synthesis of diazepines 3 n -...

146

SYNTHESIS OF DIAZEPINES

INTRODUCTION

Heterocyclic compounds are often considered privileged structures in medicinal

chemistry due to their biological effects. Benzodiazepines are one of the important classes of

therapeutic agents for example, various benzodiazepines have anticonvulsants, anti hypnotic

and anxiolytic activities.1 Benzodiazepines serve as cholecystokinin A and B antagonists,

2

opioid receptor ligands,3 platelet-activating factor antagonists,

4 HIV trans-activator (Tat)

antagonists,5 HIV reverse transcriptase inhibitors.

6 Benzodiazepines having effect on central

nervous system for example clozapine (1), olanzapine (2) and quetiapine (3) are used in the

clinic for treating schizophrenia, while clonazepam (4), diazepam (5), lorazepam (6),

nitrazepam (7) and oxazepam (8) are used as antianxiety drugs. Flurazepam (Dalmane) (9) is

a hypnotic,1 where as bromazepam (Lexotan) (10) is used as a muscle relaxant.

7 Lorazepam

(Ativam) (11) is used for the relief of neural problems.8

NH

N

N

Cl

N

1

NH

N

N

N

SH3C

2

NH

N

N

Cl

N

O

OH

3

N

HN

O

Cl

O2N

4

N

N

O

Cl

H3C

5

N

HN

O

ClCl

6

OH

N

HN

O

O2N

7

N

HN

O

Cl

OH

8

N

N

F

OCH2CH2N(C2H5)2

Cl

9

N

HN

N

O

Br

10

OH

N

HN

O

Cl

11

OH

Cl

147

PAST WORK:

Attempts have been made in the field of synthetic chemistry to synthesize the various

benzodiazepines and related compounds of pharmacological interest. The literature survey

revealed following major routes utilized for the synthesis of diazepines.

1. Reaction of chalcone (12) with ortho-phenylenediamine (13) in presence of sulfamic acid

(10mol %) as catalyst gave benzodiazapine9 (32) (scheme-1).

Scheme-1

+N

N

14

O

NH2

NH2

12 13

NH2SO3H

80oCSolvent Free

2. Reaction of N-mesyl-2-ethynylaniline (15), benzylamines (16) and paraformadehyde (17)

by three component coupling/cyclization in presence of copper iodide catalyst under MW

conditions gave indole fused diazapines10

(18) (scheme-2).

Scheme-2

NHMs

+Br

NH

R

(HCHO)n

N N

15 16 18

+

CuI (2.5mol%)dioxane

R

R = alkyl, allyl or benzyl

17

MeONa

3. Condensation of 4-hydroxy-2H-chromen-2-one (19) with o-phenylenediamine (13) in

presence of acetic acid afforded benzodiazepine (20)11

(Scheme-3).

Scheme-3

NH2

NH2

19 13

O O

OH

+

NH

N

HO

O

20

AcOH

toluene

148

4. Condensation of 4-hydroxy-2H-chromen-2-one (19) with pyridine-2,3-diamine (21) in

presence of PTSA afforded diazepine (22)12

(Scheme-4).

Scheme-4

19

N NH2

NH2

21

O O

OH

+toluene

N

NH

N

HO

O

22

PTSA

5. Reaction of halogen containing pyrazole-3-carbaldehyde (23) with o-phenylenediamine

(13) in ethanol and triethylamine gave 4-Pyrazole-1,4-diazepines13

(24) (Scheme-5).

Scheme-5

NN

OHC I

R1

R

+

NH2

NH2N

N

R

N

HN

R1

23 13

24

CuI

6. Reaction of 4-chloro-2-oxo-2H-chromene-3-carbaldehyde (25) with diamines (13a-d) in

ethanol and triethylamine gave diazepines14

(26a-d) (Scheme-6).

Scheme-6

O O

Cl

CHO+

X

Y

R

H2N

H2N

EtOH, TEA

reflux

O O

HN N

Y

X

R25

13a-d

26a-d

a) R = H, X = Y = C b) R = CH3, X = Y = C c) R = H, X = N, Y = C d) R = H, X = C, Y = N

7. Reaction of 4-azido-2-oxo-2H-chromene-3-carbaldehyde (27) with diamines (13a-d) in

DMF gave coumarin annulated diazepines14

(28a-d) (Scheme-7).

149

Scheme-7

O O

N3

CHO+

X

Y

R

H2N

H2N 110oC

O O

HN N

Y

X

R

27 13a-d 28a-d

a) R = H, X = Y = C b) R = CH3, X = Y = C c) R = H, X = N, Y = C d) R = H, X = C, Y = N

DMF

MICROWAVE ASSISTED ORGANIC SYNTHESIS (MAOS)

A BRIEF REVIEW

Microwave chemistry is the science of applying microwave irradiation to chemical reactions.

Microwaves act as high frequency electric fields and will generally heat any material

containing mobile electric charges, such as polar molecules in a solvent or conducting ions in

a solid. Polar solvents are heated as their component molecules are forced to rotate with the

field and lose energy in collisions. Microwave heating is able to heat the target compounds

without heating the entire furnace or oil bath, which saves time and energy.

It is also able to heat sufficiently thin objects throughout their volume, in theory

producing more uniform heating. Microwave assisted organic synthesis is an enabling

technology for accelerating drug discovery and development processes.15

Microwave assisted

reactions have received great interest because of their simplicity in operation, enhanced

reaction rates, products with high purity and better yields compared to those conducted by

conventional heating.16,17

Microwave have been used to speed up chemical reactions in the

laboratories and to identify the advantages of the technique for chemical synthesis.18

Microwaves have been extensively used for carrying out chemical reactions and have become

a useful non-conventional energy source for performing organic synthesis.19

Microwave-

assisted organic synthesis in aqueous medium has resulted in the development of relatively

sustainable and environmentally benign protocols for the synthesis of drugs and has emerged

as a tool towards green chemistry. Microwave-assisted synthesis under controlled conditions

has many applications in the field of medical chemistry and pharmaceutical research. Mingos

et al. and Loupy et al have given a thorough explanation of microwave theory.20,21

150

The Microwave assisted organic synthesis (MAOS) is one of the nonconventional

techniques used nowadays in the laboratory and is superior in many ways to traditional

heating for the synthesis of novel compounds.

Advantages of microwave assisted reactions over the conventional reactions

The practical advantages of microwave-assisted reactions are:

Reduction in reaction temperatures

Increases in reaction rates over 10-10,000 times

Increased yields of 10-30% on an average.

Increased selectivity in the product.

Minimum side reactions due to rapid quenching

Reduced solvent usage creates less wastage

Environmentally clean solvent free processes

We have made an attempt to synthesize novel substituted benzodiazepines derivatives by

using both microwave assisted as well as conventional synthetic methods.

SECTION-A: SYNTHESIS OF 7-(2-HYDROXYPHENYL)-2-PHENYL-

4,6-DIHYDROPYRAZOLO[4,3-b][1,4]DIAZEPIN-5(2H)-ONES AND 4-(2-

HYDROXYPHENYL)-1H- BENZO[b][1,4]DIAZEPIN-2(3H)-ONES.

PRESENT WORK:

The objective of the present work is to develop new benzo[b][1,4] diazapine derivatives. The

substituted 7-(2-hydroxyphenyl)-2-phenyl-4,6-dihydropyrazolo[4,3-b][1,4]diazepin-5(2H)-

ones (38i-vi) and 4-(2-hydroxyphenyl)-1H-benzo[b][1,4] diazepin-2(3H)-ones (40a-o) were

synthesized from corresponding 4-hydroxy-2H-chromen-2-ones and diamines. All these

compounds were synthesized under conventional heating method and microwave irradiation

method. The time and yields were compared in both the methods. The newly synthesized

compounds are characterized by spectral studies and the results are discussed in the Section-

A.

151

Synthesis of compounds 38a-f and 40a-o involves three steps.

1. Synthesis of aryl substituted ortho phenylenediamines (31d-f) and 1-aryl-1H-

pyrazole-3,4-diamines (37a-d).

2. Synthesis of 7-(2-hydroxyphenyl)-2-phenyl-4,6-dihydropyrazolo[4,3-b][1,4] diazepin-

5(2H)-ones (38a-f)

3. Synthesis of 4-(2-hydroxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-ones (40a-o).

1. Synthesis of aryl substituted ortho-phenylenediamines (31d-f):

Diamines (31d-f) were prepared by adopting literature procedures.22-24

The suzuki cross-

coupling reaction of 4-bromo-2-nitro aniline (29) with organoboron acids in the presence of

palladium catalyst gave the products 30d-f. The obtained suzuki coupled products 30d-f on

further reduction in presence of Pd/C under H2 atmosphere afforded aryl substituted ortho-

phenylenediamines (31d-f). (Scheme-8)

Scheme-8: Synthesis of aryl substituted ortho-phenylenediamines (31d-f)

NO2

Br

NH2

Na2CO3, Pd(PPh3)4DME/H2O, 90oC, 16h

NO2

NH2

Ar

Pd/C

MeOH,H2

NH2

NH2

Ar

Ar-B(OH)2

d) Ar =S F N

29 30d-f 31d-f

e) Ar = f) Ar =

Synthesis of 1-aryl-1H-pyrazole-3,4-diamines (37a-d):

Substituted 1-aryl-1H-pyrazole-3,4-diamines (36a-d) were prepared by adopting

literature procedure.25

The reaction of acid 32 with thionyl chloride in methanol afforded

ester 33. The aryl boronic acids on reaction with ester 33 under chan-lam conditions gave

chan-lam intermediates 34a-d which were hydrolyzed with KOH to afford acids 35a-d. These

on curtius reaction in presence of DPPA and tert-butanol as solvent afforded crude boc

protected amines, which were deprotected by using TFA to afford nitroanilines (36a-d).The

nitro anilines were reduced by using Pd/C under H2 atmosphere to afford 1-aryl-1H-pyrazole-

3,4-diamines (37a-d) (Scheme-9).

152

Scheme-9: Synthesis of 1-aryl-1H-pyrazole-3,4-diamines (37a-d)

NNH

HOOC NO2

32

NNH

MeO2C NO2Cu(OAc)2,Ar'-B(OH)2

NN

MeO2C NO2

NN

HOOC NO2

Ar'

1.DPPA, TEAt BuOH, dioxane

NN

H2N NO2

Ar'2. TFA, DCM

33 34a-d 35a-d

36a-d

Pd/C,H2

NN

H2N NH2

Ar'

37a-d

Ar'= Ar'=

F

Ar'= Ar'=

CF3

37a-d

a) b) c) d)

Ar'MeOH

SOCl2

Pyridine, DCM,rt

THF:H2O

KOH

MeOH

2. Synthesis of 7-(2-hydroxyphenyl)-2-phenyl-4,6-dihydropyrazolo[4,3-b][1,4]diazepin-

5(2H)-ones (38a-f) under conventional heating and microwave irradiation method:

Conventional method

4-hydroxy-2H-chromen-2-one (19a) was condensed with corresponding diamine

(37a) in acetic acid for 1-3h to afford 7-(2-hydroxyphenyl)-2-phenyl-4,6-

dihydropyrazolo[4,3-b][1,4]diazepin-5(2H)-one (38a).

