The present work includes synthesis of some new...

__ EXPERIMENTAL ______________________43

The present work includes synthesis of some new heterocyclic

compounds having combination of mesoionic sydnone ring with different

heterocyclic rings such as quinazoline, thiazole and benzothiazole. Our

approach to the preparation of these compounds is based on the

condensation of sulfonyl chloride derivative of sydnone with different

derivatives of heterocyclic rings such as quinazoline, thiazole and

benzothiazole.

Scheme I: Synthesis of 3-(4-methylphenyl)-4-{[4-(substitutedphenyl)-

1,3-thiazol-2-yl] sulfamoyl}sydnone

Part A: Synthesis of 3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone

The synthesis of 4-(chlorosulfonyl)-3-(4-methylphenyl)sydnone has

been done by five step procedure e.g. esterification, hydrolysis, nitrosation,

cyclization and chlorosulfonation.

Ethyl-N-(4-methylphenyl)glycinate

4-Methylaniline (1.07 g, 0.01 mol), ethylchloroacetate (1.06 mL, 0.01 mol)

and anhydrous sodium acetate (1.64 g, 0.02 mol) were refluxed in ethanol

(10 mL) for 5 hours. The mixture was diluted with 10 mL of water and kept

in refrigerator over night. The product was directly used for the next step

without further purification. Yield 87 %. m.p. 45-47 oC, lit.[258]

m.p. 48-49 oC.

N-(4-Methylphenyl)glycine

Ethyl N-(4-methylphenyl)glycinate (1.93 g, 0.01 mol) and sodium hydroxide

(0.6 g, 0.015 mol) in solution of aqueous ethanol (18 mL:4 mL) was heated

for 0.5 hour. It was then cooled in ice and acidified with hydrochloric acid

till complete precipitation. Crystalline white product obtained was

recrystallized from ethanol. Yield 85 %, m.p. 163-164 ºC, lit. [259] m.p.

163-164 oC

__ EXPERIMENTAL ______________________44

(4-Methylphenyl)-N-nitrosoglycine

To a solution of N-(4-methylphenyl)glycine (1.65 g, 0.01 mol) in

concentrated hydrochloric acid (20 mL), a solution of sodium nitrite (0.69 g,

0.01 mol) in water (5 mL) was added dropwise at 0-5 oC with stirring for

2 hour. Product obtained was filtered. Recrystallization from ethanol. Yield

80 %. m.p. 99-100 oC. lit. [259] m.p. 98-99

oC.

3-(4-Methylphenyl)sydnone

The mixture of (4-methylphenyl)-N-nitrosoglycine (2.44 g, 0.0126 mol) and

acetic anhydride (15 mL) was stirred at room temperature for 12 hours in a

dark. The solution was poured slowly into cold water which was very well

stirred. The pH of the content was adjusted to 7.0 with 10 % sodium

bicarbonate solution. The crude sydnone obtained was washed well with

water and dried. Recrystallization from ethanol. Yield 71 %. m.p. 141-143

oC. lit.[259] m.p. 143-144

oC.

3-(4-Methylphenyl)-4-(chlorosulfonyl)sydnone

Chlorosulfonic acid (0.66 mL, 0.01 mol) was added drop wise into the

mixture of 3-(4-methylphenyl)sydnone (1.76 g, 0.01 mol) and catalytic

amount of P2O5 over 30 minutes with constant stirring at 0-5 oC. The

temperature of the well-stirred mixture does not rise above 5 oC. When all

the chlorosulfonic acid has been added, reflux the mixture at about 60 oC for

about 1 hour. The solution was then poured into a mixture of crushed ice and

water with vigorous stirring. Precipitation was collected by filtration,

washed with water and dried. Recrystallised from ethanol. Yield 74 %. m.p.

122-124 oC.

__ EXPERIMENTAL ______________________45

Part B: Synthesis of 4-(substitutedphenyl)-1,3-thiazol-2-amine

2,2-dibromo-1-(substitutedphenyl)ethanone

To a solution of substituted phenylethanone (0.01 mol) in chloroform

(20 mL) was added a solution of bromine (0.025 mol) in chloroform (20

mL) at room temperature. The solution was stirred for 12 hours and then

washed with sodium bisulfite solution. Recrystallisation from methanol.

4-(substitutedphenyl)-1,3-thiazol-2-amine

Thiourea (0.76 g, 0.01 mol) was added to a solution of 2,2-dibromo-1-

(substituted phenyl)ethanone in methanol (0.01 mol) and the reaction

mixture was stirred for 1 hours. The solid product was separated out.

Recrystallised from ethanol.

