Synthesis  of New Indoline-2-Ones and Their Microbial Activity

 

Freddy H. Havaldar*, Azadkumar S. Sharma and Peter Roni F. Pinto

Nadkarny-Sacasa Research Laboratory, Department of Chemistry, St. Xavier’s College, Mumbai - 400 001.

*Corresponding Author E-mail: azadsharma83@gmail.com

 

ABSTRACT:

The acid hydrazides (I and IV) were condensed with indole-2,3-dione in ethanol to yield hydrazono-indolin-2-ones (II and V) which on aminomethylation with formaldehyde and different amines furnished 1-(substituted aminomethyl)-hydrazono-indolin-2-ones (IIIa-e and VIa-e).  The structures of the newly synthesized compounds have been confirmed by IR, 1H NMR and Mass spectra.  These compounds have shown promising biological activity.

 

KEYWORDS: Synthesis, Mannich bases, biological activity and spectral data.

 

 

 

INTRODUCTION:

Mannich bases1 having indolin-2-one moiety are found to be good antifungal agent. Isatin and its derivatives are a class of biologically active compounds which have been associated with antibacterial2, amoebicidal3, cysticidal4 and CNS depressant5 activity. In view of these observations it was contemplated to synthesize Mannich bases containing indolin-2-one nucleus with the objective of screening them for their antibacterial activity.

 
RESULTS AND DISCUSSION:

The substituted aryl acid hydrazides required were prepared from the corresponding esters of different aromatic acids by reaction with hydrazine hydrate following the reported method6-7. The acid hydrazides (I and IV) on condensation with indole-2,3-dione in ethanol containing catalytic amount of glacial acetic acid  gave indolin-2-ones (II and V).  The compounds (II and V) were reacted with formaldehyde and different amines to afford 1-(substituted aminomethyl)-hydrazino-indolin-2-ones (IIIa-e and VIa-e) [SCHEMES – 1 and 2].

 

 

SCHEME 1.

 

SCHEME 2.

 

(V)
 
BIOLOGICAL ACTIVITY:

Antibacterial activity:

All the newly synthesized compounds (IIIa-e and VIa-e) were screened in vitro for their antibacterial activity against Staphylococcus aureus, Escherichia coli, Bacillus subtilis and Salmonella typhosa by the ditch-plate technique8 using concentrations of 2 mg/ml and 5 mg/ml. Nutrient agar was employed as culture media and DMF was used as solvent control for antibacterial activity.

 

The known compounds such as ampicillin, amoxicillin, norfloxacin, penicillin and griseofulvin were used for comparison studies. The diameter of zone of inhibition was measured in mm. The antibacterial screening data are recorded in Table I.

 

MATERIAL AND METHODS:

Melting points were taken in open capillaries and are uncorrected. IR spectra (KBr in cm-1) were recorded on Jasco 410 plus FTIR spectrophotometer. 1H NMR spectra were recorded on a Bruker 500 MHz NMR spectrophotometer using DMSO-d6 as solvent and TMS as internal standard (chemical shifts in d ppm). Mass spectra were recorded on LC-MS Shimadzu 2010A using dimethyl sulfoxide as solvent. The elemental analysis was carried out on a Perkin Elmer CHN analyzer. The purity of the compounds was monitored by thin layer chromatography. TLC was carried out on precoated 0.2 mm silica gel 60F254 plates.

 

TABLE   I: Biological  Activity Data

Comp ounds

S. aureus

E. coli

B. subtilis

S. typhosa

 

2 mg

5 mg

2 mg

5 mg

2 mg

5 mg

2 mg

5 mg

IIIa

-

-

-

-

-

-

-

+

IIIb

-

+

+

++

-

+

+

++

IIIc

+

+

+

++

+

+

+

++

IIId

-

+

-

+

-

+

+

++

IIIe

+

++

-

+

-

+

-

+

VIa

+

+

+

+

-

+

-

-

VIb

-

+

-

+

+

+

-

+

VIc

+

++

-

+

+

+

-

-

VId

+

++

+

+

+

+

+

+

VIe

-

+

+

++

-

+

-

+

Inhibition zone diameter in mm:    (-)     < 11 mm

(+)     11-14 mm; (++)   15-18 mm

 

 

3-(4'-Acetamido-2'-methoxybenzoylhydrazono) indolin-2-one (II) :

To a solution of 4-acetamido-2-methoxybenzoyl hydrazine (I, 2.23g, 0.01 mole) in 50 cm3 ethanol, indole-2,3-dione (1.47 g, 0.01 mole) was added. A catalytic amount of glacial acetic acid was added and the mixture was refluxed for half an hour. The reaction mixture was then allowed to cool to room temperature. The separated yellow coloured solid was filtered, washed with methanol and crystallized from N,N-dimethylformamide, m.p. >300°C, yield 80% (Found :    C, 61.38 ; H, 4.60 ; N, 15.94. C18H16N4O4 requires  C, 61.36; H, 4.58; N, 15.90%); IR (KBr) 3302 (N-H str.), 3101 (C-H, aromatic), 2900 (C-H str.), 1707 (C=O str.), 1667 (C=N str.), 1596, 1493, 1460 (C=C, aromatic), 1190 (C-O-C str.), 1139-847 (C-C str.), 1025 (C-N str.); 1HNMR(DMSO-d6): 2.11 (s, 3H, -CH3), 3.85 (s, 3H, -OCH3), 5.70 (s, 1H, CH2-NH), 7.0-7.80 (m, 7H, ArH), 10.4 (s, 1H, NHCOCH3), 11.2 (s, 1H, NHCOC);  MS: m/z 352 [M]+.

