Synthesis and bioassay of amino-pyrazolone, amino-isoxazolone and amino-pyrimidinone derivatives

Article abstract of DOI:10.1248/cpb.55.1704

Novel amino-pyrazolone, amino-isoxazolone and amino-pyrimidinone derivatives were prepared from ethyl 4-phenylsulfonyl-2-(2′- phenylsulfonylethyl)-2-cyanobutyrate (1), ethyl 4-arylsulfonyl-3-aryl-2- cyanobutyrate (7) and ethyl 4-arylmethylsulfonyl-3-aryl-

Full text of DOI:10.1248/cpb.55.1704

1704
Chem. Pharm. Bull. 55(12) 1704—1709 (2007)
Vol. 55, No. 12
Synthesis and Bioassay of Amino-pyrazolone, Amino-isoxazolone and
Amino-pyrimidinone Derivatives
Venkatapuram PADMAVATHI,* Dandu Rangayapalle Chinna VENKATA SUBBAIAH, Konda MAHESH, and
Thunga RADHA LAKSHMI
Department of Chemistry, Sri Venkateswara University; Tirupati-517 502, India.
Received July 24, 2007; accepted September 25, 2007
Novel amino-pyrazolone, amino-isoxazolone and amino-pyrimidinone derivatives were prepared from ethyl
4-phenylsulfonyl-2-(2ꢀ-phenylsulfonylethyl)-2-cyanobutyrate (1), ethyl 4-arylsulfonyl-3-aryl-2-cyanobutyrate (7)
and ethyl 4-arylmethylsulfonyl-3-aryl-2-cyanobutyrate (8). The lead molecules have been tested for their antimi-
crobial activity and antioxidant property.
Key words amino-pyrazolone; amino-isoxazolone; amino-pyrimidinone; antimicrobial activity; antioxidant property
Heterocyclic compounds particularly five and six mem- fonylethyl)-1,3-dimethylpyrimidine-2,4-dione (5), 6-imino-5-
bered heterocycles have attracted the attention of pharmaceu- (2ꢀ-arylsulfonyl-1ꢀ-arylethyl)-1,3-dimethylpyrimidine-2,4-
tical community over the years due to their therapeutic value. dione (15) and 6-imino-5-(2ꢀ-arylmethylsulfonyl-1ꢀ-
A number of barbiturate and thiobarbiturate derivatives ex- arylethyl)-1,3-dimethylpyrimidine-2,4-dione (16) are ob-
hibit anticonvulsant, anaesthetic, sedative and hypnotic prop- tained by the cyclocondensation of 1, 7 and 8 with urea and
erties.1—5) In fact, phenobarbital and mephobarbital6) are 1,3-dimethylurea, respectively. In addition, 6-amino-5,5-bis-
used for clinical treatment of epilepsy. Barbiturates still are (2ꢀ-phenylsulfonylethyl)-2-mercaptopyrimidine-4-one (6), 6-
used world wide in hospitals as injection narcotics.7,8) Be- amino-5-(2ꢀ-arylsulfonyl-1ꢀ-arylethyl)-2-mercaptopyrimi-
sides this, pyrazole and isoxazole derivatives possess bacte- dine-4-one (17) and 6-amino-5-(2ꢀ-arylmethylsulfonyl-1ꢀ-
riostatic, antidiabetic, analgesic, antiarrhythmic, anti-inflam- arylethyl)-2-mercaptopyrimidine-4-one (18) are prepared by
matory, antifungal and antiviral properties.9—14) Celecoxib, a refluxing the compounds 1, 7 and 8 with thiourea. Summary
pyrazole derivative, and valdecoxib, an isoxazole derivative of the reactions involved in the synthesis is given in Charts 1
are now being used as anti-inflammatory drugs.15) A continu- and 2.
oues effort is maintained in our laboratories for the develop-
The IR spectra of 2—6 and 9—18 displayed an absorption
ment of biologically potent heterocycles. The present com- band at 3435—3475 and 3345—3370 cmꢁ1 for NH2 and at
munication deals with the synthesis of amino substituted 1125—1145 and 1310—1340 cmꢁ1 for SO2. Apart from
pyrimidine, thioxopyrimidine, pyrazoline and isoxazoline de- these compounds 4—6 and 13—18 exhibited an absorption
rivatives from Michael adducts by cyclocondensation with band at 1645—1682 cmꢁ1 (CꢂO of pyrimidine ring) while 6,
different nucleophiles.
17 and 18 exhibited a band at 2545—2560 cmꢁ1 (SH). Be-
sides the compounds 2—4, 6, 9—14, 17 and 18 showed an
absorption band at 1600—1620 cmꢁ1 (CꢂN). In the 1H-
Chemistry
The Michael adduct, ethyl 4-phenylsulfonyl-2-(2ꢀ-phenyl- NMR spectra of 2—6 the methylene protons displayed multi-
sulfonylethyl)-2-cyanobutyrate (1) is prepared by the addi- plets at 1.83—2.01, 2.11—2.23 for C1ꢀ-H and 2.80—
tion of ethyl cyanoacetate to vinyl sulfone in the presence of 3.05 ppm for C2ꢀ-H. However, a singlet is observed at 2.70—
Trition-B in benzene. However, ethyl 4-arylsulfonyl-3-aryl-2- 2.74 ppm due to N-methyl protons in 5. The compounds 2, 3,
cyanobutyrate (7) and ethyl 4-arylmethylsulfonyl-3-aryl-2- 4 and 6 exhibited a broad singlet at 5.77—5.97 ppm for NH2.
cyanobutyrate (8) are obtained by the reaction of aryl styryl Also the compounds 2 and 5 showed a broad singlet at
sulfones and benzyl styryl sulfones with ethyl cyanoacetate 9.18—9.96 ppm for NH. The signals due to NH2 and NH dis-
in the presence of K2CO3 in methyl ethyl ketone.16) The appeared on deuteration. The 1H-NMR spectra of 9—12 dis-
cyclocondensation of 1, 7 and 8 with hydrazine hydrate in played a doublet at 4.29—4.44 ppm for C4-H while 13—18 at
the presence of piperidine in ethanol afforded 5-amino-4,4- 4.31—4.35 ppm for C5-H. The compounds 9—18 showed a
bis-(2ꢀ-phenylsulfonylethyl)-pyrazol-3-one (2), 5-amino-4- multiplet in the region 4.08—4.29 ppm for C1ꢀ-H, two double
(2ꢀ-arylsulfonyl-1ꢀ-arylethyl)-pyrazol-3-one (9) and 5- doublets at 3.01—3.13 and 3.68—3.78 ppm for C2ꢀ-H. a
amino-4-(2ꢀ-arylmethylsulfonyl-1ꢀ-arylethyl)-pyrazol-3-one broad singlet at 5.77—5.91 ppm is observed for NH2 in 9—
(10). Similarly, 3-amino-4,4-bis-(2ꢀ-phenylsulfonylethyl)- 14, 17 and 18. The compounds 10, 12, 14, 16 and 18 showed
isoxazol-5-one (3), 3-amino-4-(2ꢀ-arylsulfonyl-1ꢀ-arylethyl)- a sharp singlet at 4.25—4.35 ppm for benzylic protons.
