chpater-iii synthesis of 1,5-benzodiazepine and its...

CHPATER-III

Synthesis of 1,5-benzodiazepine and its derivatives

using silica gel supported sulfuric acid and cage type

mesoporous aluminosilicate catalysts

3.1. Introduction:

Benzodiazepines constitute an impotant class of biologically active

compounds and their synthesis has been receiving much attention in

the field of medicinal and pharmaceutical chemistry owing to their

application as anticonvulsant, anti-inflammatory, analgesic, sedative

agents,and hypnotic activity.1–6 The derivatives of 1,5-benzodiazepines

are also used as dyes for acrylic fibers in photography.7 In addition,

benzodiazepines are the useful precursors for the synthesis of other

fused ring compounds such as oxadiazolo-, oxazino- and triazolo-, or

furano-benzodiazepines.8–11 Benzodiazepines are generally synthesized

by the condensation of o-phenylenediamine (OPDA) with α,β-

unsaturated carbonyl compounds, β-haloketones or with ketones12

using acidic catalysts which are critical to enhance the condensation

process. Different reagents such as BF3-etherate, polyphosphoric acid,

NaBH4, MgO/POCl3, Yb(OTf)3, Ga(OTf)3, lead nitrate, L-proline, acetic

acid under microwave conditions, molecular iodine, and ionic liquids

have also been used for the synthesis of benzodiazepines.13–23

Recently the synthesis of benzodiazepines was also reported using

different solid acid catalysts such as sulfated zirconia, Al2O3/P2O5,

Ag3PW12O40, PVP-FeCl3, and zeolite catalysts.24–28 Unfortunately, many

of these catalysts suffer from one or more limitations such as drastic

reaction conditions, long reaction times, occurrence of several side

reactions, tedious work-up procedure and low yields. In addition, the

solid acid catalyst used previously had poor textural parameters such

as low surface area and pore volume which do not support a better

performance in the synthesis of benzodiazepines.

In recent years, ordered mesoporous silica materials have received

considerable importance because of their unique structures with

organized porosity, high specific surface area and pore volume, and

well-ordered mesopores that are considerably larger than zeolites and

zeotype molecular sieves, and find potential applications mainly in the

field of catalysis, adsorption, separation, sensors, and fuel cells.29-37

These materials can be prepared by using either a cationic or an

anionic or a neutral surfactant as a structure directing agent. There

are numerous reports which deal with the preparation of various types

of one and three dimensional mesoporous materials, such as MCM-

41, MCM-48, SBA-1, SBA-15, AMS, HMS, and MSU etc.37 Among the

various materials, materials with three-dimensional cage type pore

arrangements are more resistant to pore blocking, allow faster

diffusion of reactants, and provide more adsorption sites, which can

be easily accessible through three dimensional pore channels. In spite

of these interesting features, surprisingly, the majority of studies

published so for deal with phases having a one-dimensional pore

system, viz. MCM-41 and SBA-15.

Despite these interesting features, the KIT-5 materials have

several disadvantages including neutral framework, poor stability,

weak acidity, and low ion exchange capacity, which limit their

applications, especially in catalysis and adsorption. These problems

can be overcome by introducing the hetero-atoms in the silica

framework of KIT-5 materials. Moreover, the content of the hetero-

atoms in the silica framework is a major factor, which determines the

properties of the catalysts such as acidity and catalytic reactivity.

However, it is highly difficult to incorporate the metal atoms in the

silica framework of KIT-5 because the preparation of the materials

requires highly acidic medium where the solubility of the metal source

is very high. Moreover, at highly acidic medium, the hetero-atoms

exist only in the cationic forms rather than their corresponding oxo

species which suppress the contact between the hetero-atoms and the

silica species.

Therefore, particular interest was focused on the design and

fabrication of highly ordered mesoporous materials with three-

dimensional (3D) pore structures such as SBA-1 and KIT-5 as they are

believed to be more advantageous for catalytic applications than

phases having a 1D array of pores.34-38 Moreover, these materials can

offer more resistant to pore locking and allow faster diffusion of

reactants which are highly necessary to obtain a stable and a high

catalytic activity. Recently, Vinu et al. reported the preparation of

various mesoporous metallosilicate catalytic materials with 3D cage

type structure and investigated their catalytic activity in the alkylation

and acylation of aromatics.34,36,37,38 They found that the activity of the

3D mesoporous catalysts is much better than the catalysts with

unidimensional mesoporous structure. Among the 3D metallosilicate

catalysts, aluminium supported mesoporous KIT-5 material (AlKIT-5)

was found to be interesting as it possesses 3D mesostructure with

Fm3m symmetry and large cage type pores, a high acidity which

mainly comes from the Brönsted acid sites on the surface of the

catalyst, and a large pore diameter.37 These features are clearly

reflected in its high catalytic activity towards various acid catalyzed

reactions.37,38 The activity of the AlKIT-5 catalyst has been studied on

the acetylation of veratrole by acetic anhydride and it has been found

that the AlKIT-5(10) shows37 higher activity than that of the zeolites,

such as ZSM-5, HY, mordenite, and Hb. Although these materials

possess interesting textural and catalytic properties, unfortunately,

with the best of our knoeledge, there has been no publication available

on the synthesis of benzodiazepines using such materials as catalysts

in the open literature so far.

Here we are expressing first time for the synthesis of 1,5-

benzodiazepine using AlKIT-5 as the catalyst through a condensation

reaction between OPDA and ketones in acetonitrile. The effect of the

aluminium content of the catalyst and the catalyst concentration on

the above process has also been investigated in detail. We also

demonstrate the preparation of various derivatives of 1,5-

benzodiazepine using substituted OPDAs and various ketones.

3.2. Present work:

Initially we focused on the synthesis of 1,5-benzodiazepines using

10 mol% silica gel supported sulfuric acid39 and the results are

presented in Table 3.3. However, mesoporous AlKIT-5(10)40 catalyst

gave the better yields and recoverability than the previous catalyst.

Since AlKIT-5 is better choice, we focused our synthesis using this

catalyst. Thus, condensation of OPDA or substituted OPDA 1 with

various ketones 2 in acetonitrile at room temperature gave the

products 3(a-t) in good yields (Scheme 1).

HN

N

CH2

R1

R1

NH2

NH2

+ R1 C

O

CH2

R2

R2

R1 = Alkyl, Phenyl

R2 = H, Alkyl

1 3 (a-t)2

R = H, Cl

R RCH3CN, R.T

SiO2-H2SO4/ AlKIT-5

Scheme1: Synthesis of 1,5-benzodiazepines at R.T

The role and activity of the catalyst in this transformation was

shown in Table.3.1. The role of the Brönsted acid site of the AlKIT-5

catalyst in the formation of 1,5-benzodiazepines and the reaction

mechanism are clearly depicted in scheme 2.

Scheme 2: A plausible mechanism for the synthesis of 1,5-

benzodiazepines using AlKIT-5 catalyst at R.T

Table 3.1 shows the textural parameters and the acidity of the

AlKIT-5 samples with different ‘Al’ content. All the materials possess

well-ordered 3D mesostructure with cage type pores, high surface area

and large pore diameter. It can be seen from Table 3.1 that the acidity,

surface area, pore volume and pore diameter of the materials increase

with increasing the ‘Al’ content in the AlKIT-5. The specific surface

area, pore volume, pore diameter, cage diameter and the acidity of the

AlKIT-5(10) is found to be 989 m2/g, 0.68 cm3/g, 6 nm, 12 nm, and

0.51 mmol of NH3/g, respectively. These features make this material

special among other metal substituted mesoporous materials. As the

detailed characterization of the materials can be found in earlier

reports.37,38

Here, the acidity and the catalytic activity of the novel AlKIT-5

materials were investigated. This suggests that the amount of

NH2

NH2

RC

CH3

OH

NH2

NH R

NH2

N

R

R

O=CCH3

+

N

HN

R

R

NH

HN

R

R

HN

NH

C

C CH2

R

R

CH3 HN

N

C

C CH3

R

R

CH3

R

O=CCH3

-H2O

-H+

H+

-H2O

-H+

OSi

OAl

O

OO OO

H

tetrahedral ‘Al’ incorporation in AlKIT-5 materials increases

remarkably with decreasing the nSi/nAl ratio. Moreover, the catalytic

activity of the AlKIT-5 materials with different ratios on the BDPs

synthesis was investigated and the results are compared with silica

gel supported sulfuric acid (Table 3.3). Interestingly, among the

catalysts examined under the optimized reaction conditions, the

AlKIT-5(10) shows much higher activity. The silica and AlKIT-5

structures are given below.

