CHAPTER - 3 SYNTHESIS OF SUBSTITUTED 1,2,4-TRIAZOLE, 1,3,4- THIADIAZOLE, 1,3-THIAZINE-2-AMINE AND HYPOXANTHINE, DERIVATIVES.

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1 67 CHAPTER - 3 SYNTHESIS OF SUBSTITUTED 1,2,4-TRIAZOLE, 1,3,4- THIADIAZOLE, 1,3-THIAZINE-2-AMINE AND HYPOXANTHINE, DERIVATIVES. 3.1 INTRODUCTION: Substituted 1,2,4-triazole [ ], 1,3,4-thiadiazole [103], 1,3-thiazine [104] and hypoxanthine [105] derivatives have been reported to possess diverse biological activity like anti-inflammatory, antifungal, antiglaucoma, diuretic etc. These are also known to be used in the treatment of acute mountain sickness, sedative, analgesic, muscle relaxant and antianginal. Triptan drugs are used for the treatment of migraine headaches. Many of these triptamines such as naratriptan [106], almotriptan [107], sumatriptan [108] and avitriptan [109] have the common feature of possessing a sulfonamide group attached to the indole ring at 5 position through a methane/ethane spacer. 2-(4-Aminophenyl)-N-methylethane sulfonamide is a crucial structural part in naratriptan. However, not much systematic work has been done on 2-(4-aminophenyl)-N-methylethanesulfonamide. Hence, it was thought worthwhile to synthesize new heterocycles containing benzene methane/ethane sulfonamide functionality as potentially biologically active compounds.

2 LITERATURE SURVEY: Several synthetic methods have been reported in the literature for the synthesis of 1,2,4-Triazole, 1,3,4-thiadiazole, 1,3-thiazine and hypoxanthine derivatives and few of them are discussed below ,2,4-TRIAZOLE Bany et. al. [110] reported that the condensation of ethoxycarbonylmethyl isothiocyanate (33) with amidrazone salts (34) on thermal heating gave 1,2,4-triazoline-5-thione (35) (Scheme-3.1)... Scheme Hoggarth et. al. [111] reported the synthesis of 3-substituted 1,2,4-triazoline-5-thione derivatives by the reaction of substituted benzoylisothiocyanate (36) and excess of hydrazine hydrate to give the corresponding thiosemicarbazide derivatives 37, which on cyclization yielded 3-aryl-1,2,4-triazoline-5-thione (38) (Scheme-3.2)... Scheme Zamani et. al. [112] reported the condensation of 4- methylphenyl isothiocyanate (39) with pyridinecarboxylic hydrazide

3 69 (40) giving 1-(4-methyl phenyl)-(pyridoyl) thiosemicarbazide (41) which on cyclization in the presence of aq.naoh solution, gave 2,4- dihydro-4-(4-methylphenyl)-5-(pyridyl)-3h-1,2,4-triazole (42) (Scheme-3.3)... Scheme Iqbal et. al. [113] reported the condensation of 2-phenylmethyl isothiocyanate (43) with the hydrazide derivative 40 giving N-benzyl-2- isonicotinoylhydrazine carbothioamide (44), which on cyclization in the presence of aq.naoh solution, gave 4-benzyl-5-(pyridin-4-yl)-4H- 1,2,4-triazole-3-thiol (45) (Scheme-3.4)... Scheme Dimova et. al. [114] reported that the condensation of allylisothiocyanate (46) with phenylcarboxylic hydrazide (47) to give N-allyl-2-benzoylhydrazinecarbothioamide (48), which on cyclization in the presence of aq.naoh solution, affords 4-allyl-5-phenyl-4H- 1,2,4-triazole-3-thiol (49) (Scheme-3.5).

4 70.. Scheme Hameed et. al. [115] reported the condensation of R-(+)-1- phenyl propylisothiocyanate (50) with benzohydrazide 47 giving (R)-2- benzoyl-n-(1-phenylpropyl)hydrazinecarbothioamide (51), which on cyclization in the presence of aq.naoh solution gives 3-phenyl-4-(1- phenylpropyl)-1h-1,2,4-triazole-5(4h)-thione (52) (Scheme-3.6)... Scheme Zamani et. al. [116] reported that the condensation reaction of 1-isothiocyanatonaphthalene (53) with acid hydrazide 40 affords thiosemicarbazide (54) derivative, which on cyclization in aq.naoh solution, yields 4-(naphthalen-1-yl)-5-(pyridin-4-yl)-4H-1,2,4-triazole- 3-thiol (55) (Scheme-3.7)... Scheme - 3.7

5 ,3,4-THIADIAZOLE Zamani et. al. [112] reported that the condensation of 4- methylphenylisothiocyanate (39) with 4-pyridinecarboxylic acid hydrazide (40) yield 1-(4-methylphenyl)-4-(isomericpyridoyl)thiosemi carbazide (41) which on cyclization in the presence of Con. sulphuric acid, affords 2-(4-methylphenylamino)-5-(isomericpyridyl)-1,3,4-thia - diazole (56) (Scheme-3.8). N-(1-oxo-3-phenyl-1-(2-(p-tolylcarbamothioyl)hydrazinyl).. Scheme Profire et. al. [117] reported that the condensation of isothiocyanate derivate 39 with N-(1-hydrazinyl-1-oxo-3-phenyl propan-2-yl)-4-nitrobenzamide (57) results in the formation of 4-nitro- propan-2- yl)benzamide (58), which on cyclization in the presence of Con. sulphuric acid, yields 4-nitro-N-(2-phenyl-1-(5-(p-tolylamino)-1,3,4- thiadiazol-2-yl)ethyl)benzamide (59) (Scheme-3.9).