Part C: Condensation of 3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone

with 4-(substitutedphenyl)-1,3-thiazol-2-amine

Or

Synthesis of 3-(4-methylphenyl)-4-{[4-(substitutedphenyl)-1,3-thiazol-2-

yl]sulfamoyl}sydnone

3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone (3.02 g, 0.011 mol) was

dissolved in acetone at room temperature. A solution of appropriate 4-

(substitutedphenyl)-1,3-thiazol-2-amine (0.011 mol) in acetone was added

dropwise into 3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone solution over a

period of 5 hours with constant stirring. 1.0 mL of pyridine was added to the

well stirred solution after 1 hour and 2 hour respectively during the reaction.

The solution was poured on to ice with stirring. The precipitate was

collected by filtration, washed with water and dried. Recrystallization of the

crude product was performed from ethanol.

__ EXPERIMENTAL ______________________46

Following the above procedure thiazole substituted sydnone

derivatives 1(a-j) were synthesized using ten different substituted thiazole

derivatives stated as in table I.

__ EXPERIMENTAL ______________________47

Schematic diagram for 3-(4-methylphenyl)-4-{[4-(substitutedphenyl)-

1,3-thiazol-2-yl] sulfamoyl}sydnone (scheme I)


CH3 NH2

4-methylaniline

ClCH2COOC2H5

CH3COONa

CH3 NH CH2COOC2H5

ethyl-N-(4-methylphenyl)glycinate

NaOH

CH3 NH CH2COOH

N-(4-methylphenyl)glycine

NaNO2/HCl

0-5 °CCH3 NH CH2COOH

(4-methylphenyl)-N-nitrosoglycine

(CH3CO)2O

CH3 N

C

N

C

O

O

H

3-(4-methylphenyl)sydnone

ClSO3H

55-60 °CCH3 N

C

N

C

O

O

S OO

Cl

4-(chlorosulfonyl)-3-(4-methylphenyl)sydnone

Part B: Synthesis of 4-(substitutedphenyl)-1,3-thiazol-2-amine

C

O

CH3

R

2.5 Br2/CHCl3 C

O

CH

R

Br

Br

NH2CSNH2R

N

S

NH2

4-(substitutedphenyl)-1,3-thiazol-2-amine 2,2-dibromo-1-(substitutedphenyl)ethanone1-(substitutedphenyl)ethanone

__ EXPERIMENTAL ______________________48


with 4-(substitutedphenyl)-1,3-thiazol-2-amine

CH3 N

C

N

C

O

O

SO

O

Cl

+ R

N

S

NH2

CH3 N

C

N

C

O

O

S OO

NHN

SR

3-(4-methylphenyl)-4-{[4-(substitutedphenyl)-1,3-thiazol-2-yl]sulfamoyl}sydnone

pyridine

4-(chlorosulfonyl)-3-(4-methylphenyl)sydnone

__ EXPERIMENTAL ______________________49

TABLE- I

No

R

Mol.Form.

and M.W.

Yield

%

MP. oC

Elemental Analysis

Calculated/found (%)

C H N

1a

4-Br

C18H13O4N4BrS2 68 %

160-163

43.82

(43.74)

2.66

(2.60)

11.36

(11.28)

1b

4-Cl

C18H13ClN4O4S2

71 % 145-148

48.16

(48.25)

2.92

(2.81)

12.48

(12.56)

1c 4-OCH3 C19H16N4O5S2 70 % 120-123

51.34

(51.42)

3.63

(3.69)

12.60

(12.68)

1d 4-CH3 C19H16N4O4S2 74 % 152-158

53.26

(53.38)

3.76

(3.84)

13.08

(13.15)

1e 4-NO2 C18H13N5O6S2 72 % 148-150

47.05

(47.11)

2.85

(2.78)

15.24

(15.30)

1f 4-O(CH2)3CH3 C22H22N4O5S2 65 % 133-136

54.31

(54.38)

4.56

(4.63)

11.51

(11.63)

1g 2,4-F C18H12F2N4O4S2 68 % 164-167 48.00

(47.89)

2.69

(2.75)

12.44

(12.53)

1h 2,4-Cl C18H12Cl2N4O4S2 64 % 154-157 44.73

(44.68)

2.50

(2.61)

11.59

(11.64)

1i 2,4-Cl-6-F C18H11Cl2FN4O4S2 71 % 140-143 43.12

(43.23)

2.21

(2.34)

11.18

(11.27)

1j 2,6-Cl C18H12Cl2N4O4S2 65 % 168-170 44.73

(44.78)

2.50

(2.57)