OSi

OSi

OSi

OSi

OSi

OSi

OSi

O

O O O O O O O O O O OO OO

Structure 1: Silica structure

Structure 2: AlKIT-5 structure

The prepared 3D mesoporous aluminosilicate nanocage in a

“Highly Acidic Media” will give high Al content upto nSi/nAl = 10. From

the above structures, 3D silica is neutral in charge and AlKIT-5 is

acidic as per the charge shown on the structure. Therefore, the

conversion is superior over other catalysts37 such as AlKIT-5 catalysts

with the nSi/nAl ratio lower than 10, mordenite, zeolite HY, zeolite Hb,

and ZSM-5. The higher activity of the AlKIT-5(10) could be due to the

OSi

OAl

OSi

OAl

OSi

OSi

OAl

O

O O O O O O O O O O OO OO

H H H

fact that the sample exhibits three dimensional cage type porous

networks with a high surface area and comparable acidity, which

enhance the diffusion of the reactant molecules and allows the easy

access to all the active sites. These catalytic results also confirm that

the AlKIT-5(10) material indeed possesses more amount of tetrahedral

Al, which provides the Bronsted acid sites. The promising catalytic

activity of the materials encouraged us to discover these catalysts in

the synthesis of benzodiazepine and its derivatives (Scheme 1).

Table: 3.1. Textural parameters, acidity and the catalytic activity of the AlKIT-5 catalysts with different ‘Al’ content

S.No. Catalyst a0 (nm) nSi/nAl SBET (m2/g)

Vp (cm3/g) Dp BJH (nm)

Cage diameter

(nm)

Acidity (mmol/g)

Yield (%)

Gel Product

1 AlKIT-5(10) 18.44 7 10 989 0.68 6.0 12.0 0.50 97

2 AlKIT-5(28) 17.76 10 28 815 0.56 5.6 11.2 0.32 84

3 AlKIT-5(44) 16.97 12 44 713 0.45 5.2 10.3 0.14 75

4 SiO2-H2SO4

(10 mol %)

- - - - - - - - 97

ao unit cell constant; SBET specific surface area; Vp specific pore volume; Dp pore diameter; Reaction conditions: substrate = OPDA

and acetone, weight of the catalyst = 100 mg, reaction temperature = RT, solvent = acetonitrile.

Initially we have focused on the synthesis of 1,5-benzodiazepines

from o-phenylenediamines and ketones. Thus, OPDA was treated with

acetone in the presence of mesoporous AlKIT-5(10) in acetonitrile at

room temperature and the outcome results are also presented in Table

3.1. The catalyst was found to be highly active, affording 97% isolated

yield of 1,5-benzodiazepine in 30 min. In order to understand the role

of acidity ofAlKIT-5 on the yield of the final product, we carried out the

reaction using AlKIT-5 with different Al content. Among the catalysts

studied, AlKIT-5(10) was found to be highly active and selective. It

must also be noted that when the reaction was conducted without any

catalyst, the reaction was not occurred. These outcome results

indicate that the role and activity of the catalyst in this transformation

and dictate the activity of the catalyst. As AlKIT- 5(10) showed a much

higher activity than other catalysts used in this transformation under

the optimized reaction conditions, we have used AlKIT-5(10) for the

remaining reactions.

The synthesis of 1,5-benzodiazepines was also carried out over

different amounts of AlKIT-5(10) at room temperature for 30 min and

the outcome results are given in Table.3.2. Theweight of the catalyst

was increased between 25 and 150 mg. It was found that the yield

increases from 24% to 97% with increasing the weight of the catalyst

from 25 to 100 mg, respectively. This could be mainly due to the

availability of huge acidic sites on the porous surface of the

aluminosilicate catalysts as the weight of the catalyst is increased. It

must be noted that the yield of the product is remain constant with

the further increase of the weight of the catalyst from 100 to 150 mg.

Hence, we used the weight of the catalyst was 100 mg for the rest of

the studies.

Table: 3.2. Effect of the weight of AlKIT-5(10) on the synthesis of 1,5-

benzodiazepine

S.No. Weight of

AlKIT-5(10) (mg)

Reaction

time (min)

Yield (%)

1 25 30 24

2 50 30 52

3 100 30 97

4 150 30 97

Reaction conditions: substrate = OPDA and acetone, reaction temperature = RT, solvent = acetonitrile.

The effect of solvents on the synthesis of BDPs was also

investigated. Among various solvents like methylene chloride (87%),

tetrahydrofuran (THF) (89%), acetonitrile and methanol studied,

methanol and acetonitrile (97%) were found to be the excellent

solvents for this synthesis (Table 3.3, entry 1).

Table: 3.3. Synthesis of 1,5-benzodiazepines and its derivatives using silica gel supported sulfuric acid and AlKIT-

5(10) through a condensation reaction between a series of OPDA and various ketones

Entry Diamine (1) Ketone (2) Product (3) Timea

(min)

Yieldb

(%)

Timec

(min)

Yieldd

(%)

1 NH2

NH2

Acetone

HN

N3a

30 97 30 97

2 NH2

NH2

2-butatone

HN

N3b

40 95 60 95

3 NH2

NH2

2-pentatone

3c

HN

N

50 90 60 93

4 NH2

NH2

Methyl Iso Butyl

Ketone

HN

N3d

60 94 60 92

5 NH2

NH2

Acetophenone

HN

N3e

40 92 60 96

6 NH2

NH2

4-methyl

Acetophenone

HN

N

CH3

CH3

3f

50 96 60 96

7 NH2

NH2

4- Chloro

Acetophenone 3g

HN

N

Cl

Cl

50 95 60 95

8 NH2

NH2

Cyclopentanone

HN

N3h

60 92 60 92

9 NH2

NH2

2-Acetyl thiophene

3iN

HN

S

S

120 86 120 86

10 NH2

NH2

3-Acetyl thiophene

3j

N

HN

S

S

120 82 120 82

11 NH2

NH2Cl

Acetone

HN

N

3l

Cl

50 94 60 94

12 NH2

NH2Cl

2-butatone

HN

N

3k

Cl

60 92 60 92

13 NH2

NH2Cl

2-pentatone

3m

HN

NCl

120 88 120 88

14 NH2

NH2Cl

Methyl Iso Butyl

Ketone

HN

N3n

Cl

90 88 120 88

15

NH2

NH2Cl

Acetophenone

HN

N3o

Cl

120 90 120 92

16

NH2

NH2Cl

4-methyl

Acetophenone

HN

N

CH3

CH3

3p

Cl

120 90 120 90

17

NH2

NH2Cl

4- Chloro

Acetophenone 3q

HN

N

Cl

ClCl

120 85 120 86

18

NH2

NH2Cl

Cyclopentanone

HN

N3rCl

90 86 120 86

19

NH2

NH2Cl

2-Acetyl thiophene

3s N

HN

S

S

Cl

140 82 150 85

20 NH2

NH2Cl

3-Acetyl thiophene

3tN

HN

S

S

Cl

150 80 150 85

a Reaction time for the BDPs with silica gel supported sulfuric acid b Isolated yields for the BDPs with silica gel supported sulfuric acid c Reaction time for the BDPs with AlKIT-5

d Isolated yields for the BDPs with AlKIT-5

The excellent catalytic performance of the AlKIT-5(10) in the

synthesis of 1,5-benzodiazepine stimulated us to extend this process

for the synthesis of various derivatives of benzodiazepines using

various substituted OPDAs and a series of symmetrical and

unsymmetrical ketones and the results are shown in Table 3.3. In all

cases, the reactions are highly selective and are completed within 1.0–

2.5 h. The catalyst showed excellent activity in all the cases, affording

85–97% isolated yield of the corresponding derivatives of 1,5-

benzodiazepine. It was found that the catalyst showed superior

performance with high yields in a relatively shorter reaction time than

Ersorb-4 (E4), a clinoptylolite-type zeolite catalyst reported

previously.28 Furthermore, E4 needed a high temperature and a longer

reaction time to achieve high isolated yield of the final product

whereas AlKIT-5(10) was active even at room temperature. These

findings reveal the superior nature of our catalyst in this

transformation.

