Chapter IV. Synthesis of 1,3,4-oxadiazole derivatives containing quinoline moiety bearing azetidin-2-one / thiazolidin-4- one / tetrazole.

Transcription

1 Chapter IV Synthesis of 1,3,4-oxadiazole derivatives containing quinoline moiety bearing azetidin-2-one / thiazolidin-4- one / tetrazole.

2 Introduction Oxadiazole [1] is five member cyclic compound with one oxygen and two nitrogen atoms in the ring ,3,4-oxadiazoles have occupied unique place in the field of medicinal chemistry due to their wide range of activities 197. The review of literature shows that 1,3,4-oxadiazole nucleus possess antimicrobial 198, antifungal 199, antiinflammatory 200, anticonvulsant 201, antioxidant, analgesic 202 and mutagenic acctivity 203. Number of drugs available in the market such as tiodazosin, nosapidil, furamizole are 1,3,4-oxadiazole derivatives 204. Apart from these biological activities, 1,3,4-oxadiazole derivatives were found to have some material applications in the field of liquid crystals and photosensitizer 205. Literature survey reveals that 1,3,4-oxadiazole derivatives posses a broad spectrum of biological activities Some important biologically potent 1,3,4-oxadiazole derivatives reported in the literature were shown in the following table-4.0.

3 113 Table-4.0 Biologically potent 1,3,4-oxadiazole derivatives S.No Compound Activity Reference 1 Antimicrobial Liszkiewicz et al [210] 2 Antimicrobial 3 Antibacterial Shawali and co-workers [211] Lokanatha Rai and Lingann [212] 4 Anti convulsant Khan and coworkers [213] 5 Antimicrobial Lee et al [214] 6 Antibacterial Zhang [215] 7 Antimicrobial Gadaginamath and Pujar [216] 8 Antiinflammatory Virginija Jakubkiene [217] 9 Antiinflammatory and antibacterial Khan and coworked [218]

4 Milda Malvina Burbuliene et al [219] 11 Antimicrobial and anti inflammatory Ravindra [220] 12 Anti mycobacterial Mohamed Ashraf Ali et al [221] 13 Analgesic A. Husain et al [222] 14 Anti proliferative Al-Masoudi et al [223] 15 Antimicrobial H.S.Yathirajan [224] 16 Antiinflammatory Antiinflammatory Trilok Chandra et al [225]

5 Present work 1,3,4-oxadiazoles belong to the group of heterocycles that have been attracting attention of chemist in search for the new therapeutic molecules. Many of them exhibit antibacetrial, antitubercular, antifungal, anti-inflammatory activities Substituted 1,3,4-Oxadiazoles are of considerable pharmaceutical and material interest, which is documented by a steadily increasing number of publications and patents. For instance, 1,3,4-oxadiazole derivatives of biphenyl-4-yloxy acetic acid were synthesized and tested for their anti-inflammatory activity and analgesic activity. Furthermore a series of 5-(2-hydroxyphenyl)-3- substituted-2,3-dihydro-1,3,4-oxadiazole-2-thione derivatives were synthesized and evaluated for their in vitro anticancer activity. Similarly a broad spectrum pharmacological active 1,3,4-oxadiazoles containing 2-mercapto moiety were synthesised and screened for in vivo anticonvulsant activity. Prompted by the above observations, a project was under taken to synthesize a series of quinoline-oxadiazole derivatives containing azetidin-2-one, thiazolidin-4-one and tetrazole nuclei and the newly formed compounds were screened for their antimicrobial activities. In this chapter, we describe the synthesis and characterization of 5-((4-(trifluoromethyl)benzylidene)amino)quinolin-8-ol (C) 3-chloro-1-(8-hydroxyquinolin-5-yl)-4-(4-(trifluoromethyl)phenyl) azetidin-2-one (1a)

6 116 3-(8-hydroxyquinolin-5-yl)-2-(4-(trifluoromethyl)phenyl) thiazolidin-4-one (1b) 5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8-ol (1c) 1-yl)quinolin-8-yl)oxy)acetate(2a) Ethyl-2-((5-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl) quinolin-8-yl)oxy)acetate (2b) yl)quinolin-8-yl)oxy)acetate (2c) 2-((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl)phenyl)azetidin-1-yl) quinolin-8-yl)oxy)acetohydrazide (3a) yl)quinolin-8-yl)oxy) acetohydrazide (3b) yl) oxy)acetohydrazide (3c) 3-chloro-1-(8-((5-(4-substitutedphenyl)-1,3,4-oxadiazol-2-yl) one (4a-e) 3-(8-((5-(4-substitutedphenyl)-1,3,4-oxadiazol-2-yl)methoxy) quinolin-5-yl)-2-(4-(trifluoromethyl) phenyl)thiazolidin-4-one (5a-e) Ethyl-2-((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl)phenyl)azetidin- Ethyl-2-((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-2-((5-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-2-((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8- methoxy)quinolin-5-yl)-4-(4-(trifluoromethyl)phenyl)azetidin-2-2-(4-substitutedphenyl)-5-(((5-(5-(4-(trifluoromethyl)phenyl)-1htetrazol-1-yl)quinolin-8-yl)oxy)methyl)-1,3,4-oxadiazole (6a-e)

7 117 The synthetic routes pertaining to the synthesis of 1,3,4- oxadiazole derivatives were shown in six schemes Synthesis of 3-chloro-1-(8-hydroxyquinolin-5-yl)-4-(4- (trifluoro methyl)phenyl)azetidin-2-one (1a) The synthon 5-((4-(trifluoromethyl)benzylidene)amino)quinolin- 8-ol (C) used in the synthesis of 3-chloro-1-(8-hydroxyquinolin-5-yl)-4- (4-(trifluoromethyl)phenyl)azetidin-2-one (1a) was described in the chapter-3. The compound 5-((4-(trifluoromethyl)benzylidene)amino) quinolin-8-ol (C) on treatment with chloro acetylchloride yielded 3- chloro-1-(8-hydroxyquinolin-5-yl)-4-(4-(trifluoromethyl)phenyl) azetidin-2-one (1a) 31,32. The progress of the reaction was monitored by TLC with acetone:ethyl acetate (7:3) as eluent. The structure of 3- chloro-1-(8-hydroxyquinolin-5-yl)-4-(4-(trifluoromethyl)phenyl)azetidin -2-one (1a) was confirmed by IR, 1 H-NMR. Reagents and Conditions: (i) Chloroacetyl chloride, Triethyl amine, Dioxane, 8h, 58% Scheme-4.2: Synthesis of 3-chloro-1-(8-hydroxyquinolin-5-yl)-4-(4- (trifluoromethyl) phenyl)azetidin-2-one (1a)

8 118 IR (KBr) spectra of 3-chloro-1-(8-hydroxyquinolin-5-yl)-4-(4- (trifluoromethyl)phenyl) azetidin-2-one (1a) shows signals at around 3340 cm -1, 1690 cm -1 and 677 cm -1 due to stretching vibrations of OH, >C=O, C-Cl respectively supported the structural formation of 1a. 1 H NMR(300MHz) spectra of 3-chloro-1-(8-hydroxyquinolin-5- yl)-4-(4-(trifluoromethyl)phenyl) azetidin-2-one (1a) was recorded in DMSO-d6 solvent. The 3-chloro-1-(8-hydroxyquinolin-5-yl)-4- phenylazetidin-2-one (1a) shows signals at δppm:4.6(s,1h,- OH),5.16(d,1H,-CH of azetidin attached to phenyl ring), 5.44(d,1H,-CH of azetidin attached to Cl), (m, 9H, C6H4, C9H5N of quinoline ring) supported the structural formation of 1a Synthesis of 3-(8-hydroxyquinolin-5-yl)-2-(4-(trifluoro methyl)phenyl)thiazolidin-4-one (1b) The compound 5-((4-(trifluoromethyl)benzylidene)amino) quinolin-8-ol (C) was converted into 3-(8-hydroxyquinolin-5-yl)-2-(4- (trifluoromethyl)phenyl)thiazolidin-4-one (1b) on treatment with mercaptoacetic acid in presence of anhydrous zinc chloride 31,32. The progress of the reaction was monitored by TLC with acetone:ethyl acetate (7:3) as eluent. The structure of 3-(8-hydroxyquinolin-5-yl)-2- phenylthiazolidin-4-one (1b) was established by IR, 1 H-NMR.

