Agar plate technique [20]. The
compounds 4e and 5b were highly active against Candida
albicans. Other compounds showed moderate to good
activity. The antifungal activity of the compounds was
compared with the known antibiotic fluconazole and the
results are presented in Table 1.
The compounds 4b and 5b were highly active
against all the three organisms employed. Compounds
4d, 4e, 5e and 5f were highly active against E.coli and
S.aureus, compound 4f was highly active against
Scheme 2
HO
OH
H2NCONH2
aq.NaOH
R
R
N
NH
N
HN
4
HO
OH
O
O
R
R
O
O
HO
N
OH
3
H2NCSNH2
aq.NaOH
R
R
N
N
N
5
Compound 4 and 5, R=
SH
SH
-NO2
d) 4
a) H
e) 4-Br
f ) 2-Cl
b) 4-OMe
c) 4-Cl

Sep-Oct 2007
Synthesis and Biological Study of Novel Methylene-bis-pyrimidines
1183
Table 1
Antibacterial and Antifungal Activity of 4a-f and 5a-f
Antibacterial activity
Antifungal activity
Spore germination inhibition (in%) at different conc. (μg/mL)
against Candida albicans
Compound
Minimum inhibition conc. μg/mL
E.coli
100
25
50
25
25
25
75
25
50
75
25
25
S.aureus
Inactive
25
75
25
25
50
100
25
25
50
25
25
B.subtilis
160
32.1
49.4
46.0
19.6
79.0
77.1
68.7
83.1
72.7
59.2
76.2
75.1
320
23.0
79.1
43.1
29.0
87.3
79.3
75.2
86.4
78.6
66.1
78.1
78.2
480
29.1
89.7
81.7
29.7
89.0
81.0
83.0
87.6
79.4
69.9
82.3
80.3
640
26.3
91.0
86.9
33.1
90.1
86.5
86.7
93.3
87.6
72.1
84.0
84.1
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
Inactive
25
50
75
50
25
Inactive
25
25
Inactive
50
75
Streptomycin
Neomycin
Fluconozole
10
30
10
30
10
30
84.0
87.0
95.0
98.0
EXPERIMENTAL
ꢂ-H), 7.70 (2H, d, J=16.4 Hz, ꢃ-H), 10.10 (2H, s, OH), 6.97–7.10
(4H, d, J=9 Hz, 3'-H, 5'-H), 8.0– 8.1 (4H, d, J=9 Hz, 2'-H, 6'-H),
7.82–8.18 (6H, m, aromatic); ms: m/z 520 (M+). Anal. Calcd. for
C33H28O6: C, 76.14; H, 5.42. Found: C, 76.11; H, 5.39.
Melting points were determined on a Fisher-Johns melting
point apparatus and were uncorrected. The purity of the
compounds was checked using precoated TLC plates (Merck,
60F-254). IR spectra were obtained on a Perkin-Elmer BX series
FTIR 5000 spectrophotometer, using KBr pellet. 1H NMR
spectra were obtained with a Varian Gemini 200 MHz
spectrometer and the chemical shifts were reported as parts per
million (ꢀ ppm) downfield using TMS as an internal standard.
Mass spectra were obtained on a VG micromass 7070H
spectrometer operating at 70 eV. UV spectra were obtained on a
UV-2401 spectrometer. Elemental analyses were performed on
a Perkin-Elmer 240 CHN elemental analyzer. All solvents and
chemicals were purchased from Sigma-Aldrich chemical
company and used without further purification.
General procedure for the synthesis of methylene-bis-
chalcones (3a-f). A solution of 2 (2.56 g, 0.01 mol) and the
corresponding acetophenone (0.02 mol) in 20 mL of ethanol was
treated with 20 mL of 60% KOH solution at 5-10 °C. The
reaction mixture was stirred at room temperature for 4 hours. It
was then diluted with water (50 mL) and extracted with diethyl
ether (3 x 20 mL). The aqueous solution was acidified with
dilute HCl. The solid obtained was filtered, washed thoroughly
with water, dried the crude product and purified by
crystallization from benzene: MeOH (3:2).
