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Synthesis of some thiopyrimidine and thiazolopyrimidines starting from 2,6-dibenzylidene-3-methylcyclohexanone and its antimicrobial activities
*Corresponding author. Tel.: +966 565148750 aamr1963@yahoo.com (Abdel Galil E. Amr)
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Abstract
A series of novel N-substituted arylidene, pyrazole, thioxopyrimidine and thiazolopyrimidine derivatives 2–7 were synthesized by initial reactions of 2-methyl-cyclohexanone with aromatic aldehydes to give 2,6-dibenzylidene-3-methylcyclohexanone 2. Some of the synthesized compounds were tested as antimicrobial agents. The detailed synthesis, spectroscopic data, and antimicrobial activities of the synthesized compounds were reported.
Keywords
2,6-Dibenzylidene-3-methyl-cyclohexanone
Thiopyrimidine
Thiazolopyridine
Antimicrobial agents
1 Introduction
Some of the pyrimidine and fused heterocyclic pyrimidine derivatives have provided to be active antiviral, antitumor, analgesic and antimicrobial (Amr et al., 2006; Mohamed et al., 2010; Amr et al., 2009; Said et al., 2009; Mostafa et al., 2008; Abd El-Hafez et al., 2009; Mohamed et al., 2008; El-Gaby et al., 1999; Sayed and Ali, 2008; Mc Guigan and Balzarini, 2006). In addition, pyrimidothiazine, thiazolopyrimidine and oxazolidinione derivatives are antimicrobial agents (Tozkoparan et al., 1999; Leach et al., 2007). Recently, we have found that certain substituted pyrimidine and their heterocyclic derivatives show antimicrobial, anti-inflammatory (Amr et al., 2006; Amr and Abdalla, 2006; Amr et al., 2005) and antitumor activities (Abo-Ghalia et al., 2004; Hammam et al., 2003). On the other hand, thioxopyrimidine and thiazolopyrimidine derivatives have promising biological and anticancer activities (Amr and Abdulla, 2002; Sayed et al., 2007; Hafez et al., 2008; El-Gazzar et al., 2009; Hebat-Allah et al., 2010). In view of these observations and in continuation of our previous work in heterocyclic chemistry, we synthesized some new pyrimidine and thiazolopyrimidine derivatives and tested their antimicrobial activities.
2 Results and discussion
A reaction of 3-methylcyclohexanone 1 with aromatic aldehydes, namely, 3,4-dimethoxy-, 3,4,5-trimethoxy-, p-chloro-, p-flouro-, or p-N,N-dimethylaminobenzaldehyde in ethanolic potassium hydroxide gave the corresponding bis-arylmethylene derivatives 2a–e, respectively (Amr et al., 2006; Hammam et al., 2003). Thioxopyrimidine derivatives 5a–d were obtained from the reaction of the arylmethylene derivatives 2a–d with thiourea in refluxing ethanolic potassium hydroxide. Condensation of compound 2a,b with hydrazine hydrate in glacial acetic acid or with phenyl hydrazine in absolute ethanol in the presence of triethylamine as a catalyst afforded the corresponding pyrazole derivatives 3a,b and 4a,b, respectively (Scheme 1).
Synthetic routes of compounds 2-5.
Thioxopyrimidines 5a–d were condensed with chloroacetic acid in a mixture of acetic acid/acetic anhydride in the presence of anhydrous sodium acetate to yield the corresponding thiazolopyrimidines 6a–d, which were condensed with aromatic aldehydes, namely, 3-bromo- or p-chloro- or 3,4,5-trimethoxy- or 3-bromobenzaldehyde in the presence of anhydrous sodium acetate and glacial acetic acid/acetic anhydride to yield the target arylmethylene thiazolopyrimidine derivatives 7a–d, respectively. However, the latter compounds were also prepared directly from 5a–d by the action of chloroacetic acid, aromatic aldehydes, namely, 3-bromo- or p-chloro- or 3,4,5-trimethoxy- or 3-bromobenzaldehyde and anhydrous sodium acetate in the presence of an acetic acid/acetic anhydride (Scheme 2).
Synthetic routes of compounds 6a–d and 7a–d.
