Chapter 2shodhganga.inflibnet.ac.in/bitstream/10603/33054/7/07... · 2018. 7. 2. · Section-I Synthesis of tetrahydropyrimidine derivatives Department of Chemistry, Saurashtra University,

Chapter 2

Synthesis and characterization

Section-I

Synthesis of tetrahydropyrimidine

derivatives

Section-I Synthesis of tetrahydropyrimidine derivatives

Department of Chemistry, Saurashtra University, Rajkot-360005 7

INTRODUCTION

Recently, synthesis of tetrahydropyrimidine and their derivatives is of high

interest in organic chemistry. The pyrimidine fragment is present in various biologically

active compounds, many of which have been found use in medical practice1,2. Thus,

recently, much attention has been paid to derivatives of pyrimidine, including their

hydrogenation products. This class of compounds displays wide ranges of biological and

pharmacological properties which show a very similar pharmacological profile to

classical dihydropyridine calcium channel modulators3-12.

Literature survey shows that lots of work has been done for

tetrahydropyrimidines. Many researchers have been synthesized tetrahydropyrimidines

using different methods13-15. Recently, one-pot multicomponent reactions have emerged

as a powerful tool in synthetic organic chemistry because of their significant

advantages16-19. Polyethylene glycol (PEG)-mediated facile one-pot synthesis of

polysubstituted-tetrahydropyrimidines under mild and green reaction conditions have

been developed by Kidwai et al.20. Iodine catalyst one pot synthesis of tetrahydro

pyrimidine derivatives have been reported by Veerababurao et al.21.

Molecular docking of tetrhydropyrimidine derivatives have been studied by Sun et

al.22. Ghorai and co-workers have reported a convenient synthetic route to 2-aryl-N-

tosylazetidines and their ZnX2 (X = I, OTf) mediated regioselective nucleophilic ring

opening reactions for the synthesis of tetrahydropyrimidine23. Baltork and co-workers24

have synthesized chemo selective tetrahydropyrimidines using nano-SiO2 as reusable

solid acid catalyst under microwave irradiation. Zhao et al. were synthesized

fluoroalkylated multifunctional 1,2,3,4-tetrahydropyrimidines for the first time by the

reaction of 3-fluoroalkyl-3-anilinoacrylic acid esters with primary amines and

formaldehyde under mild conditions25. Muravyova et al. have carried out multicomponent

reactions with ultrasonic activation used as key methods for the synthesis of

tetrahydropyrimidine derivatives26.

Using microwave irradiation, Roy and Bordoloi have synthesized some new

tetrahydropyrimidines27. The stereo mutations of conformational atropisomers of

hindered 1,2-diaryl tetrahydropyrimidines has been reported by Gracia and co-workers28.

Baldev et al. have reported the thermal and microwave assisted synthesis of



tetrahydropyrimidines29. Synthesis and polymorph study of tetrahydropyrimidine

derivatives reported by Anatoly et al.30

Tetrahydropyrimidines are known to be versatile heterocyclic compound, which

has been subjected to a large variety of structural modifications in order to synthesize

derivatives with different biological properties. Many researchers have been worked on

QSAR study of tetrahydropyrimidines31-33. Their various condensed derivatives are

reported to possess calcium antagonist,34-36 anti-inflammatory,37-39 analgesic,40,41

antitumor,42,43 antidepressant44, antibacterial and antifungal effects45-47. Several synthetic

approaches have been reported for the synthesis of fused heterocyclic pyrimidine

derivatives48-50. These compounds also act as muscarinic agonist in the rat central nervous

system51, 52. Upshall53 has reported the nicotinic activity of these compounds.

In present chapter, some new tetrahydropyrimidines have been synthesized and

characterization of these synthesized compounds is done by IR, NMR and mass spectral

data.



EXPERIMENTAL SECTION

Synthesis of 2,4-diamino-6-phenyl-1,4,5,6-tetrahydropyrimidine-5-carbonitrile

(PAB-101 - PAB-110):

A substituted aldehyde (0.01 mole), malenonitrile (0.01 mole) and freshly

prepared 30 ml of sodium ethoxide was taken in a flask. When the solution becomes

clear, guanidine hydrochloride (0.01 mole) was added and the reaction mixture was

refluxed for 12 hours. After the completion of reaction, the reaction mixture was poured

into crushed ice. The solution was neutralized with aqueous HCL solution and product

was extracted using chloroform (50 ml × 3), the combined organic layer was washed

using brine solution (20 ml × 2). The organic layer was dried on anhydrous sodium

sulphate and the solvent was removed under reduced pressure to acquire the solid

product. All the synthesized compounds were recrystallized from chloroform.

The formation of the compounds was checked by thin-layer chromatography and

accomplished on 0.2-mm pre coated plates of silica gel G60 F254 (Merck). Visualization

was made with UV light (254 and 365nm) or with an iodine vapor.

The melting point of all the synthesized compounds was determined in open

capillary tubes and was uncorrected.

The characterization of all these compounds was done by IR, NMR and mass

spectral data. The IR spectra were recorded on Shimadzu FT-IR-8400 instrument using

KBr pellet method. The Mass spectra were recorded on Shimadzu GC-MS-QP-2010

model using direct inlet probe technique. 1H NMR and 13C NMR was determined in

DMSO solution on a Bruker Ac 400 MHz spectrometer.

The physical constants of all the synthesized compounds are given in Table 2.1.1

Figures 2.1.1 to 2.1.4 show the IR, mass and NMR spectrum of a compound.



Table 2.1.1: Synthesis of substituted tetrahydropyrimidine

Code R M.F M.W Yield (%) Rf valuePAB-101 C6H5- C11H13N5 215.25 78 0.68PAB-102 C6H4-CH=CH- C13H15N5 241.29 60 0.73PAB-103 3-Cl,C6H4- C11H12ClN5 249.70 68 0.44PAB-104 4-Cl,C6H4- C11H12ClN5 249.70 66 0.46PAB-105 4-F,C6H4- C12H15FN5 233.24 62 0.52PAB-106 4-OCH3,C6H4- C12H15N5O 245.28 84 0.42PAB-107 3-NO2,C6H4- C11H12N6O2 260.25 60 0.62PAB-108 3-0CH3,4-OHC6H4- C12H15N5O2 261.28 74 0.34PAB-109 4(α-C4H3O)- C9H11N5O 205.22 82 0.36PAB-110 4-OH-C6H4- C11H13N5O 231.25 56 0.30

SPECTRAL DATA

2,4-diamino-6-phnyl-1,4,5,6-tetrahydropyrimidine-5-carbonitrile (PAB-101). mp 141-

143°C; IR (KBr): 3151(N-H str), 3093(Ar, C-H str), 2943(C-Hstr), 2867(C-H str),

2245(C≡N str), 1610(Ar, C=C str), 1519(Ar, C=C str), 1512(Ar, C=C str), 1490(C-H ben),

1427(C-H ben), 1377(C-H ben), 1265(C-Cstr) cm-1; MS: m/z = 215 [M ]+

2,4-diamino-6-styryl-1,4,5,6-tetrahydropyrimidine-5-carbonitrile (PAB-102). mp 112-

114 °C; IR (KBr): 3161(N-H str), 3021(CH=CH str), 3091(Ar, C-H str), 2952(C-Hstr),

2879(C-H str), 2267(C≡N str), 1609(Ar, C=C str), 1515(Ar, C=C str), 1508(Ar, C=C str),

1481(C-H ben), 1425(C-H ben), 1379(C-H ben), 1252(C-C str) cm-1; MS: m/z = 241 [M ]+

2,4-diamino-6-(3-chlorophenyl)- 1,4,5,6-tetrahydropyrimidine-5-carbonitrile (PAB-

103). mp 153-155 °C; IR (KBr): 3163(N-H str), 3097(Ar, C-H str), 2933(C-Hstr), 2877(C-

H str), 2265(C≡N str), 1608(Ar, C=C str), 1514(Ar, C=C str), 1502(Ar, C=C str), 1489(C-

H ben), 1421(C-H ben), 1371(C-H ben), 1255(C-Cstr), 744(C-Cl str) cm-1; MS: m/z = 249

[M ]+.

2,4-diamino-6-(4-chlorophenyl)- 1,4,5,6-tetrahydropyrimidine-5-carbonitrile (PAB-

104). mp 162-164°C; IR (KBr): 3167(N-H str), 3092(Ar, C-H str), 2942(C-Hstr), 2876(C-


H ben), 1422(C-H ben), 1376(C-H ben), 1250(C-Cstr), 742(C-Cl str) cm-1; MS: m/z = 249

[M ]+.