6 72..Scheme Shashikanth et. al. [119] has reported the condensation of phenyl isothiocyanate (63) with 2-(2-(3-chlorobenzoyl)-4-methyl phenoxy)acetohydrazide (64), to give..scheme Hussain et. al. [118] reported the condensation of arylisothiocynate derivative 39 with 5-amino-2-hydroxybenzo hydrazide (60) to give 2-(4-amino-2-hydroxy benzoyl)-n-p-tolyl hydrazinecarboxamide (61), which on cyclization in the presence of Con. sulphuric acid yields 5-amino-2-(5-(p-tolyl amino)-1,3,4- thiadiazol-2-yl)phenol (62) (Scheme-3.10). 2-(2-(2-(3-chlorobenzoyl)-4- methyl phenoxy)acetyl)-n-phenylhydrazinecarbothioamide (65), which on cyclization in the presence of phosphoric acid, results in the

7 73 formation of (3-chlorophenyl)(3-((5-(phenylamino)-1,3,4-thiadiazol-2- yl) methoxy) phenyl) methanone (66) (scheme-3.11)...scheme Zamani et. al. [116] reported that condensation of 1- isothiocyanatonaphthalene (53) with acidhydrazide derivative 40 to give 1-(4-methylphenyl)-4-(isomericpyridoyl) thiosemicarbazide (54) which on cyclization in the presence of Con. sulphuric acid, yields N- (naphthalen-1-yl)-5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine (67) (Scheme-3.12)..Scheme

8 74 Karale et. al. [120] reported the condensation of phenylisothiocynate 63 with substituted phenoxyaceto hydrazide (68) to give the corresponding substituted thiosemicarbazide (69), which on cyclization in the presence of Con. sulphuric acid, affords the substituted 1,3,4-thiadiazol-2-amine (70) (Scheme-3.13)..Scheme Vosooghi et. al. [121] reported the condensation of substituted isothiocyanate (71) with substituted 2-(4-nitro-1H-imidazol-1- yl)acetohydrazide (72) to give the corresponding substituted thiosemicarbazide (73), which on cyclization in the presence of Con. sulphuric acid, affords the substituted 1,3,4-thiadiazol-2-amine (74) (Scheme-3.14).

9 75.Scheme ,3- THIAZINE-2-AMINE Ruehle et. al. [122] described a method for the condensation of 2,6-dimethylphenylisothiocyanate (75) with 3-amino-1-propanol (76) to afford 1-(2,6-dimethylphenyl)-3-(3-hydroxypropyl)urea (77), which on cyclization in the presence of Con. HCl, yields N-(2,6- dimethylphenyl)-5,6-dihydro-4h-1,3-thiazin-2-amine (78) (Scheme- 3.15)..Scheme

10 76 Hiroyukai et. al. [123] described a method for the condensation of (2-isopropylphenyl)isothiocyanate (79) with 3-amino-2,2dimethyl propanol (80) gives N-(2-isopropylphenyl)-N -(1-hydroxy-2,2-dimethyl) propylthiourea (81) which on cyclization in the presence of Con. HCl afforded (2-isopropylphenyl)imino-5,5-dimethyl-5,6-dihydro-4H-1,3- thiazine (82) (Scheme-3.16)..Scheme Caujolle et. al. [124] described a method for the condensation of 1-naphthaleneisothiocynate (53) with 3-aminopropanol (76) to give 1- (3-hydroxypropyl)-3-(naphthalen-1-yl) urea (83), which on cyclization in the presence of Con. HCl, affords N-(naphthalen-1-yl)-5,6-dihydro- 4H-1,3-thiazin-2-amine (84) (scheme-3.17)..scheme Audia et. al. [125] describes a novel method for the condensation of 2-(3-bromophenyl)-4-methylpent-4-en-2-amine (87) with benzoyl isothiocyanate (88) gives (S)-N-(2-(3-bromophenyl)-4-

11 77 methylpent-4-en-2-ylcarbamothioyl) benzamide (89), which on treatment with excess of iodine yields the N-((4S)-4-(3-bromophenyl)- 6-(iodomethyl)-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-2-yl)benz amide (90). Finally addition of tri-n-butyl amine and AIBN in the presence of THF solvent affords (S)-N-(4-(3-bromophenyl)-4,6,6-3.18)..Scheme HYPOXANTHINE Mckenzie et. al. [126] prepared another purine derivative from benzyl amine (92) and 2-aminocyanoacetamide (93) in the presence of triethyl orthoformate in acetonitrile gave trimethyl-5,6-dihydro-4h-1,3-thiazin-2-yl)benzamide (91) (Scheme- 5-amino-1-benzyl-1Himidazole-4-carboxamide (94), which on acetylation with trifluoroacetic anhydride gave acetyl derivative 95 that cyclized on heating yielded 9-benzyl-2-(trifluoromethyl)-4,9-dihydro-1H-purin- 6(5H)-one (96) (Scheme- 3.19).

12 78.Scheme Glasky et. al. [127] reported that the condensation of ethyl 4-(3- aminopropanamido)benzoate (97) and 2-aminocyanoacetamide (93) with triethylorthoformate in acetonitrile gave ethyl 4-(3-(5-amino-4- carbamoyl-1h-imidazol-1-yl)propanamido)benzoate (98), which on cyclisation with triethylorthoformate gave 2-ethyl-4-(3-(6-oxo-1Hpurin-9(6H)-yl)propanamido)benzoate (99). Subsequently on hydrolysis with aq.naoh solution gave 4-(3-(6-oxo-1H-purin-9(6H)- yl)propanamido)benzoic acid (100) (scheme-3.20)..scheme Terret et. al. [128] reported the reaction of N-propylamine (101) with 93 in the presence of triethylorthoformate in acetonitrile yielded 5-amino-1-propyl-1H-imidazole-4-carboxamide (102), which on

13 79 treatment with 2-ethoxybenzoyl chloride (103), gave 5-(2- ethoxybenzamido)-1-propyl-1h-imidazole-4-carboxamide (104). This derivative 104, on cyclisation with hydrogen peroxide, resulted in 2- (2-ethoxyphenyl)-9-propyl-1H-purin-6(9H)-one (105) (scheme-3.21) PRESENT WORK.Scheme It is obvious from the references cited above that a good number of researchers have synthesized substituted 1,2,4-triazole, 1,3,4- thiadiazole, 1,3-thiazines and hypoxanthines which are biologically active molecules. In this chapter we have synthesized some substituted sulfonamide derivatives of 1,2,4-triazole, 1,3,4-thiadiazole, 1,3- thiazine and hypoxanthine from substituted amino benzene methane/ethane sulfonamide derivatives as new chemical entities (NCE S ).

