CHAPTER 4 AN EFFICIENT ORGANIC SYNTHESIS USING METAL …shodhganga.inflibnet.ac.in/.../93487/10/10_chapter4.pdf · 2018-07-03 · AN EFFICIENT ORGANIC SYNTHESIS USING METAL OXIDE

135

CHAPTER-4

AN EFFICIENT ORGANIC SYNTHESIS USING METAL OXIDE AND

METAL SULPHIDE NANOPARTICLES

Metal oxides and metal sulphides are used as a catalyst in many organic

transformations. They have catalytic activity due to, i) the redox properties,

ii) coordination of surface atoms, and iii) oxidation state. In the metal oxides or metal

sulphides s, p, d or f outer electrons are in their valence shell and therefore these act as

a catalyst. The acid/base and redox properties are interrelated with each other362

. The

nanoparticles have high activities, and selectivity due to their large surface area and

these catalysts can be recycled363, 364

. These nanoparticles are used as nanocatalysts in

reduction, oxidation, decomposition, and coupling reactions365, 366

. Heterogeneous

catalysis is being widely used in fine chemical industry due to its environmentally

friendly production technology. The nanomaterials have high specific active sites on

its surface, and exhibit more catalytic activity367

.

Nanocatalysis is a rapidly growing field involves the use of nanomaterials as

catalysts for a variety of homogeneous and heterogeneous reactions. Heterogeneous

catalysis represents one of the commercial practices of nanoscience, nanoparticles of

metals, semiconductors, oxides, and other compounds have been widely used for

important chemical reactions. They are promising, can be expected decrease in the

energy usage in chemical processes, and resulted greener chemical industry.

Significance of nanocatalysts:

The nanoctystalline material has many advantages some of are listed below:

i) Nanomaterials increases selectivity, activity by controlling pore size and particle

characteristics as compared to bulk material in catalysis. The nanocatalysts are

136

more efficient because they have large surface area which acts as active centers in

catalysis.

ii) Recently, the precious metal catalyst replaced by nanoscale catalyst thus improving

chemical reactivity and reducing process cost, therefore it is possible to achieve

cost effectiveness.

iii) The nanoscale catalytic material can remove unwanted molecules from gases or

liquids by controlling their properties so they are environmentally friendly

catalyst.

iv) Some of the nanocatalyst can develop partial and net charges that help in process

of making and braking bonds at more efficient scale.

v) The nanocatalyst minimizes the usage of fossil fuels and reduces the energy

consumption.

vi) The nanocrystalline catalyst gives high yields with high quality and increased the

atom economy of the process.

Nowadays, the development of environmentally benign protocol is gaining the

importance in chemical processes. Generally, reactions are carried out using organic

acids such as H2SO4, HCl, HNO3, and in another hand the use of Lewis acid like HF

and BF3. Despite its high selectivity these homogeneous acid catalyst have several

disadvantages such as high toxicity, corrosive nature, generating maximum waste,

difficulty in recovery, and reusability. In view of enviro-economical aspects it is

necessary to replace these toxic acid catalyst by newer solid metal oxides and metal

sulphide catalyst as an excellent alternative source over this conventional acid catalyst

as they can be inexpensive, non-toxic, non-corrosive, easy to recover, and reuse.

Metal oxide or metal sulphide based catalysts are active over a wide range of

temperature, and more resistant to thermal excursion.

137

In the present work, efforts are made for the synthesis, characterization, and

catalytic application of metal oxide or metal sulphide solid catalysts for chemical

synthesis. The noticeable advantage of the present work is to introduce simple and

eco-friendly procedure for the preparation of organic compounds, and their

derivatives.

Chapter 4 is divided into five sections,

Section-A: An efficient synthesis of benzylidene malononitrile and

tetrahydrobenzopyrans using PbO nanoparticles.

Section-B: An efficient synthesis of acridinediones using CdO nanoparticles as

catalyst under solvent free condition.

Section-C: PbS nanoparticles as an effective catalyst for the one pot synthesis of

amidoalkyl naphthols under solvent free condition.

Section-D: ZnS nanoparticles as an efficient solid catalyst for synthesis of 5-arylidene

barbituric acids under solvent free condition.

Section-E: Comparative study on catalytic efficiency of synthesized nanoparticles

towards synthesis of pyranopyrazoles.

138

Section-A

I) Synthesis of Benzylidene Malononitriles using PbO Nanoparticles as an

Efficient and Reusable Catalyst

4.1A. Introduction:

Benzylidene malononitriles are the main products of the condensation of

substituted benzaldehyde with malononitrile. Derivatives of benzylidene

malononitriles have important applications in chemotherapeutic treatment of

cancer368

. Moreover, benzylidene malononitriles were used as cytotoxic agents

against tumours or as riot control agents369

, and have been reported to be effective

anti-fouling agents, fungicides, and insecticides370

. The small molecules have been

found to possess inhibitory activity to HER2, including compounds belonging to the

benzylidene malononitrile family371

. The derivatives of benzylidene malononitriles

possess antimicrobial activity372

and used as potent tyrosine kinase inhibitors373

. The

benzylidene malononitrile derivatives also used for the treatment of leukemia374

.

Several methods used for the synthesis of substituted benzylidene

malononitrile, Heravi et al375

have reported the Na2S/Al2O3 catalyzed condensation

between various aldehydes and active methylene compounds in a heterogeneous

system (Scheme 1).

R2

O

R1+

R3

CN R1

R2 R3

CNNa2S(20mol%),Al 2O3(0.05gm)

CH2Cl 2

Scheme 1

139

Bhuiyan et al372

have reported the condensation reaction of malononitrile with

aromatic aldehydes in presence of ammonium acetate (NH4OAc) using microwave

irradiation under solvent free condition (Scheme 2).

Scheme 2

Balalaie et al376

have reported the condensation reaction between aromatic

aldehydes and active methylene compounds in presence of ammonium acetate

(NH4OAc) basic alumina (Scheme 3).

Scheme 3

Verma et al377

have been reported the use of p-methoxyphenyltellurium

trichloride as an efficient catalyst for condensation reaction of active methylene with

aromatic aldehydes (Scheme 4).

Scheme 4

Ye et al378

have reported the condensation of aromatic aldehydes with active

methylene using diethylamine functionalized polyethylene glycol-600 (PEG-600) at

room temperature without solvent (Scheme 5).

Scheme 5

Ar

H

O

+CN

CN NH4OAc

MWI CN

CNAr

H

Ar

H

O

+CN

CN NH4OAc

basic alumina CN

CNAr

H

Ar

H

O

+R

CN

R

CNAr

H

R' TeCl 3

900C-100

0C

R1

H

O

+CN

R2

CN

R2

R1

H

PEG-600

solvent free

140

Gupta et al379

have reported the hydroxyapatite supported cesium carbonate in

water as an efficient catalyst for condensation reaction of active methylene with

aromatic aldehydes (Scheme 6).

Scheme 6

Mogilaiah et al380

have reported ammonium sulphamate catalyzed

condensation of aromatic aldehydes with active methylene in solvent free condition

under microwave irradiation (Scheme 7).

Scheme 7

Bhaumik et al381

have reported highly efficient mesoporous base catalyzed

Knoevenagel condensation of different aromatic aldehydes with malononitrile by

amine functionalized mesoporous silica (Scheme 8).

Scheme 8

Su et al382

have reported deprotonated mesoporous graphite carbon nitride

(mpg-C3N4) as a solid base catalyst for condensation of aromatic aldehydes with

malononitrile (Scheme 9).

Scheme 9

R

H

O

+CN

X

CN

XR

H

HAP-Cs 2CO3, 80-1000C

reflux, H 2O

Ar

H

O

+R

CN

R

CNAr

H

NH2SO3NH4

MW

Ar

H

O

+CN

CN

CN

CNAr

H

amine functionalized

mesoporus silica

Ar

H

O

+CN

CN

CN

CNAr

H

mpg-C3N4

141

Reddy et al383

have reported sulfate ion promoted ZrO2 catalyst for

condensation of aliphatic, aromatic, and heterocyclic aldehydes with malononitrile

under solvent free condition (Scheme 10).

Scheme 10

Yuan et al384

have reported MgC2O4/SiO2 catalyst for condensation of

aldehydes with malononitrile under microwave irradiation and solvent free condition

(Scheme 11).

Scheme 11

Shi et al385

have reported triethylbenzylammonium chloride (TEBA) catalyzed

condensation of aromatic aldehydes with malononitrile in presence of water at 70oC

(Scheme 12).

Scheme 12

However, many of these methods suffered from drawbacks such as low yield,

long reaction time, drastic reaction condition, and tedious work up. Therefore, there is

a scope for generation of new methodology with mild reaction condition, better yield,

short reaction time, and environment friendliness. Recently, metal or metal oxides are

also used as catalyst in organic reactions, and have more advantages over organic

catalyst386

.

The present work reports the use of efficient and reusable PbO nanoparticles

as a catalyst for the synthesis of benzylidene malononitriles. The PbO nanoparticles

Ar

H

O

+CN

CN

CN

CNAr

H

sulfate ion-ZrO 2

Ar

H

O

+CN

CN

CN

CNAr

H

MgC2O4/SiO2

MWI

Ar

H

O

+R

CN

R

CNAr

H

H2O, TEBA

700C, 5h

142

have gained more importance in organic transformations due to high thermal stability,

large surface area, easy recovery, good ability to perform organic reactions at room

temperature without solvent and enviro-economic factors387

.

4.2A. Present work:

Here we are reported the synthesis of benzylidene malononitrile derivatives by

Knoevenagel condensation of substituted benzaldehyde and malononitrile using PbO

nanoparticles catalyst under solvent free condition by grinding (Scheme 13).

1 2 3 (a-i)

Scheme 13: Synthesis of benzylidene malononitriles

4.3A: Synthesis of benzylidene malononitriles:

In a clean mortar, substituted aromatic aldehyde (1.0 mmol), malononitrile

(1.0 mmol), and PbO nanoparticles (40 mg) were grinded in presence of sunlight. The

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

stir, filtered, and the residue was washed with distilled water. The crude product was

dried, extracted by diethyl ether and used PbO nanoparticles catalyst was recovered.

The organic layer on evaporation yielded product which was recrystallized using

ethanol/water afforded pure products. The recovered catalyst was dried, and reused

further in successive reactions. All the products were characterized by IR, 1H NMR,

13C NMR, and mass spectrometry.

4.4A. Results and Discussion:

The reaction of various aromatic aldehydes with malononitrile was carried out

successfully at room temperature without solvent using grinding method. The high

CHO

R

+ CN

NC PbO nanoparticles

CN

CN

R

grinding

143

conversions, and rapid reaction rates was achieved in all reactions (Table 4.1). Both

electron rich and electron deficient aldehyde worked very well giving high yield of

benzylidene malononitriles. Electron deficient aldehyde furnished excellent yield of

the corresponding benzylidene malononitriles in a short reaction time, whereas

electron rich aldehydes resulted in comparatively low yield, and required longer time.

In order to optimize the amount of catalyst the condensation reaction of

benzaldehyde (1.0 mmol), and malononitrile (1.0 mmol) was used as model reaction

using PbO nanoparticles as a catalyst. The reaction mixture was grounded at room

temperature in presence of sunlight. The reaction was optimized by varying

concentration of catalyst such as 10, 20, 30, 40, 50, 60, and 70 mg (Table 4.2). It was

observed that the 40 mg of the catalyst was sufficient to promote the reaction.

In order to study the reusability of catalyst, it was filtered, washed with

ethanol, and heated at 100oC in oven for 2 hrs. The reusability of the catalyst was

checked for several successive run under identical reaction condition. The catalyst

was stable and reusable even after five consecutive cycles without appreciable loss in

activity (Table 4.3). Moreover, the reusability of this catalyst makes the method cost

effective.

The structure of the entire synthesized compound was confirmed by

spectroscopic techniques including IR, 1H NMR,


Typical 1H NMR spectrum of compound 3g showed the presence of C=CH, and

aromatic protons which confirms the formation of 2-(4-chlorobenzylidene)

malononitrile (Fig. 4.1). 13

C NMR showed peaks at 139.58, 112.47, and 113.51 δ due

to carbon attached to -Cl group, carbon attached to -CN group and -CN carbon

confirms the formation of compound 3g (Fig. 4.2). The structure of 3c compound was

confirmed by mass spectrum which shows the (M+1)+ peak at 200 (Fig. 4.3).

144

Table 4.1. Synthesis of benzylidene malononitriles in presence of PbO nanoparticles

Entry Product

(R group)

Time (min) Yield (%) M. P. (oC)

3a H 09 91 88

3b 4-OCH3 13 92 115

3c 3-NO2 19 95 102

3d 4-OH 25 93 185

3e 3-OCH3 24 96 108

3f 2-CH3 12 94 107

3g 4-Cl 13 92 162

3h 2-NO2 18 90 139

3i 3-CH3 14 92 75

Table 4.2. Effect of amount of PbO nanoparticles catalyst

Entry Catalyst (mg) Time (min) Yield (%)

1 10 21 76

2 20 16 81

3 30 12 87

4 40 07 91

5 50 07 91

6 60 07 90

7 70 07 90

Table 4.3. Reusability of the catalyst

Cycles Time (min) Yield (%)

1 9 91

2 9 90

3 9 89

4 9 89

5 9 88

145

Similarly the formation of all other compounds was confirmed on the basis of spectral

data.

