Consecutive Pschorr–Sandmeyer reactions in a pyrazole series. Part 2.1 Access to the [2]benzopyrano[4,3-c]pyrazole system of pharmaceutical interest

Abstract

The diazonium salts obtained from 2-amino-N-methyl-N-(1-phenyl-3-methylpyrazol-5-yl)benzamide were reacted with cuprous oxide or copper at 5 or 25 °C under different pH conditions. Cuprous oxide at 25 °C and pH 6.25 yielded the racemic epimers (3′SR,4′RS)- and (3′SR,4′SR)-4′-hydroxy-2′,4′-dihydro-2,5′-dimethyl-2′-phenylspiro[isoindoline-1,3′-3′H-pyrazol]-3-ones 2 and 10 respectively, (RS)-2′,4′-dihydro-2,5′-dimethyl-2′-phenylspiro[isoindoline-1,3′-3′H-pyrazole]-3,4′-dione 9 and N-methylphthalimide 8. The thermal transformation of 2 and 10 into the potentially pharmacologically active 3-methyl-1-phenyl[2]benzopyrano[4,3-c]pyrazol-5(1H)-one 4 was strongly dependent on the structure of the two epimers. When 1 was reacted with cuprous oxide or copper sulfate and sodium halide (chloride or bromide), in the presence of ascorbic acid as initiator, a mixture of epimers (3′SR,4′RS)- and (3′SR,4′SR)-4′-chloro(or bromo)-2′,4′-dihydro-2,5′-dimethyl-2′-phenylspiro[isoindoline-1,3′-3′H-pyrazol]-3-ones 6b and 7b (or 6c and 7c) was obtained. The same epimers were obtained when the diazonium halides (chloride and bromide) 1b,c obtained from 2-amino-N-methyl-N-(1-phenyl-3-methyl-1H-pyrazol-5-yl)benzamide were treated with the appropriate classical Sandmeyer catalysts. The formation of the spiro compounds is based on consecutive Pschorr and Sandmeyer reactions. The X-ray crystal structures of the epimers 2 and 10 have been determined, confirming the given formulations.