11.59

(11.63)

__ EXPERIMENTAL ______________________50

Structure of the compounds 1(a-j)

CH3 N

C

N

C

O

O

S OO

NHN

S

Br

1a

CH3 N

C

N

C

O

O

S OO

NHN

S

Cl

1b

CH3 N

C

N

C

O

O

S OO

NHN

S

OCH3

1c

CH3 N

C

N

C

O

O

S OO

NHN

S

CH3

1d

__ EXPERIMENTAL ______________________51

CH3 N

C

N

C

O

O

S OO

NHN

S

N+

O-

O

1e

CH3 N

C

N

C

O

O

S OO

NHN

S

OCH3

1f

CH3 N

C

N

C

O

O

S OO

NHN

S

F

F

1g

CH3 N

C

N

C

O

O

S OO

NHN

S

Cl

Cl

1h

__ EXPERIMENTAL ______________________52

CH3 N

C

N

C

O

O

S OO

NHN

S

Cl

Cl

F

1i

CH3 N

C

N

C

O

O

S OO

NHN

S

Cl

Cl

1j

__ EXPERIMENTAL ______________________53

Scheme II: Synthesis of 3-(4-methylphenyl)-4-[(substituted-1,3-

benzothiazol-2-yl)sulfamoyl]sydnone


3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone was synthesized according to

scheme I (page no. 43).

Part B: Synthesis of 2-amino-4/5/6-substituted benzothiazole

Synthetic procedures for synthesis of 2-amino-6-substituted benzothiazole

and 2-Amino-4/5-substitutedbenzothiazole are described as under.

Synthesis of 2-amino-6-substituted benzothiazole

To a well stirred solution of 4-substituted aniline (0.01 mol) and potassium

thiocyanate (3.88 g, 0.04 mol) in glacial acetic acid (30 mL), bromine (0.52

mL, 0.01 mol) dissolved in glacial acetic acid (25 mL) was added dropwise.

The temperature of the reacting mixture was kept below 35 oC. After all the

bromine had been added the reaction mixture was stirred for 12 hour at this

temperature and filtered. The filtrate was neutralized with ammonium

hydroxide. The precipitate was collected and filtered. Washed the product

with water.

Synthesis of 2-amino-4/5-substitutedbenzothiazole

1-(2/3-substitutedphenyl)thiourea

The mixture of 2/3-substituted aniline (0.01 mol), ammonium thiocyanate

(0.91 g, 0.012 mol) and sodium hydrogen sulfite (0.07 g) was dissolved in

20 % hydrochloric acid (3.0 mL) and heated at 90 oC for 14 hour. The

cooled mixture was filtered, washed with water till neutral and dried to give

1-(2/3-substituted phenyl)thiourea.

__ EXPERIMENTAL ______________________54

2-Amino-4/5-substitutedbenzothiazole

A solution of bromine (7 mL, 0.136 mol) in chloroform (10 mL) was added

dropwise to a stirred suspension of 1-(2/3-substitutedphenyl)thiourea (0.068

mol) in chloroform (150 mL). After the addition, the reaction mixture was

refluxed for 2.5 hours and allowed to stand at room temperature for 12

hours. The residue was treated with dilute ammonium hydroxide solution.

The solid product was filtered and recrystallised from chloroform.


with 2-amino-4/5/6-substituted benzothiazole

Or

Synthesis of 3-(4-methylphenyl)-4-[(substituted-1,3-benzothiazol-2-

yl)sulfamoyl]sydnone


dissolved in acetone at room temperature. A solution of appropriate

2-amino-4/5/6-substituted benzothiazole (0.011 mol) in acetone was added

dropwise into 3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone solution over a

period of 5 hours with constant stirring. 1.0 mL of pyridine was added to the

well stirred solution after 1 hour and 2 hour respectively during the reaction.

The solution was poured on to ice with stirring. The precipitate was

collected by filtration, washed with water and dried. Recrystallization of the

crude product was performed from ethanol.

Following the above procedure benzothiazole substituted sydnone

derivatives 2(a-j) were synthesised using ten different substituted

benzothiazole derivatives stated as in table II.

__ EXPERIMENTAL ______________________55

Schematic diagram for the synthesis of 3-(4-methylphenyl)-4-

[(substituted-1,3-benzothiazol-2-yl)sulfamoyl]sydnone (scheme II)



schematic diagram of scheme I (page no. 47).

Part B: Synthesis of 2-amino-4/5/6-substituted benzothiazole.

2-amino-6-substitutedbenzothiazole and 2-amino-4/5-substituted-

benzothiazole were synthesized using different synthetic procedures stated

as under.