3 Antimicrobial activity
Preliminary biological activity screening of the synthesized compounds has been performed against microorganisms representing Gram-positive bacteria (Bacillus subtilis, Bacillus aureus and Staphylococcus aureus), Gram-negative bacteria (Escherichia coli), yeast (Candida albicans) and fungi (Aspergillus niger), using the bioassay technique of antibiotics (Abou-Zeid and Shehata, 1969) specified in US pharmacopeia at 50 μg/ml. The most active compounds are: 3b, 4b, 5c, 6a, 7a and 7d (Bacillus subtilis), 2e, 3a, 4a, 5b, 6c and 7b (Bacillus aureus), 2b, 2e, 4b, 5d, 6d and 7c (Staphylococcus aureus), 2d, 3b, 6b and 7b (Escherichia coli), 2c, 3a, 6a, 7a and 7c (Candida albicans), 2c, 4a, 5a, 5d, 6c and 7b (Aspergillus niger). Ampicillin and chloramphenicol were used as standards. The results obtained are summarized in Table 1.
Comp. No.
Inhibition zones (cm)
Gram-positive bacteria
Gram-negative bacteria
Yeast
Fungi
Bacillus subtilis
Bacillus aureus
Staphylococcus aureus
Escherichia coli
Candida albicans
Aspergillus niger
2a
1.05
1.35
1.20
–
–
1.75
b
1.00
1.55
1.85
0.65
–
0.90
c
0.95
1.25
–
0.45
0.65
2.10
d
0.75
–
0.95
0.70
–
–
e
1.15
1.95
1.85
0.55
–
0.85
3a
1.55
2.05
1.10
0.60
0.70
–
b
1.95
–
–
0.70
–
1.50
4a
1.40
1.85
1.00
–
–
1.95
b
1.75
1.15
1.90
0.50
–
1.60
5a
0.95
1.05
–
–
–
2.05
b
0.90
2.00
1.05
0.50
–
1.55
c
1.90
1.55
0.90
–
–
–
d
1.05
1.65
1.95
0.45
–
2.00
6a
1.85
1.70
0.95
0.55
–
b
0.95
–
0.90
0.75
–
1.65
c
0.90
2.00
0.85
0.60
–
2.10
d
1.10
1.75
1.85
–
–
1.45
7a
1.85
1.60
1.05
–
0.80
–
b
0.90
2.05
1.00
0.65
–
2.05
c
0.80
1.75
1.90
0.55
0.70
–
d
1.90
1.60
1.15
–
–
1.70
Ampicillin
1.15
2.50
1.30
0.75
–
2.30
Chloramphinicol
2.00
2.10
2.00
0.95
–
2.10
4 Conclusion
From the obtained results, we can conclude that thiazolopyrimidine and substituted thiazolopyrimidine moieties fused to 3-methycyclohexane ring are essential for antimicrobial activities. Additionally, the difference in activity between the compounds which is due to the presence of substituents in the phenyl group of the molecule.
5 Experimental section
Melting points were determined on open glass capillaries using an Electrothermal IA 9000 digital melting point apparatus and are uncorrected. Elemental analyses were performed on the Elementar, Vario EL, Micro-analytical Unit, National Research Centre, Cairo, Egypt and were found within ±0.4% of the theoretical values. Infrared spectra were recorded on the Carlzeise Spectrophotometer model “UR 10” spectrophotometer using the KBr disc technique. 1H NMR spectra were recorded on the Varian Gemini 270 MHz spectrometer (DMSO-d6) and the chemical shifts are given in δ (ppm) which used TMS as an internal standard. The mass spectra were measured using a Finnigan SSQ 7000 mass spectrometer. Follow-up of the reactions and checking of the purity of the compounds were made by TLC on silica gel-precoated aluminum sheets (Type 60 F254, Merck, Darmstadt, Germany). Compounds 2,6-bis-(3,4-dimethoxy-benzylidene)-3-methylcyclohexanone 2a and 2,6-bis-(p-chlorobenzylidene)-3-methylcyclohexanone 2c were reported before in the previous literatures (Vorlander, 1925; Nerdel and Kreseze, 1955).
5.1 Synthesis of 2,6-bisarylmethylene-3-methylcyclohexanones (2a–e)
5.1.1 Method A
A mixture of 3-methylcyclohexanone 1 (1.12 g, 10 mmol) and aromatic aldehydes, namely, 3,4-dimethoxy-, 3,4,5-trimethoxy-, p-chloro- or p-fluoro-, p-N,N-dimethylaminobenzaldehyde (20 mmol) in MeOH (50 mL) in the presence of sodium methoxide (10 mmol) was left for 14 days at room temperature. The obtained solid was filtered off, dried and crystallized from the proper solvent to give the corresponding arylmethylene derivatives 2a–e, respectively.