4.5A. Spectral data:

2-(Benzylidene) malononitrile (3a): mp: 88oC, Yield: 91 %, IR (KBr): 3182, 2224,

1691, 1592, 1090 cm-1

, 1H NMR (400 MHz, DMSO-d6): δ 7.91 (d, 2H,

J = 7.60 Hz), 7.64 (t, 1H, J = 7.60 Hz), 7.27 (t, 2H, J = 7.60 Hz), 7.12

(s, 1H), 13

C NMR (100 MHz, DMSO): δ 160.06, 134.68, 130.96,

130.77, 129.66, 113.77, 112.62, M. F: C10H6N2, M. W: 154, MS (m/z): 155 (M +1)+.

2-(4-Methoxybenzylidene) malononitrile (3b): mp: 115oC, Yield: 92 %, IR (KBr):

3117, 2222, 1605, 1561, 1217, 1026 cm-1

, 1H NMR (400 MHz, DMSO-

d6): δ 7.90 (d, 2H, J = 8.0 Hz), 7.64 (s, 1H), 7.00 (d, 2H, J = 8.0 Hz),

3.91 (s, 3H), 13

C NMR (100 MHz, DMSO): δ 164.87, 158.96, 133.49,

124.03, 115.17, 114.49, 113.41, 55.84, M. F: C11H8N2O, M. W: 184,

MS (m/z): 185 (M +1)+.

2-(3-Nitrobenzylidene) malononitrile (3c): mp: 102oC, Yield: 95 %, IR (KBr): 3107,

2225, 1610, 1595, 1529, 1479 cm-1


d6): δ 8.45-8.33 (m, 3H), 8.31 (s, 1H,), 7.86 (s, 1H), 13

C NMR

(100 MHz, DMSO): δ 159.74, 149.81, 136.96, 133.99, 132.00,

128.89, 125.99, 114.53, 113.52, M. F: C10H5N3O2, M. W: 199, MS (m/z): 200

(M +1)+.

2-(4-Hydroxybenzylidene) malononitrile (3d): mp: 185oC, Yield: 93 %, IR (KBr):

3654, 3150, 2223, 1569, 1511, 1365, 1208 cm-1

, 1H NMR 400 MHz,

DMSO-d6): δ 12.50 (s, 1H), 7.99 (s, 1H), 7.89 (d, 2H, J = 8.0 Hz), 7.03

(d, 2H, J = 8.0 Hz), 13

C NMR (100 MHz, DMSO): δ 165.34, 160.98,

134.99, 124.51, 117.46, 115.90, 114.95, M. F: C10H6N2O, M. W: 170,

CN

CN

OCH3

CN

CN

CN

CN

O2N

CN

CN

OH

146

MS (m/z): 171 (M +1)+.

2-(3-Methoxybenzylidene)-malononitrile (3e): mp: 108oC, Yield: 96 %, IR (KBr):

3088, 2225, 1593, 1567, 1161 cm-1


d6): δ 8.16 (s, 1H), 7.54 (s, 1H), 7.51 (t, 1H, J = 7.32 Hz), 7.45

(d, 1H, J = 8.0 Hz), 7.21 (d, 1H, J = 8.0 Hz), 3.84 (s, 3H).

13C NMR (100 MHz, DMSO): δ 161.90, 161.49, 133.93, 131.51,

124.51, 121.75, 115.61, 115.07, 114.04, 56.03, M. F: C11H8N2O, M. W: 184,

MS (m/z): 185 (M +1)+.

2-(2-Methylbenzylidene) malononitrile (3f): mp: 107oC, Yield: 94 %, IR (KBr):

3043, 2229, 1584, 1501 cm-1

, 1H NMR (400 MHz, DMSO-d6): δ 8.47

(s, 1H), 8.01 (d, 1H, J = 7.70 Hz), 7.50 (d, 1H, J = 7.90 Hz), 7.35

(t, 2H, J = 7.30 Hz), 2.44 (s, 3H), 13

C NMR (100 MHz, DMSO): δ

160.73, 141.30, 134.77, 132.32, 131.83, 129.23, 127.66, 114.93, 113.88, 19.65,

M. F: C11H8N2, M. W: 168, MS (m/z): 169 (M +1)+.

2-(4-Chlorobenzylidene) malononitrile (3g): mp: 162oC, Yield: 92 %, IR (KBr):

3183, 2195, 1604, 1584, 1014 cm-1

, 1H NMR (400 MHz, DMSO-d6): δ

8.34 (s, 1H), 7.90 (d, 2H, J = 8.0 Hz), 7.52 (d, 2H, J = 8.0 Hz),

13C NMR (100 MHz, DMSO): δ 159.2, 139.58, 131.88, 129.61, 129.41,

113.51, 112.47, M. F: C10H5ClN2, M. W: 189, MS (m/z): 190 (M +1)+.

2-(2-Nitrobenzylidene) malononitrile (3h): mp: 139oC, Yield: 90 %, IR (KBr): 3110,

2228, 1613, 1595, 1482 cm-1


8.47 (s, 1H), 8.34 (d, 1H, J = 8.0 Hz), 7.90-7.89 (m, 1H), 7.82-

7.79 (m, 2H), 13

C NMR (100 MHz, DMSO): δ 158.91, 146.74,

134.95, 133.43, 130.41, 126.64, 125.80, 112.24, 110.97, M. F: C10H5N3O2, M. W:

199, MS (m/z): 200 (M +1)+.

CN

CN

H3CO

CN

CN

CN

CN

Cl

CN

CN

O2N

147

2-(3-Methylbenzylidene) malononitrile (3i): mp: 75oC, Yield: 92 %, IR (KBr): 3093,

2229, 1595, 1501 cm-1

, 1H NMR (400 MHz, DMSO-d6): δ 7.72

(d, 2H, J = 5.50 Hz), 7.69 (s, 1H), 7.43 (m, 1H), 7.40 (t, 1H, J = 7.80

Hz), 2.43 (s, 3H), 13

C NMR (100 MHz, DMSO): δ 160.17, 139.59,

135.55, 131.26, 130.89, 129.47, 127.88, 113.81, 112.62, 21.24, M. F: C11H8N2,

M. W: 168, MS (m/z): 169 (M +1)+.

CN

CN

148

Fig. 4.1: 1H NMR spectrum of 3g compound

Fig. 4.2: 13

C NMR spectrum of 3g compound

CN

CN

Cl

H1

H2

H3H3

H2

CN

CN

Cl

12

34

56

4'

5'

149

Fig. 4.3: Mass spectrum of 3c compound

CN

CN

O2N

150

II) Synthesis of Tetrahydrobenzopyrans Using PbO Nanoparticles as an Efficient

and Reusable Catalyst

4.6A. Introduction:

Benzopyran and their derivatives have shown several pharmacological and

biological properties like diuretic, spasmolytic, antisterlity, antianaphylactin, and

anticancer agents388, 389

. The derivatives of benzopyrans constitute a structural unit of

series of natural products which are used as pigments, cosmetics, and biodegradable

agrochemicals390

. They have been also used as cognitive enhancer for the treatment of

neurogenerative disease including Alzheimer disease, Parkinson‟s disease, and for the

treatment of AIDS associated dementia, Downs‟s syndrome, neurodegenerative

disease, schizophrenia, and myoclonus391

. The derivatives of tetrahydrobenzopyran

are useful as photoactive materials392

. Due to their applications, the synthesis of

heterocyclic derivatives of these ring systems has great importance in medicinal

chemistry and organic synthesis. Several methods used for the synthesis of tetrahydro-

benzo[b]pyrans.

Sandhu et al393

have reported the LiBr catalyzed facile, and efficient method

for the tetrahydrobenzo[b]pyrans under solvent free and microwave heating condition

(Scheme 14).

Scheme 14

O

O

+R

CN

+

CHO

O

R

NH2

O

LiBr

MW

151

Balalaie et al394

have reported a greener method to synthesize

tetrahydrobenzo[b]pyrans from dimedone, aldehyde, and malononitrile under neutral

condition by the use of s-proline as a catalyst (Scheme 15).

Scheme 15

Feng et al395

have reported the synthesis of tetrahydrobenzo[b]pyrans by

microwave assisted multi component one pot reactions in PEG-400 (Scheme 16).

Scheme 16

Lian et al396

have reported the synthesis of tetrahydrobenzo[b]pyrans through

N-methylimidazole as organo catalyst (Scheme 17).

Scheme 17

Li et al397

have reported the synthesis of tetrahydrobenzo[b]pyran derivatives

in aqueous media using trisodium citrate as a catalyst (Scheme 18).

O

O

+R

CN

+

CHO

O

R

NH2

O

(s)-proline (5 mol%)

O

O

+R

CN

+

CHO

O

R

NH2

O

PEG-400

O

O

+R

CN

+

CHO

O

R

NH2

O

N-methyl imidazole

152

Scheme 18

Ranu et al398

have reported the synthesis of tetrahydrobenzo[b]pyrans through

basic ionic liquid (1-butyl-3-methyl imidazolium hydroxide) at room temperature by

condensation reaction of dimedone, aldehyde, and malononitrile (Scheme 19).

Scheme 19

Mobinikhaledi et al399

have reported tetrabutylammonium bromide (TBAB) as

a catalyst for the synthesis of tetrahydrobenzo[b]pyrans in water as a solvent

(Scheme 20).

Scheme 20

Tabatabaeian et al400

have reported Ru (II) complexes bearing tertiary

phosphine ligands a novel and efficient homogeneous catalyst for one pot

condensation of aldehydes, malononitrile, and dimedone for the synthesis of

tetrahydrobenzo[b]pyran derivatives (Scheme 21).

O

O

+R

CN

+

CHO

O

R

NH2

O

trisodium citrate

O

O

+R

CN

+

CHO

O

R

NH2

O

basic ionic liquid

O

O

+R

CN

+

CHO

O

R

NH2

O

TBAB/H2O

ref lux

153

Scheme 21

Kolekar et al401

have reported the synthesis of tetrahydrobenzo[b]pyran

derivatives using basic ionic liquid and 4-amino-1-(2, 3-dihydroxypropyl) pyridinium

hydroxide under mild condition (Scheme 22).

Scheme 22

Patra et al402

have reported the synthesis of tetrahydrobenzo[b]pyran

derivatives in excellent yield using trioctylmethylammonium chloride (Aliquat®336)

as a phase transfer catalyst in water under microwave irradiation (Scheme 23).

Scheme 23

Hilmy Elnagdi et al403

have reported the synthesis of polysubstituted

tetrahydrobenzo[b]pyran derivatives using l-proline as a catalyst in presence of

ethanol or by grinding at room temperature (Scheme 24).

O

O

+R

CN

+

CHO

O

R

NH2

O

Ru(II) complexes

O

O

+R

CN

+

CHO

O

R

NH2

O

(ADPPY)(OH)

O

O

+R

CN

+

CHO

O

R

NH2

O

aliquat-R-336/H2O

MWI

154

Scheme 24

The nanoporous solid acid like catalyst sulfonic acid functionalized silica

(SiO2-Pr-SO3H)404

also used in the synthesis of tetrahydrobenzo[b]pyran derivatives.

In multicomponent reaction the complex molecules could be synthesized with

maximum simplicity405

. However because of wide range of biological activities of

tetrahydrobenzo[b]pyran derivatives, the synthesis of this derivatives are carried out

to explore the catalytic activity of the nanocrystalline PbO as heterogeneous

catalyst387

towards the synthesis of tetrahydrobenzopyran derivatives.

4.7A. Present work:

The present study deals with simple and efficient method for the synthesis of

tetrahydrobenzopyrans under solvent free condition using grinding method at room

temperature. The reaction between aromatic aldehyde, malononitrile, and dimedone

using nanocrystalline PbO as a catalyst provided good yield of tetrahydrobenzopyran

derivatives (Scheme 25).

1 2 3 4 (a-j)

Scheme 25: Synthesis of tetrahydrobenzopyrans

+CN

CNAr CHO +

O

O O

CN

NH2

O

L-proline(10%mol)

EtOH, ref lux, 4h

CHO

R

+ CN

NCPbO nanoparticles

grinding

O

O+

O

O NH2

CN

R

155

4.8A. Synthesis of tetrahydrobenzopyrans:

The substituted aromatic aldehydes (1.0 mmol), malononitrile (1.0 mmol),

dimedone (1 mmol), PbO nanoparticles (50 mg) were mixed, and homogenized in a

beaker. The resulting reaction mixture was grounded in presence of sunlight at room

temperature, and the reaction was monitored by TLC technique. After completion of

reaction, the crude product was washed with distilled water, dried, and recrystallized

from ethanol/water system to afford pure product. The recovered catalyst was washed

with ethanol, dried, heated at 100oC in oven for 2 hrs, and reused further in successive

reactions. All the products were characterized by IR, 1H NMR,

13C NMR, and mass

spectrometry.