Synthesis of 2-amino-6-substituted benzothiazole

NH2

R

KSCN + Br2

CH3COOH

S

N

NH2

R

4-substituted aniline 2-amino-6-substituted benzothiazole

Synthesis of 2-amino-4/5-substitutedbenzothiazole

NH2

R

2/3-substituted aniline

NH4SCN

HCl + H2O

NH C

S

NH2

R

1-(2/3-substitutedphenyl)thiourea

Br2 / CHCl3

S

N

NH2R

2-amino-4/5-substituted benzothiazole

__ EXPERIMENTAL ______________________56


with 2-amino-4/5/6-substituted benzothiazole

CH3 N

C

N

C

O

O

SO

O

Cl

+ CH3 N

C

N

C

O

O

S OO

NH

S

N

R

NH2

S

N

R

2-amino-4/5/6-substituted benzothiazole

pyridine

3-(4-methylphenyl)-4-[substituted-1,3-benzothiazol-2-yl)sulfamoyl]sydnone

__ EXPERIMENTAL ______________________57

TABLE- II

No

R

Mol. Form.

and M.W.

Yield

%

MP.

oC

Elemental Analysis


C H N

2a

6-CH3 C17H14N4O4S2

67

105-107

50.74

(50.83)

3.51

(3.58)

13.92

(14.01)

2b

6-OCH3 C17H14N4O5S2

69

125-127

48.80

(48.86)

3.37

(3.46)

13.39

(13.47)

2c 6-Cl C16H11ClN4O4S2 68 130-133 45.44

(45.52)

2.62

(2.75)

13.25

(13.36)

2d 6-Br C16H11BrN4O4S2 74 90-92 41.12

(41.06)

2.37

(2.46)

11.99

(12.14)

2e 6-NO2 C16H11N5O6S2 61 120-122 44.34

(44.50)

2.56

(2.64)

16.16

(16.36)

2f 6-F C16H11FN4O4S2 61 100-104 47.28

(47.35)

2.73

(2.66)

13.79

(13.84)

2g 6-OCH2CH3 C18H16N4O5S2 67 136-139 49.99

(50.15)

3.73

(3.70)

12.95

(12.90)

2h 4-NO2 C16H11N5O6S2 64 95-98 44.34

(44.47)

2.56

(2.67)

16.16

(16.07)

2i 5-Cl C16H11ClN4O4S2 73 104-106 45.44

(45.53)

2.62

(2.73)

13.25

(13.37)

2j 5-CH3 C17H14N4O4S2

66

138-140

50.74

(50.65)

3.51

(3.69)

13.92

(13.83)

__ EXPERIMENTAL ______________________58


CH3 N

C

N

C

O

O

S OO

NH

S

N

CH3

2a

CH3 N

C

N

C

O

O

S OO

NH

S

N

H3CO

2b

CH3 N

C

N

C

O

O

S OO

NH

S

N

Cl

2c

CH3 N

C

N

C

O

O

S OO

NH

S

N

Br

2d

__ EXPERIMENTAL ______________________59

CH3 N

C

N

C

O

O

S OO

NH

S

N

N+

O-

O

2e

CH3 N

C

N

C

O

O

S OO

NH

S

N

F

2f

CH3 N

C

N

C

O

O

S OO

NH

S

N

O

CH3

2g

__ EXPERIMENTAL ______________________60

CH3 N

C

N

C

O

O

S OO

NH

S

N

NO2

2h

CH3 N

C

N

C

O

O

S OO

NH

S

NCl

2i

CH3 N

C

N

C

O

O

S OO

NH

S

NCH3

2j

__ EXPERIMENTAL ______________________61

Scheme III: Synthesis of 4-[({4-[2-(substitutedphenyl)-4-oxoquinazolin-

3(4H)-yl]phenyl} amino) sulfonyl]-3-(4-methylphenyl)sydnone




Part B: Synthesis 3-(4-aminophenyl)-2-(substitutedphenyl)quinazolin-

4(3H)-one

2-(Substitutedphenyl)-4H-3,1-benzoxazin-4-one

To a stirred solution of 2-aminobenzoic acid (1.37 g, 0.01 mol) in dry

pyridine (15 mL), a solution of substituted acid chloride (0.015 mol) in dry

pyridine (15 mL) was added dropwise, maintaining the temperature at 0-5 oC

for 2 hour. The reaction mixture was stirred for another 2 hours at room

temperature. Whole reaction mixture was neutralized with

sodiumbicarbonate solution. The solid that separated was filtered off and

washed with water. Recrystallized from benzene.

