chapter-ii - shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/2211/11/11_chapter 2.pdf ·...

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SECTION-A: SYNTHESIS OF 5-(2’-AMINO-6’-ARYL PYRIMIDIN-4’-YL)-

2-BENZOYL-6-HYDROXY-3-METHYL BENZO[b]FURANS UNDER

CONVENTIONAL HEATING AND MICROWAVE IRRADIATION

METHODS

2.1 Introduction

Many heterocyclic compounds show wide range of physiological

activities. Hence they were claimed as potential biologically active

compounds, for instance a number of benzofuran derivatives have been

reported to possess a wide variety of biological activities such as

antiinflammatory66-70, antifungal71, antibacterial 72-76, antiallergic 77,

estrogenic and anti- implantation 78-84 properties. Benzofuran (2.1) and

its derivatives are known to be present in many natural products 85. They

exhibit physiological and pharmacological properties. Derivatives of

benzofuran act as sedatives 86, hypnotics 86 and have application in

agrochemicals 87, pharmaceuticals 88-93 and cosmetics 94.

O

2.1

Natural benzofurans such as toxol (2.2) and dehydrotremetone (2.3) are

bacteriostatic against a number of bacteria. Euparin (2.4), toxol (2.2),

CHAPTER-II

33

and toxylangelate (2.5) show antitumor activity against P388

lymphocytic leukemia tumors 1, 2. Tremetone (2.6), dehydrotremetone

(2.3) and hydroxytremetone (2.7) are toxic to goldfish.

CH3

O

O

OH CH3

O

OCH3

O

O

HO

CH3

O

O

HO

CH3

O

O

CH3

O

O

O

H

CH3O

H3C

2.2 2.3 2.4

2.5 2.6 2.7

Benzofuran derivatives possess diverse biological activities such as

Uricosuric agent (Benzobromarone) (2.8), coronary vasodilator

(Benzarone) (2.9), coronory vasodilator (Benziodazone)(2.10),

antiarrythmic (Amiodazarone) (2.11), antianginal (Amidarone) (2.12)

antiasthma (Amethone)(2.13). Diarylamidine derivative such as 5-

Amidino-2-(5-amidino-2-benzofuranyl) indole (2.14) possess the most

potent “recorniviral” 5 effect against moloneymurine leukemia virus. 5-

Methyl-3-p-toluoyl-2[4-(3-diethylaminopropoxy) phenyl] benzofuran

(2.15) exhibits β-amyloid aggregation inhibitor6.

34

O CH3

O

Br

OH

Br

OH3CO O

O

H3CO

O CH3

O OH

O CH3

O OH

I

I

O

O O

I

I

N

CH3

2.8

2.12

2.9 2.10

2.11

O

N

O

2.13

O

O

O N2.15

NH2

HNO

HN NH2

NH

2.14

Several pyrimidine derivatives show wide spectrum of pharmacological

activities such as anti-inflammatory95, antihypertensive96, analgesic97,

antipyretic98 and antiviral99 activities. Many aminopyrimidine derivatives

have been found to possess antiulcer100, anti-inflammatory101, 102,

antitumor103, antibacterial104 and anticancer105 activities. Most commonly

known pyrimidines used in antitumor therapy are Methotrexate (2.16)

and 5-Fluorouracil (2.17). 2-Aminopyrimidine is an interesting

structural element present in several marketed drugs, such as Aronixil

(2.18) (antiatherosclerotic), Thonzylamine (2.19) (antihistaminic),

35

Busprione (2.20) antianxiolytic, Enazadrem (2.21) (antipsoriatic),

Imatinib (2.22) anticancer.

N

N

NN

N

H2N NH2

NHHO OH

OO

O

HN

HN

F

O O

H3C

H3C HNN

N

Cl

HNOH

O2.16

2.172.18

NN

NNCH3

CH3

H3CO

2.19

N NN N

NO

O 2.20

N

N

NH

HOCH3

H3C

2.21

HN

HN

N

N

N NO

CH3

CH3

2.22

Keeping in view the pharmacological importance of 2-Aminopyrimidines

and benzofuran moieties, we have taken up the synthesis of 2-

aminopyrimidinyl benzofurans to know the combined effect of

benzofuran and 2-amino pyrimidines on biological activity and their ease

of formation. Thus the synthesis of some 5-(2’-Amino-6’-aryl pyrimidin-4’-

yl)-2-benzoyl-6-hydroxy-3-methylbenzo[b]furans (2.23a-g) was

36

undertaken in the present investigation with a view to evaluate their

antibacterial activity.

OO OH

N

N NH2

Ar2.23a-g

12

34 5

67

1'

2'3'

4'

5'6'

Ar = a) phenyl e) 4-methoxyphenyl b) 2-chlorophenyl f) 1-naphthyl c) 4-chlorophenyl g) 2-furyl d) 3-nitrophenyl

2.2 PAST WORK

The methods which are adopted for the synthesis of Benzofuran and 2-

Aminopyrimidines are useful for the synthesis of title compounds.

Therefore these methods are briefly reviewed in the following pages.

2.3 Methods for the synthesis of Benzofurans

A number of synthetic approaches for the construction of benzofuran

ring exist in which the key step is dehydrative annulation of phenols

bearing appropriate ortho vinyllic substituents and ring closure of

arylacetylenes. The most straightforward method for one-pot preparation

of benzofuran is the Rap-Stroemer condensation of salicylaldehyde with

α-haloketones.

2.3.1 T. R. Sheshadri et al., 106 have synthesized 2-Benzoyl-5-methyl-3-

phenylbenzofuran (2.26) by refluxing 2-hydroxy-5-methylbenzophenone

37

and ω-bromo acetophenone in the presence of potassium carbonate in

absolute ethyl alcohol for 6 hrs.

Scheme-2.1: Synthesis of 2-Benzoyl-5-methyl-3-phenylbenzofuran (2.26)

OH

MeO

OBr O

Me

K2CO3 , EtOH

2.242.25

O

+

2.26

2.3.2 Esther Dominguez et al., 107 have synthesized 2-(2-Chlorophenyl)

benzofuran(2.28) by reacting a mixture of 2-(2-Bromophenyl)-1-(2-

chlorophenyl)ethanone, 8.5mol% of Copper(1)iodide and tetramethyl

ethylene diamine in water at 120 0C for overnight.

Scheme-2.2: Synthesis of 2-(2-Chlorophenyl) benzofuran (2.28)

BrO

O8.5 mol.% CuI3.5 e.q. TMEDA

H2O, 1200C

Cl Cl

2.27 2.28

2.3.3 Cheng-yi Chen et al.,108 have synthesized 2-Phenylbenzo[b]furan-3-

carbonitrile (2.30) by reacting a mixture of 2-(2-Bromophenyl)-3-oxo-3-

phenylpropanenitrile(2.29), 10 mol% of copper (1) iodide, K3PO4 (1.5eq.)

in DMF at 1050C for 16 hrs.

38

Scheme-2.3: Synthesis of 2- Phenylbenzo[b]furan-3-carbonitrile (2.30)

O

10 mol% CuI1.5 e.q. K3PO4

DMF,O

Br

CNCN

2.29 2.30

1050 C

2.3.4 M. Mahumun Hossain et al., 109 have synthesized 3-Ethoxycarbonyl

benzofuran (2.32), by reacting salicylaldehyde, ethyldiazo acetate

solution (8% in dichloromethane), in the presence of HBF4.OEt2 at room

temperature for 1 hr.

Scheme-2.4: Synthesis of 3-Ethoxycarbonyl benzofuran (2.32)

CHO

OHO

CO2Et

HBF4.Et2ON2CHCOOEt

2.312.32 RT

+

2.33

2.3.5 A. Sharifi et al., 110 have synthesized (3-methyl benzofuran-2-yl)

phenyl methanone (2.35) by reacting a mixture of 2-

hydroxyacetophenone, ω-bromo acetophenone and KF/Al2O3 at room

temperature for 20 hrs.

Scheme-2.5: Synthesis of (3-methylbenzofuran-2-yl) phenyl methanone

(2.35)

OH

O

+Br

O

KF/Al2O3

O O2.34 2.25 2.35

RT

39

2.4 Methods for the synthesis of 2-Aminopyrimidines:

Synthesis of pyrimidines commonly involves cyclocondensation reactions

of amidine, guanidine, urea or thiourea derivatives with 1, 3-diketone, 1,

3-diester systems, or α, β-unsaturated carbonyl systems

2.4.1 Ragini et al., 111 have synthesized Diaryl amino pyrimidines (2.37)

by heating a mixture of chalcone dibromides and guanidinium carbonate

in DMF (Scheme-2.6)

Scheme-2.6: Synthesis of Diaryl amino pyrimidines (2.37)

O

RR1

R2

R3

R4

R5

Br

Br

H2N

NH.H2CO3

NH2

DMF,N

N

NH2

R

R1

R2

R3

R4

R5

2.36 2.37

R =H, OH, R1 =H, R2 =H, R3 =H, R4 =H, NO2, R5 = H, NO2,OCH3, Cl

2.4.2 Pascal et al., 112 have synthesized 2-Aminopyrimidines (2.40) by

cyclocondensation of alkynones or chalcones with guanidine.

40

Scheme-2.7: Synthesis of 2-Aminopyrimidines (2.40)

R1

R2

Oor

R1 O

R2

H2N NH2

NH

N

N

R1

R2 NH2

2.38 2.402.39 R1, R2 : Ar,alkyl, alkyne, NR’R’’

2.4.3 Olugbade et al., 113 have synthesized 2-Amino-4,6-

dimethylpyrimidine (2.42) by reacting guanidine nitrate with

acetylacetone in the presence of potassium carbonate at room

temperature.

Scheme-2.8: Synthesis of 2-Amino-4, 6-dimethylpyrimidine (2.42)

H3C

H3C

O

O

H2N NH2

NH.HNO3

K2CO3/H2O N N

NH2

CH3H3C

2.41 2.42 2.4.4 Jachak et al., 114 have synthesized 2-Amino-5-cyanopyrimidine

(2.44) by condensing (E)-3-(Dimethylamino)-2-formylacrylonitrile (2.43)

with guanidine.

Scheme-2.9: Synthesis of 2-Amino-5-cyanopyrimidine (2.44).