5.1.2 Method B
To a mixture of 3-methylcyclohexanone 1 (1.12 g, 10 mmol), the appropriate aromatic aldehydes, namely, 3,4-dimethoxy-, 3,4,5-trimethoxy-, p-chloro-, p-fluoro- or p-N,N-dimethyl aminobenzaldehyde (20 mmol) in ethanol (50 mL), potassium hydroxide (10 mmol) in 5 mL H2O was added. The reaction mixture was stirred at room temperature for 2 h, the solid formed was collected by filtration and crystallized from the proper solvent to give the corresponding arylmethylene derivatives 2a–e, respectively.
5.1.3 2,6-Bis-(3,4-dimethoxybenzylidene)-3-methylcyclohexanone (2b)
Yield 95% [A], 82% [B]; mp 157–159 °C (EtOH); IR (KBr, cm–1): 1680, 1660; 1H NMR: 7.72 and 7.65 (2s, 2H, benzylic proton), 7.54 and 7.33 (2s, 4H, ArH), 3.83, 3.75, 3.61 (3s, 18H, 6OCH3), 3.28 (m, 1H, CH), 1.92–1.54 (m, 4H, cyclohexene protons), 1.24 (d, J = 6.8 Hz, 3H, CH3); MS (EI): m/z 468 [M+] (100), 453 [M+-CH3] (65), 285 [453-Ph(OCH3)3, H] (54); Anal. Calcd for C27H32O7: C, 69.21; H, 6.88. Found: C, 69.18; H, 6.84.
5.1.4 2,6-Bis-(p-fluorobenzylidene)-3-methylcyclohexanone (2d)
Yield 85% [A], 78% [B]; mp 103–105 °C (EtOH); IR (KBr, cm–1): 1658, 1598; 1H NMR: 7.70 and 7.68 (2s, 2H, benzylic protons), 7.54–7.33 (m, 8H, ArH), 3.51 (m, 1H, CH), 2.92–1.85 (m, 4H, cyclohexene protons), 1.26 (d, J = 6.8 Hz, 3H, CH3); MS (EI): m/z 324 [M+] (100), 296 [M+-C⚌O] (38), 281 [296-CH3] (37); Anal. Calcd for C21H18F2O: C, 77.76; H, 5.59. Found: C, 77.73; H, 5.57.
5.1.5 2,6-Bis-(p-N-dimethylbenzylidene)-3-methylcyclohexanone (2e)
Yield 80% [A], 65% [B]; mp 123–125 °C (EtOH); IR (KBr, cm–1): 1681, 1663; 1H NMR: 7.54 and 7.32 (2s, 2H, benzylic protons), 7.28–6.87 (m, 8H, ArH), 2.94, 2.81 (2s, 12H, 4-NCH3), 3.45 (m, 1H, CH), 2.86–1.64 (m, 4H, cyclohexene protons), 1.18 (d, J = 6.80 Hz, 3H, CH3); MS (EI): m/z 374 [M+] (100), 359 [M+-CH3] (65), 239 [359-Ph-N-CH3)2]; Anal. Calcd for C25H30N2O: C, 80.17; H, 8.07; N, 7.48. Found: C, 80.07; H, 8.00; N, 7.42.
5.2 Synthesis of 3a,b and 4a,b
To a solution of compounds 2a,b (5 mmol) in acetic acid (50 mL), hydrazine hydrate or phenylhydrazine (5 mmol) was added. The reaction mixture was refluxed for 3 h, after cooling; the mixture was poured onto cold water. The obtained solid was collected by filtration, dried and crystallized from the proper solvent to give the corresponding indazole derivatives 3a,b and 4a,b, respectively.