3-(4-Aminophenyl)-2-(substitutedphenyl)quinazolin-4(3H)-one

A solution of 2-(substitutedphenyl)-4H-3,1-benzoxazin-4-one (0.01 mol)

and 4-phenylenediamine (1.08 g, 0.01 mol) in pyridine (20 mL) was

refluxed for 6 hour. After cooling the solution was poured over ice to obtain

the product. Recrystallized from ethanol.


with different 3-(4-Aminophenyl)-2-(substitutedphenyl)quinazolin-

4(3H)-one

Or

Synthesis of 4-[({4-[2-(substitutedphenyl)-4-oxoquinazolin-3(4H)-

yl]phenyl} amino) sulfonyl]-3-(4-methylphenyl)sydnone

__ EXPERIMENTAL ______________________62


dissolved in acetone at room temperature. A solution of appropriate 3-(4-

aminophenyl)-2-(substitutedphenyl)quinazolin-4(3H)-one (0.01 mol) in

acetone was added dropwise into 3-(4-methylphenyl)-4-

(chlorosulfonyl)sydnone solution over a period of 5 hours with constant

stirring. 1.0 mL of pyridine was added to the well stirred solution after 1

hour and 2 hour respectively during the reaction. The solution was poured on

to ice with stirring. The precipitate was collected by filtration, washed with

water and dried. Recrystallization of the crude product was performed by

ethanol.

Following the above procedure quinazoline substituted sydnone

derivatives 3(a-j) were synthesized using different substituted quinazoline

derivatives stated as in table III.

__ EXPERIMENTAL ______________________63

Schematic diagram for the synthesis of 4-[({4-[2-(substitutedphenyl)-4-

oxoquinazolin-3(4H)-yl]phenyl} amino) sulfonyl]-3-(4-methylphenyl)

sydnone (Scheme III)




Part B: Synthesis of 3-(4-aminophenyl)-2-(substitutedphenyl)quinazolin

-4(3H)-one

COCl

R +HOOC

NH2

pyridine

0-5 °C

Substituted benzoilchloride 2-aminobenzoic acid

O

N

O

R

2-(Substitutedphenyl)-4H-3,1-benzoxazin-4-one

N

N

O

R

NH2

4-phenylenediamine

Pyridine

3-(4-aminophenyl)-2-(substitutedphenyl)quinazolin-4(3H)-one

__ EXPERIMENTAL ______________________64


with different 3-(4-Aminophenyl)-2-(substitutedphenyl)quinazolin-

4(3H)-one

CH3 N

C

N

C

O

O

SO

O

Cl

+N

N

O

R

NH2

Pyridine

3-(4-aminophenyl)-2-(substitutedphenyl)quinazolin-

4(3H)-one

CH3 N

C

N

C

O

O

SO O

NH

N

N

O

R

4-[({4-[substitutedphenyl)-4-oxoquinazolin-3(4H)-yl]phenyl}amino)sulfonyl]-3-(4-methylphenyl)sydnone

__ EXPERIMENTAL ______________________65

TABLE- III

No

R

Mol. Form.

and M.W.

Yield

%

MP

oC

Elemental Analysis


C H N

3a

H C29H21N5O5S 68

94-96

63.15

(63.07)

3.84

(3.74)

12.70

(12.76)

3b

4-NO2 C29H20N6O7S

64

110-114

58.39

(58.46)

3.38

(3.42)

14.09

(14.16)

3c 4-OCH3 C30H23N5O6S 66 70-72 61.95

(62.10)

3.99

(3.91)

12.04

(12.17)

3d 4-Cl C29H20ClN5O5S 68 82-84 59.44

(59.61)

3.44

(3.36)

11.95

(11.83)

3e 3-NO2 C29H20N6O7S

61

134-136

58.39

(58.50)

3.38

(3.47)

14.09

(14.14)

3f 3-Cl C29H20ClN5O5S 66 127-129 59.44

(59.52)

3.44

(3.58)

11.95

(11.83)

3g 3-Br C29H20BrN5O5S 62 90-94 55.25

(55.67)

3.20

(3.31)

11.11

(11.02)

3h 2-NO2 C29H20N6O7S

62

112-114

58.39

(58.48)

3.38

(3.44)

14.09

(14.15)

3i 2-Cl C29H20ClN5O5S 70 118-120 59.44

(59.53)

3.44

(3.57)

11.95

(12.14)

3j 2-Cl-6-NO2 C29H19ClN6O7S 68 105-107 55.20

(55.35)

3.03

(3.20)

13.32

(13.19)

