Synthesis of 5-hydroxy- and 5,6-dihydroxy-derivatives of spiro[indane-2,2′-pyrrolidine], rigid analogues of tyramine and dopamine respectively

Abstract

Benzyl chloride and its 3-methoxy-, 4-methoxy-, and 3,4-dimethoxy-derivatives react with N-benzoylproline in the presence of lithium di-isopropylamide in THF to afford the correspondingly substituted N-benzoyl-2-benzylprolines (2g), (2h), (2i), and (2k), respectively. Intramolecular cyclisation of the acid chloride of (2g) with aluminium chloride afforded N-benzoylspiro[1-oxoindane-2,2′-pyrrolidine](3g). Compound (2h) was cyclised in polyphosphoric acid to a mixture of the 5-methoxy- and 7-methoxy-derivatives, (3h) and (3j), of N-benzoylspiro[1-oxoindane-2,2′-pyrrolidine], whereas cyclisation of (2k) was best achieved in trifluoroacetic anhydride, affording the 5,6-dimethoxy-derivative (3k) in moderate yield. Compound (2i) failed to cyclise under a variety of conditions. Compound (3k) and the isomeric mixture of (3h) and (3j) were each reduced with lithium aluminium hydride, to the corresponding N-benzylspiro[1-hydroxyindane-2,2′-pyrrolidine] derivative followed by catalytic N-debenzylation and reductive dehydroxylation with diborane in THF to afford respectively, spiro[5,6-dimethoxyindane-2,2′-pyrrolidine](1f) and a mixture of the 5-methoxy-(1d) and 4-methoxy-(1e) derivatives of (1 a), from which (1d) was separated by preparative t.l.c. The mixture of spiro[1-hydroxyindane-2,2′-pyrrolidine] epimers [(5a) and (6a)] was resistant to reductive dehydroxylation. An alternative route to (1d) was via initial Michael condensation of 5-methoxy-2-nitroindane with methyl acrylate to give (10), which could be reductively cyclised with Raney nickel to spiro[5-methoxyindane-2,2′-(5′-oxopyrrolidine)](11) followed by LAH reduction to give (1d). O-Demethylation of (1d) and (1f) in HBr afforded spiro[5-hydroxyindane-2,2′-pyrrolidine](1b) and spiro[5,6-dihydroxyindane-2,2′-pyrrolidine](1c), rigid analogues of tyramine and dopamine, respectively.