In the similar way condensation of 19b and 37a, 19c and 37a, 19a and 37b, 19a and

37c, 19a and 37d were yielded compounds 38b, 38c, 38d, 38e, 38f respectively (Scheme-10).

The structures of 38a-f were established by spectral means.

Microwave irradiation method

When the above reactions were performed under microwave irradiation

(power=100watts) using glacial acetic acid as solvent resulted in the formation of same

products 38a-f in about maximum of 4-6 mins, the parameters of time and yields were

reported in Table-1.

153

Scheme-10: Synthesis of 7-(2-hydroxyphenyl)-2-phenyl-4,6-dihydropyrazolo[4,3-

b][1,4]diazepin-5(2H)-ones (38a-f)

O O

OH

19a-c

R

R18

1

2

3

44a5

6

7

37a-d

38a-f

NN

H2N NH2

R3

R2

39a-f (notformed)

+

AcOHMW; 100w;5-6 mins

8a

or

a) R = R1= H

b) R = H, R1 = Me

c) R = Cl, R1 = H

+

a) R = R1= R2 = R3 = H d) R = R1 = R2 = H ,R3 = F

b) R = R2 = R3 = H, R1 = Me e) R = R1 =R3 = H, R2 = CH3

c) R = Cl, R1= R2 = R3 = H f) R = R1 = R3 = H R2 = CF3

AcOH N NH

NN

OH

R2

R3

O

R1

R

1''

2''

3 ''

4''

5''

6''

7

8

8a

1

23

4

5

5a

6

1'

2'

3'

4'

5'6'

N NH

NN

OH

R2

R3

O

R1

R

1''

2''

3 ''

4''

5''

6''

7

8

8a

1

23

4

5

5a

6

1'

2'

3'

4'

5'6'

The FT-IR spectrum of 38a showed the presence of hydroxyl group at 3428 cm-1

and

amide function carbonyl, NH observed at 1672 cm-1

and 1597 cm-1

(N-Hdef). In the 1H NMR

(DMSO-d6, 500 MHz) spectrum of 38a (Fig-5.1) the newly formed diazepine ring C-3 protons

resonated at 3.83 as singlet, hydroxy proton at 13.8 (s, 1H, D2O exchangeable) and NH

proton appeared at 10.7 (s, 1H, D2O exchangeable). The characteristic H-8 proton of

pyrazole ring appeared at 8.41 as singlet and the aromatic protons at 7.94-7.90 (m, 3H, H-

6'', H-2'', H-4'), 7.55-7.46 (m, 3H, H-3'', H-5'', H-4''), 7.38-7.34 (m, 1H, H-5'), 7.04-7.00

(m, 2H, H-6').

In the 13

C NMR (DMSO-d6, 125 MHz) of 38a (Fig-5.2), the signal at 163.6 revealed

presence of carbonyl carbon (C=O, C-2). The characteristic C-3 carbon of diazepine

resonated at 39.8, pyrazole carbon C-8 at 117.6 and the imine (C=N) carbon at 161.3

(C-4). The signals due to aryl ring moiety appeared at 163.3 (C-2'), 147.0 (C-1''), 139.1 (C-

8a), 134.0 (C-4', C-6'), 129.7 (C-5a), 129.5 (C-3'', C-5''), 126.7 (C-4''), 119.0 (C-5'), 118.7 (C-

6'', C-2''), 118.2 (C-1'), 117.8 (C-3').

In the APCI MS of 38a (Fig-5.3) the quasimolecular ion peak was appeared at m/z

319 [M+H].

The distinction between the two structures 38a and 39a was achieved by performing

the 1D-ROESY of 38a (Fig-5.4) (rotating frame nuclear Ovehauser experiment). The nOe

154

enhancement of 3.9% observed on the H-8 proton at 8.44, when the amide proton at 10.7

was irradiated which confirms the assigned structure of the compound 38a and ruled out the

other possible structure for 39a.

The plausible mechanism for the formation of 38a-f is shown below

O O

OH

R

R1 NN

H2N NH2

R3

R2

+

-H2O

19a-c

37a-d

O O

HN

R

R1

NN

NH2

HN NH

NN

O

OH

R2

R3R2

R3

N NH

NN

O

OH

R2

R3

38a-f

+

39a-f (not formed)

R1

R

N NH

NN

O

OH

R2

R3

R1

R

R1

R

The pathway of reaction probably involves condensation of diamine onto the 4th

position of

4-hydroxy coumarin with elimination of water molecule followed by intramolecular

cyclization by nucleophilic attack of free NH2 group on 2nd

position with opening of

coumarin ring.

155

Table 1: Comparison of reaction time and % yield of products 38a-f by conventional and

microwave irradiation methods.

S.No. Compounds Mol. Formula Comparative study

Conventional Microwave

Time(mins) Yield(%) Time(mins) Yield(%)

a 38a C18H14N4O2 60 62 5 93

b 38b C19H16N4O2 60 68 5 88

c 38c C18H13ClN4O2 60 66 5 90

d 38d C18H13FN4O2 60 60 5 88

e 38e C19H16N4O2 60 67 6 97

f 38f C19H13F3N4O2 60 63 5 80

3. Synthesis of 4-(2-hydroxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-ones (40a-o) under

conventional and microwave irradiation method:

Conventional method

The 4-hydroxy-2H-chromen-2-ones (19a-c) were reacted with corresponding diamines (31a-

f) in acetic acid at 100 oC for 1-3h to yield the products 4-(2-hydroxyphenyl)-1H-

benzo[b][1,4]diazepin-2(3H)-ones (40a-o) (Scheme-11).

Microwave irradiation method

When the above same reactions were performed under microwave irradiation condition using

glacial acetic acid as solvent resulted in formation of same products 40a-o in about maximum

of 4-7 min (Scheme-11)

Scheme-11: Synthesis of 4-(2-hydroxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-ones (40a-o)

N NH

OH

O

R1

RO O

OH

19 a-c

R

R18 1

2

3

44a5

6

7

+NH2

NH2

R4

31a-f

40a-o

8a

a) R = R1= H

b) R = H, R1 = Me

c) R = Cl, R1 = H

AcOH/

AcOHMW, 100w;

t4-7mins

or1

2

34

5

5a

6

7

R4

8

9

9a

1'

2 '

3'4'

5'

6'

a) R= R1 = H , R4 = thiophenyl f) R = H , R1 = Me, R4 = F k) R = Cl, R1 = H, R4 = Br

b) R= R1= H , R4= para flurophenyl g) R = H, R1= Me, R4 = thiophenyl l) R = Cl, R1 = H, R4 = F

c) R = R1 =H , R4 = 4-pyrdiyl h) R = H, R1 = Me, R4 = para flurophenyl m) R = Cl, R1 = H, R4 = thiophenyl

d) R = H , R1 = Me, R4 = Cl i) R = H, R1= Me, R4 = 4-pyrdiyl n) R = Cl, R1 = H, R4 = para flurophenyl

e) R = H, R1 = Me, R4 = Br j) R = Cl, R1 = H, R4 = Cl o) R = Cl, R1 = H, R4 = 4-pyrdiyl

156

The experimental conditions used were similar to those used by conventional heating,

with the same concentration of starting material, volume of solvent and temperature. The

parameters of time and yields were reported in Table-2

The compounds (40a-o) were characterized by spectral analysis.

In the FT-IR of 40a bands at 3412 cm-1

indicating the presence of hydroxyl group and

the carbonyl group (C=O) and N-H bands of amide function appeared at 1675 cm-1

and 1595

cm-1

(N-Hdef) respectively.

In the 1H NMR (DMSO-d6, 500 MHz) spectrum of 40a (Fig-5.5) characteristic proton

C-3 of diazepine ring appeared at 3.68 as singlet, the phenolic hydroxy proton at 13.9 (s,

1H, D2O exchangeable) and NH proton observed at 10.7 (s, 1H, D2O exchangeable). The

aromatic protons at 7.93 (d, 1H, J=7.2 Hz, H-4''), 7.73 (s, 1H, H-9), 7.66-7.56 (m, 3H,

H-4', H-5', H-2''), 7.48 (t, 1H, J=8.4 Hz, H-3''), 7.27 (d, 1H, J=8.4 Hz, H-3'), 7.00 (d,

2H, J=5.6 Hz, H-3', H-6').

In the 13

C NMR (DMSO-d6, 125 MHz) of 40a (Fig-5.6), the carbonyl carbon

resonated at 165.8. The characteristic signal C-3 carbon of newly formed diazepine ring

appeared at 38.7 and imine carbon (C=N) at 161.1 (C-4) .The signals due to aromatic ring

carbons appeared at 163.4 (C-2'), 142.1 (C-5a), 136.8 (C-1''), 134.0 (C-8), 130.4 (C-9a),

130.2 (C-4'), 129.8 (C-6'), 128.6 (C-4''), 125.8 (C-3''), 124.3 (C-2''), 124.1 (C-7), 123.6 (C-6),

122.8 (C-5'), 119.1 (C-9), 118.3 (C-1'), 117.6 (C-3').

In the APCI MS of 40a (Fig-5.7) the quasimolecular ion peak was observed at m/z

335 [M+H].

The pathway of reaction involves the nucleophilic attack of the diamine at 4th

position

of the coumarin followed by internal cyclization with ring opening to produce products 40a-

o.

157

Mechanism

O O

OH

R

R1

+

H2N

H2N R4

O O

HN

R

R1

NH2

R4

AcOH

OH

HNNH

O

N NH

OH

O

R1

R

R4

19a-c 31a-f

40a-o

-H2O

R1

R

R4

Table 2: Comparison of reaction time and % yield of products 40a-o by conventional and

microwave irradiation methods.

S.No.

Compounds

Mol. Formula

Comparative study

Conventional Microwave

Time(mins) Yield(%) Time(mins) Yield(%)

i 40a C19H14N2O2S 90 65 5 92

ii 40b C21H15FN2O2 90 67 5 95

iii 40c C20H15N3O2 120 63 5 89

iv 40d C16H13ClN2O2 90 60 6 95

v 40e C16H13BrN2O2 90 68 6 97

vi 40f C16H13FN2O2 90 70 4 96

vii 40g C20H16N2O2 60 70 5 95

viii 40h C22H17FN2O2 120 71 6 96

ix 40i C21H17N3O2 180 63 5 95

x 40j C15H10Cl2N2O2 90 71 5 96

xi 40k C15H10BrClN2O2 90 68 5 94

xii 40l C15H10ClFN2O2 120 71 4 95

xiii 40m C19H13ClN2O2S 180 63 5 90

xiv 40n C21H14ClFN2O2 180 60 7 92

xv 40o C20H14ClN3O2 120 69 6 90

158

EXPERIMENTAL

2. Synthesis of 7-(2-hydroxyphenyl)-2-phenyl-4,6-dihydropyrazolo[4,3-b][1,4]diazepin-

5(2H)-ones (38a-f):

i) 7-(2-Hydroxyphenyl)-2-phenyl-4,6-dihydropyrazolo[4,3-b][1,4]diazepin-5(2H)-one (38a)

N NH

NN

OH

O

1

2

3

4

5

5a

67

8

8a

1'

2'

3 '

4'

5 '

6'

1''2''

3''

4''5''

6''

Conventional method-A: To a stirred solution of 4-hydroxy-2H-

chromen-2-one (19a) (0.2g, 1.23 mmol) in acetic acid (1mL) was

added diamine (37a) (0.214 g, 1.23 mmol) at rt. The reaction

mixture was heated to 120 oC for 60mins, The reaction was

monitored by thin- layer chromatography (TLC). After completion

of the reaction, the precipitated product was separated through

filtration and washed with ether to give the pure product7-(2-

Hydroxyphenyl)-2-phenyl-4,6-dihydropyrazolo [4,3- b] [1,4]

diazepin-5(2H)-one (38a) as yellow solid in 62% yield.