Chloro-substituted OPDA and substituted ketones were also used

with similar success to provide the corresponding benzodiazepines in

high yields, which are also of much interest with regard to biological

activity. Chloro-substituted benzodiazepines were prepared easily in

good yields by using this catalyst. Especially, chloro-substituted

OPDA and acetyl thiophenes were used to obtain the corresponding

thiophene derivatives of benzodiazepines. It was reported previously

that thiophene derivatives of 1,5-benzodiazepines possess good

biological activities.41 Cyclopentanone also worked well with chloro-

substituted OPDA.

It is also significant to note down the work-up of the reaction

mixture is very simple. The catalyst can be filtered out easily and the

solvent was evaporated. Recycling experiments were conducted to find

out the stability of the catalyst after the reaction. The catalyst was

easily separated by centrifuge and reused after activation at 5000C for

3.0–4.0 h. The efficiency of the recovered catalyst was verified with the

reaction of OPDA and acetone (Entry 1). Using the fresh catalyst, the

yield of product (3a) was 97%, while the recovered catalyst in the three

subsequent recyclization gave the yields of 95%, 93% and 90%,

respectively. The small reduction in the catalytic activity after three

cycles can be mainly due to the loss of the catalyst or catalyst

structure during the recovery process. These results reveal that the

catalyst can be recycled several times without lacking its activity. The

AlKIT-5 with 3D structure having better recyclable nature than silica

gel supported sulfuric acid.

Structural assignments of compounds (Table 3.3, 3a-3t) were

made based on IR, 1H NMR and MALDI-MS spectral data.

The compound 4a IR spectrum (Fig.5.1) showed the absorption

peaks at 3295, 2964, 1633, 1475 and 770 cm-1. The peak at 3295

cm−1 indicates the occurrence of –NH group in diazepine ring, peak at

2964 cm−1 indicates CH stretching, peak at 1633 cm-1 indicates the

presence of >C=N, peak at 1475 cm-1 indicates the presence of

conjugated >C=C< stretching, peak at 770 cm-1 assigns the aromatic –

CH bending and these peaks are confirmed the formation of diazepine.

The 1H NMR spectrum (300 MHz, CDCl3) for compound 3a (Fig.3.4)

showed the signals at δ 1.25 (s, 6H, 2CH3) was assigned to two methyl

groups on 4th position of benzodiazepine ring and signal at δ 2.14 (s,

2H, -CH2-) was assigned to -CH2- group in diazepine ring, and signal

at δ 2.28 (s, 3H, -CH3) indicates the methyl protons at 2nd position in

diazepine ring, and signal at δ 3.40 (brs, 1H, -NH) indicates the

presence of -NH proton in diazepine ring. The remaining signals at δ

6.65 (d, 1H, J = 8.2 Hz, Ar-H), 6.88-6.92 (m, 2H, J = 3.2 Hz, Ar-H),

7.05 (d, 1H, J = 8.2 Hz, Ar-H) confirms the presence of aromatic

protons.

MALDI-MS spectrum (Fig.3.5) for compound 3a showed molecular

ion peak at m/z [M+] =188, corresponds to molecular formula

C12H16N2 and which is equal to calculated mass 188.27g/mol.

All other compounds spectral data results are presented in

experimental section.

3.3. Conclusions:

BDPs are synthesized by using silica gel supported sulfuric acid

and AlKIT-5 catalysts. These two catalysts are heterogeneous and

additional to the present existing procedures. We designed and

synthesized some biologically active chloro and thiophene derivatives

of BDPs. We have established for the first time the synthesis of 1,5-

benzodiazepine using silica gel supported sulfuric acid and AlKIT-5

catalysts through a condensation reaction between substituted OPDA

and a series of symmetrical and unsymmetrical ketones at room

temperature in acetonitrile solvent. But AlKIT-5 showed better

performance in terms of yields and recyclability. The AlKIT-5 catalyst

was found to be highly active and selective, recyclable, affording a

high yield of benzodiazepines. The effect of the ‘Al’ content of the

catalyst and the catalyst concentration on the above process was

investigated. The catalyst was also successfully employed for the

preparation of various derivatives of 1,5-benzodiazepine using

substituted OPDAs and various ketones. In all cases, the reactions are

highly selective and are completed within 1.0–2.5 h. The catalyst

showed excellent activity in all the cases, affording 85–97% isolated

yield of the corresponding derivatives of 1,5-benzodiazepine. The high

activity of the catalyst is mainly due to its high acidity; excellent

textural parameters such as high surface area, large pore volume and

cage type 3D porous structure.

This method is quite simple and selective. The catalyst gave high

isolated yield of the derivatives of 1,5-benzodiazepine in a shorter

reaction time at room temperature and can be recycled several times.

We strongly hope that the highly stable AlKIT-5 catalyst could pave

the way for the production of 1,5-benzodiazepine and its derivatives

and create the platform for the commercialization of the process by

replacing the existing homogenous catalysts which suffered from

various drawbacks such as corrosion, toxicity, waste production, and

a high cost.

3.4. Experimental:

General procedure for the synthesis of 1,5-benzodiazepines: A

mixture of OPDA (1) (1 mmol), ketone (2) (2.5 mmol) and AlKIT-5 (100

mg) was stirred in acetonitrile (4 ml) at room temperature until thin

layer chromatography indicated the reaction was completed. Ethyl

acetate (10%) in hexane was used as the mobile phase and both the

reactant and the final product were spotted on the TLC plate. The

product retention factor (Rf) was observed at around 0.4-0.5. The

disappearance of the reactant spot on the TLC plate indicates the

completion of the reaction. After completion of the reaction, ethyl

acetate (20 ml) was added to the reaction mixture and the catalyst was

recovered by filtration. The organic layer was concentrated and the

crude product was purified by silica gel column chromatography using

ethyl acetate-n-hexane (1:9) as eluent to afford the desired product (3).

The spectral data of entry 1, 2, 4, 5, 8 and 11,42 entry 9, 10,43 and

entry 6, 7 and 1544 in Table 3.3 are in full agreement with the

reported literature and the spectral data of all the compounds are

described in the following sections.

Entry 1: 2,2,4-Trimethyl-2,3-duhydro-1H-1,5-benzodiazepine (3a):

To a mixture of o-phenylenediamine (0.108 g, 1 mmol), acetone (0.145

g, 2.5 mmol) and AlKIT-5 (0.100 g) was stirred at room temperature

for 30 min under 4 mL of acetonitrile solvent. The completion of

reaction was monitored by TLC. After completion of the reaction, 20

ml of ethyl acetate was added to the reaction mixture and the catalyst

was recovered by filtration. The organic layer was concentrated and

the crude product was purified by silica gel column chromatography

using ethyl acetate–n-hexane (1:9) as eluent to afford the desired

product 3a as yellow solid crystals (0.182 g, 97% yield): m.p. 137-

139°C. IR (KBr): νmax 3295, 2964, 1633, 1591, 1475, 770 cm−1

(Fig.3.3). 1HNMR (300 MHz, CDCl3): δ 1.25 (s, 6H, 2CH3), 2.14 (s, 2H, -

CH2-), 2.28 (s, 3H, -CH3), 3.40 (brs, 1H, -NH), 6.65 (d, 1H, J = 8.2 Hz,

Ar-H), 6.90 (d, 2H, J = 3.2 Hz, Ar-H) 7.05 (d, 1H, J = 8.2 Hz, Ar-H)

ppm (Fig.3.4). MALDI-MS: m/z [M+] = 188 (Fig.3.5). M.F. C12H16N2.