14 RESULTS AND DISCUSSION: The required starting materials, 26a, 26d and 26e were synthesized by using the reported procedure [95] as described in chapter-1. The synthetic scheme is depicted in scheme Thus, treatment of 24 with excess of amines like pyrrolidine, and monomethylamine, gave the corresponding 4-(secondary amine-1- sulfonylmethyl)-nitrobenzene (26a, 26d, 26e). These later compounds were then hydrogenated using palladium on carbon as a catalyst in methanol to yield the corresponding aminoderivatives 26a, 26d and 26e Conversion of amine to isothiocyanate 106:.Scheme (4-Aminophenyl)-N-methylethanesulfonamide (26e) (i.e. 26, R = -NHCH3, n=2) was reacted with thiophosgene in chloroform at reflux temperature to obtain a new product 1-(4-isothiocyanatophenyl)-Nmethylethane sulfonamide (106c) (i.e. 26, R = -NHCH3, n=2) (Scheme-3.23). The structure of the product was established by its spectral data. The characteristic peaks at 2185 and 2140 cm 1 in the IR spectrum of 106c (Fig. 3.1) have been attributed to N=C=S group.

15 81 The peaks at 1310 cm -1 and 1122 cm -1 confirming the asymmetric and symmetric stretchings of SO2 group. Its 1 H NMR (DMSO-d6/TMS) spectrum (Fig. 3.2) showed signals at 2.51 (d, J=4.1 HZ, 3H, - NHCH3), (t, 2H, Ar-CH2), (t, 2H, -SO2CH2), 7.00 (m, 1H, -NHCH3, D2O exchangable), 7.60 (d, J=8.05 HZ, 2H, Ar-H), 8.20 (d, J=8.05 HZ, 2H, Ar-H). Its APCI mass spectrum (Fig. 3.3) showed M + +1 ion peak at 257 corresponding to a molecular mass of 256..Scheme The above reaction of arylamino derivatives 26e with thiophosgene has been found to be a general one and has been extended to other substituted sulfonyl phenyl amine 26a and 26d. The products obtained have assigned structures 106a-c on the basis of their spectral data Condensation of 106 with Pyridine-4-carboxylic acid hydrazide 107: 106c (i.e. 106, R=-NHCH3, n=2) was reacted with 40 in refluxing methanol to yield 2-isonicotinoyl-N-(4-(2-(N-methylsulfamoyl) ethyl) phenyl) hydrazinecarbothioamide (107c) (i.e. 107c, R=-NHCH3, n=2) (Scheme-3.24). Its IR (KBr) spectrum (Fig. 3.4) showed a characteristic peak at 1292 cm 1 which can be attributed to C=S

16 82 group and a peak at 1693 cm 1 conforming the carbonyl group. Peaks at 1292 cm -1 and 1141 cm -1 have been attributed to the asymmetric and symmetric stretchings of SO2 group. It s 1 H-NMR spectrum showed signals at δ 9.7 and 9.8 confirming the protons of NH-NHgrouping. The signal at δ 10.8 is NH proton between thio ketone and aromatic groups. Its 1 H NMR (DMSO-d6/TMS) spectrum (Fig. 3.5) showed signals at 2.50 (d, J=4.8 HZ, 3H, -NHCH3), (t, J=7.6 HZ, 2H, Ar-CH2), (t, 2H, J=7.6 HZ, -SO2CH2), 7.00 (m, 1H, - NHCH3), 7.30 (d, J=8.0 HZ, 2H, Ar-H), 7.50 (d, J=8.0 HZ, 2H, Ar-H,), 7.90 (d, J=4.8 HZ, 2H, pyridine ring protons,), 8.80 (d, J=4.8 HZ, 2H, pyridine ring protons,), 9.90 (br, s, 2H, -NH-NH- portons), (s, 1H, NH, D2O exchangable). Its APCI mass spectrum (Fig. 3.6) showed M + +1 ion peak at 394 corresponding to a molecular mass of 393. Its 13 C NMR spectrum (Fig. 3.7) showed signals at δ 28.97, 29.06, 50.70, , , , , , , and Based on the above spectral data, the compound was assigned the structure 107c..Scheme The above reaction of aryl isothiocyanate derivative 106c with acid hydrazide derivative 40 has been found to be a general one and has

17 83 been extended to other substituted isothiocyanates. The products obtained have been assigned structures 107a-b on the basis of their spectral data Cyclization of 107 in sodium hydroxide 108: Cyclisation of the aryl thiosemicarbazide derivative 107c (i.e. 107, R=-NHCH3, n=2) in aq. sodium hydroxide solution yielded 2-(4- (3-mercapto-5-(pyridin-4-yl)-4H-1,2,4-triazol-4-yl)phenyl)-N-methyl ethanesulfonamide (108c) (i.e. 108, R=-NHCH3, n=2) (Scheme-3.25). Its IR (KBr) spectrum (Fig. 3.8) showed a peak at 2726 cm 1 attributed to SH and peaks at 1322 cm -1 and 1130 cm -1 confirming the asymmetric and symmetric stretchings of SO2 group. The signal at δ in its 1 H-NMR confirmed the proton of -SH. Its mass spectrum showed molecular ion at m/z 376 which further confirmed the structure. Its 1 H NMR (DMSO-d6/TMS) spectrum (Fig. 3.9) showed signals at 2.50 (d, J=4.1 HZ, 3H, -NHCH3), (t, 2H, -Ar-CH2), (t, 2H, -SO2CH2), 7.00 (m, 1H, -NHCH3, D2O exchangable), (m, 4H, Ar-H), 7.60 (d, J=5.0 Hz, 2H, pyridine ring protons), 8.70 (d, J=5.0 Hz, 2H, pyridine ring protons), (s, 1H, SH, D2O exchangable). Its APCI mass spectrum (Fig. 3.10) showed M + +1 ion peak at 376 corresponding to a molecular mass of 375. Its 13 C NMR spectrum (Fig. 3.11) showed the peaks at 28.94, 29.20, 50.28, , , , , , , , and Based on the above spectral data, the compound was assigned as structure 108c.