Microwave irradiation method-B: A mixture of 4-hydroxy-2H-chromen-2-one (19a)

(0.2g,1.23 mmol) and diamine (37a) (0.214 g,1.23 mmol) in acetic acid (1mL) were taken in

a quartz tube and inserted into teflon vial with screw capped and then subjected to microwave

irradiation(Biotage® Initiator) especially designed for organic synthesis for 5 mins at 120 oC.

The reaction was monitored by thin-layer chromatography (TLC). After completion of the

reaction, the reaction mixture was diluted with water and precipitated product was separated

through filtration and washed with ether to give the pure product 7-(2-Hydroxyphenyl)-2-

phenyl-4,6-dihydropyrazolo[4,3-b][1,4]diazepin-5(2H)-one (38a) as yellow solid in 93%

yield.mp 233.1-237.9 oC.

FT-IR (KBr): 3428 (OH), 1672 (C=O), 1597 (N-Hdef) cm-1

.

1H NMR (DMSO-d6, 500 MHz): 13.8 (s, 1H, OH), 10.7 (s, 1H, NH), 8.41 (s, 1H, H-8),

7.94-7.90 (m, 3H, H-6'', H-2'', H-4'), 7.55-7.46 (m, 3H, H-3'', H-5'', H-4''), 7.38-7.34 (m, 1H,

H-5'), 7.04-7.00 (m, 2H, H-6'), 3.83 (s, 2H, H-3).

13C NMR (DMSO-d6, 125 MHz): 163.6 (C=O, C-2), 163.3 (C-2'), 161.3 (C-4), 147.0 (C-1''),

139.1 (C-8a), 134.0 (C-4', C-6'), 129.7 (C-5a), 129.5 (C-3'', C-5''), 126.7 (C-4''), 119.0 (C-5'),

118.7 (C-6'', C-2''), 118.2 (C-1'), 117.8 (C-3'), 117.6 (C-8), 39.8 (C-3).

ESI-MS: m/z 319 [M+H].

159

Employing the similar procedures as mentioned for 38a, compounds 38b-f, were synthesized

by condensation of diamines (37a-d) with 4-hydroxy-2H-chromen-2-ones (19a-c) in the

range of 62-70% yield using conventional method-A.

Whereas compounds 38a-f, were obtained from the same starting material in the range of 80-

95% yield using microwave irradiation method-B.

ii) 7-(2-Hydroxy-4-methylphenyl)-2-phenyl-4,6-dihydropyrazolo[4,3-b][1,4]diazepin-5(2H)-

one (38b)

NNH

NN

OH

O

1

2

3

4

5

5a

6

7

8

8a

1'

2'

3 '4'

5'

6 '

1''2''

3''

4''5''

6''

H3C

The compound 38b was prepared by condensation of compounds

19b with diamine 37a by using method A and method B.

Pale yellow solid. mp 236.1-240.3 oC. yield (method-A: 68%,

Time: 60mins, method-B: 88%, Time: 5mins).

FT-IR (KBr):3436 (OH), 1682 (C=O), 1596 (N-Hdef) cm-1

.

1H NMR (DMSO-d6, 400 MHz): 13.9 (s, 1H, OH), 10.8 (s, 1H,

NH), 8.69-8.67 (m, 2H, H-8, H-6'), 7.83 (d, 1H, J=8.4 Hz, H-

4''), 7.72-7.70 (m, 3H, H-2'', H-6'', H-3'), 7.69-7.59 (m, 2H, H-3'', H-5''), 6.84 (d, 1H, J=7.2

Hz, H-5'), 3.67 (s, 2H, H-3), 2.33 (s, 3H, 4'-CH3).


139.6 (C-8a), 134.2 (C-4'), 129.8 (C-5a), 129.3 (C-3'', C-5''), 128.1 (C-5'), 126.4 (C-4''), 123.6

(C-6'), 118.8 (C-6'', C-2''), 118.4 (C-1'), 118.1 (C-3'), 117.6 (C-8), 39.6 (C-3), 23.6 (4'-CH3).

Agilent 6310 Ion Trap MS: m/z 333[M+H]

iii) 7-(5-Chloro-2-hydroxyphenyl)-2-phenyl-4,6-dihydropyrazolo[4,3-b][1,4]diazepin-5(2H)-

one (38c)

NNH

NN

OH

O

1

2

3

4

5

5a

6

7

8

8a

1'

2'

3'

4'

5'6'

1''2''

3''

4''5''

6''

Cl

The compound 38c was prepared by condensation of compounds

19c with diamine 37a by using method A and method B.

Pale yellow solid. mp 291.1-293.5 C. yield (method-A: 66%,

Time: 60mins method-B: 90%, Time: 5min).


.


NH), 8.44 (s, 1H, H-8), 7.92-7.89 (m, 3H, H-6'', H-2'', H-4'), 7.54-

7.50 (m, 3H, H-3'', H-5'', H-4''), 7.35 (t, 1H, J=7.0 Hz, H-3'), 7.04 (d, 1H, J=9.0 Hz, H-6'),

3.83 (s, 2H, H-3).

160


139.1 (C-8a), 134.0 (C-4', C-6'), 129.7 (C-5a), 129.5 (C-3'', C-5''), 126.7 (C-4''), 119.0 (C-5'),

118.7 (C-6'', C-2''), 118.2 (C-1'), 117.8 (C-3'), 117.6 (C-8), 39.8 (C-3).

Agilent 6310 Ion Trap MS: 353 [M+H].

iv) 2-(4-Fluorophenyl)-5-(2-hydroxyphenyl)-6,8-dihydropyrazolo[4,3-b][1,4]diazepin-7(2H)-

one (38d)

N NH

NN

OH

O

1

2

3

4

5

5a

67

8

8a

1'

2'

3 '

4'

5'

6'

1''2''

3''

4''

5''

6''

F

The compound 38d was prepared by condensation of compounds

19a with diamine 37b by using method A and method B.

Pale yellow solid. mp 238.1-242.3 oC. yield (method-A: 60%, Time:

60mins, method-B: 88%, Time: 5mins).


.


NH), 8.44 (s, 1H, H-8), 7.99-7.91 (m, 3H, H-6'', H-2'', H-4'), 7.50-

7.36 (m, 3H, H-5',H-3'', H-5''), 7.04-7.01 (m, 2H, H- 3', H-6'), 3.83

(s, 2H, H-3).


147.2 (C-1''), 139.0 (C-8a), 134.2 (C-4', C-6'), 129.6 (C-5a), 129.5 (C-3'', C-5''), 119.3 (C-5'),

118.8 (C-1'), 118.4 (C-6'', C-2''), 117.6 (C-3'), 117.5 (C-8), 39.8 (C-3).


e) 7-(2-Hydroxyphenyl)-2-m-tolyl-4,6-dihydropyrazolo[4,3-b][1,4]diazepin-5(2H)-one (38e)

N NH

NN

OH

O

1

2

3

4

5

5a

67

8

8a

1'

2'

3'

4'

5'

6'

1''2''

3''

4 ''

5''

6''

CH3

The compound 38e was prepared by condensation of compounds

19a with diamine 37c by using method A and method B.

Pale yellow solid. mp 232.1-235.3 oC. yield ( method-A: 67%,



.


NH), 8.39 (s, 1H, H-8), 7.93-7.49 (m, 3H, H-6'', H-2'', H-4'),

7.50-7.39 (m, 3H, H-5', H-4'', H-5''), 7.18-7.01 (m, 2H, H-3', H- 6'), 3.83 (s, 2H, H-3), 2.37 (s,

3H, 3''-CH3).


139.6 (C-3''), 139.0 (C-8a), 134.4 (C-4'), 134.2 (C-6'), 129.8 (C-5a), 129.6 (C-5''), 126.4 (C-

161

4''), 119.6 (C-5'), 119.0 (C-2''), 118.6 (C-1'), 118.0 (C-3'), 117.8 (C-6''), 117.4 (C-8), 39.6 (C-

3), 23.1 (3''-CH3).


f) 7-(2-Hydroxyphenyl)-2-(3-(trifluoromethyl)phenyl)-4,6-dihydropyrazolo[4,3-

b][1,4]diazepin-5(2H)-one (38f)

N NH

NN

OH

O

1

2

3

4

5

5a

67

8

8a

1'

2'

3'

4'

5'

6'

1''2''

3''

4 ''

5''

6''

CF3

The compound 38f was prepared by condensation of compounds

19a with diamine 37d by using method A and method B.

Pale yellow solid. mp 243.1-248.2 oC. yield ( method-A: 63%,



.


NH), 8.39 (s, 1H, H-8), 7.68-7.49 (m, 3H, H-6'', H-2'', H-4'),

7.55-7.41 (m, 3H, H-5', H-4'', H-5''), 7.18-7.01 (m, 2H, H-3', H-6'), 3.83 (s, 2H, H-3).


139.2 (C-8a), 134.8 (C-4'), 134.4 (C-6'), 131.6 (C-3''), 130.0 (C-5a), 129.4 (C-5''), 127.4 (3''-

CF3), 126.8 (C-6''), 126.2 (C-4''), 119.8 (C-5'), 118.6 (C-1'), 118.0 (C-3'), 117.4 (C-8), 115.2

(C-2''), 39.8 (C-3).


3. Synthesis of 4-(2-hydroxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-ones

(40a-o).

i) 4-(2-Hydroxyphenyl)-8-(thiophen-2-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one (40a)

NNH

OH

O

S

1

2

34

5

5a

6

78

9

9a

1'

2'3'

4'

5'

6'

1''

2''

3''

4 ''

5''

Conventional method-A:To a stirred solution of 4-hydroxy-2H-

chromen-2-one (19a) (0.2g, 1.23 mmol) in acetic acid (1 mL)

was added corresponding diamine (31d) (0.234 g, 1.23 mmol) at

rt. The reaction mixture was heated to 120oC for 90mins. The

reaction was monitored by TLC. After completion of the

reaction, the precipitated product was separated through

filtration and washed with ether to give the pure product

4-(2-hydroxyphenyl)-8-(thiophen-2-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one (40a) as yellow

solid in 65% yield.

162

Microwave irradiation method-B: A mixture of 4-hydroxy-2H-chromen-2-one (19a) (0.2g,

1.23 mmol) and diamine (31d) (0.234 g,1.23 mmol) in acetic acid (1 mL) was taken in a

quartz tube and inserted into teflon vial with screw capped and then subjected to microwave

irradiation(Biotage® Initiator) especially designed for organic synthesis for 5 mins at 120oC.

