CHAPTER - 3. SYNTHESIS OF INDENO[1,2-d]PYRIMIDINE-2-THIONES AND EXPERIMENTAL. plates and spots were located by iodine vapours. Infra red spectra were

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1 CAPTER - 3 YTEI OF IDEO[1,2-d]PYRIMIDIE-2-TIOE AD TEIR ALKYL/ARALKYL DERIVATIVE EXPERIMETAL Melting points were determined in open end capillaries and are uncorrected. Compounds were checked for their purity by TLC on silica gel G plates and spots were located by iodine vapours. Infra red spectra were recorded on Perkin-Elmer RX IFT-IR system using KBr pellets. Proton magnetic resonance spectra were recorded on Bruker Advance II 400 MR spectrometer with tetra methyl silane as internal standard. Mass spectra were recorded by the ational Institute of Pharmaceutical Research (IPER), Mohali. The microwave irradiated reactions were performed in domestic household microwave oven amsung M177. For all the reactions, chemicals of igma Aldrich standard were used. All solvents were distilled before use. YTEI OF 4-UBTITUTED PEYL-1,3,4,5-TETRAYDRO- 2-IDEO[1,2-d]PYRIMIDIE-2-TIOE General Procedure 117

2 A mixture of 1-indanone (0.01 mole, 1.32g), thiourea (0.01mole, 0.76g) and substituted aromatic aldehydes (0.01 mole) were irradiated in unmodified domestic microwave oven (at 30% microwave power) using absolute alcohol (5 ml) as an energy transfer medium and conc. Cl (3-4 drops) as a catalyst. The same reaction was also carried out through thermal heating. The reaction was monitored by thin layer chromatography (TLC) using silica gel-g plates. Ethyl acetate and n-hexane mixture was used as eluting solvent taken in ratio of 1:1. After drying of plates in air, spots were marked and exposed to iodine chamber. The reaction mixture on standing for a few hours afforded solid product which was filtered under reduced pressure and recrystallized out of alcohol. A typical procedure is given below: (VIIa) 4-(4-Methoxyphenyl)-1,3,4,5-tetrahydro-2-indeno[1,2-d] pyrimidine-2-thione A mixture of 1-indanone (0.01 mole, 1.32 g), 4-methoxy benzaldehyde ( 0.01 mole, 1.36 ml), thiourea (0.01 mole, 0.76 g) and concentrated Cl (3-4 drops) was dissolved in absolute alcohol (5 ml) taken in borosil beaker (100 ml) and was irradiated in unmodified domestic microwave oven at 30% microwave power for 8.00 min. The same reaction mixture was refluxed. But, 118

3 it took 5.30 hrs. to complete the reaction. The reaction was monitored by thin layer chromatography (TLC) using silica gel-g plates. Ethyl acetate and n- hexane mixture was used as eluting solvent (1:1). After drying the plates, spots were exposed to iodine chamber. The reaction mixture on standing for a few hours afforded solid product which was filtered under reduced pressure and recrystallized out of alcohol for 2-3 times to give pure product. M.P. = C. Yield = 52 %. PMR (CDCl 3 DMO) : 8.26 (s, 1, ), 7.94 (s, 1, ), (m, 8, Ar- ), 5.66 (s, 1, 4- C), 4.00 (s, 2, C 5 C 2 ), 3.88 (s, 3, OC 3 ) Mass fragments (m/z): 308 M, 307, 249, 188, 178, 129, 120 IR (KBr) cm -1 : (- str), & (C- str), (C=C str). 119

4 Other compounds (VII b VII j) were also synthesized similarly and are listed in Table 6 along with their characterization data. O CO 2 R 2 C 30 % w Conc. Cl abs. alcohol R VIIa-VIIj TABLE 6 CARACTERIZATIO DATA OF PRODUCT (VIIa VIIj):. o M.P. Microwave Reflux Microwave Reflux Compd R Reaction time % Yield a Time (min) Time (hrs) ( 0 C) VIIa 4-OC VIIb 3-O VIIc 2,3-(O-C O) VIId 4-O,3-OC

5 VIIe 4-O VIIf 2-C VIIg 2,4-(Cl) VIIh 2-O VIIi VIIj 4-(C 3 ) a Yield of crude product pectral data of compounds (VIIb-VIIi) are listed below: (VIIb) PMR (CDCl 3 DMO) : (s, 1, ), 8.90 (s, 1, ), (m, 8, Ar-), 5.68 (s, 1, 4-C), 4.13 (s, 2, C 5 C 2 ). IR (KBr, cm -1 ): (- str.), (C- str.), (C=C str.), & (O 2 ), (C --- C), (C-), (C=). 121