2,4-diamino-6-(4-fluorophenyl)- 1,4,5,6-tetrahydropyrimidine-5-carbonitrile (PAB-

105). mp 128-130°C; IR (KBr): 3170(N-H str), 3094(Ar, C-H str), 2949(C-Hstr), 2875(C-


H ben), 1422(C-H ben), 1371(C-H ben), 1259(C-Cstr), 1065(C-F str) cm-1; MS: m/z = 233

[M ]+.

2,4-diamino-6-(4-methoxyphenyl)- 1,4,5,6-tetrahydropyrimidine-5-carbonitrile (PAB-

106). mp 116-118 °C; IR (KBr): 3170(N-H str), 3094(Ar, C-H str), 2949(C-Hstr), 2875(C-


H ben), 1426(C-H ben), 1368 (C-H ben), 1254(C-C str), 1157(C-O-C str) cm-1; MS: m/z =

245 [M ]+.

2,4-diamino-6-(3-nitrophenyl)- 1,4,5,6-tetrahydropyrimidine-5-carbonitrile (PAB-

107). mp 141-143°C; IR (KBr): 3107(N-H str), 3086 (Ar, C-H str), 3047 (C-Hstr), 1597

(Ar, C=C str), 1527 (Ar, C=C str), 1512(Ar, C=C str), 1479(C-H ben), 1427(C-H ben),

1315(C-H ben), 1217(C-C str) cm-1; 1H NMR (400 MHz, DMSO): δ ppm 2.56 (s, 1H, -

CH) 3.20-3.34 (t, 1H, -CH), 4.06-4.08 ( d, J = 9.80 Hz 1H, -CH), 6.24 (s, 2H, NH2),

6.60(s, 2H, NH2), 7.84-7.88 (t, 1H, Ar-H), 8.35-8.37 (d, 1H, Ar-H), 8.44-8.47 (m, 1H, Ar-

H), 8.63 (s, 1H, -NH), 8.83(s, 1H, Ar-H). 13C NMR (100 MHz, DMSO): δ ppm 38.96,

39.17, 58.50, 119.68, 123.40, 128.37, 133.56, 138.54, 164.05 MS: m/z = 260 [M ]+.

2,4-diamino-6-(4-hydroxy-3-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine-5

carbonitrile (PAB-108). Mp 132-134°C; IR (KBr): 3480(OH str), 3164(N-H str), 3023

(Ar, C-H str), 2947(C-H str), 2822(C-H str), 2241(C≡N str), 1606(Ar, C=C str), 1523(Ar,

C=C str), 1538(Ar, C=C str), 1482(C-H ben), 1357(C-H ben), 1330(C-H ben), 1230(C-C

str), 1078(C-O-C str), cm-1; MS: m/z = 261 [M ]+.

2,4-diamino-6-(furan -2-yl)- 1,4,5,6-tetrahydropyrimidine-5-carbonitrile (PAB-109).

m.p 72-74°C; IR (KBr): 3124(N-H str), 3043(Ar, C-H str), 2922(C-H str), 2847(C-H str),

2245(C≡N str), 1606(Ar, C=C str), 1552(Ar, C=C str), 1529(Ar, C=C str), 1456(C-H ben),

1394(C-H ben), 1330(C-H ben), 1230(C-C str), 1070(C-O-C str), 1022(C-O-C str) cm-1;

MS: m/z = 205 [M ]+.



2,4-diamino-6-(4-hydroxyphenyl)-1,4,5,6-tetrahydropyrimidine-5-carbonitrile (PAB-

110). Mp 176-178°C; IR (KBr): 3635(O-H str), 3165(N-H str), 3088(Ar, C-H str), 2942(C-

H str), 2865(C-H str), 2250(C≡N str), 1619(Ar, C=C str), 1510(Ar, C=C str), 1528(Ar,

C=C str), 1482(C-H ben), 1426(C-H ben), 1371(C-H ben), 1259(C-C str), 1210 (C-O str)

cm-1; MS: m/z = 231 [M ]+.



Figure 2.1.1: IR spectrum of compound PAB-107

Figure 2.1.2: Mass spectrum of compound PAB-107

45075010501350165019502250255028503150345037501/cm

-22.5

-15

-7.5

0

7.5

15

22.5

30

37.5

45

52.5

60

67.5

75

82.5

90

97.5

105%T

3107

.43

3086

.21

3047

.63

1597

.11

1566

.25

1527

.67

1479

.45

1357

.93

1315

.50

1217

.12

1111

.03

949.

0182

7.49

817.

8573

6.83

692.

4767

3.18

621.

1059

7.95



Figure 2.1.3: 1H NMR Spectrum of compound PAB-107

Expanded 1H NMR spectrum of compound PAB-107



Figure 2.1.4: 13C NMR spectrum of compound PAB-107



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tetrahydropyrimidin-5-yl) propanoic acid derivatives” Bioorg. Med. Chem. Lett.

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in preparing anti-inflammatory and analgesic medical preparations” Faming

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gemcitabine and tetrahydropyrimidine or tetrahydropyrimidine derivative for

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43. Ji-Xin, Y.; Xiao-Qing, C.; Di-Mei, C. and Mao-Lin, H.; “Synthesis, Structure

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Section-II

Synthesis of Tetrazolopyrimidine

derivatives

Section-II Synthesis of tetrazolopyrimidine derivatives


INTRODUCTION

Pyrimidine nucleus is one of the most important heterocycles exhibiting

remarkable pharmacological activities. The practice of medicinal chemistry is devoted to

the discovery and development of new agents for treating diseases. The process of

establishing a new drug is exceeding complex and involves talent of people from variety

of disciplines 1. An important aspect of medicinal chemistry has been to establish a

relationship between chemical structure and pharmacological activity 2. Pyrimidine is a

six membered cyclic compound containing four carbon and two nitrogen atoms and is

pharmacologically inactive but its synthetic derivatives possess an important role in

modern medicine.

In medicinal chemistry, pyrimidine derivatives have been very well known for

their therapeutic applications. The presence of a pyrimidine base in thymine, cytosine and

uracil, which are the essential building blocks of nucleic acids, DNA and RNA is one of

possible reasons for their activities3.

Literature survey shows that lots of work has been done for tetrazolopyrimidines.

In recent years, synthesis of Tetreazolopyrimidine and their derivatives is of high interest

in organic chemistry4-8.

Tetrazolopyrimidines are known to be synthesized using mineral acid9, sulfamic

acid10, strontium chloride hexahydrate11 etc. Recently, in synthetic organic chemistry,

one-pot multicomponent reactions are very popular because of their significant

advantages12. Chemoselective reduction of fused tetrazoles using phase-Transfer

condition has been reported by Desai et al.13.

Their related fused heterocycles are of interest as potential bioactive molecules.

They are known to exhibit biological activities such as anti algeric15,16, anti microbial17,18,

anti malerial19, anti hypertensive20, anti cancer21, anti tumor22, anti inflamatory23, anti

bacterial24, analgesic25,26, anti fungal27, anti viral28 etc. These derivatives have also been

reported to be used for the treatment of thyroid cancer29.

Thus, in present chapter, some new tetrazolopyrimidine derivatives have been

synthesized and characterization of these synthesized compounds is done by IR, NMR

and mass spectral data.




Synthesis of 3-oxo-N-phenylbutanamide:

A mixture of aniline (0.01 mole), ethyl acetoacetate (0.01 mole), and catalytic

amount of sodium or potassium hydroxide (10 %) in 50 ml toluene was refluxed at 110 oC

for 12-15 hours. After completion of reaction, the solvent was removed under vacuum

and the residue was crystallized from methanol.

Synthesis of 7-(4-bromophenyl)-4, 7-dihydro-5-methyl-N-phenyl tetrazolo [1,5-a]

pyrimidine-6-carboxamide (PAB-201-PAB-210):

A mixture of 3-oxo-N-phenylbutanamide (0.01mol), aromatic aldehyde (0.01

mol), 5-aminotetrazole (0.01 mol) and (10 mol% I2/i-PrOH) was dissolved in 10 ml

isopropyl alcohol. The reaction mixture was refluxed for 3-4 hrs and then was cooled at

room temperature. The resulting precipitate was filtered, washed with chilled isopropyl

alcohol to give pure product.


accomplished on 0.2-mm precoated plates of silica gel G60 F254 (Merck). Visualization



capillary tubes and was uncorrected. The characterization of all these compounds was

done by IR, NMR and mass spectral data. The IR spectra were recorded on Shimadzu FT-

IR-8400 instrument using KBr pellet method. The Mass spectra were recorded on

Shimadzu GC-MS-QP-2010 model using direct inlet probe technique. 1H NMR and 13C

NMR was determined in DMSO solution on a Bruker Ac 400 MHz spectrometer.





