Lactams. XI. Construction of Lactam Carbonyl Function in 1,3-Disubstituted Piperidines by Mercuric Acetate-EDTA Oxidation : Effects of Carbonyl and Related Groups at the 3-Position

1-(3,4-Dimethyoxyphenyl)-2-(3-substituted piperidino) ethanols (3a-d), which carry the carbamoyl, methoxycarbonyl, acetyl, and 1,1-ethylenedioxyethyl group as the 3-substituent in the piperidine ring, have been prepared from 3-substituted pyridines (type 1) through 1-(3,4-dimethoxyphenacyl) pyridinium bromides (type 2). In the mercuric acetate-EDTA oxidation of 3a-d, these 3-substituents have been found to orient the lactam carbonyl formation to the 6-position almost exclusively. It is suggested that the 3-substituents exert both steric and electronic effects

Lactams. XII. Improvements in the Synthesis of Ethyl trans-5-Ethyl-2-oxo-4-piperidineacetate

A highly stereoselective, efficient synthetic route to ethyl trans-5-ethyl-2-oxo-4-piperidineacetate (11a) from 1-benzyl-2,4-dioxo-5-ethylpiperidine (2) is described. The steps involved are conversion of 2 into 1-benzyl-5-ethyl-2-oxo-1,2,5,6-tetrahydropyridine (6) through the lactam alcohol (5), the Michael condensation of 6 with diethyl malonate followed by alkaline hydrolysis, decarboxylation of the resulting trans-lactam dicarboxylic acid (8a) to the trans-lactam acid (9a), and debenzylation of 9a followed by esterification

Preparation of Some Ring-Oxygenated Phenacyl Bromides

3,4-Dimethoxy, 3-benzyloxy-4-methoxy, 3,4,5-trimethoxy, 2-hydroxy-3,4-dimethoxy, and 2-benzyloxy-3,4-dimethoxy derivatives (3a-e) of phenacyl bromide have been prepared in 44-84% yields from the corresponding acetophenones by bromination with bromine in a mixture of ether and chloroform

Quinolizidines. XIII. Syntheses of (±)-and (-)-Alangimarckines

The first total synthesis of the Alangium alkaloid alangimarckine (8) has been accomplished in the form of a racemic modification by means of an initial coupling of the (±)-tricyclic amino acid 6 with tryptamine and succeeding steps proceeding through the intermediates (±)-7,(±)-10,and (±)-9. The 1\u27-epimers (±)-12 and (±)-11 were also produced in this reaction sequence. A parallel sequence of conversions starting with the (-)-tricyclic amino acid 6 yielded the chiral molecule (-)-8 via the intermediates (+)-7,(+)-10,and (+)-9,together with the 1\u27-epimer (-)-11 via (-)-12. The identity of the synthetic (-)-8 with natural alangimarckine unequivocally established the structure and absolute configuration of this alkaoid. The assignments of the configuration at C-1\u27of 8,9,11,and 12 were based on five criteria, namely, the ratio of products from the NaBH_4 reduction of (±)-10,thin-layer chromatographic mobility, and proton and carbon-13 nuclear magnetic resonance and circular dichroism spectroscopic features

Latams. X. The Alkaline Ferricyanide Oxidation of 3-Substituted 1-(3,4-Dimethoxyphenethyl) pyridinium Salts : Effects of Functional Substituents

In the alkaline ferricyanide oxidation at 32°of 3-substituted 1-(3,4-dimethoxyphenethyl) pyridinium bromides (type 3), the hydroxymethyl, N, N-dimethylaminomethyl, carbamoyl, and 1,1-ethylenedithioethyl groups at the 3-position have been found to orient the oxidation to both the 2-(type 4) and the 6-position (type 5) in ratios of 70 : 30,26 : 74,50 : 50,and 4 : 96. The carboxyl or 1,1-ethylenedioxyethyl group at the 3-position has oriented the oxidation to the 6-position exclusively, and possible factors in determining the regioselectivity in the ferricyanide oxidation of the 1,3-disubstituted pyridinium salts are discussed. For preparation of additional pyridone derivatives, 1-(3,4-dimethoxyphenethyl)-5-carboxy-2(1H)-pyridone (5d) was esterified with methanolic hydrogen chloride to the methyl ester (5h), and 1-(3,4-dimethoxyphenethyl)-5-(1,1-ethylenedioxyethyl)-2 (1H)-pyridone (5e) was converted into the methyl ketone (5i) by acid hydrolysis. The structures of the pyridones (4a, b, c, f, 5a-i) thus prepared have assigned on the basis of their ultraviolet, infrared, and nuclear magnetic resonance spectra

Lactams. XXIII. Thermal cis-trans isomerization of the 5-ethyl-2-oxo-4-piperidineacetic acid system: Effect of an N-substituent

In order to investigate the effect of an N-substituent on thermal cis-trans isomerization of the 5-ethyl-2-oxo-4-piperidineacetic acid system, the N-alkyl analogs (±)-1b, c and (±)-2b, c and the N-(2-arylethyl) analogs (-)-1f, g, i and (+)-2f, g, i were separately heated neat at 180℃, and the propress of their cis-trans isomerization reactions was followed by determining the isomer ratios in the reaction mixtures according to the previously reported C-13 nuclear magnetic resonance spectroscopic method. It has been found that in all cases the reaction comes to equilibrium within 28-130 min, when the cis and trans isomers exist in a ration of 1 : 2. These results together with those obtained previously with the analogs (±)-1a, d, e, (-)-1h, (±)-2a, d, e, and (+)-2h indicate that a higher and/or bulkier N-substituent tends to decrease the rate of cis-trans isomerization of the 5-ethyl-2-oxo-4-piperidineacetic acid system, which is a useful synthon for the synthesis of benzo-[a] quinolizidine-type Alangium alkaloids. Among the substrates used in the present equilibration study, (±)-1b, c and (±)-2b, c were prepared from the corresponding N-unsubstituted lactam esters (±)-3 and (±)-7 by the"lactim ether method.

Lactams. IX. Generation of Lactam Carbonyl Function in 1,3-Disubstituted Piperidines by Mercuric Acetate-EDTA Oxidation : Effects of Hydrocarbon Substituents at the 3-Position

The mercuric acetate-(ethylenedinitrilo) tetraacetic acid oxidation of 1-(3,4-dimethoxyphenyl)-2-(3-substituted piperidino) ethanols (7c-f), which carry the n-butyl, isopropyl, benzyl, and phenyl group as the 3-substituent in the piperidine ring, has been found to produce the corresponding 2- (8c-f) and 6-piperidones (12c-f) in good yields in ratios of 41 : 59,29 : 71,26 : 74,and 15 : 85. It is suggested that the 3-substituents exert both steric and electronic effects. The structures of the lactam alcohols (8c-f, 12c-f) have been confirmed by the chemical correlation with the known pyridones (11c-f, 15c-f) through the lactams (10c-f, 14c-f). The starting piperidinoethanols (7c-f) have been synthesized from the 3-substituted pyridines (5c-f) by quaternization with 3,4-dimethoxyphenacyl bromide followed by catalytic and sodium borohydride reductions