Me2N

H CHO

CN

H2N NH2

NH

N

NNC

NH2

2.43 2.44

41

2.4.5 Anjani solankee et al.,115 have synthesized 2-Phenyl amino-4-(3’-

fluoro phenylamino)-6-[4’-{2”-amino-6’’-{2”’,5”’-substitutedphenyl)-

pyrimidin-1-4”-yl} -phenylamino]-s-triazine (2.46a-f) by refluxing 2-

Phenylamino-4-(3’-fluorophenylamino)-6-[4’-{2”-amino-6”-{2”’,5”’-

substitutedphenyl)-2”-propenon-1”-yl}-phenylamino]-s-triazine with

guanidine nitrate and 40% KOH in dioxane.

Scheme-2.10: Synthesis of 2-phenylamino-4-(3’ fluoro phenyl amino)-6-[4’ -

{2’’amino-6’’-{2”’, 5”’-substituted phenyl)-pyrimidin-1-4”-yl}-phenylamino ]-

s-triazine(2.46a-f).

NH

N

N

N

HN

O

R

NH

N

N

N

HN

N N

R

NH22.45

2.46a-f

NH

NH2H2N

.HNO3

Aq. KOH

FF

R= a) phenyl d) 2,3-dichlorophenyl b)4-chlorophenyl e) 2,5-dimethoxyphenyl c)4-methoxyphenyl f) 3,4,5-trimethoxyphenyl

2.4.6 Y. L. N. Murthy et al., 116 have synthesized 2-Amino-4-substituted

phenyl-6-(2’’, 2’’-dimethyl-7-hydroxy chroman) pyrimidines (2.48a-e) by

condensing five different chromano chalcones with guanidine

hydrochloride and potassium tertiary butoxide in tert. butylalcohol.

42

Scheme-2.11: Synthesis of 2-Amino-4-substituted phenyl-6-(2’’, 2’’-

dimethyl, 7-hydroxy chroman) pyrimidines (2.48a-e)

O OH

O

R1

R2R3

R4R5

NH

NH2H2N

.HCl

t-BuOK

O OH

N

R1

R2R3

R4R5

NH2

N

2.47 2.48a-e

R1=R4=R5=H, R2=R3=-OCH3R1=R2=R4=R5=H, R3=-N(CH3)2R1=R2=R4=R5=H, R3=-ClR1=R2=R4=R5=H, R3=-OCH3R1=R2=R4=R5=H, R3=-CN

a)b)c)d)e)

2.4.7 S. Chandrasekaran et al., 117 have reported the microwave assisted

synthesis 2-Amino-6-aryl-4-(2-thienyl) pyrimidines (2.50) by the

treatment of 3-Aryl-1-thien-2-yl prop-2-ene-1-ones (2.49) and guanidine

hydrochloride in the presence of aq. NaOH.

Scheme- 2.12: Synthesis 2-Amino-6-aryl-4-(2-thienyl) pyrimidines (2.50)

O

SR

H2N NH2

NHR

N N

S

NH2

.H Cl

Aq. NaOH MWI

2.492.50

R = H, N(CH3)2, F, Cl , Br

2.4.8 S. S. Panda et al.,118 have synthesized 4-(1H-Indol-3-yl)-6-(4-

substituted phenyl)pyrimidin-2-amines (2.52a-j) by refluxing a mixture

of 1-(4-substituted phenyl)-3-indolyl-2-propen-1-ones, guanidine hydro

chloride and few drops of Conc. HCl in absolute alcohol.

43

Scheme- 2.13: Synthesis of 4-(1H-Indol-3-yl)-6-(4-substituted phenyl)

pyrimidin-2-amines (2.52a-j)

HN

N

NH2N

HN

O

NH2H2N

NH.HCl

Conc.HCl

2.51 2.52a-j

R R

R =a) H f) p-fluoro b) p-methyl g) p-amino c) p-methoxy h p-bromo d) p-hydroxy i) p-chloro e) p-nitro j) o,p-dihydroxy

2.4.9 Mayank J. Patel et al., 119 have synthesized 4-(2,4-Dichloro-5-

fluorophenyl)-6-phenylpyrimidine-2-amines(2.54) by refluxing (E)-(2,4-

Dichloro-5-fluorophenyl)-3-phenyl prop-2-en-1-ones guanidine nitrate

and 25% sodium methoxide in methanol for 7 hrs.

Scheme-2.14: Synthesis of 4-(2, 4-Dichloro-5-fluorophenyl) -6-phenyl

pyrimidine -2-amines (2.54)

F

Cl

Cl O

F

Cl

Cl

R

N N

NH2

NH2H2N

NH.HNO3

NaOMe, MeOH25%R

2.53 2.54

R = 3,4,5-(OCH3),4-Cl, 2-OCH3, 4-CH3, 4-OCH3, 4-F, 2-OH

44

2.4.10 T. Balashankar et al., 120 have synthesized 2-Amino-4-(1,1’-

biphenyl-4-yl-6-arylpyrimidines (2.56) by refluxing 1-(1, 1’-biphenyl-4-

yl)-3-aryl prop-2-en-1-ones, guanidine nitrate and aq. NaOH in ethyl

alcohol for 12 hrs.

Scheme-2.15: Synthesis of 2-Amino-4-(1, 1’ - biphenyl-4-yl-6-aryl

pyrimidines (2.56)

O

R

NH

NH2H2N

.HNO3

N RN

NH2

2.55 2.56

Aq.NaOH

R = H, p-OCH3, p-Cl, m-OCH3, m-Br, m-NO2, p- NO2, p-Fl, o-Cl, o-CH3

2.4.11 A. S. R. Anjaneyulu et al., 121 have synthesized some 2-Amino-

4,6-diarylpyrimidines (2.58) by refluxing chalcones with guanidine

hydrochloride and potassium t-butoxide in tert. butylalcohol for 3-4 hrs.

Scheme- 2.16: Synthesis of some 2-Amino 4, 6-diaryl pyrimidines (2.58)

O

OCH3H3CO

H3CO

R1

R2

R3

N

OCH3H3CO

H3CO

R1

R2

R3

N

NH2

NH

NH2H2N

.HCl

2.58

2.57

t BuOK

45

a) R1=R2=R3=Hb) R1=OCH3R2=R3=Hc) R1= R3=H, R2= OCH3d) R1= R3=H, R2= OH

2.5 PRESENT WORK

Encouraged by the biological activities of benzofuran and 2-Amino

pyrimidine moieties, we have taken up the synthesis of 5-(2’-Amino-6’-

arylpyrimidin-4’-yl)-2-benzoyl-6-hydroxy-3-methyl benzo[b]furans (2.23a-

g) with a view to test their antibacterial activity. Microwave Assisted

Organic Synthesis (MAOS) has gained popularity as a non-conventional

technique for rapid organic synthesis25-48,122 it is eco-friendly, economical

and is believed to be a step towards Green chemistry. It has been

reported that a variety of reactions such as Diels-Alder reaction, Claisen

reaction, Fischer cyclization, synthesis of heterocycles, hydrolysis of

esters, hydrogenation, deprotection of benzyl ester, deacetylation of

diacetates, and polymer synthesis could be facilitated by microwave

irradiation in a good energy transferring medium. In order to provide a

method that is economic, eco-friendly, we have taken up the synthesis of

5-(2’-Amino-6’-arylpyrimidin-4’-yl)-2-benzoyl-6-hydroxy-3-methylbenzo[b]

furans (2.23a-g) under microwave irradiation. The advantages obtained

by the use of microwave irradiation in relation to a conventional heating

method were demonstrated (Table-2.1).

2.5.1 Synthesis of 5-(2’-Amino-6’-aryl pyrimidin-4’-yl)-2-benzoyl-6-

hydroxy-3-methyl benzo[b]furans (2.23a-g) consist of four stages:

46

2.5.1.1 Synthesis of 4, 6-Diacetyl resorcinol (2.60).

2.5.1.2 Synthesis of 5-Acetyl-2-benzoyl-6-hydroxy-3-methyl benzofuran

(2.62).

2.5.1.3 Synthesis of (E)-1-(2-Benzoyl-6-hydroxy-3-methyl benzo[b] furan-

5-yl)-3-aryl-2-propen-1-ones (2.63a-g)

2.5.1.4 Synthesis of 5-(2’-Amino-6’-phenylpyrimidin-4’-yl)-2-benzoyl-6-

hydroxy-3-methyl benzo[b]furans (2.23a).

These have been discussed below.

2.5.2 Synthesis of 4,6-Diacetyl resorcinol123 (2.60) :

4, 6-Diacetyl resorcinol was synthesized under conventional heating and

microwave irradiation.

2.5.2.1 Conventional heating method

A mixture of resorcinol, acetic anhydride and FeCl3 was heated at 140°C

for ten min to afford 4,6-Diacetyl resorcinol.

2.5.2.2 Microwave irradiation method

A mixture of resorcinol, acetic anhydride and FeCl3 was taken in quartz

tube and inserted into teflon vial with screw capped and then subjected

to microwave irradiation at the constant temperature 140°C for two min

to afford 4,6-Diacetyl resorcinol.

Scheme-2.11: Synthesis of 4, 6-Diacetyl resorcinol (2.60).

47

HO OHHO OH

O O

FeCl3

MWIAc2O

2.59 2.60

or

2.5.3 Synthesis of 5-Acetyl-2-benzoyl-6-hydroxy-3-methylbenzo

furan124a,125 (2.62):

5-Acetyl-2-benzoyl-6-hydroxy-3-methyl benzofuran was synthesized

under conventional heating and microwave irradiation methods.

2.5.3.1 Conventional heating method:

5-Acetyl-2-benzoyl-6-hydroxy-3-methylbenzofuran(2.62) was synthesized

by refluxing an equimolar mixture of 4,6-Diacetyl resorcinol and 2-

Bromo-1-phenyl ethanone in dry acetone and anhydrous K2CO3 by

adopting Rap method126.

2.5.3.2 Microwave irradiation method:

5-Acetyl-2-benzoyl-6-hydroxy-3-methylbenzofuran(2.62) was synthesized

by adsorbing an equimolar mixture of 4,6-Diacetyl resorcinol and 2-

Bromo-1-phenyl ethanone on anhydrous K2CO3 and then irradiating

under microwave oven for seven min. The product obtained was

characterized by analytical and spectra data. Its m.p., I.R, 1H-NMR

spectral data were found to be in agreement with the data reported for

this compound in literature 124a,125 and also compared with authentic

sample.

48

Scheme-2.12: Synthesis of 5-Acetyl-2-benzoyl-6-hydroxy-3-methylbenzo

furan 124a (2.62).