6 Mass fragments (m/z): 323 M, 264, 201, 188, 135, 114, 92. (VIIc) PMR (CDCl 3 DMO) : 8.50 (s, 1, ), (m, 8, Ar- & -), 6.06 (s, 2, O-C 2 - O), 5.42 (s, 1, 4-C), 4.01 (s, 2, C 5 C 2 ). IR (KBr, cm -1 ): (- str.), (C- str.), (C=C str.), (C --- C), (C-), (C=). (VIId) PMR (CDCl 3 DMO) : 9.96 (s, 1, O-), 8.78 (s, 1, ), (m, 8, Ar- & -), 5.45 (s, 1, 4-C), 4.09 (s, 2, C 5 C 2 ), 3.79 (s, 3, OC 3 ). IR (KBr, cm -1 ): (O-), (- str.), (C- str.), (C=C str.), (C --- C), (C-), (C=). (VIIe) PMR (CDCl 3 DMO) : 122

7 10.56 (s, 1, ), 8.78 (s, 1, ), (m, 8, Ar-), 5.55 (s, 1, 4-C), 4.11 (s, 2, C 5 C 2 ). IR (KBr, cm -1 ): (- str.), (C- str.), (C=C str.), & (O 2 ), (C --- C), (C-), (C=). (VIIf) PMR (CDCl 3 DMO) : 9.62 (s, 1, ), 8.65 (s, 1, ), (m, 8, Ar-), 5.48 (s, 1, 4-C), 4.02 (s, 2, C 5 C 2 ), 1.23 (s, 3, C 3 ). IR (KBr, cm -1 ): (- str.), (C- str.), (C=C str.), (C --- C), (C-), (C=). (VIIg) PMR (CDCl 3 DMO) : 8.42 (s, 1, ), (m, 7, Ar-), 6.86 (s, 1, -), 6.08 (s, 1,4-C), (d, 1, C 5 C 2 ), (d, 1, C 5 C 2 ). IR (KBr, cm -1 ): 123

8 (- str.), (C- str.), (C=C str.), 1528 (C --- C), (C-), (C=). (VIIh) PMR (CDCl 3 DMO) : (s, 1, ), 8.76 (s, 1, ), (m, 8, Ar-), 5.62 (s, 1, 4-C), 4.10 (s, 2, C 5 C 2 ). IR (KBr, cm -1 ): (- str.), (C- str.), (C=C str.), & (O 2 ), (C --- C), (C-), (C=). (VIIi) PMR (CDCl 3 DMO) : (s, 1, ), 8.57 (s, 1, -), (m, 9, Ar-), 5.51 (s, 1, 4-C), 4.21 (s, 2, C 5 C 2 ). IR (KBr, cm -1 ): (- str.), (C- str.), (C=C str.), (C --- C), (C-), (C=). Mass fragments (m/z): 278 M, 277, 218, 201,188, 173, 149, 129, 114, 105, 90, 77,

9 YTEI OF 2-(METYLTIO)-4-ARYL-4,5-DIYDRO-1- IDEO[1,2-d]PYRIMIDIE General Procedure Indeno[1,2-d]pyrimidine-2-thiones (0.004 mole) were dissolved in 25 ml ethanol. To it, added ao solution, which was prepared by dissolving ao (0.004 mole, g) in water (2 ml). The reaction mixture was cooled. To this cold mixture, dimethyl sulphate (0.5 ml, mole) was added dropwise while stirring the mixture continuously. The reaction mixture was refluxed for 3 hours. The reaction was monitored by thin layer chromatography (TLC) using silica gel-g plates. Ethyl acetate and n-hexane mixture (1:1) was used as eluting solvents and used as eluting solvents and spots were exposed to iodine chamber. The mixture was cooled and poured over crushed ice. olid separated was filtered under reduced pressure, washed with ethanol and dried. It was recrystallized from ethanol to provide a pure sample of the product. 125