isoxazol-5-one (11) and 3-amino-4-(2ꢀ-arylmethylsulfonyl-
Antimicrobial Testing The compounds 2—6 and 9—18
1ꢀ-arylethyl)-isoxazol-5-one (12) are obtained by treating 1, were tested for in vitro antimicrobial activity against the
7 and 8 with hydroxylamine hydrochloride. Likewise, Gram-positive bacteria Staphylococcus aureus, Bacillus sub-
six membered heterocycles, 6-amino-5,5-bis-(2ꢀ-phenylsul- tilis, the Gram-negative bacteria Klebsiella pneumoniae, Pro-
fonylethyl)-2-hydroxypyrimidine-4-one (4), 6-amino-5-(2ꢀ- teus vulgaris and fungi Fusarium solani, Curvularia lunata
arylsulfonyl-1ꢀ-arylethyl)-2-hydroxypyrimidine-4-one (13), and Aspergillus niger. The primary screen was carried out by
6-amino-5-(2ꢀ-arylmethylsulfonyl-1ꢀ-arylethyl)-2-hydrox- agar disc-diffusion method17) using nutrient agar medium.
ypyrimidine-4-one (14), 6-imino-5,5-bis-(2ꢀ-phenylsul- The minimal inhibitory concentration for the most active
∗ To whom correspondence should be addressed. e-mail: vkpuram2001@yahoo.com
© 2007 Pharmaceutical Society of Japan

December 2007
1705
Chart 1
Table 1. Antibacterial Activity of 2—6 and 9—18
Zone of inhibition (mm)
Concentra-
tion
Com-
pound
Gram (ꢃ)ve
Gram (ꢁ)ve
Klebsiella Proteus
(mg)
Staphylococcus Bacillus
aureus
subtilis
pneumoniae
vulgaris
2
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
34
39
28
32
16
18
14
17
20
23
19
23
32
37
17
20
27
31
14
16
29
32
15
18
12
15
15
18
18
21
35
41
36
38
26
30
14
17
13
15
17
21
16
18
37
39
19
22
28
33
16
17
30
34
14
16
11
13
15
17
20
22
38
44
29
33
25
26
15
18
11
14
18
20
18
20
33
36
17
20
27
29
12
15
24
28
14
17
16
18
14
16
16
20
37
42
27
31
29
31
16
18
12
15
16
19
19
20
31
34
16
18
26
29
14
17
26
29
16
19
14
17
12
15
16
18
42
45
3
4
5
6
9a
10a
11a
12a
13a
14a
15a
16a
17a
18a
Chart 2
compounds 2 and 10a against the same microorganisms used
in the preliminary screening was carried out using microdilu-
tion susceptibility method.18) Chloramphenicol and ketocona-
zole were used as control drugs. The observed data on the
antimicrobial activity of the compounds and control drugs
were given in Tables 1, 2 and 3.
Chloram-
phenicol
The results of the compounds of preliminary antibacterial
testing are shown in Table 1. The results revealed that major- amino-4,4-bis-(2ꢀ-phenylsulfonylethyl)-pyrazol-3-one (2), 3-
ity of the synthesized compounds showed varying degrees of amino-4,4-bis-(2ꢀ-phenylsulfonylethyl)-isoxazol-5-one (3),
inhibition against the tested microorganisms. Among them 5- 5-amino-4-[2ꢀ-(4-chlorophenylmethylsulfonyl)-1ꢀ-(phenyl)-

1706
Vol. 55, No. 12
ethyl]-pyrazol-3-one (10a), 3-amino-4-[2ꢀ-(4-chlorophenyl- (2ꢀ-phenylsulfonylethyl)-1,3-dimethylpyrimidine-2,4-dione
methylsulfonyl)-1ꢀ-(phenyl)ethyl]-isoxazol-5-one (12a) and (5), 6-amino-5-(2ꢀ-phenylsulfonyl-1ꢀ-phenylethyl)-2-hydrox-
6-amino-5-[2ꢀ-(4-chlorophenylmethylsulfonyl)-1ꢀ-phenyl- ypyrimidine-4-one (13a), 6-imino-5-(2ꢀ-phenylsulfonyl-1ꢀ-
ethyl]-2-hydroxypyrimidine-4-one (14a) exhibited high ac- phenylethyl)-1,3-dimethylpyrimidine-2,4-dione (15a), 6-
tivity (24—39 mm) on both gram (ꢃ)ve and gram (ꢁ)ve imino-5-[2ꢀ-(4-chlorophenylmethylsulfonyl)-1ꢀ-phenylethyl]-
bacteria. In fact, compounds 2 and 10a showed pronounced 1,3-dimethylpyrimidine-2,4-dione (16a) and 6-amino-5-(2ꢀ-
activity (36—39 mm) towards gram (ꢃ)ve bacteria. The phenylsulfonyl-1ꢀ-phenylethyl)-2-mercaptopyrimidine-4-one
compounds, 6-amino-5,5-bis-(2ꢀ-phenylsulfonylethyl)-2- (17a) exhibited least activity against both bacteria.
mercaptopyrimidine-4-one (6), 5-amino-4-(2ꢀ-phenylsul-
Antifungal Testing All the test compounds inhibited the
fonyl-1ꢀ-phenylethyl)-pyrazol-3-one (9a), 3-amino-4-(2ꢀ- spore germination of tested fungi Aspergillus niger, Fusar-
phenylsulfonyl-1ꢀ-phenylethyl)-isoxazol-5-one (11a) and 6- ium solani and Curvularia lunata. Results of the investiga-
amino-5-[2ꢀ-(4-chlorophenylmethylsulfonyl)-1ꢀ-phenyl- tion presented in Table 2 revealed that all the compounds ex-
ethyl)-2-mercaptopyrimidine-4-one (18a) displayed moderate cept 4, 13a, 15a and 17a possess relatively high inhibitory
to high activity towards gram (ꢃ)ve bacteria (16—23 mm) effect on Fusarium solani and Curvularia lunata than on
and moderate activity (16—20 mm) towards gram (ꢁ)ve bac- Aspergillus niger. Further, the compounds having amino-
teria. On the other hand, 6-amino-5,5-bis-(2ꢀ-phenylsul- pyrazolone and amino-isoxazolone units displayed greater
fonylethyl)-2-hydroxypyrimidine-4-one (4), 6-imino-5,5-bis- activity.
The MIC values were determined as the lowest concentra-
tion that completely inhibited visible growth of the microor-
Table 2. Antifungal Activity of 2—6 and 9—18
ganisms (Table 3). The structure–antimicrobial activity rela-
tionship of the synthesized compounds revealed that the
Zone of inhibition (mm)
Concentration
Compound
compounds having amino-hydroxypyrimidinone and N,N-di-
methyliminopyrimidinedione exhibited least activity when
compared with compounds having amino-pyrazolone and
amino-isoxazolone moieties. Besides, the compounds having
benzyl sulfonyl group were the most active. The maximum
activity was observed with the compounds 2 and 10a having
amino-pyrazolone unit (Table 3).