Table 2.2.1: Physical constant of tetrazolopyrimidine derivatives.

Code R M.F M.W Yield (%) Rf valuePAB-201 4-OH C18H16N6O2 348.36 67 0.42PAB-202 2,5diOCH3 C20H20N6O3 392.41 62 0.51PAB-203 4-Br C18H15BrN6O 411.26 70 0.48PAB-204 4-CH3 C19H18N6O 346.39 68 0.52PAB-205 2-OCH3 C19H18N6O2 362.39 75 0.56PAB-206 4-NO2 C18H15N7O3 377.36 72 0.44PAB-207 3-Cl C18H15ClN6O 366.80 73 0.41PAB-208 3-NO2 C18H15N7O3 377.36 66 0.53PAB-209 3-OCH3 C19H18N6O3 378.38 69 0.52PAB-210 3-Br C18H15BrN6O 411.26 62 0.56

SPECTRAL DATA

7-(4-hydroxyphenyl)-5-methyl-N-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-

carboxamide (PAB-201). mp 140-142°C; IR (KBr): 3629(O-H str), 3452(N-H str),

3300(N-H str), 3034(Ar, C-H str), 2944(C-H str), 1682 (C=O str), 1540(Ar, C=C str),

1520(C-N str), 1497(Ar, C=C str), 1479(C-H ben), 1053(C-O str) cm-1; MS: m/z = 348

[M ]+

7-(2,5-dimethoxyphenyl)-5-methyl-N-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-

6-carboxamide (PAB-202). mp 128-130°C; IR (KBr): 3452(N-H str), 3300(N-H str),

3034(Ar, C-H str), 2944(C-H str), 1682 (C=O str), 1540(Ar, C=C str), 1520(C-N str),

1497(Ar, C=C str), 1479(C-H ben), 1153(C-O-C str)cm-1; MS: m/z = 392 [M ]+

7-(4-bromophenyl)-5-methyl-N-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-

carboxamide (PAB-203). mp 162-164°C; IR (KBr): 3483(N-H str), 3377(N-H str), 3198

(Ar, C-H str), 2943(C-H str), 1672 (C=O str), 1530(Ar, C=C str), 1589(C-N str), 1489(Ar,

C=C str), 1450(C-H ben), 1068(C-O str),756(C-Br str) cm-1; 1H NMR (400 MHz,

DMSO): δ ppm 2.51 (s, 3H, -CH3), 5.32 (s, 1H, -CH), 6.90-6.94 (t, 3H,- ArH), 7.33-7.35

(d, 2H, ArH), 7.47-7.49 (d, 2H, ArH) 7.87-7.89 (d, 2H, ArH), 9.94 (S, 1H, -NH), 10.73

(S, 1H, -NH), 13C NMR (100 MHz, DMSO): δ ppm 17.38, 55.39, 104.84, 112.62,

113.93, 114.70, 115.85, 122.91, 127.84, 137.00, 147.77, 153.82, 160.08. MS: m/z =411

[M ]+



5-methyl-N-phenyl-7-(p-tolyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide

(PAB-204). mp 156-158°C; IR (KBr): 3452(N-H str), 3350(N-H str), 3031(Ar, C-H str),

2944(C-H str), 1682 (C=O str), 1520(C-N str), 1497(Ar, C=C str), 1454(C-H ben)cm-1;

MS: m/z = 346 [M ]+

7-(2-methoxyphenyl)-5-methyl-N-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-

carboxamide (PAB-205). mp 134-136°C; IR (KBr): 3456(Amide, N-H str), 3343(N-H

str), 3023(Ar, C-H str), 2946(C-H str), 1687 (C=O str), 1542(Ar, C=C str), 1492(Ar,

C=C str), 1453(C-H ben), 1154(C-O-C str) cm-1; MS: m/z = 362 [M ]+

5-methyl-7-(4-nitrophenyl)-N-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-

carboxamide (PAB-206). mp 150-152°C; IR (KBr): 3432(N-H str), 3338(N-H str),

3054(Ar, C-H str), 2954(C-H str), 2830(C-H str), 1679 (C=O str), 1531(Ar, C=C str),

1525(C-N str), 1486(Ar, C=C str), 1472(C-H ben)cm-1; MS: m/z =377 [M ]+

7-(3-chlorophenyl)-5-methyl-N-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-


3037(Ar, C-H str), 2946(C-H str), 1689 (C=O str), 1540(Ar, C=C str), 1520(C-N str),

1495(Ar, C=C str), 1474(C-H ben), 755(C-Cl str)cm-1; MS: m/z = 366 [M ]+

5-methyl-7-(3-nitrophenyl)-N-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-


2954(Ar, C-H str), 2830(C-H str), 1684 (C=O str), 1517(Ar, C=C str), 1486(Ar, C=C str),

1472(C-H ben)cm-1; MS: m/z = 377 [M ]+

7-(4-hydroxy-3-methoxyphenyl)-5-methyl-N-phenyl-4,7-dihydrotetrazolo[1,5-

a]pyrimidine-6-carboxamide (PAB-209). mp 167-169°C; IR (KBr): 3638(O-H str),

3443(Amide, N-H str), 3310(N-H str), 3034(Ar, C-H str), 2944(C-H str), 1686 (C=O str),

1530(Ar, C=C str), 1497(Ar, C=C str), 1459(C-H ben),1160(C-O-C str) 1053(C-O

str)cm-1; MS: m/z = 378 [M ]+

7-(3-bromophenyl)-5-methyl-N-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-


3022(Ar, C-H str), 2941(C-H str), 1689 (C=O str), 1530(Ar, C=C str), 1481(Ar, C=C str),

1471(C-H ben), 722(C-Br str) cm-1; MS: m/z = 411 [M ]+



Figure: 2.2.1 IR spectrum of compound PAB-203

Figure: 2.2.2 Mass spectrum of compound PAB-203

45075010501350165019502250255028503150345037501/cm

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100%T

3483

.56

3377

.47

3198

.08

2943

.47

2794

.95

1672

.34

1641

.48

1589

.40 14

89.1

014

50.5

213

94.5

812

98.1

4

1157

.33

1068

.60

997.

23

902.

7282

7.49

756.

1269

4.40

663.

5358

0.59

N

NH

NNN

O

NH

Br

N

NH

NNN

O

NH

Br



Figure: 2.2.3 1H NMR Spectrum of compound PAB-203


N

NH

NNN

O

NH

Br

N

NH

NNN

O

NH

Br



Figure: 2.2.4 13C NMR spectrum of compound PAB-203

N

NH

NNN

O

NH

Br



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Section-III

Synthesis of Dihydropyrazole

derivatives

Section-III Synthesis of dihydropyrazole derivatives


INTRODUCTION

The chemistry of pyrazoles has been reviewed by Jarobe in 1967. Pyrazoles have

attracted attention of medicinal chemists for both with regard to heterocyclic chemistry

and the pharmacological activities associated with them. Pyrazoles are well known

nitrogen containing five member heterocycles.

Pyrazoles have been studied extensively because of ready accessibility, diverse

chemical reactivity, broad spectrum of biological activity1-6 and varieties of industrial

applications7.

As evident from the literature, in recent years a significant portion of research

work in heterocyclic chemistry has been devoted to pyrazoles containing different alkyl,

aryl and heteroaryl groups as substituents.

Different methods are available from the literature for the preparation of 2-

pyrazole derivatives8-13.The most common procedure for the synthesis of 2-pyrazoles is

the reaction of an aliphatic or aromatic hydrazine with α,β-unsaturated carbonyl

compounds14,15.

Suzuki et al. have reported gold catalyzed synthesis of some dihydropyrazoles16.

De17 et al. have reported cellulose beads as a new versatile solid support for microwave

assisted synthesis of pyrazole and isoxazole libraries.A solid-phase synthesis of pyrazole

dicarboxylic acid derivatives by functionalization of cyanoformate have been reported by

Morelli et al.18. Ren and coworkers19 have synthesized pyrazole derivatives using liquid

phase synthesis strategy. Kim et al. have reported the synthesis of cyanopyrazoline

derivatives20 whereas Koval et al. have synthesized and studied the structures of new

copper complexes with the pyrazole-containing ligands21. Ali has reported stereoselective

synthesis of N-vinyl pyrazoles in solvent-free conditions using dipotassium hydrogen

phosphate powder22.