18 84.Scheme 3.25 The above cyclisation reaction of 107c in aq.naoh was found to be a general one and has been extended to substituted carbothioamide. The products obtained have been assigned structures 108a-b on the basis of their spectral and analytical data Cyclization of 107 in sulphuric acid 109: Cyclization of 107c (i.e. 107, R=-NHCH3, n=2) in Con.sulphuric acid medium at ºC yielded N-methyl-2-(4-(5-(pyridin-4-yl)-1,3,4- thiadiazol-2-ylamino)phenyl)ethanesulfonamide (109c) (i.e. 109, R=- NHCH3, n=2) (Scheme-3.26). Absence of carbonyl absorption in its IR spectrum (Fig.3.12) supported the assigned structure of 109c which was further confirmed by 1 H-NMR and mass spectral data. Its 1 H NMR (DMSO-d6/TMS) spectrum (Fig. 3.13) showed signals at 2.60 (d, J=4.8 Hz, 3H, -NHCH3), (t, 2H, -Ar-CH2), (t, 2H, - SO2CH2), 7.00 (m, 1H, -NHCH3, D2O exchangable), 7.2 (d, J=6.0 Hz, 2H, pyridine ring protons ), 7.3 (d, J=8.4 Hz, 2H, Ar-H), 7.4 (d, J=8.4 Hz, Ar-H), 8.50 (d, J= 6.0 Hz, 2H, pyridine ring protons), (s, 1H, NH D2O exchangable). Its APCI mass spectrum (fig. 3.14) showed M + +1 ion peak at 376 corresponding to a molecular mass of 375. Its 13 C NMR spectrum (Fig. 3.15) showed the peaks at 28.94, 29.20,

19 , , , , , , , , and Based on the above spectral data, the structure of the compound was assigned the structure 109c..Scheme The above cyclisation reaction of 107c in sulphuric acid has been found to be a general one and has been extended to substituted carbothioamide. The products obtained have all been assigned structures 109a-b on the basis of their spectral and analytical data Conversion of 106 to 110: Condensation reaction of 106c (i.e. 106, R=-NHCH3, n=2) with hydroxybutyl)thioureido)phenyl)-n-methyl ethane sulfonamide, which on cyclisation in hydrochloric acid yielded 3-aminopropanol (76) in refluxing tetrahydrofuran to give 1-(4-(3-(4-2-(4-(5,6-Dihydro-4H-1,3- thiazin-2-ylamino)phenyl)-n-methylethanesulfonamide (111c) (i.e. 110, R=-NHCH3, n=2) (Scheme ). Its IR (KBr) spectrum (Fig. 3.16) showed a peak at 3288 cm 1 attributed to -NH and peaks at 1322 cm -1 and 1130 cm -1 confirmed the asymmetric and symmetric stretchings of SO2. Its 1 H NMR (DMSO-d6/TMS) spectrum (Fig.3.17) showed signals at 1.70 (m, 2H, CH2 Thiazine ring), 2.60 (d, J=4.5 HZ, 3H, -NHCH3), 2.80 (m, 2H, CH2 Thiazine ring), 3.00 (m, 2H, -Ar-CH2) 3.10 (m, 2H, CH2 Thiazine ring), 3.40 (m, 2H, -SO2CH2), 6.90 (m, 1H, -

20 86 NHCH3), (m, 4H, Ar-H), 8.50 (s, 1H, NH, D2O exchangable). Its APCI mass spectrum (Fig.3.18) showed M + +1 ion peak at 314 corresponding to a molecular mass of 313. Its 13 C NMR spectrum (Fig. 3.19) showed peaks at 21.02, 26.35, 28.60, 43.79, 50.64, , , , and Based on the above spectral data, the compound was assigned structure 110c..Scheme The above cyclisation reaction of 106c with 76 in hydrochloric acid has been found to be a general one and has been extended to substituted isocyanates. The products obtained have been assigned structures 110a-b on the basis of their spectral data Condensation of 26e with 2-amino-2-cyanoacetamide 111: Reaction of 26e (i.e. 26, R=-NHCH3, n=2) with 2-amino-2- cyanoacetamide (93) and triethylorthoformate in acetonitrile to give a compound whose structure was established by its spectral data as 5- amino-1-(4-(n-methyl sulfamoyl ethyl) phenyl)-1h-imidazole-4- carboxamide (111c) (i.e. 111, R=-NHCH3, n=2) (Scheme ). Thus, its IR (KBr) spectrum (Fig. 3.20) showed peaks at 3423 cm -1 (due to the NH2 stretching), 1640 cm -1 (due to the amide carbonyl) and at 1315 and 1143 cm -1 (due to the -SO2). Its 1 H NMR (DMSOd6/TMS) spectrum (Fig. 3.21) showed signals at 2.60 (d, J=4.4 HZ,