5.2.1 2-Acetyl-7-(34-dimethoxybenzylidene)-3-(3,4-dimethoxyphenyl)-4-methyl-3,3a,4,5,6,7-hexahydro-2H-indazole (3a)
Yield 55%; mp: 161–163 °C (EtOH); IR (KBr, cm–1): 1627, 1673; 1H NMR: 7.53–6.68 (m, 7H, ArH + CH-benzylic), 4.58 (d, J = 7.20 Hz, 1H, CH), 3.92, 3.88 (2s, 12H, 4OCH3), 3.32 (m, 1H, CH), 2.74 (m, 2H, CH2), 2.51 (s, 3H, COCH3), 1.89 (m, 1H, CH), 1.65 (m, 2H, CH2), 1.42 (d, J = 6.76 Hz, 3H, CH3); MS (EI): m/z 464 [M+] (100), 284 [M+-dimethoxybenzyl-idene] (45); Anal. Calcd for C27H32N2O5: C, 69.81; H, 6.94; N, 6.03. Found: C, 69.76; H, 6.90; N, 5.95.
5.2.2 2-Acetyl-7-(3,4,5-trimethoxybenzylidene)-3-(3,4,5-trimethoxyphenyl)-4-methyl-3,3a,4,5,6,7-hexahydro-2H-indazole (3b)
Yield 52%; mp 208–210 °C (Dioxane); IR (KBr, cm–1): 1625, 1670; 1H NMR: 7.12–6.65 (m, 5H, ArH + benzylic proton), 4.68 (d, J = 7.18 Hz, 1H, CH), 3.82, 3.73, 3.65 (3s, 18H, 6OCH3), 3.45 (m, 1H, CH), 2.82 (m, 2H, CH2), 2.43 (s, 3H, COCH3), 2.12 (m, 1H, CH), 1.87 (m, 2H, CH2), 1.34 (d, J = 6.75 Hz, 3H, CH3); MS (EI): m/z 524 [M+] (57), 481 [M+-COCH3] (100), 313 [481-trimethoxy-benzilidine, H] (74), 287 [313-CN]; Anal. Calcd for C29H36N2O7: C, 66.39; H, 6.92; N, 5.34. Found: C, 66.32; H, 6.86; N, 5.28.
5.2.3 7-(3,4-Dimethoxybenzylidene)-3-(3,4-dimethoxyphenyl)-2-phenyl-4-methyl-3,3a,4,5,6,7-hexahydro-2H-indazole (4a)
Yield 65%; mp 127–129 °C (MeOH); IR (KBr, cm–1): 1650; 1H NMR: 7.71–6.68 (m, 12H, ArH + benzylic proton), 4.58 (d, J = 7.25 Hz, 1H, CH), 3.95, 3.93 (2s, 12H, 4OCH3), 3.32 (m, 1H, CH), 2.74 (m, 2H, CH2), 1.89 (m, 1H, CH), 1.65 (m, 2H, CH2), 1.42 (d, J = 6.75 Hz, 3H, CH3); MS (EI): m/z 498 [M+] (15), 408 [M+-PhNH] (100), 285 [408-4OCH3 -H] (74), 257 [285- N,CH2] (54); Anal. Calcd for C31H34N2O4: C, 74.67; H, 6.87; N, 5.62. Found: C, 74.60; H, 6.81; N, 5.56.
5.2.4 7-(3,4,5-Trimethoxybenzylidene)-3-(3,4,5-trimethoxyphenyl)-2-phenyl-4-methyl-3,3a,4,5,6,7-hexa-hydro-2H-indazole (4b)
Yield 60%; mp 133–135 °C (EtOH); IR (KBr, cm–1): 1656; 1H NMR: 7.34–6.62 (m, 10H, ArH + CH-benzylic), 4.58 (d, J = 7.30 Hz, 1H, CH), 3.93, 3.88, 3.82 (3s, 18H, 6OCH3), 3.32 (m, 1H, CH), 2.80 (d, 2H, CH2), 1.94 (m, 1H, CH), 1.62 (m, 2H, CH2), 1.27 (d, J = 6.82 Hz, 3H, CH3); MS (EI): m/z 558 [M+] (100), 377 [M+-trimethoxybenzylidene] (25), 255 [377-PhNN, OCH3] (18); Anal. Calcd for C33H38N2O6: C, 70.95; H, 6.86; N, 5.01. Found: C, 70.90; H, 6.80; N, 4.95.
5.3 Synthesis of 8-(substituted-benzylidene)-4-(substituted-phenyl)-5-methyl-3,4,5,6,7,8-hexahydro-1H-quinazoline-2-thione (5a–d)
A mixture of compound 2a–d (10 mmol) and thiourea (0.76 g, 10 mmol) in ethanolic potassium hydroxide (2 g in 100 mL ethanol) was refluxed for 3 h. The reaction mixture was poured onto cold water acidified with hydrochloric acid (1N); the obtained precipitate was filtered off, washed with water, dried and crystallized from the proper solvent to give the corresponding thioxopyrimidine derivatives 5a–d, respectively.