10 A typical procedure is given below: VIIIa 2-(methylthio)-4-(4-methoxyphenyl)-4,5-dihydro-1indeno [1,2-d]pyrimidines 4-(4-Methoxyphenyl)-1,3,4,5-tetrahydro-2-indeno[1,2- d]pyrimidine-2-thione Ia (0.004 mole, 1.232g) was dissolved in 25 ml ethanol. To it, added ao solution, which was prepared by dissolving ao (0.004 mole, g) in water (2 ml). The mixture was cooled. To this mixture, dimethyl sulphate (0.5 ml, mole) was added dropwise while stirring the mixture continuously. Then, the reaction mixture was refluxed for 3 hours. The reaction was monitored by thin layer chromatography (TLC) using silica gel-g plates. Ethyl acetate and n- hexane mixture was used as eluting solvents (1:1) and after drying, the plates were exposed to iodine chamber. The reaction mixture was cooled and poured over crushed ice. olid separated was filtered under reduced pressure, washed with ethanol and dried. It was recrystallized from ethanol to provide a pure sample of the product. M.P. = C Yield = 39% PMR (CDCl 3 DMO) : 126

11 (m, 9, Ar- & ), 5.35 (s, 1, 4-C), 4.10 (s, 2, C 5 C 2 ), 3.89 (s, 3, OC 3 ), 2.72 (s, 3, -C 3 ). IR (KBr, cm -1 ): (- str.), (C- str.), (C=C str.), (C --- C), (C-). Mass fragments (m/z): 322 M, 321, 320, 289, 274, 178, 167, 155, 129, 77 (VIIIb) PMR (CDCl 3 DMO) : 9.00 (s, 1, ), (m, 8, Ar-), 6.89 (s, 1, 4-C), 4.12 (s, 2, C 5 C 2 ), 2.75 (s, 3, -C 3 ). (VIIIc) PMR (CDCl 3 DMO) : (m, 8, Ar- & -), (s, 2, O-C 2 -O), 5.92 (s, 1, 4-C), 3.99 (s, 2, C 5 C 2 ), (s, 3, -C 3 ). Mass fragments (m/z): 336M, 335, 320, 263, 246, 222, 207, 178, 129, 114, 90. (VIIIf) PMR (CDCl 3 DMO) : 127

12 8.89 (s, 1, -), (m, 7, Ar-), 6.08 (s, 1, 4-C), (d, 1 of C 5 C 2 ), (d, 1 of C 5 C 2 ), 1.24 (s, 3, -C 3 ). YTEI OF 2-(ETYLTIO)-4-ARYL-4,5-DIYDRO-1- IDEO[1,2-d]PYRIMIDIE General Procedure Indeno[1,2-d]pyrimidine-2-thione (0.004 mole) was dissolved in ethanol. To it, added ao solution, which was prepared by dissolving ao (0.004 mole, 0.16 g) in water (2 ml). The mixture was cooled. To this mixture, diethyl sulphate (0.6 ml, mole) was added drop wise while stirring the mixture continuously. The reaction mixture was refluxed for 3 hours. The reaction was monitored by thin layer chromatography (TLC) using silica gel-g plates. Ethyl acetate and n-hexane mixture was used as eluting solvents (1:1) and after drying, the plates were exposed to iodine chamber. The reaction mixture was cooled and poured over crushed ice. olid separated was filtered under reduced pressure, washed with ethanol and dried. It was recrystallised from ethanol to provide a pure sample of the product. A typical procedure is given below: 128

13 VIIIg 2-(ethylthio)-4-(4-methoxyphenyl)-4,5-dihydro-1indeno[1,2-d]pyrimidines 4-(4-methoxyphenyl)-1,3,4,5-tetrahydro-2-indeno[1,2-d] pyrimidine-2-thione (0.004 mole, g) was dissolved in ethanol. To it, added ao solution, which was pepared by dissolving ao (0.004 mole, 0.16 g) in water (2 ml). The mixture was cooled. To this mixture, diethyl sulphate (0.6 ml, mole) was added drop wise while stirring the mixture continuously. The reaction mixture was refluxed for 3 hours. The reaction was monitored by thin layer chromatography (TLC) using silica gel-g plates. Ethyl acetate and n-hexane mixture was used as eluting solvents (1:1) and after drying, the plates were exposed to iodine chamber. The mixture was cooled and poured over crushed ice. olid separated was filtered under reduced pressure, washed with ethanol and dried. It was recrystallized from ethanol to provide a pure sample of the product. M.P. = C Yield = 79-87%. PMR (CDCl 3 DMO) : (m, 9, Ar- & -), 5.83 (s, 1, 4-C), 3.94( s, 2, C 5 C 2 ), 3.86(s, 3, OC 3 ), ( q, 1 of -C 2 ), (q, 1 of - C 2 ), (t, 3, -C 2 -C 3 ). 129