3k 3-NO2-4-

OCH3

C30H22N6O8S 64 140-142 57.50

(57.43)

3.54

(3.63)

13.41

(13.48)

__ EXPERIMENTAL ______________________66

Structure of the compounds 3(a-k)

CH3 N

C

N

C

O

O

SO O

NH

N

N

O

3a

CH3 N

C

N

C

O

O

SO O

NH

N

N

O

O2N

3b

CH3 N

C

N

C

O

O

SO O

NH

N

N

O

H3CO

3c

CH3 N

C

N

C

O

O

SO O

NH

N

N

O

Cl

3d

__ EXPERIMENTAL ______________________67

CH3 N

C

N

C

O

O

SO O

NH

N

N

O

O2N

3e

CH3 N

C

N

C

O

O

SO O

NH

N

N

O

Cl

3f

CH3 N

C

N

C

O

O

SO O

NH

N

N

O

Br

3g

CH3 N

C

N

C

O

O

SO O

NH

N

N

O

N+

O-

O

3h

__ EXPERIMENTAL ______________________68

CH3 N

C

N

C

O

O

SO O

NH

N

N

O

Cl

3i

CH3 N

C

N

C

O

O

SO O

NH

N

N

O

Cl

NO2

3j

CH3 N

C

N

C

O

O

SO O

NH

N

N

O

O2NH3CO

3k

__ EXPERIMENTAL ______________________69

Scheme IV: 3-(4-methylphenyl)-4-(substituted-1/4-ylmethyl)sydnone

Part A: Synthesis of 3-(4-methylphenyl)sydnone

3-(4-Methylphenyl)sydnone was synthesized according to scheme I (page

no. 43).

Part B: Synthesis of 3-(4-methylphenyl)-4-(substituted-1/4-

ylmethyl)sydnone

3-(4-Methylphenyl)sydnone (3.52 g, 0.02 mol), paraformaldehyde (0.75 gm)

and substituted secondary amine (0.02 mol) were suspended in ethanol (5

mL) and glacial acetic acid (5 mL). The resulting solution was refluxed for 4

hour. The solution was poured in ice and neutralized by sodium bicarbonate

solution. Recrystallization from ethanol.

Following the above procedure sydnone derivatives 4(a-j) were

synthesized using N-methylpiperazine, piperazine, morpholine, piperidine,

N-acetyl piperazine, N-phenylpiperazine, N-(dibenzo[b,f][1,4]thiazepine), 1-

(3-chlorophenyl)piperazine, 1-(2,3-dichlorophenyl)piperazine, 1-methyl-2-

phenylpiperazine and 1-ethoxyethanol piperazine as secondary amine.

__ EXPERIMENTAL ______________________70

Schematic diagram for the synthesis of 3-(4-methylphenyl)-4-

(substituted-1/4-ylmethyl)sydnone (scheme 4)

Part A: Synthesis of 3-(4-methylphenyl)sydnone

3-(4-Methylphenyl)sydnone was synthesized according to schematic

diagram of scheme I (page no. 47).

Part B: Synthesis of 3-(4-methylphenyl)-4-(substituted-1/4-

ylmethyl)sydnone

CH3 N

C

N

C

O

O

H

2o-amine + HCHO

CH3COOH

CH3 N

C

N

C

O

O

XN

3-(4-methylphenyl)-4-(substituted-1/4-ylmethyl)sydnone3-(4-methylphenyl)sydnone

__ EXPERIMENTAL ______________________71

TABLE- IV

No

X

Mol.Form.

and M.W.

Yield

%

MP

oC

Elemental Analysis


C H N

4a

N-CH3 C15H20N4O2

73

142-144

62.48

(62.55)

6.99

(7.43)

19.43

(19.56)

4b

NH C14H18N4O2

76

130-132

61.30

(61.46)

6.61

(6.68)

20.42

(20.53)

4c O C14H17N3O3 74 150-152 61.08

(61.16)

6.22

(6.84)

15.26

(15.35)

4d CH2 C15H19N3O2 71 123-125 65.91

(65.82)

7.01

(7.17)

15.37

(15.44)

4e N-COCH3 C16H20N4O3 74 85-87 60.75

(60.83)

6.37

(6.45)

17.71

(17.83)

4f N-C6H5 C20H22N4O2 70 60-62 68.55

(68.62)

6.33

(6.41)

15.99

(15.84)

4g N-(dibenzo[b,f]

[1,4]thiazepine)

C27H25N5O2S 66 150-152 67.06

(67.25)

5.21

(5.36)

14.48

(14.57)