21 87 3H, -NHCH3), (t, 2H, -Ar-CH2), (t, 2H, -SO2CH2), 5.70 (s, 2H, NH2, D2O exchangable), (d, 2H, NH2) 7.00 (m, 1H, -NHCH3, D2O exchangable), 7.35 (s, 1H, CH imidazole) (m, 4H, Ar-H). Its APCI mass spectrum (Fig.3.22) showed M + +1 ion peak at 324 corresponding to a molecular mass of 323. Its 13 C NMR spectrum (Fig. 3.23) showed peaks at 28.99, 29.11, 50.44, , , , , , , and Scheme The above reaction of 26e with 93 has been found to be a general one and has been extended to substituted amines 26a and 26d. The products obtained have been assigned structures 111a-b on the basis of their spectral data Cyclization of 111 with formic acid. 112: Cyclization of 111c (i.e. 111, R=-NHCH3, n=2) in formic acid under refluxing conditions at 120 º C yielded N-methyl-2-(4-(6-oxo-1Hpurin-9(6H)-yl)phenyl)ethanesulfonamide (112c) (i.e. 112, R=-NHCH3, n=2) (Scheme-3.29), which was found to be homogeneous on TLC. Its IR (KBr) spectrum (Fig. 3.24) showed stretching frequencies at 3443 cm -1 (due to the -NH) and at 1712 cm -1 (sharp, strong, due to the

22 88 carbonyl) and 1309 and 1131 cm -1 (due to -SO2 group). Its 1 H NMR spectrum (Fig.3.25) at 2.60 (d, 3H J=4.8, -NHCH3), 3.00 (t, 2H, -Ar- CH2), (t, 2H, -SO2CH2), 7.00 (m, 1H, -NHCH3, D2O exchangable), 7.50 (d, 2H J=8.4 HZ, Ar-H), 7.70 (d, 2H J=8.4 HZ, Ar- H), 8.10 (s, 1H, CH pyrimidine), 8.50 (s, 1H, CH imidazole), (s, 1H, NH pyrimidine, D2O exchangable); Its mass spectrum (Fig. 3.26) in APCI mode showed the M + +1 ion peak at 334 confirming the molecular mass of the compound as 333. Its 13 C NMR spectrum (Fig. 3.27) showed peaks at 28.99, 29.14, 50.52, , , , , , , , and Based on the above spectral data the compound was assigned the structure 112c..Scheme 3.29 The above cyclization reaction of 111c with formic acid has been found to be a general one and has been extended to substituted amino amides. The products obtained have all been assigned structures 112a-b on the basis of their spectral and analytical data. 2-amino-2-cyanoacetamide (93) required in this reaction was prepared as per the literature method [126]. In this method, ethyl cyanoacetate (113) reacted with sodium nitrite to yield the nitroso

23 89 compound 114 which on reduction with sodium dithionite gave the required 2-amino-2-cyanoacetamide (Scheme-3.30)..Scheme Pyridinecarboxylic acid hydrazide (40) required in this reaction was prepared as per the literature method [129]. In this method, nicotinic acid (115) was converted into ethyl ester to yield ethyl nicotinate (116), which on reaction with hydrazine hydrate gave the required 4-pyridine carboxylic acid hydrazide (Scheme-3.31)..Scheme All the above sequences of reactions are summarized in Scheme & 3.33

24 90.Scheme Scheme

25 EXPERIMENTAL SECTION: PREPARATION OF 108, 109, 110, 111 & 112: GENERAL PROCEDURE FOR THE PREPARATION OF 106(ac): A mixture of 26(a, d, e) (0.046 mol), chloroform (60 ml) and water (50 ml) was cooled to about 10 º C. Thiophosgene (0.063 mol) was added dropwise to the reaction mixture with continuous stirring at º C. After addition, the mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC. The organic layer was seperated and washed with excess of water and finally with brine solution. The organic layer was dried over anh.na2so4 and concentrated under reduced pressure. The residue was stirred with hexane (20 ml) for I hour at room tempreature. The solid was filtered, washed with hexane to give pure compound 107(ac). 106a: R = Pyrrolidine, n=1, Yield: 8.5 gm (65 %), M.R: C; IR (KBr, cm -1 ) 2185 and 2140 (-N=C=S), 1310 and 1122 (-SO2); 1 H NMR (DMSO-d 6 /TMS) at (m, 4H, pyrrolidine), (m, 4H, pyrrolidine), 4.40 (s, 2H, -SO2CH2), 7.60 (d, 2H, Ar-H), 8.20 (d, 2H, Ar-H); M + +1: 283; Anal.Calcd for (C12H14N2O2S2) requires: C, 51.04; H, 5.00; N, Found: C, 51.00; H, 4.90; N, b: R = -NHCH3, n=1, Yield: 6.1 gm (55 %), M.R: º C; IR (KBr, cm -1 ) 2185 and 2140 (-N=C=S), 1310 and 1122 (-SO2); 1 H NMR (DMSO-d 6 /TMS) at 2.60 (d, 3H, -NHCH3), 4.40 (s, 2H, -SO2CH2), 7.00 (m, 1H, -NH, D2O exchangable), 7.60 (d, 2H, Ar-H), 8.20 (d, 2H,

26 92 Ar-H); M + +1: 243; Anal.Calcd for (C9H10N2O2S2) requires: C, 51.04; H, 5.00; N, Found: C, 51.00; H, 4.90; N, c: R = -NHCH3, n=2, Yield: 7.0 gm (60 %), M.R: º C; IR (KBr, cm -1 ) 2185 and 2140 (-N=C=S), 1310 and 1122 (-SO2); 1 H NMR (DMSO-d 6 /TMS) at 2.50 (d, 3H, -NHCH3), (t, 2H, -Ar-CH2), (t, 2H, -SO2CH2), 7.00 (m, 1H, -NH, D2O exchangable), 7.60 (d, 2H, Ar-H), 8.20 (d, 2H, Ar-H); M + +1: 257; Anal.Calcd for (C10H12N2O2S2) requires: C, 46.85; H, 4.72; N, Found: C, 46.80; H, 4.70; N, GENERAL PROCEDURE FOR THE PREPARATION OF 107(ac): 4-Pyridinecarboxylic acid hydrazide (40) (0.004 mol) was dissolved in absolute ethanol (80 ml). A solution of 106(a-c) (0.004 mol) in absolute ethanol was added into the solution of hydrazide with continuous stirring. The reaction mixture was refluxed by monitoring on TLC for completion of reaction. After the completion of the reaction, the mixture was cooled to room temperature. The resultant white solid was filtered and recrystallized from methanol to get pure product 107(a-c). 107a: R = Pyrrolidine, n=1, Yield: 1.34 gm (80 %); M.R: C; IR (KBr, cm -1 ) 1292 (-C=S), 1693 (C=O), 1310 and 1122 (-SO2); 1 H NMR (DMSO-d 6 /TMS) at (m, 4H, pyrrolidine), (m, 4H, pyrrolidine), 4.40 (s, 2H, -SO2CH2), 7.00 (s, 1H, -NH, D2O exchangable), (m, 4H, Ar-H), 7.90 (d, 2H, pyridine ring protons), 8.80 (d, 2H, pyridine ring protons), 9.90 (s, 2H, -NH-NH