9 119 Reagents and Conditions: (i) Thioglycolic acid, Zinc Chloride, Dioxane, 8h, 62% Scheme-4.2: Preparation of 3-(8-hydroxyquinolin-5-yl)-2-(4- (trifluoromethyl)phenyl)thiazolidin-4-one (1b) IR (KBr) spectra of 3-(8-hydroxyquinolin-5-yl)-2-(4- (trifluoromethyl) phenyl)thiazolidin-4-one (1b) shows signals at around 3340cm -1, 1690 cm -1 and 1156 cm -1 due to stretching vibrations of OH, >C=O, C-S / bending vibrations of OH respectively supported the structural formation of 1b. 1 HNMR(300MHz) spectra of 3-(8-hydroxyquinolin-5-yl)-2-(4- (trifluoro methyl)phenyl)thiazolidin-4-one (1b) was recorded in DMSOd6 and showed the signals at δppm: 4.6(s,1H,-OH),6.44(s,1H,-CH of thiazolidinone attached to phenyl ring), 3.85(d,1H,-CH2 of thiazolidinone), 3.97(d,1H,-CH2 of thiazolidinone), (m, 9H, C6H4, C9H5N of quinoline) supported the structural formation of 1b Synthesis of 5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1- yl)quinolin-8-ol (1c) 33 The compound 5-((4-(trifluoromethyl)benzylidene)amino) quinolin-8-ol (C) was converted 55-(5-(4-(trifluoromethyl)phenyl)-1Htetrazol-1-yl)quinolin-8-ol (1c) on treatment with sodium azide in

10 120 Tetrahydrofuran. The progress of the reaction was monitored by TLC with acetone:ethylacetate (7:3) as eluent. The structure of 5-(5-phenyl- 1H-tetrazol-1-yl)quinolin-8-ol (1c) was established by IR, 1 H-NMR and analytical data. Reagents and Conditions: (i) PCl3, C, 1h (ii) Sodium azide (icecold), Zinc Chloride, Sodium acetate, acetone, water RT, 55% Scheme-4.3: Preparation of 5-(5-(4-(trifluoromethyl)phenyl)-1Htetrazol-1-yl)quinolin-8-ol (1c) IR (KBr) spectra of 5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol- 1-yl)quinolin-8-ol (1c) shows signals at around 3340cm -1, 1157, 2120 cm -1 due to stretching vibrations of OH, tetrazole, Azide respectively supported the structural formation of 1c. 1 H NMR(300MHz) Spectra of 5-(5-(4-(trifluoromethyl)phenyl)- 1H-tetrazol-1-yl)quinolin-8-ol (1c) was recorded in DMSO-d6 solvent and showed the signals at δppm: 4.6(s,1H,-OH), (m, 9H, C6H4, C9H5N of quinoline ring) supported the structural formation of 1c.

11 Synthesis of Ethyl-2-((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl) phenyl) azetidin-1-yl) quinolin-8-yl) oxy) acetate(2a) /Ethyl- 2- ((5-(4-oxo -2- (4-(trifluoro methyl) phenyl) thiazolidin -3-yl) quinolin-8-yl)oxy)acetate (2b)/ Ethyl 2-((5-(5- (4-(trifluoro methyl) phenyl)-1h-tetrazol-1-yl) quinolin-8-yl)oxy)acetate (2c) A mixture of 3-chloro-1-(8-hydroxyquinolin-5-yl)-4-(4- (trifluoromethyl) phenyl)azetidin-2-one (1a) / 3-(8-hydroxyquinolin-5- yl)-2-(4-(trifluoro methyl)phenyl)thiazolidin-4-one (1b) / 5-(5-(4- (trifluoromethyl)phenyl)-1h-tetrazol-1-yl)quinolin-8-ol (1c) anhydrous K2CO3, chloro ethyl acetate and DMF were stirred at room temperature for 8 hours. The progress of the reaction was monitored by TLC with acetone:ethylacetate (7:3) as eluent. The reaction mixture was diluted with ice cold water. The separated solid was identified as Ethyl-2-((5- (3-chloro-2-oxo-4-(4-(trifluoromethyl)phenyl) azetidin-1-yl)quinolin-8- yl)oxy)acetate (2a) / Ethyl-2-((5-(4-oxo-2-(4-(trifluoromethyl)phenyl) thiazolidin-3-yl)quinolin-8-yl)oxy)acetate (2b) / Ethyl-2-((5-(5-(4- (trifluoromethyl)phenyl)-1h-tetrazol-1-yl)quinolin-8-yl)oxy)acetate (2c).

12 122 Reagents and conditions: (i) Chloroethylacetate, DMF, K2CO3, RT, 8h, 68-74% Scheme-4.4: preparation of Ester derivatives Synthesis of 2-((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl) phenyl)azetidin-1-yl)quinolin-8-yl)oxy)acetohydrazide (3a) /2-((5-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl) quinolin-8-yl) oxy) acetohydrazide (3b)/ 2- ((5- (5- (4- (trifluoromethyl) phenyl) -1H-tetrazol -1-yl) quinolin-8-yl) oxy) acetohydrazide (3c) A solution of Ethyl-2-((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl) phenyl) azetidin-1-yl)quinolin-8-yl)oxy)acetate (2a)/ Ethyl-2-((5-(4-oxo- 2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)quinolin-8-yl)oxy) acetate (2b)/Ethyl- 2- ((5- (5- (4- (trifluoro methyl) phenyl) -1H-tetrazol -1-yl)

13 123 quinolin-8-yl)oxy)acetate (2c) and hydrazine hydrate in ethanol was refluxed for 5 hours. The reaction mixture was cooled and poured on to ice cold water with stirring. The separated solid was filtered, washed with water and recrystalised from ethanol to afford 2-((5-(3- chloro-2-oxo-4-(4-(trifluoromethyl)phenyl)azetidin-1-yl)quinolin-8-yl) oxy) aceto hydrazide(3a)/2-((5-(4-oxo-2-(4-(trifluoro methyl)phenyl) thiazolidin-3-yl) quinolin- 8-yl) oxy) acetohydrazide (3b)/2-((5-(5-(4- (trifluoromethyl) phenyl) -1H tetrazol -1-yl) quinolin- 8-yl) oxy) aceto hydrazide (3c) respectively. The structures of these newly synthesized compounds (3a-c) were characterized by their spectral data ( 1 H-NMR, and IR) and analytical data was given in the table O N S CF 3 i O N S CF3 N O O 2b O CH 3 N O NH 3b NH 2 O Reagents and conditions: (i) N2H4.H2O, Ethanol,reflux, 5h, 68% Scheme-4.5: Preparation acidhydrazides