Entry 2: 2,4-Diethyl-2-methyl -2,3-dihydro-1H-1,5-benzo

diazepine (3b): To a solution of o-phenylenediamine (0.108 g,

1 mmol), 2-butanone (0.180 g, 2.5 mmol), and AlKIT-5 (0.100 g) in 4

mL of acetonitrile was added. The resulting mixture was stirred for 60

min at room temperature. The completion of the reaction was

monitored by TLC. 20 ml of ethyl acetate was added to the reaction

mixture and the catalyst was recovered by filtration. The mixture was

extracted from ethyl acetate, washed with water, brine and dried over

magnesium sulfate. The organic layer was concentrated and the crude

product was purified by silica gel column chromatography using ethyl

acetate – n-hexane (1:9) as eluent to afford the desired benzodiazepine

3b as a yellow solid (0.205 g, 95% yield): m.p. 137–139°C. IR (KBr):

νmax 3341, 2966, 1592, 1375, 750 cm−1 (Fig.3.6). 1HNMR (300 MHz,

CDCl3): δ 0.95 (t, 3H, J = 3.5 Hz, -CH3), 0.99-1.05 (m, 6H, 2CH3), 1.58

-1.64 (m, 2H, -CH2-), 2.12-2..21 (m, 2H, -CH2-), 2.55-2.63 (m, 2H, -

CH3), 3.57 (brs, 1H), 6.70-6.74 (m, 1H, Ar-H), 6.94-7.00 (m, 2H, Ar-H),

7.09–7.15 (m, 1H, Ar-H) ppm (Fig.3.7). MALDI-MS: m/z [M+] = 216

(Fig.3.8). M.F. C14H20N2.

Entry 3: 2-methyl-2,4-dipropyl -2,3-dihydro-1H-1,5-benzo

diazepine (3c): This compound was prepared as described in general

procedure from a solution of o-phenylenediamine (0.108 g, 1mmol),

and 2-pentanone (0.215 g, 2.5 mmol) in acetonitrile (4 mL) and AlKIT-

5 (0.100 g) were added. The reaction mixture was stirred at room

temperature for 60 min. The completion of reaction was monitored by

TLC. The catalyst was filtered off and phases were separated and the

aqueous layer was extracted with EtOAc (3x15 mL). The combined

organic phase was dried over MgSO4 and concentrated. The residue

was chromatographed using silica gel, eluting with n-hexane-EtOAc

(9:1), to give the desired product 3c as a yellow solid (0.227 g, 93%

yield): m.p. 140–142°C. IR (KBr): νmax 3341, 3060, 1589, 1371, 687

cm−1 (Fig.3.9). 1HNMR (300 MHz, CDCl3): δ 0.92-0.98 (m, 6H, 2CH3),

1.13 (s, 3H, -CH3), 1.18-1.36 (m, 4H, 2CH2), 1.52-1.62 (m, 1H, -CHa),

2.10-2.20 (m, 1H, -CHb), 2.51-2.59 (m, 4H, 2CH2), 3.05 (brs, 1H, -NH),

6.70-6.73 (m, 1H, Ar-H), 6.95-6.98 (m, 2H, Ar-H), 7.12-7.14 (m, 1H,

Ar-H) ppm (Fig.3.10). MALDI-MS: m/z [M+] = 244 (Fig.3.11). Anal.

Calcd. for C16H24N2: C, 78.64; H, 9.90; N, 11.46. Found: C, 78.50; H,

9.85; N, 11.

Entry 4: 2,4-diisobutyl -2methyl- -2,3-dihydro-1H-1,5-benzo

diazepine (3d): This compound was prepared according to the gereal

procedure, from o-phenylenediamine (0.108 g, 1 mmol) and methyl

isobutyl ketone (MIBK) (0.250 g, 2.5 mmol), was dissolved in

acetonitrile (4 ml) and AlKIT-5 (0.100 g) were added. The reaction

mixture was allowed to stir at room temperature for 60 min. The

completion of the reaction was monitored by TLC. 20 ml of ethyl

acetate was added to the reaction mixture and the catalyst was

recovered by filtration. The organic layer was concentrated and the

crude product was purified by silica gel column chromatography using

ethyl acetate–n-hexane (1:9) as eluent to afford resulting

benzodiazepine 3d yellow solid (0.250 g, 92% yield): mp -145-147°C.

IR (KBr): νmax 3403, 2955, 2353, 1674, 1464, 750 cm−1 (Fig.3.12).

1HNMR (300 MHz, CDCl3): δ 0.90-1.01 (m, 12H, 4CH3), 1.32 (s, 3H, -

CH3), 1.44-1.58 (m, 2H, 2CH of MIBK), 1.71-1.73 (m, 2H,-CH2-), 2.11-

2.30 (m, 2H,-CH2-), 2.43-2.46 (m, 2H,-CH2-), 3.13 (brs, 1H, -NH),

6.67-6.70 (m, 1H, Ar-H), 6.94-6.97 (m, 2H, Ar-H), 7.11-7.15 (m, 1H,

Ar-H) ppm (Fig.3.13). MALDI-MS: m/z[M+] = 272 (Fig.3.14). M.F.

C18H28N2.

Entry 5: 2-Methyl-2,4-diphenyl -2,3-dihydro-1H -1,5-benzo

diazepine (3e): To the 4 mL of acetonitrile, o-phenylenediamine (0.108

g, 1 mmol), acetophenone (0.300 g, 2.5 mmol) and AlKIT-5 (0.100 g)

were combined in a 100 mL round-bottom flask. The reaction mixture

was stirred for 60 min at room temperature. After completion of

reaction, 20 ml of ethyl acetate was added to the reaction mixture and

the catalyst was recovered by filtration. The organic layer was

concentrated and the crude product was purified by silica gel column

chromatography using ethyl acetate– n-hexane (1:9) as eluent to afford

the desired product 3e yellow crystalline solid. (0.299 g, 96% yield):

m.p. 152–154°C. IR (KBr): νmax 3278, 2960, 1634, 1466, 749 cm−1

(Fig.3.15). 1HNMR (300 MHz, CDCl3): δ 1.31 (s, 3H, -CH3), 2.29 (d, 1H,

J = 12.8 Hz, -CHa), 2.58 (d, 1H, J = 12.8 Hz, -CHb), 3.34 (brs, 1H, -

NH), 6.68-6.78 (m, 3H, Ar-H), 7.01-7.31 (m, 4H, Ar-H), 7.42-7.46 (m,

4H, Ar-H), 7.92-8.03 (m, 3H, Ar-H) ppm (Fig.3.16). MALDI-MS: m/z

[M+] = 312 (Fig.3.17). M.F. C22H20N2.

Entry 6: 2-Methyl-2,4-ditoluyl -2,3-dihydro-1H-1,5-benzo

diazepine (3f): The title compound was prepared using o-phenylene-

diamine (0.108 g, 1 mmol), 4-methyl acetophenone (0.335 g, 2.5

mmol), catalyst AlKIT-5 (0.100 g) and 4 mL of acetonitrile were

combined in a 100mL round-bottom flask. The reaction mixture was

stirred at room temperature for 60 min. The completion of reaction

was monitored by TLC. 20 ml of ethyl acetate was added to the

reaction mixture and the catalyst was recovered by filtration. The

organic layer was concentrated and the crude product was purified by

silica gel column chromatography using ethyl acetate – n-hexane (1:9)

as eluent to give desired product 3f as a pale yellow crystalline solid

(0.326 g, 96% yield): m.p. 210-2120C. IR(KBr): νmax 3307, 2974, 1603,

1471, 759 cm−1 (Fig.3.18). 1HNMR (300 MHz, CDCl3): δ 1.32 (s, 6H, -

CH3 of 4-methyl acetophenone), 2.40 (s, 3H, -CH3), 2.71-2.72 (s, 2H, -

CH2-), 3.05 (brs, 1H, -NH), 6.76-6.80 (m, 1H, Ar-H), 6.98-7.07 (m, 3H,

Ar-H), 7.23-7.33 (m, 5H, Ar-H), 7.84-7.93 (m, 3H, Ar-H) ppm

(Fig.3.19). MALDI-MS: m/z [M+] = 340 (Fig.3.20). M.F. C24H24N2.

