Serotonin and related compounds

Abstract

To an ice-cooled mixt. of 9.2 Na, 100 cc. EtOH, and 340 cc. Et2O was added 48.6 g. 2-nitro-5-benzyloxytoluene and 60 g. (CO2Et)2 in 100 cc. PhMe, keeping the temp. below 8° throughout the reaction, the mixt. kept overnight at 10° then at room temp. 72 h., the sepd. mass collected, washed with Et2O, dissolved in a mixt. of 120 cc. 2N NaOH and 700 cc. H2O, washed with Et2O twice, and acidified with HCl to give 78% 2-nitro-5-benzoyloxyphenylpyruvic acid (I), m. 112-13°. I (26 g.) and 52 g. NaOH in 300 cc. H2O was boiled with 156 g. Fe2SO4 in 300 cc. H2O 2 h., acidified with HCl, and extd. with MeOH to give 70% 5-benzyloxyindole-2-carboxylic acid (II), m. 194-5° (C6H6). II (1 g.) in 5 cc. quinoline was heated with 0.5 g. Cu powder at 245-50°, the quinoline evapd., and the residue extd. with Et2O to give 78% 5-benzyloxyindole (III), m. 102° (C6H6). Similarly were prepd. 2-nitro-4-benzyloxyphenylpyruvic acid (m. 92-3°), 6-benzyloxyindole-2-carboxylic acid (m. 196-7°), and 6-benzyloxyindole (IV), m. 117-18°. III (1 g.) in 20 cc. Et2O was treated with oxalyl chloride in ether at 0° to give 93% 5-benzyloxyindole-3-oxalyl chloride (V), m. 149-51°. V (1 g.) was treated with 33% Me2NH soln. to give 5-benzyloxyindole-3-oxalyl dimethylamide (VI), m. 185-7°. VI (2.8 g.) in 30 cc. THF was refluxed with 100 cc. Et2O and 2.8 g. LiAlH4 6 h., H2O added, the mixt. made alk. with 40% NH4OH, filtered, the filtrate evapd., and oxalic acid in ether added to give 84% bufotenine benzyl ether oxalate (VII), m. 178-9° (MeOH). VII was made alk., extd. with Et2O, and treated with MeI to give methiodide, m. 212-13° (MeOH). Catalytic redn. of 0.3 g. VII in MeOH using 0.2 g. 10% Pd-BaSO4 gave 87% bufotenine oxalate, pink needles, m. 93-4°. Also were prepd. bufotenine methiodide, m. 214-15° (MeOH), and bufotenine flavianate, m. 194-4.5°. III (1 g.) in 10 cc. C6H6 was refluxed with 0.2 g. NaNH2 3 h., then refluxed with β-dimethylaminoethyl chloride 2 h., 5% H2SO4 added after cooling, the mixt. made alk., and extd. with ether to give 1-(β-dimethylaminoethyl)-5-benzyloxyindole; oxalate, needles, m. 159-60° (MeOH). Similarly was prepd. 1-(β-diethylaminoethyl)-5-benzyloxyindole oxalate, m. 158-9° (MeOH). V (0.8 g.) with 50% aq. soln. of Et2NH gave 89% 5-benzyloxyindole-3-oxalyl diethylamide (VIII), m. 176-7° (petr.-ether). Similarly were prepd. monomethylamide, m. 247-9° (petr. ether), and piperidide, m. 163-4° (petr. ether). VIII (0.5 g.) in 10 cc. THF was refluxed with 50 cc. Et2O and 0.5 g. LiAlH4 6 h., H2O added, the mixt. made alk., filtered, the filtrate evapd., and extd. with ether to give 5-benzyloxy-N,N-diethyltryptamine; oxalate (IX) m. 161-2° (Me2CO). IV (0.4 g.) in Et2O with oxalyl chloride gave 89% 6-benzyloxyindole-3-oxalyl chloride (X), m. 164-5° (decompn.). X (0.5 g.) with 33% aq. Me2NH gave 89% 6-benzyloxyindole-3-oxalyl dimethylamide (XI), prisms, m. 204-5° (MeOH). Redn. of 2 g. XI in THF using LiAlH4 and treating with oxalic acid gave 71% 6-benzyloxy-N,N-dimethyltryptamine, plates, m. 178-9° (MeOH). Starting from indole-3-oxalyl chloride (m. 117-18°) instead of X, indole-3-oxalyl dimethylamide (needles, m. 160-1°) and N,N-dimethyltryptamine (needles, m. 151-2°) were similarly prepd. V (2 g.) with 28% NH4OH gave 91% 5-benzyloxyindole-3-oxalyl amide (XII), m. 274-6° (MeOH). Redn. of 2.4 g. XII in 20 cc. THF with 2.4 g. LiAlH4 afforded serotonin benzyl ether (XIII); hydrochloride, flakes, m. 265-6° (MeOH). Catalytic redn. of XIII oxalate using 10% Pd-BaSO4 gave 84% serotonin, m. 197-8°. [on SciFinder(R)]