14 IR (KBr, cm -1 ): (- str.), (C- str.), (C=C str.), (C --- C), (C-). Mass fragments (m/z): 336 M, 335, 334, 249, 219, 178, 140, 129. (VIIIh) PMR (CDCl 3 DMO) : 9.00 (s, 1, ), (m, 8, Ar-), 5.75 (s, 1, 4-C), 4.12 ( s, 2, C 5 C 2 ), ( q, 2, -C 2 ), (t, 3, -C 2 - C 3 ). IR (KBr, cm -1 ): (- str.), (C- str.), (C=C str.), & (O 2 ), (C --- C), (C-). Mass fragments (m/z): 264, 216, 155, 135, 90, 77. (VIIIi) PMR (CDCl 3 DMO) : (m, 8, Ar- & -), (s, 2, O-C 2 -O), 5.92 (s, 1, 4-C), 3.98 ( s, 2, C 5 C 2 ), (q, 1 of -C 2 ), ( q, 1 of -C 2 ), (t, 3, -C 2 -C 3 ). 130

15 IR (KBr, cm -1 ): (- str.), (C- str.), (C=C str.), ( C --- C), (C-). (VIIIj) PMR (CDCl 3 DMO) : 8.17 (s, 1, -), (m, 7, Ar- ), 8.01(s, 1, O), 5.92 (s, 1, 4), 4.14 ( s, 2, C 5 C 2 ), 3.98 (s, 3, OC 3 ), (q, 1 of -C 2 ), ( q, 1 of -C 2 ), (t, 3, -C 2 - C 3 ). IR (KBr, cm -1 ): (O- str.), (- str.), (C- str.), (C=C str.), (C --- C), (C-). (VIIIl) PMR (CDCl 3 DMO) : 8.91 (s, 1, -), (m, 7, Ar- ), 6.08 (s, 1, 4), (q, 2, -C 2 ), (d, 1 of C 5 C 2 ), (d, 1 of C 5 C 2 ), (t, 3, -C 2 -C 3 ). IR (KBr, cm -1 ): (- str.), (C- str.), (C=C str.), ( C --- C), (C-). 131

16 (VIIIm) PMR (CDCl 3 DMO) : 8.17 (s, 1, -), (m, 9, Ar- ), 5.30 (s, 1, 4), 4.13 (s, 2, C 5 C 2 ), (q, 2, -C 2 ), (t, 3, -C 2 - C 3 ). IR (KBr, cm -1 ): (- str.), (C- str.), (C=C str.), ( C --- C), (C-). Mass fragments (m/z): 305, 290, 276, 244,230, 219, 218, 216, 191,178, 128,114, 90, 77. YTEI OF 2-(BEZYLTIO)-4-ARYL-4,5-DIYDRO-1- IDEO[1,2-d]PYRIMIDIE General Procedure Indeno[1,2-d]pyrimidine-2-thiones (0.004 mole) were dissolved in alcohol (2-3 ml). The solution was diluted with water (2 ml). To it, benzyl chloride (0.5 ml, mole) was added and the mixture was refluxed for 5 hours. The reaction was monitored by thin layer chromatography (TLC) using silica gel-g plates. Ethyl acetate and n-hexane mixture was used as eluting solvents (1:1) and after drying, the plates were exposed to iodine chamber. The reaction mixture was cooled and poured over crushed ice. 132

17 olid separated was filtered under reduced pressure, washed with ethanol and dried. It was recrystallized from ethanol to provide a pure sample of the product. A typical procedure is given below: VIIIn 2-(benzylthio)-4-(4-methoxyphenyl)-4,5-dihydro-1- indeno[1,2-d]pyrimidines 4-(4-methoxyphenyl)-1,3,4,5-tetrahydro-2-indeno[1,2- d]pyrimidine-2-thione (0.004 mole, g) was dissolved in alcohol (2-3 ml). The solution was diluted with water (2 ml). To it, benzyl chloride (0.5 ml, mole) was added and the mixture was refluxed for 5 hours. The reaction was monitored by thin layer chromatography (TLC) using silica gel-g plates. Ethyl acetate and n-hexane mixture was used as eluting solvents (1:1) and after drying, the plates were exposed to iodine chamber. The reaction mixture was cooled and poured over crushed ice. olid separated was filtered under reduced pressure, washed with ethanol and dried. It was recrystallized from ethanol to provide a pure sample of the product. M.P. = C Yield = 29% 133