14 124 IR SPECTRAL DATA The IR (KBr) spectral data of 2-((5-(3-chloro-2-oxo-4-(4-(trifluoro methyl)phenyl)azetidin-1-yl)quinolin-8-yl)oxy)acetohydrazide (3a) / 2-((5-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)quinolin-8-yl) oxy)acetohydrazide (3b)/ 2- ((5- (5- (4- (trifluoro methyl) phenyl)-1htetrazol-1-yl)quinolin-8-yl)oxy)acetohydrazide (3c) was given in the table 4.1. The spectrum of 3c was shown in the fig 4.1. Table 4.1: IR spectral data of 2-((5-(3-chloro-2-oxo-4-(4-(trifluoro methyl)phenyl)azetidin-1-yl)quinolin-8-yl)oxy) aceto hydrazide (3a)/ 2-((5- (4-oxo -2-(4- (trifluoro methyl) phenyl) thiazolidin- 3- yl) quinolin- 8- yl) oxy) aceto hydrazide (3b) / 2-((5-(5-(4-(trifluoromethyl)phenyl)-1Htetrazol-1-yl)quinolin-8-yl)oxy) acetohydrazide (3c) Comp vmax in cm -1 3a 3b 3c 3496, 3413 (2 bands), 3205, 1620, 1690 cm -1 and these are due to NH2, >NH exo > C = N & cyclic carbonyl in four membered hetero cyclic ring respectively. 3498, 3416 (2 bands), 3200, 3040, 1620, 1698, 1188 cm -1 and these are due to NH2, >NH, Ar -H str, exo > C = N, cyclic carbonyl in five membered hetero cyclic ring and C-S respectively. 3498, 3416 (2 bands), 3200, 3040, 1620, 1698, 1157, 2107 cm -1 and these are due to NH2, >NH, Ar -H str, exo>c=n, C=O, Tetrazole and azide respectively

15 125 1 H-NMR SPECTRAL DATA The 1 H NMR (300MHz) spectra of 2-((5-(3-chloro-2-oxo-4-(4- (trifluoromethyl)phenyl)azetidin-1-yl)quinolin-8-yl)oxy)acetohydrazide (3a)/ 2-((5-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)quinolin -8-yl)oxy)acetohydrazide (3b) / 2-((5-(5-(4-(trifluoromethyl)phenyl)-1Htetrazol-1-yl)quinolin-8-yl)oxy)acetohydrazide (3c) was recorded in DMSO-d6. The data was given in the table 4.2. The spectrum of 3c was shown in the fig: 4.2. Table 4.2: 1 HNMR spectral data of 2-((5-(3-chloro-2-oxo-4-(4- (trifluoromethyl)phenyl)azetidin-1-yl)quinolin-8-yl)oxy) aceto hydrazide (3a) / 2-((5-(4-oxo-2-(4-(trifluoro methyl)phenyl) thiazolidin-3-yl)quinolin-8-yl)oxy) aceto hydrazide (3b) / 2-((5-(5-(4-(trifluoromethyl)phenyl)- 1H-tetrazol-1-yl)quinolin-8-yl)oxy) acetohydrazide (3c) Comp 1 HNMR (DMSO-d6) (δ ppm) 3a 3b 3c 2.10(s,2H,-NH2), 5.16(d,1H,-CH of azetidin attached to phenyl ring), 5.44(d,1H,-CH of azetidin attached to Cl), 4.8(s,2H,-O-CH2), (m,9H, C6H4, C9H5N of quinoline ring), 9.54(s, 1H, -NH). 2.05(s,2H,-NH2), 6.44(s,1H,-CH of Thiazolidin attached to phenyl ring), 3.85(d,1H,-CH2 of Thiazolidin attached to S), 3.99(d,1H,-CH2 of Thiazolidin attached to S), 4.58(s,2H,-O-CH2), (m, 9H of C6H4 & C9H5N of quinoline), 10.10(s, 1H, -NH) 2.05(s,2H,-NH2), 4.58(s,2H,-O-CH2), (m, 9H of C6H4 & C9H5N of quinoline), 10.10(s, 1H, -NH).

16 Synthesis of 3-chloro-1-(8-((5-(4-substitutedphenyl)-1,3,4- oxadiazol -2-yl) methoxy) quinolin- 5-yl) -4- (4- (trifluoro methyl) phenyl)azetidin-2-one (4a-e) Regents and Conditions: (i) 4-substituted benzoic acid, POCl3, reflux, 5-6h, 48%. Scheme-4.6: Preparation of 1,3,4-Oxadiazoles of quinoline- Azetidinone Comp 4a 4b 4c 4d 4e R 4-F 4-Cl 4-Br 4-NO2 4-CF3 A mixture of different 4-fluorobenzoic acid (0.01mol) with compound 2-((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl)phenyl)azetidin- 1-yl)quinolin-8-yl)oxy)acetohydrazide (3a) (0.01mol) in phosphoryl chloride (15ml) was refluxed over a steam bath for 5-6 h. The progress of the reaction was monitored by TLC using acetone:ethylacetate (6:4) as eluent. The reaction mixture was cooled and poured on to crushed ice (~200g) with continuous stirring. The solid mass separated was neutralized with sodium bicarbonate solution (10% w/v). The resulting solid thus obtained was collected by filtration, washed well with cold water, dried in vacuum and recrystallized from absolute ethanol (95%) and analysed. Based on the spectral data the compound was assigned 3-chloro-1-(8- ((5- (4-fluorophenyl) -1,3,4- oxadiazol -2-yl) methoxy) quinolin-5-yl)-4-(4- (trifluoromethyl)phenyl)azetidin-2-one (4a). By adopting the similar

17 127 procedure, other compounds of this series (4b-e) were prepared and their analytical data are given in Table The structures of these newly synthesized compounds (4a-e) were characterized by spectral data 1 H-NMR, 13 C-NMR, IR, and Mass. 1 H NMR Spectra The 1 HNMR (300 MHz) spectrum of 3-chloro-1-(8-((5-(4- fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolin-5-yl)-4-(4- (trifluoromethyl)phenyl)azetidin-2-one (4a) in DMSO d6 showed the following signals at δppm 4.21(s,2H,-O-CH2), 5.16(d,1H,-CH of azetidin attached to phenyl ring), 5.44(d,1H,-CH of azetidin attached to Cl), (m,13H, C6H4 & C6H4 of two phenyl groups & C9H5N of quinoline ring) supported the structural formation of 4a. The 1 H-NMR data of (4a-e) were shown in the Table 4.3 and 1 H-NMR spectra of 4a was shown in the fig 4.3. Table 4.3: 1 H NMR spectral data of 3-chloro-1-(8-((5-(4-substituted phenyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolin-5-yl)-4-(4- (trifluoromethyl) phenyl)azetidin-2-one (4a-e) Comp R 1 HNMR (DMSO-d6) (δ ppm) 4a F 4.21(s,2H,-O-CH2), 5.16(d,1H,-CH of azetidin attached to phenyl ring), 5.44(d,1H,-CH of azetidin attached to Cl), (m,13h, C6H4, C6H4 of two phenyl groups & C9H5N of quinoline). 4b Cl 4.20(s,2H,-O-CH2), 5.14(d,1H,-CH of azetidin attached to phenyl ring), 5.42(d,1H,-CH of azetidin attached to Cl), (m,13h, C6H4, C6H4 of two phenyl groups & C9H5N of quinoline).

18 128 4c Br 4.22(s,2H,-O-CH2), 5.15(d,1H,-CH of azetidin attached to phenyl ring), 5.43(d,1H,-CH of azetidin attached to Cl), (m,13h, C6H4, C6H4 of two phenyl groups & C9H5N of quinoline). 4d NO2 4.28(s,2H,-O-CH2), 5.16(d,1H,-CH of azetidin attached to phenyl ring), 5.44(d,1H,-CH of azetidin attached to Cl), (m,13h, C6H4, C6H4 of two phenyl groups & C9H5N of quinoline). 4e CF3 4.24(s,2H,-O-CH2), 5.16(d,1H,-CH of azetidin attached to phenyl ring), 5.44(d,1H,-CH of azetidin attached to Cl), (m,13h, C6H4, C6H4 of two phenyl groups & C9H5N of quinoline). 13 C NMR Spectra The 13 C-NMR (75MHz) spectra of 3-chloro-1-(8-((5-(4- fluorophenyl) -1,3,4 -oxadiazol- 2-yl) methoxy) quinolin-5 -yl) -4- (4- (trifluoromethyl) phenyl)azetidin-2-one (4a) was recorded in CDCl3 showed the signals at δppm 146, 107, 116, 133, 131, 120, 139, 126, 129, 162, 62, 68, 72, 163, 165 and the signals are ascribed to C1, 7&10, C2, C3&23, C4, C5, C6, 9&21, C8, C11, 12&14, C13&22, C14, C15, C16, C17, C18, C19&24 and C20 carbon atoms respectively supported the structural formation of 4a. The 13 C-NMR data of (4a-e) were shown in the Table 4.4 and the 13 C-NMR of 4a was shown in fig 4.4.