Thus, in literature, various catalysts have been used for the synthesis of pyrazoles.

Some of these catalysts are metals23, conjugate base24, iodine25, hafnium chloride26,

tungstophosphoricacid27, p-toluene sulphonic acid28, sulfamicacid29, ytterbium(III)

perfluorooctanoate30, silver31, organocatalysts32, etc..

Much attention was paid to pyrazole as a potential antimicrobial agent after the

discovery of the natural pyrazole C-glycoside pyrazofurin which demonstrated a broad

spectrum of antimicrobial activity33. Some pyrazole derivatives used as potent and



selective inhibitors against DNA gyrase are capable to cause bacterial cell death, for

example, Hoffmann – La Roche’s group34,35 has developed a new lead DNA gyrase

inhibitor. Literature survey shows that 2-pyrazolines are better therapeutic agents. They

possess valuable bioactivities like, antiinflammatory36,37, antitumor38,39, analgesic40,41,

bactericidal42, Fungicidal43, anticancer44, anticonvulsant45, pesticidal46, antidepressant47,

antiamoebic48, insecticidal49 ,antineoplastic50,51,antitubercular52 etc.

Thus, in present chapter, some new dihydropyrazoles have been synthesized and

characterization of these synthesized compounds is done by IR, NMR and mass spectral

data.




[A] Synthesis of substituted chalcones:

Substituted aldehydes (0.01 mole) was dissolved in 15 ml of methanol. 0.01 mole

of substituted acetophenones and 3-4 drops of saturated sodium hydroxide solution (as a

catalyst) was added and the reaction mixture was stirred for 24 hours. After the

completion of reaction, the reaction mass was filtered and washed with chilled methanol.

Similarly, other compounds are also prepared using different aldehydes.

[B] Synthesis of 6-chloro-4-phenylchroman-2-one:

To a mixture of cinnamic acid (0.1 mole), p-chloro phenol (0.1, mole), catalytic

amount of concentrated H2SO4 was added with stirring and the reaction mixture was

heated at 70o-80oC to become clear solution. The temperature was then increased up to

120o-125oC and heating was continued for 3-4 hours. After the completion of reaction,

the reaction mixture was cooled up to 80oC. Then 40 ml of toluene and 40 ml of water

was added to the reaction mixture and stirred it for 30 minutes. The toluene layer was

separated and washed with saturated sodium bicarbonate solution (2 x 20 ml) and water

(2 x 20 ml). The resulting toluene layer was then dried using sodium sulphate under

vacuum. 25 ml of isopropyl alcohol added to the resulting oily mass and stirring was done

for 30 minutes at 0-5o C. The product was filtered and washed with chilled iso-propyl

alcohol (2 x 5 ml) and dried to give 6-chloro-4-phenylchroman-2-one

[C] Synthesis of methyl 3-(2-(benzyloxy)-5-chlorophenyl)-3-phenylpropanoate:

A mixture of 6-chloro-4-phenylchroman-2-one (0.1 mole), potassium carbonate

(0.12 mole), benzyl chloride (0.12 mole), sodium iodide (0.05 mole), 100 ml of acetone

and 100 ml of methanol was heated with stirring. After the completion of reaction,

solvent was removed under vacuum. Then, dichloromethane (100 ml) and water (100 ml)

was added to the reaction mixture and was stirred for 30 minutes. The organic layer was



separated and dried using sodium sulphate and distilled completely under vacuum to get

oily residue of 3-(2-(benzyloxy)-5-chlorophenyl)-3-phenylpropanoate.

[D] Synthesis of 3-(2-(benzyloxy)-5-chlorophenyl)-3-phenylpropanehydrazide:

3-(2-(benzyloxy)-5-chlorophenyl)-3-phenylpropanoate (0.01 mole) was dissolved

in 20 ml of methanol. 2 ml of hydrazine hydrate (99 %) was added to this solution and the

resulting mixture was heated for 10-12 hours at reflux temperature. After the completion

of reaction, the reaction mass was filtered and washed with chilled methanol (2 x 5 ml) to

give pure product.

Cl

OH H2SO4

120-125 oC

O

Cl

O

K2CO3, NaI

Acetone, MeOH

55-60 oC

COOCH3

O

Cl

NH2-NH2.H2OMeOHReflux

CONHNH2

O

Cl

COOH

Cl

BC

D

[E] Synthesis of 3-(2-benzyloxy)-5-chlorophenyl)-1-(3-(4-chlorophenyl)-5-(p-

tolyl)-4,5-dihydro-1H-pyrazol-1yl)-3-phenylpropan-1-one:

To a mixture of 3-(2-benzyloxy)-5-chlorophenyl)-3-phenylpropanehydrazide

(0.01 mol) and different substituted chalcones (0.01 mol), 10 ml of glacial acetic acid was

added with stirring. The reaction mixture was refluxed on oil bath for 12 hours. After the

completion of reaction, the mixture was poured into crushed ice to give solid product. The

solid mass was filtered and purified by column chromatography using eluent hexane:

ethyl acetate (7:3). Similarly other compounds were also prepared with different

chalcones.













The physical constants of all the synthesized compounds are given in Table 2.3.1.




Table 2.3.1: Physical constant of dihydropyrazole derivatives

Code R R1 M.F M.W

Yield

(%) Rf value

PAB-301 2-Cl 4-F C37H29Cl2FN2O 623.54 71 0.52

PAB-302 4-NO2 4-CH3 C38H32ClN3O4 630.13 64 0.58

PAB-303 4-F 3-NO2 C37H29ClFN3O4 634.10 70 0.54

PAB-304 3,4 di –OCH3 4-Cl C39H34Cl2N2O4 665.60 62 0.48

PAB-305 4-F 4-NO2 C37H29ClFN3O4 634.10 65 0.56

PAB-306 4-NO2 2-NO2 C37H29ClN4O6 661.10 60 0.55

PAB-307 C6H5 4-Cl C37H30Cl2N2O2 605.55 58 0.58

PAB-308 2-NO2 4-Cl C37H29Cl FN2O4 650.55 66 0.62

PAB-309 3,4 di –OCH3 4-F C39H34Cl2N2O4 649.15 74 0.51

PAB-310 2-NO2 C6H5 C37H30Cl2N3O4 616.10 72 0.60

PAB-311 4-CH3 4-Cl C38H32Cl2N2O2 619.58 70 0.64

PAB-312 4-Cl C6H5 C37H30Cl2N2O2 605.55 61 0.48

PAB-313 4-F 4-Br C37H29BrClFN2O2 667.99 67 0.47

PAB-314 4-NO2 4-Cl C37H29Cl2N3O4 650.55 71 0.51

PAB-315 4-Cl 4-F C37H29Cl2FN2O2 623.54 74 0.56

PAB-316 4-NO2 4-F C37H29ClFN3O4 634.10 69 0.48

PAB-317 4-F 4-Cl C37H29Cl2FN2O2 623.54 63 0.55

PAB-318 4-OCH3 4-Cl C38H32Cl2N2O3 635.58 70 0.62

PAB-319 4-OCH3 4-F C38H32ClFN2O3 619.12 77 0.58

PAB-320 4-F C6H5 C37H30ClFN2O2 589.10 76 0.64



SPECTRAL DATA

3-(2-benzyloxy)-5-chlorophenyl)-1-(5-(2-chlorophenyl)-3(4-fluorophenyl)-4,5-

dihydro-1H-pyrazol-1yl)-3-phenylpropan-1-one (PAB-301). mp 162-164°C; IR (KBr):

3030(Ar, C-H str), 2956(C-H str), 2821(C-H str), 1692(C=O str), 1616(Ar, C=C str),

1563(Ar, C=C str), 1535(Ar, C=C str), 1479(C-H ben), 1078(C-O-C str), 1030(C-F

str),736(C-Cl str) cm-1; MS: m/z = 623 [M ]+

3-(2-(benzyloxy)-5-chlorophenyl)-1-(3-(4-nitrophenyl)-5-(p-tolyl)-4,5-dihydro-1H-

pyrazol-1-yl)-3-phenylpropan-1-one (PAB-302). mp 154-156°C; IR (KBr): 3026(Ar, C-

H str), 2914(C-Hstr), 1662(C=O str), 1613(Ar, C=C str), 1551(Ar, C=C str), 1533(Ar,