4.9A. Results and Discussion:

Using optimized reaction conditions a range of substituted tetrahy-

drobenzopyran derivatives were synthesized at room temperature without solvent by

simple grinding technique. All these reactions are found to be very fast (10-18 min),

and gives high yields (82-92 %) without side product (Table 4.4). In all cases

aromatic aldehydes substituted with either electron donating or electron withdrawing

groups undergoes smooth reaction and gave the products in good yields under the

optimized reaction condition. The aromatic aldehydes with hydroxyl substituents

disfavored the reaction, which gives a comparative lower yield and required longer

time for the completion of the reaction. The yields and reaction time depends on the

structure of aromatic aldehydes. The aromatic aldehydes containing electron donating

groups have taken longer reaction time with low yields whereas the reaction time is

less for the aldehyde containing electron withdrawing groups with high yields.

The condensation reaction between benzaldehyde (1.0 mmol), malononitrile

(1.0 mmol), and dimedone (1.0 mmol) was used as model reaction using PbO

156

nanoparticles as a catalyst to optimize the amount of catalyst. The reaction mixture

was grind at room temperature in presence of sunlight and the reaction was optimized

by varying the concentration of catalyst in the range of 20 to 70 mg (Table 4.5). It was

observed that the 50 mg of the catalyst was sufficient to perform the reaction. Increase

in amount of catalyst does not show any significant increase in the yield of products.

The reusability of the catalyst was checked for several successive runs under identical

reaction condition. The catalyst was found to be stable and reusable even after five

consecutive cycles without appreciable loss in activity (Table 4.6).

The structure of all the synthesized compound was confirmed by IR, 1H NMR,

13C NMR, and mass spectrometry. Typical

1H NMR spectrum of compound 4a

showed the presence of -C=O, -NH2, -CH3, and aromatic protons which confirms the

formation of 2-amino-3-cyano-4-(phenyl)-7, 7-dimethyl-5-oxo-4H-5, 6, 7, 8-tetrahy-

drobenzo[b]pyran (Fig. 4.4). 13

C NMR showed peaks at 195.32, 113.01, 28.52, and

27.00 δ due to -C=O carbon, -CN carbon, and -CH3 carbon confirms the formation of

compound 4a (Fig. 4.5). The structure of 4d compound was confirmed by mass

spectrum which shows the (M+1)+ peak at 330 (Fig. 4.6). Similarly the formation of

all other compounds was confirmed on the basis of their spectral data.

157

Table 4.4. PbO nanoparticles catalyzed synthesis of tetrahydrobenzopyran

Entry Product

(R group)


4a H 15 83 229

4b 4-Cl 12 90 212

4c 4-OCH3 18 85 201

4d 2-Cl 15 86 202

4e 4-NO2 10 91 180

4f 4-OH 15 82 208

4g 3-NO2 15 85 212

4h 2-NO2 13 88 227

4i 3-Cl 15 87 230

4j 4-CH3 12 92 214

Table 4.5. Effect of amount of PbO nanoparticles catalyst

Entry Catalyst (mg) Time (min) Yield (%)

1 20 32 63

2 30 21 75

3 40 18 81

4 50 15 83

5 60 15 83

6 70 15 83

Table 4.6. Result of the reaction using recycled PbO nanoparticles catalyst


1 15 83

2 15 81

3 15 79

4 15 77

5 15 75

158

4.10A. Spectral data:

2-Amino-3-cyano-4-(phenyl)-7, 7-dimethyl-5-oxo-4H-5, 6, 7, 8-tetrahydrbenzo[b]-

pyran (4a): mp: 229oC, Yield: 83 %, IR (KBr): 3396, 2960,

2200, 1685, 1617, 1214 cm-1

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

δ 7.25-7.22 (m, 2H), 7.19-7.12 (m, 3H), 6.59 (s, 2H), 4.22

(s, 1H), 2.46 (s, 2H), 2.19 (d, 1H, J = 16.0 Hz), 2.08 (d, 1H,

J = 16.0 Hz), 1.06 (s, 3H), 0.98 (s, 3H), 13

C NMR (100 MHz, DMSO): δ 195.32,

161.93, 158.35, 144.32, 128.01, 127.08, 126.34, 119.54, 113.01, 58.83, 50.13, 35.49,

31.68, 28.52, 27.00, M. F: C18H18N2O2, M. W: 294, MS (m/z): 295 (M +1)+.

2-Amino-3-cyano-4-(4-chloro-phenyl)-7, 7-dimethyl-5-oxo-4H-5, 6, 7, 8-tetrahydro-

benzo[b]pyran (4b): mp: 212oC, Yield: 90 %, IR (KBr): 3373,

2994, 2246, 1653, 1613, 1490 cm-1

, 1H NMR (400 MHz,

DMSO-d6): δ 7.34 (d, 2H, J = 8.40 Hz), 7.16 (d, 2H, J = 8.40

Hz), 7.07 (s, 2H), 4.18 (s, 1H), 2.48 (m, 2H), 2.26 (d, 1H,

J = 15.90 Hz), 2.10 (d, 1H, J = 15.90 Hz), 1.01 (s, 3H), 0.92 (s, 3H), 13

C NMR (100

MHz, DMSO): δ 196.17, 163.09, 158.93, 144.19, 131.55, 129.56, 128.74, 120.01,

117.13, 112.75, 58.20, 50.37, 35.54, 32.25, 28.75, 27.29, M. F: C18H17ClN2O2,

M. W: 329, MS (m/z): 330 (M +1)+.

2-Amino-3-cyano-4-(4-methoxy-phenyl)-7, 7-dimethyl-5-oxo-4H-5, 6, 7, 8-tetra-

hydrobenzo[b]pyran (4c): mp: 201oC, Yield: 85 %, IR (KBr):

3395, 2990, 2204, 1680, 1510, 1252 cm-1

, 1H NMR (400 MHz,

DMSO-d6): δ 7.15 (d, 2H, J = 8.70 Hz), 6.97 (s, 2H), 6.84

(d, 2H, J = 8.70 Hz), 4.37 (s, 1H), 3.78 (s, 3H), 2.43 (s, 2H),

2.22 (d, 1H, J = 16.0 Hz), 2.09 (d, 1H, J = 16.0 Hz), 1.04 (s, 3H), 0.97 (s, 3H),

13C NMR (100 MHz, DMSO): δ 195.60, 162.02, 158.47, 136.81, 128.15, 125.11,

O

O

CN

NH2

O

O

CN

NH2

Cl

O

O

CN

NH2

OCH3

159

119.72, 118.17, 113.61, 113.03, 58.65, 54.91, 50.06, 35.10 31.71, 28.37, 26.74,

M. F: C19H20N2O3, M. W: 324, MS (m/z): 325 (M + 1)+.


benzo[b]pyran (4d): mp: 202oC, Yield: 86 %, IR (KBr): 3379,

2994, 2195, 1682, 1481 cm-1


δ 7.36-7.13 (m, 4H), 7.01 (s, 2H), 4.67 (s, 1H), 2.48 (m, 2H),

2.26 (d, 1H, J = 15.90 Hz), 2.07 (d, 1H, J = 15.90 Hz), 1.03 (s, 3H), 0.96 (s, 3H),

13C NMR (100 MHz, DMSO): δ 196.04, 163.62, 159.12, 142.02, 132.52, 130.40,

129.90, 128.67, 127.89, 119.70, 115.10, 112.21, 50.37, 45.77, 33.28, 32.21, 28.85,

27.31, M. F: C18H17ClN2O2, M. W: 329, MS (m/z): 330 (M + 1)+.

2-Amino-3-cyano-4-(4-nitro-phenyl)-7, 7-dimethyl-5-oxo-4H-5, 6, 7, 8-tetrahydro-

benzo[b]pyran (4e): mp: 180oC, Yield: 91 %, IR (KBr): 3394,

2970, 2193, 1683, 1523, 1365 cm-1

, 1H NMR (400 MHz,

DMSO-d6): δ 8.18-8.16 (m, 2H), 7.46-7.44 (m, 2H), 7.20 (s, br,

2H), 4.39 (s, 1H), 2.57 (m, 2H), 2.30 (d, 1H, J = 16.0 Hz), 2.14

(d, 1H, J = 16.0 Hz), 1.06 (s, 3H), 0.99 (s, 3H), 13


196.21, 163.54, 159.07, 146.72, 129.06, 124.14, 121.71, 119.75, 115.12, 112.12,

57.47, 50.34, 40.42, 39.44, 32.20, 28.77, 27.46, M. F: C18H17N3O4, M. W: 339,

MS (m/z): 340 (M +1)+.

2-Amino-3-cyano-4-(4-hydroxy-phenyl)-7, 7-dimethyl-5-oxo-4H- 5, 6, 7, 8-tetra-

hydrobenzo[b]pyran (4f): mp: 208oC, Yield: 82 %, IR (KBr):

3464, 3364, 2192, 1663, 1491 cm-1

, 1H NMR (400 MHz,

DMSO-d6): δ 11.59 (s, 1H), 7.22 (s, 2H), 6.91 (d, 2H, J = 7.0

Hz), 6.78 (d, 2H, J = 7.0 Hz), 4.35 (s, 1H), 2.48 (m, 2H), 2.19

(s, 2H), 1.00 (s, 3H), 0.925 (s, 3H), 13

C NMR (100 MHz, DMSO): δ 195.95, 156.10,

O

O

CN

NH2

OH

O

O

CN

NH2

Cl

O

O

CN

NH2

NO2

160

140.19, 135.61, 129.45, 128.45, 126.13, 115.01, 114.02, 112.11, 50.69, 45.10, 34.78,

32.07, 28.10, 27.52, M. F: C18H18N2O3, M. W: 310, MS (m/z): 311 (M + 1)+.


benzo[b]pyran (4g): mp: 212oC, Yield: 85 %, IR (KBr): 3313,

3003, 2200, 1683, 1513, 1355 cm-1

, 1H NMR (400 MHz,

DMSO-d6): δ 8.02-7.61 (m, 4H), 7.18 (s, br, 2H), 4.42 (s, 1H),

2.55 (m, 2H), 2.28 (d, 1H, J = 16.0 Hz), 2.13 (d, 1H, J = 16.0

Hz), 1.06 (s, 3H), 0.96 (s, 3H), 13

C NMR (100 MHz, DMSO): δ 196.34, 163.63,

159.09, 148.23, 147.44, 134.63, 130.48, 122.23, 122.09, 121.21, 119.80, 112.23,

53.66, 50.32, 35.86, 32.28, 28.77, 27.19, M. F: C18H17N3O4, M. W: 339, MS (m/z):

340 (M +1)+.


benzo[b]pyran (4h): mp: 227oC, Yield: 88 %, IR (KBr): 3302,

3195, 2193, 1687, 1664, 1596, 1524 cm-1

, 1H NMR (400 MHz,

DMSO-d6): δ 7.82 (d, 1H, J = 8.40 Hz), 7.68-7.64 (m, 1H),

7.44-7.41 (m, 1H), 7.38 (d, 1H, J = 8.40 Hz), 7.20 (s, br, 2H),

4.93 (s, 1H), 2.55 (m, 2H), 2.24 (d, 1H, J = 16.0 Hz), 2.04 (d, 1H, J = 16.0 Hz), 1.02

(s, 3H), 0.91 (s, 3H), 13

C NMR (100 MHz, DMSO): δ 196.32, 163.24, 159.65, 149.41,

135.15, 130.72, 128.35, 124.11, 120.13, 119.55, 114.12, 112.74, 50.06, 42.51, 35.46,

32.37, 28.72, 27.11, M. F: C18H17N3O4, M. W: 339, MS (m/z): 340 (M +1)+.


benzo[b]pyran (4i): mp: 230oC, Yield: 87 %, IR (KBr): 3391,

3182, 2192, 1662, 1630, 1600, 1483 cm-1

, 1H NMR (400 MHz,

DMSO-d6): δ 7.32-7.10 (m, 4H), 7.09 (s, 2H), 4.21 (s, 1H),

2.53 (m, 2H), 2.27 (d, 1H, J = 15.90 Hz), 2.25 (d, 1H, J = 15.90

O

O

CN

NH2

NO2

O

O

CN

NH2

NO2

O

O

CN

NH2

Cl

161

Hz), 1.11 (s, 3H), 1.07 (s, 3H), 13

C NMR (100 MHz, DMSO): δ 196.22, 163.34,

159.01, 147.66, 140.27, 135.37, 130.72, 127.54, 126.40, 120.12, 119.91, 112.55,

50.33, 42.54, 36.40, 32.36, 28.71, 27.23, M. F: C18H17ClN2O2, M. W: 329, MS (m/z):

330 (M + 1)+.

2-Amino-3-cyano-4-(4-methyl-phenyl)-7, 7-dimethyl-5-oxo-4H-5, 6, 7, 8-tetrahydro-

benzo[b]pyran (4j): mp: 214oC, Yield: 92 %, IR (KBr): 3324,

2957, 2193, 1684, 1602, 1480 cm-1

, 1H NMR (400 MHz,

DMSO-d6): δ 7.09 (d, 2H, J = 8.0 Hz ), 7.02 (d, 2H, J = 8.0

Hz), 6.97 (s, 2H), 4.34 (s, 1H), 2.51 (m, 2H), 2.24 (s, 3H), 2.26

(d, 1H, J = 16.0 Hz), 2.11 (d, 1H, J = 16.0 Hz), 1.03 (s, 3H), 0.94 (s, 3H), 13

C NMR

(100 MHz, DMSO): δ 196.12, 162.73, 158.94, 142.27, 136.13, 129.35, 127.51,

120.20, 118.31, 113.34, 50.43, 41.51, 37.44, 32.22, 28.87, 27.23, 21.04, M. F:

C19H20N2O2, M. W: 308, MS (m/z): 309 (M + 1)+.