19 129 Table 4.4: 13 C NMR spectral data of 3-chloro-1-(8-((5-(4- substitutedphenyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolin-5-yl)-4-(4- (trifluoromethyl)phenyl)azetidin-2-one (4a-e) Comp Structure 13 CNMR (CDCl3) (δ ppm) 4a 146, 107, 116, 133, 131, 120, 139, 126, 129, 162, 62, 68, 72, 163, 165 and the signals are ascribed to C1, 7&10, C2, C3&23, C4, C5, C6, 9&21, C8, C11, 12&14, C13&22, C14, C15, C16, C17, C18, C19&24 and C20 respectively 4b 4c 4d 4e 6 N O N O Cl O N N CF NO 146, 107, 116, 133, 131, 120, 139, 126, 129, 162, 62, 68, 72, 163, 165, 134 and the signals are ascribed to C1, 7&10, C2, C3, C4, C5, C6, 9, C7, C8, C11, 12, 14&21, C13, 22&23, C15, C16, C17, C18, C19, C20 & C24 respectively. 146, 107, 116, 133, 131, 121, 139, 125, 129, 162, 62, 68, 72, 163, 165, 130, 132 and the signals are ascribed to C1, 7&10, C2, C3, C4, C5, C6, 9, C8, C11, 12, 14, 21&24, C13C15, C16, C17, C18, C19, C20, C22 & C23 respectively. 146, 107, 116, 133, 130, 122, 139, 126, 129, 162, 62, 68, 72, 163, 165, 132, 148 and the signals are ascribed to C1, 7&10, C2, C3, C4, C5&22, C6, 9, C8, C11, C12&14, C13&23, C15, C16, C17, C18, C19, C20, C21 and C24 respectively. 146, 107, 116, 133, 130, 121, 139, 126, 129, 162, 62, 68, 72, 163, 165, 127, 131 and the signals are ascribed to C1,7&10, C2, C3, C4, C5, C6,9, C8, C11,12,14,23&25, C13, C15, C16, C17, C18, C19, C20, C21, C22 and C24 respectively.

20 130 IR Spectra The IR (KBr) spectra 3-chloro-1-(8-((5-(4-fluorophenyl)-1,3,4- oxadiazol-2-yl)methoxy)quinolin-5-yl)-4-(4-(trifluoromethyl)phenyl) azetidin-2-one (4a) showed characteristic strong absorption bands around 3040(Ar-H str), 1692 (C=O), 1617 (-C=N), 1150 (-C-O-C), 1135(N-N) and 833(C-Cl) cm -1 which supports the structural formation of 4a.The IR data of (4a-e) were shown in the Table 4.5 and IR spectra of 4a was shown in the fig 4.5. Table 4.5 : IR data of 3-chloro-1-(8-((5-(4-substitutedphenyl)- 1,3,4-oxadiazol-2-yl)methoxy)quinolin-5-yl)-4-(4- (trifluoro methyl)phenyl)azetidin-2-one (4a-e) Comp R vmax in cm -1 Ar-H C=O C=N C-O-C N-N C-Cl 4a F b Cl c Br d NO e CF Mass spectra The mass spectrum of 3-chloro-1-(8-((5-(4-fluoro phenyl)-1,3,4- oxadiazol- 2-yl) methoxy) quinolin- 5-yl) -4- (4-(trifluoromethyl)phenyl) azetidin-2-one (4a) exhibited the molecular ion (M + ) peak at m/z = The m/z value of molecular ion indicates that molecule is having even number of nitrogens.

21 131 The primary fragmented pattern in the mass spectrum of 3- chloro-1- (8- ((5- (4- substituted phenyl)-1,3,4-oxadiazol-2-yl)methoxy) quinolin -5-yl) -4-(4- (trifluoro methyl) phenyl) azetidin-2-one was presented in Chart 4-1. The molecular ion ( ) peak was observed at m/z= (22.5%) and the base peak was at m/z= (100%). Other important primary fragmented peaks appeared at different m/z values were shown in the following table Table 4.6 : The primary fragmented mass spectral data of 3-chloro-1-(8-((5- (4-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolin-5-yl)-4- (4-(trifluoromethyl) phenyl)azetidin-2-one (4a) Molecular Ion C28H17ClF4N4O3 (M + ) M + : Lost free radical C6H4F. C7H4F3. C8H4FN2O. C9H6FN2O. Primary fragmented ion C22H13ClF3N4O3 + (A) C21H13ClFN4O3 + (B) C20H13ClF3N2O2+ (C) C19H11ClF3N2O2+ (D) m/z RA % C10H6ClF3NO. C18H11FN3O2+ (E) C18H11FN3O2. C10H6ClF3NO+ (F) C19H11ClF3N2O2. C9H6FN2O+ (G) C20H13ClF3N2O2. C8H4FN2O+ (H) C21H13ClFN4O3. C7H4F3+(I) C22H13ClF3N4O3. C6H4F+(J)

22 132 The molecular ion signal is obeying nitrogen rule, while the primary fragmented ions derived from molecular ion signal are not obeying nitrogen rule. M and M+2 peaks of molecular ion was observed at m/z at and in a ratio of 3:1 indicates the presence of one chlorine atom in molecular ion Synthesis of 3-(8-((5-(4-substitutedphenyl)-1,3,4-oxadiazol- 2-yl)methoxy)quinolin-5-yl) -2-(4- (trifluoro methyl) phenyl) thiazolidin-4-one (5a-e) Regents and Conditions: (i) 4-substituted benzoic acid, POCl3, reflux, 5-6h, 62%. Scheme-4.7: Preparation of 1,3,4-Oxadiazoles of quinolinethiazolidine. Comp 5a 5b 5c 5d 5e R 4-F 4-Cl 4-Br 4-NO2 4-CF3 A mixture of 4-Fluorobenzoic acid (0.01mol) with compound 2- ((5-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)quinolin-8-yl) oxy)acetohydrazide (3b) in phosphoryl chloride (15ml) was refluxed over a steam bath for 5-6 h. The progress of the reaction was monitored by TLC using acetone:ethylacetate (6:4) as eluent. The reaction mixture was cooled and poured on to crushed ice (~200g) with continuous stirring. The solid mass separated was neutralized with sodium bicarbonate solution (10% w/v). The resulting solid thus

23 133 obtained was collected by filtration, washed well with cold water, dried in vacuum and recrystallized from absolute ethanol (95%) and analysed. Basedon the spectral data the compound was assigned 3-(8- ((5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolin-5-yl)-2-(4- (trifluoromethyl) phenyl)thiazolidin-4-one (5a). The reaction process leading to the synthesis of 3-(8-((5-(4-fluorophenyl)-1,3,4-oxadiazol-2- yl)methoxy)quinolin-5-yl)-2-(4-(trifluoromethyl)phenyl)thiazolidin-4- one (5a) was extended to the syntheses of (5b-e) and their analytical data were given in Table The structures of these newly synthesized compounds (5a-e) were characterized by their elemental analysis and spectral data ( 1 H- NMR, IR, and Mass). 1 HNMR Spectra The 1 HNMR (300 MHz) spectra of 3-(8-((5-(4-fluorophenyl)-1,3,4- oxadiazol-2-yl)methoxy)quinolin-5-yl)-2-(4-(trifluoromethyl) phenyl)thiazolidin-4-one (5a) was recorded in DMSO-d6 showed the following signals at δppm 3.87(d,1H,-CH2 of Thiazolidinone), 3.99(d,1H,-CH2 of Thiazolidinone), 4.21(s,2H,-O-CH2), 6.44(s,1H,-CH of Thiazolidin attached to phenyl ring), (m,14h, C6H5, C6H4 and C9H5N of quinoline ring) supported the structural formation of 5a. The 1 H-NMR spectra of (5a-e) were shown in the Table 4.7. The 1 H- NMR spectra of (5a) was shown in the figure 4.6