27 93 portons), 10.90(s, 1H, -NH, D2O exchangable); M + +1: 420; Anal.Calcd for (C18H21N5O3S2) requires: C, 51.53; H, 5.05; N, Found: C, 51.50; H, 5.00; N, b: R = -NHCH3, n=1, Yield: 1.21 gm (80 %), M.R: C; IR (KBr, cm -1 ) 1292 (-C=S) 1693 (C=O), 1310 and 1122 (-SO2); 1 H NMR (DMSO-d 6 /TMS) at 2.60 (d, 3H, -NHCH3), 4.40 (s, 2H, -SO2CH2), 7.00 (s, 1H, -NH, D2O exchangable), (m, 4H, Ar-H), 7.90 (d, 2H, pyridine ring protons), 8.80 (d, 2H, pyridine ring protons), 9.90 (s, 2H, -NH-NH protons), (s, 1H, -NH, D2O exchangable); M + +1: 380; Anal.Calcd for (C15H17N5O3S2) requires: C, 47.48; H, 4.52; N, Found: C, 47.45; H, 4.50; N, c: R = -NHCH3, n=2, Yield: 1.1 gm (75 %), M.R: C; IR (KBr, cm -1 ) 1292 (-C=S) 1693 (C=O), 1310 and 1122 (-SO2); 1 H NMR (DMSO-d 6 /TMS) at 2.50 (s, 3H, -NHCH3), (t, 2H, -Ar-CH2), (t, 2H, -SO2CH2), 7.00 (s, 1H, -NH, D2O exchangable), (m, 4H, Ar-H), 7.90 (d, 2H, pyridine ring protons), 8.80 (d, 2H, pyridine ring protons), 9.90 (s, 2H, -NH-NH portons), (s, 1H, - NH, D2O exchangable); M + +1: 394; 13 C NMR δ 28.97, 29.06, 50.70, , , , , , , Anal.Calcd for (C16H19N5O3S2) requires: C, 48.84; H, 4.87; N, Found: C, 48.80; H, 4.83; N, GENERAL PROCEDURE FOR THE PREPARATION OF 108(ac): Thiosemicarbazide 107(a-c) (0.003 mol) was added portion wise to sodium hydroxide solution (2N, 25 ml). The reaction mixture was

28 94 refluxed, and the completion of the reaction was monitored by TLC. The reaction mass was cooled to room temperature and filtered. The filterate was acidified with 2N hydrochloric acid to p H = 2. The precipitated solid was filtered, washed thoroughly with water (20 ml), dried. The crude compound was recrystallized from ethanol/water (4:1) to get compounds of 108(a-c). 108a: R = Pyrrolidine, n=1, Yield: 0.95 (80 %); M.R: C; IR (KBr, cm -1 ) 2726 (-SH), 1310 and 1122 (-SO2); 1 H NMR (DMSOd 6 /TMS) at 1.90 (m, 4H, pyrrolidine), 3.20 (m, 4H, pyrrolidine), 4.40 (s, 2H, -SO2CH2), (m, 4H, Ar-H), 7.60 (d, 2H, pyridine ring protons), 8.70 (d, 2H, pyridine ring protons), (s, 1H, -SH, D2O exchangable); M + +1: 402; Anal.Calcd for (C18H19N5O2S2) requires: C, 53.85; H, 4.77; N, Found: C, 53.81; H, 4.72; N, b: R = -NHCH3, n=1, Yield: 0.85 gm (80 %); M.R: C; IR (KBr, cm -1 ) 2726 (-SH), 1310 and 1122 (-SO2); 1 H NMR (DMSOd 6 /TMS) at 2.60 (d, 3H, -NHCH3), 4.40 (s, 2H, -SO2CH2), 7.00 (m, 1H, -NH, D2O exchangable), (m, 4H, Ar-H), 7.60 (d, 2H, pyridine ring protons), 8.70 (d, 2H, pyridine ring protons), (s, 1H, -SH, D2O exchangable); M + +1: 362; Anal.Calcd for (C15H15N5O2S2) requires: C, 49.84; H, 4.18; N, Found: C, 49.80; H, 4.14; N, c: R = -NHCH3, n=2, Yield: 0.90 gm (80 %); M.R: º C; IR (KBr, cm -1 ) 2726 (-SH), 1310 and 1122 (-SO2); 1 H NMR (DMSOd 6 /TMS) at 2.50 (d, 3H, -NHCH3), (t, 2H, -Ar-CH2), (t, 2H, -SO2CH2), 7.00 (s, 1H, -NH, D2O exchangable),