4h N-C6H4-3-Cl C20H21ClN4O2 71 145-147 62.64

(62.78)

5.50

(5.62)

14.56

(14.42)

4i N-C6H3-2,3-Cl C20H20Cl2N4O2 68 110-112 57.29

(57.35)

4.81

(4.63)

13.36

(13.29)

4j N-CH3, 3-C6H5 C21H24N4O2 69 131-133 69.21

(69.28)

6.64

(6.74)

15.37

(15.26)

4k N-(CH2)2O(CH2)2OH C18H26N4O4 74 168-170 59.65

(59.71)

7.23

(7.33)

15.46

(15.58)

__ EXPERIMENTAL ______________________72

Structure of the compounds 4(a-k)

CH3 N

C

N

C

O

O

NN CH3

4a

CH3 N

C

N

C

O

O

NHN

4b

CH3 N

C

N

C

O

O

ON

4c

CH3 N

C

N

C

O

O

N

4d

__ EXPERIMENTAL ______________________73

CH3 N

C

N

C

O

O

NN

O

CH3

4e

CH3 N

C

N

C

O

O

NN

4f

CH3 N

C

N

C

O

O

NN

N

S

4g

__ EXPERIMENTAL ______________________74

CH3 N

C

N

C

O

O

NN

Cl

4h

CH3 N

C

N

C

O

O

NN

Cl Cl

4i

CH3 N

C

N

C

O

O

NN CH3

4j

CH3 N

C

N

C

O

O

NN CH2 CH2 O CH2 CH2 OH

4k

__ EXPERIMENTAL ______________________75

Scheme V: 3,3’-(methylenedi-1,4-phenylene)bis{4-[(subsitituted-1/4-yl)

methyl]}sydnone

2,2’-[Methylenebis(1,4-phenyleneimino)]diethyl acetate

4,4’-Diaminodiphenyl methane (1.98 g, 0.01 mol), ethylchloroacetate (2.13

mL, 0.02 mol) in ethanol (10 mL) and anhydrous sodium acetate (3.28 g,

0.04 mol) were refluxed for 5 hours. The mixture was diluted with water

(10 mL). After standing overnight in the refrigerator, crystalline ester was

obtained. The crude solid was purified by recrystallization from ethanol.

Yield 80 %., m.p. 110-112 oC.

2,2'-[Methylenebis(1,4-phenyleneimino)]diacetic acid

2,2’-[Methylenebis(1,4-phenyleneimino)]diethyl acetate (3.70 g, 0.01 mol)

and sodium hydroxide (1.2 g, 0.03 mol) were dissolved in a solution of

distilled water and ehanol (36:4mL). The mixture was stirred at reflux

temperature for 30 minutes. The resultant mixture was cooled and acidified

with hydrochloric acid. White crystalline product was obtained, it was

recrystallized from ethanol. Yield 70 %, m.p. 130-135 oC.

2,2'-{Methylenebis[1,4-phenylene (nitrosoimino)]}diacetic acid

To an ice-cold and well stirred solution of 2,2'-[methylenebis(1,4-

phenyleneimino)]diacetic acid (5.02 g, 0.016 mol) in water (40 mL), a

freshly prepared sodium nitrate solution (3.32 g, 0.049 mol) was added

dropwise over a period of 40 minutes. Concentrated hydrochloric acid was

added till complete precipitation and allowed to stir cold solution for several

minutes. The solid nitroso compound was filtered off and washed with cold

water and dried. Yield 64 %. m.p. 130-135 oC.

__ EXPERIMENTAL ______________________76

3,3’-(4,4’-Diphenyl)bissydnonyl methane

The dried 2,2'-{Methylenebis[1,4-phenylene (nitrosoimino)]}diacetic acid

(4.00 g, 0.0107 mol) was stirred for 12 hours in 40 mL acetic anhydride. The

solution was poured slowly into cold water which was very well stirred. The

pH of the content was adjusted to 7.0 with 10 % sodium bicarbonate

solution. The solid crude product was washed well with water and dried. The

crude sydnone was recrystallized from benzene-petroleum ether. The

product obtained was orange solid. Yield 70 %. m.p. 120-123 oC.

3,3’-(Methylenedi-1,4-phenylene)bis{4-[(subsitituted-1/4-yl)methyl]}-

sydnone

3,3’-(4,4’-Diphenyl)bissydnonyl methane (6.72 g, 0.02 mol),

paraformaldehyde (1.50 gm) and substituted secondary amine (0.04 mol)

were suspended in ethanol (15 mL) and glacial acetic acid (10 mL). The

resulting solution was refluxed for 6 hour. The solution was poured in ice

and neutralized by sodiumbicarbonate solution. Recrystallized from ethanol.

