CHAPTER - 3 SYNTHESIS OF SUBSTITUTED 1,2,4-TRIAZOLE, 1,3,4 ...shodhganga.inflibnet.ac.in/bitstream/10603/4395/8/08_chapter 3.pdf · 68 3.2 LITERATURE SURVEY: Several synthetic methods

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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 [100-102], 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.

http://en.wikipedia.org/wiki/Migraine

http://en.wikipedia.org/wiki/Headache

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3.2 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.

3.2.1. 1,2,4-TRIAZOLE

Bany et. al. [110] reported that the condensation of ethoxy-

carbonylmethyl isothiocyanate (33) with amidrazone salts (34) on

thermal heating gave 1,2,4-triazoline-5-thione (35) (Scheme-3.1).

….. Scheme - 3.1

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 - 3.2

Zamani et. al. [112] reported the condensation of 4-

methylphenyl isothiocyanate (39) with pyridinecarboxylic hydrazide

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 - 3.3

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 - 3.4

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).

70

….. Scheme - 3.5

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 - 3.6

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

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3.2.2. 1,3,4-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).

….. Scheme - 3.8

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-

N-(1-oxo-3-phenyl-1-(2-(p-tolylcarbamothioyl)hydrazinyl) 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).

72

…..Scheme - 3.9

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).

…..Scheme - 3.10

Shashikanth et. al. [119] has reported the condensation of

phenyl isothiocyanate (63) with 2-(2-(3-chlorobenzoyl)-4-methyl

phenoxy)acetohydrazide (64), to give 2-(2-(2-(3-chlorobenzoyl)-4-

methyl phenoxy)acetyl)-N-phenylhydrazinecarbothioamide (65), which

on cyclization in the presence of phosphoric acid, results in the

73

formation of (3-chlorophenyl)(3-((5-(phenylamino)-1,3,4-thiadiazol-2-

yl) methoxy) phenyl) methanone (66) (scheme-3.11).

…..Scheme - 3.11

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 - 3.12

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 - 3.13

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).

75

……….Scheme - 3.14

3.2.3. 1,3- 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 - 3.15

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 - 3.16

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 - 3.17

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-

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-

trimethyl-5,6-dihydro-4H-1,3-thiazin-2-yl)benzamide (91) (Scheme-

3.18).

……….Scheme - 3.18

3.2.4. 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 5-amino-1-benzyl-1H-

imidazole-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).

78

……….Scheme - 3.19

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-1H-

purin-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 - 3.20

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

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).

……….Scheme - 3.21

3.3. PRESENT WORK

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

(NCES).

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3.4 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- 3.22. 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.

……….Scheme - 3.22

3.4.1. Conversion of amine to isothiocyanate 106:

2-(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)-N-

methylethane 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.

81

The peaks at 1310 cm-1 and 1122 cm-1 confirming the asymmetric and

symmetric stretchings of –SO2 group. Its 1H NMR (DMSO-d6/TMS)

spectrum (Fig. 3.2) showed signals at 2.51 (d, J=4.1 HZ, 3H, -

NHCH3), 3.00-3.20 (t, 2H, Ar-CH2), 3.40-3.50 (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 - 3.23

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.

3.4.2. 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

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 1H-NMR spectrum

showed signals at δ 9.7 and 9.8 confirming the protons of –NH-NH-

grouping. The signal at δ 10.8 is –NH proton between thio ketone and

aromatic groups. Its 1H NMR (DMSO-d6/TMS) spectrum (Fig. 3.5)

showed signals at 2.50 (d, J=4.8 HZ, 3H, -NHCH3), 2.9-3.00 (t, J=7.6

HZ, 2H, Ar-CH2), 3.40-3.50 (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), 10.90 (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

13C NMR spectrum (Fig. 3.7) showed signals at δ 28.97, 29.06, 50.70,

122.06, 126.45, 128.44, 137.86, 139.96, 150.53, and 164.84. Based

on the above spectral data, the compound was assigned the structure

107c.