O

O

CN

NH2

162

Fig. 4.4: 1H NMR spectrum of 4a compound

Fig. 4.5: 13

C NMR spectrum of 4a compound

O

CN

NH2

O

CH3CH3

H1

H3

H2

H1

H2

H4

6

5

O

CN

NH2

O

CH3CH3

H1

H3

H2

H1

H2

H4

6

5

163

Fig. 4.6: Mass spectrum of 4d compound

O

O

CN

NH2

Cl

164

Section-B

An Efficient Synthesis of Acridinediones Using CdO Nanoparticles as Catalyst

Under Solvent Free Condition

4.1B. Introduction:

Acridinediones and their derivatives are polyfunctionalized 1, 4-

dihydropyridine derivatives which are bioactive compounds such as vasodilator,

bronchodilator, anti-atherosclerotic, anti-cancer, and antidiabetic agents406, 407

.

Derivatives of 1, 4-dihydropyridine are employed as potential drug for the treatment

of congestive heart failure408

. Acridinediones and their derivatives possess a wide

range of pharmaceutical activities including antitumor409

, antimicrobial410

,

antibacterial411

, antimalarial412

, DNA binding413

, and fungicidal properties414

. In

addition acridinediones exhibit important properties like high fluorescence efficiency

allowing them to be used as laser dyes415

. 1, 4-Dihydropyridine derivatives show very

high lasing efficiency therefore used as photoinitiators416

, and important core for

many bioactive compounds417

. It has antiaggregatory activity so used in Alzheimer

disease418

and also have calcium channel blocking activity419

. Due to importance of

such activities and properties a number of methods for the synthesis of acridinedione

derivatives have been reported.

Sangshetti et al420

have reported the water mediated oxalic acid catalyzed one

pot synthesis of 1, 8-dioxodecahydroacridines from condensation of aromatic

aldehydes, cyclic diketones, and ammonium acetate (Scheme 26).

165

Scheme 26

Wang et al421

have reported the synthesis of acridinediones under thermal

heating condition from the condensation reaction of aromatic aldehydes, dimedone,

and ammonium acetate (Scheme 27).

Scheme 27

Moeinpour et al422

have reported synthesis of 1, 8-dioxodecahydroacridines

via one pot three component condensation reaction using silica gel supported

polyphosphoric acid (Scheme 28).

Scheme 28

To et al423

have reported efficient one pot synthesis of acridinediones through

the reaction between dimedone, aromatic aldehyde, and ammonium acetate or anilline

using Indium (III) triflate as catalyst (Scheme 29).

CHO

R

+

O

OR2

R3

2 + NH4OAc

NH

R2R3R3

R2

O O

R

oxalic acid (20 mol %)

ref lux ( 60-80 min)

CHO

R

+

O

OR2

R3

2 + NH4OAc

NH

R2R3R3

R2

O O

R

solvent f ree

1200C, 1.5h

CHO

R

+

O

OR2

R3

2 + NH4OAc

NH

R2R3R3

R2

O O

R

PPA-SiO 2

solvent f ree, 1000C

166

Scheme 29

Davoodnia et al424

have reported carbon based solid acid (CBSA) as reusable,

and efficient catalyst for the synthesis of 1, 8-dioxodecahydroacridines under solvent

free condition (Scheme 30).

Scheme 30

Ziarani et al425

have reported as an efficient catalyst for the synthesis of 1, 8-

dioxodecahydroacridines under solvent free condition using sulfonic acid

functionalized silica catalyst (Scheme 31).

Scheme 31

Vahdat et al426

have reported synthesis of 1, 8-dioxodecahydroacridines under

ambient temperature in ethanol solvent using Indium (III) chloride as catalyst

(Scheme 32).

CHO

R

+

O

OR

R

2 + NH4OH or Ar-NH2

NRR

R

R

O O

R1

R

In(OTf )3

heating

CHO

R

+

O

O

2 + NH4OAc or Ar-NH2

N

O O

R

R

CBSA

solv ent f ree

CHO

R

+

O

O

2 + NH4OAc or R-NH2

N

O O

R

R

SiO2-Pr-SO3H

solv ent f ree

167

Scheme 32

Balalaie et al415

have reported synthesis of 1, 8-dioxodecahydroacridine

derivatives using ammonium chloride or Zn(OAc)2 2H2O or l-proline in water

(Scheme 33).

Scheme 33

The silica gel supported ferric chloride427

, ceric ammonium nitrate in presence

of polyethylene glycol419

, and silica bonded s-sulfonic acid428

are used as a catalyst

for the synthesis of 1, 8-dioxodecahydroacridine derivatives. However, many of these

methods suffered from some drawbacks such as low yield, long reaction time, drastic

reaction conditions, and tedious work up. Occurrence of several side reaction and in

some cases more than one step is involved in the synthesis of compound. Therefore,

there is a need for generation of new methodology with mild reaction conditions,

better yields, short reaction time, and environment friendliness. Now a day‟s metal

oxide nanoparticles are known to be promising material for the heterogeneous catalyst

in a variety of condensation reactions386

. The nanocrystalline CdO also reported as a

catalyst in a few organic transformations429

.

CHO

R2

+

O

O

2 + NH4OAc or R3-NH2

N

O O

R3

R2

InCl3, 1 mol %

C2H5OH, rt

CHO

R

+

O

O

2 + NH4OAc

N

O O

H

R

NH4Cl or Zn(OAc)2.2H2O

or L-proline

168

The CdO nanoparticles were used as catalyst for the synthesis of acridinedione

derivatives from condensation reaction between aromatic aldehydes, dimedone, and

ammonium acetate. The CdO nanoparticles have gained more importance in organic

transformations due to high thermal stability, large surface area, easy recovery, and

good ability to perform organic reactions at room temperature without solvent.

4.2B. Present work:

An efficient method for the synthesis of acridinedione derivatives was

developed under solvent free condition. The reaction between aromatic aldehydes,

dimedone, and ammonium acetate using synthesized nanocrystalline CdO as a

catalyst provided good yield of acridinedione derivatives (Scheme 34).

+

CHO

CdO nanoparticles

R1 2 3

4(a-i)

RO

O

+ NH4OAc

NH

O O

solvent free

1200C

Scheme 34: Synthesis of acridinediones

4.3B. Synthesis of acridinediones:

A mixture of dimedone (2.0 mmol), aromatic aldehyde (1.0 mmol),

ammonium acetate (1.0 mmol), and CdO nanoparticles (60 mg) were heated in an oil

bath at 120oC (Scheme 34). The reaction was monitored by thin layer

chromatography. After completion of reaction, the crude product was collected after

cooling to room temperature and recrystallized from ethanol to furnish compounds

4 (a-i) in high yields. The formation of product was confirmed by comparison of their

physical and spectral data with the authentic samples reported in literature. The

catalyst was separated by filtration, dried at 100oC, and reused for similar reaction.

All the products were characterized by IR, 1H NMR, and mass spectrometry.

169

4.4B. Results and Discussion:

Initially, the three component reaction of dimedone (2.0 mmol), benzaldehyde

(1.0 mmol), and ammonium acetate (1.0 mmol) was carried out in presence of CdO

nanoparticles used as a model reaction to optimize the amount of catalyst. No product

was obtained in the absence of the catalyst even after 60 mins indicating that the

catalyst is necessary for the reaction. It was observed that with increase in amount of

catalyst, the reaction rate, and yield of products was increased. The optimum amount

of the catalyst was found to be 60 mg to proceeds the reaction (Table 4.7). The

increase in the amount of the catalyst beyond optimum amount did not increase the

yield noticeably.

The reaction was carried out in different solvents, under solvent free condition

to study the effect of solvents and temperature on the reaction (Table 4.8). The yield

of reaction under solvent free reaction condition was greater, and short time was

required for completion of reaction. The reaction under solvent free condition was

carried out at different temperatures such as 80o, 100

o, and 120

oC. The best result was

obtained at 120oC for 8 mins under solvent free condition. A series of acridinedione

derivatives was synthesized by using CdO nanoparticles as a catalyst under solvent

free reaction condition (Table 4.9). In all cases aromatic aldehydes with substituents

carrying either electron donating or electron withdrawing groups reacted successfully,

and gave the expected product in excellent yield, and shorter reaction time. The

aromatic aldehydes with electron withdrawing groups react faster than electron

donating groups.

The catalytic efficiency was also checked by its reusability. The catalyst was

recovered, and used four times in a model reaction [dimedone (2.0 mmol),

benzaldehyde (1.0 mmol), and ammonium acetate (1.0 mmol) in presence of CdO]

170

Table 4.7. Optimization of catalyst amount

Entry Amount of catalyst (mg) Time (min) Yield (%)

1 20 10 84

2 40 9 89

3 60 8 92

4 80 8 92

5 100 8 92

Table 4.8. Effect of solvent, and temperature on the synthesis of acridinediones

Entry Solvent Temperature (oC) Time (min) Yield

(%)

1 MeOH 60 210 80

2 EtOH 70 207 82

3 CH3CN 82 202 70

4 H2O 100 194 60

5 Solvent free 80 12 81



171

Table 4.9. Synthesis of acridinediones in presence of CdO nanoparticles

Entry Product

(R)


4a H 8 92 278

4b 2-Cl 16 91 221

4c 4-Cl 4 93 300

4d 2-OCH3 14 88 294

4e 4-OCH3 12 90 272

4f 2-NO2 12 90 288

4g 4-NO2 4 95 286

4h 4-CH3 16 91 269

4i 4-OH 8 89 285

Table 4.10. Reusability of CdO nanoparticles


1 8 92

2 8 92

3 8 92

4 8 91

172

It was found that catalyst showed good results after four turns, and it showed the same

activity as fresh catalyst without any significant loss in its activity (Table 4.10).


and mass spectrometry. Typical 1H NMR spectrum of compound 4g showed the

presence of -NH, -C=O, -CH3, and aromatic protons, which confirms the 3, 3, 6, 6-

tetramethyl-1, 8-dioxo-9-(4-nitrophenyl)-decahydroacridine compound (Fig. 4.7). The

structure of 4g compound was also confirmed by mass spectrum which shows the

(M+1)+

peak at 395 (Fig. 4.8). Similarly the formation of all other compounds was

confirmed on the basis of spectral data.

4.5B. Spectral data:

3, 3, 6, 6-Tetramethyl-1, 8-dioxo-9-(phenyl)-decahydroacridine (4a): mp: 278oC,

Yield: 92 %, IR (KBr): 3474, 2958, 1641, 1617, 1513 cm-1

,

1H NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1H), 7.16-7.03

(m, 5H), 4.83 (s, 1H), 2.48-1.84 (m, 8H), 1.01 (s, 6H), 0.84

(s, 6H), M. F: C23H27NO2, M. W: 349, MS (m/z): 350

(M+1)+.

3, 3, 6, 6-Tetramethyl-1, 8-dioxo-9-(2-chlorophenyl)-decahydroacridine (4b): mp:

221oC, Yield: 91 %, IR (KBr): 3295, 1662, 1601, 1499,

1387, 1221 cm-1

, 1H NMR (400 MHz, DMSO-d6): δ 11.60

(s, 1H), 7.35-7.09 (m, 4H), 5.22 (s, 1H), 2.35-1.80 (m, 8H),

1.16 (s, 6H), 0.98 (s, 6H), M. F: C23H26ClNO2, M. W: 384,

MS (m/z): 385 (M+1)+.

NH

O O

NH

O OCl

173

3, 3, 6, 6-Tetramethyl-1, 8-dioxo-9-(4-chlorophenyl)-decahydroacridine (4c): mp:

300oC, Yield: 93 %, IR (KBr): 3250, 2960, 1653, 1608,

1489, 1367, 1223 cm-1


11.78 (s, 1H), 7.28 (d, 2H, J = 8.0 Hz), 7.19 (d, 2H, J = 8.0

Hz), 5.22 (s, 1H), 2.23-1.99 (m, 8H), 1.11 (s, 6H), 0.96

(s, 6H), M. F: C23H26ClNO2, M. W: 384, MS (m/z): 385

(M+1)+.

3, 3, 6, 6-Tetramethyl-1, 8-dioxo-9-(2-methoxyphenyl)-decahydroacridine (4d):

mp: 294oC, Yield: 88 %, IR (KBr): 3310, 3032, 1637, 1605,

1486, 1364, 1224 cm-1


11.30 (s, 1H), 7.01-6.76 (m, 4H), 5.25 (s, 1H), 3.80 (s, 3H),

2.30-2.02 (m, 8H), 1.03 (s, 6H), 0.92 (s, 6H), M. F:

C24H29NO3, M. W: 379, MS (m/z): 380 (M+1)+.