Entry 7: 2,4-bis(4-chlorophenyl) -2-methyl-2,3-dihydro -1H-1,5-

benzodiazepine (3g): To a mixture of o-phenylenediamine (0.108 g, 1

mmol), 4-chloroacetophenone (0.385 g, 2.5 mmol) and AlKIT-5

(0.100 g) was stirred for 60 min at room temperature under 4 mL of

acetonitrile solvent. The completion of reaction was monitored by TLC.

After completion of reaction, 20 ml of ethyl acetate was added to the


organic layer was concentrated, dried over MgSO4 and the crude

product was purified by silica gel column chromatography using ethyl

acetate–n-hexane (1:9) as eluent to afford the desired product 3g as

pale yellow crystalline solid (0.361 g, 95% yield): m.p.143–145°C. IR

(KBr): νmax 3332, 2974, 1607, 1468, 762 cm−1 (Fig.3.21). 1HNMR (300

MHz, CDCl3): δ 1.73 (s, 3H, -CH3), 2.86 (d, 1H, J = 13.3 Hz, -CHa),

3.04 (d, 1H, J = 13.3 Hz, -CHb), 3.42 (brs, -NH), 6.80–6.84 (m, 1H, Ar-

H), 7.02-7.12 (m, 2H, Ar-H), 7.18-7.22 (m, 4H, Ar-H), 7.27-7.30 (m,


[M+] = 380 (Fig.3.23). M.F. C22H18Cl2N2.

Entry 8: 10-Spirocyclopentane -1, 2, 3, 9, 10, 10a -hexahydro

benzo [b] cyclopenta [e][1,4]-diazepine (3h): To a solution of o-

phenylenediamine (0.108 g, 1 mool), cyclopentanone (0.210 g, 2.5

mmol) and AlKIT-5 (0.100 g) in 4 mL of acetonitrile was added. The

resulting mixture was stirred for 60 min at room temperature. The

completion of reaction was monitored by TLC. 20 ml of ethyl acetate

was added to the reaction mixture and the catalyst was recovered by

filtration. The organic layer was extracted with ethyl acetate,

concentrated and dried over magnesium sulphate. The crude product

was purified by silica gel column chromatography using ethyl acetate-

n-hexane (1:9) as eluent to yield desired benzodiazepine 3h as a yellow

solid (0.220 g, 92% yield): m.p. 138–140°C. IR (KBr) νmax 3326, 2950,

1629, 1371, 676 cm−1 (Fig.3.24). 1HNMR (300 MHz, CDCl3): δ 1.25 (s,

1H, -CH of diazepine ring), 1.66–2.65 (m, 14H, 7CH2), 2.78 (brs, 1H, -

NH), 6.64-6.94 (m, 1H, Ar-H), 7.25 (dd, J = 1.4 Hz, 7.2 Hz, 2H, Ar-H),

7.85 (d, J = 7.2 Hz, 1H, Ar-H) ppm (Fig.3.25). MALDI-MS: m/z [M+]

= 240 (Fig.3.26). M.F. C16H20N2.

Entry 9: 2-Methyl -2,4-di(thiophen-2-yl) -2,3-dihydro-1H-1,5-

benzodiazepines (3i): To a solution of o-phenylenediamine (0.108 g, 1

mmol) and 2-acetyl thiophene (0.315 g, 2.5 mmol) in acetonitrile (4

mL) and AlKIT-5 (0.100 g) were added. The reaction mixture was

stirred at room temperature for 120 min. The completion of reaction

was monitored by TLC. The catalyst was filtered off and phases were

separated and the aqueous layer was extracted with EtOAc (3x15 mL).

The combined organic phase was dried over MgSO4 and concentrated.

The residue was chromatographed using silica gel, eluting with

hexane-EtOAc (9:1), to give the desired product 3i as a brown solid

(0.278 g, 86% yield): m.p. 92–93°C. IR (KBr): νmax 3373, 3106, 1615,

1487, 760 cm−1 (Fig.3.27). 1HNMR (300 MHz, CDCl3): δ 1.60 (s,1H, -

CH2a), 2.16 (s, 1H,- CH2b), 2.33 (s, 3H, -CH3), 3.73 (brs, 1H, -NH),

6.60–6.66 (m, 2H, thiophenyl-H), 6.71–6.99 (m, 4H, thiophenyl-H),

7.08-7.12 (m, 1H, Ar-H), 7.24-7.25 (m, 1H, Ar-H), 7.43-7.48 (m, 2H,

Ar-H) ppm (Fig.3.28). MALDI-MS: m/z [M+] = 324. M.F (Fig.3.29).

C18H16N2S2.

Entry 10: 2-Methyl -2,4-di(thiophen-3-yl) -2,3-dihydro-1H -1,5-

benzodiazepine (3j): o-phenylenediamine (0.108 g, 1 mmol) and 3-

acetyl thiophene (0.315 g, 2.5 mmol) was dissolved in acetonitrile (4

mL) and AlKIT-5 (0.100 g) were added. The reaction mixture was

allowed to stir for 120 min at room temperature. The completion of

reaction was monitored by TLC. 20 ml of ethyl acetate was added to

the reaction mixture and the catalyst was recovered by filtration. The

organic layer was concentrated and the crude product was purified by

silica gel column chromatography using ethyl acetate– n-hexane (1:9)

as eluent to afford the desired product 3j light yellow solid (0.265 g,

82% yield): m.p.112-114°C. IR (KBr) νmax 3303, 2920, 1600, 1468, 763

cm−1 (Fig.3.30). 1HNMR (300 MHz, CDCl3): δ 1.65 (s, 1H, -CHa), 1.74 (s,

1H, -CHb), 2.54 (s, 3H, -CH3), 3.46 (brs, 1H, -NH), 6.78-7.25 (m, 6H,

thiophenyl-H), 7.26-8.04 (m, 4H, Ar-H) ppm (Fig.3.31). MALDI-MS:

m/z [M+] = 324 (Fig.3.32). M.F. C18H16N2S2.

Entry 11: 2,2,4-Trimethyl -2,3-dihydro-7-chloro-1H-1,5-benzo

diazepine (3k): To a mixture of 4-chloro-1,2-phenylenediamine (0.142

g, 1 mmol), acetone (0.145 g, 2.5 mmol) and AlKIT-5 (0.100 g) was

stirred at room temperature for 60 min under 4 mL of acetonitrile

solvent. The completion of reaction was monitored bt TLC. After

completion of the reaction, 20 ml of ethyl acetate was added to the


mixture was extracted from ethyl acetate, washed with water, brine

and dried over magnesium sulfate. The organic layer was concentrated

and the crude product was purified by silica gel column

chromatography using ethyl acetate–n-hexane (1:9) as eluent to afford

the desired product 3k as a yellow solid (0.209 g, 94%): m.p. 92-94°C.

IR (KBr): νmax 3282, 2962, 1630, 1453, 750 cm−1 (Fig.3.33). 1HNMR

(300 MHz, CDCl3): δ 1.33 (m, 6H, 2CH3), 2.22 (t, 2H, -CH2-), 2.34 (s,

3H, -CH3), 3.01 (brs, 1H, -NH), 6.63-6.72 (m, 1H,Ar-H), 6.90-6.95 (m,


[M+] = 222 (Fig.3.36). M.F. C12H15ClN2.

Entry 12: 7-chloro -2,4-diethyl- 2-methyl -2,3-dihydro-1H-1,5-

diazepine (3l): This compound was prepared as described in general

procedure from a solution of 4-chloro-1,2-phenylenediamine (0.142 g,

1 mmol), 2-butanone (0.180 g, 2.5 mmol) and AlKIT-5 (0.100 g) in 4

mL of acetonitrile was added. The resulting mixture was stirred for 60

min at room temperature. The completion of reaction was monitored

by TLC. 20 ml of ethyl acetate was added to the reaction mixture and

the catalyst was recovered by filtration. The organic layer was



the desired product 3l as a yellow solid (0.230 g, 92% yield): m.p. 94-

96°C. IR (KBr): νmax 3424, 2971, 1596, 1499, 798 cm-1 (Fig.3.36).