Antioxidant Testing The compounds 2—6 and 9—18
are tested for antioxidant property by nitric oxide19,20) and
DPPH21) methods. The compounds 2, 3, 10a and 12a exhib-
ited high antioxidant property in both nitric oxide and DPPH
(mg)
Fusarium
solani
Curvularia
lunata
Aspergillus
niger
2
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
22
25
24
26
18
22
21
23
24
26
19
21
28
31
24
27
29
32
17
20
18
20
16
20
20
23
16
19
27
29
38
42
21
24
24
27
16
19
18
20
19
22
22
24
25
27
23
25
27
31
16
21
21
23
18
22
19
21
17
19
25
29
41
44
19
22
18
20
15
17
17
21
18
21
17
21
20
23
17
20
22
24
14
17
16
19
15
17
16
19
15
16
24
27
36
39
3
4
5
6
9a
Table 4. Antioxidant Property of 2—6 and 9—18
10a
% Inhibition at 100 mM
11a
Compound
Nitric oxide method
DPPH method
12a
2
3
4
5
6
9a
10a
11a
12a
13a
14a
15a
16a
17a
18a
82.25
91.18
34.33
29.21
41.15
40.62
93.65
42.57
96.42
24.78
40.16
22.18
34.62
28.36
42.44
84.74
93.65
38.10
24.75
44.52
41.34
91.22
41.26
94.38
24.78
40.89
28.61
37.83
31.22
41.56
13a
14a
15a
16a
17a
18a
Ketoconazole
Table 3. Minimum Inhibitory Concentration of 2 and 10a
Minimal inhibitory concentration (MIC), mg/ml
Compound
S. aureus
B. subtilis
K. pneumoniae
P. vulgaris
F. solani
C. lunata
A. niger
2
10a
100
25
6.25
—
100
25
6.25
—
200
50
6.25
—
200
100
12.5
—
100
100
—
100
50
—
100
50
—
Chloramphenicol
Ketoconazole
12.5
6.25
6.25

December 2007
1707
14.0 Hz), 3.76 (dd, 1H, C2ꢀ-H, Jꢂ9.2, 13.8 Hz), 4.18—4.25 (m, 1H, C1ꢀ-H),
4.31 (s, 2H, Ar-CH2), 4.33 (d, 1H, C4-H, Jꢂ5.4 Hz), 5.91 (bs, 2H, NH2),
7.19—7.32 (m, 9H, Ar-H), 9.84 (bs, 1H, NH); 13C-NMR (CDCl3ꢃDMSO-
d6) d: 53.3 (C-2ꢀ), 53.9 (C-1ꢀ), 58.2 (Ar-CH2), 62.4 (C-4), 154.2 (C-5),
175.3 (C-3), 127.4, 128.1, 128.9, 129.5, 131.2, 131.3, 139.7; MS m/z: 391
methods at 100 mM concentration (Table 4).
Conclusion
A new class of amino-pyrazolone, amino-isoxazolone, and
amino-pyrimidinone derivatives were prepared from Michael
adducts 4-phenylsulfonyl-2-(2ꢀ-phenylsulfonylethyl)-2-
cyanobutyrate (1), ethyl 4-arylsulfonyl-3-aryl-2-cyanobu-
tyrate (7) and ethyl 4-arylmethylsulfonyl-3-aryl-2-cyanobu-
tyrate (8) by cyclocondensation with appropriate nucle-
(Mꢃ ). Anal. Calcd for C18H18ClN3O3S: C, 55.17; H, 4.63; N, 10.72; Found
·
C, 55.11; H, 4.65; N, 10.80.
5-Amino-4-[2ꢀ-(4-chlorophenylmethanesulfonyl)-1ꢀ-(4-chlorophenyl)-
ethyl]-pyrazol-3-one (10b): Light yellow solid; yield 82%, mp 216—218 °C;
IR (KBr) cmꢁ1: 3358, 3446 (NH2), 3208 (NH), 1633 (CꢂO), 1620 (CꢂN),
1327, 1133, (SO2). 1H-NMR (CDCl3ꢃDMSO-d6) d: 3.07 (dd, 1H, C2ꢀ-H,
ophiles. The antimicrobial testing showed that compounds Jꢂ4.2, 14.2 Hz), 3.79 (dd, 1H, C2ꢀ-H, Jꢂ9.3, 13.9 Hz), 4.21—4.26 (m, 1H,
C1ꢀ-H), 4.28 (s, 2H, Ar-CH2), 4.34 (d, 1H, C4-H, Jꢂ5.3 Hz), 5.84 (bs, 2H,
having amino-pyrazolone and amino-isoxazolone possess
greater antibacterial activity.
NH2), 7.07—7.33 (m, 8H, Ar-H), 9.87 (bs, 1H, NH); 13C-NMR
(CDCl3ꢃDMSO-d6) d: 54.1 (C-2ꢀ), 56.4 (C-1ꢀ), 58.9 (Ar-CH2), 63.6 (C-4),
155.8 (C-5), 176.2 (C-3), 125.4, 126.4, 128.1, 129.5, 130.7, 132.1, 133.7,
139.2; MS m/z: 425 (Mꢃ ). Anal. Calcd for C18H17Cl2N3O3S: C, 50.71; H,
·
Experimental
Melting points were determined in open capillaries on a Mel-Temp appa-
ratus and are uncorrected. The purity of the compounds was checked by
TLC (silica gel H, BDH, ethyl acetate/hexane, 3 : 1). The IR spectra were
recorded on a Thermo Nicolet infrared spectrophotometer, model Nicolet
4.02; N, 9.86; Found C, 50.80; H, 4.06; N, 9.82.
General Procedure of Synthesis of 3-Amino-4,4-bis-(2ꢀ-benzenesul-
fonylethyl)-isoxazol-5-one (3)/3-Amino-4-(2ꢀ-arylsulfonyl-1ꢀ-arylethyl)-
isoxazol-5-one (11a—b)/3-Amino-4-(2ꢀ-arylmethylsulfonyl-1ꢀ-arylethyl)-
isoxazol-5-one (12a—b) To a solution of 1/7/8 (0.01 mol) in EtOH
(20 ml), hydroxylamine hydrochloride (0.01 mol) and piperidine (5 ml) were
added and refluxed for 4—5 h. The solution was cooled and poured onto
crushed ice, acidified with conc. HCl. The reaction mixture was extracted
with ethyl acetate. The organic layer was washed with brine, dried over an-
hydrous Na2SO4. Removal of the solvent under reduced pressure gave crude
product which was purified by recrystallization from MeOH.
1
IR-200 in KBr pellets. The H-NMR (300 MHz) and 13C-NMR (75.5 MHz)
spectra were recorded in CDCl3/DMSO-d6 (1 : 0.4) on a Varian EM-360
spectrometer with TMS as an internal standard. The elemental analyses were
performed by using perkin-elmer 240c elemental analyzer. The mass spectra
were recorded on Finnigan Mat 1210 B and Waters Micromass Quattro
Micro API at 70 eV with an emission current of 100 mA. The antioxidant
property was carried out by using Shimadzu UV-2450 spectrophotometer.
The compounds ethyl 4-phenylsulfonyl-2-(2ꢀ-phenylsulfonylethyl)-2-
cyanobutyrate (1), ethyl 4-arylsulfonyl-3-aryl-2-cyanobutyrate (7)/ethyl 4-
arylmethylsulfonyl-3-aryl-2-cyanobutyrate (8) were prepared according to
the literature procedure.16)
3-Amino-4,4-bis-(2ꢀ-phenylsulfonylethyl)-isoxazol-5-one (3): White
solid, yield 65%, mp 178—180 °C; IR (KBr) cmꢁ1: 3467, 3356 (NH2), 1646
1
(CꢂO), 1610 (CꢂN), 1322, 1139 (SO2). H-NMR (CDCl3ꢃDMSO-d6) d:
1.85—1.98 (m, 2H, C1ꢀ-H), 2.16—2.21 (m, 2H, C1ꢀ-H), 2.87—3.05 (m, 4H,
C2ꢀ-H), 5.86 (bs, 2H, NH2), 7.41—7.98 (m, 10H, Ar-H); 13C-NMR
(CDCl3ꢃDMSO-d6) d: 24.3 (C-1ꢀ), 46.7 (C-4), 50.3 (C-2ꢀ), 156.9 (C-3),
General Procedure of Synthesis of 5-Amino-4,4-bis-(2ꢀ-phenylsul-
fonylethyl)-pyrazol-3-one (2)/5-Amino-4-(2ꢀ-arylsulfonyl-1ꢀ-arylethyl)-
pyrazol-3-one (9a—b)/5-Amino-4-(2ꢀ-arylmethylsulfonyl-1ꢀ-arylethyl)-
pyrazol-3-one (10a—b) A mixture of 1/7/8 (0.01 mol), hydrazine hydrate
(0.015 mol), EtOH (20 ml) and piperidine (5 ml) was refluxed for 6—8 h.