……….Scheme - 3.24

The above reaction of aryl isothiocyanate derivative 106c with acid

hydrazide derivative 40 has been found to be a general one and has

83

been extended to other substituted isothiocyanates. The products

obtained have been assigned structures 107a-b on the basis of their

spectral data

3.4.3. 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

14.20 in its 1H-NMR confirmed the proton of -SH. Its mass spectrum

showed molecular ion at m/z 376 which further confirmed the

structure. Its 1H NMR (DMSO-d6/TMS) spectrum (Fig. 3.9) showed

signals at 2.50 (d, J=4.1 HZ, 3H, -NHCH3), 2.9-3.00 (t, 2H, -Ar-CH2),

3.40-3.50 (t, 2H, -SO2CH2), 7.00 (m, 1H, -NHCH3, D2O exchangable),

7.20-7.40 (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), 14.20 (s, 1H,

SH, D2O exchangable). Its APCI mass spectrum (Fig. 3.10) showed


13C NMR spectrum (Fig. 3.11) showed the peaks at 28.94, 29.20,

50.28, 122.25, 128.94, 129.92, 132.88, 133.60, 140.68, 148.79,

150.43 and 159.60. Based on the above spectral data, the compound

was assigned as structure 108c.

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.

3.4.4. Cyclization of 107 in sulphuric acid 109:

Cyclization of 107c (i.e. 107, R=-NHCH3, n=2) in Con.sulphuric

acid medium at 25-30ºC 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 1H-NMR and mass spectral data. Its 1H NMR

(DMSO-d6/TMS) spectrum (Fig. 3.13) showed signals at 2.60 (d,

J=4.8 Hz, 3H, -NHCH3), 2.9-3.00 (t, 2H, -Ar-CH2), 3.30-3.40 (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), 10.80 (s, 1H,

NH D2O exchangable). Its APCI mass spectrum (fig. 3.14) showed


13C NMR spectrum (Fig. 3.15) showed the peaks at 28.94, 29.20,

85

50.88, 118.36, 120.91, 129.55, 132.98, 137.57, 139.17, 150.97,

155.42 and 165.78. Based on the above spectral data, the structure of

the compound was assigned the structure 109c.

……….Scheme - 3.26

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.

3.4.5. Conversion of 106 to 110:

Condensation reaction of 106c (i.e. 106, R=-NHCH3, n=2) with

3-aminopropanol (76) in refluxing tetrahydrofuran to give 1-(4-(3-(4-

hydroxybutyl)thioureido)phenyl)-N-methyl ethane sulfonamide, which

on cyclisation in hydrochloric acid yielded 2-(4-(5,6-Dihydro-4H-1,3-

thiazin-2-ylamino)phenyl)-N-methylethanesulfonamide (111c) (i.e.

110, R=-NHCH3, n=2) (Scheme - 3.27). 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 1H 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, -

86

NHCH3), 7.00-7.20 (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 13C NMR spectrum (Fig.

3.19) showed peaks at 21.02, 26.35, 28.60, 43.79, 50.64, 119.93,

128.33, 130.93, 142.54 and 147.10. Based on the above spectral data,

the compound was assigned structure 110c.

……….Scheme - 3.27

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.

3.4.6. 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 - 3.28).

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 1H NMR (DMSO-

d6/TMS) spectrum (Fig. 3.21) showed signals at 2.60 (d, J=4.4 HZ,

87

3H, -NHCH3), 2.9-3.00 (t, 2H, -Ar-CH2), 3.30-3.40 (t, 2H, -SO2CH2),

5.70 (s, 2H, NH2, D2O exchangable), 6.8-6.9 (d, 2H, NH2) 7.00 (m, 1H,

-NHCH3, D2O exchangable), 7.35 (s, 1H, CH imidazole) 7.40-7.60 (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 13C NMR

spectrum (Fig. 3.23) showed peaks at 28.99, 29.11, 50.44, 113.36,

124.93, 130.04, 130.23, 133.37, 139.04, 142.93 and 167.10.

……….Scheme - 3.28

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.