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

was diluted with water and precipitated product was separated through filtration and washed

with ether to give the pure product 4-(2-hydroxyphenyl)-8-(thiophen-2-yl)-1H-

benzo[b][1,4]diazepin-2(3H)-one (40a) as yellow solid in 92% yield mp 262-264.3oC.


.

1H NMR (DMSO-d6, 400 MHz): 13.9 (s, 1H, OH), 10.7 (s, 1H, NH), 7.93 (d, 1H, J=7.2 Hz,

H-4''), 7.73 (s, 1H, H-9), 7.66-7.56 (m, 3H, H-4', H-5', H-2''), 7.48 (t, 1H, J=8.4 Hz, H-3''),

7.27 (d, 1H, J=8.4 Hz, H-3'), 7.00 (d, 2H, J=5.6 Hz, H-3', H-6'), 3.68 (s, 2H, H-3).

13C NMR (DMSO-d6, 125 MHz): 165.8 (C=O, C-2), 163.4 (C-2'), 161.1 (C-4), 142.1 (C-

5a), 136.8 (C-1''), 134.0 (C-8), 130.4 (C-9a), 130.2 (C-4'), 129.8 (C-6'), 128.6 (C-4''), 125.8

(C-3''), 124.3 (C-2''), 124.1 (C-7), 123.6 (C-6), 122.8 (C-5'), 119.1 (C-9), 118.3 (C-1'), 117.6

(C-3'), 38.7 (C-3).


Employing the similar procedures as mentioned for 40a, compounds 40b-o were obtained

from 4-hydroxy-2H-chromen-2-ones (19a-c) in the range of 60-71% yield using conventional

method-A.

Compounds 40a-o, were obtained from the same starting material in the range of 85-97%

yield using microwave irradiation method-B.

ii) 8-(4-Fluorophenyl)-4-(2-hydroxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (40b)

NNH

OH

O

1

2

34

5

5a

6

7 8

9

9a

1'

2'3'

4'

5'

6'

F

1'' 2''

3''

4''5''

6 ''



FT-IR (KBr):3435 (OH), 1677 (C=O), 1617 (N-Hdef) cm-1

.

1H NMR (DMSO-d6, 400 MHz): 14.0 (s, 1H, OH), 10.8 (s,

1H, NH), 7.93 (s, 1H, H-9), 7.83-7.71 (m, 3H, H-4', H-2'', H-

6''), 7.57-7.56 (m, 1H, H-5'), 7.50-7.45 (m, 1H, H-6), 7.37-7.28

(m, 3H, H-7, H-3'', H-5''), 7.07-6.99 (m, 2H, H-3', H-6'), 3.68

(2, 2H, H-3).

163


142.6 (C-5a), 136.6 (C-1''), 134.2. (C-8), 130.6 (C-9a), 131.4 (C-2'', C-6''), 130.4 (C-4'), 130.2

(C-6'), 127.4 (C-5'), 125.6 (C-7), 124.3 (C-6), 121.2 (C-9), 118.7 (C-1'), 117.6 (C-3'), 116.0

(C-3'', C-5''), 38.8 (C-3).


iii) (4-(2-Hydroxyphenyl)-8-(pyridin-4-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one (40c)

NNH

OH

O

1

2

34

5

5a

6

7 8

9

9a

1'

2'3'

4'

5'

6'

N

1 ''2''

3''

4''5''

6 ''




.


1H, NH), 8.78 (d, 2H, J=7.2 Hz, H-3'', H-5''), 7.93 (s, 1H, H-9),

7.76-7.69 (m, 3H, H-7, H-2'', H-6''), 7.63-7.59 (m, 2H, H-4', H-

5'), 7.48 (t, 1H, J= 8.4 Hz, H-6), 7.08 (d, 2H, J=8.4 Hz, H-3',

H- 6'), 3.68 (s, 2H, H-3).

13C NMR (DMSO-d6, 100 MHz): 165.4 (C=O, C-2), 163.4 (C-2'), 161.2 (C-4), 149.8 (C-3'',

C-5''), 147.2 (C-1''), 142.6 (C-5a), 134.4 (C-8), 132.8 (C-4'), 132.6 (C-9a), 130.2 (C-6'), 125.4

(C-7), 124.0 (C-6), 121.8 (C-5'), 120.9 (C-9), 120.6 (C-2'', C-6''), 118.8 (C-1'), 117.8 (C-3'),

38.9 (C-3).


iv) 8-Chloro-4-(2-hydroxy-4-methylphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (40d)

N NH

OH

O

1

2

34

5

5a

6

7 8

9

9a

1'

2'3'

4'

5'

6 '

H3C

Cl





NH), 7.81 (s, 1H, H-9), 7.68 (s, 1H, H-6'), 7.50-7.48 (m, 1H, H-

6), 7.40 (d, 1H, J=7.0 Hz, H-7), 7.10 (d, 1H, J=8.5 Hz, H-7), 6.81 (s, 1H, H-5'), 3.62 (s, 2H,

H-3), 2.32 (s, 3H, 4'-CH3).


5a), 130.7 (C-9a), 130.6 (C-4'), 129.8 (C-6'), 128.5 (C-5'), 127.1 (C-7), 123.6 (C-6), 123.1 (C-

9), 119.7 (C-8), 118.3 (C-1'), 117.6 (C-3'), 38.4 (C-3), 23.6 (4'-CH3).

Agilent 6310 ion Trap MS: m/z 301 [M+H].

164

v) 8-Bromo-4-(2-hydroxy-4-methylphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (40e)

N NH

OH

O

1

2

34

5

5a

6

7 8

9

9a

1'

2'3'

4'

5'

6'

H3C

Br

Pale yellow solid. mp 281.5 oC. yield (method-A: 68%, Time:



.


NH), 7.83 (s, 1H, H-9), 7.65 (s, 1H, H-6'), 7.52-7.46 (m, 1H, H-

6), 7.42 (d, 1H, J=7.5 Hz, H-7), 7.12 (d, 1H, J=8.0 Hz, H-7),

6.81 (s, 1H, H-5'), 3.61 (s, 2H, H-3), 2.32 (s, 3H, 4'-CH3).


5a), 130.8 (C-9a), 130.6 (C-4'), 129.6 (C-6'), 128.4 (C-5'), 127.2 (C-7), 123.4 (C-6), 123.2 (C-

9), 120.0 (C-8), 118.2 (C-1'), 117.8 (C-3'), 38.4 (C-3), 23.4 (4'-CH3).


vi) 8-Fluoro-4-(2-hydroxy-4-methylphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (40f)

N NH

OH

O

1

2

34

5

5a

6

7 8

9

9a

1'

2'3'

4'

5'

6'

H3C

F




.


NH), 7.79 (s, 1H, H-9), 7.49-7.36 (m, 1H, H-6'), 7.22-7.18 (m,

2H, H-6, H-5'), 6.82 (d, 2H, J=7.5 Hz, H-3', H-7), 3.68 (s, 2H,

H-3), 2.32 (s, 3H, 4'-CH3).

13C NMR (DMSO-d6, 125 MHz): 165.6 (C=O, C-2), 163.2 (C-2'), 161.4 (C-4), 156.8 (C-8),

142.4 (C-5a), 130.7 (C-9a), 130.6 (C-4'), 130.2 (C-6'), 128.1 (C-5'), 127.6 (C-7), 123.2 (C-9),

122.8 (C-6), 118.2 (C-1'), 117.6 (C-3'), 38.8 (C-2), 23.8 (4'-CH3).

Agilent 6310 ion Trap MS: m/z 285 [M-H].

165

vii) 4-(2-Hydroxy-4-methylphenyl)-8-(thiophen-2-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one

(40g)

NNH

OH

O

S

1

2

34

5

5a

6

7 8

9

9a

1'

2'3'

4'

5'

6'

1''

2''

3''

4''

5''

H3C

Pale yellow solid. mp 252.1-257.3 oC. yield (method-A:

70%, Time: 60mins, method-B: 95%, Time: 5mins).


.


1H, NH), 7.82 (d, 1H, J=7.6 Hz, H-4''), 7.73 (s, 1H, H-9),

7.64-7.53 (m, 3H, H-6', H-7, H-2''), 7.48 (d, 1H, J=8.4 Hz,

H-3''), 7.27-7.14 (m, 1H, H-6): 165.4 (C=O, C-2), 163.2

(C-2'), 161.2 (C-4), 142.8 (C-5a), 141.6 (C-4'), 136.6 (C-1''), 134.2 (C-8), 130.6 (C-9a), 129.5

(C-6'), 128.8 (C-4''), 125.4 (C-3''), 124.1 (C-2''), 123.8 (C-5'), 124.2 (C-7), 123.3 (C-6), 119.3

(C-9), 118.2 (C-1'), 117.8 (C-3'), 38.6 (C-3), 23.6 (4'-CH3).

Agilent 6310 ion Trap MS: m/z 349[M+H].

viii) 8-(4-Fluorophenyl)-4-(2-hydroxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (40h)

NNH

OH

O

1

2

34

5

5a

6

7 8

9

9a

1'

2'3'

4'

5'

6'

F

1'' 2''

3''

4''5''

6''

H3C




.


1H, NH), 8.39 (s, 1H, H-9), 7.92 (d, 2H, J=7.6 Hz, H-2'', H-

6''), 7.80 (d, 1H, J=8.8 Hz, H-6'), 7.53 (t, 2H, J=7.6 Hz, H-

3'', H-5''), 7.35-7.33 (m, 2H, H-6, H-7), 6.85-6.84 (m, 2H, H-

3', H-5'), 3.80 (s, 2H, H-3), 2.33 (s, 3H, 4'-CH3).


142.4 (C-5a), 142.2 (C-4'), 136.4 (C-1''), 134.1 (C-8), 130.8 (C-9a), 131.2 (C-2'', C-6''), 127.8

(C-5'), 125.4 (C-7), 124.0 (C-6'), 124.1 (C-6), 121.1 (C-9), 118.6 (C-1'), 117.3 (C-3'), 116.1

(C-3'', C-5''), 38.8 (C-3), 23.7 (4'-CH3).


166

ix) 4-(2-Hydroxy-4-methylphenyl)-8-(pyridin-4-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one

(40i)

NNH

OH

O

1

2

34

5

5a

6

7 8

9

9a

1'

2'3'

4'

5'

6'

N

1'' 2''

3''

4''5''

6''

H3C

Pale yellow solid. mp 258.7-261.6 oC. yield (method-A:

63%, Time: 180mins, method-B: 95%, Time: 5mins).

FT-IR (KBr): 3436 (OH), 1671 (C=O), 1621 (N-Hdef)cm-1

.


1H, NH), 7.82-7.63 (m, 4H, H-3'', H-5'', H-9, H-6'), 7.57-

7.28 (m, 4H, H-6, H-7, H-2'', H-6''), 6.83 (d, 2H, J=7.2 Hz,

H-3', H-5'), 3.65 (s, 2H, H-3), 2.33 (s, 3H, 4'-CH3).