The solution was cooled and poured onto crushed ice containing conc. HCl.
The reaction mixture was extracted with ethyl acetate. The organic layer was
washed with brine, dried over anhydrous Na2SO4 and the solvent was re-
moved under vacuum. The solid obtained was recrystallized from MeOH.
5-Amino-4,4-bis-(2ꢀ-phenylsulfonylethyl)-pyrazol-3-one (2): White crys-
tals; yield 85%, mp 209—211 °C; IR (KBr) cmꢁ1: 3475, 3369 (NH2), 3209
(NH), 1638 (CꢂO), 1607 (CꢂN), 1146, 1309 (SO2). 1H-NMR (CDCl3ꢃ
DMSO-d6) d: 1.90—2.00 (m, 2H, C1ꢀ-H), 2.13—2.23 (m, 2H, C1ꢀ-H), 2.83—
3.04 (m, 4H, C2ꢀ-H), 5.91 (bs, 2H, NH2), 7.57—7.85 (m, 10H, Ar-H), 9.96
(bs, 1H, NH); 13C-NMR (CDCl3ꢃDMSO-d6) d: 25.3 (C-1ꢀ), 49.3 (C-4),
50.0 (C-2ꢀ), 158.1 (C-5), 171.9 (C-3), 126.7, 128.3, 132.8, 137.5; MS m/z:
174.6 (C-5), 125.7, 129.5, 131.2, 138.5; MS m/z: 436 (Mꢃ ). Anal. Calcd for
·
C19H20N2O6S2: C, 52.28; H, 4.62; N, 6.42; Found C, 52.43; H, 4.64; N, 6.53.
3-Amino-4-(2ꢀ-phenylsulfonyl-1ꢀ-phenylethyl)-isoxazol-5-one (11a):
White crystals, yield 68%, mp 184—186 °C; IR (KBr) cmꢁ1: 3435, 3349
(NH2), 1636 (CꢂO), 1612 (CꢂN), 1333, 1135 (SO2). 1H-NMR (DMSO-d6)
d: 3.05 (dd, 1H, C2ꢀ-H, Jꢂ4.3, 14.1 Hz), 3.68 (dd, 1H, C2ꢀ-H, Jꢂ9.5,
14.0 Hz), 4.24—4.28 (m, 1H, C1ꢀ-H), 4.37 (d, 1H, C4-H, Jꢂ5.0 Hz), 5.77 (bs,
2H, NH2), 7.08—7.85 (m, 10H, Ar-H); 13C-NMR (CDCl3ꢃDMSO-d6) d:
54.5 (C-2ꢀ), 56.2 (C-1ꢀ), 63.3 (C-4), 159.2 (C-3), 175.4 (C-5), 124.2, 125.3,
126.7, 127.5, 129.1, 131.4, 137.2, 138.3; MS m/z: 344 (Mꢃ ). Anal. Calcd
for C17H16N2O4S: C, 59.29; H, 4.68; N, 8.13; Found C, 59.39; H, 4.65; N,
8.05.
·
3-Amino-4-[2ꢀ-phenylsulfonyl-1ꢀ-(4-chlorophenyl)ethyl]-isoxazol-5-one
(11b): White solid, yield 73%, mp 189—191 °C; IR (KBr) cmꢁ1: 3441, 3352
(NH2), 1621 (CꢂO), 1619 (CꢂN), 1337, 1141 (SO2). 1H-NMR (DMSO-d6)
d: 3.04 (dd, 1H, C2ꢀ-H, Jꢂ4.4, 14.2 Hz), 3.68 (dd, 2H, C2ꢀ-H, Jꢂ9.6,
14.2 Hz), 4.08—4.19 (m, 1H, C1ꢀ-H), 4.44 (d, 1H, C4-H, Jꢂ5.2 Hz), 5.87 (bs,
2H, NH2), 7.18—7.39 (m, 9H, Ar-H); 13C-NMR (CDCl3ꢃDMSO-d6) d:
53.5 (C-2ꢀ), 58.7 (C-1ꢀ), 64.8 (C-4), 158.3 (C-3), 176.2 (C-5), 127.3, 127.4,
435 (Mꢃ ). Anal. Calcd for C19H21N3O5S2: C, 52.40; H, 4.86; N, 9.65; Found
·
C, 52.52; H, 4.82; N, 9.75.
5-Amino-4-(2ꢀ-phenylsulfonyl-1ꢀ-phenylethyl)-pyrazol-3-one (9a): White
crystals, yield 80%, mp 201—202 °C; IR (KBr) cmꢁ1: 3475, 3369 (NH2),
3209 (NH), 1639 (CꢂO), 1607 (CꢂN), 1309, 1146 (SO2). 1H-NMR
(CDCl3ꢃDMSO-d6) d: 3.07 (dd, 1H, C2ꢀ-H, Jꢂ4.3, 14.1 Hz), 3.70 (dd, 1H,
C2ꢀ-H, Jꢂ9.4, 14.0 Hz), 4.22—4.27 (m, 1H, C1ꢀ-H), 4.33 (d, 1H, C4-H,
Jꢂ5.1 Hz), 5.82 (bs, 2H, NH2), 7.11—7.84 (m, 10H, Ar-H), 9.89 (bs, 1H,
NH); 13C-NMR (CDCl3ꢃDMSO-d6) d: 52.3 (C-2ꢀ), 54.6 (C-1ꢀ), 61.8 (C-4),
157.1 (C-5), 174.7 (C-3), 125.9, 126.4, 127.2, 128.9, 129.7, 131.2, 136.8,
127.5, 128.2, 128.7, 136.7, 140.3, 142.7: MS m/z: 378 (Mꢃ ). Anal. Calcd
for C17H15ClN2O4S: C, 53.90; H, 3.99; N, 7.39; Found C, 54.01; H, 4.04; N,
7.46.
·
3-Amino-4-[2ꢀ-(4-chlorophenylmethylsulfonyl)-1ꢀ-phenylethyl]-isoxazol-
5-one (12a): Light yellow solid, yield 67%, mp 195—197 °C; IR (KBr)
cmꢁ1: 3444, 3359 (NH2), 1642 (CꢂO), 1603 (CꢂN), 1331, 1128 (SO2). 1H-
NMR (DMSO-d6) d: 3.08 (dd, 1H, C2ꢀ-H, Jꢂ4.5, 14.4 Hz), 3.74 (dd, 1H, C2ꢀ-
H, Jꢂ9.7, 14.3 Hz), 4.21—4.27 (m, 1H, C1ꢀ-H), 4.29 (d, 1H, C4-H,
Jꢂ5.1 Hz), 4.34 (s, 2H, Ar-CH2), 5.88 (bs, 2H, NH2), 7.02—7.63 (m, 9H,
Ar-H); 13C-NMR (CDCl3ꢃDMSO-d6) d: 54.2 (C-2ꢀ), 57.8 (C-1ꢀ), 58.8 (Ar-
CH2), 62.9 (C-4), 158.3 (C-3), 173.7 (C-5), 126.3, 127.5, 128.7, 129.4,
138.8; MS m/z: 343 (Mꢃ ). Anal. Calcd for C17H17N3O3S: C, 59.46; H, 4.99;
·
N, 12.24; Found C, 59.55; H, 4.95; N, 12.18.