18 PMR (CDCl 3 DMO) : (m, 14, & Ar-), 5.97 (s, 1, 4-C), 4.60 ( d, 1 of - C 2 ), 4.12 ( d, 1 of -C 2 ), 4.01 (s, 2, C 5 C 2 ), 3.86 ( s, 3, OC 3 ). Mass fragments (m/z): 398 M, 396, 365, 320, 308, 307, 273, 249, 219, 175, 149, 132, 91, 90. (VIIIo) PMR (CDCl 3 DMO) : 8.96 (s, 1, ), (m, 13, Ar-), 6.13 (s, 1, 4-C), ( d, 1 of -C 2 ), ( d, 1 of -C 2 ), 4.15 (s, 2, C 5 C 2 ). IR (KBr, cm -1 ): (- str.), (C- str.), (C=C str.), & (O 2 ), (C --- C), (C-). (VIIIp) PMR (CDCl 3 DMO) : (m, 13, Ar- & -), 6.02 (s, 2, O-C 2 -O), 5.93 (s, 1, 4-C), 3.97 (s, 2, C 5 C 2 ), 4.58 ( d, 1 of -C 2 ), 4.06 ( d, 1 of -C 2 ). IR (KBr, cm -1 ): 134

19 (- str.), (C- str.), (C=C str.), ( C --- C), (C-). YTEI OF 2-(BUTYLTIO)-4-ARYL-4,5-DIYDRO-1- IDEO[1,2-d]PYRIMIDIE General Procedure A mixture of powdered Indeno[1,2-d]pyrimidine-2-thiones ( mole), butyl bromide (0.004 mole) and absolute alcohol (2ml) was taken in round bottom flask ( 100 ml) and was refluxed for 5 hours. The reaction was monitored by thin layer chromatography (TLC) using silica gel-g plates. Ethyl acetate and n-hexane mixture was used as eluting solvents (1:1) and after drying, the plates were exposed to iodine chamber. After refluxing, the reaction mixture was transferred to 100 ml beaker. It was allowed to stand at room temperature for hours. The product separated after continuous scratching with the glass rod. It was filtered under reduced pressure and washed with alcohol and dried. The product was recrystallized from ethanol. A typical procedure is given below: (VIIIt) 2-(butylthio)-4-(4-methoxyphenyl)-4,5-dihydro-1- indeno[1,2-d]pyrimidines 135

20 A mixture of powdered 4-(4-methoxyphenyl)-1,3,4,5-tetrahydro-2indeno[1,2-d]pyrimidine-2-thione (0.004 mole, g), butyl bromide (0.004 mole) and absolute alcohol ( 2ml) was taken in round bottom flask ( 100 ml) and was refluxed for 5 hours. The reaction was monitored by thin layer chromatography (TLC) using silica gel-g plates. Ethyl acetate and n- hexane mixture was used as eluting solvents (1:1) and after drying, the plates were exposed to iodine chamber. After refluxing the reaction mixture was transferred to 100 ml beaker. After a long standing for hrs., the product separated was filtered under reduced pressure and washed with alcohol and dried. Then, the product was recrystallized from ethanol. M.P. = C Yield = 56.49% PMR (CDCl 3 DMO) : (m, 9, & Ar-), 5.76 (s, 1, 4-C), 4.10 (s, 2, C 5 C 2 ), 3.89 (s, 3, OC 3 ), (t, 2, -C 2 -C 2 -C 2 -C 3 ), ( m, 4, -C 2 -C 2 -C 2 -C 3 ), (t, 3, -C 2 -C 2 -C 2 -C 3 ). IR (KBr, cm -1 ): (- str.), (C- str.), (C=C str.), (C --- C), (C-). 136

21 Mass fragments (m/z): 364 M, 363, 329, 249, 178. (VIIIu) PMR (CDCl 3 DMO) : (m, 8, Ar- & -), (s, 2, O-C 2 -O), 5.98 (s, 1, 4-C), 3.98 (s, 2, C 5 C 2 ), (t, 2, -C 2 -C 2 - C 2 -C 3 ), ( m, 2, -C 2 -C 2 -C 2 -C 3 ), (m, 2, -C 2 -C 2 -C 2 -C 3 ), (t, 3, -C 2 -C 2 -C 2 -C 3 ). IR (KBr, cm -1 ): (- str.), (C- str.), (C=C str.), ( C --- C), (C-). Mass fragments (m/z): 265, 250, 245, 168, 129, 115, 114, 90, 89, 65. (C 3 ) 2 O 4 X R (C 2 5 ) 2 O 4 n - C 4 9 Br C 2 C 6 5 Cl R VIIa-j VIIIa-z 137