13C NMR (DMSO-d6, 100 MHz): 165.3 (C=O, C-2), 163.2 (C-2), 161.0 (C-4), 149.9 (C-3'', C-

5''), 147.1 (C-1''), 142.5 (C-5a), 139.6 (C-4'), 134.4 (C-8), 132.8 (C-9a), 131.6 (C-5'), 130.2 (C-6'),

125.4 (C-7), 124.0 (C-6), 120.8 (C-9), 120.8 (C-2'', C-6''), 118.6 (C-1'), 117.9 (C-3'), 38.8 (C-3),

23.4 (4'-CH3).

Agilent 6310 ion Trap MS: m/z 344[M+H].

x) 8-Chloro-4-(5-chloro-2-hydroxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (40j)

NNH

OH

O

1

2

34

5

5a

6

7 8

9

9a

1 '

2'3'

4'

5'6'

Cl

Cl

Pale yellow solid. mp 278-280.5 oC. yield (method-A: 71%, Time:



.


NH), 7.93 (s, 1H, H-9), 7.62 (d, 1H, J=2.5 Hz, H-6'), 7.54-7.50

(m, 1H, H-4'), 7.43-7.41 (m, 1H, H-6), 7.28-7.23 (m, 1H, H-7),

7.04-7.02 (m, 1H, H-3'), 3.67 (s, 2H, H-3).


5a), 130.8 (C-9a), 130.4 (C-4'), 129.6 (C-6'), 128.6 (C-5'), 127.0 (C-7), 123.4 (C-6), 123.2 (C-

9), 119.4 (C-8), 118.3 (C-1'), 117.8 (C-3'), 38.6 (C-2).

ESI-MS: m/z 322[M+H].

167

xi) 8-Bromo-4-(5-chloro-2-hydroxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (40k)

NNH

OH

O

1

2

34

5

5a

6

7 8

9

9a

1 '

2'3'

4'

5'6'

Br

Cl

Pale yellow solid. mp 284.5-285 oC. yield (method-A: 68%, Time:



.


1H, NH), 7.93 (s, 1H, H-9), 7.62 (d, 1H, J=2.5 Hz, H-6'), 7.54-

7.50 (m, 1H, H-4'), 7.45-7.41 (m, 1H, H-6), 7.18 (d, 1H, J=8.5

Hz, H-7), 7.04-7.02 (m, 1H, H-3'), 3.67 (s, 2H, H-3).

13C NMR (DMSO-d6,125 MHz): 165.5 (C=O, C-2), 163.3 (C-2'), 161.1 (C-4), 142.2 (C-5a),

130.8 (C-9a), 130.6 (C-4'), 130.1 (C-6'), 128.4 (C-5'), 127.2 (C-7), 123.6 (C-6), 123.1 (C-9),

119.4 (C-8), 118.4 (C-1'), 117.6 (C-3'), 38.5 (C-2).

ESI-MS: m/z 363 [M-H].

xii) 4-(5-Chloro-2-hydroxyphenyl)-8-fluoro-1H-benzo[b][1,4]diazepin-2(3H)-one (40l)

NNH

OH

O

1

2

34

5

5a

6

7 8

9

9a

1 '

2'3'

4'

5'6'

F

Cl




.


NH), 7.92 (s, 1H, H-9), 7.52-7.51 (m, 1H, H-6'), 7.42-7.40 (m,

1H, H-4'), 7.26 (d, 2H, J=6.5 Hz, H-6, H-7), 7.03(d, 1H, J= 9.0

Hz, H-3'), 3.67 (s, 2H, H-3).


142.4 (C-5a), 130.7 (C-9a), 130.4 (C-4'), 130.1 (C-6'), 128.2 (C-5'), 127.1 (C-7), 123.6 (C-6),

123.2 (C-9), 118.2 (C-1'), 117.4 (C-3'), 38.6 (C-2).

ESI-MS: m/z 303 [M-H].

168

xiii) 4-(5-Chloro-2-hydroxyphenyl)-8-(thiophen-2-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one

(40m)

N NH

OH

O

S

1

2

34

5

5a

6

7 8

9

9a

1 '

2'3'

4'

5'6'

1 ''

2''

3''

4 ''

5''

Cl

Pale yellow solid. mp 262-264.3 oC. yield ( method-A: 63%,



.


1H, NH), 7.92 (d, 1H, J=8.0 Hz, H-4''), 7.74 (s, 1H, H-9),

7.60-7.49 (m, 4H, H-4'', H-7, H-6, H-2''), 7.26 (d, 1H, J=8.5

Hz, H-3'), 7.18-7.14 (m, 1H, H-3''), 7.04-7.01 (m, 1H, H-3'),

3.68 (s, 2H, H-3).


5a), 136.6 (C-1''), 134.2 (C-8), 130.2 (C-9a), 130.1 (C-4'), 129.6 (C-6'), 129.0 (C-7), 128.4

(C-4''), 125.5 (C-3''), 124.4 (C-2''), 123.5 (C-6), 122.6 (C-5'), 120.2 (C-9), 118.4 (C-1'), 117.8

(C-3'), 38.7 (C-3).


xiv) 4-(5-Chloro-2-hydroxyphenyl)-8-(4-fluorophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one

(40n)

NNH

OH

O

1

2

34

5

5a

6

7 8

9

9a

1'

2'3'

4'

5'6'

1'' 2''

3''

4''5 ''

6 ''

F

Cl

Pale yellow solid. mp 268.9-274 oC. yield (method-A: 60%,


FT-IR (KBr): 3435 (OH), 1676 (C=O), 1617(N-Hdef) cm-1

.


1H, NH), 7.95 (s, 1H, H-9), 7.94-7.67 (m, 3H, H-6', H- 2'', H-

6''), 7.58 (s, 1H, H-6), 7.52-7.48 (m, 4H, H-7, H-4', H-3'', H-

5''), 7.36 (d, 1H, J=11.0 Hz, H-3), 3.70 (s, 2H, H-3).


142.4 (C-5a), 136.5 (C-1''), 134.2 (C-8), 130.4 (C-9a), 131.2 (C-2'', C-6''), 130.4 (C-4'), 130.1

(C-6'), 127.2 (C-5'), 125.4 (C-7), 124.2 (C-6), 121.1 (C-9), 118.8 (C-1'), 117.4 (C-3'), 116.2

(C-3'', C-5''), 38.8 (C-3).

Agilent 6310 Ion Trap MS: m/z 381 [M+H].

169

xv) 4-(5-Chloro-2-hydroxyphenyl)-8-(pyridin-4-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one

(40o)

NNH

OH

O

1

2

34

5

5a

6

7 8

9

9a

1'

2'3'

4'

5'6'

N

1'' 2''

3''

4''5''

6 ''

Cl




.


1H, NH), 8.68 (d, 2H, J=5.0 Hz, H-3'', H-5''), 7.94 (s, 1H, H-

9), 7.76-7.62 (m, 4H, H-6, H-2'', H-6'', H-6'), 7.52-7.50 (m,

1H, H-4'), 7.41 (d, 1H, J=9.0 Hz, H-7), 7.03 (d, 1H, J=8.5

Hz, H-3'), 3.71 (s, 2H, H-3).

13C NMR (DMSO-d6, 125 MHz): 165.6 (C=O, C-2), 163.2 (C-2'), 161.0 (C-4), 149.5 (C-3'',

C-5''), 147.3 (C-1''), 142.6 (C-5a), 134.6 (C-8), 132.8 (C-4'), 132.3 (C-9a), 130.1 (C-6'), 125.4

(C-7), 124.2 (C-6), 122.0 (C-5'), 120.5 (C-9), 119.8 (C-2''), 119.0 (C-6''), 118.4 (C-1'), 117.6

(C-3'), 38.8 (C-3).


170

SECTION-B:SYNTHESIS OF NOVEL 10-ARYL-10,12-DIHYDRO-6H-

CHROMENO[4,3-e]PYRAZOLO[4,3-b][1,4]DIAZEPIN-6-ONES.

PRESENT WORK:

The compounds 4-chloro-2-oxo-2H-chromene-3-carbaldehydes (41a-d) were

prepared from 4-hydroxy-2H-chromen-2-ones (19a-d) under Vilsmeier conditions (POCl3/

DMF). 4-chloro-2-oxo-2H-chromene-3-carbaldehydes (41a-d) on condensation with

diamines (37a-d) under mild basic conditions in presence of triethylamine and ethanol

afforded 10-aryl-10,12-dihydro-6H-chromeno[4,3-e]pyrazolo[4,3-b][1,4]diazepin-6-ones

(42a-p)

Synthesis of 10-aryl-10,12-dihydro-6H-chromeno[4,3-e]pyrazolo[4,3-b][1,4]diazepin-6-

ones(42a-p) involves 2 steps.

1. Synthesis of 4-chloro-2-oxo-2H-chromene-3-carbaldehydes (41a-d).

2. Synthesis of novel 10-aryl-10,12-dihydro-6H-chromeno[4,3-e]pyrazolo[4,3-

b][1,4]diazepin-6-ones (42a-p).

1. Synthesis of 4-chloro-2-oxo-2H-chromene-3-carbaldehydes (41a-d):

The 4-hydroxy-2H-chromen-2-ones (19a-d) on reaction with POCl3 and DMF in CH2Cl2 at

50oC gave 4-chloro-2-oxo-2H-chromene-3-carbaldehydes

(41a-d) (Scheme-11).

Scheme-11: 4-Chloro-2-oxo-2H-chromene-3-carbaldehydes (41a-d)

a) R = H, R1 = H b) R = H, R1 = CH3 c) R = H, R1 = OBn d) R = Cl, R1 = H

19a-d

O O

OH

R

R1

POCl3,DMF

1

2

3

456

7

8

4a

8a O O

Cl

R

R1

CHO

41a-d

1

2

3

44a

56

7

88a

CH2Cl2

In the FT-IR spectrum of 41a, the absence of OH peak and the intense peaks at 1720

cm-1

and 1702 cm-1

due to aldehyde carbonyl and ester carbonyl of coumarin.

In the 1H NMR (CDCl3, 300 MHz) spectrum of 41a (Fig 5.8), the signal from hydroxy

group not observed and the proton of aldehyde group appeared at 10.3 (s, 1H) indicating the

presence of chlorine at C-4 and CHO group at C-3 position and aromatic protons at 8.16-

8.12 (m, 1H, H-5), 7.78-7.72 (m, 1H, H-7), 7.49-7.39 (m, 2H, H-6, H-8).

171

In the 13

C NMR (CDCl3, 75 MHz) of 41a (Fig-5.9), the aldehyde and coumarin

carbonyl carbons resonated at 186.6 (CHO) and 158.2 (C=O, C-2). The signals due to

chromene moiety at 153.4 (C-4), 153.0 (C-8a), 135.6 (C-4a), 127.5 (C-7), 125.5 (C-5),

118.1 (C-6), 118.0 (C-8), 117.0 (C-3).

In the Agilent 6310 Ion Trap MS of 41a, (Fig-5.10) the quasimolecular ion peak

appeared at m/z 209 [M+H].

2. Synthesis of 10-aryl-10,12-dihydro-6H-chromeno[4,3-e]pyrazolo [4,3-

b][1,4]diazepin-6-ones (42a-p).

The 4-chloro-2-oxo-2H-chromene-3-carbaldehydes (41a-d) on treating successively

with corresponding diamines (37a-d) under mild basic conditions in presence of

triethylamine and ethanol yielded 10-aryl-10, 12-dihydro-6H-chromeno[4,3-e]pyrazolo[4,3-

b][1,4]diazepin-6-ones (42a-p) (Scheme-12). The obtained compounds 42a-p were

characterized by FT-IR, 1H NMR,

13C NMR, MS and NOESY-2D.