HO OH

O OBr

O

O OH

O

OK2CO3

2.60 2.612.62

MWIor

+

The IR spectrum (KBr, Fig. 2.1) of compound 2.62 showed characteristic

absorption peaks at 3434 cm-1 (chelated OH, stretching), 1643 cm-1

(acetyl carbonyl), 1600 cm-1 (benzoyl carbonyl)124, 1105 cm-1 (C-O-C

stretching). The 1H-NMR spectrum (200 MHz, CDCl3 Fig. 2.2) of 2.62

showed two singlets at δ 2.62 and 2.78 integrating for three protons each

were assigned to C3-methyl and methyl group of C5-acetyl group

respectively. The C7 proton appeared as a singlet at δ 6.95. The C2’, C6’,

protons along with C4 proton appeared as a multiplet at δ 7.95-8.15.

Another multiplet between δ 7.42-7.61 integrating for three protons was

assigned to C3’,4’,5’ protons. C6 hydroxy proton appeared as a singlet at δ

12.5. In the mass spectrum (Fig.2.3) of 2.62 [M]+ peak was observed at

m/z=294 (25%). The above spectral data is in agreement with the

structure proposed.

49

Fig. 2.1: IR spectrum of 5-Acetyl-2-benzoyl-6-hydroxy-3-methyl benzofuran (2.62)

OO OH

O

CH3

50

Fig. 2.2: 1H-NMR spectrum of 5-Acetyl-2-benzoyl-6-hydroxy-3-methyl benzofuran (2.62)

51

Fig. 2.3: Mass spectrum of 5-Acetyl-2-benzoyl-6-hydroxy-3-methyl benzofuran (2.62)

OO OH

O

CH3

52

2.5.4 Synthesis of (E)-1-(2-Benzoyl-6-hydroxy-3-methyl benzo[b]

furan-5-yl)-3-aryl-2-propen-1-ones (2.63a-g)

(E)-1-(2-Benzoyl-6-hydroxy-3-methylbenzo[b]furan-5-yl)-3-aryl-2-propen-1-

ones were synthesized under conventional and microwave irradiation

methods.

2.5.4.1 Conventional method: 5-Acetyl-2-benzoyl-6-hydroxy-3-methylbenzofuran (2.62a-g) condensed

with appropriate aromatic/hetero aromatic aldehydes in the presence of

sodium methoxide in ethanol at room temperature to give (E)-1-(2-

Benzoyl-6-hydroxy-3-methylbenzo[b]furan-5-yl)-3-aryl-2-propen-1-

ones127 (2.63a-g).

2.5.4.2 Microwave irradiation method: 5-Acetyl-2-benzoyl-6-hydroxy-3-methylbenzofuran (2.62a-g) condensed

with appropriate aromatic/hetero aromatic aldehydes in the presence of

sodium methoxide in ethanol under microwave irradiation to afford (E)-1-

(2-Benzoyl-6-hydroxy-3-methylbenzo[b]furan-5-yl)-3-aryl-2-propen-1-

ones (2.63a-g).

53

Scheme-2.13: Synthesis of (E)-1-(2-Benzoyl-6-hydroxy-3-methylbenzo

[b]furan-5-yl)-3-aryl-2-propen-1-ones (2.63a-g).

O OH

O

OArCHONaOMe

MWI

O OH

O

O

Ar

2.62 2.63a-gRT or

12

3 4 5

67

Ar = a) phenyl e) 4-methoxyphenyl b) 2-chlorophenyl f) 1-naphthyl c) 4-chlorophenyl g )2-furyl d) 3-nitrophenyl

As a representative case the spectral identification of (E)-1-(2-Benzoyl-6-

hydroxy-3-methylbenzo[b]furan-5-yl)-3-(p-methoxyphenyl)-2-propen-1-

one 127 (2.63e) has been discussed. The infrared spectrum of 2.63e (KBr,

Fig 2.4) showed absorptions at 1639 cm-1(acetyl carbonyl), 1604 cm-1

(benzoyl carbonyl), 1097 cm-1 (C-O-C stretching), 3434 cm-1 (OH

stretching). The 1H-NMR spectrum (300 MHz, CDCl3, Fig.2.5) of 2.63e

region at δ 8.25 and 7.08 integrating for one proton each was assigned to

C4 and C7 protons respectively. Two doublets which appeared at δ 6.97

and 8.05 integrating for one proton each due to α-H and β-H

respectively. A doublet appeared at 7.95 integrating for two protons was

assigned to C-2’ and C-6’ protons of benzoyl moiety. Aromatic region of the

spectrum also showed a multiplet between δ 7.50-7.70 integrating for

seven protons was assigned to C2’’, 3’’, 5’’, 6’’ 3’, 4’, 5’ protons. Aliphatic region

of the spectrum showed two singlets at δ 2.68 and 3.90 integrating for

54

three protons each were assigned to C3-methyl and C4’-methoxy group

respectively. A singlet at δ 13.2 integrating for one proton was assigned

to hydroxyl group.

2.5.5 Synthesis of 5-(2’-Amino-6’-arylpyrimidin-4’-yl)-2-benzoyl-6-

hydroxy-3-methyl benzo[b]furans (2.23 a-g).

5-(2’-Amino-6’-arylpyrimidin-4’-yl)-2-benzoyl-6-hydroxy-3-methylbenzo[b]

furans were synthesized under conventional heating and microwave

irradiation methods.

2.5.5.1 Conventional heating method: A mixture of (E)-1-(2-Benzoyl-6-hydroxy-3-methylbenzo[b]furan-5-yl)-3-

aryl-2-propen-1-ones (2.63a-g), guanidine nitrate and aq. KOH, in

ethanol was refluxed for 8-10 hrs to afford 5-(2’-Amino-6’-arylpyrimidin-

4’-yl)-2-benzoyl-6-hydroxy-3-methyl benzo[b]furans (2.23 a-g).

2.5.5.2 Microwave irradiation method A mixture of (E)-1-(2-Benzoyl-6-hydroxy-3-methylbenzo[b]furan-5-yl)-3-

aryl-2-propen-1-ones (2.63a-g), guanidine nitrate and aq. KOH, in DMF

was subjected to microwave irradiation at the constant temperature

120°C for 6-7 min to afford 5-(2’-Amino-6’-arylpyrimidin-4’-yl)-2-benzoyl-

6-hydroxy-3-methyl benzo[b]furans (2.23 a-g).

55

Fig. 2.4: IR spectrum of (E)-1-(2-Benzoyl-6-hydroxy-3-methylbenzo[b]furan-5-yl)-3-(p-methoxy phenyl)-2-propen-1-one (2.63e)

OO OH

O

OCH3

56

OO OH

O

O CH 31

2

3

4

5

67

Fig. 2.5: 1H-NMR spectrum of (E)-1-(2-Benzoyl-6-hydroxy-3-methylbenzo[b]furan-5-yl)-3-(p-methoxyphenyl)-2-propen-1-one (2.63e)

57

Fig. 2.5: 1H-NMR spectrum of (E)-1-(2-Benzoyl-6-hydroxy-3-methylbenzo[b]furan-5-yl)-3-(p-methoxyphenyl)-2-propen-1-one (2.63e) (expansion)

OO O H

O

O CH 31

2

3

4

5

67

58

Scheme-2.14: Synthesis of 5-(2’-Amino-6’-aryl pyrimidin-4’-yl)-2-benzoyl-6-

hydroxy-3-methyl benzo[b]furans (2.23 a-g).

OO OH

O

Ar

2.63

H2N NH2

NH

2.23 a-g

.HNO3

EtOH,or

OO OH

N

N NH2

Ar

12

4

5

67

1'

2'3'

4'

5'

6'

3

aq. KOH

DMF, MWI


The products formed in the above methods were characterized on the

basis of IR, 1H-NMR, 13C-NMR and mass spectral data. As a

representative case the spectral analysis of 5-{2’-Amino-6’-(p-methoxy

phenyl)pyrimidin-4’-yl}-2-benzoyl-6-hydroxy-3-methylbenzo[b]furan

(2.23e) is discussed below.

The IR spectrum (KBr, Fig.2.6) of 2.23e showed characteristic peaks at

3468 cm-1 (OH), 3349 cm-1 (NH2), 1622 cm-1 (C=O), 1574 cm-1 (C=N),

1151, 1094 cm-1 (C-O-C). The 1H-NMR spectrum of (200MHz, DMSO-d6,

Fig.2.7) of compound 2.23e showed singlets at δ 2.59 and 3.81

integrating for three protons each were assigned to methyl and methoxy

protons respectively. A singlet at δ 5.55 (D2O exchangeable) integrating

for two protons was assigned to NH2 group, two more singlet at δ 7.25

59

and 8.10 integrating for one proton each were assigned to C5’-H, and C4-

H. A multiplet between δ 6.92-6.97 integrating for three protons was

assigned to C7-H and two aromatic protons. Two more multiplets

appeared between δ 7.44-7.48 integrating for four protons and δ 7.96-

8.10 integrating for three protons were assigned to aromatic protons. A

singlet at δ 14.4 integrating for one proton was assigned to hydroxyl

group. 13C NMR(50 MHz, DMSO-d6, Fig.2.8) spectrum of 2.23e showed

characteristic peaks at δ 9.84 (CH3), 54.90(OCH3), 99.05 (C5’), 99.41 (C7),

113.48 (C3’’’, C5’’’), 115.87 (C5), 121.03 (C4), 127.88 (C2’’ & C6’’), 128.55

(C3’’’ & C5’’’), 128.88 (C2’’’, & C6’’’), 131.94 (C4’’’), 137.52 (C1’’’), 147.50 (C2),

156.44(C6), 160.63 (C4’’), 161.33 (C4’), 162.42 (C7a), 164.39 (C6’), 165.09

(C2), 184.16 (>C=O). The mass spectrum of 2.23e (Fig.2.9) showed

[M+H]+ ion peak at m/z=452 (90%) and other ions appeared at

292((100%), 230(15%). The above spectral data is in agreement with the

structure proposed.