3.4.7. 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 ºC yielded N-methyl-2-(4-(6-oxo-1H-

purin-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

88

carbonyl) and 1309 and 1131 cm-1 (due to -SO2 group). Its 1H NMR

spectrum (Fig.3.25) at 2.60 (d, 3H J=4.8, -NHCH3), 3.00 (t, 2H, -Ar-

CH2), 3.30-3.40 (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), 12.50

(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 13C NMR spectrum (Fig.

3.27) showed peaks at 28.99, 29.14, 50.52, 124.19, 125.15, 129.93,

133.27, 139.05, 139.76, 146.45, 148.29 and 157.09. 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

89

compound 114 which on reduction with sodium dithionite gave the

required 2-amino-2-cyanoacetamide (Scheme-3.30).

……….Scheme - 3.30

4-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 - 3.31

All the above sequences of reactions are summarized in Scheme -

3.32 & 3.33

90

……….Scheme - 3.32

……….Scheme - 3.33

91

3.5. EXPERIMENTAL SECTION:

PREPARATION OF 108, 109, 110, 111 & 112:

3.5.1. GENERAL PROCEDURE FOR THE PREPARATION OF 106(a-

c):

A mixture of 26(a, d, e) (0.046 mol), chloroform (60 mL) and

water (50 mL) was cooled to about 10 ºC. Thiophosgene (0.063 mol)

was added dropwise to the reaction mixture with continuous stirring

at 10-20 ºC. 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(a-

c).

106a: R = Pyrrolidine, n=1, Yield: 8.5 gm (65 %), M.R: 141-143 °C; IR

(KBr, cm-1) 2185 and 2140 (-N=C=S), 1310 and 1122 (-SO2); 1H NMR

(DMSO-d6/TMS) at 1.60-1.80 (m, 4H, pyrrolidine), 3.00-3.20 (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, 9.92. Found: C, 51.00; H, 4.90; N, 9.90.

106b: R = -NHCH3, n=1, Yield: 6.1 gm (55 %), M.R: 146-148 ºC; IR


(DMSO-d6/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,

92

Ar-H); M++1: 243; Anal.Calcd for (C9H10N2O2S2) requires: C, 51.04; H,

5.00; N, 9.92. Found: C, 51.00; H, 4.90; N, 9.89.

106c: R = -NHCH3, n=2, Yield: 7.0 gm (60 %), M.R: 166-168 ºC; IR


(DMSO-d6/TMS) at 2.50 (d, 3H, -NHCH3), 3.00-3.20 (t, 2H, -Ar-CH2),

3.40-3.50 (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, 10.93. Found: C, 46.80;

H, 4.70; N, 10.90.


c):

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: 160-163 °C; IR

(KBr, cm-1) 1292 (-C=S), 1693 (C=O), 1310 and 1122 (-SO2); 1H NMR

(DMSO-d6/TMS) at 1.60-1.80 (m, 4H, pyrrolidine), 3.00-3.20 (m,

4H, pyrrolidine), 4.40 (s, 2H, -SO2CH2), 7.00 (s, 1H, -NH, D2O

exchangable), 7.20-7.40 (m, 4H, Ar-H), 7.90 (d, 2H, pyridine ring

protons), 8.80 (d, 2H, pyridine ring protons), 9.90 (s, 2H, -NH-NH

93

portons), 10.90(s, 1H, -NH, D2O exchangable); M++1: 420; Anal.Calcd

for (C18H21N5O3S2) requires: C, 51.53; H, 5.05; N, 16.69. Found: C,

51.50; H, 5.00; N, 16.63.

107b: R = -NHCH3, n=1, Yield: 1.21 gm (80 %), M.R: 182-184 °C; IR

(KBr, cm-1) 1292 (-C=S) 1693 (C=O), 1310 and 1122 (-SO2); 1H NMR


7.00 (s, 1H, -NH, D2O exchangable), 7.20-7.40 (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), 10.90 (s, 1H, -NH, D2O exchangable); M++1:

