Novel method for synthesis of some biologically active aminocoumarins

Nitration of coumarin 4-methyl acetates using concentrated HN0 3 in solvents like chloroform or dichloromethane at lower temperature 'Cheparon effect' was found to occur only on aromatic part of coumarin. Yields of nitrocoumarins are almost quantitative and isomers were separated using column chromatographic technique. Reduction of the nitrocoumarins was car ried out in environmentally friendly hydride transfer system using Pd/C as catalyst and formic acid or phosphorous acid as hydride generating reagent. Functional groups like -OH, Br. COCH 3, -CH 2 COOH_ 1 and lactone were not interfering in the reduction of nitro group to amino.

In continuation of our work on substituted coumarins (part-1), we reported here synthesis of a few more of this type of coumarins.

Experimental
Melting points are uncorrected. 1 H NMR spectra were recorded on a Bruker spectrometer with TMS as internal reference. The lR spectra were recorded on JASCO-FTIR spectrometer with KBr pellets.

Methods of preparation of nitro derivatives:
(a) Nirations using HN0 3 /CH 2 CI 2 : Nitro dimethyl coumarin-4-methyl acetate : The precooled solution of concentrated HN0 3 (98%) (0.85 ml, 21 mmol) in 40 ml CH 2 CI 2 was added to the solution of dimethyl coumarin-4-methyl acetate (lOe-i) (5g • 20 mmol) in CH 2 Cl 2 (100 ml) at so over a period of one hour. Reaction mixture was stirred at so for l-2 h. Reaction was monitored by TLC till the starting ester completely consumed. Reac-2S8 tion mass was then added to mixture of ice and water and stirred for 30 min. The organic layer was separated and washed with water. The organic layer was then dehydrated and solvent was removed completely under reduced pressure.
In case of S,7-dimethyl and 6,7-dimethyl coumarins, two isomers were seen in the product and were purified by crystallization from ethyl acetate to get one pure isomer. Other isomer was separated by column chromatography on silica column using toluene: ethyl acetate (90: 10) mixture as an eluent.
In case of7-hydroxy-4-methyl coumarin, the crude product of nitration was purified by crystallization from glacial acetic acid and methyl ethyl ketone to give 6-nitro derivative.
In case of 6-hydroxy-4-methyl coumarin, 2m/m HN0 3 was used to obtain 5,7-dinitro coumarin as major product. In case of7-hydroxy-4-methyl-3-bromo coumarin, the crude product was purified by column chromatography on silica column first using toluene : pet. ether (50 : 50) mixture to isolate 6-nitro derivative and then using methanol to isolate 8-nitro derivative. Yields, melting points and spectral analysis of the nitro derivatives are as follows. lle yield 79%, m.p. 213-214°; 1  (c) Nitrations using HN0 3 !acetic acid: Nitration of simple coumarin :To 20 g (0.14 mol) coumarin dissolved in 24 ml glacial acetic acid was added a mixture of ll.S ml nitric acid (sp. gr. 1.5) in 8 ml glacial acetic acid. No appreciable rise of temperature was observed. 7 ml concentrated sulfuric acid was then added to the mixture, when a vigorous reaction started. The reaction mixture was cooled at first and finally heated for a short time on a water bath. A portion of 6-nitrocoumarin which crystallized out, was filtered off. The remaining 6nitrocoumarin was precipitated by pouring the acid mother liquor into water. The precipitate was collected and washed thoroughly with water. The solids were dissolved in 20% sodium hydroxide solution to give a red colored solution. It was then cooled to room temperature. A very dilute solution of hydrochloric acid was then added until the solution was slightly acidic. The bulky yellow precipitate that formed was allowed to stand for fifteen minutes and then filtered. The product was washed with dilute sodium bicarbonate solution followed by water till free of alkali and dried. It was crystallized from methanol when pale yellowish crystals of 6-nitrocoumarin were obtained.
When the nitration was carried out using mix acid i.e. without using any acetic acid both the isomers were obtained. 6-Nitrocoumarin was isolated by crystallization from methanol and the 8-nitro isomer was isolated from mother liquor by column chromatography after concentration.
Nitration of 8-allyl coumarin : 7-Hydroxy-4-methyl-8allyl coumarin (21.7 g, 0.1 mol) was dissolved in 25 ml glacial acetic acid. A solution of 70% HN0 3 (15 ml) in glacial acetic acid (25 ml) was added to it at 0-4° over 2 h. Reaction mixture was stirred for l 0-12 h at 0-5°. The reaction was monitored on TLC. On completion, the reaction mixture was poured into ice water and stirred for 1 h. Precipitated solids were filtered and washed well with water and dried to obtain crude product containing mixture of 3nitro and 6,3-dinitro derivatives. The nitro derivatives thus obtained were separated by column chromatography on silica column using dichloroethane as an eluent, to isolate 6-nitro and 6,3-dinitro derivatives.