(E)-1-(4-Chlorophenyl)-3-(5-{3-[(E)-3-(4-chlorophenyl)-3-
oxo-1-propenyl]-4-hydroxybenzyl}-2-hydroxyphenyl)-2-pro-
pen-1-one (3c). This compound was obtained as yellow solid,
yield 82%; mp 101-103°C; ir (KBr): ꢄ 3420, 3054, 1576, 1640,
1487, 1223 cm-1; uv : ꢁmax (EtOH) 370, 306, 269 nm; 1H nmr: ꢀ
3.84 (2H, s, -CH2-), 6.90 (2H, d, J=16.4 Hz, ꢂ-H), 7.85 (2H, d,
J=16.4 Hz, ꢃ-H), 10.20 (2H, s, OH), 7.26 (4H, d, J=9 Hz, 3'-H,
5'-H), 8.0 (4H, d, J=9 Hz, 2'-H, 6'-H), 7.82–8.18 (6H, m,
aromatic); ms: m/z 529 (M+). Anal. Calcd. for C31H22Cl2O4: C,
70.33; H, 4.19. Found: C, 70.23; H, 4.13.
(E)-3-(2-Hydroxy-5-{4-hydroxy-3-[(E)-3-(4-nitrophenyl)-3-
oxo-1-propenyl]benzyl}phenyl)-1-(4-nitrophenyl)-2-propen-
1-one (3d). This compound was obtained as red solid; yield
95%; mp 130-132°C; ir (KBr): ꢄ 3420, 3054, 1574 , 1640, 1487,
1452, 1523, 1347, 852, 1222 cm-1; uv: ꢁmax (EtOH) 370.4, 303.9,
266.4 nm; 1H nmr: ꢀ 3.84 (2H, s, -CH2-), 7.85 (2H, d, J=16.4 Hz,
ꢂ-H), 8.23 (2H, d, J=16.4 Hz, ꢃ-H), 10.20 (2H, s, OH), 8.20
(4H, d, J=9 Hz, 3'-H, 5'-H), 8.0 (4H, d, J=9 Hz, 2'-H, 6'-H),
7.82–8.18 (6H, m, aromatic); ms: m/z 550 (M+). Anal. Calcd. for
C31H22N2O8: C, 67.63; H, 4.03; N, 5.09. Found: C, 67.60; H,
4.0; N, 5.01.
(E)-1-(4-Bromophenyl)-3-(5-{3-[(E)-3-(4-bromophenyl)-3-
oxo-1-propenyl]-4-hydroxybenzyl}-2-hydroxyphenyl)-2-pro-
pen-1-one (3e). This compound was obtained as yellow solid;
yield 91%; mp 160-161°C; ir (KBr): ꢄ 3440, 3056, 1571, 1640,
(E)-3-(2-Hydroxy-5-{4-hydroxy-3-[(E)-3-oxo-3-phenyl-1-
propenyl]benzyl}phenyl)-1-phenyl-2-propen-1-one (3a). This
compound was obtained as yellow solid, yield 92%; mp 108-
109°C; ir (KBr): ꢀ 3440, 3058, 1574, 1640, 1487, 1224 cm-1; uv:
1
1482, 1224 cm-1; uv: ꢁmax (EtOH) 370.5, 304.9, 268.1 nm; H
1
ꢁmax (EtOH) 372, 302, 266 nm; H nmr: ꢀ 3.84 (2H, s, -CH2-),
nmr: ꢀ 3.84 (2H, s, -CH2-), 6.84 (2H, d, J=16.4 Hz, ꢂ-H), 7.70
(2H, d, J=16.4 Hz, ꢃ-H), 10.21 (2H, s, OH), 7.18 (4H, d, J=9 Hz,
3'-H, 5'-H, 3"-H, 5"-H ), 8.05 (4H, d, J=9 Hz, 2'-H,6'-H, 2"-H,
6"-H) 7.82-8.18 (6H, m, aromatic ); ms: m/z 618 (M+). Anal.
Calcd. for C31H22Br2O4: C, 60.22; H, 3.59; Br, 25.85. Found: C,
60.12; H, 3.59; Br, 25.61.