5-Amino-4-[2ꢀ-phenylsulfonyl-1ꢀ-(4-chlorophenyl)ethyl]-pyrazol-3-one
(9b): White solid, yield 86%, mp 212—214 °C; IR (KBr) cmꢁ1: 3355, 3449
1
(NH2), 3200 (NH), 1626 (CꢂO), 1614 (CꢂN), 1315, 1139 (SO2). H-NMR
(CDCl3ꢃDMSO-d6) d: 3.04 (dd, 1H, C2ꢀ-H, Jꢂ4.5, 14.3 Hz), 3.72 (dd, 1H,
C2ꢀ-H, Jꢂ9.5, 14.1 Hz), 4.23—4.29 (m, 1H, C1ꢀ-H), 4.35 (d, 1H, C4-H,
Jꢂ5.2 Hz), 5.87 (bs, 2H, NH2), 7.14—7.99 (m, 9H, Ar-H), 9.78 (bs, 1H,
NH); 13C-NMR (CDCl3) d: 53.1 (C-2ꢀ), 54.8 (C-1ꢀ), 62.7 (C-4), 156.7 (C-
5), 175.0 (C-3), 126.3, 127.1, 127.6, 128.5, 129.2, 133.2, 137.4, 138.5; MS
129.9, 131.8, 139.2; MS m/z: 392 (Mꢃ ). Anal. Calcd for C18H17ClN2O4S: C,
·
55.03; H, 4.36; N, 7.13; Found C, 55.15; H, 4.32; N, 7.09.
3-Amino-4-[2ꢀ-(4-chlorophenylmethylsulfonyl)-1ꢀ-(4-chlorophenyl)-
ethyl]-isoxazol-5-one (12b): Colourless crystals, yield 70%, mp 200—
202 °C; IR (KBr) cmꢁ1: 3453, 3343 (NH2), 1631 (CꢂO), 1606 (CꢂN),
1338, 1145 (SO2). 1H-NMR (DMSO-d6) d: 3.03 (dd, 1H, C2ꢀ-H, Jꢂ4.6,
14.5 Hz), 3.71 (dd, 1H, C2ꢀ-H, Jꢂ9.8, 14.4 Hz), 4.19—4.25 (m, 1H, C1ꢀ-H),
4.31 (d, 1H, C4-H, Jꢂ5.3 Hz), 4.35 (s, 2H, Ar-CH2), 5.91 (bs, 2H, NH2),
7.03—7.45 (m, 8H, Ar-H); 13C-NMR (DMSO-d6) d: 53.8 (C-2ꢀ), 54.9 (C-
1ꢀ), 57.7 (Ar-CH2), 62.4 (C-4), 159.1 (C-3), 174.2 (C-5), 125.2, 126.4,
m/z: 377 (Mꢃ ). Anal. Calcd for C17H16ClN3O3S: C, 54.04; H, 4.27; N,
·
11.12; Found C, 53.97; H, 4.24; N, 11.08.
5-Amino-4-[2ꢀ-(4-chlorophenylmethylsulfonyl)-1ꢀ-phenylethyl]-pyrazol-
3-one (10a): White crystals; yield 78%, mp 206—208 °C; IR (KBr) cmꢁ1
:
3364, 3471 (NH2), 3204 (NH), 1635 (CꢂO), 1603 (CꢂN), 1313, 1142
(SO2). 1H-NMR (CDCl3ꢃDMSO-d6) d: 3.03 (dd, 1H, C2ꢀ-H, Jꢂ4.1,

1708
Vol. 55, No. 12
127.3, 129.5, 131.8, 131.9, 133.5, 140.3; MS m/z: 426 (Mꢃ ). Anal. Calcd
for C18H16Cl2N2O4S: C, 50.59; H, 3.77; N, 6.56; Found C, 50.50; H, 3.75; N,
6.60.
·
contents were diluted with ice-cold water, acidified with conc. HCl and ex-
tracted with ethyl acetate. The organic layer was washed with brine and
dried over anhydrous Na2SO4. Removal of the solvent under vacuum af-
forded crude product which was purified by recrystallization from MeOH.
6-Imino-5,5-bis-(2ꢀ-phenylsulfonylethyl)-1,3-dimethylpyrimidine-2,4-
dione (5): White powder, yield 64%, mp 273—275 °C; IR (KBr) cmꢁ1: 3215
General Procedure of Synthesis of 6-Amino-5,5-bis-(2ꢀ-phenylsul-
fonylethyl)-2-hydroxypyrimidine-4-one (4)/6-Amino-5-(2ꢀ-arylsulfonyl-
1ꢀ-arylethyl)-2-hydroxypyrimidine-4-one (13a—b)/6-Amino-5-(2ꢀ-aryl-
methylsulfonyl-1ꢀ-arylethyl)-2-hydroxypyrimidine-4-one (14a—b) The
compound 1/7/8 (0.01 mol) was dissolved in EtOH (10 ml). To this urea
(0.01 mol) in EtOH (10 ml) and piperidine (5 ml) were added and refluxed
for 6—9 h. The contents were cooled, poured onto crushed ice containing
conc. HCl and extracted with ethylacetate. The organic layer was washed
with brine and dried over anhydrous Na2SO4. Removal of the solvent in
vacuo gave crude product which was purified by recrystallization from
MeOH.
1
(NH), 1634 (CꢂO), 1612 (CꢂN), 1327, 1133 (SO2). H-NMR (CDCl3) d:
1.88—1.96 (m, 2H, C1ꢀ-H), 2.11—2.20 (m, 2H, C1ꢀ-H), 2.70 (s, 6H, N-CH3),
2.80—2.96 (m, 4H, C2ꢀ-H), 7.44—7.87 (m, 10H, Ar-H), 9.18 (bs, 1H, NH);
13C-NMR (CDCl3) d: 23.8 (C-1ꢀ), 28.9 (N-CH3), 29.2 (N-CH3), 42.5 (C-5),
49.4 (C-2ꢀ), 158.4 (C-2), 164.2 (C-6), 178.0 (C-4), 126.6, 130.1, 132.5,
136.3; MS m/z: 491 (Mꢃ ). Anal. Calcd for C22H25N3O6S2: C, 53.75; H,
·
5.13; N, 8.55; Found C, 53.89; H, 5.15; N, 8.67.
6-Imino-5-(2ꢀ-phenylsulfonyl-1ꢀ-phenylethyl)-1,3-dimethylpyrimidine-
2,4-dione (15a): White solid, yield 64%, mp 287—288 °C; IR (KBr) cmꢁ1
:
6-Amino-5,5-bis-(2ꢀ-phenylsulfonylethyl)-2-hydroxypyrimidine-4-one
(4): White needles, yield 66%, mp 270—272 °C; IR (KBr) cmꢁ1: 3458,
3362 (NH2), 3335 (OH), 1635 (CꢂO), 1604 (CꢂN), 1335, 1145 (SO2). 1H-
NMR (CDCl3ꢃDMSO-d6) d: 1.92—2.01 (m, 2H, C1ꢀ-H), 2.15—2.22 (m,
2H, C1ꢀ-H), 2.85—3.01 (m, 4H, C2ꢀ-H), 5.94 (bs, 2H, NH2), 6.84 (s, 1H,
OH), 7.42—7.85 (m, 10H, Ar-H); 13C-NMR (CDCl3ꢃDMSO-d6) d: 24.7
(C-1ꢀ), 47.2 (C-5), 49.1 (C-2ꢀ), 157.4 (C-6), 161.2 (C-2), 178.7 (C-4), 125.8,
3212 (NH), 1641 (CꢂO), 1603 (CꢂN), 1326, 1137 (SO2). 1H-NMR
(CDCl3ꢃDMSO-d6) d: 2.73 (s, 6H, N-CH3), 3.02 (dd, 1H, C2ꢀ-H, Jꢂ4.1,
14.0 Hz), 3.75 (dd, 1H, C2ꢀ-H, Jꢂ9.6, 14.3 Hz), 4.15—4.21 (m, 1H, C1ꢀ-H),
4.34 (d, 1H, C5-H, Jꢂ5.1 Hz), 7.05—7.87 (m, 10H, Ar-H), 9.21 (bs, 1H,
NH); 13C-NMR (CDCl3ꢃDMSO-d6) d: 27.9 (N-CH3), 28.5 (N-CH3), 52.8
(C-2ꢀ), 54.1 (C-1ꢀ), 64.3 (C-5), 159.7 (C-2), 163.2 (C-6), 176.5 (C-4), 125.5,
126.4, 126.8, 127.8, 129.5, 131.3, 138.5, 141.2; MS m/z: 399 (Mꢃ ). Anal.