22 TABLE 7 CARACTERIZATIO DATA OF PRODUCT (VIIIa-VIIIz):. o. Product R X Reagent Time (hrs.) M.P. ( 0 C) Yield (%) 1. VIIIa 4-OC 3 -C 3 Dimethyl ulphate VIIIb 3-O 2 -C 3 Dimethyl ulphate 3. VIIIc 2,3-(O-C 2 -O) -C 3 Dimethyl ulphate 4. VIIId 4-O,3-OC 3 -C 3 Dimethyl ulphate 5. VIIIe 4-O 2 -C 3 Dimethyl ulphate 6. VIIIf 2,4-(Cl) -C 3 Dimethyl ulphate 7. VIIIg 4-OC 3 -C 2 5 Diethyl ulphate 8. VIIIh 3-O 2 -C 2 5 Diethyl ulphate 9. VIIIi 2,3-(O-C 2 -O) -C 2 5 Diethyl ulphate 10. VIIIj 4-O,3-OC 3 -C 2 5 Diethyl ulphate 11. VIIIk 4-O 2 -C 2 5 Diethyl ulphate

23 12. VIIIl 2,4-(Cl) -C 2 5 Diethyl ulphate 13. VIIIm -C 2 5 Diethyl ulphate 14. VIIIn 4-OC 3 -C 2 Benzyl C 6 5 Chloride 15. VIIIo 3-O 2 -C 2 Benzyl C 6 5 Chloride 16. VIIIp 2,3-(O-C 2 -O) -C 2 Benzyl C 6 5 Chloride VIIIq 4-O,3-OC 3 -C 2 Benzyl C 6 5 Chloride VIIIr 2-O 2 -C 2 C 6 5 Benzyl Chloride 20. VIIIs 4-OC 3 -C 4 9 Butyl bromide 21. VIIIt 3-O 2 -C 4 9 Butyl bromide 22. VIIIu 2,3-(O-C 2 -O) -C 4 9 Butyl bromide 23. VIIIv 4-O,3-OC 3 -C 4 9 Butyl bromide 24. VIIIw 4-O 2 -C 4 9 Butyl bromide 25. VIIIx 2-O 2 -C 4 9 Butyl bromide

24 26. VIIIy -C 4 9 Butyl bromide ote: All the above compounds were recrystallized from ethanol. 140

25 REULT AD DICUIO ifedipine and its related derivatives which have appeared commercially have one asymmetric centre at C4 if the ester functions are varied at position 3 & 5. The second important aspect for its activity is the boat shaped conformation of the dihydropyridine ring. This aspect is the most important factor in its activity as calcium channel blocker. R 2 R 1 OOC COOR 3 3 C C 3 ifedipine: R 1 = -C 3, R 2 = 2-O 2, R 3 = -C 3 itrendipine : R 1 = - C 3, R 2 = 3-O 2, R 3 = -C 2 C 3 icardipine : R 1 = -C 2 C 2 (C 3 )Bu, R 2 = 3-O 2, R 3 = -C 2 5 Considering these aspects, instead of varying the ester functions, we thought of introducing nitrogen at one of the position C3. Thus, creating the optical activity at C4. It was the thought of preparing such systems and looking back at literature Biginelli had already prepared such systems by acid catalysed condensation of acetoacetic ester, urea & aromatic aldehyde. In line with this, besides substituting thiourea, we introduced cyclic ketone 141

26 viz. 1-indanone as active methylene compound. During the past decade a number of publications and reviews have advocated the advantages of microwave irradiations to carry out organic synthesis. o MORE technique was used for improving the results. The acid catalysed condensation of aromatic aldehyde, 1-indanone & thiourea was carried out in open borosil glass beaker. Ethanol was used as energy transfer medium & reaction mixture was irradiated in domestic microwave oven for minutes. The reaction conditions were optimized. The reaction was followed by thin layer chromatography (TLC) and it was found that maximum yields were obtained at 30% microwave power level. The same reaction was also carried out through thermal heating and it took approx. 5 to 6 hours to complete the reaction. The results have shown that through microwave heating, there is reduction in time, enhancement in the yields and besides this cleaner products are formed i.e. side products are minimized and therefore work-up of the reaction mixture becomes easier. The details about the synthetic procedure are given under experimental section. In most of the cases, the product separated out on keeping the reaction mixture at room temperature for 3-4 hours. 142

27 Other compounds (VIIb VIIj) were also synthesized similarly and are listed in Table 6 along with their characterization data. O CO 2 R 2 C 30 % w Conc. Cl abs. alcohol R VIIa-j TABLE 6 CARACTERIZATIO DATA OF PRODUCT (VIIa VIIj):. o Compd R Reaction time % Yield a M.P. Micro wave Time (min) Reflux Time (hrs) Micro wave Reflux ( 0 C) VIIa 4-OC VIIb 3-O VIIc 2,3-(O-C 2 -O) VIId 4-O,3-OC VIIe 4-O