(E)-1-(2-Chlorophenyl)-3-(5-{3-[(E)-3-(2-chlorophenyl)-3-
oxo-1-propenyl]-4-hydroxybenzyl}-2-hydroxyphenyl)-2-pro-
pen-1-one (3f). This compound was obtained as brown solid;
yield 90%; mp 96-97°C; ir (KBr): ꢄ 3420, 3056, 1568, 1640,
7.01 (2H, d, J=16.4 Hz, ꢂ-H), 7.85 (2H, d, J=16.4 Hz, ꢃ-H),
10.24 (2H, s, OH), 7.34– 8.34 (16H, m, aromatic); ms: m/z 460;
(M+). Anal. Calcd. For C31H24O4: C, 80.85; H, 5.20. Found: C,
80.80; H, 5.21.
(E)-3-(2-Hydroxy-5-{4-hydroxy-3-[(E)-3-(4-methoxyphenyl)-
3-oxo-1-propenyl]benzyl}phenyl)-1-(4-methoxyphenyl)-2-
propen-1-one (3b). This compound was obtained as orange solid,
yield 95%; mp 95-97°C; ir (KBr): ꢀ 3380, 3058, 1563, 1646,
1
1482, 1223 cm-1; uv: ꢁmax (EtOH) 373, 304, 266 nm; H nmr: ꢀ
3.82 (6H, s, OCH3), 3.84 (2H, s, -CH2-), 6.94 (2H, d, J=16.4 Hz,

1184
A. Nagaraj and C. Sanjeeva Reddy
Vol 44
1489, 1224 cm-1; uv: ꢀmax (EtOH) 372, 305.2, 268.2 nm; 1H nmr:
ꢁ 3.84 (2H, s, -CH2-), 6.90 (2H, d, J=16.4 Hz, ꢂ-H), 7.85 (2H, d,
J=16.4 Hz, ꢃ-H), 10.24 (2H, s, OH), 7.82-8.18 (14H, m,
aromatic); ms: m/z 529 (M+). Anal. Calcd. for C31H22Cl2O4: C,
70.33; H, 4.19. Found: C, 70.26; H, 4.17.
General procedure for the synthesis of methylene-bis-pyri-
midinones (4a-f). A solution of 3 (0.01 mol) and urea (0.03
mol) in 20 mL ethanol was treated with 3 mL of NaOH (0.02
mol). The reaction mixture was refluxed. Tlc (EtOAc: Pet-
ether, 2:1) showed that the reaction was complete after 6 hours.
The reaction mixture was poured in 50 mL of cold 10% HCl
solution and the precipitate was filtered, washed with water until
it was free from acid and on recrystallization from benzene-
ethanol gave 4.
698 (M+). Anal. Calcd. for C33H22Br2N4O4: C, 56.76; H, 3.18; N,
8.02; Br, 22.88. Found: C, 56.70; H, 3.15; N, 8.01; Br, 22.62.
4-(2-Chlorophenyl)-6-(5-{3-[6-(2-chlorophenyl)-2-oxo-2,3-
dihydro-4-pyrimidinyl]-4-hydroxybenzyl}-2-hydroxyphenyl)-
1,2-dihydro-2-pyrimidinone (4f). This compound was obtained
as brown solid; yield 90%; mp 145-146°C; ir (KBr): ꢄ 3233,
3035, 2920, 1690, 1621, 1592, 1482 cm-1; 1H nmr: ꢁ 4.22 (2H, s,
-CH2-), 6.10 (2H, s, OH), 7.16-8.21 (14H, m, aromatic), 7.20
(2H, s, 4-H, 4'-H), 8.31 (2H, s, NH); ms: m/z 609 (M+). Anal.
Calcd. for C33H22Cl2N4O4: C, 65.03; H, 3.64; N, 9.19. Found: C,
64.96; H, 3.58; N, 9.13.
General Procedure for the synthesis of methylene-bis-
mercaptopyrimidine (5a-f). A solution of 3 (0.01 mol) and
thiourea (0.03 mol) in 20 mL ethanol was treated with 3 mL of
NaOH (0.02 mol). The reaction mixture was refluxed. Tlc
(EtOAc: Pet-ether, 2:1) showed that the reaction was complete
after 6 hours. The reaction mixture was poured in 50 mL of cold
10% HCl solution and the precipitate was filtered, washed with
water until it was free from acid and on recrystallization from
benzene-ethanol gave 5.