29 95 (m, 4H, Ar-H), 7.60 (d, 2H, pyridine ring protons), 8.70 (d, 2H, pyridine ring protons), (s, 1H, -SH, D2O exchangable); M + +1: 376; 13 C NMR 28.94, 29.20, 50.28, , , , , , , , , Anal.Calcd for (C16H17N5O2S2) requires: C, 51.18; H, 4.56; N, Found: C, 51.11; H, 4.52; N, GENERAL PROCEDURE FOR THE PREPARATION OF 109(ac): Thiosemicarbazide 107(a-c) ( mmol) was added portion wise to Con. sulfuric acid (25 ml) at 0 º C with continuous stirring. The reaction mixture was stirred further for 3 hours at room temperature. The reaction mass was poured into crushed ice (100 gm) and stirred for 30 minutes. The separated product was filtered and recrystallized from a mixture of acetic acid and water (1:1) to get compounds 109(ac). 109a: R = Pyrrolidine, n=1, Yield: 0.80 gm (80 %); M.R: >270 C; IR (KBr, cm -1 ) 3440 (-NH), 1310 and 1122 (-SO2); 1 H NMR (DMSOd 6 /TMS) at 1.90 (d, 4H, pyrrolidine), 3.20 (d, 4H, pyrrolidine), 4.40 (s, 2H, -SO2CH2), (m, 4H, Ar-H), 7.80 (d, 2H, pyridine ring protons), 8.80 (d, 2H, pyridine ring protons), (s, 1H, -NH, D2O exchangable); M + +1: 402; Anal.Calcd for (C18H19N5O2S2) requires: C, 53.85; H, 4.77; N, Found: C, 53.80; H, 4.73; N, b: R = -NHCH3, n=1), Yield: 0.71 gm (80 %); M.R: >270 C; IR (KBr, cm -1 ) 3440 (-NH), 1310 and 1122 (-SO2); 1 H NMR (DMSOd 6 /TMS) at 2.60 (d, 3H, -NHCH3), 4.40 (s, 2H, -SO2CH2), 7.00 (m,

30 96 1H, -NH, D2O exchangable), (m, 4H, Ar-H), 7.80 (d,2h, pyridine ring protons), 8.80 (d, 2H, pyridine ring protons), (s, 1H, -NH, D2O exchangable); M + +1: 362; Anal.Calcd for (C15H15N5O2S2) requires: C, 49.84; H, 4.18; N, Found: C, 49.81; H, 4.14; N, c: R = -NHCH3, n=2, Yield: 0.75 gm (80 %); M.R: >300 C; IR (KBr, cm -1 ) 3440 (-NH), 1310 and 1122 (-SO2); 1 H NMR (DMSO-d 6 /TMS) at 2.60 (d, 3H, -NHCH3), (t, 2H, -Ar-CH2), (t, 2H, - SO2CH2), 7.00 (m, 1H, -NHCH3 D2O exchangable), (m, 4H, Ar-H), 7.80 (d, 2H, pyridine ring protons), 8.80 (d, 2H, pyridine ring protons), (s, 1H, -NH, D2O exchangable), M + +1: 376; Its 13 C NMR spectrum (Fig. 3.14) showed the signals at 28.94, 29.20, 50.88, , , , , , , , and Anal.Calcd for (C16H17N5O2S2) requires: C, 51.18; H, 4.56; N, Found: C, 51.12; H, 4.50; N, GENERAL PROCEDURE FOR THE PREPARATION OF 110(ac): Compound 106(a-c) (0.013 mmol) was added portion wise to a mixture of tetrahydrofuran (35.0 ml) and 4-aminobutane-1-ol (76) (0.014 mol, 1.08 gm) at room temperature. The reaction mixture was stirred further for 1 h at º C and completion of the reaction monitored by TLC. After the completion of the reaction, the mixture was cooled to room temperature and added Con.HCl (3.8 gm). The reaction mixture was refluxed by monitoring on TLC for completion of reaction. After the completion of the reaction, the mixture was

31 97 concentrated under reduced pressure at 90 º C. To the resultant crude was added water (20 ml) and the p H adjusted to neutral with saturated aq.sodium bicarbonate. The separated product was filtered and recrystallized from methanol to get pure compounds 110(a-c). 110a: R = Pyrrolidine, n=1, Yield: 3.0 gm (68 %); M.R: C; IR (KBr, cm -1 ) 1625 (-C=N), 1310 and 1150 (-SO2); 1 H NMR (DMSOd 6 /TMS) at 1.90 (d, 4H, pyrrolidine), 2.00 (m, 2H, CH2), 2.40 (m, 2H, CH2), 3.00 (m, 2H, CH2), 3.20 (d, 4H, pyrrolidine), 4.40 (s, 2H, - SO2CH2), (m, 4H, Ar-H), 8.80 (s, 1H, -NH, D2O exchangable); M + +1: 340; Anal.Calcd for (C15H21N3O2S2) requires: C, 53.07; H, 6.24; N, Found: C, 53.01; H, 6.20; N, b: R = -NHCH3, n=1, Yield: 2.7 gm (70 %); M.R; C; IR (KBr, cm -1 ) 3278 (-NH), 1624 (-C=N), 1310 and 1150 (-SO2); 1 H NMR (DMSO-d 6 /TMS) at 1.90 (m, 2H, CH2), 2.6 (d, 3H, -NHCH3), 2.90 (m, 2H, CH2), 3.50 (m, 2H, CH2), 4.20 (s, 2H, -SO2CH2), 6.90 (s, 1H, -NH D2O exchangable), (m, 4H, Ar-H), 8.40 (s, 1H, -NH, D2O exchangable); M + +1: 300; Anal.Calcd for (C12H17N3O2S2) requires: C, 48.14; H, 5.72; N, Found: C, 48.11; H, 5.70; N, c: R = -NHCH3, n=2, Yield: 2.6 gm (65 %); M.R: C; IR (KBr, cm -1 ) 3288 (-NH), 1625 (-C=N), 1310 and 1150 (-SO2) ; 1 H NMR (DMSO-d 6 /TMS) at 1.80 (m, 2H, CH2), 2.6 (d, 3H, -NHCH3), 2.80 (m, 2H, CH2), 3.00 (t, 2H, -Ar-CH2), 3.20 (t, 2H, -SO2CH2), 3.40 (m, 2H, CH2), 6.90 (s, 1H, -NH, D2O exchangable), (m, 4H, Ar-H), 8.40 (s, 1H, -NH, D2O exchangable); M + +1: 314; Anal.Calcd for