60

Fig. 2.6: IR spectrum of 5-(2’-Amino-6’-(4-methoxy phenyl) pyrimidin-4’-yl)-2-benzoyl-6-hydroxy-3-methyl

benzo[b]furan (2.23e)

OO OH

N

N NH2

OCH3

61

Fig. 2.7: 1H-NMR spectrum of 5-(2’-Amino-6’-(4-methoxy phenyl) pyrimidin-4’-yl)-2-benzoyl-6-hydroxy-3-methyl benzo[b]furan (2.23e) expansion

OO OH

N

N NH2

OCH3

12

3

4

5

67

1'

2'3'

5'

4'

6'

62

Fig. 2.7: 1H-NMR spectrum of 5-(2’-Amino-6’-(4-methoxy phenyl) pyrimidin-4’-yl)-2-benzoyl-6-hydroxy-3-

methyl benzo[b]furan (2.23e)

OO OH

N

N NH2

OCH3

12

3

4

5

67

1'

2'3'

5'

4'

6'

63

Fig ( ): 5-(21-Amino-61-(4-methoxy phenyl) pyrimidin-41-yl)-2-benzoyl-6-hydroxy-3-methyl benzo[b]

OO OH

N

N NH2

OCH3

12

3

4

5

67

1'

2'3'

5'

4'

6'

64

Fig (2.9): Mass spectrum of 5-(2’-Amino-6’-(4-methoxy phenyl) pyrimidin-4’-yl)-2-benzoyl-6-hydroxy-3-methyl benzo[b]furan (2.23e)

OO OH

N

N NH2

OCH3

65

TABLE 2.1

Analytical data of 5-(2’-Amino-6’-arylpyrimidin-4’-yl)-2-benzoyl-6-hydroxy-3-methyl benzo (b) furans (2.23a-g)

S.No Compound M.P. (°C)

M.F. (M.Wt.)

Conventional heating

Microwave irradiation

Time (hr)

Yield (%)

Time (min)

Yield (%)

1

5-(2’-Amino-6’-phenylpyrimidin-4’-yl)-2-benzoyl-6-hydroxy-3-methyl benzo[b]furan(2.23a)

242

C26H19N3O3 (421)

8

68

6

92

2

5-(2’-Amino-6’-(o-chlorophenyl) pyrimidin-4’-yl)-2-benzoyl-6-hydroxy-3-methyl benzo[b]furan(2.23b)

220

C26H18N3O3Cl (455)

10

64

7

90

3

5-(2’-Amino-6’-(p-chlorophenyl) pyrimidin-4’-yl)-2-benzoyl-6-hydroxy-3-methyl benzo[b]furan(2.23c)

270

C26H18N3O3Cl (455)

10

65

6

94

4

5-(2’-Amino-6’-(m-nitrophenyl) pyrimidin-4’-yl)-2-benzoyl-6-hydroxy-3-methyl benzo[b]furan(2.23d)

272

C26H18N4O5 (466)

8

62

7

88

5

5-(2’-Amino-6’-(p-methoxyphenyl) pyrimidin-4’-yl)-2-benzoyl-6-hydroxy-3-methyl benzo[b]furan(2.23e)

246

C27H21N3O4 (451)

8

65

6

92

6

5-{2’-Amino-6’-(α-naphthyl) pyrimidin-4’-yl}-2-benzoyl-6-hydroxy-3-methyl benzo[b]furan(2.23f)

275

C30H21N3O3 (471)

8

64

6

94

7

5-{2’-Amino-6’-(2-furyl)pyrimidin-4’-yl}-2-benzoyl-6-hydroxy-3-methyl benzo[b]furan(2.23g)

255

C24H17N3O4 (411)

8

66

6

90

66

Scheme-2.14: Mechanism of 5-{2’-Amino-6’-aryl pyrimidin-4’-yl}-2-benzoyl

-6-hydroxy-3-methyl benzo[b]furan (2.23a-g):

2.6 Mechanism:

OO OH

O

Ar

H2N NH

NH2O

O OH

HO Ar

NNH

NH2

-H2O

Michael addition

Imine-Amine tautomerism

-2H

Dihydropyrimidine (unstable)

OO OH

N

N NH2

Ar

OO OH

N

N NH2

ArH

H

H

OO OH

NH

N NH

ArH

H

H

OO OH

NH2

N NH

Ar

H

67

SECTION-B: SYNTHESIS OF 3-(2-BENZOYL-6-HYDROXY-3-METHYL

BENZO[b]FURAN-5-YL)-5-(ARYL)-4,5-DIHYDRO-1H-PYRAZOLE

CARBOTHIOAMIDES UNDER CONVENTIONAL HEATING AND

MICROWAVE IRRADIATION METHODS

2.7 Introduction

A number of pyrazoline derivatives have been shown to exhibit a broad

spectrum of biological and pharmaceutical activities such as

antiinflammatory128-129, antibacterial130, analgesic131, antifungal132,

anticancer133, and anticonvulsant134 activities. Many 1-Thiocarbamoyl-

3,5-diphenyl-2-pyrazolines135-144 are reported to have

antimycobacterial107, antidepressant 104 and monoamine oxidase

inhibitory activity 135. Recently it has been reported that 1-

Thiocarbamoyl-3-phenyl-5-(2’-furyl)-pyrazoline (2.64), 1-Thiocarbamoyl-

3-phenyl-5-(2’-thienyl)-pyrazoline (2.65), 1-Thiocarbamoyl-3-phenyl-5-

(2’-pyrrolyl)-pyrazoline (2.66) exhibited antidepressant activity 104

equivalent or higher than those of pargyline hydrochloride,

Tranylcypromine sulphate and 5-(4-Chlorophenyl)-4,5-dihydro-3-(4-

hydroxy-3-methylphenyl)pyrazole-1-carbothioamide (2.67) exhibited

active against Mycobacterium tuberculosis H37Rv (MTB) and INH

resistant Mycobacterium tuberculosis (INHR-MTB) 143 with minimum

inhibitory concentration of 0.43µM. Benzofuran and its derivatives are

known to be present in many natural products, possessing a variety of

68

biological and pharmacological activities. These aspects are already

discussed in section-A of this chapter.

N N

H2NS

O N N

H2NS

NH N N

H2NS

S

2.64 2.65 2.662.67

N N

H2NS

HOCH3

Cl

Microwave assisted organic synthesis becoming popular method as a

non-conventional technique for rapid organic synthesis. It is eco-friendly

and economical. In view of the biological and pharmaceutical

importance of pyrazolines, 1-thiocarbamoyl pyrazolines and benzofurans,

we have taken up the synthesis of 3-(2-Benzoyl-6-hydroxy-3-

methylbenzo[b]furan-5-yl)-5-(aryl)-4,5-dihydro-1H-pyrazole carbothio-

amides (2.68a-g) to study the ease of formation under microwave

irradiation and evaluate the antibacterial activity.

O OH

N

O

Ar

N

H2NS2.68a-g

HAHB

HX

1'

2'

3' 4'

5'

7'6'

12

3 4

5

Ar = a)phenyl e)4-methoxyphenyl b)2-chlorophenyl f)1-naphthyl c)4-chlorophenyl g)2-furyl d)3-nitrophenyl

69

2.8 PAST WORK

Methods, which are adopted for the synthesis of Thiocarbamoyl

pyrazolines are briefly reviewed in the following pages.

2.8.1 Kishor R. Desai et al., 142 have reported the microwave assisted

synthesis of 1-thiocarbamoyl-3-(2,4-dichloro-5-fluorophenyl)-5-(substitu

ted phenyl)-2-pyrazolines (2.70a-j) by condensation of 2,4-Dichloro-5-

fluoro chalcones with thiosemicarbazide over potassium carbonate.

Scheme-2.15: Synthesis of 1-Thiocarbamoyl-3-(2,4-dichloro-5-

fluorophenyl)-5-(substituted phenyl)-2-pyrazolines(2.70a-j)

NH2CSNHNH2

Basic alumina / K2CO3OCl

Cl

N N

H2NS

Cl

ClF

R

F

R

2.69a-j

2.70a-j

MWI

a b c d e f g h i j R H 2-NO2 3-NO2 2-Cl 4-Cl 4-N(CH3)2 4-OCH3,3-

OH 3,4,5-(OCH3)3

3-OC6H5

4- OCH3

2.8.2 Ahmet ozdemir et al., 138 have reported the synthesis of 1-

Thiocarbamoyl-3, 5-diphenyl-2-pyrazolines (2.72a-c) by refluxing 1-(2-

thienyl-3-aryl-2-propen-1-one derivatives (2.71a-c), thiosemicarbazide

and sodium hydroxide in ethanol for 8 hrs.

Scheme-2.16: Synthesis of 1-Thiocarbamoyl-3,5-diphenyl-2-pyrazolines

(2.72a-c)

70

O

Ar NaOH /EtOHN N

Ar

H2N

S

NH2NHCSNH2

2.71a-c2.72a-c

8 hrs.S

S

Ar = N N Na) b) c)

2.8.3 Mohammad Saharyar et al., 143 have reported the synthesis of

Amino -5-(substituted phenyl-3-(4-hydroxy-3-methylphenyl)-4, 5-

dihydro-1H-1-pyrazolylmethanethiones (2.74a-k) by refluxing 1-(4’-

hydroxy-3’-methyl phenyl)-3-(substituted phenyl) 2-propen-ones,

thiosemicarbazide in acetic acid for 12 hrs.

Scheme-2.17: Synthesis of Amino-5-(substitutedphenyl-3-(4-hydroxy-3-

methylphenyl)-4, 5-dihydro-1H-1-pyrazolylmethanethiones (2.74a-k)

O

R

HOCH3

N

R

N

H2N

S

H3C

HO

2.73a-k 2.74a-k

NH2CSNHNH2

12 hrs.Aceticacid

R =

a 4-Methoxyphenyl g 4-Fluorophenyl b 2-Chlorophenyl h 2-Chlorophenyl c 4-Chlorophenyl i 2,6-Dichlorophenyl d Phenyl j 3-Nitrophenyl e 3, 4-Dimethoxyphenyl k 2-Furyl f 2, 3, 4-Trimethoxyphenyl

71

2.9 PRESENT WORK

In the synthetic methods reported for the synthesis of 1-Thiocarbamoyl

3,5-diaryl-2-pyrazolines are useful in the synthesis of 3-(2-Benzoyl-6-

hydroxy-3-methylbenzo[b]furan-5-yl)-5-(aryl)-4,5-dihydro-1H-pyrazole

carbothioamides (2.68a-g). The advantages obtained by the use of

microwave irradiation in relation to a conventional heating method were

demonstrated (Table-2.2).

2.9.1 Synthesis of title compounds consists of four stages:

2.9.1.1 Synthesis of 4,6-Diacetyl resorcinol

2.9.1.2 Synthesis of 5-Acetyl-2-benzoyl-6-hydroxy-3-methyl benzofuran

2.9.1.3 Synthesis of (E)-1-(2-Benzoyl-6-hydroxy-3-methyl benzo[b]furan-

5-yl)-3-aryl-2-propen-1-ones (2.75a-g)

2.9.1.4 Synthesis of 3-(2-Benzoyl-6-hydroxy-3-methylbenzo[b]furan-5-

yl)-5-(aryl)-4,5-dihydro-1H-pyrazole carbothioamides (2.68a-g)

Synthesis of 4,6-Diacetyl resorcinol, 5-Acetyl-2-benzoyl-6-hydroxy-3-

methyl benzofuran and (E)-1-(2-Benzoyl-6-hydroxy-3-methyl benzo[b]

furan-5-yl)-3-aryl-2-propen-1-ones (2.75a-g) is already discussed in

section-A of this chapter.