380; Anal.Calcd for (C15H17N5O3S2) requires: C, 47.48; H, 4.52; N,

18.46. Found: C, 47.45; H, 4.50; N, 18.43.

107c: R = -NHCH3, n=2, Yield: 1.1 gm (75 %), M.R: 150-155 °C; IR

(KBr, cm-1) 1292 (-C=S) 1693 (C=O), 1310 and 1122 (-SO2); 1H NMR

(DMSO-d6/TMS) at 2.50 (s, 3H, -NHCH3), 2.9-3.00 (t, 2H, -Ar-CH2),

3.40-3.50 (t, 2H, -SO2CH2), 7.00 (s, 1H, -NH, D2O exchangable), 7.20-

7.40 (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), 10.90 (s, 1H, -

NH, D2O exchangable); M++1: 394; 13C NMR δ 28.97, 29.06, 50.70,

122.06, 126.45, 128.44, 137.86, 139.96, 150.53, 164.84. Anal.Calcd

for (C16H19N5O3S2) requires: C, 48.84; H, 4.87; N, 17.80. Found: C,

48.80; H, 4.83; N, 17.79.


c):

Thiosemicarbazide 107(a-c) (0.003 mol) was added portion wise

to sodium hydroxide solution (2N, 25 mL). The reaction mixture was

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 pH = 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: 260-262 °C; IR

(KBr, cm-1) 2726 (-SH), 1310 and 1122 (-SO2); 1H NMR (DMSO-

d6/TMS) at 1.90 (m, 4H, pyrrolidine), 3.20 (m, 4H, pyrrolidine), 4.40

(s, 2H, -SO2CH2), 7.20-7.40 (m, 4H, Ar-H), 7.60 (d, 2H, pyridine ring

protons), 8.70 (d, 2H, pyridine ring protons), 14.20 (s, 1H, -SH, D2O

exchangable); M++1: 402; Anal.Calcd for (C18H19N5O2S2) requires: C,

53.85; H, 4.77; N, 17.44. Found: C, 53.81; H, 4.72; N, 17.43.

108b: R = -NHCH3, n=1, Yield: 0.85 gm (80 %); M.R: 260-262 °C; IR


d6/TMS) at 2.60 (d, 3H, -NHCH3), 4.40 (s, 2H, -SO2CH2), 7.00 (m,

1H, -NH, D2O exchangable), 7.20-7.40 (m, 4H, Ar-H), 7.60 (d, 2H,

pyridine ring protons), 8.70 (d, 2H, pyridine ring protons), 14.20 (s,

1H, -SH, D2O exchangable); M++1: 362; Anal.Calcd for (C15H15N5O2S2)

requires: C, 49.84; H, 4.18; N, 19.38. Found: C, 49.80; H, 4.14; N,

19.33.

108c: R = -NHCH3, n=2, Yield: 0.90 gm (80 %); M.R: 248-250 ºC; IR


d6/TMS) at 2.50 (d, 3H, -NHCH3), 2.9-3.00 (t, 2H, -Ar-CH2), 3.40-

3.50 (t, 2H, -SO2CH2), 7.00 (s, 1H, -NH, D2O exchangable), 7.20-7.40

95

(m, 4H, Ar-H), 7.60 (d, 2H, pyridine ring protons), 8.70 (d, 2H,

pyridine ring protons), 14.20 (s, 1H, -SH, D2O exchangable); M++1:

376; 13C NMR 28.94, 29.20, 50.28, 122.25, 128.94, 129.92, 132.88,

133.60, 140.68, 148.79, 150.43, 159.60. Anal.Calcd for


H, 4.52; N, 18.60.


c):

Thiosemicarbazide 107(a-c) (0.0025 mmol) was added portion

wise to Con. sulfuric acid (25 mL) at 0 ºC 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(a-

c).

109a: R = Pyrrolidine, n=1, Yield: 0.80 gm (80 %); M.R: >270 °C; IR

(KBr, cm-1) 3440 (-NH), 1310 and 1122 (-SO2); 1H NMR (DMSO-

d6/TMS) at 1.90 (d, 4H, pyrrolidine), 3.20 (d, 4H, pyrrolidine), 4.40

(s, 2H, -SO2CH2), 7.20-7.60 (m, 4H, Ar-H), 7.80 (d, 2H, pyridine ring

protons), 8.80 (d, 2H, pyridine ring protons), 10.80 (s, 1H, -NH, D2O


53.85; H, 4.77; N, 17.44. Found: C, 53.80; H, 4.73; N, 17.40.