 

3-(2',4'-Dichlorophenoxy acetyl hydrazono) indolin-2-one (V) :

The 3-(2',4'-dichlorophenoxyacetylhydrazono) indolin-2-one (V) was obtained in a similar way as given for synthesis of 3-(4'-acetamido-2'-methoxy benzoylhydrazono) indolin-2-one (II), m.p. 240°C, yield 80% (Found: C, 52.78; H, 3.06; N, 11.57. C16H11N3O3Cl2 requires  C, 52.77; H, 3.04; N, 11.54%); IR (KBr) 3420 (N-H str.), 3140 (C-H, aromatic), 2910 (C-H str.), 1717 (C=O str.), 1678 (C=N str.), 1540, 1483, 1474 (C=C, aromatic), 1188 (C-O-C str.), 1107-840 (C-C str.), 1045 (C-N str.), 749 (C-Cl str.); 1HNMR(DMSO-d6): 4.20 (s, 2H, -OCH2.C), 5.90 (s, 1H, CH2-NH), 7.1-7.9 (m, 7H, ArH), 11.3 (s, 1H, NHCOC); MS: m/z 364 [M]+.

TABLE II: Physical data of compounds

Compounds

Ar

M.P.

°C

Yield

%

Molecular

Formula

Analysis

%N

Requires

Found

IIIa

Anilino

286

89

C25H23N5O4

15.31

15.33

IIIb

2-Chloroanilino

255

85

C25H22N5O4Cl

14.24

14.26

IIIc

4-Methoxyanilino

290

76

C26H25N5O5

14.37

14.39

IIId

Morpholino

199

75

C23H25N5O5

15.52

15.54

IIIe

Piperidino

270

80

C24H25N5O4

15.59

15.60

VIa

Anilino

230

68

C23H18N4O3Cl2

11.94

11.98

VIb

2-Chloroanilino

247

66

C23H17N4O3Cl3

11.13

11.16

VIc

4-Methoxyanilino

254

71

C24H20N4O4Cl2

11.22

11.25

VId

Morpholino

242

72

C21H20N4O4Cl2

12.09

12.11

VIe

Piperidino

233

75

C22H22N4O3Cl2

12.14

12.16

 

TABLE   III: Spectral data of compounds

Compd

 

IR, KBr

1H NMR (DMSO-d6)

Mass

Ms: m/z [M+]

IIIa

Anilino

3317 (N-H str.), 1663 (C=O str.), 1595 (C=N str.), 1029 (C-N str.).

2.11 (s, 3H, -CH3), 3.85 (s, 3H, -OCH3), 4.8 (s, 2H, N.CH2.N), 5.20 (s, 1H, CH2-NH), 7.0-8.05 (m, 12H, ArH), 10.0 (s, 1H, NHCOCH3), 11.05 (s, 1H, CONH-N).

457

IIIb

2-Chloroanilino

3325 (N-H str.), 1675 (C=O str.), 1605 (C=N str.), 1035 (C-N str.), 740 (C-Cl str.).

2.15 (s, 3H, -CH3), 3.9 (s, 3H, -OCH3), 4.85 (s, 2H, N.CH2.N), 5.35 (s, 1H, CH2-NH), 7.1-8.0 (m, 11H, ArH), 10.15 (s, 1H, NHCOCH3), 11.20 (s, 1H, CONH-N).

491

IIIc

4-Methoxyanilino

3320 (N-H str.), 1670 (C=O str.), 1600 (C=N str.), 1180 (C-O-C str.), 1030 (C-N str.).

2.15 (s, 3H, -CH3), 3.85 (s, 3H, -OCH3), 3.95 (s, 3H, -OCH3), 4.8 (s, 2H, N.CH2.N), 5.25 (s, 1H, CH2-NH), 7.0-8.0 (m, 12H, ArH), 10.05 (s, 1H, NHCOCH3), 11.10 (s, 1H, CONH-N).

487

IIId

Morpholino

3320 (N-H str.), 1670 (C=O str.), 1595 (C=N str.), 1180 (C-O-C str.), 1030 (C-N str.).

2.10 (s, 3H, -CH3), 2.55 (t, 4H, CH2.N.CH2), 3.7 (t, 4H, CH2.O.CH­2), 3.8 (s, 3H, -OCH3), 4.85 (s, 2H, N.CH2.N), 7.20-7.85 (m, 7H, ArH), 10.11 (s, 1H, NHCOC), 11.20 (s, 1H, CONHN-).