127.3, 131.6, 136.2; MS m/z: 463 (Mꢃ ). Anal. Calcd for C20H21N3O6S2: C,
·
·
Calcd for C20H21N3O4S: C, 60.13; H, 5.30; N, 10.52. Found C, 60.24; H,
5.28; N, 10.60.
51.82; H, 4.57; N, 9.07. Found C, 51.70; H, 4.60; N, 9.14.
6-Amino-5-(2ꢀ-phenylsulfonyl-1ꢀ-phenylethyl)-2-hydroxypyrimidine-4-
one (13a): Colourless crystals, yield 66%, mp 284—286 °C; IR (KBr) cmꢁ1
:
6-Imino-5-[2ꢀ-phenylsulfonyl-1ꢀ-(4-chlorophenyl)ethyl]-1,3-dimethyl-
pyrimidine-2,4-dione (15b): White solid, yield 67%, mp 266—267 °C; IR
(KBr) cmꢁ1: 3217 (NH), 1634 (CꢂO), 1607 (CꢂN), 1313, 1128 (SO2). 1H-
NMR (CDCl3ꢃDMSO-d6) d: 2.71 (s, 6H, N-CH3), 3.06 (dd, 1H, C2ꢀ-H,
Jꢂ4.3, 14.3 Hz), 3.78 (dd, 1H, C2ꢀ-H, Jꢂ9.7, 14.4 Hz), 4.16—4.23 (m, 1H,
C1ꢀ-H), 4.32 (d, 1H, C5-H, Jꢂ5.2 Hz), 7.01—7.88 (m, 9H, Ar-H), 9.18 (bs,
1H, NH); 13C-NMR (CDCl3ꢃDMSO-d6) d: 28.4 (N-CH3), 29.1 (N-CH3),
53.2 (C-2ꢀ), 54.7 (C-1ꢀ), 65.2 (C-5), 158.6 (C-2), 162.4 (C-6), 175.3 (C-4),
3442, 3365 (NH2), 3328 (OH), 1635 (CꢂO), 1609 (CꢂN), 1334, 1142
(SO2). 1H-NMR (CDCl3ꢃDMSO-d6) d: 3.11 (dd, 1H, C2ꢀ-H, Jꢂ4.4,
14.3 Hz), 3.79 (dd, 1H, C2ꢀ-H, Jꢂ9.4, 14.4 Hz), 4.17—4.22 (m, 1H, C1ꢀ-H),
4.33 (d, 1H, C5-H, Jꢂ5.4 Hz), 5.86 (bs, 2H, NH2), 6.92 (bs, 1H, OH), 7.11—
7.82 (m, 10H, Ar-H); 13C-NMR (CDCl3ꢃDMSO-d6) d: 52.7 (C-2ꢀ), 53.6
(C-1ꢀ), 63.9 (C-5), 158.8 (C-6), 162.5 (C-2), 176.3 (C-4), 125.3, 125.9,
126.7, 127.4, 129.1, 131.3, 137.8, 138.3; MS m/z: 371 (Mꢃ ). Anal. Calcd
for C18H17N3O4S: C, 58.21; H, 4.61; N, 11.31; Found C, 58.30; H, 4.66; N,
11.41.
·
126.5, 127.1, 127.9, 129.2, 130.5, 132.5, 138.8, 140.3; MS m/z: 433 (Mꢃ ).
·
Anal. Calcd for C20H20ClN3O4S: C, 55.36; H, 4.65; N, 9.68; Found C, 55.30;
H, 4.70; N, 9.74.
6-Amino-5-[2ꢀ-(4-chlorophenylsulfonyl)-1ꢀ-phenylethyl]-2-hydroxy-
pyrimidine-4-one (13b): White solid, yield 68%, mp 268—270 °C; IR (KBr)
cmꢁ1: 3379, 3453 (NH2), 3315 (OH), 1625 (CꢂO), 1612 (CꢂN), 1328,
1130 (SO2). 1H-NMR (CDCl3ꢃDMSO-d6) d: 3.07 (dd, 1H, C2ꢀ-H, Jꢂ4.5,
14.4 Hz), 3.74 (dd, 1H, C2ꢀ-H, Jꢂ9.5, 14.5 Hz), 4.21—4.26 (m, 1H, C1ꢀ-H),
4.31 (d, 1H, C5-H, Jꢂ5.4 Hz), 5.89 (bs, 2H, NH2), 6.87 (bs, 1H, OH), 7.04—
7.87 (m, 9H, Ar-H); 13C-NMR (CDCl3ꢃDMSO-d6) d: 52.1 (C-2ꢀ), 54.9 (C-
1ꢀ), 64.5 (C-5), 159.2 (C-6), 163.4 (C-2), 175.7 (C-4), 125.1, 126.9, 128.1,
6-Imino-5-[2ꢀ-(4-chlorophenylmethylsulfonyl)-1ꢀ-phenylethyl]-1,3-di-
methylpyrimidine-2,4-dione (16a): White solid, yield 62%, mp 270—
272 °C; IR (KBr) cmꢁ1: 3232 (NH), 1640 (CꢂO), 1615 (CꢂN), 1324, 1125
1
(SO2). H-NMR (CDCl3ꢃDMSO-d6) d: 2.74 (s, 6H, N-CH3), 3.08 (dd, 1H,
C2ꢀ-H, Jꢂ4.5, 14.5 Hz), 3.71 (dd, 1H, C2ꢀ-H, Jꢂ9.5, 14.6 Hz), 4.21—4.25
(m, 1H, C1ꢀ-H), 4.28 (s, 2H, Ar-CH2), 4.35 (d, 1H, C5-H, Jꢂ4.9 Hz), 7.06—
7.33 (m, 9H, Ar-H), 9.21 (bs, 1H, NH); 13C-NMR (CDCl3ꢃDMSO-d6) d:
27.8 (N-CH3), 28.1 (N-CH3), 52.4 (C-2ꢀ), 55.3 (C-1ꢀ), 56.8 (Ar-CH2), 63.8
(C-5), 157.4 (C-2), 163.2 (C-6), 174.9 (C-4), 125.1, 125.7, 126.6, 127.4,
129.4, 130.4, 131.8, 137.9, 140.1; MS m/z: 405 (Mꢃ ). Anal. Calcd for
·
C18H16ClN3O4S: C, 53.27; H, 3.97; N, 10.35.;Found C, 53.22; H, 4.00; N,
10.30.
128.3, 131.7, 133.8, 139.9; MS m/z: 447 (Mꢃ ). Anal. Calcd for
·
C21H22ClN3O4S: C, 56.31; H, 4.95; N, 9.38; Found C, 56.41; H, 4.94; N,
9.45.