3, 3, 6, 6-Tetramethyl-1, 8-dioxo-9-(4-methoxyphenyl)-decahydroacridine (4e):

mp: 272oC, Yield: 90 %, IR (KBr): 3202, 2980, 1642, 1609,

1450, 1362, 1221 cm-1


11.92 (s, 1H), 6.98 (d, 2H, J = 8.0 Hz), 6.78 (d, 2H, J = 8.0

Hz), 5.48 (s, 1H), 3.76 (s, 3H), 2.28-2.01 (m, 8H), 1.22

(s, 6H), 1.09 (s, 6H), M. F: C24H29NO3, M. W: 379, MS

(m/z): 380 (M+1)+.

3, 3, 6, 6-Tetramethyl-1, 8-dioxo-9-(2-nitrophenyl)-decahydroacridine (4f): mp:

288oC, Yield: 90 %, IR (KBr): 3233, 2985, 1649, 1596,

1530, 1316, 1218 cm-1


11.85 (s, 1H), 8.13-7.30 (m, 4H), 5.45 (s, 1H), 2.20-1.87

(m, 8H), 1.22 (s, 6H), 1.11 (s, 6H), M. F: C23H26N2O4,

NH

O O

Cl

NH

O OOCH3

NH

O O

OCH3

NH

O ONO2

174

M. W: 394, MS (m/z): 395 (M+1)+.

3, 3, 6, 6-Tetramethyl-1, 8-dioxo-9-(4-nitrophenyl)-decahydroacridine (4g): mp:

286oC, Yield: 95 %, IR (KBr): 3245, 2930, 1636, 1600,

1575, 1350, 1222 cm-1


11.79 (s, 1H), 8.10 (d, 2H, J = 8.0 Hz), 7.22 (d, 2H, J = 8.0

Hz), 5.52 (s, 1H), 2.49-2.29 (m, 8H), 1.19 (s, 6H), 1.09

(s, 6H), M. F: C23H26N2O4, M. W: 394, MS (m/z):

395 (M+1)+.

3, 3, 6, 6-Tetramethyl-1, 8-dioxo-9-(4-methylphenyl)-decahydroacridine (4h): mp:

269oC, Yield: 91 %, IR (KBr): 3235, 2960, 1660, 1603,

1487, 1301, 1203 cm-1


11.80 (s, 1H), 7.40 (d, 2H, J = 8.0 Hz), 7.01 (d, 2H, J = 8.0

Hz), 5.34 (s, 1H), 2.23 (s, 3H), 2.12-1.81 (m, 8H), 1.02

(s, 6H), 0.96 (s, 6H), M. F: C24H29NO2, M. W: 363, MS

(m/z): 364 (M+1)+.

3, 3, 6, 6-Tetramethyl-1, 8-dioxo-9-(4-hydroxyphenyl)-decahydroacridine (4i): mp:

285oC, Yield: 89 %, IR (KBr): 3201, 3005, 1614, 1512,

1472, 1371, 1222 cm-1


12.25 (s, 1H), 11.01 (s, 1H), 6.81 (d, 2H, J = 8.0 Hz), 6.51

(d, 2H, J = 8.0 Hz), 4.60 (s, 1H), 2.42-2.04 (m, 8H), 1.09

(s, 6H), 0.98 (s, 6H), M. F: C23H27NO3, M. W: 365, MS

(m/z): 366 (M+1)+.

NH

O O

NO2

NH

O O

NH

O O

OH

175

Fig. 4.7: 1H NMR spectrum of 4g compound

Fig. 4.8: Mass spectrum of 4g compound

NH

O O

CH3 CH3CH3CH3

H1

NO2

H1

H2H2

H3

44

55

NH

O O

CH3 CH3CH3CH3

H1

NO2

H1

H2H2

H3

44

55

176

Section-C

PbS Nanoparticles as an Effective Catalyst for the One Pot Synthesis of

Amidoalkyl Naphthols Under Solvent Free Condition

4.1C. Introduction:

The biologically active 1-aminomethyl-2-naphthol derivatives can be obtained

from 1-amidomethyl-2-naphthols by amide hydrolysis reaction, which have activities

like hypotensive and brady cardiac effects430

. This 1-aminoalkyl alcohol type ligand is

used as catalyst and in asymmetric synthesis431

. Amidoalkyl naphthols are precursors

for the synthesis of oxazines which are present in variety of biologically important

natural products, potent drugs including a number of nucleoside antibiotics, HIV

protease inhibitors such as ritonavir, and lipinavir432-435

. 1-Amidoalkyl-2-naphthols

can be converted into 1, 3-oxazine derivatives which have potentially different

biological activities including antipsychotic436

, antimalarial437

, antihypertensive438

,

antibiotic, antitumor, and antirheumatic properties439

. Due to the importance of such

activities and properties a number of methods for the synthesis of amidoalkyl

naphthols have been reported in the literature.

Gokavi et al440

have reported the silicotungstic acid (H4SiW12O40) catalyzed

one pot synthesis of amidoalkyl naphthols from condensation of aromatic aldehydes,

2-naphthol, and acetamide (Scheme 35).

Scheme 35

Shinde et al441

have reported synthesis of amidoalkyl naphthols using oxalic

acid as catalyst under solvent free condition (Scheme 36).

OH

+ ArCHO + R CONH2OH

Ar NHCOR

5 mol%, H4SiW12O40

1100C

177

Scheme 36

Xie et al442

have reported one pot multi component synthesis of amidoalkyl

naphthols in presence of potassium hydrogen sulfate under solvent free condition

(Scheme 37).

Scheme 37

Khodaei et al443

have reported synthesis of amidoalkyl naphthols by

condensation reaction of aromatic aldehydes, 2-naphthol, and amides in the presence

of p-toluene sulfonic acid in 1, 2-dichloroethane at room temperature or under solvent

free condition (Scheme 38).

Scheme 38

Ashalua et al444

have reported synthesis of amidoalkyl naphthols using

magnesium sulphate as an efficient Lewis acid catalyst (Scheme 39).

Scheme 39

Hazeri et al445

have reported a one pot three component synthesis of

amidoalkyl naphthols catalyzed by succinic acid (Scheme 40).

OH

+ ArCHO + R CONH2OH

Ar NHCOR

oxalic acid (10 mol%)

solvent free, 1250C

OH

+ R1CHO + R2 CONH2OH

R1 NHCOR2

KHSO4

solvent free, 1000C

OH

+ ArCHO + R CONH2OH

Ar NHCOR

p-TSA

ClCH2-CH2Cl, rt

or neat conditions, 1250C

OH

+ R1CHO + R2 CONH2OH

R1 NHCOR2

MgSO4.7H2O

solvent free, 1000C

178

Scheme 40

Shaterian et al446

have reported synthesis of amidoalkyl naphthols and

carbamatoalkyl naphthols using P2O5/SiO2 as catalyst under solvent free condition

(Scheme 41).

Scheme 41

Aswin et al447

have reported synthesis of amidoalkyl naphthols under solvent

free conditions by ZrOCl2.8H2O recyclable catalyst (Scheme 42).

Scheme 42

Maheria et al448

have reported one pot synthesis of amidoalkyl naphthols using

zeolite H-BEA as heterogeneous catalyst (Scheme 43).

Scheme 43

Several Lewis, and Bronsted acids have been applied to catalyze this

transformation are such as silica gel supported-SO3H functionalized benzimidazolium

based ionic liquid449

, bismuth nitrate450

, amberlite IR-120451

, 1-hexanesulphonic

sodium salt452

, and sodium hydrogen sulfate453

etc. However, some of this catalyst

OH

+ ArCHO + R CONH2OH

Ar NHCOR

succinic acid (5 mol%)

solvent free, 1200C

OH

+ ArCHO + R CONH2OH

Ar NHCOR

P2O5/SiO2

solvent free, 1000C

OH

+ ArCHO + R2 CONH2OH

Ar NHCOR2

ZrOCl2.8H2O (2mol%)

solvent free, 800C

OH

+ ArCHO + OH

Ar NHCOCH3

CH3CONH2

zeolite H-BEA

179

suffers from the drawback of long reaction time, low yields, and use of solvents.

Therefore, the clean process, and heterogeneous green catalysts which can be simply

recycled at the end of the reaction have been under permanent attention.

An efficient and recyclable PbS nanocrystalline catalyst is used for the

synthesis of amidoalkyl naphthols from condensation reaction between aromatic

aldehydes, β naphthol, and acetamide under solvent free reaction condition at 120oC.

4.2C. Present work:

Amidoalkyl naphthol was synthesized using PbS nanoparticles under solvent

free condition by the reaction of aromatic aldehydes, β naphthol, and acetamide. A

series of amidoalkyl naphthols was synthesized in good yield (Scheme 44).

Scheme 44: Synthesis of amidoalkyl naphthols

4.3C. Synthesis of amidoalkyl naphthols:

To a mixture of β naphthol (1.0 mmol), aldehydes (1.0 mmol), and acetamide

(1.2 mmol) the PbS nanoparticles was added as a catalyst. The mixture was stirred

under solvent free condition at 120oC in oil bath for few minutes (Scheme 44). The

reaction was monitored by TLC. The crude product was collected after cooling, and

recrystallized from ethanol to give products 4(a-j) in high yields. The catalyst was

separated by filtration, dried at 100oC for 2 hrs, and reused for similar reaction. All

the products were characterized by IR, 1H NMR, and mass spectrometry. The

formation of product was confirmed by comparison of their physical, and spectral

data with the authentic samples reported in literature.

CHO

R

+OH

+NH2

OOH

NH

O

R

PbS nanoparticles

solvent free, 1200C

1 2 3

4(a-j)

180

4.4C. Results and Discussion:

A series of amidoalkyl naphthol derivatives were prepared by using PbS

nanoparticles as a catalyst (Table 4.11) with excellent yields (85-95 %). An ortho

substituted aromatic aldehydes decrease the yield of the reaction due to the steric

effect while meta and para substituted aromatic aldehydes gave good results. In all the

cases aromatic aldehydes with electron withdrawing groups or electron donating

groups reacted successfully and gave the products in high yields. It was shown that

the aromatic aldehydes with electron withdrawing groups reacted faster than the

aromatic aldehydes with electron releasing group. The reactions proceeds smoothly

and no undesirable side products were observed.

The three component one pot reaction of β naphthol (1.0 mmol), benzaldehyde

(1.0 mmol), acetamide (1.2 mmol), and PbS nanoparticles was used as a model

reaction to optimize amount of the catalyst. The reaction rate and yield was increased

with the amount of catalyst. It was found that 40 mg of the catalyst was appropriate

amount for completion of reaction (Table 4.12). Small amount of catalyst gave low

yield even after a long reaction time while more amounts did not cause a significant

increase in the yield of product.

The reusability of the catalyst is one of the most important benefits, and makes

it useful for commercial applications. The reusability of the PbS nanoparticles catalyst

was checked for model condition. The catalyst was found to be recovered and reused

for five times for a model reaction (Table 4.13).


and mass spectrometry. Typical 1H NMR spectrum of compound 4a showed the

presence of -CH3, -NH, and phenolic -OH protons which confirms the formation of

181

Table 4.11. Synthesis of amidoalkyl naphthols in presence of PbS nanoparticles

Entry Product

(R)

Time (min) Yield (%) M. P.(oC)

4a H 6 95 242

4b 4-CH3 8 90 223

4c 4-Cl 5 92 224

4d 4-OCH3 8 89 185

4e 4-NO2 4 85 249

4f 3-NO2 5 89 240

4g 2-Cl 7 87 214

4h 2-NO2 9 86 181

4i 2-CH3 9 89 201

4j 3-OCH3 9 93 202



1 20 9 81

2 30 8 89

3 40 6 95

4 50 6 94

5 60 6 93

Table 4.13. Reusability of the catalyst

Cycles Yield (%)

1 95

2 95

3 95

4 94

5 93

182

N-[phenyl-(2-hydotroxynapthalen-1-yl)-methyl]-acetamide compound (Fig. 4.9). The

structure of 4e compound was confirmed by mass spectrum which shows the (M+1)+

peak at 337 (Fig. 4.10). Similarly the formation of all other compounds was

confirmed on the basis of their spectral data.

4.5C. Spectral data:

N-[Phenyl-(2-hydroxynapthalen-1-yl)-methyl]-acetamide (4a): mp: 242oC, Yield:

95 %, IR (KBr): 3406, 3243, 3067, 1642, 1587, 1511, 1374, 1067,

804, 746 cm-1

, 1H NMR (400 MHz, DMSO-d6): δ 9.85 (s, 1H),

8.29 (d, 1H, J = 8.50 Hz), 7.94-7.69 (m, 3H), 7.39-7.12 (m, 9H),

2.02 (s, 3H), M. F: C19H17NO2, M. W: 291, MS (m/z): 292

(M+1)+.

