The compounds prepared in Examples Z1-Z14 and depicted in Table Z1 were prepared according to the Schemes Z1-Z6. The preparation of spiro[2H-1-benzopyran-2,4′-piperidine] derivatives 15 (Example Z1), 16 (Example Z2) and 18 (Example Z3) is outlined in Scheme Z1. The 2′-hydroxyacetophenone derivatives 1, 2 and 3 (commercially available from Aldrich Chemical Company) were condensed with 1-Boc-4-piperidone 4 in methanol in the presence of pyrrolidine to provide N-Boc-spiro[2H-1-benzopyran-2,4′-piperidine]-4(3H)-one derivatives 5-7 respectively. Compounds 12-14 were prepared by conversion of the ketones 5-7 to the enol triflate derivatives 8-10 and subsequent Suzuki coupling reaction with 4-(N,N-diethylaminocarbonyl)phenylboronic acid 11. The Boc protecting groups of 12-14 were subsequently removed using trifluoroacetic acid to generate the corresponding spiro[2H-1-benzopyran-2,4′-piperidine] derivatives 15 (Example Z1), 16 (Example Z2) and 17. Demethylation of the methyl ether 17 using boron tribromide in anhydrous dichloromethane afforded the phenolic derivative 18 (Example Z3). Hydrogenation of 15 in methanol in the presence of palladium hydroxide (Pearlman's catalyst) afforded the 3,4-dihydrospiro[2H,1-benzopyran-2,4′-piperidine] derivative 19 (Example Z4) (Scheme Z2). Treatment of 15 with formaldehyde in the presence of sodium cyanoborohydride gave the N-methyl derivative 20 (Example Z5) (Scheme Z2).