1HNMR (300 MHz, CDCl3): δ 0.93 (t, J = 6.7 Hz, 3H, -CH3), 1.24-1.25

(m, 6H, 2CH3), 1.60-1.65 (m, 2H, -CH2-), 2.22 (m, 2H, -CH2-), 2.59 (q,

2H, J = 3.2 Hz, -CH2-), 3.10 (brs,1H, -NH), 6.62–6.71 (m, 1H, Ar-H),

6.88-6.93 (m, 1H, Ar-H), 7.04-7.14 (m, 1H, Ar-H) ppm (Fig.3.37).

MALDI-MS: m/z [M+] = 250 (Fig.3.38). Anal. Calcd. for C14H19ClN2: C,

67.05; H, 7.64; N, 11.17. Found: C, 67.00; H, 7.54; N, 11.10.

Entry 13: 7-chloro-2-methyl -2,4-dipropyl -2,3-dihydro-1H-1,5-

benzodiazepine (3m): To a solution of 4-choloro-1,2-phenylene

diamine (0.142 g, 1 mmol) and 2-pentanone (0.215 g, 2.5 mmol) in

acetonitrile (4 mL) and AlKIT-5 (0.100 g) were added. The reaction

mixture was stirred at room temperature for 120 min. The completion

of reaction was monitored by TLC. The catalyst was filtered off and

phases were separated and the aqueous layer was extracted with

EtOAc (3X15 mL). The combined organic phase was dried over MgSO4

and concentrated. The residue was chromatographed using silica gel,

eluting with hexane-EtOAc (9:1), to give the desired product 3m as a

reddish yellow solid (0.244 g, 88% yield): m.p. 160-162°C. IR (KBr):

νmax 3338, 2959, 1638, 1468, 806 cm-1 (Fig.3.39). 1HNMR (300 MHz,

CDCl3): δ 0.82-0.92 (m, 6H, 2CH3), 1.15 (s, 3H, -CH3), 1.23-1.49 (m,

4H, 2CH2), 1.58-1.68 (m, 2H, -CH2-), 2.02-2.10 (m, 2H, -CH2-), 2.39-

2.45 (m, 2H, -CH2-), 3.10 (brs, 1H, -NH), 6.51–6.60 (m, 1H, Ar-H),


MALDI-MS: m/z [M+ ] = 278 (Fig.3.41). Anal. Calcd. for C16H23ClN2:

C, 68.92; H, 8.31; N, 10.05. Found: C, 68.83; H, 8.21; N,10.00.

Entry 14: 7-chloro-2,4-diisobutyl -2-methyl -2,3-dihydro-1H-1,5-

benzodiazepine (3n): This compound was prepared according to the

general procedure, 4-chloro-1,2-phenylenediamine (0.142 g, 1 mmol)

and methyl isobutyl ketone (0.250 g, 2.5 mmol) was dissolved in


mixture was allowed to stir at room temperature for 120 min. The



filtration. The mixture was extracted from ethyl acetate, washed with

water, brine and dried over magnesium sulfate. The organic layer was



the desired product 3n as light yellow solid (0.269 g, 88% yield):

m.p.140-142°C. IR (KBr): νmax 3196, 2959, 1589, 1496, 817 cm-1.

(Fig.3.42). 1HNMR (300 MHz, CDCl3): δ 0.98-1.02 (m, 12H, 4CH3), 1.25

(m, 2H, 2CH), 1.32 (s, 3H, -CH3), 1.70-1.73 (m, 2H, -CH2-), 2.15-2.20

(m, 2H, -CH2-), 2.38-2.42 (m, 2H, -CH2-), 3.50 (brs, 1H, -NH), 6.60–

6.67 (m, 1H, Ar-H), 6.86-6.94 (m, 1H, Ar-H), 7.04-7.13 (m, 1H, Ar-H)

ppm (Fig.3.43). MALDI-MS: m/z [M+] = 306 (Fig.3.44). Anal. Calcd. for

C18H27ClN2: C, 70.45; H, 8.87; N, 9.13. Found: C, 70.35; H, 8.76; N,

9.09.

Entry 15: 7-chloro-2-methyl -2,4-diphenyl-2,3-dihydro-1H-1,5-

benzodiazepine (3o): To the 4 mL of acetonitrile, 4-chloro-1,2-

phenylenediamine (0.142 g, 1 mmol), acetophenone (0.300 g, 2.5

mmol) and AlKIT-5 (0.100 g) were combined in a 100mL round-bottom

flask. The reaction was stirred at room temperature for 120 min. After

completion of reaction, 20 ml of ethylacetate was added to the reaction

mixture and the catalyst was recovered by fitration. The organic layer

was concentrated and the crude product was purified by silica gel

column chromatography using ethyl acetate – n-hexane (1:9) as eluent

to afford the desired product 3o yellow solid. (0.318 g, 92% yield):

m.p. 121–123°C. IR (KBr): νmax 3352, 3066, 1584, 1457, 835 cm-1

(Fig.3.45). 1HNMR (300 MHz, CDCl3): δ 1.76 (s, 3H, -CH3), 2.93-2.99

(d, 1H, J = 12.8 Hz, -CHa), 3.10-3.18 (d, 1H, J = 12.8 Hz, -CHb), 3.59

(brs, 1H, -NH), 6.83–6.84 (m, 1H, Ar-H), 6.96–7.04 (m, 1H, Ar-H),


MALDI-MS: m/z [M+]=346 (Fig.3.47). M.F. C22H19ClN2.

Entry 16: 7-chloro-2methyl -2,4-dip-toluyl -2,3-dihydro-1H-1,5-

benzodiazepine (3p): The title compound was prepared using 4-

chloro-1,2-phenylenediamine (0.142 g, 1 mmol), 4-methylaceto-

phenone (0.335 g, 2.5 mmol), catalyst AlKIT-5 (0.100 g) and 4 mL of

acetonitrile were combined in 100 mL round-bottom flask. The

reaction mixture was stirred at room temperature for 120 min. The



filtration. The organic layer was concentrated and the crude product

was purified by silica gel column chromatography using ethyl acetate

– n-hexane (1:9) as eluent to afford the desired product 3p as a pale

yellow solid (0.336 g, 90% yield): m.p. 138-140°C, IR(KBr): νmax 3318,

2955, 1604, 1444, 817 cm-1 (Fig.3.48). 1HNMR (300 MHz, CDCl3): δ

1.72 (s, 3H, -CH3), 2.17 (s, 2H, -CH2-), 2.33 (s, 6H, 2CH3 of 4-methyl

acetophenone), 3.00 (brs, 1H, -NH), 6.80–6.81 (m, 1H, Ar-H), 7.06-

7.10 (m, 5H, Ar-H), 7.42-7.53 (m, 5H, Ar-H) ppm (Fig.3.49). MALDI-

MS: m/z [M+] = 374 (Fig.3.50). Anal. Calcd. for C24H23ClN2: C, 76.89;

H, 6.18; N, 7.47. Found: C, 76.79; H,6.08; N, 7.37.

Entry 17: 7-chloro-2,4-bis(4-chlorophenyl)-2-methyl -2,3-dihydro-

1H-1,5-benzodiazepine (3q): To a mixture of 4-chloro-1,2-phenylene

diamine (0.142 g, 1 mmol), 4-chloro acetophenone (0.385 g, 2.5 mmol)

and AlKIT-5 (0.100 g) was stirred for 120 min at room temperature

under 4 mL of acetonitrile solvent. The completion of reaction was

monitored by TLC. After completion of reaction, 20 ml of ethyl acetate




– n-hexane (1:9) as eluent to afford the desired product 3q as a yellow

solid (0.356 g, 86% yield): m.p. 145-147°C, IR (KBr): νmax 3265, 2967,

1588, 1475, 829 cm-1 (Fig.3.51). 1HNMR (300 MHz, CDCl3): δ 1.75 (s,

3H, -CH3), 2.86 (d, 1H, J = 12.8 Hz, -CH2-), 3.14 (d, 1H, J = 12.8 Hz, -

CH2-), 3.50 (brs, 1H, -NH), 6.74–6.84 (m, 1H, Ar-H), 6.98-7.06 (m,

1H, Ar-H), 7.19-7.29 (m, 4H, Ar-H), 7.42-7.52 (m, 5H, Ar-H) ppm

(Fig.3.52). MALDI-MS: m/z [M+] = 415 (Fig.3.53). Anal. Calcd. for

C22H17Cl3N2: C. 63.56; H, 4.12; N, 6.74. Found: C, 63.46; H, 4.06; N,

6.64.