2.9.2 Synthesis of 3-(2-Benzoyl-6-hydroxy-3-methylbenzo[b]furan-5-

yl)-5-aryl-4,5-dihydro-1H-pyrazole carbothioamides (2.68a-g).

(i) Synthesis of 3-(2-Benzoyl-6-hydroxy-3-methylbenzo[b]furan-5-yl)-5-aryl-

4, 5-dihydro-1H-pyrazolecarbothioamides (2.68a-g):

72

2.9.2.1 Conventional heating method:

A mixture of (E)-1-(2-Benzoyl-6-hydroxy-3-methyl benzo[b]furan-5-yl)-3-

aryl-2-propen-1-ones(2.63a-g), thiosemicarbazide and aq. NaOH, in

ethanol were refluxed for 8-10 hrs to afford 3-(2-Benzoyl-6-hydroxy-3-

methylbenzo[b]furan-5-yl)-5-aryl-4,5-dihydro-1H-pyrazolecarbothio

amides (2.68a-g).

2.9.2.2 Microwave irradiation method:


aryl-2-propen-1-ones(2.63a-g), thiosemicarbazide and aq. NaOH in DMF

was taken in a quartz tube and inserted into teflon vial with screw

capped and then subjected to microwave irradiation at the constant

temperature 120°C for 5-6 min to afford 3-(2-Benzoyl-6-hydroxy-3-

methylbenzo[b]furan-5-yl)-5-aryl-4,5-dihydro-1H-pyrazolecarbo

thioamides (2.68a-g).

Scheme-2.18: Synthesis of 3-(2-Benzoyl-6-hydroxy-3-methyl benzo[b]furan-

5-yl)-5-(aryl)-4, 5-dihydro-1H-pyrazolecarbothioamides (2.68a-g).

NH2CSNHNH2

EtOH,

2.63a-g or

O OH

O

O

Ar

MWI DMF,

O OH

N

O

Ar

N

H2NS2.68a-g

HAHB

HX

1'

2'

3' 4'

5'

7'6'

12

3 4

5aq.NaOH


73

All the products were characterized by analytical and spectral data such

as IR, 1H-NMR, 13C-NMR and mass. As a representative case the spectral

analysis of 3-(2-Benzoyl-6-hydroxy-3-methylbenzo[b]furan-5-yl)-5-(p-

methoxyphenyl)-4,5-dihydro-1H-pyrazolecarbothioamide(2.68e) has been

discussed below.

The IR spectrum (KBr, Fig.2.10) of 2.68e, showed absorptions at 3413

(OH), 3261 (NH2), 1631 (C=O), 1596(C=N), 1342(C=S), 1101 cm-1 (C-O-C).

The 1H-NMR spectrum (300MHz, CDCl3, Fig.2.11) of 2.68e showed two

singlets at δ 2.63 and 3.78 integrating for three protons each were

assigned to methyl and methoxy protons respectively. A broad singlet at

δ 6.33 integrating for two protons was assigned for NH2 protons. Two

singlets at δ 7.26 and 10.12 integrating for one proton each were

assigned for C7-H and hydroxyl protons respectively. The spectrum

showed three double doublets (ABX pattern) at δ 3.44, 4.06 and 6.04

integrating for one proton each were assigned to HA , HB, Hx proton of

pyrozoline ring138 respectively. The two doublets at δ 6.88 and 7.18

integrating for two protons each were assigned to aromatic protons of

anisyl ring. A doublet at δ 8.05 integrating for two protons was assigned

to ortho protons of benzoyl moiety. The spectrum also showed one

multiplet between 7.50-7.64 integrating for remaining four aromatic

protons. 13C-NMR(75 MHz, CDCl3+DMSO-d6, Fig. 2.12) spectrum of

2.68e, showed characteristic peaks at δ 9.48, 43.5, 54.6, 61.2, 98.8,

113.6, 121.8, 126.2, 126.5, 127.7, 128.8, 131.9, 133.5, 137.1, 148.0,

74

156.1, 156.8, 158.2, 158.3, 175.8, 184.4. The chemical shift values of

carbon atoms C-3 (δ 156.8), C-4 (δ 43.5) and C-5(δ 61.2) confirm the 2-

pyrazoline structure145. In the mass spectrum of (EIMS Fig. 2.13) 2.68e,

the molecular ion [M]+ peak was observed at m/z=485 (10%), and other

fragments at 466 (20%), 455 (25%), 426 (20%), 410(20%), 394(20%),

350,(32%), 308(10%), 293(30%), 278(10%), 257(10%), 250(10%),

207(10%), 193(7%), 175(7%), 167(10%),149(30%), 134(20%), 129(15%),

121(20%), 111(12%), 105(100%), 97(22%), 91(12%), 85(20%),

81(32%),77(86%), 73(30%), 69(70%), 57(52%), 51(18%), 43(50%). The

above spectral data is in agreement with the structure proposed.

75

Fig. 2.10: IR spectrum of 3-(2-Benzoyl-6-hydroxy-3-methyl benzo[b] furan-5-yl)-5-(p-methoxy phenyl)-4, 5-dihydro-1H-pyrazole carbothioamide (2.68e)

OO OH

N N

H2N

S

OCH3

76

O OH

N

O

N

H2NS

HAHB

HX

1'

2'

3' 4'

5'

7'6'

12

3 4

5

OCH3

Fig. 2.11: 1H-NMR spectrum of 3-(2-Benzoyl-6-hydroxy-3-methyl benzo[b] furan-5-yl)-5-(p-methoxy phenyl)-4,5-dihydro-1H-pyrazole carbothioamide (2.68e)

77

Fig. 2.11: 1H-NMR spectrum of 3-(2-Benzoyl-6-hydroxy-3-methyl benzo[b] furan-5-yl)-5-(p-methoxy phenyl)-4,5-dihydro-1H-pyrazole carbothioamide (2.68e) (expansion).

O OH

N

O

N

H2NS

HAHB

HX

1'

2'

3' 4'

5'

7'6'

12

3 4

5

OCH3

78

Fig. 2.12: 13C-NMR spectrum of 3-(2-Benzoyl-6-hydroxy-3-methyl benzo[b] furan-5-yl)-5-(p-methoxy phenyl)-4,5-dihydro-1H-pyrazole carbothioamide (2.68e)

O OH

N

O

N

H2NS

HAHB

HX

1'

2'

3' 4'

5'

7'6'

12

3 4

5

OCH3

79

Fig. 2.13: Mass spectrum 3-(2-Benzoyl-6-hydroxy-3-methyl benzo[b] furan-5-yl)-5-(p-methoxy phenyl)-4,5- dihydro-1H-pyrazole carbothioamide (2.68e)

OO OH

N N

H2N

S

OCH3

80

TABLE 2.2 Analytical data of 3-(2-Benzoyl-6-hydroxy-3-methylbenzo[b]furan-5-yl)-5-aryl-4, 5-dihydro-1H-

pyrazole carbothioamides (2.68a-g)

S.No Compound M.P. (°C)

M.F. (M.Wt.)

Conventional heating

Microwave irradiation

Time (hr)

Yield (%)

Time (min)

Yield (%)

1. 3-(2-Benzoyl-6-hydroxy-3-methyl benzo[b]furan-5-yl)-5-(phenyl)-4,5-dihydro-1H-pyrazolecarbothioamide(2.68a)

250 C26H21N3O3S

(455)

8 76 5 82

2. 3-(2-Benzoyl-6-hydroxy-3-methyl benzo[b]furan-5-yl)-5-(o-chlorophenyl)-4,5-dihydro-1H-pyrazolecarbothio amide(2.68b)

255

C26H20N3O3ClS

(489)

8 65 5 86

3. 3-(2-Benzoyl-6-hydroxy-3-methyl benzo[b]furan-5-yl)-5-(p-chlorophenyl)-4,5-dihydro-1H-pyrazolecarbothioamide(2.68c)

185

C26H20N3O3ClS

(489)

8 65 5 85

4. 3-(2-Benzoyl-6-hydroxy-3-methyl benzo[b]furan-5-yl)-5-(m-nitro phenyl)-4,5-dihydro-1H-pyrazolecarbothioamide(2.68d)

242 C26H20N4O5S

(500)

8 62 5 80

5. 3-(2-Benzoyl-6-hydroxy-3-methyl benzo[b]furan-5-yl)-5-(p-methoxy phenyl)-4,5-dihydro-1H-pyrazolecarbo thioamide(2.68e)

240 C27H23N3O4S

(485)

10 65 5 82

6. 3-(2-Benzoyl-6-hydroxy-3-methyl benzo[b]furan-5-yl)-5-( α-naphthyl)-4,5-dihydro-1H-pyrazolecarbothioamide(2.68f)

205 C30H23N3O3S

(505)

8 62 6 83

7. 3-(2-Benzoyl-6-hydroxy-3-methyl benzo[b]furan-5-yl)-5-(2-furyl)-4,5-dihydro-1H-pyrazolecarbothioamide(2.68g)

245 C24H19N3O4S

(445)

8 66 5 90

81

2.10 Mechanism: 146, 147

Scheme-2.18: Synthesis of 3-(2-Benzoyl-6’-hydroxy-3-methyl benzo[b]

furan-5-yl)-5-(aryl)-4,5-dihydro-1H-pyrazole carbothioamides. (2.68a-g).

OO OH

O

Ar

H2NHN NH2

S

Via hydrazoneformation

OO OH

N

Ar

NH

SH2N

OO OH

N

Ar

N

S

NH2

OO OH

N

Ar

N

S

NH2

H

82

2.11 EXPERIMENTAL

2.11.1 SECTION-A: SYNTHESIS OF 5-{2’-AMINO-6’-(ARYL)

PYRIMIDIN-4’-YL}-2-BENZOYL-6-HYDROXY-3-METHYLBENZO[b]

FURANS (2.23a-g) UNDER CONVENTIONAL AND MICROWAVE

IRRADIATION METHODS

2.12 Synthesis of 4,6-Diacetyl resorcinol (2.60).

4,6-Diacetyl resorcinol (2.60) was synthesized under conventional heating

and microwave irradiation methods.