109b: R = -NHCH3, n=1), Yield: 0.71 gm (80 %); M.R: >270 °C; IR

(KBr, cm-1) 3440 (-NH), 1310 and 1122 (-SO2); 1H NMR (DMSO-

d6/TMS) at 2.60 (d, 3H, -NHCH3), 4.40 (s, 2H, -SO2CH2), 7.00 (m,

96

1H, -NH, D2O exchangable), 7.20-7.60 (m, 4H, Ar-H), 7.80 (d ,2H,

pyridine ring protons), 8.80 (d, 2H, pyridine ring protons), 10.80 (s,

1H, -NH, D2O exchangable); M++1: 362; Anal.Calcd for (C15H15N5O2S2)

requires: C, 49.84; H, 4.18; N, 19.38. Found: C, 49.81; H, 4.14; N,

19.33.

109c: R = -NHCH3, n=2, Yield: 0.75 gm (80 %); M.R: >300 °C; IR (KBr,

cm-1) 3440 (-NH), 1310 and 1122 (-SO2); 1H NMR (DMSO-d6/TMS) at

2.60 (d, 3H, -NHCH3), 2.9-3.00 (t, 2H, -Ar-CH2), 3.30-3.40 (t, 2H, -

SO2CH2), 7.00 (m, 1H, -NHCH3 D2O exchangable), 7.20-7.60 (m, 4H,

Ar-H), 7.80 (d, 2H, pyridine ring protons), 8.80 (d, 2H, pyridine ring

protons), 10.80 (s, 1H, -NH, D2O exchangable), M++1: 376; Its 13C

NMR spectrum (Fig. 3.14) showed the signals at 28.94, 29.20,

50.88, 118.36, 120.91, 129.55, 132.98, 137.57, 139.17, 150.97,

155.42 and 165.78. Anal.Calcd for (C16H17N5O2S2) requires: C, 51.18;

H, 4.56; N, 18.65. Found: C, 51.12; H, 4.50; N, 18.61.


c):

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 50-55 ºC 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

97

concentrated under reduced pressure at 90 ºC. To the resultant crude

was added water (20 mL) and the pH adjusted to neutral with

saturated aq.sodium bicarbonate. The separated product was filtered

and recrystallized from methanol to get pure compounds 110(a-c).


(KBr, cm-1) 1625 (-C=N), 1310 and 1150 (-SO2); 1H NMR (DMSO-

d6/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), 7.20-7.60 (m, 4H, Ar-H), 8.80 (s, 1H, -NH, D2O


53.07; H, 6.24; N, 12.38. Found: C, 53.01; H, 6.20; N, 12.33.

110b: R = -NHCH3, n=1, Yield: 2.7 gm (70 %); M.R; 152-155 °C; IR

(KBr, cm-1) 3278 (-NH), 1624 (-C=N), 1310 and 1150 (-SO2); 1H NMR

(DMSO-d6/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), 7.20-7.60 (m, 4H, Ar-H), 8.40 (s, 1H, -NH, D2O


48.14; H, 5.72; N, 14.03. Found: C, 48.11; H, 5.70; N, 14.00.

110c: R = -NHCH3, n=2, Yield: 2.6 gm (65 %); M.R: 184-187 °C; IR

(KBr, cm-1) 3288 (-NH), 1625 (-C=N), 1310 and 1150 (-SO2) ; 1H NMR

(DMSO-d6/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), 7.20-7.60 (m, 4H, Ar-H),

8.40 (s, 1H, -NH, D2O exchangable); M++1: 314; Anal.Calcd for

98


H, 6.08; N, 13.39.


c):

A mixture of 2-amino-2-cyanoacetamide (93) (0.018 mol),

triethylorthoformate (0.0321 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).