24 134 Table 4.7: 1 H NMR spectral data of 3-(8-((5-(4-substituted phenyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolin-5-yl)- 2-(4-(trifluoromethyl) phenyl)thiazolidin-4-one (5a-e) Comp R 1 HNMR (DMSO-d6) (δ ppm) 5a F 3.87(d,1H,-CH2 of Thiazolidinone), 3.99(d,1H,- CH2 of Thiazolidinone),4.21(s,2H,-O-CH2), 6.44 (s,1h,-ch of Thiazolidin attached to phenyl ring), (m,13h, C6H4, C6H4 and C9H5N of quinoline). 5b Cl 3.85(d,1H,-CH2 of Thiazolidinone), 3.99(d,1H,- CH2 of Thiazolidinone), 4.20(s,2H,-O-CH2), 6.44(s,1H,-CH of Thiazolidin attached to phenyl ring), (m,13h, C6H4, C6H4 and C9H5N of quinoline). 5c Br 3.80(d,1H,-CH2 of Thiazolidinone), 3.92(d,1H,- CH2 of Thiazolidinone), 4.24(s,2H,-O-CH2), 6.44(s,1H,-CH of Thiazolidin attached to phenyl ring), (m,13H, C6H4, C6H4 and C9H5N of quinoline). 5d NO2 3.87(d,1H,-CH2 of Thiazolidinone), 3.94(d,1H,- CH2 of Thiazolidinone), 4.26(s,2H,-O-CH2), 6.44(s,1H,-CH of Thiazolidin attached to phenyl ring), (m,13h, C6H4, C6H4 and C9H5N of quinoline). 5e CF3 3.87(d,1H,-CH2 of Thiazolidinone), 3.95(d,1H,- CH2 of Thiazolidinone), 4.22(s,2H,-O-CH2), 6.48(s,1H,-CH of Thiazolidin attached to phenyl ring), (m,13h, C6H4, C6H4 and C9H5N of quinoline).

25 CNMR Spectra The 13 C-NMR(75MHz) spectra of 3-(8-((5-(4-fluorophenyl)-1,3,4- oxadiazol-2-yl)methoxy)quinolin-5-yl)-2-(4-(trifluoromethyl)phenyl) thiazolidin-4-one (5a) was recorded in CDCl3 showed the 20 signals at δppm: 146, 107, 116, 133, 130, 121, 139, 142, 129, 126, 171, 33, 74, 72, 163, 165, 162 and the signals are ascribed to C1&7, C2, C3&23, C4, C5, C6, 9&21, C8, C10, C11, 12, 13, 14&22, C12, C14, C15, C16, C17, C18, C19, C20 and C24 carbon atoms respectively supported the structural formation of 5a. The 13 C-NMR data of (5a-e) were shown in the Table 4.8 and the 13 C-NMR spectra of (5a) was shown in the fig 4.7. Table 4.8: 13 C NMR spectral data of 3-(8-((5-(4-substitutedphenyl)- 1,3,4-oxadiazol-2-yl)methoxy)quinolin-5-yl)-2-(4-(trifluoro methyl) phenyl)thiazolidin-4-one (5a-e) Comp Structure 13 CNMR (CDCl3) (δ ppm) 5a 146,107,116,133,130,121,139,142,129,126, 171,33,74,72,163,165,162 and the signals are ascribed to C1&7,C2,C3&23,C4,C5,C6,9&21,C8, 5b 5c C10,C11,12,13,14&22,C12,C15,C16,C17,C18,C19,C20 and C24 respectively. 147,107,116,133,130,120,139,142,129,125, 171,33,74,72,163,165,135 and the signals are ascribed to C1&7,C2,C3,C4,C5,C6&9,C7,C8, C10,C11&13,22&23,C12,14&21,C15,C16,C17,C18, C19,C20 and C24, respectively. 146,107,116,133,130,121,139,142,129,126, 171,33, 74,72,163,165,125,132,123 and the signals are ascribed to C1&7,C2,C3,C4,C5,C6&9, C8,C10,C11,13&22,C12&14,C15,C16,C17,C18, C19,C20, C21,C23 and C24, respectively.

26 ,107,116,133,130,120,139,142,129,125, 171,33,74,72,163,165,132,131,147 and the 5d signals are ascribed to C1&7,C2,C3, C4, C5, C6&9,C7,C8,C9,C10,C11,13&23,C12&14,C15,C16,C17, C18,C19,C20,C21,C22 and C24, respectively. 146,107,116,133,130,120,139,142,129,126, 171,33,74,72,163,165,128,131 and the 5e signals are ascribed to C1&7,C2,C3, C4, C5, C6&9,C8,C10, C11&13,C12,14,23&25,C15,C16,C17, C18, C19,C20, C21, C22 and C24 respectively. IR Spectra The IR (KBr) spectra of 3-(8-((5-(4-fluorophenyl)-1,3,4-oxadiazol- 2-yl)methoxy)quinolin-5-yl)-2-phenylthiazolidin-4-one (5a) exhibited characteristic bands around 3190 (-NH-str), 3048( Ar-H str), 1698 (- C=O), 1613(-C=N), 1188 (-C-S), 1160(C-O-C), 1145(N-N) supports the structural formation of 5a. The IR data of (5a-e) were shown in the Table 4.9 and IR spectrum of 5a was shown in the fig 4.8. Table 4.9: IR data 3-(8-((5-(4-substitutedphenyl)-1,3,4-oxadiazol- 2-yl) methoxy) quinolin -5-yl) -2- (4- (trifluoro methyl) phenyl) thiazolidin-4-one (5a-e) Comp R vmax in cm -1 Ar-H C=O C=N C-S C-O-C N-N 5a F b Cl c Br d NO e CF

27 137 Mass spectra The mass spectrum of 3-(8-((5-(4-fluorophenyl)-1,3,4-oxadiazol- 2-yl)methoxy)quinolin-5-yl)-2-phenylthiazolidin-4-one (5a) exhibited the molecular ion (M + ) peak at m/z = The m/z value of molecular ion indicates that molecule is having even number of nitrogens. The primary fragmented pattern in the mass spectrum of 3-(8- ((5- (4-fluoro phenyl) -1,3,4 oxadiazol -2-yl) methoxy) quinolin-5-yl)- 2-phenylthiazolidin-4-one (5a) were presented in Chart 4-2. The molecular ion ( ) peak was observed at m/z=566.10(18.5%) and the base peak was at m/z=320.08(100%). Other important primary fragmented peaks appeared at different m/z values were shown in the following table Molecular Ion Table 4.10: The primary fragmented mass spectral data of 3-(8-((5-(4- fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolin-5-yl)-2- phenylthiazolidin-4-one (5a) Lost free radical Primary fragmented ion m/z Intensity % C6H4F C22H14F3N4O3S + (A) C7H4F3 C21H14FN4O3S + (B) C8H4FN2O C20H14F3N2O2S + (C) C28H18F4N3 M + : C9H6FN2O C19H12F3N2O2S + (D) C10H7F3NOS C18H11FN3O2 + (E) C18H11FN3O2 C10H7F3NOS + (F) C19H11ClF3N2O2 C9H6FN2O + (G) C20H14F3N2O2S C8H4FN2O + (H) C21H13FN4O3S C7H4F3 + (I) C22H14F3N4O3S C6H4F + (J)