5.3.1 8-(3,4-Dimethoxybenzylidene)-4-(3,4-dimethoxyphenyl)-5-methyl-3,4,5,6,7,8-hexahydro-1H-quina-zoline-2-thione (5a)
Yield 85%; mp 204–206 °C (EtOH); IR (KBr, cm–1): 3400–3320, 1600, 1250; 1H NMR: 8.89, 9.15 (2s, 2H, 2NH exchangeable with D2O), 7.19–7.03 (m, 7H, ArH + benzylic proton), 5.42 (d, J = 7.32 Hz, 1H, CH), 3.85, 3.78 (2s, 12H, 4OCH3), 3.48 (m, 1H, CH), 2.98–1.80 (m, 4H, 2CH2), 1.31 (d, J = 6.68 Hz, 3H, CH3); MS (EI): m/z 466 [M+] (68.6), 382 [M+-C⚌S, 2NH] (100), 205 [414-CH2-C⚌CH-Ph(OCH3)2] (54); Anal. Calcd for C26H30N2O4S: C, 66.92; H, 6.48; N, 6.00; S, 6.87. Found: C, 66.90; H, 6.46; N, 5.99; S, 6.85.
5.3.2 8-(3,4,5-Timethoxybenzylidene)-4-(3,4,5-trimethoxyphenyl)-5-methyl-3,4,5,6,7,8-hexahydro-1H-quinazoline-2-thione (5b)
Yield 90%; mp 152–154 °C (MeOH); IR (KBr, cm–1): 3368–3312, 1610, 1248; 1H NMR: 9.30, 9.10 (2s, 2H, 2NH exchangeable with D2O), 7.43 (s, 1H, benzylic proton), 6.94, 6.86 (2s, 4H, ArH), 5.21 (d, J = 7.29 Hz, 1H, CH), 3.44 (m, 1H, CH), 2.4–1.80 (m, 4H, 2CH2), 1.23 (d, J = 6.68 Hz, 3H, CH3); MS (EI): m/z 526 [M+] (68.6), 348 [M+-trimethoxybenzlidine] (100), 181 [348-trimethoxyphenyl, 3H] (62); Anal. Calcd for C28H34N2O6S: C, 63.85; H, 6.50; N, 5.32; S, 6.08. Found: C, 63.87; H, 6.47; N, 5.31; S, 6.05.
5.3.3 8-(p-Chlorobenzylidene)-4-(p-chlorophenyl)-5-methyl-3,4,5,6,7,8-hexahydro-1H-quinazoline-2-thione (5c)
Yield 85%; mp: 230–232 °C (EtOH); IR (KBr, cm–1): 3350–3255, 1605, 1252; 1H NMR: 9.50, 9.20 (2s, 2H, 2NH exchangeable with D2O), 7.60–7.20 (m, 9H, ArH + CH-benzylic), 5.34 (d, J = 7.48 Hz, 1H, CH), 3.20 (m, 1H, CH), 2.40–1.80 (m, 4H, 2CH2), 1.18 (d, J = 6.72 Hz, 3H, CH3); MS (EI): m/z 414 [M+] (68), 413 [M+-H] (100), 303 [414- p-Cl-Ph] (54), 176 [303- p-Cl-Ph, CH3, H] (43); Anal. Calcd for C22H20Cl2N2S: C, 63.61; H, 4.85; Cl, 17.07; N, 6.74; S, 7.72. Found: C, 63.67; H, 4.82; Cl, 17.00; N, 6.72; S, 7.73.
5.3.4 8-(p-Fluorobenzylidene)-4-(p-fluorophenyl)-5-methyl-3,4,5,6,7,8-hexahydro-1H-quinazoline-2-thione (5d)
Yield 87%; mp 173–175 °C (MeOH); IR (KBr, cm–1): 3380–3290, 1602, 1245; 1H NMR: 9.70, 9.40 (2s, 2H, 2NH exchangeable with D2O), 7.74–7.36 (m, 9H, ArH + CH-benzylic), 5.28 (d, J = 7.25 Hz, 1H, CH), 3.29 (m, 1H, CH), 2.78–1.96 (m, 4H, 2CH2), 1.19 (d, J = 6.80 Hz, 3H, CH3); MS (EI): m/z 382 [M+] (100), 287 [M+-(p-F-Ph)] (65), 146 [287-(p-F-Ph), SH] (54); Anal. Calcd for C22H20F2N2S: C, 69.08; H, 5.27; N, 7.32; S, 8.38. Found: C, 69.05; H, 5.30; N, 7.31; S, 8.34.