28 5 247 VIIf 2-C VIIg 2,4-(Cl) VIIh 2-O VIIi VIIj 4-(C 3 ) a Yield of crude product As a case in illustration, compound VIIa was synthesized by taking 4-methoxy benzaldehyde, 1-indanone & thiourea dissolved in absolute alcohol to which catalytic amount of conc. hydrochloric acid was added in a open borosil glass beaker. The reaction mixture was irradiated at 30% microwave power level for 8.00 minutes. The progress of reaction was followed by TLC. The reaction mixture was allowed to stand at room temperature for 5.00 hours and 30 minutes. The product separated was filtered, washed with alcohol and recrystallized out of ethanol. The product had a sharp melting point at C and it was obtained in 52 % yield. The PMR spectra of compound VIIa (Plate 21) showed a characteristic singlet at 5.66 due to 4-C proton. The singlet at

29 and 8.26 were assigned to 1 & 3 protons which got exchanged with D 2 O. A multiplet due to eight protons were observed at A broad singlet was obtained at due to 5-C 2 protons. And a singlet at 3.88 was due to 4-OC 3. IR spectra of compound VIIa (Plate 22) exhibit band for secondary - stretching at cm -1, C- stretching at & cm -1 and C=C stretching vib. at cm -1. Mass spectra of compound VIIa (Plate 23) showed the M peak at m/z 308, M1 peak at m/z 309 and other important peaks at m/z 307, 249, 178, 129, 120. Thus, all the spectral data support the assigned structure VIIa. OC 3 VIIa 145

30 The fragmentation pattern of this compound (VIIa) is given below (Plate 23):. -. m/z = 129 OC 3 m/z = 308 m/z = 307 OC 3 C C 2 C OC 3. m/z = 178 m/z = 249 OC 3 m/z = 129 C OC 3. m/z = 178. C. m/z = 188 OC 3 m/z =

31 A possible fragmentation pattern for the compound VIIi is given below (Plate 24):.. C m/z = 59 m/z = 278 m/z = 219 (12.6%)... m/z = 77 m/z = 201 (9.74%) (91.8%).. C C. m/z = 188 (7.89%). C m/z = 129 m/z = 149 m/z = 90 (1.03%) (1.85%). C. m/z = 173 (2.97%) m/z = 105 (2.77%). C (1.74%) m/z = 114 (18.81%) 147

32 The second aspect of these derivatives was to convert the pyrimidine ring into dihydropyrimidine system. As dihydropyrimidines are commonly proposed to adopt a boat shaped conformation to bind itself to the receptor site. The stereochemical relationship between the aryl group and the dihydropyrimidine ring was found to be one of the factors having pronounced effect on the biological activity. These thiones were converted to their enol derivatives. X A R (C 3 ) 2 O 4 (C 2 5 ) 2 O 4 n - C 4 9 Br C 2 C 6 5 Cl A R VIIa-j VIIIa-y The thiones were converted to their thio ethers where X was -C 3, - C 2 5, - C 2 (C 2 ) 2 C 3 & -C 2 C 6 5. In these cases, thiones was treated with dimethyl sulphate, diethyl sulphate, butyl bromide and benzyl chloride respectively as explained in the experimental section. 148

33 TABLE 7 CARACTERIZATIO DATA OF PRODUCT (VIIIa-VIIIz):. o. Product R X Reagent Time (hrs.) M.P. ( 0 C) Yield (%) 1. VIIIa 4-OC 3 -C 3 Dimethyl ulphate VIIIb 3-O 2 -C 3 Dimethyl ulphate 3. VIIIc 2,3-(O-C 2 -O) -C 3 Dimethyl ulphate 4. VIIId 4-O,3-OC 3 -C 3 Dimethyl ulphate 5. VIIIe 4-O 2 -C 3 Dimethyl ulphate 6. VIIIf 2,4-(Cl) -C 3 Dimethyl ulphate 7. VIIIg 4-OC 3 -C 2 5 Diethyl ulphate 8. VIIIh 3-O 2 -C 2 5 Diethyl ulphate 9. VIIIi 2,3-(O-C 2 -O) -C 2 5 Diethyl ulphate 10. VIIIj 4-O,3-OC 3 -C 2 5 Diethyl ulphate 11. VIIIk 4-O 2 -C 2 5 Diethyl ulphate