6-{2-Hydroxy-5-[4-hydroxy-3-(2-oxo-6-phenyl-2,3-dihydro-
4-pyrimidinyl)benzyl]phenyl}-4-phenyl-1,2-dihydro-2-pyrim-
idinone (4a). This compound was obtained as brown solid; yield
93%; mp 125-126°C; ir (KBr): ꢄ 3235, 3040, 2920, 1685, 1615,
1
1594, 1471 cm-1; H nmr: ꢁ 4.20 (2H, s, -CH2-), 6.23 (2H, s,
OH), 7.20 (2H, s, 4-H, 4'-H), 7.22–8.24 (16H, m, aromatic), 8.31
(2H, s, NH); ms: m/z 540 (M+). Anal. Calcd. for C33H24N4O4: C,
73.32; H, 4.47; N, 10.36. Found: C, 73.06; H, 4.42; N, 10.27.
6-(2-Hydroxy-5-{4-hydroxy-3-[6-(4-methoxyphenyl)-2-oxo-
2,3-dihydro-4-pyrimidinyl]benzyl}phenyl)-4-(4-methoxy-
phenyl)-1,2-dihydro-2-pyrimidinone (4b). This compound was
obtained as brown solid; yield 94%; mp 132-133°C; ir (KBr): ꢄ
3230, 3030, 2920, 1690, 1626, 1596, 1480, 1122 cm-1; 1H nmr: ꢁ
3.81 (6H, s, OCH3), 4.10 (2H, s, -CH2-), 6.10 (2H, s, OH), 6.9-
7.0 (4H, d, J=9 Hz, 3-H, 3'-H, 5-H, 5'-H), 7.10-7.91 (6H, m,
aromatic), 7.19 (2H, s, 4-H, 4'-H), 7.7-8.80 (4H, d, 2-H, J=9 Hz,
2-H, 2'-H, 6-H, 6'-H), 8.31 (2H, s, NH); ms: m/z 600 (M+). Anal.
Calcd. for C35H28N4O6: C, 69.99; H, 4.70; N, 9.33. Found: C,
73.06; H, 4.42; N, 10.27.
4-[4-Hydroxy-3-(6-phenyl-2-sulfanyl-4-pyrimidinyl)benzyl]-
2-(6-phenyl-2-sulfanyl-4-pyrimidinyl)phenol (5a). This
compound was obtained as brown solid; yield 86%; mp 119-
120°C; ir (KBr): ꢄ 3326, 3040, 2590, 1620, 1595, 1470, 1216,
1
795 cm-1; H nmr: ꢁ 3.31 (2H, s, SH), 4.20 (2H, s, -CH2-), 6.17
(2H, s, OH), 7.10-8.24 (16H, m, aromatic), 7.60 (2H, s, 4-H, 4'-
H); ms: m/z 572 (M+). Anal. Calcd. for C33H24N4O2S2: C, 69.21;
H, 4.22; N, 9.78. Found: C, 69.14; H, 4.19; N, 9.73.
4-{4-hydroxy-3-[6-(4-methoxyphenyl)-2-sulfanyl-4-pyrimi-
dinyl]benzyl}-2-[6-(4-methoxyphenyl)-2-sulfanyl-4-pyrimi-
dinyl]phenol (5b). This compound was obtained as brown solid;
yield 91%; mp 170-171°C; ir (KBr): ꢄ 3326, 3035, 2590, 1630,
1
1592, 1470, 1216, 795 cm-1; H nmr: ꢁ 3.30 (2H, s, SH), 3.92
4-(4-Chlorophenyl)-6-(5-{3-[6-(4-chlorophenyl)-2-oxo-2,3-
dihydro-4-pyrimidinyl]-4-hydroxybenzyl}-2-hydroxyphenyl)-
1,2-dihydro-2-pyrimidinone (4c) This compound was
obtained as brown solid; yield 91%; mp 137-139°C; ir (KBr):
(6H, s, OCH3), 4.20 (2H, s, -CH2- ), 6.10 (2H, s, OH), 6.9-7.20
(4H, d, J=9 Hz, 3-H, 3'-H, 5-H, 5'-H), 7.10–7.91 (6H, m,
aromatic), 7.60 (2H, s, 4-H, 4'- H), 7.7-8.60 (4H, d, J=9 Hz, 2-H,
2'-H, 6-H, 6'-H); ms: m/z 632 (M+). Anal. Calcd. for
C35H28N4O4S2: C, 66.44; H, 4.46; N, 8.85. Found: C, 67.21; H,
3.18; N, 8.88.