Entry 18: 7-chloro-10-Spirocyclopentane -1, 2, 3, 9, 10, 10a

pentahydrobenzo [b] cyclopenta [e] [1,4]-diazepine (3r): To a

solution of 4-chloro-1,2-phenylenediamine (0.142 g, 1mmol),

cyclopentanone (0.210 g, 2.5 mmol), and AlKIT-5 (0.100 g) in 4 mL of

acetonitrile was added. The resulting mixture was stirred for 120 min

at room temperature. The completion of reaction was monitored by

TLC. 20 ml of ethyl acetate was added to the reaction mixture and the

catalyst was recovered by filtration. The organic layer was


chromatography using ethyl acetate – n-hexane (1:9) as eluent to

afford the desired product 3r as a yellow solid (0.235 g, 86% yield):

m.p. 156-158°C. IR (KBr): νmax 3342, 2959, 1650, 1499, 837 cm-1

(Fig.3.54). 1HNMR (300 MHz, CDCl3): δ 1.88-2.10 (m, 12H, 6CH2),

2.90-2.95 (d, J = 13.2 Hz, 1H, -CH), 3.90-4.25 (m, 2H, -CH2-), 3.05

(brs, 1H, -NH), 6.63–6.64 (m, 1H, Ar-H), 6.73-6.77 (m, 1H, Ar-H),

7.87-7.90 (m, 1H, Ar-H) ppm (Fig.3.55). MALDI-MS: m/z [M+] = 274

(Fig.3.56). Anal. Calcd. for C16H19ClN2: C, 69.93; H, 6.97; N, 10.19.

Found: C, 69.83; H, 6.87; N, 10.09.

Entry 19: 7-chloro -2-methyl -2,4-di(thiophen-2-yl) -2,3-dihydro-

1H-1,5-benzodiazepine (3s): To a solution of 4-chloro-1,2-

phenylenediamine (0.142 g, 1 mmol) and 2-acetyl thiophene (0.315 g,

2.5 mmol) in acetonitrile (4 mL) and AlKIT-5(0.100 g) were added. The

reaction mixture was stirred at room temperature for 150 min. The

completion of reaction was monitored by TLC. The catalyst was filtered

off and phases were separated and the aqueous layer was extracted

with EtOAc (3X15 mL). The combined organic phase was dried over

MgSO4 and concentrated. The residue was chromatographed using

silica gel, eluting with n-hexane–EtOAc (9:1), to give the desired

product 3s as a yellow solid (0.304 g, 85% yield): m.p. 130-132°C, IR

(KBr): νmax 3303, 2967, 1577, 1471, 705 cm-1 (Fig.3.57). 1HNMR (300

MHz, CDCl3): δ 1.83 (s, 3H, -CH3), 2.99 (d, 1H, J = 13.2 Hz, -CH2-),

3.08 (d, 1H, J = 13.2 Hz, -CH2-), 3.58 (brs, 1H, -NH), 6.79–6.82 (m,

1H, Ar-H), 6.90-6.93 (m, 2H, Ar-H), 7.01-7.10 (m, 4H, Ar-H), 7.30-

7.40 (m, 1H, Ar-H), 7.63-7.69 (m, 1H, Ar-H) ppm (Fig.3.58). MALDI-

MS: m/z [M+] = 358 (Fig.3.59). Anal. Calcd. for C18H15ClN2S2: C, 60.24;

H, 4.21; N, 7.81. Found: C, 60.14; H, 4.15; N, 7.71.

Entry 20: 7-chloro-2-methyl -2,4-di(thiophen-3-yl) -2,3-dihydro-

1H-1,5-benzodiazepine (3t): 4-chloro-1,2-phenylenediamine (0.142 g,

1 mmol) and 3-acetyl thiophene (0.315 g, 2.5 mmol) was dissolved in


mixture was allowed to stir for 150 min at ambient temperature. The





– n-hexane (1:9) as eluent to afford the desired benzodiazepine 3t as

light yellow crystalline solid (0.304 g, 85% yield): m.p.120-122°C, IR

(KBr): νmax 3394, 2962, 1592, 1469, 781 cm-1 (Fig.3.60). 1HNMR (300

MHz, CDCl3): δ 1.73 (s, 3H, -CH3), 2.86 (d, 1H, J = 13.2 Hz, CH2), 2.93

(d, 1H, J = 13.2 Hz, -CH2-), 3.43 (brs, 1H, -NH), 6.70 – 6.79 (m, 1H,

Ar-H), 6.99-7.01 (m, 2H, Ar-H), 7.10-7.17 (m, 1H, Ar-H), 7.20-7.30 (m,

5H, Ar-H) ppm (Fig.3.61). MALDI-MS: m/z [M+] = 358 (Fig.3.62). Anal.

Calcd. for C18H15ClN2S2: C, 60.24; H, 4.21; N, 7.81. Found: C, 60.14;

H, 4.15; N, 7.71.

Fig: 3.1. 1H NMR spectrum of o-phenylenediamine

Fig: 3.2. 1H NMR spectrum of 4-Chloro-1,2-phenylenediamine

Fig: 3.3. IR spectrum of 2,2,4-Trimethyl-2,3-dihydro-1H-1,5-

benzodiazepine (3a)

Fig: 3.4. 1H NMR spectrum of 2,2,4-Trimethyl-2,3-dihydro-1H-1,5-

benzodiazepine (3a)

Fig: 3.5. Mass spectrum of 2,2,4-Trimethyl-2,3-dihydro-1H-1,5-

benzodiazepine (3a) (MW=188)

Fig: 3.6. IR spectrum of 2,4-Diethyl-2-methyl-2,3-dihydro-1H-1,5-

benzodiazepine (3b)

Fig: 3.7. 1H NMR spectrum of 2,4-diethyl-2-methyl-2,3-dihydro-1H-1,5-benzodiazepine (3b)

Fig: 3.8. Mass spectrum of 2,4-Diethyl-2-methyl-2,3-dihydro-1H-1,5-benzodiazepine (3b) (MW=216)

Fig: 3.9. IR spectrum of 2-methyl-2,4-dipropyl-2,3-dihydro-1H-1,5-

benzodiazepine (3c)

Fig: 3.10. 1H NMR spectrum of 2-methyl-2,4-dipropyl-2,3-dihydro-1H-

1,5-benzodiazepine (3c)

Fig: 3.11. Mass spectrum of 2-methyl-2,4-dipropyl-2,3-dihydro-1H-

1,5-benzodiazepine (3c) (MW=244)

Fig: 3.12. IR spectrum of 2,4-diisobutyl-2-methyl-2,3-dihydro-1H-1,5-

benzodiazepine (3d)

Fig: 3.13. 1H NMR spectrum of 2,4-diisobutyl-2-methyl-2,3-dihydro-

1H-1,5-benzodiazepine (3d)

Fig: 3.14. Mass spectrum of 2,4-diisobutyl-2-methyl-2,3-dihydro -1H-

1,5-benzodiazepine (3d) (MW=272)

Fig: 3.15. IR spectrum of 2-Methyl-2,4-diphenyl-2,3-dihydro-1H-1,5-

benzodiazepine (3e)

Fig: 3.16. 1H NMR spectrum of 2-Methyl-2,4-diphenyl-2,3-dihydro-1H-

1,5-benzodiazepine (3e)

Fig: 3.17. Mass spectrum of 2-Methyl-2,4-diphenyl-2,3-dihydro-1H-

1,5-benzodiazepine (3e) (MW=312)

Fig: 3.18. IR spectrum of 2-Methyl-2,4-ditoluyl-2,3-dihydro-1H-1,5-

benzodiazepine (3f)

Fig: 3.19. 1H NMR spectrum of 2-Methyl-2,4-ditoluyl-2,3-dihydro-1H-

1,5-benzodiazepine (3f)