N-[(4-Methylphenyl-(2-hydroxynapthalen-1-yl)-methyl]-acetamide(4b): mp: 223oC,

Yield: 90 %, IR (KBr): 3418, 3315, 3068, 1620, 1597, 1560,

1467, 1394, 1057, 940, 884 cm-1


d6): δ 9.92 (s, 1H), 8.37 (d, 1H, J = 8.0 Hz), 7.83 (br, 1H), 7.79

(d, 1H, J = 8.0 Hz), 7.75 (d, 1H, J = 8.0 Hz), 7.35 (m, 1H), 7.25

(t, 1H, J = 7.10 Hz), 7.20 (d, 1H, J = 8.0 Hz), 7.09-7.03 (m, 5H), 2.21 (s, 3H), 1.96

(s, 3H), M. F: C20H19NO2, M. W: 305, MS (m/z): 306 (M+1)+.

N-[(4-Chlorophenyl-(2-hydroxynapthalen-1-yl)-methyl]-acetamide(4c): mp: 224oC,

Yield: 92 %, IR (KBr): 3391, 3350, 2961, 1636, 1577, 1491,

1437, 1374, 1091, 820, 746 cm-1


d6): δ 9.95 (s, 1H), 8.23 (d, 1H, J = 8.0 Hz), 7.71-7.61 (m, 3H),

7.67 (d, 1H, J = 8.0 Hz), 7.30-7.21 (m, 5H), 7.16-7.12 (m, 2H),

2.04 (s, 3H), M. F: C19H16ClNO2, M. W: 326, MS (m/z): 327 (M+1)+.

OH

NH

O

OH

NH

O

OH

NH

OCl

183

N-[(4-Methoxyphenyl)-(2-hydroxynapthalen-1-yl)-methyl]-acetamide (4d): mp:

185oC, Yield: 89 %, IR (KBr): 3393, 3252, 3065, 1692,

1584, 1511, 1434, 1374, 1083, 984 cm-1

, 1H NMR (400

MHz, DMSO-d6): δ 9.45 (s, 1H), 8.31 (d, 2H, J = 8.0 Hz),

7.80-7.74 (m, 2H), 7.51 (t, 2H, J = 7.30 Hz), 7.45-7.31

(m, 3H), 6.68 (s, 1H), 6.61 (d, 2H, J = 8.0 Hz), 3.52 (s, 3H), 2.01 (s, 3H), M. F:

C20H19NO3, M. W: 321, MS (m/z): 322 (M+1)+.

N-[(4-Nitrophenyl)-(2-hydroxy-napthalen-1-yl)-methyl]-acetamide (4e): mp: 249oC,

Yield: 85 %, IR (KBr): 3375, 3260, 3094, 1677, 1571, 1544,

1457, 1091, 837 cm-1


9.82 (s, 1H), 8.50 (d, 1H, J = 8.0 Hz), 8.00-7.88 (m, 3H),

7.73 (d, 2H, J = 8.0 Hz), 7.64-7.55 (m, 2H), 7.31-7.14 (m,

4H), 2.05 (s, 3H), M. F: C19H16N2O4, M. W: 336, MS (m/z): 337 (M+1)+.

N-[(3-Nitrophenyl)-(2-hydroxy-napthalen-1-yl)-methyl]-acetamide (4f): mp: 240oC,

Yield: 89 %, IR (KBr): 3373, 3224, 2921, 1647, 1573, 1438,

1374, 1039, 1002, 924, 809 cm-1


δ 10.11 (s, 1H), 8.54 (d, 1H, J = 8.0 Hz), 7.79-7.77 (m, 5H), 7.64

(d, 1H, J = 8.0 Hz), 7.20-7.16 (m, 5H), 2.07 (s, 3H), M. F:

C19H16N2O4, M. W: 336, MS (m/z): 337 (M+1)+.

N-[(2-Chlorophenyl)-(2-hydroxy-napthalen-1-yl)-methyl]-acetamide (4g):

mp: 214oC, Yield: 87 %, IR (KBr): 3325, 3062, 1647, 1513, 1267,

809 cm-1

, 1H NMR (400 MHz, DMSO-d6): δ 9.77 (s, 1H), 8.50

(s, 1H), 8.00 (t, 1H, J = 7.0 Hz), 7.77 (d, 1H, J = 7.0 Hz), 7.71

(d, 1H, J = 7.0 Hz), 7.54-7.07 (m, 8H), 1.92 (s, 3H), M. F: C19H16ClNO2, M. W: 326,

MS (m/z): 327 (M+1)+.

OH

NH

OH3CO

OH

NH

OO2N

OH

NH

O

NO2

OH

Cl

NH

O

184

N-[(2-Nitrophenyl)-(2-hydroxy-napthalen-1-yl)-methyl]-acetamide (4h): mp: 181oC,

Yield: 86 %, IR (KBr): 3370, 3234, 3104, 1677, 1573, 1312,

1039 cm-1


(d, 1H, J = 8.30 Hz), 8.04 (d, 1H, J = 8.30 Hz), 7.91 (d, 1H,

J = 8.30 Hz), 7.83-7.71 (m, 4H), 7.40-7.12 (m, 5H), 2.02 (s, 3H),

M. F: C19H16N2O4, M. W: 336, MS (m/z): 337 (M+1)+.

N-[(2-Methylphenyl-(2-hydroxynapthalen-1-yl)-methyl]-acetamide (4i): mp: 201oC,

Yield: 89 %, IR (KBr): 3384, 3264, 2933, 1677, 1570, 1507,

1316, 1050 cm-1


8.38 (d, 1H, J = 8.0 Hz), 7.78-7.60 (m, 4H), 7.22-6.48 (m, 7H),

2.23 (s, 3H), 1.97 (s, 3H), M. F: C20H19NO2, M. W: 305, MS

(m/z): 306 (M+1)+.

N-[(3-Methoxyphenyl)-(2-hydroxynapthalen-1-yl)-methyl]-acetamide(4j):

mp: 202oC, Yield: 93 %, IR (KBr): 3382, 3262, 3081, 1682,

1566, 1237, 1025 cm-1

, 1H NMR (400 MHz, DMSO-d6): δ 9.84

(s, 1H), 8.10-8.07 (m, 2H), 7.77-7.71 (m, 2H), 7.32-6.93 (m, 7H),

6.74 (s, 1H), 3.60 (s, 3H), 2.05 (s, 3H), M. F: C20H19NO3, M. W:

321, MS (m/z): 322 (M+1)+.

OH

NH

O

OCH3

OH

NH

O

OH

NO2

NH

O

185


Fig. 4.10: Mass spectrum of 4e compound

OH

H1

H2H3

H4

H5

H8

H9

H10

CH3

H6

NH

O H11

H7

H12

OH

NH

OO2N

186

Section-D

ZnS Nanoparticles as an Efficient Solid Catalyst for Synthesis of 5-Arylidene

Barbituric Acid Under Solvent Free Condition

4.1D. Introduction:

The 5-alkylidene or arylidene barbituric acid derivatives are important

members of the pyrimidine family. The barbituric acids are an excellent target

compound for organic and medicinal chemists due to their diverse biological activity

and coverage of a broad chemical space454

. Due to their ready availability and various

functionalization possibilities, the parent barbituric acid and 2-thiobarbituric acid are

convenient starting compounds for the preparation of different fused heterocycles and

their derivatives which are pharmacologically the most important class of barbituric

acid-based compounds455, 456

. Barbitals (5, 5-diethyl barbituric acid) possess sedative

and hypnotic activity457

.

Arylidene-pyrimidine-2, 4, 6-trione, arylidene-2-thioxodihydropyrimidine-4,

6-dione, and its derivatives are compounds which have variety of pharmacological

activities458

. They also possess biological activities such as hypotensive, tranquilizer,

and good antibacterial agents459

. Some barbituric acid derivatives have been widely

used as anticonvulsant, antispasmodic, and local anaesthetic agents460

. Benzylidene

barbituric acids are useful as potential organic oxidizers461

, unsymmetrical synthesis

of disulfides458

, and they have been recently studied as non linear optical materials462

.

Benzylidene barbiturates are also used as a safe tyrosinase inhibitors463

. Thus the

synthesis of arylidene barbituric acid derivatives is recently of very much importance.

There are several reported methods in the literature for the synthesis of arylidene

barbituric acid derivatives.

187

Khalafi-Nezhad et al464

have reported the basic alumina catalyzed synthesis of

arylidene barbituric acid derivatives in presence of microwave irradiation

(Scheme 45).

Scheme 45

Kikelj et al465

have reported the synthesis of arylidene barbituric acid

derivatives in presence of water at reflux condition (Scheme 46).

Scheme 46

Mashaly et al466

have reported condensation of thiobarbituric, and barbituric

acids with aromatic aldehydes in water using ethanolamine or sodium p-toluene

sulfonate as catalyst (Scheme 47).

Scheme 47

Thirupathi et al467

has reported synthesis of barbituric and thiobarbituric acid

derivatives using an efficient L-tyrosine as a catalyst in aqueous medium at room

temperatute (Scheme 48).

ArCHO +NHNH

O O

O

MW irradiation

basic alumina, 3-5 min

NHNH

O O

O

Ar

ArCHO +NHNH

O O

O

NHNH

O O

O

Ar

water, reflux 12 h

ArCHO +NHNH

O O

O

NHNH

O O

O

Ar

H2O, EA

stirr, rt

188

ArCHO +NHNH

O O

O

NHNH

O O

O

Ar

w ater / 8-16 min.

L-tyrosine / R T

X= O / S X= O / S

Scheme 48

Delgado et al468

have reported synthesis of benzylidene barbituric acids

promoted by infrared irradiation under solvent free condition (Scheme 49).

Scheme 49

Rathod et al469

have reported synthesis of 5-arylidine barbituric acid

derivatives in microwave using metal oxides containing cerium, Mg, and Zr metals

[Ce1MgxZr1-xO2] as solid heterogeneous catalyst (Scheme 50).

Scheme 50

Li et al

470 have reported synthesis of the derivatives of 5-arylidene barbituric

acid catalyzed by aminosulfonic acid with grinding method (Scheme 51).

Scheme 51

ArCHO +NHNH

O O

O

NHNH

O O

O

Ar

IR lamp

ArCHO +NHNH

O O

O

NHNH

O O

O

Ar

CMZO (1:0.6:0.4)

450 W

ArCHO +NHNH

O O

O

NHNH

O O

O

Ar

H2NSO3H, rt

grinding

189

Bhuyan et al471

have reported synthesis of 5-alkylated barbituric acids through

microwave assisted three component reaction in solvent free condition using Hantzsch

1, 4-dihydropyridines as reducing agents (Scheme 52).

Scheme 52

Several catalysts have been applied to catalyze this transformation such as

SiO2.12WO3.24H2O472

, ionic liquid473

, nickel nanoparticles474

, and LaCl3.7H2O475

etc.

However, some of these catalysts suffers from the drawback of long reaction time,

low yields, and are toxic. Therefore, solvent free clean process, and heterogeneous

green catalysts which can be simply recycled at the end of the reactions have been

under permanent attention.

Nanoparticles have the potential for improving the efficiency, selectivity, and

yield of catalytic processes. Recently, nanocrystalline ZnS was used as a catalyst in

organic synthesis476

. To explore the catalytic activity of ZnS nanoparticles in organic

synthesis, herein a simple synthesis of 5-arylidene barbituric acid derivatives using

ZnS nanoparticles as reusable catalyst under solvent free condition with grinding at

room temperature has been reported.

4.2D. Present work:

An efficient method for the synthesis of 5-arylidene barbituric acid derivatives

is developed under solvent free condition by grinding method at room temperature

using ZnS nanoparticles. The reaction between aromatic aldehydes, and barbituric

acid using synthesized nanocrystalline ZnS as a catalyst provided good yield of the

products (Scheme 53).

CHO

R

+NHNH

O

O O

NHNH

O

O O

Ar

dihydropyridines

MW

190

+

CHO

ZnS nanoparticles

catalystgrinding, rt

R1 2 3(a-i)

NHNH

O O

O NHNH

O O

O

R

Scheme 53: Synthesis of 5-arylidene barbituric acid derivatives

4.3D. Synthesis of 5-arylidene barbituric acids:

Aromatic aldehydes (1.0 mmol) and barbituric acid (1.0 mmol) were mixed

with ZnS nanoparticles as a catalyst (40 mg) in a beaker at room temperature. The

reaction mixture was grounded, and progress of reaction was monitored by thin layer

chromatography technique. The crude product was collected and recrystallized from

ethanol to give pure products 3(a-i) in high yields. The catalyst was separated by

filtration, dried at 110oC for 2 hrs and reused for similar reaction. All the products

were characterized by IR, 1H NMR,


4.4D. Results and Discussion:

The reaction between benzaldehyde (1.0 mmol) and barbituric acid (1.0 mmol)

was used as a model reaction to optimize the amount of catalyst. It was found that 40

mg of ZnS nanoparticles was the appropriate quantity of the catalyst to offer the

reaction (Table 4.14). All reactions were performed by grinding method at room

temperature, and were completed within 2-7 mins. A blank reaction of benzaldehyde

and barbituric acid was performed to confirm the effectiveness of ZnS nanoparticles.

In absence of ZnS nanoparticles the reaction was incomplete even after 2 hrs. After

optimizing the reaction conditions a variety of aromatic aldehydes were reacted with

barbituric acid under similar reaction condition to evaluate the scope of this reaction.