C=C str), 1472(C-H ben), 1076(C-O-C str), 734(C-Cl str) cm-1; MS: m/z = 630 [M ]+

3-(2-(benzyloxy)-5-chlorophenyl)-1-(5-(4-fluorophenyl)-3-(3-nitrophenyl)-4,5-

dihydro-1H-pyrazol-1-yl)-3-phenylpropan-1-one (PAB-303). mp 145-147°C; IR

(KBr): 3061(Ar, C-H str), 1666(C=O str), 1626(Ar, C=C str), 1535(Ar, C=C str), 1479(C-

H ben), 1020(C-O-C str), 1030(C-F str), 734(C-Cl str) cm-1; MS: m/z = 634 [M ]+

3-(2-benzyloxy)-5-chlorophenyl)-1-(3-(4-chlorophenyl)-5-(3,4-dimethoxyphenyl)-4,5-


(KBr): 3029(Ar, C-H str), 2959(C-H str), 2829(C-H str), 1662(C=O str), 1617(Ar, C=C

str), 1563(Ar, C=C str), 1535(Ar, C=C str), 1443(C-H ben), 1078(C-O-C str), 1030(C-F

str),739(C-Cl str) cm-1; MS: m/z = 665 [M ]+



(KBr): 3064(Ar, C-H str), 1668(C=O str), 1599(Ar, C=C str), 1404(C-H ben), 1012(C-O-

C str), 1028(C-F str), 734(C-Cl str) cm-1; MS: m/z = 634 [M ]+

3-(2-(benzyloxy)-5-chlorophenyl)-1-(3-(2-nitrophenyl)-5-(4-nitrophenyl)-4,5-



str), 1539(Ar, C=C str), 1476(C-H ben), 1026(C-O-C str), 739(C-Cl str) cm-1; MS: m/z =

661 [M ]+

3-(2-(benzyloxy)-5-chlorophenyl)-1-(3-(4-chlorophenyl)-5-phenyl-4,5-dihydro-1H-




H str), 2967(C-H str), 2842(C-H str), 1661(C=O str), 1636(Ar, C=C str), 1519(Ar, C=C

str), 1472(C-H ben), 1023(C-O-C str), 750 ( C-H ben), 729(C-Cl str) cm-1; MS: m/z =

605 [M ]+

3-(2-(benzyloxy)-5-chlorophenyl)-1-(3-(4-chlorophenyl)-5-(2-nitrophenyl)-4,5-

dihydro-1H pyrazol-1-yl)-3-phenylpropan-1-one (PAB-308). mp 161-163°C; IR


H ben), 1028(C-O-C str), 745(C-H ben), 734(C-Cl str) cm-1; MS: m/z = 650 [M ]+

3-(2-(benzyloxy)-5-chlorophenyl)-1-(5-(3,4-dimethoxyphenyl)-3-(4-fluorophenyl)-4,5-




str), 736(C-Cl str) cm-1; MS: m/z = 649 [M ]+

3-(2-(benzyloxy)-5-chlorophenyl)-1-(5-(2-nitrophenyl)-3-phenyl-4,5-dihydro-1H-

pyrazol-1-yl)3-phenylpropan-1-one (PAB-310). mp 147-149°C; IR (KBr): 3073(Ar, C-


str), 1471(C-H ben), 1025(C-O-C str), 750( C-H ben), 739(C-Cl str) cm-1; MS: m/z = 616

[M ]+

3-(2-(benzyloxy)-5-chlorophenyl)-1-(3-(4-chlorophenyl)-5-(p-tolyl)-4,5-dihydro-1H-

pyrazol-1-yl)-3-phenylpropan-1-one (PAB-311). mp 167-169°C; IR (KBr): 3043(Ar,

C-H str), 2922(C-H str), 2847(C-H str), 1606(C=O str), 1529(Ar, C=C str), 1466(C-H

ben), 1022(C-O-C str), 750 ( C-H ben), 729(C-Cl str) cm-1; 1H NMR (400 MHz,

DMSO): δ ppm 2.45 (s, 3H, -CH3), 3.0-3.04 (d, 2H, -CH2), 3.54-3.59 (d, 2H, -CH2), 3.93

(t, 1H,-CH), 4.93-5.01(m, 3H, -CH2-CH),6.58-6.62 (dd, 2H, ArH), 6.84-6.88 (t, 4H,

ArH), 6.97-7.35 (m,7H, ArH), 7.42-7.51 (m, 7H, ArH), 8.05 (s, 1H, ArH). 13C NMR

(100 MHz, DMSO): δ ppm 20.47, 36.63, 43.41, 44.63, 56.28, 61.64, 108.46, 114.13,

117.43, 119.28, 119.80, 124.11, 129.29, 130.19, 132.77, 134.38, 141.49, 143.20, 152.48,

155.79, 168.52. MS: m/z = 619 [M ]+

3-(2-(benzyloxy)-5-chlorophenyl)-1-(5-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1H-

pyrazol-1-yl)-3-phenylpropan-1-one (PAB-312.) mp 164-166°C; IR (KBr): 3069(Ar, C-




str), 1474(C-H ben), 1022(C-O-C str), 743( C-H ben), 732(C-Cl str) cm-1; MS: m/z = 605

[M ]+

3-(2-(benzyloxy)-5-chlorophenyl)-1-(3-(4-bromophenyl)-5-(4-fluorophenyl)-4,5-



str), 1529(Ar, C=C str), 1472(C-H ben), 1032(C-O-C str), 1023(C-F str), 740( C-H ben),

733(C-Cl str), 575(C-Br str) cm-1; MS: m/z = 667 [M ]+

3-(2-(benzyloxy)-5-chlorophenyl)-1-(3-(4-chlorophenyl)-5-(4-nitrophenyl)-4,5-



H ben), 1029(C-O-C str), 741( C-H ben), 731(C-Cl str) cm-1; MS: m/z = 650 [M ]+

3-(2-(benzyloxy)-5-chlorophenyl)-1-(5-(4-chlorophenyl)-3-(4-fluorophenyl)-4,5-




732(C-Cl str) cm-1; MS: m/z = 623 [M ]+




H ben), 1037(C-O-C str), 1022(C-F str), 743( C-H ben), 731(C-Cl str) cm-1; MS: m/z =

634 [M ]+

3-(2-(benzyloxy)-5-chlorophenyl)-1-(3-(4-chlorophenyl)-5-(4-fluorophenyl)-4,5-




735(C-Cl str) cm-1; MS: m/z = 623 [M ]+

3-(2-(benzyloxy)-5-chlorophenyl)-1-(3-(4-chlorophenyl)-5-(4-methoxyphenyl)-4,5-







3-(2-(benzyloxy)-5-chlorophenyl)-1-(3-(4-fluorophenyl)-5-(4-methoxyphenyl)-4,5-





3-(2-(benzyloxy)-5-chlorophenyl)-1-(5-(4-fluorophenyl)-3-phenyl-4,5-dihydro-1H-



str), 1531(Ar, C=C str), 1443(C-H ben), 1077(C-O-C str), 1022(C-F str), 731(C-Cl str)

cm-1; MS: m/z = 589 [M ]+





45075010501350165019502250255028503150345037501/cm

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100%T

3124

.79

3043

.77

2922

.25 28

47.0

3

1606

.76

1529

.60

1456

.30

1394

.58

1330

.93

1296

.21

1153

.47

1022

.31

NN O

O

ClCl

CH3

NN O

O

ClCl

CH3










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Section-IV

Synthesis of oxadiazole

Derivatives

Section-IV Synthesis of oxadiazole derivatives


INTRODUCTION

Oxadiazoles belong to an important group of heterocyclic compounds having –

N=C-O- linkage. 1,3,4-oxadiazole(1) is a thermally stable aromatic heterocycle and exist

in two partially reduced forms; 2,3-dihydro-1,3,4-oxadiazole(1,3,4-oxadiazoline)(2) and

2,5-dihydro-1,3,4-oxadiazole(1,3,4-oxadiazoline)(3) depending on the position of the

double bond. The completely reduced form of the 1,3,4-oxadiazole is known as 2,3,4,5-

tetrahydro-1,3,4-oxadiazole (1,3,4-oxadiazolidine)(4)1

1,3,4-Oxadiazole is a heterocyclic molecule with oxygen atom at 1 and two nitrogen

atoms at 3 and 4 positions. They have been known for about 80 years, it is only in the last

decade that investigations in this field have been intensified because of large number of

applications of 1,3,4-oxadiazoles in the most diverse areas viz. drug synthesis2,3, heat

resistant materials 4,5, photo luminescence6,7, light and display devices8 etc.

