INTRODUCTION:

The use of microwave irradiation for carriying out organic reaction has been well established and has recently been reviewed ¹. The application of the solvent free technology coupled with the recyclability of mineral support has led to the development of many reaction procedures, which are environment friendly, falling in the domain of green chemistry².

Isatoic anhydride has found its wide applicability in synthesis as a versatile synthones, in the preparation of a wide variety of important heterocycles^3-4. Secondary amines like pyrrolidine, morpholine, piperazine etc. are well known for their antimicrobial activities ^5-15. It has been observed that incorporation of certain bioactive pharmacophores in the existing drug molecules sometimes exert a profound influence on the biological profile of that molecule. Based on these observation, it could be anticipated that incorporation of the bioactive secondary amines moiety with the isatoic anhydride could produce interesting series of compound having a wide range of synthetic applicability with biological activity. Mannich’s bases are also very important due to their facile conversion into various pharmaceutical and natural products. So, herein we report the preliminary result of our studies on the synthesis of some novel mannich’s bases of isatoic anhydride derivatives.

EXPERIMENTAL:

Melting points were determined in an open glass capillaries and are uncorrected. TLC was done on silica gel ‘G’ coated glass plates using benzene: methanol (9.5:0.5) as eluent of the reations. IR spectra on KBr were recorded on FTIR-8400S, CE (SHIMADZU). ¹H NMR spectra were recorded on Model AC-300F (Bruker) using CDCl₃as solvent and TMS as an internal standard. Basic alumina used as aluminium oxide, basic, mesh size (100-300) Min. 90%, pH=10.

General method for the preparation of 2,3 and 4(a-g):

1. Solution phase microwave assisted method:-

Isatoic anhydride (0.001M) 1, and formaldehyde were mixed in ethanol (10ml) and placed in 100 ml flask fitted with a funnel as a loose top. The reaction mixture was subjected to microwave irradiation at 360 W microwave power for 5 min. and then 720 W for 5 min. with short interval of 1 min. to avoid the excessive evaporation of solvent. The completion of the reaction was checked by TLC. The solution obtained after the reaction had completed was kept at 0^oC for I hour and the resulting solid obtained was filtered and recrystallized from ethanol to give 2 (63%).

Compound 2 (0.001M), and HCl (5ml) were mixed in ethanol placed in 100 ml flask fitted with a funnel as a loose top. The reaction mixture was subjected to microwave irradiation at 360 W microwave power for 3 min. and then 720 W for 5 min. with short interval of 1 min. to avoid the excessive evaporation of solvent. The completion of the reaction was checked by TLC. The solution obtained after the reaction had completed was kept at 0^oC for I hour and the resulting solid obtained was filtered and recrystallized from ethanol to give 3 (67%).

Equimolar quantity of compound 2 (0.001) and secondary amines were mixed in ethanol (10ml) and placed in 100 ml flask fitted with a funnel as a loose top. The reaction mixture was subjected to microwave irradiation at 360 W microwave power for 7 min. and then 720 W for 8 min. with short interval of 1 min. to avoid the excessive evaporation of solvent. The completion of the reaction was checked by TLC. The solution obtained after the reaction had completed was kept at 0^oC for I hour and the resulting solid obtained was filtered and recrystallized from ethanol to give 4(a-g).Yield and melting point of synthesized compounds are given in table-1.

Table-1: Physical data of compounds 4(a-g)

Comp.	Molecular Weight	M. P. (^oC)	N Analysis (%) (Cald./Found)
4a	246	170-75	11.38/11.35
4b	260	177-82	10.76/10.71
4c	262	185-90	10.68/10.64
4d	275	165-65	15.26/115.21
4e	337	176-81	12.46/12.50
4f	351	175-80	11.96/11.92
4g	333	181-86	12.61/12.58

2. Solid phase microwave assisted method: -

A sullry of Isatoic anhydride (0.001M) 1, and formaldehyde (10ml) adsorbed over basic alumina (20%) by weight of reactant via a solution in ethanol (5ml). The dride slurry was powered and the free flowing powered was placed in a 100 ml borosil beaker and irradiated at 360 W microwave power for 5 min. and then at 720 W for 2 min until the completion of the reaction monitored by TLC. The recyclable in organic solid support was separated by extraction the product with ethanol .The solvent was evaporated and solid obtained was recrystallized from ethanol and dride to give 2 (63%).