2.12.1 Conventional heating method

A mixture of resorcinol (2.2g, 0.02 mol), acetic anhydride (4.08g 0.04mol)

and FeCl3 (6.48g, 0.04mol) was taken in a round bottomed flask and it

was heated in an oil bath at 140°C for 10 min. The red syrupy mass

obtained was allowed to cool to room temperature, then 12ml of 6N HCl

was added to the reaction mixture and stirred for 10 min. The reddish

brown solid mass separated was filtered and recrystallized from ethyl

acetate to give pure compound.

Yield: 3.02g, (78%), m.p. 180°C (lit.123 m.p. 1780-1800C).

2.12.2 Microwave irradiation method

A mixture of resorcinol (1.1g, 0.01 mol), acetic anhydride (2.04g,

0.02mol) and FeCl3 (3.24g, 0.02mol) was taken in a quartz tube and

inserted into teflon vial with screw capped and then subjected to

microwave irradiation at the constant temperature 140°C for 2 min. The

red syrupy mass obtained was allowed to cool to room temperature, then

83

12ml of 6NHCl was added to the reaction mixture and stirred for 10 min.

The reddish brown solid mass separated was filtered and recrystallized

from ethyl acetate to give pure compound.

Yield: 1.72g, (88%), m.p.180°C (lit.123 m.p. 1780-1800C).

2.13 Synthesis of 5-Acetyl-2-benzoyl-6-hydroxy-3-methyl benzofuran (2.62). 5-Acetyl-2-benzoyl-6-hydroxy-3-methyl benzofuran (2.62) was synthesized

under conventional heating and microwave irradiation methods.

2.13.1 Conventional heating method

A mixture of 4,6-diacetyl resorcinol(2.60) (1.94g, 0.01mol) and 2-Bromo-

1-phenyl ethanone (1.99g, 0.01mol.), 5 gm anhydrous K2CO3 and

acetone (25ml) was taken in 100 ml round bottomed flask and it was

refluxed for 6 hrs. After completion of reaction as followed by the TLC

examination, cold water was added to it. The solid separated was filtered

and washed with water and extracted with hot 5% NaOH solution. The

alkaline solution was cooled to 0-50C and neutralized with dil. HCl. The

light yellow solid precipitated was filtered, washed with cold water, dried

and recrystallized from methanol to give pure compound as yellow

powder, yield: 1.99g, (68%), m.p. 132°C (lit.124a m.p.1300C).

2.13.2 Microwave irradiation method

Thoroughly mixed mixture of 4,6-Diacetyl resorcinol(2.60) (1.94g,

0.01mol.) and 2-Bromo-1-phenyl ethanone (1.99g, 0.01mol) and 5 gm

anhydrous K2CO3 was taken in quartz tube and inserted into teflon vial

with screw capped and then subjected to microwave irradiation at the

84

constant temperature 140°C for 7 min. After the completion of reaction

as followed by the TLC examination, cold water was added to it. The solid

separated was filtered and washed with water and extracted with hot 5%

NaOH solution. The alkaline solution was cooled to 0-50C and on

neutralization with dil. HCl, light yellow solid precipitated was filtered,

washed with cold water, dried and recrystallized from methanol to afford

pure compound as light yellow powder, yield: 2.29g, (87%), m.p.

132°C(lit.124a m.p.1300C).

IR (KBr):3434, 3068, 2921, 1643, 1600, 1568, 1458, 1446, 1396, 1375,

1348, 1332, 1298, 1255, 1217, 1151, 1105, 1072, 1035, 956, 941, 916,

883, 850, 783, 721, 688, 682 cm-1.

1H-NMR (200 MHz, CDCl3): δ 2.62 (s, 3H, CH3), 2.78 (s, 3H, COCH3)

6.95(s, 1H, C7-H), 7.42-7.61 (m, 3H, C3’, 4’, 5’-H), 7.95-8.15 (m, 3H, C2’, 6’ –

H and C4-H), 12.5 (s, 1H, OH).MS: [M]+ m/z= 294(25%).

2.14 Synthesis of (E)-1-(2-Benzoyl-6-hydroxy-3-methyl benzo[b]

furan-5-yl)-3-aryl-2-propen-1-ones (2.63 a-g)

2.14.1 Synthesis of (E)-1-(2-Benzoyl-6-hydroxy-3-methyl benzo[b]furan-5-

yl)-3-phenyl-2-propen-1-one (2.63 a)

2.14.1.1 Conventional method

A mixture of 5-Acetyl-2-benzoyl-6-hydroxy-3-methyl benzofuran (2.62)

(2.94g, 0.01 mol), benzaldehyde (1.06g, 0.01mol), sodium methoxide

(1.36g 0.02 mole) and 20ml of ethanol was taken in a round bottomed

flask and it was stirred at room temperature for 16 hrs. Progress of the

85

reaction was monitored by TLC. After completion of the reaction, it was

poured on to crushed ice with stirring. The aqueous layer was

neutralized with dil.HCl and the solid separated was filtered, washed

with water and recrystallized from methanol as yellow powder, yield:

2.67g, (70%), m.p. 116°C.

2.14.1.2 Microwave irradiation method A mixture of 5-Acetyl-2-benzoyl-6-hydroxy-3-methyl benzofuran (2.62)

(0.294g, 0.001 mol), benzaldehyde (0.106g, 0.001mol), sodium methoxide

(0.136g, 0.004 mol) and 5 ml of ethanol was taken in a quartz tube and

inserted into teflon vial with screw capped and then subjected to

microwave irradiation at the constant temperature 70°C for 5 min.

Progress of the reaction was monitored by TLC. After completion of the

reaction, it was poured on to crushed ice with stirring. The aqueous layer

was neutralized with dil.HCl and the solid separated was filtered, washed

with water and recrystallized from methanol as yellow powder, yield:

0.366g, (96%), m.p. 116°C.

IR (KBr): 3510, 1639, 1597, 1571, 1494, 1458, 1447, 1381, 1347, 1295

cm-1.

Employing the similar procedure as mentioned for 2.63a, the remaining

compounds 2.63b-g was synthesized from 2.62.


yl)-3-(2-chlorophenyl)-2-propen-1-one (2.63b)


86

Recrystallized from methanol

Yellow powder, 68%, m.p. 162°C



Yellow powder, Yield: 94%, m.p. 162°C

IR (KBr):3514, 1641, 1598, 1564, 1467, 1446, 1379, 1344, 1296 cm- 1.

1H-NMR(300 MHz, CDCl3): δ 2.67 (s, 3H, CH3), 7.10(s, 1H, C7-H), 7.53-

7.62 (m, 7H, C3’’, 4’’, 5’’, 3’, 4’, 5’, 6’-H), 7.68 ( d, 1H, α-H), 7.82 (dd, 2H, C2’, 6’ -

H), 8.07 (d, 1H, β-H ), 8.24 (s, 1H, C4-H), 13.2 (s, 1H, OH)


yl)-3-(4-chlorophenyl)-2-propen-1-one (2.63 c)

2.14.3.1 Conventional method Recrystallized from methanol





IR (KBr): 3510, 1641, 1577, 1569, 1508, 1490, 1458, 1448, 1375, 1361,

1340, 1296 cm-1.


yl)-3-(3-nitrophenyl)-2-propen-1-one (2.63 d)


87


Yellow powder, Yield: 65%, m.p. 212°C.




IR (KBr): 3436, 1643, 1596, 1571, 1529, 1477, 1460, 1448, 1380, 1348,

1299 cm-1.


yl)-3-(4-methoxyphenyl)-2-propen-1-one (2.63e)






IR (KBr): 3434, 1639, 1604, 1579, 1510, 1454, 1377, 1344, 1388, 1377,

1294, 1251, 1172, 1149, 1097 cm-1.

1H-NMR(300 MHz, CDCl3): δ 2.68 (s, 3H, CH3), 3.90(s, 3H, OCH3), 6.97 (

d, 1H, α-H), 8.05 (d, 1H, β-H ), 7.95 (d, 2H, C-2’, 6’ -H), 7.08 (s, 1H, C7-H),

8.25 (s, 1H, C4-H), 7.50-7.70 (m 7H, C-2’’, 3’’, 5’’, 6’’, 3’, 4’, 5’, -H), 13.2 (s, 1H,

OH)

88


yl)-3-(α-naphthyl)-2-propen-1-one (2.63f)





Yellow powder, Yield: 4.14g, (96%), m.p. 172°C

IR (KBr): 3496, 1639, 1596, 1564, 1554, 1461, 1446, 1380, 1348, 1346.

1296 cm-1


yl)-3-(2-furyl)-2-propen-1-one (2.63 g)






IR (KBr): 3533, 1641, 1598, 1571, 1548, 1460, 1454, 1382, 1348, 1292

cm-1. 1H-NMR(300 MHz, CDCl3): δ 2.68 (s, 3H, CH3), 6.57 ( d, 1H, Hβ-

furyl), 6.82(d, 1H, α-H), 7.95 (dd, 2H, C-2’, 6’ -H), 7.25 (s, 1H, C7-H), 8.26

(s, 1H, C4-H), 7.50-7.77 (m, 6H, Ar-H & β-H ), 13.2 (s, 1H, OH)

89

2.15 Synthesis of 5-{2’-Amino-6’-(aryl) pyrimidin-4’-yl}-2-benzoyl-6-

hydroxy-3-methyl benzo[b]furans (2.23a-g).

2.15.1 Synthesis of 5-{2’-Amino-6’-phenyl pyrimidin-4’-yl}-2-benzoyl-6-

hydroxy-3-methyl benzo[b]furan (2.23 a).


A mixture of (E)-1-(2-Benzoyl-6-hydroxy-3-methylbenzo[b]furan-5-yl)-3-

phenyl-2-propen-1-one (2.63a) (0.412g, 0.001 mol), guanidine nitrate,

(0.122g, 0.001 mol), aq.KOH, (0.11g, 0.002 mol) in 1 ml of water and

15ml of ethanol was taken in a 100 ml round bottomed flask and it was

refluxed for 8hrs. Progress of the reaction was monitored by TLC. After

completion of the reaction, the reaction mass was diluted with cold water

and acidified with dil.HCl. The precipitate thus formed was filtered,

washed with water and recrystallized from DMF:water (1:2 v/v) as yellow

powder, yield: 0.286g, 68%, m.p. 242°C.