There were several routes for the synthesis of 1,3,4-oxadiazoles reported in the

literature, among which the most important aspects of synthesis were discussed as under.

One of the popular methods involves cyclization of diacylhydrazines prepared from the

reaction of acyl chlorides and hydrazine. Several cyclodehydrating agents such as BF3–

OEt29 ,1,1,1,3,3,3-hexamethydisilazane10, triflic anhydride11, phosphorus pentoxide12,

polyphosphoric acid13, thionyl chloride14, phosphorus oxychloride15 and sulfuric acid16

have been used.

One-pot syntheses of 1,3,4-oxadiazoles from hydrazine with carboxylic acids have

also been reported17. Green chemistry and one-pot, solvent-free using microwave

mediated synthesis of 1,3,4-oxadiazoles were reported by Polshettiwar18. Ali et al. have

synthesized some derivatives of 1,3,4-oxadiazoles by four-component condensation19

reaction. Microwave assisted 1,3,4 oxadiazole have synthesized by Jha et al.20 whereas

Kumar et al.21 have given electrochemical synthesis of oxadiazoles.

Another synthetic route for the preparation of these compounds is via acylation of

tetrazoles22. 1,3,4-Oxadiazoles have also been prepared by oxidation of acyl hydrazones

with different oxidizing agents23-26, Reaction of acyl hydrazides with orthoesters in the



presence of an acidic catalyst27 and solid phase synthesis of oxadiazoles28 are other

approaches for the synthesis of this group of compounds.

Oxidation of acylhydrazones derived from aldehydes has been developed into a

useful route to disubstituted oxadiazoles29. A mild, general, convenient, and efficient one-

pot synthesis of 2-phenyl-5-substituted-1,3,4-oxadiazoles were reported by Stabile30. The

use of potassium permanganate with acetone as solvent was claimed to give better yields

than the use of other oxidizing agents (e.g.halogens) 31. An improved synthesis of bis-

oxadiazolyl benzenes involved oxidation of bis hydrazones with lead tetraacetate32. The

synthesis of amino-oxadiazoles by oxidative cyclization of semicarbazone was also

reported33. Srimanta et al. have synthesized 2,5-substituted 1,3,4-oxadiazoles using cu(II)

catalyst34. Iodine (III) mediated synthesis of novel unsymmetrical 2,5-disubstituted 1,3,4-

oxadiazole were reported by Om Prakash35 . The molecular docking of 2-chloropyridine

derivatives possessing 1,3,4-oxadiazole have studied by Quing-Zhong et. Al36 .

1,3,4-Oxadiazoles are a class of heterocycles, which have attracted significant

interest in medicinal chemistry37. 1,3,4-Oxadiazoles are known as a versatile heterocyclic

compounds which has been subjected to a large variety of structural modifications in

order to synthesize derivatives with different biological properties. Their various

condensed derivatives are reported to possess antibacterial38, antiinflammatory39,

analgesic40, anticancer41 , antihypertensive42 , anticonvulsant43,44, antifungal45,

cardiovascular46, hypoglycemic47, Mao inhibitor48,49, antituberculosis50, anti-tumor51,

anthelmintic,52 antioxidant53. QSAR study of substituted 1,3,4-oxadiazole were reported

by Ravichandran54. Singh et al.55 have prepared new azole containing 1,3,4-oxadiazoles

and studied their antimicrobial activities. Zheng et al.56 have synthesized 2,5-

disubstituted-1,3,4-oxadiazole derivatives and screened for their insecticidal activity.

Thus, due to the importance of biological active 1,3,4-Oxadiazoles in the present

chapter, the synthesis and characterization of some 1,3,4-Oxadiazoles derivatives, are

discussed.



EXPERIMENTAL

[A] Synthesis of 6-chloro-4-phenylchroman-2-one:

As per Chapter 2 section III [B]

[B] Synthesis of methyl 3-(2-(benzyloxy)-5-chlorophenyl)-3-phenylpropanoate:

From Chapter 2 section III [C]

[C] Synthesis of 3-(2-(benzyloxy)-5-chlorophenyl)-3-phenylpropanehydrazide:

From Chapter 2 section III [D]

[D] Synthesis of 2-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-5-(o tolyl)-

1,3,4-oxadiazole:

A mixture of 3-(2-(benzyloxy)-5-chlorophenyl)-3-phenylpropanehydrazide (0.01

mole) and different aryl acids (0.01 mole) in phosphorous oxychloride (10 ml) was

refluxed for 10-12 hours at 100 oC with continue stirring. After completion of the

reaction, reaction was poured in to ice and neutralized with saturated sodium bicarbonate

solution. The product was extracted in ethyl acetate. The organic extract was washed with

water (2 x 10 ml) and the resulting crude product was purified by column

chromatography.










The physical constants of all the synthesized compounds are given in Table 2.4.1.


Table 2.4.1: Physical constant of oxadiazole derivatives

Code R M.F M.W Yield (%)

Rf value

PAB-401 4-OCH3C6H4 C30H25ClN2O3 496.98 71 0.65

PAB-402 4-Br C6H4 C29H22BrClN2O2 545.85 62 0.70

PAB-403 4-Cl C6H4 C29H22Cl2N2O2 501.40 59 0.62

PAB-404 4-CH3 C6H4 C30H25ClN2O2 480.98 70 0.68

PAB-405 C6H5 C29H23ClN2O2 466.96 64 0.71PAB-406 2,4 di Cl C6H3 C29H21Cl3N2O2 535.85 61 0.60

PAB-407 C7H7 C30H25ClN2O2 480.98 56 0.58

PAB-408 2-OCOCH3C6H4 C31H25ClN2O4 524.99 55 0.72

PAB-409 2-Cl, 5-NO2C6H4 C29H21Cl2N3O4 546.40 58 0.64

PAB-410 2-Cl C6H4 C29H22Cl2N2O2 501.40 62 0.62PAB-411 3-Cl C6H4 C29H22Cl2N2O2 501.40 65 0.54

PAB-412 3-NO2 C6H4 C29H22ClN3O4 511.96 55 0.57

PAB-413 3,4 di OCH3 C31H27ClN2O4 527.01 73 0.71

PAB-414 2-CH3 C6H4 C30H25ClN2O2 480.98 75 0.62

PAB-415 4-OH C6H4 C29H23ClN2O3 482.96 68 0.55PAB-416 3-CH3 C6H4 C30H25ClN2O2 480.98 70 0.58

PAB-417 2-OH C6H4 C29H23ClN2O3 482.96 65 0.60

PAB-418 2-Cl C7H6 C30H24Cl2N2O2 515.43 59 0.56

PAB-419 2-Cl C7H6O C30H24Cl2N2O3 531.43 54 0.59

PAB-420 4-Cl C7H6O C30H24Cl2N2O3 531.43 66 0.67

SPECTRAL DATA

2-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-5-(4-methoxyphenyl)-1,3,4-

oxadiazole (PAB-401) mp 182-184°C; IR (KBr): 3055(Ar, C-H str), 2959(C-H str),

2838(C-H str), 1611(Ar, C=C str), 1553(Ar, C=C str), 1528(Ar, C=C str), 1452(C-H ben),

1237(C-C str), 1080(C-O-C str), 1034(C-O-C str), 748(C-Cl str) cm-1; MS: m/z = 496[M

]+

2-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-5-(4-bromophenyl)-1,3,4-





1230(C-Cstr), 1078(C-O-C str), 1044(C-O-C str), 768(C-Cl str), 728(C-Br str) cm-1; MS:

m/z = 545 [M ]+

2-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-5-(4-chlorophenyl)-1,3,4

oxadiazole (PAB-403). mp 158-160°C; IR (KBr): 3040(Ar, C-H str), 2953(C-H str),


1222(C-Cstr), 1071(C-O-C str), 1033(C-O-C str), 745(C-Cl str) cm-1; MS: m/z =501 [M ]+

2-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-5-(p-tolyl)-1,3,4-oxadiazole

(PAB-404). mp 172-174°C; IR (KBr): 3035(Ar, C-H str), 2949(C-H str), 2858(C-H str),

1543(Ar, C=C str), 1521(Ar, C=C str), 1462(C-H ben), 1247(C-C str), 1063(C-O-C str),

1032(C-O-C str), 745(C-Cl str) cm-1; MS: m/z = 480 [M ]+

2-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-5-phenyl-1,3,4-oxadiazole