28 138 The molecular ion signal is obeying nitrogen rule, while the primary fragmented ions derived from molecular ion signal are not obeying nitrogen rule Synthesis of 2-(4-substitutedphenyl)-5-(((5-(5-(4-(trifluoro methyl)phenyl)-1h-tetrazol-1-yl)quinolin-8-yl)oxy)methyl)- 1,3,4-oxadiazole (6a-e) Regents and Conditions: (i) 4-substituted benzoic acid, POCl3, reflux, 5-6h, 58%. Scheme-4.8: Preparation of 1,3,4-Oxadiazoles of quinoline-tetrazole. Comp 6a 6b 6c 6d 6e R 4-F 4-Cl 4-Br 4-NO2 4-CF3 A mixture of 4-fluorobenzoic acid (0.01mol) with compound 2- ((5-(5-(4-(trifluoro methyl) phenyl)-1h-tetrazol-1-yl) quinolin-8-yl) oxy) acetohydrazide (3c) (0.01mol) in phosphoryl chloride (15ml) was refluxed over a steam bath for 5-6 h The progress of the reaction was monitored by TLC with acetone : ethyl acetate (6:4) as eluent The reaction mixture was cooled and poured on to crushed ice (~200g) with continuous stirring. The solid mass separated was neutralized with sodium bicarbonate solution (10% w/v). The resulting solid thus obtained was collected by filtration, washed well with cold water, dried in vacuum and recrystallized from absolute ethanol (95%) and

29 139 analysed. Basedon the spectral data the compound was assigned 2-(4- fluorophenyl)-5-(((5-(5-(4-(trifluoromethyl)phenyl)-1h-tetrazol-1-yl) quinolin-8-yl)oxy)methyl)-1,3,4-oxadiazole(6a). The reaction procedure leading to (6a) was then extended to the syntheses of (6b-e) and their characterization data was given in Table The structures of these newly synthesized compounds (6a-e) were characterized by their elemental analysis and spectral data ( 1 H- NMR, IR, and Mass). 1 HNMR Spectra The 1 HNMR (300 MHz) spectra of 2-(4-fluorophenyl)-5-(((5-(5-(4- (trifluoro methyl) phenyl)-1h tetrazol -1-yl) quinolin-8-yl) oxy)methyl)- 1,3,4-oxadiazole (6a) was recorded in DMSO-d6 showed the following signals at δ ppm 4.21(s,2H,-O-CH2), (m,13h, C6H4, C6H4 and C9H5N of quinoline ring) supported the structural formation of 6a. The 1 H-NMR data of (6a-e) were shown in the Table The 1 H-NMR spectra of (6a) was shown in the fig 4.9. Table 4.11: 1 H NMR spectral data of 2-(4-substitutedphenyl)-5-(((5- (5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin- 8-yl)oxy) methyl)-1,3,4-oxadiazole (6a-e) Comp R 1 HNMR (DMSO-d6) (δ ppm) 6a 6b 6c F Cl Br 4.21(s,2H,-O-CH2), (m,13h, C6H4, C6H4 of two phenyl groups & C9H5N of quinoline). 4.20(s,2H,-O-CH2), (m,13H, C6H4, C6H4 of two phenyl groups & C9H5N of quinoline). 4.24(s,2H,-O-CH2), (m,13H,C6H4, C6H4 of two phenyl groups&c9h5n of quinoline).

30 140 6d 6e NO2 CF3 4.26(s,2H,-O-CH2), (m,13H,C6H4, C6H4 of two phenyl groups & C9H5N of quinoline). 4.22(s,2H,-O-CH2), (m,13H,C6H4, C6H4 of two phenyl groups & C9H5N of quinoline ). 13 CNMR Spectra (trifluoromethyl) The 13 CNMR spectra of 2-(4-fluorophenyl)-5-(((5-(5-(4- phenyl)-1h-tetrazol-1-yl)quinolin-8-yl)oxy)methyl)- 1,3,4-oxadiazole (6a) was recorded in CDCl3 showed the 18 signals at δppm: 155, 107, 126, 117, 132, 122, 149, 139, 134, 125, 131, 163, 72, 165, 129, 163 and these signals are due to at C1, C2, C3,9,11,12&14, C4&21, C5, C6&19, C7, C8, C10, C13, C15&17, C16, C18, C19, C20 and C22 carbon atoms respectively supported the structural formation of (6a). The 13 C-NMR data of (6a-e) were shown in the Table 4.12 and the 13 C- NMR spectra of (6a) was shown in the fig Table 4.12: 13 C NMR spectral data of 2-(4-substitutedphenyl)-5-(((5- (5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin- 8-yl)oxy) methyl)-1,3,4-oxadiazole (6a-e) Comp Structure 13 CNMR (CDCl3) (δ ppm) 155,107,126,117,132,122,149,139,134, 125,131,163,72,165,129 and these 6a signals are due to at C1,C2,C3,9,11,12&14 C4&21,C5,C6&19,C7,C8,C10,C13,C15.17&22,C16, C18,C19,C20 and C22 carbon atoms respectively.

31 141 6b 155,107,126,117,132,122,149,139,134, 131,163,72, 165,124,129, and the signals are ascribed to C1, C2,C3,9,11,12&14, C4, C5, C6, C7, C8, C10&22, C13, C15&17, C16, C18,C19 and C20&21 carbon atoms respectively. 6c 6d 6e 155,107,126,117,132,122,149,139,134, 131,163,72,165,125,129,123 and the signals are ascribed to C1,C2,C3,9,11,12&14, C4,C5&21,C6,C7,C8,C10,C13,C15&17,C16,C18, C19, C20 and C22 carbon atoms respectively. 155,107,126,117,132,122,149,139,134, 131,163,72, 165,129,148 and the signals are ascribed to C1, C2, C3,9,11,12&14, C4, C5, C6,C7,C8,C10,C13,19&20, C15&17, C16, C18,C19, C21 and C22 carbon atoms respectively. 155,107,126,117,132,122,149,139,134, 131,163,72,165,127,128, and the signals are ascribed to C1,C2,C3,9,11,12,14&23, C4,C5,C6,C7,C8,C10,C13&22,C15&17, C16, C18,C19,C20 and C21 carbon atoms respectively. IR Spectra The IR (KBr) spectra of 2-(4-flurophenyl)-5-(((5-(5-phenyl-1Htetrazol-1-yl)quinolin-8-yl)oxy)methyl)-1,3,4-oxadiazole (6a) exhibited characteristic bands around 3045( Ar-H str), 2115(azide),1694 ( C=O), 1618(-C=N), 1158(tetrazole), 1165 (-C-O-C), 1138(N-N) supports the

32 142 structural formation of 6a. The IR data of (6a-e) were shown in the Table 4.13 and IR spectrum of 6a was shown in the fig Table 4.13: IR spectral data of 2-(4-substitutedphenyl)-5-(((5-(5-(4- (trifluoromethyl)phenyl)-1h-tetrazol-1-yl)quinolin-8-yl)oxy) methyl)-1,3,4-oxadiazole (6a-e) Comp R vmax in cm -1 Ar-H Azide C=O C=N C-O-C Tetrazole N-N 6a F b Cl c Br d NO e CF Mass spectra The mass spectrum of 2-(4-flurophenyl)-5-(((5-(5-phenyl-1Htetrazol-1-yl)quinolin-8-yl)oxy)methyl)-1,3,4-oxadiazole (6a) exhibited the molecular ion (M + ) peak at m/z = The m/z value of molecular ion indicates that molecule is having odd number of nitrogens. The primary fragmented pattern in the mass spectrum of 2-(4- flurophenyl)-5-(((5-(5-phenyl-1h-tetrazol-1-yl)quinolin-8-yl)oxy)methyl) -1,3,4-oxadiazole (6a) are presented in Chart 4-3. The molecular ion ( ) peak was observed at m/z= (18.8%) and the base peak was at m/z=320.08(100%). Other important primary fragmented peaks appeared at different m/z values were shown in the following table-4.14.