A series of 5-arylidene barbituric acid derivatives were prepared by using ZnS

nanoparticles as a catalyst (Table 4.15) with excellent yields (89-96 %) at room

191

temperature. The reaction proceeds smoothly and no undesirable side reactions were

observed. The nature of substituents on the aromatic ring does not affect on the

condensation reaction. The condensation reactions of aromatic aldehydes carrying

electron donating or electron drawing groups were also successfully carried out with

this method in excellent yields and short reaction time.

The catalytic efficiency of ZnS nanoparticles was also checked by its

reusability. It was found that catalyst showed good results after four successive runs

without any significant loss in its activity (Table 4.16).

The structure of all of the synthesized compound was confirmed by IR, 1H

NMR, 13

C NMR, and mass spectrometry. Typical 1H NMR spectrum of compound 3e

showed the presence of -NH, phenolic -OH, and aromatic protons which confirms the

formation of 5-(4-hydroxybenzylidene) barbituric acid (Fig. 4.11). 13

C NMR showed

peaks at 164.01, 163.16, and 162.02 δ due to –C=O carbon and 156.25 δ due to

carbon attached to phenolic -OH group which confirms the formation of compound 3e

(Fig. 4.12). The structure of 3a compound was confirmed by its mass spectrum which

shows the (M+1)+ peak at 217 (Fig. 4.13). Similarly the formation of all other

compounds was confirmed on the basis of their spectral data.

192



1 10 5 87

2 20 4 89

3 30 3 91

4 40 2 92

5 50 2 92

6 60 2 92

Table 4.15. Synthesis of 5-arylidene barbituric acids using ZnS nanoparticles

Entry Product

(R group)


3a H 2 92 263

3b 4-Cl 3 94 299

3c 4-CH3 7 93 279

3d 4-Br 2 95 293

3e 4-OH 3 96 >300

3f 3-NO2 4 88 246

3g 4-NO2 2 94 294

3h 4-OCH3 3 89 277

3i 2-Cl 3 90 253

Table 4.16. Reusability of ZnS nanoparticles catalyst

Cycles Yield (%)

1 92

2 92

3 91

4 89

193

4.5D. Spectral data:

5-Benzylidenebarbituric acid (3a): mp: 263oC, Yield: 92 %, IR (KBr): 3459, 3219,

3062, 1747, 1565 cm-1

, 1H NMR (400 MHz, DMSO-d6): δ 11.22

(s, 1H), 11.10 (s, 1H), 10.58 (s, 1H), 8.33-8.27 (m, 3H), 6.85

(d, 2H, J = 7.10 Hz), 13

C NMR (100 MHz, DMSO): δ 163.6, 162.2,

155.7, 150.4, 133.7, 133.3, 132.4, 128.3, 119.2, M. F: C11H8N2O3,

M. W: 216, MS (m/z): 217 (M+1)+.

5-(4-Chlorobenzylidene) barbituric acid (3b): mp: 299oC, Yield: 94 %, IR (KBr):

3430, 3214, 3087, 1752, 1675, 1578, 1090 cm-1

, 1H NMR (400

MHz, DMSO-d6): δ 11.37 (s, 1H), 11.20 (s, 1H), 8.24 (d, 2H,

J = 8.0 Hz), 8.07 (s, 1H), 7.51 (d, 2H, J = 8.0 Hz), 13

C NMR (100

MHz, DMSO): δ 163.6, 162.1, 153.4, 150.1, 137.5, 135.3, 132.1,

128.3, 120.2, M. F: C11H7ClN2O3, M. W: 251, MS (m/z): 252 (M+1)+.

5-(4-Methylbenzylidene) barbituric acid (3c): mp: 279oC, Yield: 93 %, IR (KBr):

3490, 3350, 3092, 1729, 1679, 1658, 1574 cm-1

, 1H NMR (400

MHz, DMSO-d6): δ 11.43 (s, 1H), 11.26 (s, 1H), 8.34 (s, 1H),

8.13-7.38 (m, 4H), 2.15 (s, 3H), 13


163.8, 162.1, 155.7, 150.6, 143.8, 134.5, 130.2, 129.4, 118.1,

21.6, M. F: C12H10N2O3, M. W: 230, MS (m/z): 231 (M+1)+.

5-(4-Bromobenzylidene) barbituric acid (3d): mp: 293oC, Yield: 95 %, IR (KBr):

3495, 3360, 3090, 1737, 1672, 1561 cm-1

, 1H NMR (400 MHz,

DMSO-d6): δ 11.41 (s, 1H), 11.24 (s, 1H), 8.24 (s, 1H), 8.01-7.77

(m, 4H), 13

C NMR (100 MHz, DMSO): δ 165.11, 160.2, 153.2,

150.2, 134.5, 131.8, 131.1, 127.6, 119.7, M. F: C11H7BrN2O3,

M. W: 295, MS (m/z): 296 (M+1)+.

NHNH

O O

O

NHNH

O O

O

Cl

NHNH

O O

O

NHNH

O O

O

Br

194

5-(4-Hydroxybenzylidene) barbituric acid (3e): mp: >300oC, Yield: 96 %, IR (KBr):

3542, 3418, 3260, 3080, 1742, 1660, 1581, 1527, 1281 cm-1

,

1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 11.10 (s, 1H),

10.58 (s, 1H), 8.33-8.27 (m, 3H), 6.85 (d, 2H, J = 8.80 Hz),

13C NMR (100 MHz, DMSO): δ 164.01, 163.16, 162.02,

156.25, 150.09, 138.57, 123.65, 115.37, 113.45, M. F: C11H8N2O4, M. W: 232,

MS (m/z): 233 (M+1)+.

5-(3-Nitrobenzylidene) barbituric acid (3f): mp: 246oC, Yield: 88 %, IR (KBr): 3442,

3240, 3095, 1780, 1697, 1596, 1537, 1435 cm-1

, 1H NMR (400

MHz, DMSO-d6): δ 11.45 (s, 1H), 11.30 (s, 1H), 8.90 (s, 1H), 8.34

(s, 1H), 8.31-8.28 (m, 1H), 8.23-8.21 (m, 1H), 7.73 (t, 1H, J = 8.0

Hz), 13

C NMR (100 MHz, DMSO): δ 165.0, 162.4, 152.3, 150.4,

150.1, 145.0, 135.0, 133.4, 132.4, 131.2, 118.1, M. F: C11H7N3O5,

M. W: 261, MS (m/z): 262 (M+1)+.

5-(4-Nitrobenzylidene) barbituric acid (3g): mp: 294oC, Yield: 94 %, IR (KBr):

3323, 3242, 3095, 1742, 1692, 1596, 1517 cm-1

, 1H NMR (400

MHz, DMSO-d6): δ 11.46 (s, 1H), 11.30 (s, 1H), 8.31 (s, 1H),

8.23 (d, 2H, J = 8.70 Hz), 8.01 (d, 2H, J = 8.70 Hz), 13

C NMR

(100 MHz, DMSO): δ 165.2, 162.0, 157.3, 150.2, 136.4,

136.2, 135.1, 134.4, 118.1, M. F: C11H7N3O5, M. W: 261, MS (m/z): 262 (M+1)+.

5-(4-Methoxybenzylidene) barbituric acid (3h): mp: 277oC, Yield: 89 %, IR (KBr):

3401, 3233, 3094, 1712, 1672, 1546, 1206 cm-1

, 1H NMR

(400 MHz, DMSO-d6): δ 11.32 (s, 1H), 11.17 (s, 1H), 8.30

(s, 1H), 8.12-7.35 (m, 4H), 3.84 (s, 3H), 13

C NMR (100

MHz, DMSO): δ 164.4, 163.6, 162.7, 155.2, 150.2, 137.5,

NHNH

O O

O

OH

NHNH

O O

O

NO2

NHNH

O O

O

O2N

NHNH

O O

O

H3CO

195

125.4, 115.7, 114.2, 56.2, M. F: C12H10N2O4, M. W: 246, MS (m/z): 247 (M+1)+.

5-(2-Chlorobenzylidene) barbituric acid (3i): mp: 253oC, Yield: 90 %, IR (KBr):

3360, 3230, 3075, 1732, 1657, 1547 cm-1

, 1H NMR (400 MHz,

DMSO-d6): δ 11.56 (s, 1H), 11.29 (s, 1H), 8.33 (s, 1H), 7.77 (d, 1H,

J = 7.60 Hz), 7.72 (d, 1H, J = 7.60 Hz), 7.49 (d, 1H, J = 7.60 Hz),

7.38 (d, 1H, J = 7.60 Hz), 13

C NMR (100 MHz, DMSO): δ 162.7,

161.1, 150.9, 150.1, 133.6, 132.4, 132.1, 130.9, 129.4, 126.7, 122.3, M. F:

C11H7ClN2O3, M. W: 251, MS (m/z): 252 (M+1)+.

NHNH

O O

O

Cl

196

Fig. 4.11: 1H NMR spectrum of 3e compound

Fig. 4.12: 13

C NMR Spectrum of 3e compound

N

NO

O

O

H

H

H1

H2

H2' H3

H3' OH

N

NO

O

O

H

H

H1

H2

H2' H3

H3' OH

197

Fig. 4.13: Mass spectrum of 3a compound

NHNH

O O

O

198

Section-E

Comparative Study on Catalytic Efficiency of Synthesized Nanoparticles

Towards Synthesis of Pyranopyrazoles

4.1E Introduction:

Pyranopyrazoles and their derivatives are important class of heterocyclic

compounds due to their pharmacological and biological properties477

. They are widely

used in biodegradable agrochemicals and pharmaceutical ingredients478

.

Pyranopyrazoles exhibit biological properties such as anti-inflammatory, anticancer,

antimicrobial, analgesic activity, and act as a hypoglycemic, hypotensive, and

vasodilators agents479, 480

. The derivatives of pyranopyrazole have an affinity toward

A1 and A2a adenosine receptors481

. They also exhibits molluscicidal activity and used

as a screening kit for Chk1kinase inhibitor482

. Substituted pyranopyrazoles derivatives

have been found to be effective antiplatelet agents483

. Therefore, the synthesis of

pyranopyrazole derivatives is recently of much interest. There are several methods

reported in the literature for the synthesis of pyranopyrazoles.

Otto et al484

have reported a base catalyzed two component Michael type

reaction between 4-arylidiene-1-phenyl-1H-pyrazol-5-one and malononitrile for the

synthesis of various 4-aryl-4H-pyrano[2,3-c] pyrazoles (Scheme 54).

Scheme 54

O

NN

CN

NH2Ph

+CN

CN

R

N

N

OPh

R

EtOH

base

199

Shestopalov et al485, 486

have reported the synthesis of spiropyrazolopyran by

three component condensation between pyrazol-5-one, N-methylpiperidone and

malononitrile in absolute ethanol by heating or electrochemical method under an inert

atmosphere (Scheme 55).

Scheme 55

Bihani et al487

have reported the synthesis of dihydropyrano [2, 3-c] pyrazoles

by a four component reaction of ethyl acetoacetate, hydrazine hydrate, aldehyde, and

malononitrile in boiling water (Scheme 56).

Scheme 56

Pasha et al488

have reported synthesis of pyranopyrazoles at 25oC using iodine

as a catalyst through four component reaction of ethyl acetoacetate, hydrazine

hydrate, malononitrile, and aldehydes (Scheme 57).

Scheme 57

Mohammadi et al489

have reported synthesis of dihydropyranopyrazole

derivatives through a four component reaction of benzaldehyde, ethyl acetoacetate,

+CN

CNN

NH

O

+N

O

electrochemical

or heatingO

NNH

CN

NH2

N

NH2 NH2 +O

OEt

O

+ R CHO+CN

CN

O

NNH

R

CN

NH2

boiling water

NH2 NH2 +O

OEt

O

+ +CN

CN

O

NNH

CN

NH2

R

CHO

R

H2O

Iodine

200

hydrazine hydrate, and malononitrile in the presence of 3-methyl-1-(4-sulphonic acid)

butyl imidazolium hydrogen sulphate as a catalyst under solvent free condition

(Scheme 58).

Scheme 58

Bandgar et al490

have reported synthesis of pyranopyrazoles through one pot

four component reaction of ethyl acetoacetate, hydrazine hydrate, aldehydes, and

malononitrile in the presence of silicotungstic acid under solvent free condition

(Scheme 59).

Scheme 59

Peng et al491

have reported two component reaction involving pyran

derivatives, and hydrazine hydrate to obtain pyranopyrazoles in water using

combination of microwave, and ultrasonic irradiation (Scheme 60).

Scheme 60

Patel et al492

have reported microwave assisted multi component synthesis of

3 indolyl substituted pyranopyrazole derivatives, and their antimicrobial activity

(Scheme 61).

NH2 NH2 +O

OEt

O

+ R CHO+CN

CN ((CH2)4SO3HMIM)(HSO 4)

solvent f ree, rtO

NNH

R

CN

NH2

NH2 NH2 +O

OEt

O

+ R CHO+CN

CN

O

NNH

R

CN

NH2

silicotungstic acid

neat, 600C

NH2 NH2 +O

NNH

CN

NH2O

OEt

OCN

NH2

w ater, CMUI

piperidine

201

Scheme 61

However, some of these methods suffer from the drawback of long reaction

time, and low yield. Therefore, use of solvent free condition, heterogeneous, and

green catalysts is under permanent attention. Recently, nanocrystalline metal oxide,

and metal sulphide are used as a catalyst in organic synthesis476

. To explore the

catalytic activity of metal oxide and metal sulphide nanoparticle in organic synthesis,

the synthesis of pyranopyrazole derivatives using metal oxide, and metal sulphide

nanoparticles catalyst under solvent free condition with grinding at room temperature

has been reported.