6-Amino-5-[2ꢀ-(4-chlorophenylmethylsulfonyl)-1ꢀ-phenylethyl]-2-hy-
droxypyrimidine-4-one (14a): White crystals, yield 70%, mp 262—264 °C;
IR (KBr) cmꢁ1: 3360, 3445 (NH2), 3331 (OH), 1637 (CꢂO), 1601 (CꢂN),
1328, 1146 (SO2). 1H-NMR (CDCl3ꢃDMSO-d6) d: 3.05 (dd, 1H, C2ꢀ-H,
Jꢂ4.2, 14.1 Hz), 3.67 (dd, 1H, C2ꢀ-H, Jꢂ9.2, 14.1 Hz), 4.14—4.21 (m, 1H,
C1ꢀ-H), 4.26 (s, 2H, Ar-CH2), 4.33 (d, 1H, C5-H, Jꢂ5.2 Hz), 5.78 (bs, 2H,
NH2), 6.93 (bs, 1H, OH), 7.09—7.46 (m, 9H, Ar-H); 13C-NMR (CDCl3ꢃ
DMSO-d6) d: 53.8 (C-2ꢀ), 55.2 (C-1ꢀ), 59.8 (Ar-CH2), 63.3 (C-5), 158.7 (C-
6), 162.7 (C-2), 174.2 (C-4), 126.1, 126.9, 127.0, 127.7, 129.3, 131.3, 137.8,
6-Imino-5-[2ꢀ-(4-chlorophenylmethylsulfonyl)-1ꢀ-(4-chlorophenyl)ethyl]-
1,3-dimethylpyrimidine-2,4-dione (16b): Light yellow solid, yield 64%, mp
250—252 °C; IR (KBr) cmꢁ1: 3225 (NH), 1636 (CꢂO), 1604 (CꢂN), 1318,
1132 (SO2). 1H-NMR (CDCl3ꢃDMSO-d6) d: 2.73 (s, 6H, N-CH3), 3.13 (dd,
1H, C2ꢀ-H, Jꢂ4.7, 14.6 Hz), 3.74 (dd, 1H, C2ꢀ-H, Jꢂ9.6, 14.4 Hz), 4.11—
4.17 (m, 1H, C1ꢀ-H), 4.27 (s, 2H, Ar-CH2), 4.34 (d, 1H, C5-H, Jꢂ5.0 Hz),
7.12—7.41 (m, 8H, Ar-H), 9.18 (bs, 1H, NH); 13C-NMR (CDCl3ꢃDMSO-
d6) d: 28.9 (N-CH3), 29.4 (N-CH3), 53.3 (C-2ꢀ), 54.8 (C-1ꢀ), 57.3 (Ar-CH2),
64.2 (C-5), 157.0 (C-2), 162.6 (C-6), 175.3 (C-4), 126.4, 126.9, 127.2,
140.4; MS m/z: 419 (Mꢃ ). Anal. Calcd for C19H18ClN3O4S: C, 54.35; H,
·
4.32; N, 10.01; Found C, 54.44; H, 4.33; N, 10.08.
129.3, 130.4, 131.3, 133.6, 138.7; MS m/z: 481 (Mꢃ ). Anal. Calcd for
·
6-Amino-5-[2ꢀ-(4-chlorophenylmethylsulfonyl)-1ꢀ-(4-chlorophenyl)-
ethyl]-2-hydroxypyrimidine-4-one (14b): White crystals, yield 69%, mp
280—282 °C; IR (KBr) cmꢁ1: 1134, 1325 (SO2), 1610 (CꢂN), 1630
(CꢂO), 3324 (OH), 3372, 3443 (NH2). 1H-NMR (CDCl3ꢃDMSO-d6) d:
3.09 (dd, 1H, C2ꢀ-H, Jꢂ4.3, 14.2 Hz), 3.77 (dd, 1H, C2ꢀ-H, Jꢂ9.3, 14.2 Hz),
4.19—4.24 (m, 1H, C1ꢀ-H), 4.32 (d, 1H, C5-H, Jꢂ5.3 Hz), 4.25 (s, 2H, Ar-
CH2), 5.86 (bs, 2H, NH2), 6.89 (bs, 1H, OH), 7.04—7.39 (m, 8H, Ar-H);
13C-NMR (CDCl3ꢃDMSO-d6) d: 54.2 (C-2ꢀ), 54.4 (C-1ꢀ), 58.5 (Ar-CH2),
64.9 (C-5), 158.7 (C-6), 161.8 (C-2), 173.8 (C-4), 125.4, 126.1, 127.3,
C21H21Cl2N3O4S: C, 52.29; H, 4.39; N, 8.71; Found C, 52.21; H, 4.43; N,
8.68.
General Procedure of Synthesis of 6-Amino-5,5-bis-(2ꢀ-phenylsul-
fonylethyl)-2-mercaptopyrimidine-4-one (6)/6-Amino-5-(2ꢀ-arylsulfonyl-
1ꢀ-arylethyl)-2-mercaptopyrimidine-4-one (17a—b)/6-Amino-5-(2ꢀ-aryl-
methylsulfonyl-1ꢀ-arylethyl)-2-mercaptopyrimidine-4-one (18a—b) To
a solution of 1/7/8 (0.01 mol) in EtOH (20 ml), thiourea (0.01 mmol) and
piperidine (5 ml) were added and refluxed for 7—12 h. The reaction mixture
was cooled, poured onto crushed ice containing conc. HCl and extracted
with ethyl acetate. The organic layer was washed with brine and dried over
anhydrous Na2SO4. The solvent was removed with rotary evaporator. The re-
sulted solid was purified by recrystallization from MeOH.
128.7, 129.8, 131.7, 134.2, 138.1; MS m/z: 453 (Mꢃ ). Anal. Calcd for
·
C19H17Cl2N3O4S: C, 50.23; H, 3.77; N, 9.25; Found C, 50.29; H, 3.80; N,
9.20.
General Procedure of Synthesis of 6-Imino-5,5-bis-(2ꢀ-phenylsul-
fonylethyl)-1,3-dimethylpyrimidine-2,4-dione (5)/6-Imino-5-(2ꢀ-arylsul-
fonyl-1ꢀ-arylethyl)-1,3-dimethylpyrimidine-2,4-dione (15a—b)/6-Imino-
5-(2ꢀ-arylmethylsulfonyl-1ꢀ-arylethyl)-1,3-dimethylpyrimidine-2,4-dione
(16a—b) A mixture of 1/7/8 (0.01 mol), 1,3-dimethylurea (0.01 mol),
EtOH (15 ml) and piperidine (5 ml) was taken and refluxed for 6—10 h. The
6-Amino-5,5-bis-(2ꢀ-phenylsulfonylethyl)-2-mercaptopyrimidine-4-one
(6): White solid, yield 68%, mp 269—271 °C; IR (KBr) cmꢁ1: 3462, 3357
1
(NH), 2558 (SH), 1630 (CꢂO), 1616 (CꢂN), 1338, 1142 (SO2). H-NMR
(CDCl3ꢃDMSO-d6) d: 1.35 (s, 1H, SH), 1.83—1.94 (m, 2H, C1ꢀ-H), 2.14—
2.22 (m, 2H, C1ꢀ-H), 2.89—3.05 (m, 4H, C2ꢀ-H), 5.97 (bs, 2H, NH2), 7.37—

December 2007
1709
7.86 (m, 10H, Ar-H); 13C-NMR (CDCl3ꢃDMSO-d6) d: 22.9 (C-1ꢀ), 43.2
(C-5), 49.1 (C-2ꢀ), 163.8 (C-6), 179.1 (C-4), 187.5 (C-2), 127.2, 129.4,
tration of test compounds dissolved in a suitable solvent (dioxane/methanol)
and tubes were incubated at 25 °C for 120 min. Control experiment was con-
ducted with equal amount of solvent in an identical manner. At intervals,
0.5 ml of incubation solution was taken and diluted with 0.5 ml of griess
reagent (1% sulfanilamide, 0.1% N-naphthylethylenediamine dihydrochlo-
ride and 2% o-phosphoric acid dissolved in distilled water). The absorbance
of the chromophore formed during diazotization of nitrite with sulfanil-
amide and subsequent N-naphthylethylenediamine dihydrochloride was read
at l 546 nm. The experiment was repeated in triplicate.