Fig: 3.20. Mass spectrum of 2-Methyl-2,4-ditoluyl-2,3-dihydro-1H-1,5-

benzodiazepine (3f) (MW=340)

Fig: 3.21. IR spectrum of 2,4-bis(4-chlorophenyl)-2-methyl-2,3-

dihydro-1H-1,5-benzodiazepine (3g)

Fig: 3.22. 1H NMR spectrum of 2,4-bis(4-chlorophenyl)-2-methyl-2,3-

dihydro-1H-1,5-benzodiazepine (3g)

Fig: 3.23. Mass spectrum of 2,4-bis(4-chlorophenyl)-2-methyl-2,3-

dihydro-1H-1,5-benzodiazepine (3g) (MW=380)

Fig: 3.24. IR spectrum of 10-Spirocyclopentane-1, 2, 3, 9, 10, 10a-

hexahydrobenzo[b] cyclopenta [e][1,4]-diazepine (3h)

Fig: 3.25. 1H NMR spectrum of 10-Spirocyclopentane-1, 2, 3, 9, 10,

10a-hexahydrobenzo[b]cyclopenta[e][1,4]-diazepine (3h)

Fig: 3.26. Mass spectrum of 10-Spirocyclopentane-1, 2, 3, 9, 10, 10a-

hexahydrobenzo[b]cyclopenta[e][1,4]-diazepine(3h)(MW=240)

Fig: 3.27. IR spectrum of 2-Methyl-2,4-di(thiophen-2-yl)-2,3-dihydro-

1H-1,5-benzodiazepine (3i)

Fig: 3.28. 1H NMR spectrum of 2-Methyl-2,4-di(thiophen-2-yl)-2,3-

dihydro-1H-1,5-benzodiazepine (3i)

Fig: 3.29. Mass spectrum of 2-Methyl-2,4-di(thiophen-2-yl)-2,3-

dihydro-1H-1,5-benzodiazepine (3i) (MW=324(2T))

Fig: 3.30. IR spectrum of 2-methyl-2,4-di(thiophen-3-yl)-2,3-dihydro-

1H-1,5-benzodiazepine (3j)

Fig: 3.31. 1H NMR spectrum of 2-Methyl-2,4-di(thiophen-3-yl)-2,3-

dihydro-1H-1,5-benzodiazepine (3j)

Fig: 3.32. Mass spectrum of 2-Methyl-2,4-di(thiophen-3-yl)-2,3-

dihydro-1H-1,5-benzodiazepine (3j) (MW=324(3T))

Fig: 3.33. IR spectrum of 2,2,4-Trimethyl-2,3-dihydro-7-chloro-1H-

1,5-benzodiazepine (3k)

Fig: 3.34. 1H NMR spectrum of 2, 2, 4-Trimethyl-2,3-dihydro-7-chloro-

1H-1,5-benzodiazepine (3k)

Fig: 3.35. Mass spectrum of 2,2,4-Trimethyl-2,3-dihydro-7-chloro-1H-

1,5-benzodiazepine (3k) (MW=222)

Fig: 3.36. IR spectrum of 7-chloro-2,4-diethyl-2-methyl-2,3-dihydro-

1H-1,5-benzodiazepine (3l)

Fig: 3.37. 1H NMR spectrum of 7-chloro-2,4-diethyl-2-methyl-2,3-dihydro-1H-1,5-benzodiazepine (3l)

Fig: 3.38. Mass spectrum of 7-chloro-2,4-diethyl-2-methyl-2,3-

dihydro-1H-1,5-benzodiazepine (3l) (MW=250)

Fig: 3.39. IR spectrum of 7-chloro-2-methyl-2,4-dipropyl-2,3-dihydro-

1H-1,5-benzodiazepine (3m)

Fig: 3.40. 1H NMR spectrum of 7-chloro-2-methyl-2,4-dipropyl-2,3-

dihydro-1H-1,5-benzodiazepine (3m)

Fig: 3.41. Mass spectrum of 7-chloro-2-methyl-2,4-dipropyl-2,3-

dihydro-1H-1,5-benzodiazepine (3m) (MW=278)

Fig: 3.42. IR spectrum of 7-chloro-2,4-diisobutyl-2-methyl-2,3-

dihydro-1H-1,5-benzodiazepine (3n)

Fig: 3.43. 1H NMR spectrum of 7-chloro-2,4-diisobutyl-2-methyl-2,3-

dihydro-1H-1,5-benzodiazepine (3n)

Fig: 3.44. Mass spectrum of 7-chloro-2,4-diisobutyl-2-methyl-2,3-

dihydro-1H-1,5-benzodiazepine (3n) (MW=306)

Fig: 3.45. IR spectrum of 7-chloro-2-methyl-2,4-diphenyl-2,3-dihydro-

1H-1,5-benzodiazepine (3o)

Fig: 3.46. 1H NMR spectrum of 7-chloro-2-methyl-2,4-diphenyl-2,3-

dihydro-1H-1,5-benzodiazepine (3o)

Fig: 3.47. Mass spectrum of 7-chloro-2-methyl-2,4-diphenyl-2,3-

dihydro-1H-1,5-benzodiazepine (3o) (MW=346)

Fig: 3.48. IR spectrum of 7-chloro-2-methyl-2,4-di-p-tolyl-2,3-dihydro-

1H-1,5-benzodiazepine (3p)

Fig: 3.49. 1H NMR spectrum of 7-chloro-2-methyl-2,4-di-p-tolyl-2,3-

dihydro-1H-1,5-benzodiazepine (3p)

Fig: 3.50. Mass spectrum of 7-chloro-2-methyl-2,4-di-p-tolyl-2,3-

dihydro-1H-1,5-benzodiazepine (3p) (MW=374)

Fig: 3.51. IR spectrum of 7-chloro-2,4-bis (4-chlorophenyl)-2-methyl-

2,3-dihydro-1H-1,5-benzodiazepine (3q)

Fig: 3.52.1H NMR spectrum of 7-chloro-2,4-bis(4-chlorophenyl)-2-

methyl-2,3-dihydro-1H-1,5-benzodiazepine (3q)

Fig: 3.53. Mass spectrum of 7-chloro-2,4-bis(4-chlorophenyl)-2-

methyl-2,3-dihydro-1H-1,5-benzodiazepine(3q) (MW=415)

Fig: 3.54. IR spectrum of 7-chloro-10-Spirocyclopentane -1, 2, 3, 9,

10, 10a -pentahydrobenzo [b] cyclopenta [e] [1,4]-diazepine (3r)

Fig: 3.55. 1H NMR spectrum of 7-chloro-10-Spirocyclopentane-1, 2, 3,

9, 10, 10a -pentahydrobenzo [b] cyclopenta [e] [1,4]-diazepine (3r)

Fig: 3.56. Mass spectrum of 7-chloro-10-Spirocyclopentane -1, 2, 3, 9,

10,10a-pentahydrobenzo[b] cyclopenta [e] [1,4]-diazepine (3r) (MW=274)

Fig: 3.57. IR spectrum of 7-chloro-2-methyl-2,4-di(thiophen-2-yl)-2,3-

dihydro-1H-1,5-benzodiazepine (3s)

Fig: 3.58. 1H NMR spectrum of 7-chloro-2-methyl-2,4-di(thiophen-2-

yl)-2,3-dihydro-1H-1,5-benzodiazepine (3s)

Fig: 3.59. Mass spectrum of 7-chloro-2-methyl-2,4-di(thiophen-2-yl)-2,3-dihydro-1H-1,5-benzodiazepine(3s) (MW=358(2T))

Fig: 3.60. IR spectrum of 7-chloro-2-methyl-2,4-di(thiophen-3-yl)-2,3-

dihydro-1H-1,5-benzodiazepine (3t)

Fig: 3.61. 1H NMR spectrum of 7-chloro-2-methyl-2,4-di(thiophen-3-

yl)-2,3-dihydro-1H-1,5-benzodiazepine (3t)

Fig: 3.62. Mass spectrum of 7-chloro-2-methyl-2,4-di(thiophen-3-yl)-

2,3-dihydro-1H-1,5-benzodiazepine (3t) (MW=358 (3T))

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