32 98 (C13H19N3O2S2) requires: C, 49.81; H, 6.11; N, Found: C, 49.78; H, 6.08; N, GENERAL PROCEDURE FOR THE PREPARATION OF 111(ac): A mixture of 2-amino-2-cyanoacetamide (93) (0.018 mol), triethylorthoformate ( mol) and acetonitrile (55.0 ml) was heated to reflux for 30 minutes then allowed to cool to room temperature. (26a,d,e) (0.018mol) was added portion wise, and then resulting mixture was stirred at reflux temperature for 3 hours. The solid which was precipitated was filtered and recrystallized from methanol to give pure compound (111a-c). 111a: R = Pyrrolidine, n=1, Yield: 5.1 gm (80 %); M.R: C; IR (KBr, cm -1 ) 3445 (-NH), 1648 (-C=O) 1315 and 1143 (-SO2); 1 H NMR (DMSO-d 6 /TMS) at 1.90 (m, 4H, pyrrolidine), 3.20 (m, 4H, pyrrolidine), 4.40 (s, 2H, -SO2CH2), 5.80 (s, 2H, -CONH2 D2O exchangable), (d, 2H, -NH2 D2O exchangable), 7.40 (s, 1H, imidazole ring protons), (d, 4H, Ar-H), M + +1: 350; Anal.Calcd for (C15H19N5O3S) requires: C, 51.56; H, 5.48; N, Found: C, 51.53; H, 5.42; N, b: R = -NHCH3, n=1, Yield: 4.4 gm (80 %); M.R: C; IR (KBr, cm -1 ) 3435 (-NH), 1644 (-C=O) 1315 and 1143 (-SO2); 1 H NMR (DMSO-d 6 /TMS) at 2.70 (d, 3H, -NHCH3), 4.20 (s, 2H, -SO2CH2), 5.80 (s, 2H, -CONH2, D2O exchangable), (d, 2H, -NH2, D2O exchangable), 7.00 (m, 1H, -NH, D2O exchangable), 7.40 (s, 1H, CH imidazole), (m, 4H, Ar-H), M + +1: 310; Anal.Calcd for

33 99 (C12H15N5O3S) requires: C, 46.59; H, 4.89; N, Found: C, 46.55; H, 4.87; N, c: R=-NHCH3, n=2, Yield: 3.4 gm (60 %); M.R: C; IR (KBr, cm -1 ) 3423 (-NH2), 1640 (-C=O) 1315 and 1143 (-SO2); 1 H NMR (DMSO-d 6 /TMS) at 2.70 (s, 3H, -NHCH3), 3.00 (m, 2H, -Ar-CH2), 3.40 (m, 2H, -SO2CH2), 5.80 (s, 2H, -CONH2, D2O exchangable), (d, 2H, -NH2, D2O exchangable), 7.00 (m, 1H, -NHCH3, D2O exchangable), 7.40 (s, 1H, CH imidazole), (m, 4H, Ar-H), M + +1: 324; 13 C NMR 28.99, 29.11, 50.44, , , , , , , and Anal.Calcd for (C13H17N5O3S) requires: C, 48.28; H, 5.30; N, Found: C, 48.24; H, 5.28; N, GENERAL PROCEDURE FOR THE PREPARATION OF 112(ac): A mixture of 111(a-c) (0.005 mol) and formic acid (20 ml) was refluxed for 1 hour. The solution was cooled, and then poured into water (50 ml). The solid that seperated was collected and crystallized from suitable solvent gave the pure product 112(a-c). 112a: R = Pyrrolidine, n=1, Yield: 1.4 gm (80 %); M.R: >270 C; IR (KBr, cm -1 ) 3440 (-NH), 1712 (-C=O), 1519 and 1131 (-SO2); 1 H NMR (DMSO-d 6 /TMS) at 1.90 (m, 4H, pyrrolidine), 3.20 (m, 4H, pyrrolidine), 4.40 (s, 2H, -SO2CH2), (m, 4H, Ar-H), 8.10 (s, 1H, CH pyrimidine), 8.50 (s, 1H, CH imidazole), (s, 1H, -NH, pyrimidine, D2O exchangable); M + +1: 360; Anal.Calcd for

34 100 (C16H17N5O3S) requires: C, 53.47; H, 4.77; N, Found: C, 53.42; H, 4.75; N, b: R = -NHCH3, n=1, Yield: 1.2 gm (80 %); M.R: >270 C; IR (KBr, cm -1 ) 3440 (-NH), 1712 (-C=O), 1519 and 1131 (-SO2); 1 H NMR (DMSO-d 6 /TMS) at 2.60 (d, 3H, -NHCH3), 4.40 (s, 2H, -SO2CH2), 7.00 (m, 1H, -NH, D2O exchangable), (m, 4H, Ar-H), 8.10 (s, 1H, CH pyrimidine), 8.50 (s, 1H, CH imidazole), (s, 1H, -NH, pyrimidine, D2O exchangable); M + +1: 320; Anal.Calcd for (C13H13N5O3S) requires: C, 48.89; H, 4.10; N, Found: C, 48.86; H, 4.08; N, c: R=-NHCH3, n=2, Yield: 1.1gm (70 %); M.R: >270 C; IR (KBr, cm -1 ) 3443 (-NH), 1712 (-C=O), 1309 and 1131 (-SO2); 1 H NMR (DMSO-d 6 /TMS) at 2.60 (d, 3H J=4.8, -NHCH3), (t, 2H, -Ar- CH2), (t, 2H, -SO2CH2), 7.00 (m, 1H, -NH, D2O Exchangable), 7.50 (d, 2H J=8.4, Ar-H), 7.70 (d, 2H J=8.4, Ar-H), 8.10 (s, 1H, CH pyrimidine), 8.50 (s, 1H, CH imidazole), (s, 1H, - NH, pyrimidine, D2O exchangable); M + +1: 334; 13 C NMR 28.99, 29.14, 50.52, , , , , , , , and Anal.Calcd for (C14H15N5O3S) requires: C, 50.44; H, 4.54; N, Found: C, 50.41; H, 4.51; N,