Reduction of 1,1-Diphenyl-2-picrylhydrazyl (DPPH) Free Radical
(DPPH Method) The nitrogen centered stable free radical 1,1-diphenyl-2-
picrylhydrazyl (DPPH) has often been used to characterize antioxidants. It is
reversibly reduced and the odd electron in the DPPH free radical gives a
strong absorption maximum at l 517 nm, which is purple in color. This
property makes it suitable for spectrophotometric studies. A radical scaveng-
ing antioxidant reacts with DPPH stable free radical and converts into 1,1-
diphenyl-2-picrylhydrazine. The resulting decolorization is stoichiometric
with respect to the number of electrons captured. The change in the ab-
sorbance produced in this reaction has been used to measure antioxidant
properties.
133.4, 137.5; MS m/z: 479 (Mꢃ ). Anal. Calcd for C20H21N3O5S3: C, 50.09;
·
H, 4.41; N, 8.76.; Found C, 50.00; H, 4.39; N, 8.84.
6-Amino-5-(2ꢀ-phenylsulfonyl-1ꢀ-phenylethyl)-2-mercaptopyrimidine-4-
one (17a): White crystals, yield 65%, mp 285—287 °C; IR (KBr) cmꢁ1
:
3462, 3357 (NH), 2557 (SH), 1638 (CꢂO), 1610 (CꢂN), 1325, 1137 (SO2).
1H-NMR (CDCl3ꢃDMSO-d6) d: 1.38 (s, 1H, SH), 3.01 (dd, 1H, C2ꢀ-H,
Jꢂ4.6, 14.4 Hz), 3.75 (dd, 1H, C2ꢀ-H, Jꢂ9.7, 14.5 Hz), 4.14—4.21 (m, 1H,
C1ꢀ-H), 4.31 (d, 1H, C5-H, Jꢂ5.2 Hz), 5.77 (bs, 2H, NH2), 7.11—7.84 (m,
10H, Ar-H); 13C-NMR (CDCl3ꢃDMSO-d6) d: 52.0 (C-2ꢀ), 53.4 (C-1ꢀ), 63.7
(C-5), 162.9 (C-6), 178.3 (C-4), 186.8 (C-2), 125.2, 126.0, 126.6, 127.5,
128.4, 132.3, 137.6, 140.2; MS m/z: 387 (Mꢃ ). Anal. Calcd for
·
C18H17N3O3S2: C, 55.79; H, 4.42; N, 10.84; Found C, 55.73; H, 4.45; N,
10.93.
6-Amino-5-[2ꢀ-phenylsulfonyl-1ꢀ-(4-chlorophenyl)ethyl]-2-mercaptopy-
rimidine-4-one (17b): White crystals, yield 70%, mp 276—278 °C; IR
(KBr) cmꢁ1: 3450, 3338 (NH), 2545 (SH), 1645 (CꢂO), 1606 (CꢂN),
1
1316, 1134 (SO2). H-NMR (CDCl3ꢃDMSO-d6) d: 1.35 (s, 1H, SH), 3.08
(dd, 1H, C2ꢀ-H, Jꢂ4.8, 14.2 Hz), 3.77 (dd, 1H, C2ꢀ-H, Jꢂ9.8, 14.3 Hz),
4.16—4.22 (m, 1H, C1ꢀ-H), 4.37 (d, 1H, C5-H, Jꢂ5.1 Hz), 5.85 (bs, 2H,
NH2), 7.05—7.96 (m, 9H, Ar-H); 13C-NMR (CDCl3ꢃDMSO-d6) d: 53.1 (C-
2ꢀ), 55.8 (C-1ꢀ), 62.9 (C-5), 163.7 (C-6), 176.2 (C-4), 187.4 (C-2), 125.5,
The solutions of test compounds (100 mM) were added to DPPH (100 mM)
in dioxane/ethanol. The tubes were kept at an ambient temperature for
20 min and the absorbance was measured at l 517 nm. The difference be-
tween the test and the control experiments was taken and expressed as the
per cent scavenging of the DPPH radical.
126.3, 127.2, 129.6, 131.5, 132.2, 138.9, 140.6; MS m/z: 421 (Mꢃ ). Anal.
·
Calcd for C18H16ClN3O3S2: C, 51.24; H, 3.82; N, 9.96; Found C, 51.32; H,
3.86; N, 10.04.
Acknowledgements The authors are thankful to DST New Delhi, India
for the financial assistance under major research project and to Ch. Kishore
Kumar, Department of Botany, Sri Venkateswara University, Tirupati, India
for his help in antimicrobial testing. One of the authors D.R.C. Venkata Sub-
baiah is thankful to CSIR, New Delhi, India for the sanction of Senior Re-
search Fellowship.
6-Amino-5-[2ꢀ-(4-chlorophenylsulfonyl)-1ꢀ-phenylethyl]-2-mercaptopy-
rimidine-4-one (18a): White crystals, yield 75%, mp 204—206 °C; IR (KBr)
cmꢁ1: 3457, 3351 (NH), 2543 (SH), 1634 (CꢂO), 1608 (CꢂN), 1321, 1131
(SO2). 1H-NMR (CDCl3ꢃDMSO-d6) d: 1.32 (s, 1H, SH), 3.05 (dd, 1H, C2ꢀ-
H, Jꢂ4.7, 14.5 Hz), 3.74 (dd, 1H, C2ꢀ-H, Jꢂ9.4, 14.4 Hz), 4.18—4.23 (m,
1H, C1ꢀ-H), 4.29 (s, 2H, Ar-CH2), 4.33 (d, 1H, C5-H, Jꢂ5.3 Hz), 5.78 (bs,
2H, NH2), 7.04—7.37 (m, 9H, Ar-H); 13C-NMR (CDCl3ꢃDMSO-d6) d:
52.9 (C-2ꢀ), 54.7 (C-1ꢀ), 57.6 (Ar-CH2), 63.7 (C-5), 162.7 (C-6), 175.5 (C-
4), 185.9 (C-2), 125.3, 126.6, 127.1, 128.6, 129.5, 131.7, 133.9, 141.5; MS
References
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m/z: 435 (Mꢃ ). Anal. Calcd for C19H18ClN3O3S2: C, 52.35; H, 4.16; N, 9.64;
·
Found C, 52.43; H, 4.18; N, 9.60.
6-Amino-5-[2ꢀ-(4-chlorophenylsulfonyl)-1ꢀ-(4-chlorophenyl)ethyl]-2-
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1
1330, 1138 (SO2). H-NMR (CDCl3ꢃDMSO-d6) d: 1.37 (s, 1H, SH), 3.02
(dd, 1H, C2ꢀ-H, Jꢂ4.9, 14.3 Hz), 3.71 (dd, 1H, C2ꢀ-H, Jꢂ9.5, 14.1 Hz),
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8.98.
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Antibacterial and Antifungal Assays Preliminary antimicrobial activi-
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method. Sterile filter paper discs (6 mm diameter) moistened with the test
compound solution in DMSO of specific concentration 100 mg and 200
mg/disc were carefully placed on the agar culture plates that had been previ-
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Antioxidant Testing The compounds 2—6 and 9—18 are tested for an-
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