1553(Ar, C=C str), 1527(Ar, C=C str), 1474(C-H ben), 1246(C-C str), 1073(C-O-C str),

1029(C-O-C str), 748(C-Cl str), cm-1; MS: m/z = 466 [M ]+

2-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-5-(2,4-dichlorophenyl)-1,3,4-



1237(C-C str), 1070(C-O-C str), 1064(C-O-C str), 749(C-Cl str) cm-1; MS: m/z =535[M ]+

2-benzyl-5-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-1,3,4-oxadiazole (PAB-

407). mp 122-124°C; IR (KBr): 3032(Ar, C-H str), 2937(C-H str), 2839(C-H str),

1546(Ar, C=C str), 1522(Ar, C=C str), 1476(C-H ben), 1073(C-O-C str), 1031(C-O-C


2-(5-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-1,3,4-oxadiazol-2-yl)phenyl

acetate (PAB-408). mp 176-178°C; IR (KBr): 3042(Ar, C-H str), 2932(C-H str), 2831(C-

H str), 1687(C=O str), 1556(Ar, C=C str), 1532(Ar, C=C str), 1465(C-H ben), 1063(C-O-

C str), 1032(C-O-C str), 737(C-Cl str) cm-1; MS: m/z = 524 [M ]+

2-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-5-(2-chloro-5-nitrophenyl)-1,3,4-




2857(C-H str), 1542(N=O str), 1521 (Ar, C=C str), 1469(C-H ben), 1053(C-O-C str),

747(C-Cl str) cm-1; MS: m/z = 546 [M ]+

2-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-5-(2-chlorophenyl)-1,3,4


2863(C-H str), 1535(Ar, C=C str), 1521(Ar, C=C str), 1467(C-H ben), 1062(C-O-C str),

1042(C-O-C str), 744(C-Cl str) cm-1; MS: m/z =501 [M ]+

2-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-5-(3-chlorophenyl)-1,3,4-




2-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-5-(3-nitrophenyl)-1,3,4-


2856(C-H str), 1540(N=O str), 1533(Ar, C=C str), 1514(Ar, C=C str), 1469(C-H ben),

1053(C-O-C str), 1042(C-O-C str), 743(C-Cl str) cm-1; MS: m/z = 511 [M ]+

2-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-5-(3,4-dimethoxyphenyl)-1,3,4-




2-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-5-(o-tolyl)-1,3,4-oxadiazole


1632(Ar, C=C str), 1585(Ar, C=C str), 1533(Ar, C=C str), 1457(C-H ben), 1093(C-O-C

str), 1010(C-O-C str), 748(C-Cl str) cm-1; 1H NMR (400 MHz, DMSO): δ ppm 2.51 (s,

3H, -CH3), 2.89-3.03 (dd, 2H, -CH2), 4.41 (t, 1H,-CH), 4.75 (s, 2H,-CH2), 8.15-8.17 (d,

2H, ArH) 6.96-7.00 (t, 3H, ArH), 7.14-6.7.25 (m, 4H, ArH), 7.44-7.46 (d, 2H, ArH),

7.57-7.59 (d, 3H, ArH), 8.04 (m, 3H, ArH), 8.15-8.17 (d, 2H, ArH). 13C NMR (100

MHz, DMSO): δ ppm 21.92, 37.86, 38.01, 69.12, 117.65, 118.98, 123.22, 129.91, 133.22,

140.17, 141.14, 148.84, 163.91, 164.21. MS: m/z =480 [M ]+

4-(5-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-1,3,4-oxadiazol-2-yl)phenol

(PAB-415). mp 128-130°C; IR (KBr): 3635(O-H str), 3043(Ar, C-H str), 2941(C-H str),





2-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-5-(m-tolyl)-1,3,4-oxadiazole


1626(Ar, C=C str), 1533(Ar, C=C str), 1510(Ar, C=C str), 1459(C-H ben), 1073(C-O-C

str), 1054(C-O-C str), 750(C-Cl str) cm-1; MS: m/z =480 [M ]+

2-(5-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-1,3,4-oxadiazol-2-yl)phenol




2-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-5-(2-chlorobenzyl)-1,3,4-




2-(5-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-1,3,4-oxadiazol-2-yl)-5-((2-

chlorophenoxy)methyl)phenol (PAB-419). mp 118-120°C; IR (KBr): 3636(O-H str),

3032(Ar, C-H str), 2921(C-H str), 2876(C-H str), 1556(Ar, C=C str), 1532(Ar, C=C str),

1465(C-H ben), 1067(C-O-C str), 1039(C-O-C str), 749(C-Cl str) cm-1; MS: m/z = 531

[M ]+

2-(2-(2-(benzyloxy)-5-chlorophenyl)-2-phenylethyl)-5-((4-chlorophenoxy)methyl)-

1,3,4-oxadiazole (PAB-420). mp 126-128°C; IR (KBr): 3043(Ar, C-H str), 2941(C-H

str), 2853(C-H str), 1543(Ar, C=C str), 1521(Ar, C=C str), 1475(C-H ben), 1063(C-O-C

str), 1032(C-O-C str), 737(C-Cl str) cm-1; MS: m/z = 531 [M ]+





5007501000125015001750200025003000350040001/cm

30

45

60

75

90

105

%T

30

01

.34

29

33

.83

29

08

.75

28

50

.88 16

87

.77

16

26

.05

15

85

.54

15

33

.46

14

65

.95

13

44

.43

12

92

.35

11

97

.83

11

72

.76

11

22

.61 10

93

.67

10

49

.31

10

10

.73

98

7.5

99

02

.72

82

9.4

27

48

.41 70

9.8

36

51

.96

56

9.0

25

05

.37

46

4.8

6

JP- 504










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Section-V

Synthesis of thiazolidinones

Section-V Synthesis of thiazolidinones


INTRODUCTION

4-Thiazolidinones are the derivatives of thiazolidine, which belong to an

important group of heterocyclic compounds containing sulfur and nitrogen in a five

member ring. Some of the thiazolidinones are found to possess interesting biological

activities, such as anticancer2, anti-HIV3, antimalarial4, tuberculostatic5, antihistaminic6,

anticonvulsunt7-8, antibacterial9, antiarrythmic10, antiproliferative11-12, antiinflamatory13,

cox I inhibition14, anti tumor15, analgesic16 and antidiabatic17-18 etc. In view of the

biological/pharmacological significance of 4-thiazolidinones, considerable synthetic

efforts have been made to construct this class of heterocycles19.

Several synthetic protocols for 4-thiazolidinones have been reported in the

literature20-26. Recently, one-pot multicomponent reactions have emerged as a powerful

tool in synthetic organic chemistry because of their significant advantages27-30 Some

copper complexes of 4-thiazolidinone have been synthesized by Vries et al.31.Various

workers have applied the Green chemistry approach to the synthesis of 4-thiazolidinone

derivatives by using microwave assisted and multi component reaction method32-33.

Lohary et al.34 have synthesized some 4-thiazolidinone derivatives and studied their

hypolipidemic activity. Bioactive venlafaxine analogs such as 2,3-disubstituted-1, 3-

thiazolidinones have also been synthesized and their anti microbial activity have been

reprted35. One-pot three component cyclocondensation of carbonyl compounds, amines,

and mercaptoacetic acid or its derivatives has been widely used as a synthetic route for

the 4-thiazolidinones. The above mentioned cyclo condensation can be either run in one-

pot or in two steps with prolonged heating in toluene or benzene36. Pratap et al.37 have

reported one pot three component synthesis of thiazolidinones. There are reports for

accelerating the above cyclo condensation using catalysts like N,N’-

dicyclohexylcarbodiimide38, O-(benzotriazol-yl)-N,N,N’,N’-tetramethyluroniumhexa

fluoro phosphate39, iodine40, ferrite41, ZnCl242, [bmim][PF6]43 and activated fly ash44. The

use of microwave heating45,46, solid phase47, and polymer supported 48 systems for the

cyclo condensation leading to 2,3-disubstitiuted 4-thiazolidinones have also been

reported.

Many researchers have been worked on QSAR study of thiazolidinones49-50.

Singh51 have reported the fungicidal activity of 5-methyl-3-aryl-2-arylimino-4-



thiazolidinones and their acetoxy mercuric derivatives. Graciet et al.52 have studied the

antiviral activity of some 4-thiazolidinone derivatives. Kumar et al53. have studied

antiparkinsonian activity of some new adamantly thiazolidinonyl indole derivatives. The

anti cancer54 and antitubercular55 activity of some other derivatives have also been

studied. The anti bacterial activity of various thiazolidinone derivatives has also been

reported56-60.