Scheme-12: Synthesis of 10-aryl-10,12-dihydro-6H-chromeno[4,3-e]pyrazolo[4,3-

b][1,4]diazepin-6-ones (42a-p)

NN

H2N NH2

37a-d

TEA

12

3

44a

5

6

7

O O

HN N

NN

6a

8

9

8a

10

11

11a

12

12a

1'

2'

3 '

4'5'

6'

R2

R3

R2

R3

1a

O O

Cl

R

R1

CHO

41a-d

1

2

3

44a

56

7

88a

42a-p43a-p

R

R1

++

ethanol

not found

a) R = R1 = H c) R = H, R1 = OBn

b) R = H, R1 = CH3 d) R = Cl, R1 = H

12

3

44a

5

6

7

O O

HN N

NN

6a

8

9

8a

10

11

11a

12

12a

1'

2'

3'

4'5'

6'

R2

R3

1a

R

R1

42 a) R = R1 = R2 = H, R3 = H e) R = R2 = R3 = H, R1 = CH3 i) R = R2 = R3 = H, R1 = OBn m) R = Cl, R1 = R2 = R3 = H

b) R = R1 = R2 = H , R3 = F f) R = R2 = H, R1= CH3, R6 = F j) R = R2 = H, R1= OBn, R3 = F n) R = Cl, R1 = R2= H , R3 = F

c) R = R1 = R3 = H, R2 = CH3 g) R = R6 = H, R1 = CH3, R2 = CH3 k) R = R3 = H, R1 = OBn R2 = CH3 o) R = Cl, R1 = R3 = H, R2 = CH3

d) R = R1= R3 = H, R2 = CF3 h) R = R3 = H, R1 = CH3, R2 = CF3 l) R = R3 = H, R1 = OBn, R2 = CF3 p) R = Cl, R1 = R3 = H, R2 = CF3

The FT-IR spectrum of the 42a, displayed bands at 3343 (N-H), 1654 (C=N) and 1632 (C=O)

cm-1

respectively. In the 1H NMR (DMSO-d6, 400 MHz) spectrum of 42a (Fig-5.11), the NH

proton appeared at 10.2 as broad singlet (D2O exchangeable). The characteristic signal of

pyrazole proton H-9 observed at 7.90 (s, 1H, H-9). The newly formed diazepine H-7 proton

merged with (H-2, H-4) and appeared in the region 7.45-7.40 (m, 3H, H-2, H-4, H-7), the

other aromatic protons at 7.82 (d, 1H, J=7.2 Hz, H-1), 7.52 (d, 2H, J=8.0 Hz, H-3', H-5'),

172

7.22 (t, 1H, J=7.6 Hz, H-3), 7.13 (t, 1H, J=7.6 Hz, H-4'), 7.07 (s, 1H, H-2'), 7.00 (d,

1H, J=8.4 Hz, H-6').

In the 13

C-NMR (DMSO-d6, 400 MHz) of 42a (Fig-5.12) the carbonyl carbon

resonated at 161.9 (C=O, C-6). The signals of pyrazole C-9 carbon and diazapine C-7

carbon appeared at 123.8 and 157.2. The carbon signals assignments for the aryl moiety are

as follows 152.3 (C-12a), 138.1 (C-1', C-8a), 132.6 (C-3, C-4a ), 129.3 (C-3', C-5'), 125.4

(C-4', C-11a), 125.2 (C-2, C-4), 123.8 (C-1), 116.4 (C-2', C-6'), 116.1 (C-1a), 97.3 (C-6a).

As shown in above (Schme-10) the reaction product may be either 42a or 43a.

The proof for the formation of 10-aryl-10,12-dihydro-6H-chromeno[4,3-

e]pyrazolo[4,3-b][1,4]diazepin-6-one 42a rather than 10-aryl-10,12-dihydro-6H-

chromeno[4,3-e]pyrazolo[3,4-b][1,4]diazepin-6-one 43a is from the analysis of NOESY

spectrum (Fig-5.13). When the pyrazole C-9 proton is irradiated in 42a the N-H at 10.2 did

not show nOe, which indicates the C9-H is spatially faraway from N-H as in structure in 42a.

Therefore NOESY experiment clearly confirms the assigned structure 42a only.

In the APCI MS of 42a (Fig-5.14) the quasimolecular ion peak was observed at m/z

329 [M+H].

The possible mechanism for the formation of 42a from 19a and 37a is shown below and no

intermediate was isolated due to probably cascade pathway.

NN

H2N NH2

TEA

O O

HN N

NN

ethanol

O O

Cl

+

H

O

-H2O, -HCl

19a

37a

42a

NN

NHN

OO

+

43anot found

The antibacterial and antifungal screening of 10-aryl-10, 12-dihydro-6H-chromeno[4,3-e]

pyrazolo[4,3-b][1,4]diazepin-6-ones (42a-p) are described in Chapter-VI

173

EXPERIMENTAL

1. Synthesis of 4-Chloro-2-oxo-2H-chromene-3-carbaldehydes (41a-d)

i) 4-Chloro-2-oxo-2H-chromene-3-carbaldehyde (41a) 26

O O

Cl

CHO

1

2

3

45

6

7

8

4a

8a

To a stirred solution of 4-hydroxycoumarin (19a) (9.72 g, 60 mmol)

in anhydrous DMF (45 mL), added dropwise POCl3 (27.6 g, 180

mmol) at –10° to –5°C. The reaction mixture was then stirred for 1

h at room temperature and heated and stirred for 2 h at 60 °C.

After the reaction completed, the mixture was poured onto crushed ice under vigorous

stirring. After storing the mixture overnight at 0 °C the pale yellow solid was collected by

filtration and washed successively with Na2CO3 (5%) and water and then was air–dried,

recrystallization of solid in acetone afforded 8.9 g of 4-chloro-2-oxo-2H-chromene-3-

carbaldehyde (41a) as a pale yellow powder in 72% yield, mp 154.3-160.1.3 oC( lit

26 mp

160-161 oC).

FT-IR (KBr): 1720 (CHO), 1702 (C=O) cm-1

.

1H NMR (CDCl3, 300 MHz): 10.3 (s, 1H, CHO), 8.16-8.12 (m, 1H, H-5), 7.78-7.72 (m, 1H,

H-7), 7.49-7.39 (m, 2H, H-6, H-8).

13C NMR (CDCl3, 75 MHz): 186.6 (CHO, C-3), 158.2 (C-2), 153.4 (C-4), 153.0 (C-8a),

135.6 (C-4a), 127.5 (C-7), 125.5 (C-5), 118.1 (C-6), 118.0 (C-8), 117.0 (C-3).


Employing the similar procedure as mentioned for 41a, compounds 41b-d were obtained

from 19b-d in the range of 70-80% yield.

ii) 4,6-Dichloro-2-oxo-2H-chromene-3-carbaldehyde (41b)27

O O

Cl

CHO

1

2

3

45

7

8

4a

8a

6Cl

Yellow solid. mp 158.3-162.1 oC( lit

27 mp 163.2-161.5

oC)

yield 80%.

FT-IR (KBr): 1718 (CHO), 1705 (C=O) cm-1

.

1H NMR (DMSO-d6, 500 MHz): 9.75 (s, 1H, CHO), 7.54

(dd, 1H, J=8.0 Hz, 1.6 Hz, H-5), 7.51 (dd, 1H, J=8.0 Hz, 0.6 Hz, H-7), 7.41 (dd, 1H, J=1.6

Hz, 0.6 Hz, H-8).

13C NMR (DMSO-d6, 125MHz): 186.8 (CHO, C-3), 158.1 (C-2), 153.6 (C-4), 153.1 (C-8a),

135.8 (C-4a), 130.6 (C-6), 127.6 (C-7), 125.3 (C-5), 118.1 (C-8), 117.1 (C-3).


174

iii) 4-Chloro-7-methyl-2-oxo-2H-chromene-3-carbaldehyde(41c)28

12

3

45

78

4a

8a

6

O OH3C

Cl

CHO

Yellow solid. mp 158.3-162.1 oC( lit

28 mp 163.2-161.5

oC)

yield 78%.

FT-IR (KBr): 1725 (CHO), 1708 (C=O) cm-1

.

1H NMR (DMSO-d6, 500 MHz): 9.82 (s, 1H, CHO), 7.52 (m,

1H, H-5), 7.26-7.14 (m, 2H, H-7, H-8), 2.25 (s, 3H, 7-CH3).


144.6 (C-7), 135.5 (C-4a), 130.4 (C-6), 125.2 (C-5), 118.2 (C-8), 117.0 (C-3), 23.6 (7-CH3).

ESI-MS: m/z 223 [M+H]

iv) 7-(Benzyloxy)-4-chloro-2-oxo-2H-chromene-3-carbaldehyde (41d)

2'

3 '

O O

Cl

1

2

3

44a

5

6

7

88aO1'

4'

5'

6'

CHO

Yellow solid. mp 170.1 oC yield 75%.

FT-IR (KBr): 1730 (CHO), 1706 (C=O) cm-1

.

1H NMR (DMSO-d6, 400 MHz): 9.80 (s, 1H,CHO),

7.92 (d, 1H, J=8.4 Hz,H-5), 7.48-7.36 (m, 5H, H-2',

H-3', H-4', H-5', H-6'), 7.011-7.08 (m, 2H, H-6, H-8),

5.28 (s, 1H, benzylic CH2).


144.6 (C-7), 136.5 (C-1'), 135.6 (C-4a), 130.2 (C-6), 128.2 (C-3', C-5'), 127.6 (C-4'), 126.8

(C-2', C-6'), 125.4 (C-5), 118.1 (C-8), 117.2 (C-3), 68.6 (7-benyzlic CH2).

ESI-MS: m/z 315[M+H]

175

2. Synthesis of novel 10-aryl-10,12-dihydro-6H-chromeno[4,3-e]

pyrazolo[4,3-b][1,4]diazepin-6-ones (42a-p).

i) 10-Phenyl-10,12-dihydro-6H-chromeno[4,3-e]pyrazolo[4,3-b][1,4]diazepin-6-one (42a)

1

2

3

44a

5

6

7

O O

HN N

NN

6a

8

9

8a

10

11

11a

12

12a

1 '

2'

3'

4'

5'

6'

1a

To a stirred solution of 4-chloro-2-oxo-2H-chromene-3-

carbaldehyde (41a) (0.2g, 0.96 mmol) in ethanol (5 mL) were

added corresponding diamine (37a) (0.168 g, 0.96 mmol) and TEA

(0.26mL, 1.92 mmol) at rt. The reaction mixture was refluxed for

2h. The reaction was monitored by thin-layer chromatography

(TLC). After completion of the reaction, the precipitated product

was separated through filtration and washed with ether to give the

pure product 10- phenyl-10,12-dihydro-6H-chromeno[4,3-e]

pyrazolo[4,3-b] [1,4]diazepin-6-one (42a) as brown solid in 88% yield. mp 299.8-303.6 oC.