34 12. VIIIl 2,4-(Cl) -C 2 5 Diethyl ulphate 13. VIIIm -C 2 5 Diethyl ulphate 14. VIIIn 4-OC 3 -C 2 Benzyl C 6 5 Chloride 15. VIIIo 3-O 2 -C 2 Benzyl C 6 5 Chloride 16. VIIIp 2,3-(O-C 2 -O) -C 2 Benzyl C 6 5 Chloride VIIIq 4-O,3-OC 3 -C 2 Benzyl C 6 5 Chloride VIIIr 2-O 2 -C 2 C 6 5 Benzyl Chloride 20. VIIIs 4-OC 3 -C 4 9 Butyl bromide 21. VIIIt 3-O 2 -C 4 9 Butyl bromide 22. VIIIu 2,3-(O-C 2 -O) -C 4 9 Butyl bromide 23. VIIIv 4-O,3-OC 3 -C 4 9 Butyl bromide 24. VIIIw 4-O 2 -C 4 9 Butyl bromide 25. VIIIx 2-O 2 -C 4 9 Butyl bromide

35 26. VIIIy -C 4 9 Butyl bromide The ultraviolet spectra of -methyl, -ethyl, -butyl and -benzyl did not show any bathochromic shift which would have been possible if the two double bonds in pyrimidine ring got conjugated in the preparation of these derivatives. Thus, the structure VIIIa-VIIIy for two double bonds is suggested. Further, conformation of the total structure was done through PMR, IR and Mass spectral data which is completely in line with the fragmentation of -derivatives. In case of compound VIIIa (Plate 25), the PMR spectrum showed a characteristic singlet at 5.35 due to 4-C proton and a two proton singlet at 2.1due to C 5 -C 2. A multiplet was observed at due to eight aromatic protons and 1 proton. And a singlet at 3.89 was due to 4-OC 3. Also a singlet was obtained at 2.72 due to -C 3 protons. Thus, the PMR spectra of VIIIa (Plate 25) showed a characteristic difference when compared with PMR spectra of VIIa (Plate 21). The obvious and expected difference in PMR spectra was due to -methyl group. Mass spectra of compound VIIIa (Plate 26) showed the M peak at m/z 322, M1 peak at m/z 323 and other important peaks at m/z 321, 320, 289, 274, 155,

36 A possible fragmentation pattern for the compound VIIIa is given below (Plate 26): C 3. C 3 OC 3 OC 3 m/z = C 3 C C 3 m/z = 321 OC 3 m/z = OC 3 C 3 m/z = 155 OC 3 - C 3. - C 3. m/z = 289 m/z = 274 OC 3 - CO m/z = 129 m/z = 178 OC 3 m/z = 167 m/z =

37 A possible fragmentation pattern for the compound VIIIg is given below (Plate 28): C 2 C 3. C 2 C 3 -. OC 3 OC 3 m/z = 336 m/z = C 2 C. C 2 C 3 OC 3 OC 3 m/z = 87 m/z = 249 m/z = CO. 3 C 2 C m/z = 140 OC 3 m/z = 219. C 2 C 3 m/z = 129 OC 3 m/z =

38 A possible fragmentation pattern for the compound VIIIn is given below (Plate 29): C 2 C C 2 C 6 5 C 2 m/z = 398 OC 3 m/z = 90 m/z = C 2 C 6 5 OC 3 C -. m/z = 396 OC 3 C 2 C 6 5 m/z = 149 OC 3 - C 2 C 6 5 m/z = OC 3 m/z = CO m/z = 273 OC 3 C 2 C 6 5 m/z = 365 m/z = C 6 2 C C C 2 m/z = 320 OC 3 C 2 C C 6 2 C m/z = 307 OC 3 m/z = 91 C 2. m/z = 77 m/z = 175 C C OC 3 m/z =

39 A possible fragmentation pattern for the compound VIIIs is given below (Plate 31): C 4 9 C OC 3 m/z = 364 OC 3 m/z = C 4 9 m/z = OC 3 OC 3 C 4 9 C C 4 9. m/z = 275 m/z = 331 m/z = 249. m/z = 129 OC 3 m/z =

40 A possible fragmentation pattern for the compound VIIIm is given below (Plate 32):.. C 2 5 C m/z = 306 m/z = C C 2 5. m/z = 61. m/z = 77 (32%) C m/z = 276 (100%) m/z = C 2 =C 2 m/z = 244 (45.4%).. m/z = 202 (10%) C C 2 5 m/z = 219 (50%). m/z = 87 (11%) 156