5.4 Synthesis of 9-(substituted-benzylidene)-5-(substituted-phenyl)-6-methyl-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]quinazolin-3-one (6a–d)
A mixture of compound 5a–d (2 mmol), chloroacetic acid (∼0.1 g, 2 mmol), sodium acetate anhydrous (25 g) glacial acetic acid and acetic anhydride (40 mL, 3:1) was refluxed for 3 h. After cooling, the reaction mixture was poured gradually with stirring onto cold water, the solid formed was filtered off, washed with water, dried and crystallized from proper solvent to give the corresponding thiazolopyrimidine derivatives 6a–d, respectively.
5.4.1 9-(3,4-Dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-6-methyl-6,7,8,9-tetrahydro-5H-thiazolo [2,3-b]quinazolin-3-one (6a)
Yield 70%; mp 104–106 °C (EtOH); IR (KBr, cm–1): 1718, 1639; 1H NMR: 7.52 (s, 1H, benzylic proton), 7.48–7.32 (m, 6H, ArH), 5.54 (s, 1H, CH), 3.82 (s, 2H, CH2, thiazole), 2.89 (m, 2H, CH2), 2.46 (m, 1H, CH), 1.76 (m, 2H, CH2), 1.10 (d, J = 6.74 Hz, 3H, CH3); MS (EI): m/z 466 [M+] (68), 382 [M+-C⚌S, CHCH2CH3, 2H], 205 [382-3,4-dimethoxybenzlidene, CH2]; Anal. Calcd for C28H30N2O5S: C, 66.38; H, 5.96; N, 5.53; S, 6.33. Found: C, 66.35; H, 5.99; N, 5.50; S, 6.31.
5.4.2 9-(3,4,5-Trimethoxybenzylidene)-5-(3,4,5-trimethoxyphenyl)-6-methyl-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]quinazolin-3-one (6b)
Yellow solid, yield 65%; mp: 135–137 °C (MeOH); IR (KBr, cm–1): 1724, 1626; 1H NMR: 7.48 (s, 1H, benzylic proton), 7.41, 7.32 (2s, 4H, ArH), 5.49 (s, 1H, CH), 3.79 (s, 2H, CH2, thiazole), 2.88 (m, 2H, CH2), 2.35 (m, 1H, CH), 1.69 (m, 2H, CH2), 1.00 (d, J = 6.68 Hz, 3H, CH3); MS (EI): m/z 566 [M+] (68), 565 [M+-H] (100), 506 (45), 369 (16), 233 (75); Anal. Calcd for C30H34N2O7S: C 63.59, H 6.05, N 4.94, S 5.66, found: C 63.52, H 5.98, N 4.88, S 5.60.
5.4.3 9-(p-Chlorobenzylidene)-5-(p-chlorophenyl)-6-methyl-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]-quinazolin-3-one (6c)
Yellow solid, yield 80%; mp: 158–160 °C (EtOH); IR (KBr, cm–1): 1724, 1622; 1H NMR: 7.58 (s, 1H, benzylic proton), 7.76–7.23 (m, 8H, ArH), 5.53 (s, 1H, CH), 3.79 (s, 2H, CH2, thiazole), 2.68 (m, 2H, CH2), 2.35 (m, 1H, CH), 1.98 (m, 2H, CH2), 1.12 (d, J = 6.69 Hz, 3H, CH3); MS (EI): m/z 454 [M+-1] (83), 343 [M+-(p-chlorophenyl)] (100), 217 [343-(p-chlorophenyl), CH3] (54); Anal. Calcd for C24H20Cl2N2OS: C 63.29, H 4.42, N 6.15, S 7.04, found: C 63.25, H 4.40, N 6.12, S 7.06.