2.15.1.2 Microwave irradiation method A mixture of (E)-1-(2-Benzoyl-6-hydroxy-3-methyl benzo[b]furan-5-yl)-3-

phenyl-2-propen-1-one (2.63a) (0.412g, 0.001 mol), guanidine nitrate

(0.122g, 0.001 mol), KOH, (0.11g, 0.002 mol) in 1 ml of water and DMF

(5 ml) was taken in a quartz tube and inserted into teflon vial with screw


temperature 120°C for 6 min. Progress of the reaction was monitored by

TLC. After completion of the reaction, the reaction mass was diluted with

cold water and acidified with dil.HCl. The precipitate thus formed was

90

filtered, washed with water and recrystallized from DMF:water (1:2 v/v)

as yellow powder, yield: 0.387g, (92%), m.p. 242°C.

IR (KBr):3411 (OH), 3355 (NH2); 1622 (C=O), 1570 (C=N), 1153, 1097cm-1

(C-O-C).

1H-NMR: δ 5.55 (s, 2H, D2O exchangeable, NH2), 7.01 (s, 1H, C7-H), 8.13

(s, 1H, C4-H), 7.25 (s 1H, C51-H), 7.98-8.02 (m, 4H, Ar-H), 7.46-7.57 (m,

6H, Ar-H), 2.62 (s, 3H, CH3).

MS: [M+H]+ m/z=422 (25%), 404 (2%), 393(4%), 384(4%), 344(2%),

294(10%), 288(5%), 279(10%), 268(8%), 250(2%), 236(6%), 228(2%),

213(4%), 199(2%), 194(8%), 185(4%), 165(4%), 157(4%), 149(15%),

143(4%), 137(10%), 129(10%), 125(8%), 121(14%), 115(10%), 111(12%),

105(36%), 97(22%), 85(26%), 81(30%), 77(36%), 73(25%), 69(72%),

57(66%), 57(64%), 51(10%), 43(54%).

Elemental Analysis: Found: C, 74.16; H, 4.43; N, 9.84%, C26H19N3O3,

Requires: C, 74.10; H, 4.51; N, 9.97%.


compounds 2.23b-g were prepared from 2.63b-g

2.15.2 Synthesis of 5-{2’-Amino-6’-(2-chlorophenyl) pyrimidin-4’-yl}-2-

benzoyl-6-hydroxy-3-methyl benzo[b]furan (2.23 b).

2.15.2.1 Conventional heating method Recrystallized from DMF:water (1:2 v/v)


91

2.15.2.2 Microwave irradiation method Recrystallized from DMF:water (1:2 v/v)


IR (KBr): 3411(OH), 3361(NH2); 1623 (C=O), 1558 (C=N), 1149, 1093 cm-1

(C-O-C).

1H-NMR (200 MHz, DMSO-d6): δ 5.29 (s, 2H, D2O exchangeable NH2),

7.10 (s, 1H, C7-H), 7.25 (s, 1H, C51-H), 8.04-8.10 (m, 3H, Ar-H), 7.41-

7.61(m, 7H, Ar-H), 2.63 (s, 3H, CH3).

MS: [M+H]+ m/z 456 (5%), 294(18%), 284(6%), 279(20%), 223(6%),

191(12%), 184(10%), 175(6%), 149(96%), 141(16%), 137(8%), 119(12%),

105(62%), 91(70%), 83(32%), 77(50%), 57(92%), 51(18%), 45(6%).

Elemental Analysis: Found: C, 68.49; H, 3.86; N, 9.19%, C26H18N3O3Cl,

Requires: C, 68.57; H, 3.95; N, 9.23%.

2.15.3 Synthesis of 5-{2’-Amino-6’-(4-chlorophenyl) pyrimidin-4’-yl}-2-

benzoyl-6-hydroxy-3-methyl benzo[b]furan (2.23 c).




Recrystallized from DMF:water (1:2 v/v)


IR (KBr): 3479 (OH), 3352 (NH2), 1624 (C=O), 1575 (C=N), 1153, 1095

cm-1 (C-O-C).

92

1H-NMR (200 MHz, DMSO-d6): δ 5.24 (s, 2H, D2O exchangeable NH2), δ

7.10 (s, 1H, C7-H), 7.35 (s, 1H, C51-H), 8.03 (s, 1H, C4-H), 7.48-7.52 (m,

5H, Ar-H), 7.90-8.10 (m, 4H, Ar-H), 2.64 (s, 3H, CH3)

MS: [M+H]+ m/z=456 (45%), 438(4%), 426(4%), 393(12%), 366(2%),

350(4%), 294(4%), 279(4%), 175(8%), 135(22%), 105(50%), 97(18%),

91(68%), 85(32%), 77(44%), 73(52%), 57(84%), 51(12%), 43(70%).

Elemental Analysis: Found: C, 68.51; H, 4.07; N, 9.17%, C26H18N3O3Cl,

Requires: C, 68.57; H, 3.95; N, 9.23%.

2.15.4 Synthesis of 5-{2’-Amino-6’-(3-nitro phenyl) pyrimidin-4’-yl}-2-

benzoyl-6-hydroxy-3-methyl benzo[b]furan (2.23 d)






IR (KBr): 3487 (OH), 3350 (NH2); 1633 (C=O), 1569 1(C=N), 1151, 1099

cm-1 (C-O-C).

1H-NMR (200 MHz, DMSO-d6): δ 5.35(s, 2H, D2O exchangeable, NH2),

7.11 (s, 1H, C7-H), 8.98 (s, 1H, C4-H), 7.25 (s, 1H, C51-H), 8.05-8.09 (m,

4H, Ar-H), 7.52-7.73 (m, 5H, Ar-H), 2.70 (s, 3H, CH3).

93

MS: [M+H]+ m/z=467 (18%), 455(80%), 438(4%), 429(4%), 421(12%),

411(2%), 394(4%), 386(8%), 370(4%), 366(6%), 295(4%), 262(2%),

115(6%), 105(72%), 89(4%), 77(60%), 69(4%), 51(14%), 44(80%).


Requires: C, 66.95; H, 3.86; N, 9.01%.

2.15.5 Synthesis of 5-{2’-Amino-6’-(4-methoxyphenyl) pyrimidin-4’-yl}-2-

benzoyl-6-hydroxy-3-methyl benzo[b]furan (2.23 e).






IR (KBr): 3468 (OH), 3349 (NH2), 1622 (>C=O), 1574 (C=N), 1151,

1094cm-1 (C-O-C)

1H-NMR (200 MHz, DMSO-d6): δ 5.55 (s, 2H, D2O exchangeable, NH2),

7.25 (s, 1H, C51-H), 8.10 (s, 1H, C4-H), 6.92-6.97(m, 3H, C7-H & Ar-H)

7.44-7.48(m, 4H, Ar-H), 7.96-8.10(m, 3H, Ar-H), 14.4(s, 1H, OH), 3.81(s,

3H, OCH3), 2.59 (s, 3H, CH3).

13C-NMR(50 MHz, DMSO-d6): δ 9.84(CH3), 54.90(OCH3), 99.05(C5’),

99.41(C7), 113.48(C3”, C5”), 115.87(C5), 121.03(C4), 127.88(C2” & C6”),

128.55 (C3’’’& C5’’’128.88(C2’’’& C6’’’), 131.94(C4’’’), 137.52(C1’’’),147.50(C2),

94

156.44(C6), 160.63(C4”), 161.33(C4’), 162.42(C7a), 164.39(C6’) , 165.09(C2’),

184.16( C=O). MS: [M+H]+ m/z=452 (90%), 292((100%), 230(15%).


Requires: C, 71.84; H, 4.65; N, 9.31%.

2.15.6 Synthesis of 5-{2’-Amino-6’- (α-naphthyl) pyrimidin-4’-yl}-2-benzoyl-

6-hydroxy-3-methyl benzo[b]furan (2.23 f).






IR (KBr): 3413(OH), 3352 (NH2), 1624(C=O), 1577 (C=N), 1151, 1091 cm-1

(C-O-C).


7.11 (s, 1H, C7-H), 7.25 (s, 1H, C51-H), 7.52- 7.72 (m, 8H, Ar-H), 7.92-

8.15 (m, 5H, Ar-H), 2.59 (s, 3H, CH3).

MS: [M+H]+ m/z =472 (15%). Elemental Analysis: Found: C, 76.54; H,

4.52; N 8.82%, C30H21N3O3, Requires: C, 76.43; H, 4.45; N, 8.91%.

2.15.7 Synthesis of 5-{2’-Amino-6’- (2-furyl) pyrimidin-4’-yl}-2-benzoyl-6-

hydroxy-3-methyl benzo[b]furan (2.23g).


95





IR (KBr): 3411, (OH), 3336 (NH2), 1624 (C=O), 1568 cm-1 (C=N), 1151,

1097 cm-1(C-O-C).


7.07 (s, 1H, C7-H), 7.26 (s, 1H, C51-H), 8.16 (s, 1H, C4-H), 8.06 (d, 2H, Ar-

H), 7.52-7.65(m, 6H Ar-H), 2.62 (s, 3H, CH3).

MS: [M+H]+ m/z=412 ( 100 %). Elemental Analysis: Found: C, 70.18; H,

4.21; N, 10.30%, C24H17N3O4, Requires: C, 70.07; H, 4.13; N, 10.21%.

96

2.16 SECTION-B:

2.16.1 SYNTHESIS OF 3-(2-BENZOYL-6-HYDROXY-3-METHYL

BENZO[b]FURAN-5-YL)-5-ARYL-4,5-DIHYDRO-1H-PYRAZOLE

CARBOTHIOAMIDES (2.68a-g) UNDER CONVENTIONAL HEATING

AND MICROWAVE IRRADIATION METHODS:

Synthesis of 4, 6-Diacetyl resorcinol, 5-Acetyl-2-benzoyl-6-hydroxy-3-

methylBenzofuran, (E)-1-(2-Benzoyl-6-hydroxy-3-methyl benzo [b]furan-

5-yl)-3-aryl-2-propen-1-ones is already discussed in section-A of this

chapter.

2.17 Synthesis of 3-(2-Benzoyl-6-hydroxy-3-methylbenzo[b]furan-5-

yl) -5-(aryl)-4,5-dihydro-1H-pyrazolecarbothioamides (2.68a-g).

2.17.1 Synthesis of 3-(2-Benzoyl-6-hydroxy-3-methylbenzo[b]furan-5-yl)-5-

(phenyl)-4,5-dihydro-1H-pyrazole carbothioamide (2.68a).



phenyl-2-propen-1-one(2.63a) (0.382g, 0.001mol), thiosemicarbazide

(0.0911g, 0.001mol) and aq. NaOH (0.08g) in 1 ml of water and 10ml of

ethanol, was taken in a 25ml round bottomed flask and the reaction

mixture was refluxed for 8 hrs. The progress of the reaction was

monitored by TLC. After completion of the reaction, the reaction mixture

was diluted with cold water and acidified with dil. HCl. The precipitate

thus formed was filtered washed with water and recrystallized from

methanol as yellow powder, yield: 0.345g, (76%), m.p. 250°C.