(KBr, cm-1) 3445 (-NH), 1648 (-C=O) 1315 and 1143 (-SO2); 1H NMR

(DMSO-d6/TMS) at 1.90 (m, 4H, pyrrolidine), 3.20 (m, 4H,

pyrrolidine), 4.40 (s, 2H, -SO2CH2), 5.80 (s, 2H, -CONH2 D2O

exchangable), 6.7-6.9 (d, 2H, -NH2 D2O exchangable), 7.40 (s, 1H,

imidazole ring protons), 7.50-7.60 (d, 4H, Ar-H), M++1: 350;

Anal.Calcd for (C15H19N5O3S) requires: C, 51.56; H, 5.48; N, 20.04.

Found: C, 51.53; H, 5.42; N, 20.01.

111b: R = -NHCH3, n=1, Yield: 4.4 gm (80 %); M.R: 193-196 °C; IR

(KBr, cm-1) 3435 (-NH), 1644 (-C=O) 1315 and 1143 (-SO2); 1H NMR


5.80 (s, 2H, -CONH2, D2O exchangable), 6.7-6.9 (d, 2H, -NH2, D2O

exchangable), 7.00 (m, 1H, -NH, D2O exchangable), 7.40 (s, 1H, CH

imidazole), 7.50-7.60 (m, 4H, Ar-H), M++1: 310; Anal.Calcd for

99

(C12H15N5O3S) requires: C, 46.59; H, 4.89; N, 22.64. Found: C, 46.55;

H, 4.87; N, 22.61.

111c: R=-NHCH3, n=2, Yield: 3.4 gm (60 %); M.R: 220-225 °C; IR

(KBr, cm-1) 3423 (-NH2), 1640 (-C=O) 1315 and 1143 (-SO2); 1H NMR

(DMSO-d6/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), 6.7-

6.9 (d, 2H, -NH2, D2O exchangable), 7.00 (m, 1H, -NHCH3, D2O

exchangable), 7.40 (s, 1H, CH imidazole), 7.50-7.60 (m, 4H, Ar-H),

M++1: 324; 13C NMR 28.99, 29.11, 50.44, 113.36, 124.93, 130.04,

130.23, 133.37, 139.04, 142.93 and 167.10. Anal.Calcd for


H, 5.28; N, 21.61.


c):

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); 1H NMR

(DMSO-d6/TMS) at 1.90 (m, 4H, pyrrolidine), 3.20 (m, 4H,

pyrrolidine), 4.40 (s, 2H, -SO2CH2), 7.40-7.60 (m, 4H, Ar-H), 8.10 (s,

1H, CH pyrimidine), 8.50 (s, 1H, CH imidazole), 12.50 (s, 1H, -NH,

pyrimidine, D2O exchangable); M++1: 360; Anal.Calcd for

100


H, 4.75; N, 19.45.

112b: 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); 1H NMR


7.00 (m, 1H, -NH, D2O exchangable), 7.20-7.60 (m, 4H, Ar-H), 8.10

(s, 1H, CH pyrimidine), 8.50 (s, 1H, CH imidazole), 12.50 (s, 1H, -NH,

pyrimidine, D2O exchangable); M++1: 320; Anal.Calcd for


H, 4.08; N, 21.89.

112c: 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); 1H NMR

(DMSO-d6/TMS) at 2.60 (d, 3H J=4.8, -NHCH3), 2.9-3.00 (t, 2H, -Ar-

CH2), 3.30-3.40 (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), 12.50 (s, 1H, -

NH, pyrimidine, D2O exchangable); M++1: 334; 13C NMR 28.99,

29.14, 50.52, 124.19, 125.15, 129.93, 133.27, 139.05, 139.76,

146.45, 148.29 and 157.09. Anal.Calcd for (C14H15N5O3S) requires: C,

50.44; H, 4.54; N, 21.01. Found: C, 50.41; H, 4.51; N, 21.00.

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CHAPTER - 3 SYNTHESIS OF SUBSTITUTED 1,2,4-TRIAZOLE, 1,3,4 ...shodhganga.inflibnet.ac.in/bitstream/10603/4395/8/08_chapter 3.pdf · 68 3.2 LITERATURE SURVEY: Several synthetic methods