In present chapter, some new thiazolidinones derivatives have been synthesized

and characterization of these synthesized compounds is done by IR, NMR and mass

spectral data.




Synthesis of azomethines:

A mixture of 4-((1H-1,2,4-triazol-1yl)methyl) aniline (0.01 mol) and different

substituted aromatic aldehydes (0.01 mol) was dissolved in 20 ml of methanol. In this

solution, catalytic amount of glacial acetic acid was added and the reaction mixture was

heated with stirring for 10-12 hrs. After the completion of reaction, the reaction mass was

filtered, washed with chilled methanol and then dried to give substituted azomethines.

The other compounds were prepared similarly by treating with corresponding aldehydes.

Synthesis of 3-(4-((1H-1,2,4-triazole-1-yl)methyl)phenyl)-2-(4-nitrophenyl) thia

zolidin-4-one:

A mixture of 4-((1H-1,2,4-triazole-1-yl)methyl)-N-(4-nitrobenzylidene)aniline

(0.01 mol) and 2-merccapto acetic acid (0.03 mol) in toluene (20 ml) was refluxed for

10-12 hours in a dean-stark assembly with continuous stirring. After completion of the

reaction, the content was cooled to room temperature and then neutralized with sodium

bicarbonate solution. The organic extract was washed with water (2 x 10 ml), dried using

sodium sulphate and distilled completely under vacuum and give yellow colored product.





capillary tubes and was uncorrected. The characterization of all these compounds was

done by IR, NMR and mass spectral data. The IR spectra were recorded on Shimadzu FT-

IR-8400 instrument using KBr pellet method. The Mass spectra were recorded on

Shimadzu GC-MS-QP-2010 model using direct inlet probe technique. 1H NMR and 13C

NMR was determined in DMSO solution on a Bruker Ac 400 MHz spectrometer.





Table 2.5.1: Physical constant of thiazolidinone derivatives

Code R M.F M.W Yield (%) Rf valuePAB-501 4-Cl C18H15ClN4OS 370.86 72 0.43PAB-502 2,5diOCH3 C20H20N4O3S 396.46 68 0.37PAB-503 4-NO2 C18H15N5O3S 381.41 59 0.46PAB-504 4-Br C18H15BrN4OS 415.31 63 0.52PAB-505 4-OCH3 C19H18N4O2S 366.44 70 0.48PAB-506 2-NO2 C18H15N5O3S 381.41 61 0.61PAB-507 4-OH C18H16N4O2S 352.41 57 0.59PAB-508 3-NO2 C18H15N5O3S 381.41 53 0.52PAB-509 4-F C18H15FN4OS 354.40 64 0.47PAB-510 4-CH3 C19H18N4OS 350.44 60 0.58

SPECTRAL DATA

3-(4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)-2-(4-chlorophenyl)thiazolidin-4-one


2877(C-H str), 1685 (C=O str), 1608(Ar, C=C str), 1514(Ar, C=C str), 1502(Ar, C=C str),

1489(C-H ben), 1421(C-H ben), 1371(C-H ben), 1255(Ar, C-H ben), 744(C-Cl str) cm-1;

MS: m/z = 370 [M ]+

3-(4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)-2-(2,5-dimethoxyphenyl)thiazolidin-4-one


2838(C-H str), 1676(C=O str), 1613(Ar, C=C str), 1552(Ar, C=C str), 1429(C-H ben),

1384(C-H ben), 1303(C-H ben), 1219(Ar, C-H ben), 1178(Ar, C-H ben), 1139(Ar, C-H

ben), 1107(Ar, C-H ben), 1026(C-O-C str), 1016(Ar, C-H ben), 956(Ar, C-H ben) cm-1;

MS: m/z = 396 [M ]+

3-(4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)-2-(4-nitrophenyl)thiazolidin-4-one (PAB-

503). mp 121-123°C; IR (KBr): 3105(Ar, C-H str), 2993(C-H str), 2916(C-H str), 2872(C-

H str), 1689 (C=O str), 1602(Ar, C=C str), 1536(N=O str), 1515(Ar, C=C str), 1487(C-H

ben), 1422(C-H ben), 1376(C-H ben), 1251(Ar, C-H ben) cm-1; MS: m/z = 381 [M ]+

3-(4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)-2-(4-bromophenyl)thiazolidin-4-one

(PAB-504). mp 114-116°C; IR (KBr): 3019(Ar, C-H str), 2945(C-Hstr), 2914(C-H str),



2877(C-H str), 1689 (C=O str), 1603(Ar, C=C str), 1514(Ar, C=C str), 1505(Ar, C=C str),

1481(C-H ben), 1422(C-H ben), 1372(C-H ben), 1254(Ar, C-H ben), 575(C-Br str)cm-1;

MS: m/z = 415 [M ]+

3-(4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)-2-(4-methoxyphenyl)thiazolidin-4-one

(PAB-505). mp 130-132°C; IR (KBr): 3107 (Ar, C-H str), 2960 (C-H str), 2912 (C-H str),

2837 (C-H str), 1666 (C=O str), 1610(Ar, C=C str), 1512(Ar, C=C str), 1464(Ar, C=C str),

1429 (C-H ben), 1388 (C-H ben), 1342(C-H ben), 1303(C-H ben), 1253(Ar, C-H ben),

1219(Ar, C-H ben), 1178(Ar, C-H ben), 1139(Ar, C-H ben), 1107(Ar, C-H ben), 1026(C-

O-C str), 1016(Ar, C-H ben), 956(Ar, C-H ben) cm-1; 1H NMR (400 MHz, DMSO δ ppm

3.72 (s, 3H, -OCH3), 3.79-3.93 (dd, 2H, -CH2), 5.30 (S, 2H,-CH2), 6.22 (s, 1H,-CH), 6.76-

6.78 (t, 2H, ArH) 7.14-7.24 (m, 6H, ArH), 7.86 (s, 1H, CH), 8.32 (s, 1H, CH). 13C NMR

(100 MHz, DMSO): δ ppm 32.97, 51.82, 54.76, 64.00, 113.69, 125.54, 128.14, 130.63,

133.55, 137.16, 143.46, 151.41, 159.28, 170.30. MS: m/z = 366 [M ]+




ben), 1421(C-H ben), 1371(C-H ben) cm-1; MS: m/z = 381 [M ]+

3-(4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)-2-(4-hydroxyphenyl)thiazolidin-4-one


2917(C-H str), 2878(C-H str), 1669 (C=O str) 1600(Ar, C=C str), 1515(Ar, C=C str),

1487(C-H ben), 1427(C-H ben), 1356(C-H ben), 1251(Ar, C-H ben) cm-1; MS: m/z = 352

[M ]+




ben), 1432(C-H ben), 1376(C-H ben) cm-1; MS: m/z = 381 [M ]+

3-(4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)-2-(4-fluorophenyl)thiazolidin-4-one (PAB-


H str), 1679 (C=O str), 1607(Ar, C=C str), 1511(Ar, C=C str), 1521(Ar, C=C str), 1471(C-

H ben), 1412(C-H ben), 1372(C-H ben), 1254(Ar, C-H ben), 1024 (C-F str)cm-1; MS: m/z

= 354 [M ]+



3-(4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)-2-(p-tolyl)thiazolidin-4-one (PAB-510).

mp 147-149°C; IR (KBr): 3013(Ar, C-H str), 2951(C-H str), 2913(C-H str), 2872(C-H str),

1669 (C=O str), 1602(Ar, C=C str), 1515(Ar, C=C str), 1454(C-H ben), 1432(C-H ben),

1376(C-H ben) cm-1; MS: m/z = 350 [M ]+



Figure: 2.5.1 IR spectrum of compound PAB-505

45075010501350165019502250255028503150345037501/cm

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100

105%T

3107

.43

3010

.98

2960

.83

2912

.61

2837

.38

1666

.55

1610

.61

1512

.24

1464

.02

1429

.30

1388

.79

1342

.50

1303

.92

1253

.77

1219

.05

1178

.55

1139

.97

1107

.18

1026

.16

956.

7290

0.79

831.

3580

4.34

781.

20

Figure: 2.5.2 Mass spectrum of compound PAB-505

N

S

N

NN O

H3CO

N

S

N

NN O

H3CO



Figure: 2.5.3 1H NMR Spectrum of compound PAB-505


N

S

N

NN O

H3CO



Figure: 2.5.4 13C NMR spectrum of compound PAB-505

N

S

N

NN O

H3CO



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