97



phenyl-2-propen-1-one(2.63a) (0.382g, 0.001mol), thiosemicarbazide

(0.0911g, 0.001mol) and aq. NaOH 0.16g in 1ml of water and 5 ml DMF

was taken in a quartz tube and inserted into teflon vial with screw


temperature 120°C for 5 min. The progress of the reaction was monitored

by TLC. The reaction mixture was diluted with cold water and acidified

with dil. HCl. The precipitate thus formed was filtered, washed with

water and recrystallized from methanol as yellow powder, Yield: 0.373g,

(82%), m.p. 250°C.

IR (KBr): 3434 (OH), 3276 (NH2); 1637(C=O), 1596(C=N), 1564, 1448,

1373, 1344(C=S), 1294, 1247, 1149, 1097(C-O-C) cm-1. 1H-NMR(300

MHz, CDCl3): δ 2.57 (s, 3H, CH3), 3.47(dd, 1H, HA), 4.09(dd, 1H, HB), 6.0

(dd, 1H, HX ) 6.37 (s, 2H, NH2) 7.01 (s, 1H, C7-H), 7.26-7.77 (m, 8H, Ar-

H) 8.03-8.05 (m, 2H, Ar-H), 8.27 (s, 1H, C4-H), 10.10 (s, 1H, OH). MS:

[M+H]+ m/z=456(100%), 447(5%), 397(5%), 383(20%), 295(10%),

180(5%), 106(10%). Elemental Analysis: Found: C, 68.43; H, 4.72; N,

9.31%, C26H21N3O3S. Requires: C, 68.57; H, 4.61, N, 9.23%.


compounds 2.68b-g were prepared from 2.63b-g

2.17.2 Synthesis of 3-(2-Benzoyl-6-hydroxy-3-methylbenzo[b]furan-5-yl)-5’-

(o-chlorophenyl)-4,5-dihydro-1H-pyrazole carbothioamide (2.68b).

98

2.17.2.1 Conventional heating method Recrystallized from methanol,



Recrystallized from methanol,


IR (KBr):3444(OH), 3265(NH2); 1637 (C=O), 1596(C=N), 1562, 1473,

1446, 1377, 1344(C=S), 1294, 1247, 1184, 1149, 1097 cm-1 (C-O-C).

1H-NMR (300 MHz, CDCl3): δ 2.58 (s, 3H, CH3), 3.36(dd, 1H, HA) 4.18

(dd, 1H, HB), 6.40 (dd, 1H, HX), 7.12-7.61 (m, 11H, Ar-H, NH2), 8.03-8.05

(d, 2H, Ar-H), 10.06 (s, 1H, OH). 13C-NMR (75 MHz, DMSO-d6): δ 10.04,

60.22, 98.79, 115.1, 122.08, 123.62, 126.05, 127.66, 128.69, 128.93,

129.26, 129.87, 130.63, 132.81, 137.77, 139.88, 147.94, 156.31,

158.43, 176.05, 184.72, 190.42.MS: [M]+ m/z=489 (60%),292(100%),

214(40%). Elemental Analysis: Found: C, 63.70; H, 4.11; N, 8.67%,

C26H20N3O3ClS, Requires: C, 63.73; H, 4.08; N, 8.58%.


(p-chloro phenyl)-4,5-dihydro-1H-pyrazole carbothioamide (2.68c)






99


IR (KBr): 3467(OH), 3251(NH2); 3145, 1629 (C=O), 1598(C=N), 1560,

1488, 1473, 1460, 1342(C=S), 1292, 1247, 1182, 1149, 1091 cm-1 (C-O-

C). 1H-NMR (300 MHz, DMSO-d6): δ 2.57 (s, 3H, CH3), 3.42 (dd, 1H, HA)

4.09 (dd, 1H, HB ) 6.08 (dd, 1H, HX) 6.38 (s, 2H, NH2) 7.18-7.64 (m, 9H,

Ar-H), 8.05 (d, 2H, Ar-H), 10.37(s, 1H, OH).

MS [M]+ m/z=489 (20%), 472(7%), 455(4%), 430(5%), 413((18%),

400(8%), 367(17%), 350.7(4%), 294(5%), 105(7%).

Elemental Analysis: Found: C, 63.81; H, 4.17; N, 8.64%, C26H20N3O3ClS,

Requires: C, 63.73; H, 4.08; N, 8.58%.


(m-nitrophenyl)-4,5-dihydro-1H-pyrazolecarbothioamide (2.68d):







IR (KBr): 3458(OH), 3286(NH2); 1631 (C=O), 1596(C=N), 1562, 1529,

1477, 1446, 1346(C=S), 1294, 1247, 1149, 1097 cm-1 (C-O-C).

1H-NMR (300 MHz, DMSO-d6): δ 2.55 (s, 3H, CH3), 3.44(dd, 1H, HA ),

4.21 (dd, 1H, HB ), 6.21 (dd, 1H, HX ) 6.50 (s,2H, NH2) 7.18 (s, 1H, C7-H),

7.51-7.54 (m, 3H, Ar-H) 7.90-8.40 (m, 7H, Ar-H) 9.98(s, 1H, OH).

100

MS: [M+H]+ m/z=501 (100%), 485(10%), 471(20%), 451(10%) ,412(10%),

391(25%), 324(30%), 295(10%), 279(30%).

Elemental Analysis: Found: C, 62.31; H, 4.11; N, 11.29%, C26H20N4O5S,

Requires: C, 62.40; H, 4.00; N, 11.20%.


(p-methoxyphenyl)-4,5-dihydro-1H-pyrazolecarbothioamide (2.68e):







IR (KBr): 3413(OH), 3261(NH2), 1631(C=O), 1596 (C=N), 1554, 1514,

1492, 1460, 1369, 1342(C=S), 1292, 1247, 1180, 1145, 1101cm-1 (C-O-

C). 1H-NMR (300 MHz, CDCl3): δ 2.63 (s, 3H, CH3), 3.78 (s,3H, OCH3)

3.46(dd, 1H, HA ) 4.06(dd, 1H, HB ), 6.04 (dd, 1H, HX ), 6.33(s, 2H, NH2),

6.88(d, 2H, Ar-H), 7.18(d, 2H, Ar-H) 7.26 (s, 1H, C7-H), 7.50-7.64 (m, 4H,

Ar-H), 8.05 (d,2H, Ar-H), 10.12(s, 1H, OH ).

13C-NMR (75 MHz, DMSO-d6): δ 9.48, 28.9, 43.5, 54.6, 61.2, 121.8,

126.2, 126.5, 127.7, 128.8, 131.9, 133.5, 137.1, 148.0, 156.1, 156.8,

158.2, 158.3, 175.8, 184.4. MS: [M]+ m/z=485 (10%), 466(20%),

455(25%), 426(22%), 410(20%), 394(20%), 350(30%), 293(28%)

101


C27H23N3O4S, Requires: C, 66.81; H, 4.74; N, 8.65%.

2.17.6 Synthesis of 3-(2-Benzoyl-6-hydroxy-3-methylbenzo[b] furan-5-yl)-5-

(α-naphthyl)-4,5-dihydro-1H-pyrazolecarbothioamide (2.68f):







IR (KBr): 3483(OH), 3276(NH2); 1629 (C=O), 1596(C=N), 1560, 1475,

1458, 1444, 1344(C=S), 1292, 1245, 1149, 1099 cm-1 (C-O-C).

1H-NMR (300 MHz, CDCl3): δ 2.50 (s, 3H, CH3), 3.42(dd, 1H, HA ), 4.28

(dd, 1H, HB), 6.52 (s, 2H, NH2), 6.86 (dd, 1HX), 7.15 (s, 1H, C7-H), 7.34-

7.64 (m, 9H, Ar-H), 7.84 (d, 2H, Ar-H), 7.92 (d, 1H, Ar-H), 8.01-8.03 (d,

1H, Ar-H), 10.15(s, 1H, OH ).

MS: [M+H]+ m/z=506(100%),489(10%), 460(5%0, 447(5%), 430(10%),


C30H23N3O3S, Requires: C, 71.28; H, 4.55; N, 8.31%.


(2-furyl)-4,5-dihydro-1H-pyrazole carbothioamide (2.68g):

2.17.7.1 Conventional heating method Recrystallized from methanol

102





IR (KBr): 3446, (OH), 3261 (NH2), 1635 (C=O), 1596(C=N), 1569, 1477,

1456, 1380, 1346(C=S), 1292, 1245, 1211, 1147, 1101 cm-1(C-O-C).

1H-NMR (300 MHz, CDCl3): δ 2.60 (s, 3H, CH3), 3.70(dd, 1H, HA ) 3.90

(dd, 1H, HB ), 6.24 (dd, 1HX ), 6.35 (d,1H, H Hα-furyl), 6.52 (d, 1H, Hβ-

furyl), 7.16 (s, 1H, C7-H), 7.26-7.61 (m, 7H, 5H Ar-H, 2H-NH2), 8.04-

8.06 (d, 2H, Ar-H ) 10.02 (s, 1H, OH ). MS:[M]+ m/z=445(20%), 428(8%),

411(10%), 393(35%), 386(50%), 369(30%), 358(12%), 293(12%),

279(10%), 264(6%), 249(5%), 169(10%), 105(100%),94(6%), 81(16%),

77(75%), 73(10%), 65(5%), 59(18%),

Elemental Analysis: Found: C, 64.80; H, 4.34, N, 9.52%, C24H19N3O4S,

Requires: C, 64.71; H, 4.26; N, 9.43%.

2.18 Conclusions: In Conclusion, we have successfully synthesized some novel 5-(2’-Amino-

6’-arylpyrimidin-4’-yl)-2-benzoyl-6-hydroxy-3-methylbenzo[b]furans

(2.23a-g) and 3-(2-Benzoyl-6-hydroxy-3-methylbenzo[b]furan-5-yl)-5’(2-

furyl)-4,5-dihydro-1H-pyrazolecarbothioamides(2.68a-g)under microwave

irradiation conditions. This methodology provides an easier facile and

environmentally benign synthesis in which the reaction time is reduced

with better yields.

chapter-ii - shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/2211/11/11_chapter 2.pdf ·...

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