Trimethoxybenzaldehyde Preparation

A group of arylalkylketones containing a basic substituent in the side chain shows CNS activities. Roletamide (190) is a hypnotic agent. It is prepared from 3,4,5-trimethoxybenzaldehyde (187) by addition of sodium acetylide (to give 188), followed by Jones oxidation of ethynylarylketone 189. Michael addition... 

Trimethoxybenzaldehyde has been prepared by the classical Rosenmund3-5 reduction, from 5-hydroxyvanillin by methylation,6 and by oxidation of 3,4,5-trimethoxybenzyl alcohol.7... 

The reaction has been carried out on large- and small-scale batches (Note 10). This modification,8 as exemplified by 3,4,5-trimethoxybenzaldehyde, has been applied by the submitters to the preparation of other aldehydes9 such as 3,4-dimethyl-benzaldehyde10 (90% yield), 3-benzyloxy-4,5-dimethoxybenz-aldehyde11 (88% yield, with retention of the benzyl group), and 3-methoxy-4-nitrobenzaldehyde12 (62% yield, with retention of the nitro group). 

Thus, the N-protected indoline 211 (Scheme 33), on regiospecific metallation followed by bromination with dibromotetrafluoroethane provided the 7-bromoindoline 212. Removal of the urethane functionality and subsequent benzylation of the free amine formed, furnished the tertiary amine 213. Addition of oxazoline 214 derived from 2,4,5-trimethoxybenzaldehyde to the Grignard reagent prepared from 213, followed by acid hydrolysis of the resulting biaryl 215 afforded the 2-substituted isobutylbenzoate 216. Catalytic N-debenzylation of the methylester 217 obtained by transesterification of 216 yielded oxoassoanine (203). 

As evidenced above, the interest in peyote has shown no abatement over the past year. The 56 identified constituents of this resourceful cactus have been tabu-lated. The amino-acid analogue of mescaline, 3,4,5-trimethoxyphenethylalanine (14 R = Me, R = OMe) has been prepared in three steps and in good yield from hydantoin and 3,4,5-trimethoxybenzaldehyde. G.c.-m.s. examination... 

SYNTHESIS To a solution of 45 g 3,4,5-trimethoxybenzaldehyde in 1.2 L IPA, there was added 125 g nitropropane and 67.5 g t-butylammonium acetate and the reaction mixture was held at reflux for 16 h. This was poured into 6 L H20, and extracted with 2x250 ml hexane. The pooled extracts were stripped of solvent under vacuum giving a residue that slowly set to a crystalline mass. On filtering, there was obtained 9.4 g of a crude yellow product which, on recrystallization from hexane provided 8.7 g of slightly sticky bright yellow crystals of 2-nitro-1-(3,4,5-trimethoxyphenyl)butene-1, with a mp of 71-73 °C. A second recrystallization from hexane gave fine yellow crystals with a mp of 72-73 °C. Attempts at the preparation of this nitrostyrene by the more conventional methods with ammonium acetate in acetic acid led either to the formation of a white product C23H30N2O8 which was composed of a molecule of the nitrostyrene, one of the benzaldehyde itself, and a molecule of ammonia, or to 3,4,5-trimethoxybenzonitrile, from reaction with the decomposition products of nitropropane. 

ARIADNE itself, reduced not with LAH or AH (which would give the primary amine), but rather with sodium borohydride and borane dimethylsulfide. The product, 1-(2,5-dimethoxy-4-methylphenyl)-N-hydroxy-2-aminobutane hydrochloride, was a white crystalline material. The TOM analogue got as far as the nitrostyrene. This was made from 2-methoxy-4-methyl-5-(methylthio)benzaldehyde (see under the 5-TOM recipe for its preparation) and nitropropane in acetic acid, and gave bright yellow crystals. The true pseudo-analogue is the 2,4,6-trimethoxy material based on TMA-6, which is the "real" pseudo-TMA-2. The nitrostyrene from 2,4,6-trimethoxybenzaldehyde and nitropropane crystallized from MeOH/CH3CN as fine yellow crystals, and this was reduced with AH in cold THF to 1-(2,4,6-trimethoxyphenyl)-2-aminobutane which was a bright, white powder. 

Discotic phenanthrene derivatives have been prepared by Scherowsky and Chen [39]. Their synthesis is illustrated in Scheme 14. The phosphonium salt prepared by bromination of trimethoxybenzyl alcohol and reaction of the benzyl bromide with triphenyl phosphine was deprotonated and a Wittig reaction with 2,4-dimethoxy-or 2,3,4-trimethoxybenzaldehyde produced the stilbene. Photocyclization gives the phenanthrene, which can be demethylated with boron tribromide and acylated using the Steglich method. 

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