1
ꢄ 3225, 3035, 2922, 1690, 1624, 1590, 1486 cm-1; H nmr: ꢁ
4.20 (2H, s, -CH2-), 6.10 (2H, s, OH), 7.10–7.17 (4H, d, J=9
Hz, 3-H, 3'-H, 5-H, 5'-H), 7.6–8.0 (4H, d, J=9 Hz, 2-H, 2'-H,
6-H, 6'-H), 7.0– 8.10 (6H, m, aromatic), 7.21 (2H, s, 4-H, 4'-
H), 8.30 (2H, s, NH); ms: m/z 609 (M+). Anal. Calcd. for
C33H22Cl2N4O4: C, 65.03; H, 3.64; N, 9.19. Found: C, 64.92;
H, 3.60; N, 9.14.
2-[6-(4-Chlorophenyl)-2-sulfanyl-4-pyrimidinyl]-4-{3-[6-(4-
chlorophenyl)-2-sulfanyl-4-pyrimidinyl]-4-hydroxybenzyl}-
phenol (5c). This compound was obtained as brown solid; yield
89%; mp 142-143°C; ir (KBr): ꢄ 3035, 2580, 1634, 1590, 1216,
1
795 cm-1; H nmr: ꢁ 3.30 (2H, s, SH), 4.19 (2H, s, -CH2-), 6.17
6-(2-Hydroxy-5-{4-hydroxy-3-[6-(4-nitrophenyl)-2-oxo-2,3-
dihydro-4-pyrimidinyl]benzyl}phenyl)-4-(4-nitrophenyl)-1,2-
dihydro-2-pyrimidinone (4d). This compound was obtained as
red solid; yield 94%; mp 144-145°C; ir (KBr): ꢄ 3230, 3042,
2922, 1690, 1626, 1592, 1482, 1347 cm-1; 1H nmr: ꢁ 4.18 (2H, s,
-CH2-), 6.0 (2H, s, OH), 7.21 (2H, s, 4-H, 4'-H), 7.90 (4H, d, J=9
Hz, 2-H, 2'-H, 6-H, 6'-H), 7.82–8.16 (6H, m, aromatic), 8.21
(4H, d, J=9 Hz, 3-H, 3'-H, 5-H, 5'-H), 8.30 (2H, s, NH); ms: m/z
630 (M+). Anal. Calcd. for C33H22N6O8: C, 62.86; H, 3.52; N,
13.33. Found: C, 62.80; H, 3.48; N, 13.26.
(2H, s, OH), 7.10-7.18 (4H, d, J=9 Hz, 3-H, 3'-H, 5-H, 5'-H),
7.57 (2H, s, 4-H, 4'-H), 7.67-8.0 (4H, d, J=9 Hz, 2-H, 2'-H, 6-H,
6'-H), 7.0-8.10 (6H, m, aromatic); ms: m/z 641 (M+). Anal.
Calcd. for C33H22Cl2N4O2S2: C, 61.78; H, 3.46; N, 8.73. Found:
C, 61.71; H, 3.42; N, 8.70.
4-{4-Hydroxy-3-[6-(4-nitrophenyl)-2-sulfanyl-4-pyrim-
idinyl]benzyl}-2-[6-(4-nitrophenyl)-2-sulfanyl-4-pyrimidinyl]-
phenol (5d). This compound was obtained as red solid; yield
94%; mp 135-136°C; ir (KBr): ꢀ 3040, 2580, 1634, 1590, 1216,
1
795 cm-1; H nmr: ꢁ 3.31 (2H, s, SH), 4.22 (2H, s, -CH2-), 6.22
4-(4-Bromophenyl)-6-(5-{3-[6-(4-bromophenyl)-2-oxo-2,3-
dihydro-4-pyrimidinyl]-4-hydroxybenzyl}-2-hydroxyphenyl)-
1,2-dihydro-2-pyrimidinone (4e). This compound was obtained
as yellow solid; yield 91%; mp 147-148°C; ir (KBr): ꢄ 3230,
3038, 2920, 1695, 1620, 1590, 1470 cm-1; 1H nmr: ꢁ 4.22 (2H, s,
-CH2-), 6.02 (2H, s, OH), 7.19 (4H, d, J=9 Hz, 3-H, 3'-H, 5-H,
5'-H), 7.21 (2H, s, 4-H, 4'-H), 7.80–8.18 (6H, m, aromatic), 8.09
(4H, d, J=9 Hz, 2-H, 2'-H, 6-H, 6'-H), 8.30 (2H, s, NH); ms: m/z
(2H, s, OH), 7.60 (2H, s, 4-H, 4'-H), 7.96 (4H, d, J=9 Hz, 2-H,
2'-H, 6-H, 6'-H), 7.70-8.20 (6H, m, aromatic), 8.22 (4H, d, J=9
Hz, 3-H, 3'-H, 5-H, 5'-H); ms: m/z 662 (M+). Anal. Calcd. for
C33H22N6O6S2: C, 59.81; H, 3.35; N, 12.68. Found: C, 59.74; H,
3.31; N, 12.62.