5.4.4 9-(p-Fluorobenzylidene)-5-(p-fluorophenyl)-6-methyl-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]-quina-zolin-3-one (6d)
Yellow solid, yield 75%; mp: 198–200 °C (MeOH); IR (KBr, cm–1): 1730, 1615; 1H NMR: 7.53 (s, 1H, benzylic proton), 7.42–6.95 (m, 8H, ArH), 5.50 (s, 1H, CH), 3.72 (s, 2H, CH2, thiazole), 2.70 (m, 2H, CH2), 2.30 (m, 1H, CH), 1.50 (m, 2H, CH2), 1.15 (d, J = 6.66 Hz, 3H, 6-CH3); MS (EI): m/z 422 [M+] (100), 327 [M+-(p-fluorophenyl)], 299 [327-C⚌O]; Anal. Calcd for C24H20N2F2OS: C 68.22, H 4.77, N 6.63, S 7.59. Found: C 68.20, H 4.79, N 6.60, S 7.55.
5.5 Synthesis of 2,9-bi(substituted-benzylidene)-5-(substituted-phenyl)-6-methyl-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]quinazolin-3-one (7a–d)
5.5.1 Method A
A mixture of compounds 5a–d (2 mmol), chloroacetic acid (2 mmol), sodium acetate anhydrous (2 g) in glacial acetic acid and acetic acid anhydride (40 mL, 3:1) was refluxed for 12 min., then equimolecular amount of the appropriate aromatic aldehydes, namely, 3-bromo- or p-chloro- or 3,4,5-trimethoxy- or 3-bromobenzaldehyde (2 mmol) was added. The reaction mixture was refluxed for 2 h, allowed to cool, poured onto cold water; the formed precipitate was filtered off, dried and crystallized from proper solvent to give the corresponding arylmethylene thiazolopyrimidine derivatives 7a–d, respectively.
5.5.2 Method B
A mixture of compounds 6a–d (2 mmol), equimolecular amount of appropriate aromatic aldehydes, namely, 3-bromo- or p-chloro- or 3,4,5-trimethoxy- or 3-bromobenzaldehydes (2 mmol) in amixtur of acetic acid and acetic anhydride (40 mL, 1:3 ratio) was refluxed for 1.5 h. After cooling, the reaction mixture was poured onto cold water; the formed solid was collected by filtration and crystallized from the proper solvent to give the corresponding arylmethylene thiazolopyrimidine derivatives 7a–d, respectively. The products were identified by their m.p. and Rf-values in comparison with authentic samples previously obtained by method A. The yield from method A was better than from method B.
5.5.3 9-(3,4-Dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-2-(3-bromobenzylidene)-6-methyl-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]quinazolin-3-one (7a)
Yellow solid, yield 76% [A] and 68% [B]; mp: 188–190 °C (EtOH); IR (KBr): 1708 cm–1; 1H NMR: 7.75, 7.68 (2s, 2H, benzylic protons), 7.40–6.61 (m, 10H, ArH), 5.63 (s, 1H, CH), 3.75, 3.73 (2s, 12H, 4OCH3), 2.70 (m, 2H, CH2), 2.30 (m, 1H, CH), 1.50 (m, 2H, CH2), 1.16 (d, J = 6.82 Hz, 3H, CH3); MS (EI): m/z 672 [M+] (58), 421 [M+- (dimethoxy-benzlidine, 2OCH3, C=O, CH3)] (100), 165 [421-(3-bromobenzylidene, CH⚌Ph)] (21); Anal. Calcd for C35H33BrN2O5S: C 62.40, H 4.93, N 4.15, S 4.75, found: C 62.36, H 4.90, N 4.11, S 4.72.
5.5.4 9-(3,4,5-Trimethoxybenzylidene)-5-(3,4,5-trimethoxyphenyl)-2-(p-chlorobenzylidene)-6-methyl-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]quinazolin-3-one (7b)
Orange crystals, yield 60% [A] and 55% [B]; mp: 210–212 °C (EtOH); IR (KBr): 1706 cm–1; 1H NMR: 7.84, 7.73 (2s, 2H, benzylic protons), 7.44–6.92 (m, 8H, ArH), 5.53 (s, 1H, CH-), 3.82, 3.79, 3.72 (3s, 18H, 6OCH3), 2.70 (m, 2H, CH2), 2.30 (m, 1H, CH), 1.50 (m, 2H, CH2), 1.18 (d, J = 6.72 Hz, 3H, CH3); MS (EI): m/z 688 [M+] (24), 521 [M+-(p-chlorophenyl), H] (24), 343 [521-(trimethoxybenzylidene), C⚌O] (100), 269 [343-thiourea]; Anal. Calcd for C37H37ClN2O7S: C 64.47, H 5.41, N 4.06, S 4.65, found: C 64.40, H 5.35, N 4.00, S 4.59.