FT-IR (KBr): 3343(N-H), 1654 (C=N), 1632 (C=O) cm-1

.

1H NMR (DMSO-d6, 400 MHz): 10.2 (bs, 1H, NH), 7.90 (s, 1H, H-9), 7.82 (d, 1H, J=7.2

Hz, H-1), 7.52 (d, 2H, J=8.0 Hz, H-3', H-5'), 7.45-7.40 (m, 3H, H-2, H-4, H-7), 7.22 (t, 1H,

J=7.6 Hz, H-3), 7.13 (t, 1H, J=7.6 Hz, H-4'), 7.07 (s, 1H, H-2'), 7.00 (d, 1H, J=8.4 Hz, H-6').

13C NMR (DMSO-d6, 100 MHz): 161.9 (C=O, C-6), 157.2 (C-7), 152.3 (C-12a), 138.1 (C-

1', C-8a), 132.6 (C-3, C-4a ), 129.3 (C-3', C-5'), 125.4 (C-4', C-11a), 125.2 (C-2, C-4), 123.8

(C-1, C-9), 116.4 (C-2', C-6'), 116.1 (C-1a), 97.3 (C-6a).

APCI-MS: m/z 329 [M+H].

Employing the similar procedure as mentioned for 42a, compounds 42b-p were obtained

from 41b-d and 37a-d in the range of 55-65% yield.

ii) 10-Phenyl-10,12-dihydro-6H-chromeno[4,3-e]pyrazolo[4,3-b][1,4]diazepin-6-one (42b)

1

2

3

44a

5

6

7

O O

HN N

NN

6a

8

9

8a

10

11

11a

12

12a

1'

2'

3'

4'5'

6'

1a

F

Brick red solid. mp 295.2-300.2 oC. yield 85%.


.

1H NMR (DMSO-d6, 400 MHz): 10.2 (bs, 1H, NH), 7.86 (s,

1H, H-9), 7.80 (d, 1H, J=7.2 Hz, H-1), 7.55-7.52 (m, 2H, H-2',

H-6'), 7.43 (t, 1H, J=6.8 Hz, H-3), 7.26 (t, 2H, J=8.4 Hz, H-3',

H-5'), 7.12 (d, 1H, J=7.2 Hz, H-7), 7.06 (s, 1H, H-2), 7.00 (d,

1H, J=8.4 Hz, H-4).

13C NMR (DMSO-d6, 100 MHz): 161.8 (C=O, C-6), 160.4 (C-

176

4'), 157.2 (C-7), 152.2 (C-12a), 138.2 (C-1', C-8a), 132.8 (C-3, C-4a), 129.2 (C-3', C-5'),

126.6 (C-11a), 125.1 (C-2, C-4), 123.6 (C-1, C-9), 116.4 (C-2', C-6'), 116.2 (C-1a), 97.2 (C-

6a).


iii) 10-m-Tolyl-10,12-dihydro-6H-chromeno[4,3-e]pyrazolo[4,3-b][1,4]diazepin-6-one (42c)

1

2

3

44a

5

6

7

O O

HN N

NN

6a

8

9

8a

10

11

11a

12

12a

1'2 '

3'

4 '

5'

6 '

1a

CH3

Brick red solid. Not melted above 300 oC. yield 83%.


.

1H NMR (DMSO-d6, 400 MHz): 10.2 (bs, 1H, NH), 7.87 (s, 1H,

H-9), 7.71 (d, 1H, J=7.6 Hz, H-1), 7.53-7.51 (m, 2H, H-2', H-6'),

7.42 (t, 2H, J=7.6 Hz, H-2, H-4), 7.22 (t, 1H, J=7.2 Hz, H-4'), 7.09

(bs, 1H, H-2), 6.98 (d, 1H, J=7.2 Hz, H-7), 6.85 (bs, 1H, H-3),

2.31 (s, 3H, 3'-CH3).


1', C-8a), 132.8 (C-3, C-4a), 129.6 (C-3', C-5'), 126.5 (C-4', C-11a), 125.1 (C-2, C-4), 123.6

(C-1, C-9), 116.6 (C-2', C-6'), 116.2 (C-1a), 97.5 (C-6a), 23.6 (3'-CH3).


iv) 10-(3-(Trifluoromethyl)phenyl)-10,12-dihydro-6H-chromeno[4,3-e]pyrazolo[4,3-

b][1,4]diazepin-6-one (42d)

1

2

3

44a

5

6

7

O O

HN N

NN

6a

8

9

8a

1011

11a

12

12a

1'2'

3'

4'5'

6'

1a

CF3

Brick red solid. mp 300.1-301.3 oC. yield 81%.

FT-IR (KBr): 3304 (N-H), 1665 (C=N), 1643 (C=O) cm-1

.


H-9), 7.74 (d, 1H, J=7.8 Hz, H-1), 7.53-7.51 (m, 3H, H-2', H-6', H-

3), 7.43 (t, 2H, J=7.6 Hz, H-2, H-4), 7.24 (t, 1H, J=7.2 Hz, H-4'),

7.10 (d, 1H, J=7.2 Hz, H-7), 7.02 (bs, 1H, H-3).

13C NMR (DMSO-d6, 100 MHz): 161.6 (C=O, C-6), 157.2 (C-7),

152.3 (C-12a), 140.3(C-1', C-8a), 138.4 (C-3, C-4a), 129.4 (C-3', C-5'), 125.4 (C-4', C-11a),

125.1 (C-2, C-4), 124.4 (3'-CF3), 123.8 (C-1, C-9), 116.6 (C-2', C-6'), 116.2 (C-1a), 97.5 (C-

6a).

Agilent 6310 Ion Trap MS: m/z 397 [M+H]

177

v). 3-Methyl-10-phenyl-10,12-dihydro-6H-chromeno[4,3-e]pyrazolo[4,3-b][1,4] diazepin-6-

one (42e)

6O

HN N

NN

OH3C

1

2

34

4a

5

6a7

8

8a

9

1011

11a

1'2'

3'

4'5'

6 '

12

12a1a

Brown colour solid. mp 325.1-326.0 oC. yield 85%.


.


H-9), 7.80 (d, 1H, J=7.5 Hz, H-1), 7.43 (bs, 1H, H-3'), 7.35 (s,

1H, H-5'), 7.31-7.27 (m, 2H, H-2', H-6'), 7.13 (t, 1H, J=7.6 Hz, H-

4'), 7.13 (m, 1H, H-7), 7.03 (d, 2H, J=6.0 Hz, H-4, H-2), 2.33 (s,

3H, 3-CH3).


1', C-8a), 132.4 (C-3, C-4a), 129.2 (C-3', C-5'), 125.8 (C-4', C-11a), 125.4 (C-2, C-4),

123.6(C-1, C-9), 116.6 (C-2', C-6'), 116.3 (C-1a), 97.4 (C-6a), 23.8 (3-CH3).


vi) 10-(4-Fluorophenyl)-3-methyl-10,12-dihydro-6H-chromeno[4,3-e]pyrazolo[4,3-

b][1,4]diazepin-6-one (42f)

1

2

34

4a

5

6

7

O O

HN N

NN

6a

8

9

8a

10

11

11a

12

12a

1'2'

3'

4 '5'

6'

F

1a

H3C



.


H-9), 7.82 (d, 1H, J=7.5 Hz, H-1), 7.56-7.53 (m, 2H, H-2', H-6'),

7.27 (t, 2H, J=8.8 Hz, H-3', H-5'), 7.03-6.82 (m, 3H, H-2, H-4, H-

7), 2.30 (s, 3H, 3-CH3).


4'), 157.3 (C-7), 152.3 (C-12a), 138.1 (C- 1', C-8a), 132.2

(C-3, C-4a), 129.0 (C-3', C-5'), 126.1 (C-11a), 125.5 (C-2, C-4), 123.8 (C-1, C-9), 116.4 (C-

2', C-6'), 116.2 (C-1a), 97.2 (C-6a), 23.7 (3-CH3).


178

vii) 3-Methyl-10-m-tolyl-10,12-dihydro-6H-chromeno[4,3-e]pyrazolo[4,3-b][1,4] diazepin-6-

one (42g)

1

2

34

4a

56

7

O O

HN N

NN

6a

8

9

8a

10

11

11a12

12a

1'2'

3'

4'

5'

6'

1a

H3C

CH3



.


1H, H-9), 7.68 (d, 1H, J=6.5 Hz, H-1), 7.35-7.30 (m, 3H, H-7,

H-2', H-6'), 7.02-6.81 (m, 4H, H-5', H-4', H-2, H-4), 2.33 (s,

3H, 3-CH3), 2.32 (s, 3H, 3'-CH3).

13C NMR (DMSO-d6, 125 MHz): 162.1 (C=O, C-6), 157.4

(C-7), 152.0 (C-12a), 138.4 (C-1', C-8a), 132.5 (C-3, C-4a),

129.4 (C-3', C-5'), 125.6(C-4', C-11a), 125.6 (C-2, C-4), 123.4 (C-1, C-9), 116.8 (C-2', C-6'),

116.0 (C-1a), 97.2 (C-6a), 23.8 (3-CH3, 3'-CH3).

Agilent 6310 Ion Trap MS: m/z 357[M+H].

viii) 3-Methyl-10-(3-(trifluoromethyl)phenyl)-10,12-dihydro-6H-chromeno[4,3-

]pyrazolo[4,3-b][1,4]diazepin-6-one (42h)

1

2

34

4a

5

6

7

O O

HN N

NN

6a

8

9

8a

10

11

11a

12

12a

1'

2'

3 '

4'

5'

6'

1a

H3C

CF3

Brick red solid mp 324.4-330.3 oC. yield 79%.


.

1H NMR (DMSO-d6, 500 MHz): 10.4 (bs, 1H, NH), 8.14 (bs,

1H, H-9), 7.80-7.79 (m, 2H, H-1, H-2'), 7.69-7.62 (m, 3H, H-7,

H-6', H-4'), 7.53 (d, 1H, J=7.5 Hz, H-5'), 7.08 (bs, 2H, H-2, H-

4), 2.33 (s, 3H, 3-CH3).


7), 152.2 (C-12a), 140.4 (C-1', C-8a), 138.6 (C-3, C-4a), 130.6

(C-3', C-5'), 125.8(C-4', C-11a), 125.2 (C-2, C-4), 124.6 (3'-CF3), 123.8 (C-1, C-9), 116.8 (C-

2', C-6'), 116.1 (C-1a), 97.6 (C-6a), 23.8 (3-CH3).


179

ix) 10-Phenyl-10,12-dihydro-6H-chromeno[4,3-e]pyrazolo[4,3-b][1,4]diazepin-6-one (42i)

O

HN N

O

NN

O

1

2

3

44a

5

6

6a

7

8

8a

9

10

11

1211a

12a1a

1'2'

3 '

4'

5'

6'

1'''

2'''

3'''

4'''

5'''

6'''

Brown solid. mp 305.8-306.5 oC. yield 82%.

FT-IR (KBr): 3315 (N-H), 1663 (C=N), 1633 (C=O)

cm-1

.