Following the above procedure sydnone derivatives 5(a-j) were

synthesised using N-methylpiperazine, piperazine, morpholine, piperidine,

N-acetyl piperazine, N-phenylpiperazine, N-(dibenzo[b,f][1,4]thiazepine),

1-(3-chlorophenyl)piperazine, 1-(2,3-dichlorophenyl)piperazine and

1-methyl-2-phenylpiperazine as secondary amine.

__ EXPERIMENTAL ______________________77

Schematic diagram for the synthesis of 3,3’-(methylenedi-1,4-

phenylene)bis{4-[(subsitituted-1/4-yl) methyl]}sydnone (Scheme 5)

ClCH2COOC

2H

5

CH3COONa

NH2NH2 C

H

H

NHCH2COOC2H5H5C2OOCH2CHN C

H

H

4,4'-Diaminodiphenyl methane 2,2'-[methylenebis(1,4-phenyleneimino)]diethyl acetate

NaOH NaNO2 / HCl

0-5 °CCNH NHHOOC-H2C CH2-COOH

H

H

2,2'-[methylenebis(1,4-phenyleneimino)]diacetic acid

2,2'-{Methylenebis[1,4 -phenylene (nitrosoimino)]}diacetic acid

N-CH2COOH

NO

C

H

H

HOOCH2C-N

NO(CH

3CO)

2O

12 hr ON

N

C

N

N

C

OC

H

H

O OH

H

3,3’-(4,4’-Diphenyl)bissydnonyl methane

2o-amine + HCHO

CH3COOH

3,3'-(methylenedi-1,4-phenylene)bis[4-(substituted-4-ylmethyl)sydnone

XNX N

CN N

H

HN

C

O ON

C OO

__ EXPERIMENTAL ______________________78

TABLE- V

No

X

Mol.Form.

and M.W.

Yield

%

MP

oC

Elemental Analysis


C H N

5a

O C27H30N6O6

70

126-129

60.66

(60.72)

5.66

(5.73)

15.72

(15.79)

5b

NH C27H32N8O4

68

140-142

60.89

(60.82)

6.06

(6.17)

21.04

(21.16)

5c N-CH3 C29H36N8O4 74 170-173 62.13

(62.20)

6.47

(6.51)

19.99

(20.15)

5d CH2 C29H34N6O4 70 100-102 65.64

(65.74)

6.46

(6.41)

15.84

(15.75)

5e N-COCH3 C31H36N8O6 76 156-158 60.38

(60.45)

5.88

(5.76)

18.17

(18.25)

5f N-C6H5 C39H40N8O4 67 152-154 68.40

(68.53)

5.89

(5.93)

16.36

(16.46)

5g N-(dibenzo[b,f]

[1,4]thiazepine)

C53H48N10O4S2 70 172-174 66.79

(66.83)

5.08

(5.16)

14.70

(14.82)

5h N-C6H4-3-Cl C39H38Cl2N8O4 64 174-176 62.15

(62.29)

5.08

(4.96)

14.87

(14.74)

5i N-C6H3-2,3-Cl C39H36Cl4N8O4 68 153-155 56.95

(57.01)

4.41

(4.59)

13.62

(13.75)

5j N-CH3, 3-C6H5 C41H44N8O4 66 90-92 69.08

(69.35)

6.22

(6.34)

15.72

(15.80)

__ EXPERIMENTAL ______________________79


O N

CH2 N

C

N

C

ON

N

C

O

CO O

N O

5a

NH N

CH2 N

C

N

C

ON

N

C

O

CO O

N NH

5b

N N

CH2 N

C

N

C

ON

N

C

O

CO O

N NCH3 CH3

5c

N

CH2 N

C

N

C

ON

N

C

O

CO O

N

5d

__ EXPERIMENTAL ______________________80

N N

CH2 N

C

N

C

ON

N

C

O

CO O

N N

O O

CH3 CH3

5e

N N

CH2 N

C

N

C

ON

N

C

O

CO O

N N

5f

N N

CH2 N

C

N

C

ON

N

C

O

CO O

N N

N

S

NH

S

5g

__ EXPERIMENTAL ______________________81

N N

CH2 N

C

N

C

ON

N

C

O

CO O

N N

Cl Cl

5h

N N

CH2 N

C

N

C

ON

N

C

O

CO O

N N

ClCl Cl Cl

5i

N N

CH2 N

C

N

C

ON

N

C

O

CO O

N N CH3CH3

5j

The present work includes synthesis of some new...

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