5.5.5 9-(p-Chlorobenzylidene)-5-(p-chlorophenyl)-2-(3,4,5-trimethoxybenzylidene)-6-methyl-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]quinazolin-3-one (7c)
Yellow powder, yield 70% [A] and 65% [B]; mp: 147–149 °C (MeOH); IR (KBr): ν = 1706 cm−1; 1H NMR: 7.72, 7.50 (2s, 2H, benzylic protons), 7.48–6.97 (m, 10H, ArH), 5.56 (s, 1H, CH), 3.86 (s, 9H, 3OCH3), 2.70 (m, 2H, CH2), 2.30 (m, 1H, CH), 1.50 (m, 2H, CH2), 1.20 (d, J = 6.77 Hz, 3H, CH3); MS (EI): m/z 633 [M+] (46), 521 [M+-(p-chlorophenyl), H] (100), 299 [521-(trimethoxybenzylidene), C⚌O], 209 [299-thiourea, CH3, H]; Anal. Calcd for C34H30Cl2N2O4S: C 64.45, H 4.77, N 4.42, S 5.06, found: C 64.40, H 4.72, N 4.40, S 5.00.
5.5.6 9-(p-Fluorobenzylidene)-5-(p-fluorophenyl)-2-(3-bromobenzylidene)-6-methyl-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]quinazolin-3-one (7d)
Red solid, yield 72% [A] and 64% [B]; mp: 247–249 °C (EtOH); IR (KBr): ν = 1704 cm–1; 1H NMR: 7.80, 7.60 (2s, 2H, benzylic protons), 7.70–7.60 (m, 12H, ArH), 5.8 (s, 1H, CH), 3.60 (b, 1H, CH), 2.40–1.80 (m, 4H, 2CH2), 1.16 (d, J = 6.67 Hz, 3H, CH3); MS (EI): m/z 589 [M+] (73), 493 [M+-(p-fluorophenyl), H] (100), 465 [493-C⚌O], 251 [465-(3-bromobenzylidene), C⚌O, 2H]; Anal. Calcd for C31H23BrF2N2OS: C 63.16, H 3.93, N 4.75, S 5.43, found: C 63.10, H 3.88, N 4.70, S 5.38.
Acknowledgment
The financial support of the Research Center of the College of Pharmacy, King Saud University is greatly appreciated. The author is greatly indebted to Dr. El-Sayed E. Mostafa, Department of Microbial Chemistry, National Research Center, Cairo, Egypt, for carrying out the antimicrobial screening which is highly appreciated.
References
- Sci. Pharm.. 2009;77:539.
- Amino Acids. 2004;26:283.
- Indian J. Pharm.. 1969;31:72.
- Bioorg. Med. Chem.. 2006;14:4341-4352.
- Ind. J. Heterocycl. Chem.. 2002;12:129.
- Arch. Pharm. Chem. Life Sci.. 2005;338:433.
- Bioorg. Med. Chem.. 2006;14:5481.
- Bioorg. Med. Chem.. 2006;14:373.
- J. Med. Chem.. 2009;44:725.
- Acta Pharm.. 1999;49:149.
- Europ. Med. Chem.. 2009;44:4249.
- Acta Pharm.. 2008;58:359.
- Ind. J. Chem.. 2003;42B:1985.
- Europ. Med. Chem.. 2010;45:973.
- Mol. Cell. 2007;26:393.
- Antiviral Res.. 2006;71:149.
- Sci. Pharm.. 2008;76:279-303.
- Europ. J. Med. Chem.. 2010;45:1494.
- Phosphorous, Sulfur, and Silicon. 2008;183:115.
- Chem. Ber.. 1955;88:1006.
- Europ. J. Med. Chem.. 2009;44:4787.
- Phosphrous, Sulfer, and Silicon. 2008;183:156.
- Arch. Pharm. Chem. Life. Sci.. 2007;340:315.
- Farmaco. 1999;54:588.
- Ber.. 1925;58B:118.