4.2E. Present work:

A simple method for the synthesis of pyranopyrazole derivatives is developed

under solvent free condition by grinding method at room temperature using

synthesized PbO/CdO/PbS/ZnS nanoparticles, to compare the catalytic efficiency of

synthesized PbO/CdO/PbS/ZnS nanoparticles. The reaction between aromatic

aldehydes, hydrazine hydrate, ethyl acetoacetate, and malononitrile using synthesized

nanoparticles (PbO/CdO/PbS/ZnS) as a catalyst provided good yields of the products

(Scheme 62).

O

NNH

CN

NH2

NH2 NH2 +O

OEt

O

+

CHO

+CN

CN ZnS nanoparticles

catalystgrinding, rt

R

R1 2 3 4 5(a-h)

Scheme 62: Synthesis of pyranopyrazoles

+CN

CNN

NH

O

+ Ar CHO

O

NNH

CN

NH2

Ar

MWI

202

4.3E. Synthesis of pyranopyrazoles:

To compare the catalytic activity of synthesized nanoparticles the model

reaction was carried out in presence of PbO/CdO/PbS/ZnS nanoparticles catalyst. In a

model reaction mixture of hydrazine hydrate (1.0 mmol), ethyl acetoacetate

(1.0 mmol), catalyst (50 mg), aromatic aldehyde (1.0 mmol), and malononitrile

(1.0 mmol) was grinded at room temperature. The products were recrystallized using

hot ethanol to obtain the pure products. All the products were characterized by IR,

1H NMR, and mass spectrometry.

After optimization of the catalytic efficiency of PbO/CdO/PbS/ZnS

nanoparticles, a series of pyranopyrazoles was synthesized. To a mixture of hydrazine

hydrate (1.0 mmol) and ethyl acetoacetate (1.0 mmol), ZnS nanoparticle (50 mg) was

added, and stirred for few minutes. Then aldehyde (1.0 mmol) and malononitrile

(1.0 mmol) was added to it and the reaction mixture was grinded at room temperature.

After completion of reaction, the crude product was recrystallized from hot ethanol to

afford the pure products 5(a-h) in high yields. The catalyst was separated by filtration,

dried at 110oC for 2 hrs and reused for similar reaction. All the products were

characterized by IR, 1H NMR, and mass spectrometry.

4.4E. Results and Discussion:

The model reaction in presence of synthesized PbO/CdO/PbS/ZnS

nanoparticles reveals that among all these synthesized nanoparticles efficiency

towards synthesis of pyranopyrazoles, ZnS nanoparticles has more catalytic activity.

The catalytic activity of synthesized nanoparticles has order PbO < CdO < PbS < ZnS

for the synthesis of pyranopyrazoles (Table 4.17). This is due to average particle size

of the synthesized nanoparticles, and the average particle size of the synthesized

nanoparticles has order of PbO < CdO < PbS < ZnS (Table 4.18).

203

After optimizing the reaction conditions a variety of aromatic aldehydes with

hydrazine hydrate, ethyl acetoacetate, and malononitrile were employed under same

reaction condition to evaluate the scope of this reaction. A series of pyranopyrazoles

were prepared by using ZnS nanoparticles as a catalyst (Table 4.19) with excellent

yields at room temperature with grinding at solvent free condition. The reaction

proceeds efficiently by either electron releasing or electron withdrawing substituents

on aryl ring of aldehyde. In case of aromatic aldehydes the nature of substituents of

aromatic aldehydes did not have appreciable effect on overall yields of the product.

The electron deficient aldehydes gave excellent yield of products. The position (o, m

and p) of the substituted aromatic aldehydes did not show any noticeable effect on

either the reaction time or the yield.

The catalyst was filtered after completion of the reaction, washed with

ethanol, and heated at 120oC in oven for 2 hrs. The recovered catalyst was further

used in several successive runs under identical reaction condition. The catalyst shows

a good catalytic activity and stable even after five times (Table 4.20).

The structure of all the synthesized compound was confirmed by spectroscopic

techniques including IR, 1H NMR,

13C NMR, and mass spectrometry. Typical

1H NMR spectrum of compound 5a showed the presence of -NH, -NH2, and aromatic

protons which confirms the presence of 6-amino-3-methyl-4-phenyl-2, 4-

dihydropyrano [2, 3-c] pyrazoles-5-carbonitrile compound (Fig. 4.14). 13

C NMR

spectrum shows peaks at 154.72 and 120.75 δ due to carbon attached to -NH2 group,

and –CN carbon confirms the formation of compound 5a (Fig. 4.15). The structure of

5b compound was confirmed by its mass spectrum which shows the (M+1)+ peak at

298 (Fig. 4.16). Similarly the formation of all other compoundas was confirmed on

the basis of their spectral data.

204

Table 4.17. Comparison of catalytic activity of synthesized nanoparticles

Entry Synthesized

nanoparticles

Product

(R group)

Time

(min)

Yield

(%)

M. P.(oC)

5a

PbO

H 17 85 244

5b 4-OCH3 34 81 211

5c 4-NO2 10 92 195

5a

CdO

H 14 88 244

5b 4-OCH3 30 83 211

5c 4-NO2 8 94 195

5a

PbS

H 11 90 244

5b 4-OCH3 25 86 211

5c 4-NO2 7 96 195

5a

ZnS

H 8 92 244

5b 4-OCH3 21 88 211

5c 4-NO2 5 97 195

Table 4.18. Comparison between synthesized nanoparticles

Sr.

No.

Synthesized

nanoparticles

BET surface area

(m2/gm)

Band gap

energy

(eV)

Average

particle

size (nm)

1 PbO 29.38 3.13 69

2 CdO 29.71 3.64 47

3 PbS 15.65 4.20 31

4 ZnS 36.30 4.07 20

205

Table 4.19. Synthesis of pyranopyrazoles in presence of ZnS nanoparticles

Entry Product

(R group)

Time (min) Yield (%) M. P (oC)

5a H 8 92 244

5b 3-NO2 10 94 193

5c 4-NO2 5 97 195

5d 4-Br 11 96 206

5e 4-OCH3 21 88 211

5f 4-CH3 20 87 202

5g 4-OH 16 93 225

5h 4-Cl 20 96 175

Table 4.20. Reusability of ZnS catalyst

Cycles Yield (%)

1 92

2 92

3 92

4 91

5 90

206

4.5E. Spectral data:

6-Amino-3-methyl-4-phenyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(5a):

mp: 244oC, Yield: 92 %, IR (KBr): 3370, 3307, 2190, 1609, 1591,

1441 cm-1

, 1H NMR (400 MHz, DMSO-d6): δ 12.08 (s, 1H), 7.33-

7.15 (m, 5H), 6.85 (s, 2H), 4.58 (s, 1H), 1.78 (s, 3H), 13

C NMR

(100 MHz, DMSO): δ 160.82, 154.72, 144.39, 135.51, 128.36,

127.43, 126.67, 120.75, 97.56, 57.15, 36.24, 9.71, M. F: C14H12N4O, M. W: 252, MS

(m/z): 253 (M+1)+.

6-Amino-3-methyl-4-(3-nitrophenyl)-2, 4-dihydropyrano [2, 3-c]pyrazole-5-carboni-

trile (5b): mp: 193oC, Yield: 94 %, IR (KBr): 3381, 3288, 2192,

1626, 1510, 1451 cm-1

, 1H NMR (400 MHz, DMSO-d6): δ 12.11

(s, 1H), 7.87 (s, 1H), 7.75 (d, 1H, J = 8.40 Hz), 7.46-7.40 (m, 2H),

6.91 (s, 2H), 4.95 (s, 1H), 1.81 (s, 3H), 13

C NMR (100 MHz,

DMSO): δ 165.1, 147.5, 145.8, 141.2, 135.1, 134.6, 130.5, 127.2, 124.1, 121.8, 98.1,

59.1, 32.0, 9.71, M. F: C14H11N5O3, M. W: 297, MS (m/z): 298 (M+1)+.

6-Amino-3-methyl-4-(4-nitrophenyl)-2, 4-dihydropyrano [2, 3-] pyrazole-5-carboni-

trile (5c): mp: 195oC, Yield: 97 %, IR (KBr): 3471, 3278, 3114,

2191, 1648, 1598, 1508, 1489 cm-1


d6): δ 12.21 (s, 1H), 8.25 (d, 2H, J = 8.70 Hz), 7.43 (s, 2H), 7.41

(d, 2H, J = 8.70 Hz), 4.87 (s, 1H), 1.78 (s, 3H), 13

C NMR (100

MHz, DMSO): δ 161.3, 154.2, 151.3, 146.7, 135.3, 128.1, 123.2,

120.7, 96.1, 35.1, 9.3, M. F: C14H11N5O3, M. W: 297, MS (m/z): 298 (M+1)+.

O

NNH

CN

NH2

O

N

NH

CN

NH2

NO2

O

N

NH

CN

NH2

NO2

207

6-Amino-3-methyl-4-(4-bromo)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile

(5d): mp: 206oC, Yield: 96 %, IR (KBr): 3409, 3368, 2192, 1515,

1450 cm-1

, 1H NMR (400 MHz, DMSO-d6): δ 11.96 (s, 1H), 7.88-

6.96 (m, 4H), 6.83 (s, 2H), 4.97 (s, 1H), 1.62 (s, 3H), 13

C NMR

(100 MHz, DMSO): δ 161.3, 156.3, 148.7, 138.2, 137.2, 135.3,

130.3, 121.7, 97.6, 57.6, 27.4, 10.3, M. F: C14H11BrN4O, M. W:

331, MS (m/z): 332 (M+1)+.

6-Amino-4-(4-methoxyphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbo-

nitrile (5e): mp: 211oC, Yield: 88 %, IR (KBr): 3478, 3247, 2180,

1596, 1448 cm-1


7.12 (s, 2H), 6.82 (d, 2H, J = 8.20 Hz), 6.81 (d, 2H, J = 8.20 Hz),

4.64 (s, 1H), 3.86 (s, 3H), 1.74 (s, 3H), 13

C NMR (100 MHz,

DMSO): δ 160.1, 156.6, 155.1, 144.7, 136.2, 118.1, 114.8, 112.8,

107.8, 57.2, 54.7, 36.7, 10.5, M. F: C15H14N4O2, M. W: 282, MS (m/z): 283 (M+1)+.

6-Amino-4-(4-methyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile

(5f): mp: 202oC, Yield: 87 %, IR (KBr): 3412, 3371, 2184, 1598,

1482 cm-1


(d, 2H, J = 8.0 Hz), 7.06 (d, 2H, J = 8.0 Hz), 6.80 (s, 2H), 4.56

(s, 1H), 2.24 (s, 3H), 1.76 (s, 3H), 13

C NMR (100 MHz, DMSO):

δ 160.6, 154.3, 141.7, 135.2, 128.5, 124.3, 120.1, 118.6, 97.2, 57.6, 35.7, 20.5, 9.5, M.

F: C15H14N4O, M. W: 266, MS (m/z): 267 (M+1)+.

O

N

NH

CN

NH2

Br

O

NNH

CN

NH2

OCH3

O

N

NH

CN

NH2

208

6-Amino-4-(4-hydroxy)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile

(5g): mp: 225oC, Yield: 93 %, IR (KBr): 3374, 3305, 2182, 1595,

1492 cm-1


(s, 1H), 6.97 (d, 2H, J = 8.30 Hz), 6.81 (s, 2H), 6.70 (d, 2H,

J = 8.30 Hz), 4.46 (s, 1H), 1.78 (s, 3H), 13

C NMR (100 MHz,

DMSO): δ 160.4, 155.8, 154.6, 135.3, 134.3, 128.4, 120.6, 115.2,

97.7, 57.7, 35.5, 9.6, M. F: C14H12N4O2, M. W: 268, MS (m/z): 269 (M+1)+.

6-Amino-4-(4-chloro)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile

(5h): mp: 175oC, Yield: 96 %, IR (KBr): 3372, 3225, 2183, 1621,

1520, 1486 cm-1


7.35 (d, 2H, J = 8.30 Hz), 7.22 (d, 2H, J = 8.30 Hz), 6.91 (s, 2H),

4.63 (s, 1H), 1.80 (s, 3H), 13

C NMR (100 MHz, DMSO): δ 160.6,

154.4, 143.5, 135.4, 131.2, 129.1, 128.4, 120.2, 97.2, 57.1, 35.4,

9.7, M. F: C14H11ClN4O, M. W: 287, MS (m/z): 288 (M+1)+.

O

NNH

CN

NH2

OH

O

N

NH

CN

NH2

Cl

209


Fig. 4.15: 13

C NMR spectrum of 5a compound

O

NNH

CN

NH2

O

NNH

CN

NH2

210

Fig. 4.16: Mass spectrum of 5b compound

O

NNH

CN

NH2

NO 2

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