33 143 Molecular Ion Table 4.14: Primary fragmented mass spectral of 2-(4-flurophenyl)-5- (((5-(5-phenyl-1H-tetrazol-1-yl)quinolin-8-yl)oxy)methyl)- 1,3,4-oxadiazole (6a) Lost free radical Primary fragmented ion m/z RA % C6H4F C20H11F3N7O2 + (A) C7H4F3 C19H11FN7O2 + (B) C8H4FN2O C18H11F3N5O + (C) C26H15F4N7O2 (M + ) M + : C9H6FN2O C17H9F3N5O + (D) C8H4F3N4 C18H11FN3O2 + (E) C18H11FN3O2 C8H4F3N4 + (F) C17H9F3N5O C9H6FN2O + (G) C18H11F3N5O C8H4FN2O + (H) C19H11FN7O2 C7H4F3 + (I) C20H11F3N7O2 C6H4F + (J) The molecular ion signal is obeying nitrogen rule, while the primary fragmented ions derived from molecular ion signal are not obeying nitrogen rule Experimental Section General procedure for the preparation of 3-chloro-1-(8-hydroxy quinolin-5-yl)-4-(4-(trifluoromethyl)phenyl)azetidin-2-one(1a) 226,227 Monochloroacetyl chloride (0.01mol) was added drop wise to schiff s base (C) (0.01mol) and triethyl amine (0.02mol) in dioxane (25ml) at room temperature. The mixture was stirred for 8h and left at room temperature for 3 days. Pour the contents on crushed ice. The product thus formed was filtered and washed with sodium

34 144 bicarbonate solution. The dried product was recrystalised with absolute alcohol [1]. The MP was C with a yield of 58%. General procedure for the preparation of 3-(8-hydroxyquinolin-5- yl)-2-(4-(trifluoromethyl)phenyl)thiazolidin-4-one (1b) 226,227 A mixture of Schiff s base(c) (0.01 mol) and mercaptoacetic acid (0.01 mol) dissolved in dioxane (20 ml), anhydrous zinc chloride (0.5 mg) was added and refluxed for 8 hrs. The reaction was cooled and the resulting solid was washed with sodium bicarbonate solution and recrystalised from absolute alcohol. The yield was 62% with MP: C. General procedure for the preparation of 5-(5-(4- (trifluoromethyl)phenyl)-1h-tetrazol-1-yl)quinolin-8-ol (1c) 228 Schiff base (C) (0.004mol) and PCl5 (0.004mol) was heated at c for 1h. When the evolution of fumes of HCl ceased, excess of PCl3 was removed under reduced pressure and the residual imidoyl chloride was treated with an ice-cold solution of sodium azide( mol) and excess of sodium acetate in water (25ml) and acetone (30ml) with stirring. Stirring was continued for overnight, thereafter acetone was removed under reduced pressure. The remaining aqueous portion was extracted with chloroform and dried. The yield was 55% with MP C.

35 145 Ethyl-2-((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl)phenyl)azetidin-1- yl)quinolin-8-yl) oxy) acetate (2a)/ Ethyl-2-((5-(4-oxo-2-(4-(trifluoro methyl) phenyl) thiazolidin-3-yl) quinolin-8-yl) oxy) acetate (2b) / Ethyl- 2- ((5- (5- (4- (trifluoro methyl) phenyl) -1H tetrazol -1-yl) quinolin-8-yl)oxy)acetate (2c) A mixture of 3-chloro-1-(8-hydroxyquinolin-5-yl)-4-(4-(trifluoro methyl)phenyl)azetidin-2-one (1a) / 3-(8-hydroxyquinolin-5-yl)-2-(4- (trifluoromethyl)phenyl)thiazolidin-4-one (1b) / 5-(5-(4-(trifluoro methyl)phenyl)-1h-tetrazol-1-yl)quinolin-8-ol (1c) (0.02M) anhydrous K2CO3 (0.03M) chloro ethyl acetate (0.02M) and dimethylformamide was stirred at room temperature for 8 hours. The progress of the reaction was monitored by TLC with acetone:ethyl acetate (7:3) as eluent The reaction mixture was diluted with ice-cold water. The separated solid was identified as Ethyl-2-((5-(3-chloro-2-oxo-4-(4- (trifluoromethyl)phenyl)azetidin-1-yl)quinolin-8-yl)oxy)acetate (2a)/ Ethyl- 2- ((5- (4-oxo-2- (4- (trifluoro methyl) phenyl) thiazolidin-3-yl) quinolin -8-yl)oxy) acetate (2b) / Ethyl-2- ((5- (5- (4- (trifluoro methyl) phenyl)-1h-tetrazol-1-yl)quinolin-8-yl)oxy)acetate (2c) respectively. This was collected by filtration and recrystallized from ethanol.

36 146 2-((5- (3-chloro-2-oxo-4-(4-(trifluoromethyl) phenyl) azetidin-1-yl) quinolin- 8-yl) oxy) acetohydrazide (3a)/2-((5-(4-oxo-2-(4-(trifluoro methyl)-phenyl)thiazolidin-3-yl)quinolin-8-yl)oxy)acetohydrazide (3b)/ 2- ((5- (5- (4- (trifluoro methyl) phenyl) -1H-tetrazol -1-yl) quinolin-8-yl)oxy)acetohydrazide (3c) A solution of Ethyl-2-((5-(3-chloro-2-oxo-4-(4-(trifluoromethyl) phenyl)azetidin-1-yl)quinolin-8-yl)oxy)acetate(2a)/ Ethyl-2-((5-(4-oxo- 2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)quinolin-8-yl)oxy)acetate (2b) / Ethyl-2-((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl) quinolin-8-yl)oxy)acetate (2c) (0.01M) and hydrazine hydrate (0.015M) in ethanol 20 ml was refluxed for 5 hours. The reaction mixture was cooled and poured on to ice cold water with stirring. The progress of the reaction was monitored by TLC with acetone:ethyl acetate (7:3) as eluent. The separated solid was filtered, washed with water and recrystallized from ethanol to afford 2-((5-(3-chloro-2-oxo-4-(4- (trifluoromethyl)phenyl)azetidin-1-yl)quinolin-8-yl)oxy)acetohydrazide (3a) / 2-((5-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3- yl)quinolin-8-yl)oxy)acetohydrazide(3b) / 2-((5-(5-(4-(trifluoromethyl) phenyl)-1h-tetrazol-1-yl)quinolin-8-yl)oxy)acetohydrazide (3c). Their characterization data was given in the table 4.15.

37 147 Table 4.15 : Characterization data of 2-((5-(3-chloro-2-oxo-4-(4-(trifluoro methyl)phenyl)azetidin-1-yl)quinolin-8-yl)oxy) acetohydrazide (3a) /2-((5-(4-oxo-2-(4-(trifluoro methyl) phenyl)thiazolidin-3- yl)quinolin-8-yl)oxy)acetohydrazide (3b)/ 2-((5-(5-(4-(trifluoro methyl) phenyl) -1H-tetrazol -1-yl) quinolin -8-yl) oxy) aceto hydrazide (3c) Comp M.P. o C Yield % Mol. Formula 3a C21H16ClF3N4O3 3b C21H17F3N4O3S 3c C19H14F3N7O2 Found (%) Calculated (%) C H N S (54.26) (3.47) (12.05) (54.54) (3.71) (12.12) (6.93) (53.15) (3.29) (22.84) - 3-chloro -1- (8- ((5- (4-substituted phenyl) -1,3,4 oxadiazol -2-yl) methoxy) quinolin-5-yl) -4- (4- (trifluoro methyl) phenyl) azetidin- 2-one (4a-e) A mixture of 4-Fluorobenzoicacid (0.01mol) with compound 2- ((5- (3- chloro- 2-oxo -4- (4- (trifluoro methyl) phenyl) azetidin-1-yl) quinolin-8-yl) oxy)acetohydrazide (3a) (0.01mol) in phosphoryl chloride (15ml) was refluxed over a steam bath for 5-6 h. The progress of the reaction was monitored by TLC with acetone:ethyl acetate (6:4) as eluent. The reaction mixture was cooled and poured on to crushed ice (~200g) with continuous stirring. The solid mass separated was neutralized with sodium bicarbonate solution (10% w/v). The resulting solid thus obtained was collected by filtration, washed well with cold water, dried in vacuum and recrystallized from absolute ethanol (95%) and analysed. Based on the spectral data the compound was assigned 3-chloro-1-(8-((5-(4-fluorophenyl)-1,3,4-