2-[6-(4-Bromophenyl)-2-sulfanyl-4-pyrimidinyl]-4-{3-[6-(4-
bromophenyl)-2-sulfanyl-4-pyrimidinyl]-4-hydroxybenzyl}-
phenol (5e). This compound was obtained as brown solid; yield

Sep-Oct 2007
Synthesis and Biological Study of Novel Methylene-bis-pyrimidines
1185
[5] Hamman, A. G.; Hussain, S. M.; Kotob, I. R. J. Phosphorus,
Sulphur and Silicon. 1990, 47, 47.
[6] Ahluwalia, V. K.; Madhu, B. Indian J. Chem. 1996, 35B,
742.
[7a] Atwal, K. S.; Rovnyk, G. C.; Kimball, S. D.; Floyd, S. D.;
Moreland, S. J. Med. Chem. 1990, 33, 2629. b) Atwal, K. S.; Swanson,
B. N.; Unger, S. E.; Floyed, D. N.; Moreland, S.; Hedberg, A.; Orielly,
B. C.; Corrie, J. E. T. J. Med. Chem. 1991, 34, 806. c) Rovnyk, G. C.;
Atwal, K. S.; Kimball, S. D. J. Med. Chem. 1992, 35, 3254. d) Rovnyk,
G. C.; Kimball, S. D.; Beyer, B.; Cucinotta, G.; Dimorco, J. D.;
Gougoutas, J.; Hedberg, A.; Molley, M.; McCurthy, J. P.; Zhang, R.;
Moreland, S. J. Med. Chem. 1995, 38, 119.
[8a] Mulvad, V. V.; Shirodkar, J. M. J. Heterocycl. Chem. 2003,
40, 377. b) Ahluwalia, V. K.; Kalia, N.; Bala, S. Indian J. Chem. 1986,
25B, 663.
[9] Organesyan, E. T.; Akavenko, V. I.; Khatryan, M. M.;
Preshrou, S. R.; Cherevatyi, V. S. Khim. Farm. Zh. 1986, 20, 696.
[10] Gschwendt, M.; Kisttstein, W.; Fuerstenberger, G.; Mark, F.
Cancer Lett. 1984, 25, 177.
[11a] Sinythies, J. R. Psychoneuroendocrinology 1979, 4, 177. b)
Simmonds, M. S. J.; Baleny, W. M.; Monache, F. O.; Marini, B. G. B.
J. Chem. Ecol. 1990, 16, 365.
92%; mp 123-124°C; ir (KBr): ꢀ 3324, 3027, 2587, 1627, 1595,
1471, 1216, 790 cm-1; 1H nmr: ꢁ 3.31 (2H, s, SH), 4.21 (2H, s, -
CH2-), 6.02 (2H, s, OH), 7.15 (4H, d, J=9 Hz, 3-H, 3'-H, 5-H, 5'-
H), 7.62 (2H, s, 4-H, 4'-H), 7.80-8.16 (6H, m, aromatic), 8.05
(4H, d, J=9 Hz, 2-H, 2'-H, 6-H, 6'-H); ms : m/z 730 (M+). Anal.