1H NMR (DMSO-d6, 400 MHz): 10.2 (bs, 1H, NH),

7.85 (bs, 1H, H-9), 7.78 (bs, 1H, H-1), 7.52 (d, 2H,

J=8.0 Hz, H-2', H-6'), 7.45-7.32 (m, 7H, H-3', H-5', H-

2''', H-3''', H-4''', H-5''', H-6'''), 7.22 (t, 1H, J=7.2 Hz,

H-7), 7.13 (bs, 1H, H-4'), 6.84 (bs, 1H, H-4), 6.69 (bs,

1H, H-2), 5.15 (s, 2H, benzylic CH2).

13C NMR (DMSO-d6, 100 MHz): 161.9 (C=O, C-6), 159.6 (C-3), 157.3 (C-7), 152.2 (C-

12a), 138.2 (C-1', C-8a), 138.8 (C-4a), 136.4 (C-1'''), 129.3 (C-3', C-5'), 128.6 (C-3''', C-5'''),

127.6 (C-4'''), 127.4 (C-2''', C-6'''), 125.6 (C-4', C-11a), 125.4 (C-2, C-4), 124.0 (C-1, C-9),

117.2 (C-2', C-6'), 116.2 (C-1a), 97.2 (C-6a), 69.4 (benzylic CH2).


x) 3-(Benzyloxy)-10-(4-fluorophenyl)-10,12-dihydro-6H-chromeno[4,3-e]pyrazolo[4,3-

b][1,4]diazepin-6-one (42j)

O

HN N

O

NN

O

1

2

3

44a

5

6

6a

7

8

8a

9

10

11

12

11a

12a1a

1'2'

3'

4'5'

6'

1'''

2'''

3'''

4'''

5'''

6'''

F


FT-IR (KBr): 3317 (N-H), 1661 (C=N), 1634 (C=O)

cm-1

.

1H NMR (DMSO-d6, 400 MHz): 10.2 (bs, 1H,

NH), 7.82-7.76 (m, 2H, H-1, H-9), 7.57-7.53 (m,

2H, H-2', H-6'), 7.46-7.29 (m, 5H, H-2''', H-3''', H-

4''', H-5''', H-6'''), 7.25 (t, 2H, J=6.8 Hz, H-3', H-5'),

7.25 (bs, 1H, H-7), 6.84 (bs, 1H, H-4), 6.70 (bs, 1H,

H-2), 5.15 (s, 2H, benzylic CH2).


152.2 (C-12a), 138.8 (C-4a), 138.1 (C-1', C-8a), 134.8 (C-1'''), 128.4 (C-3', C-5'), 128.4 (C-

3''', C-5'''), 127.8 (C-4'''), 127.2(C-2''', C-6'''), 125.4 (C-11a), 125.0 (C-2, C-4), 124.2 (C-1, C-

9), 116.2 (C-2', C-6'), 116.0 (C-1a), 97.4 (C-6a), 69.7 (benzylic CH2).

APCI MS: m/z 453[M+H].

180

xi) 3-(Benzyloxy)-10-m-tolyl-10,12-dihydro-6H-chromeno[4,3-e]pyrazolo[4,3-

b][1,4]diazepin-6-one (42k)

O

HN N

O

NN

CH3

O

1

2

3

4 4a

5

6

6a

7

8

8a

9

10

11

12

11a

12a1a

1'

2'

3'

4'

5'

6'

1 '''

2'''

3'''

4'''

5'''

6'''


FT-IR (KBr): 3324 (N-H), 1659 (C=N), 1631

(C=O) cm-1

.


NH), 7.82-7.68 (m, 2H, H-1, H-9), 7.45-7.30 (m,

7H, H-2', H-6', H-2''', H-3''', H-4''', H-5''', H-6'''),

7.24 (bs, 1H, H-7), 7.03 (d, 2H, J=6.0 Hz, H-4', H-

5'), 6.83 (bs, 1H, H-4), 6.71 (bs, 1H, H-2), 5.15 (s,

2H, benzylic CH2), 2.31 (s, 3H, 3'-CH3).


12a), 139.2 (C-3'), 138.8 (C-4a), 136.1 (C-1', C-8a), 134.6 (C-1'''), 128.8 (C-5'), 128.2 (C-3''',

C-5'''), 127.6 (C-4'''), 126.1 (C-2''', C-6'''), 125.8 (C-4'), 125.4 (C-11a), 125.2 (C-2, C-4),

124.1 (C-1, C-9), 116.2 (C-2', C-6'), 116.2 (C-1a), 97.6 (C-6a), 69.8 (benzylic CH2), 23.8 (3'-

CH3).


xii) 3-(benzyloxy)-10-(3-(trifluoromethyl)phenyl)-10,12-dihydro-6H-chromeno[4,3-

e]pyrazolo[4,3-b][1,4]diazepin-6-one (42l)

O

HN N

O

NN

CF3

O

1

2

3

44a

5

6

6a

7

8

8a

9

10

11

12

11a

12a1a

1'

2'

3'

4'5'

6'

1'''

2'''

3'''

4'''

5'''

6'''


FT-IR (KBr): 3338 (N-H), 1656 (C=N), 1628

(C=O) cm-1

.


NH), 8.06 (m, 1H, H-9), 7.83-7.65 (m, 2H, H-1, H-

2'), 7.55-7.54 (m, 2H, H-4', H-6'), 7.45-7.34 (m,

5H, H-2''', H-3''', H-4''', H-5''', H-6'''), 7.25 (m, 1H,

H-5'), 7.26 (bs, 1H, H-7), 6.84 (bs, 1H, H-4), 6.68

(bs, 1H, H-2), 5.14 (s, 2H, benzylic CH2).


12a), 139.2 (C-3'), 138.6 (C-4a), 136.4 (C-1', C-8a), 134.6 (C-1'''), 128.6 (C-5'), 128.2 (C-3''',

C-5'''), 127.6 (C-4'''), 126.6 (C-2''', C-6'''), 126.2 (3'-CF3), 125.6 (C-4'), 125.4 (C-11a), 125.1

181

(C-2, C-4), 124.4 (C-1, C-9), 116.4 (C-2', C-6'), 116.2 (C-1a), 97.6 (C-6a), 69.8 (benzylic

CH2).


xiii) 2-Chloro-10-phenyl-10,12-dihydro-6H-chromeno[4,3-e]pyrazolo[4,3-b][1,4] diazepin-

6-one (42m)

6O

HN N

NN

O

12

3

44a

5

6a7

8

8a

9

10

11

11a

1'

2 '

3'

4'5'

6'

12

Cl 12a1a

Brown solid. mp Not melted above 325oC. yield 80%.


.


H-9), 7.73 (d, 1H, J=2.0 Hz, H-1), 7.50-7.39 (m, 5H, H-2', H-6', H-

3', H-5', H-3), 7.21 (t, 1H, J=7.2 Hz, H-4'), 7.04-6.99 (m, 2H, H-4,

H-7).

13C NMR (DMSO-d6, 100 MHz): 161.7 (C=O, C-6), 157.2 (C-7),

152.2 (C-12a), 138.3 (C-1', C-8a), 134.6 (C-2), 132.6 (C-3, C-4a),

129.2 (C-3', C-5'), 125.6 (C-4', C-11a), 125.4 (C-4), 123.6 (C-1, C-9), 116.8 (C-2', C-6'),

116.2 (C-1a), 97.2(C-6a).


xiv) 2-Chloro-10-(4-fluorophenyl)-10,12-dihydro-6H-chromeno[4,3-e]pyrazolo[4,3-

b][1,4]diazepin-6-one (42n)

6O

HN N

NN

O

12

3

44a

5

6a7

8

8a

9

10

11

11a

1'

2'

3'

4'

5'

6'

12

Cl

F

12a1a

Brick red solid. Not melted above 325 oC. yield 80%.


.


H-9), 7.71 (d, 1H, J=7.6 Hz, H-1), 7.53-7.51 (m, 2H, H-2', H-6'),

7.42(t, 2H, J=7.6 Hz, H-3', H-5'), 7.22 (t, 1H, J=7.2 Hz, H-4), 6.98

(d, 1H, J=7.2 Hz, H-7), 6.85 (bs, 1H, H-3).

13C NMR (DMSO-d6, 100 MHz): 161.6 (C=O, C-6), 158.8 (C-4'),

157.1 (C-7), 152.2 (C-12a), 138.4 (C-1', C-8a), 132.2 (C-3, C-4a),

129.3 (C-3', C-5'), 126.4 (C-11a), 125.1 (C-2, C-4), 123.8 (C-1, C-9), 116.6 (C-2', C-6'),

116.2 (C-1a), 97.3 (C-6a).


182

xv) 2-Chloro-10-m-tolyl-10,12-dihydro-6H-chromeno[4,3-e]pyrazolo[4,3-b][1,4] diazepin-6-

one (42o)

6O

HN N

NN

O

12

3

44a

5

6a7

8

8a

9

1011

11a

1'

2'

3'

4'5'

6'

12

Cl

CH3

12a1a

Brown solid. mp Not melted above 320oC

oC. yield 81%.


.


1H, H-9), 7.72 (d, 1H, J=2.0 Hz, H-1), 7.44 (dd, 1H, J=2.4,

J=8.8 Hz, H-2'),7.33 (s, 1H, H-3), 7.29-7.28 (m, 2H, H-6', H-

4'), 7.04-7.02 (m, 2H, H-7, H-5'), 6.98 (s, 1H, H-4), 2.31 (s,

3H, 3'-CH3).

13C NMR (DMSO-d6, 100 MHz): 161.6 (C=O, C-6), 157.6 (C-7), 152.2 (C-12a), 140.1(C-

3'), 138.3 (C-1', C-8a), 134.4 (C-2), 132.8 (C-3, C-4a), 129.6 (C-5'), 125.8 (C-4', C-11a),

125.2 (C-4), 123. 4 (C-1, C-9), 116.3 (C-2', C-6'), 116.4 (C-1a), 97.6 (C-6a), 23.8 (3'-CH3).


xvi) 2-Chloro-10-(3-(trifluoromethyl)phenyl)-10,12-dihydro-6H-chromeno[4,3-e]

pyrazolo[4,3-b][1,4]diazepin-6-one (42p)

6O

HN N

NN

O

12

3

44a

5

6a7

8

8a

9

10

11

11a

1'

2'

3'4'

5 '

6'

12

Cl

CF3

12a1a

Brick red solid mp 315.4-320.3 oC. yield 77%.


.

1H NMR (DMSO-d6, 400 MHz): 10.4 (bs, 1H, NH), 8.16 (bs,

1H, H-9), 7.82-7.76 (m, 2H, H-1, H-2'), 7.68-7.58 (m, 4H, H-7,

H-6', H-4', H-3), 7.51 (d, 1H, J=7.5 Hz, H-5'), 7.08 (bs, 1H, H-

4).

13C NMR (DMSO-d6, 100 MHz): 161.2 (C=O, C-6), 157.2

(C-7), 152.1 (C-12a), 140.2(C-1', C-8a), 138.4 (C-3, C-4a), 134.4 (C-2), 130.4 (C-3'), 129.6

(C-5'), 125.8(C-4', C-11a), 125.4 (C-4), 124.8 (C-1, C-9), 124.4 (3'-CF3), 116.6 (C-2', C-6'),

116.2 (C-1a), 97.8 (C-6a).


183

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synthesis of diazepines 3 n -...

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