38 148 oxadiazol-2-yl)methoxy)quinolin-5-yl)-4-(4-(trifluoromethyl)phenyl) azetidin-2-one(4a). Other compounds of the series (4b-e) were similarly prepared from 4-Chloro/Bromo/Nitro/trifluoromethylbenzoicacid respectively. Their characterization data was given in Table Table 4.16 : Characterization data of 3-chloro-1-(8-((5-(4-substitutedphenyl)- 1,3,4- oxadiazol- 2-yl) methoxy) quinolin- 5-yl) -4-(4- (trifluoro methyl) phenyl) azetidin-2-one (4a-e) Comp R M.P. o C Yield % Mol. Formula 4a F C28H17ClF4N4O3 4b Cl C28H17Cl2F3N4O3 4c Br C28H17BrClF3N4O3 4d NO C28H17ClF3N5O5 4e CF C29H17ClF6N4O3 Found (%) Calculated (%) C H N (59.11) (3.01) (9.85) (57.45) (2.93) (9.57) (53.40) (2.72) (9.05) (56.43) (56.28) (2.88) 2.99 (2.77) (11.75) 8.99 (9.05) 3- (8- ((5- (4-substituted phenyl) -1,3,4 oxadiazol -2-yl) methoxy) quinolin -5-yl)-2-(4-(trifluoromethyl)phenyl)thiazolidin-4-one(5a-e) A mixture of 4-Fluorobenzoicacid (0.01mol) with compound 2-((5-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)quinolin-8-yl) oxy)acetohydrazide (3b) (0.01mol) in phosphoryl chloride (15ml) was refluxed over a steam bath for 5-6 h The progress of the reaction was monitored by TLC with acetone:ethyl acetate (6:4) as eluent. The reaction mixture was cooled and poured on to crushed ice (~200g) with continuous stirring. The solid mass separated was neutralized

39 149 with sodium bicarbonate solution (10% w/v). The resulting solid thus obtained was collected by filtration, washed well with cold water, dried in vacuum and recrystallized from absolute ethanol (95%) and analysed. Basedon the spectral data the compound was assigned 3-(8- ((5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolin-5-yl)-2-(4- (trifluoromethyl) phenyl)thiazolidin-4-one (5a). Other compounds of the series (5b-e) were similarly prepared from 4-Chloro/Bromo/Nitro/trifluoromethylbenzoicacid respectively and their characterization data was given in Table Comp R oxadiazol-2-yl) methoxy) quinolin-5-yl) -2-(4-(trifluoromethyl) phenyl) thiazolidin-4-one (5a-e) M.P. o C Yield % Mol. formula 5a F C28H18F4N4O3S 5b Cl C28H18ClF3N4O3S 5c Br C28H18BrF3N4O3S 5d NO C28H18 F3N5O5S 5e CF C29H18F6N4O3S Found (%) Calculated (%) C H N (59.36) (3.20) (9.89) (57.69) (3.11) (9.61) (53.60) (2.89) (8.93) (56.66) (56.49) (3.06) 2.88 (2.94) (11.80) 9.04 (9.09) Table 4.17 : Characterization data of 3-(8-((5-(4-substitutedphenyl)-1,3,4-2-(4-substitutedphenyl)-5-(((5-(5-(4-(trifluoromethyl)phenyl)-1Htetrazol-1-yl)quinolin-8-yl)oxy)methyl)-1,3,4-oxadiazole (6a-e) A mixture of 4-Fluorobenzoicacid (0.01mol) with compound 2-((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8-yl) oxy) acetohydrazide (3c) (0.01mol) in phosphoryl chloride (15ml) was refluxed over a steam bath for 5-6 h. The progress of the reaction was

40 150 monitored by TLC with acetone:ethyl acetate (7:3) as eluent. The reaction mixture was cooled and poured on to crushed ice (~200g) with continuous stirring. The solid mass separated was neutralized with sodium bicarbonate solution (10% w/v). The resulting solid thus obtained was collected by filtration, washed well with cold water, dried in vacuum and recrystallized from absolute ethanol (95%) and analysed. Basedon the spectral data the compound was assigned 2-(4- fluorophenyl)-5-(((5-(5-(4-(trifluoromethyl)phenyl)-1h-tetrazol-1- yl)quinolin-8-yl)oxy)methyl)-1,3,4-oxadiazole (6a). Other compounds of the series (6b-e) are similarly prepared from 4-Chloro/Bromo/Nitro/trifluoromethylbenzoicacid respectively and their characterization data was given in Table Table 4.18: Characterization data of 2-(4-substitutedphenyl)-5-(((5-(5-(4- (trifluoro methyl) phenyl) -1H -tetrazol-1-yl) quinolin- 8-yl) oxy) methyl) -1,3,4-oxadiazole (6a-e) Comp R M.P. o C Yield % Mol. formula 6a F C26H15F4N7O2 6b Cl C26H15ClF3N7O2 6c Br C26H15BrF3N7O2 6d 4-NO C26H15F3N8O4 6e 4-CF C27H15F6N7O2 Found (%) Calculated (%) C H N (58.54) (2.83) (18.38) (56.79) (2.75) (17.83) (52.54) (2.54) (16.50) (55.72) (2.70) (19.99) (55.58) (2.59) (16.80)

41 151 Fig-4.1: IR Spectrum of 2-((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8-yl)oxy)acetohydrbazide (3c)

42 152 Fig-4.2: 1 HNMR Spectrum of 2-((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8-yl)oxy)acetohydrazide (3c)

43 153 Fig H-NMR spectrum of 3-chloro-1-(8-((5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolin-5-yl)-4-(4- (trifluoromethyl)phenyl)azetidin-2-one (4a).

44 154 Fig C-NMR spectrum of 3-chloro-1-(8-((5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolin-5-yl)-4-(4- (trifluoromethyl)phenyl)azetidin-2-one (4a).

45 155 Fig-4.5. IR spectrum of 3-chloro-1-(8-((5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolin-5-yl)-4-(4- (trifluoromethyl)phenyl)azetidin-2-one (4a).

46 156 Chart-4.1- Primary mass fragmentation of 3-chloro-1-(8-((5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolin-5- yl)-4-(4-(trifluoromethyl)phenyl)azetidin-2-one (4a).

47 157 Fig H-NMR Spectrum of 3-(8-((5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolin-5-yl)-2-(4- (trifluoromethyl)phenyl)thiazolidin-4-one (5a)

48 158 Fig C-NMR Spectrum of 3-(8-((5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolin-5-yl)-2-(4- (trifluoromethyl)phenyl)thiazolidin-4-one (5a)

49 159 Fig-4.8. IR Spectrum of 3-(8-((5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolin-5-yl)-2-(4-(trifluoromethyl) phenyl)thiazolidin-4-one (5a)

50 160 Chart-4.2: Primary mass spectral fragmentation of 3-(8-((5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolin-5- yl)-2-(4-(trifluoromethyl) phenyl)thiazolidin-4-one (5a).

51 161 Fig H-NMR Spectrum of 2-(4-fluorophenyl)-5-(((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8- yl)oxy)methyl)-1,3,4-oxadiazole (6a)

52 162 Fig C-NMR Spectrum of 2-(4-fluorophenyl)-5-(((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8- yl)oxy)methyl)-1,3,4-oxadiazole (6a)

53 163 Fig IR Spectrum of 2-(4-fluorophenyl)-5-(((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1-yl)quinolin-8- yl)oxy)methyl)-1,3,4-oxadiazole (6a)

54 164 Chart-4.3: Primary mass fragmentation of 2-(4-fluorophenyl)-5-(((5-(5-(4-(trifluoromethyl)phenyl)-1H-tetrazol-1- yl)quinolin-8-yl)oxy)methyl)-1,3,4-oxadiazole (6a)