Calcd. for C33H22Br2N4O2S2: C, 54.26; H, 3.04; N, 7.67; Br,
21.88. Found: C, 54.20; H, 3.0; N, 7.61; Br, 21.64.
2-[6-(2-Chlorophenyl)-2-sulfanyl-4-pyrimidinyl]-4-{3-[6-(2-
chlorophenyl)-2-sulfanyl-4-pyrimidinyl]-4-hydroxybenzyl}-
phenol (5f). This compound was obtained as red solid; yield
91%; mp 130-131°C; ir (KBr): ꢀ 3040, 2585, 1630, 1590, 1470,
1
795 cm-1; H nmr: ꢁ 3.32 (2H, s, SH), 4.20 (2H, s, -CH2-), 6.16
(2H, s, OH), 7.10-8.15 (14H, m, aromatic), 7.60 (2H, s, 4-H, 4'-
H); ms: m/z 641 (M+). Anal. Calcd. for C33H22Cl2N4O2S2: C,
61.78; H, 3.46; N, 8.73. Found: C, 61.70; H, 3.41; N, 8.69.
Acknowledgements. The authors are greateful to the director,
Indian Institute of Chemical Technology, Hyderabad, for
recording all NMR and Mass spectra of the compounds
published in this paper.
[12a] Korobeinicheva, I. K.; Sedova, V. F.; Gashev, S. B.;
Smirnov, L. D.; Yagodina, D. V.; Mamaev, V. P. Chem. Heterocycl.
Compd. 1989, 8, 913. b) Moskalenko, G. G.; Sedova, V. F.;
Akhmetova, V. R.; Odinokov, V. N.; Mamaev, V. P. Chem. Heterocycl.
Compd. 1990, 26, 557.
[13] Smitha, G.; Sanjeeva Reddy, Ch. Synth. Commun. 2006, 36,
1795.
[14] Marvel, C. S.; Tarkoy, N. J. Am. Chem. Soc., 1957, 79,
6001.
[15] Thool, A. W.; Ghiya, B. J. J. Indian Chem. Soc., 1988, 65, 522.
[16] Sabri, S. S.; Hussein, A. Q. J. Chem. Eng. Data. 1985, 30, 512.
[17] Naik, S. K.; Behera, R. K.; Nayak, A. Indian. J. Chem. 1982,
21B, 1124.
[18] Frankels, R.; Sonnenwirth, A. C. "Clinical laboratory
method and diagnosis", C.V. Mosby Company, Germany, 7th Ed. 1970,
pp 1406-1409.
[19] Ajay Kumar, R.; Lizapaul, K.; Manju, Y. K.; Vinod Kumar,
K.; Joshi, M.; Ayyappan, P.; Sathish, M.; Indralakshimi, R. Curr.
Science. 2001, 180, 70.
REFERENCES AND NOTES
[1] Yuhong, J. U.; Varma, R. S. J. Org. Chem. 2006, 71, 135.
[2a] Kawamoto, M.; Ikeda, T.; Mori, A.; Sekiguchi, A.; Masui,
K.; Shimoda, T.; Horie, M.; Osakada, M. J. Am. Chem. Soc., 2003, 125,
1700. b) Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc., 2004,
126, 5074. c) Masui, K.; Mori, A.; Okamo, K.; Takamula, K.; Kinoshita,
M.; Ikeda, T. Org. Lett. 2004, 6, 2001. d) Mori, A.; Kobayashi, K.;
Ahmed, M.; Mohamed, S. F. Org. Lett. 2005, 7, 4487. e) Yadav, J. S.;
Reddy, B. V. S.; Sathish, G.; Nagalaxmi, P.; Kiran, S.; Kunwar, A. C.
Tetrahedron Lett. 2004, 45, 8587. f) Jagath Reddy, G.; Manjula, D.;
Srinivas Rao, K. Indian J. Chem. 2005, 44B, 2412. g) Lokhande, P. D.;
Waghamure, R.Y.; Sakate, S. S. Indian J. Chem. 2005, 44B, 2338. h)
Maurizio, D. A.; Rocco, R. Lett. Org. Chem. 2004, 1, 12.
[3a] Zificsak, C. A.; Hlasta, D. J. Tetrahedron. 2004, 60, 8991. b)
Haino, T.; Tanaka, M.; Ikeda, K.; Kubo, K.; Mori, A.; Fukazawa, Y.
Tetrahedron Lett. 2004, 45, 2277.
[4] Alt, M. I.; Hamman, A. G.; Mohamed, S. F. J. Phosphorus
and Sulphur. 1988, 39, 24.
[20] Horsfall, G. J. Bot. Rev. 1945, 11, 357.