451

IIIe

Piperidino

3325 (N-H str.), 1675 (C=O str.), 1605 (C=N str.), 1035 (C-N str.).

1.05 (m, 6H, -CH2-CH2-CH2-), 2.1 (t, 4H, CH2.N.CH­2), 2.20 (s, 3H, -CH3), 3.85 (s, 3H, -OCH3), 4.8 (s, 2H, N.CH2.N), 7.20-7.85 (m, 7H, ArH), 10.20 (s, 1H, NHCOC), 11.55 (s, 1H, CONHN-).

449

VIa

Anilino

3360 (N-H str.), 1705 (C=O str.), 1625 (C=N str.), 1035 (C-N str.).

4.20 (s, 2H, -OCH2.C), 4.90 (s, 2H, N.CH2.N), 5.40 (s, 1H, CH2-NH), 7.1-7.9 (m, 12H, ArH), 11.15 (s, 1H, NHCOC),

469

VIb

2-Chloroanilino

3375 (N-H str.), 1715 (C=O str.), 1630 (C=N str.), 1038 (C-N str.), 750 (C-Cl str.).

4.30 (s, 2H, -OCH2.C), 4.95 (s, 2H, N.CH2.N), 5.45 (s, 1H, CH2-NH), 7.1-8.0 (m, 11H, ArH), 11.33 (s, 1H, NHCOC),

503

VIc

4-Methoxyanilino

3370 (N-H str.), 1705 (C=O str.), 1628 (C=N str.), 1032 (C-N str.).

3.85 (s, 3H, -OCH3), 4.25 (s, 2H, -OCH2.C), 4.85 (s, 2H, N.CH2.N), 5.35 (s, 1H, CH2-NH), 7.1-7.95 (m, 11H, ArH), 11.5 (s, 1H, NHCOC),

499

VId

Morpholino

3365 (N-H str.), 1700 (C=O str.), 1615 (C=N str.), 1190 (C-O-C str.), 1030 (C-N str.).

2.6 (t, 4H, CH2-N-CH2), 3.65 (t, 4H, CH2-O-CH2), 4.1 (s, 2H,  -O.CH2.C), 5.32 (s, 2H, N-CH2-N), 6.9-7.6 (m, 7H, ArH), 11.38 (s, 1H, CONH).

463

VIe

Piperidino

3365 (N-H str.), 1705 (C=O str.), 1620 (C=N str.), 1025 (C-N str.).

1.05 (m, 6H, -CH2-CH2-CH2-), 2.1 (t, 4H, CH2.N.CH­2), 4.18 (s, 2H, -OCH2.C), 5.40 (s, 2H, N.CH2.N), 7.0-8.6 (m, 13H, ArH).11.38 (s, 1H, CONH).

461

 

 

1-(Substituted aminomethyl)-3-(4'-acetamido-2'-methoxybenzoyl hydrazono) indolin- 2-ones (IIIa-e) :

3-(4'-Acetamido-2'-methoxybenzoylhydrazono) indolin-2-one (II, 1.40 g, 0.004 mole) was dissolved in 10 cm3 N,N-dimethylformamide. A slight excess of formaldehyde (0.125 cm3, 0.0045 mole) and appropriate amine (0.004 mole) was added with vigorous stirring. The reaction mixture was refluxed for half an hour and allowed to cool to room temperature. The crystalline product obtained was filtered, washed with water and recrystallized from petroleum ether (60°-80°C) to get compounds (IIIa-e).

 

The physical data and spectral data are given in Table (II) and Table (III) respectively.

 

1-(Substitued aminomethyl)-3-(2',4'-dichlorophenoxyacetyl hydrazono) indolin- 2-ones (VIa-e)  :

The products (VIa-e) were synthesized similarly as synthesis of 1-(substituted aminomethyl)-3-(4'-acetamido-2'-methoxybenzoylhydrazono) indolin-2-ones (VIa-e).

 

The physical data and spectral data are given in Table (II) and Table (III) respectively.

 

 

ACKNOWLEDGEMENT:

The authors are thankful to RSIC, IIT Mumbai and TIFR, Mumbai for 1H NMR and Dr. (Mrs.) Vivien Amonkar, Head, Department of Microbiology, St. Xavier’s College, Mumbai for providing biological activity.

 

REFERENCES:

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4.       Verma RS, and Khan IA. Indian J. Chem., 67; 1978: 315.

5.       Verma RS, and Pandey RK. Indian J. Chem., 21B; 1982: 157.

6.       Havaldar FH, and Sharma AS. Asian J. Chem., 23(3); 2011: 1315.

7.       Amir M, and Kumar S. Indian J. Heterocyclic chemistry, 14; 2004: 51.

8.       Collins CH, and Lyne PM. Microbiological Methods, 3rd ed., Butterworths, London, 1970: 424.

 

 

 

 

Received on 29.08.2011        Modified on 05.09.2011

Accepted on 11.09.2011        © AJRC All right reserved

Asian J. Research Chem. 4(12): Dec., 2011; Page 1840-1803