A sullry of compound 2 (0.001M), and HCl (5ml) adsorbed over basic alumina (20%) by weight of reactant via a solution in ethanol (5ml). The dride slurry was powered and the free flowing powered was placed in a 100 ml borosil beaker and irradiated at 360 W microwave power for 5 min. and then at 720 W for 1 min until the completion of the reaction monitored by TLC. The recyclable in organic solid support was separated by extraction the product with ethanol .The solvent was evaporated and solid obtained was recrystallized from ethanol and dride to give 3 (67%).

A sullry of equimolar quantity of 3 (0.001M), and secondary amines adsorbed over basic alumina (20%) by weight of reactant via a solution in ethanol (5ml). The dride slurry was powered and the free flowing powered was placed in a 100 ml borosil beaker and irradiated at 360 W microwave power for 8 min. and then at 720 W for 5 min until the completion of the reaction monitored by TLC. The recyclable in organic solid support was separated by extraction the product with ethanol .The solvent was evaporated and solid obtained was recrystallized from ethanol and dride to give 4(a-g). Yield and melting point of synthesized compounds are given in table-1.

Table 2: Spectral data of compounds 4(a-g)

Comp.

IR(KBr) cm^-1

¹H NMR ( ppm)

MS: m/z

1720,

1460

1234

7.21-8.11(4H,m,Ar-H)

4.03(2H,s,CH₂)

2.25(4H,t,CH₂)

1.59(4H,s,CH₂)

225(100%)

246(40%)

1750,

1460

1225

7.21-8.11(4H,m,Ar-H)

4.03(2H,s,CH₂)

2.24(4H,t,CH₂)

1.50(6H,m,CH₂)

240(100%)

260(30%)

1643,

1450

1210

7.21-8.11(4H,m,Ar-H)

4.03(2H,s,CH₂)

2.37(4H,t,CH₂)

3.67(4H,t,CH₂)

240(100%)

262(40%)

1650

1430

1200

7.21-8.11(4H,m,Ar-H)

4.03(2H,s,CH₂)

2.46(8H,m,CH₂)

2.27(3H,s,CH₃)

250(100%)

275(20%)

1689

1452

1286

6.59-8.11(9H,m,Ar-H)

4.03(2H,s,CH₂)

3.45(4H,t,CH₂)

2.59(4H,t,CH₂)

300(100%)

337(20%)

1680

1450

1220

7.06-8.11(9H,m,Ar-H)

4.03(2H,s,CH₂)

3.62(4H,t,CH₂)

2.46(8H,m,CH₂)

250(100%)

351(40%)

1690

1470

1240

7.21-8.11(4H,m,Ar-H)

4.12(2H,q,CH₂)

4.03(2H,s,CH₂)

3.06(4H,t,CH₂)

2.62(4H,t,CH₂)

1.30(3H,t,CH₃)

230(100%)

333(40%)

RESULT AND DISCUSSION:

The microwave irradiation technique has been shown to score over the conventional ones in terms of safety, simplicity and eco-friendliness. To our knowledge there has been no report on the synthesis of Mannich’s base of isatoic anhydride derivatives on a solid support (basic alumina) under MW conditions, therefore, an efficient microwave assisted protocol for the exclusive synthesis of Mannich’s base 4(a-g) has been developed (Scheme I) and is described in this paper.

The synthesis of 4(a-g) consisted of treating isatoic anhydride (1) with formaldehyde to give 2 followed by reaction with HCl afforded 3 which reacted smoothly with secondary amines viz- pyrrolidine, piperidine, morpholine, 1-methyl piperazine, 1-ethyl piperazine, 1-phenyl piperazine, 1-benzyl piperazine and 1-ethoxy carbonyl piperazine under microwave conditions to give 4(a-g) scheme-1 in excellent yield.

All the synthesized compounds gave satisfactory results of N analysis. IR and¹H-NMR spectral data were found to be consistent to the assigned structures. The physical, analytical and spectral data of all the synthesized compound are given in table-1 and 2 respectively.

ACKNOWLEDGEMENT:

The authors wish to thank CDRI, Lucknow, India for providing ¹H NMR spectral data.

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