the present work includes synthesis of some new...
TRANSCRIPT
__ 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)
Part A: Synthesis of 3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone
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
Part C: Condensation of 3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone
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
Part A: Synthesis of 3-(4-methylphenyl)-4-(chlorosulfonyl)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.
Part C: Condensation of 3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone
with 2-amino-4/5/6-substituted benzothiazole
Or
Synthesis of 3-(4-methylphenyl)-4-[(substituted-1,3-benzothiazol-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
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)
Part A: Synthesis of 3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone
3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone was synthesized according to
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
Part C: Condensation of 3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone
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
Calculated/found (%)
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
Structure of the compounds 2(a-j)
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 A: Synthesis of 3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone
3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone was synthesized according to
scheme I (page no. 43).
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.
Part C: Condensation of 3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone
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
3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone (3.02 g, 0.011 mol) was
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 A: Synthesis of 3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone
3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone was synthesized according to
scheme I (page no. 47).
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
Part C: Condensation of 3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone
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
Calculated/found (%)
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
Calculated/found (%)
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
Calculated/found (%)
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
Structure of the compounds 5(a-j)
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