Stereochemistry of the reactions of cyanohydrins of substituted 4-piperidones with ammonia and amines. Synthesis and structure of substituted 4-amino-, 4-methylamino-, and 4-dimethylamino-4-cyanopiperidines

The action of ammonia, methylamine, or dimethylamine on substituted 4-hydroxy-4-cyanopiperidines in a modified Strecker synthesis gave mixtures of stereoisomers of the corresponding 4-amino-, 4-methylamino- and 4-dimethylamino-4-cyanopiperidine. ¹H and ¹³C NMR spectroscopy was used to determine the structure of these products. Unusual stereocontrol was found for the reaction of methylamine and dimethylamine with cyanohydroxypiperidine with substituents at C₍₂₎ and C₍₅₎ in the ring.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1621–1627, December 1992.     

A new route to heterocyclic compounds by the mercuric acetate oxidation of N-alkyl substituted 4-piperidones

N-Alkyl substituted 4-piperidones readily undergo oxidation in high yield upon reaction with mercuric acetate. Application of the oxidation to the synthesis of the skeletal framework of several alkaloids is described.     

Synthesis and three-dimensional structure of the benzoates and p-nitrobenzoates of the geometrical isomers of substituted 4-hydroxypiperidines

The corresponding stereoisomeric p-nitrobenzoates were obtained by reaction of the geometrical isomers of 1,3-dimethyl-, 1,2,5-trimethyl-, and 1-tert-butyl-3-methyl-4-hydroxypiperidines with p-nitrobenzoyl chloride. The stereoisomers of the corresponding benzoates were also synthesized from the geometrical isomers of 1,3-dimethyl-4-hydroxypiperidines. The primary conformations of the investigated compounds in solution were established by means of their PMR spectra.     

A double Mannich approach to the synthesis of substituted piperidones—application to the synthesis of substituted E-ring analogues of methyllycaconitine

The double Mannich reaction of acyclic α,γ-substituted β-keto esters and bis(aminol) ethers gives substituted 3,5-substituted-4-piperidones with high levels of diastereoselectivity. These piperdiones can be easily transformed into substituted E-ring analogues of the delphinium alkaloid methyllycacotine.     

Synthesis of substituted 2-phenyl-4-piperidinones from styryl Β-dimethylaminoethyl ketones and their steric structure

The difficultly obtainable substituted 2-phenyl-4-piperidinones were synthesized by the reaction of styryl -dimethylaminoethyl ketone hydrochlorides with aqueous solutions of ammonia or alkylamines. It was found using ¹H and ¹³C NMR spectroscopy methods that the cyclization process proceeds with the formation of pure stereoisomers of 4-piperidones with an equatorial disposition of all the substituents in the ring. The temperature for performing the cyclization is dependent on the number and position of the methyl substituents in the molecule of the starting substituted styryl -dimethylaminoethyl ketones.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 224–227, February, 1991.     

Cross double Mannich reaction catalyzed by I2: Synthesis of highly substituted 4-piperidones

Cross double Mannich reaction and tandem cyclization were achieved under iodine catalyzed conditions,yielding a series of highly substituted 4-piperidones.Among the possible diastereomers,only one diastereomer was isolated,which could be ascribed to the chair-like transition state in six-membered ring,in which all of the hindered groups are located in the pseudoequatorial orientation.     

Synthesis and Antibacterial Activity of New 2,5‐Diaryl‐3‐styryl‐4H,2,3,3a,5,6,6a‐hexahydropyrrolo[3,4‐d]isoxazole‐4,6‐diones

The synthesis of some biologically interesting pyrrolo‐isoxazolidine derivatives has been accomplished by the 1,3‐dipolar cycloaddition reaction of substituted open chain conjugated azomethine N‐oxides 1 with substituted N‐aryl maleimides 2 leading to the formation of new stereoisomeric 2,5‐diaryl‐3‐styryl‐4H,2,3,3a,5,6,6a‐hexahydropyrrolo[3,4‐d]isoxazole‐4,6‐dione derivatives 3 in excellent yields. These stereoisomers have been characterized as cis‐ 3A and trans‐ 3B on the basis of their ¹H‐NMR spectral measurements. The synthesized compounds have been screened for their antibacterial activities and have been found to be active against the bacteria Escherichia coli and Pseudomonas aeruginosa up to a significant extent.     

Reaction of 2 -methyl-2-cinnamoyloxiranes with benzylamine and thioacetic acid

Reaction of 2-methyl-2-cinnamoyloxiranes with benzylamine gave stereoisomeric 3-hydroxy-3-methyl-1-benzyl-6-aryl-4-piperidones, which were converted to 3-hydroxy-1,3-dimethyl-6-aryl-4-piperidones by debenzylation and subsequent methylation. 3-Hydroxy-3-methyl-6-phenyltetrahydro-4-thiopyrone acetate was obtained by reaction of 2-methyl-2-cinnamoyloxirane with thioacetic acid. The three-dimensional configurations of the synthesized compounds were established by means of their IR and PMR spectra.     

Studies on substituted lactams. II

Synthesis and reactions of 4-carboxy-6-alkyl-2-piperidones and 4-carboxyl-6-alkyl-2-pyrrolidones are described. Upon heating, the substituted 4-carboxy-2-piperidones underwent both polymerization to polysuccinimides and isomerization to pyrrolidone derivatives. No polymerization but isomerization to ethylidene succinimide was observed upon heating the substituted 4-carboxy-2-pyrrolidone. Both polymerization and isomerization can be explained by mechanisms discussed previously.     

Mass spectrometry of stereoisomeric 3-hydroxy-4-piperidones

The existence of several sites of charge localization upon the mass spectrometric decomposition of stereoisomeric 3-hydroxy-4-piperidones leads to a large number of fragmentation products both with retention and destruction of the piperidine ring. Analysis of the mass spectra of the compounds studied showed that the appearance of [M — CO]⁺ ion peaks for isomers with an axial hydroxyl group may serve as a method for determining the configuration of the carbinol site of such cyclic structures.Translated from Khimiya Geterotsiklichesikh Soedinenii, No. 3, pp. 375–379, March, 1986.     

Synthesis of some substituted 1-(2-propynyl)-4-piperidones

Summary Some 1-(1,2-dimethyl-2-propynyl)-4-piperidones were synthesized, and the effect of substitution in the piperidine ring on the reversible cyclization of unsaturated-alkylamino ketones into 4-piperidones was investigated.     

Transition-Metal-Free Multiple Functionalization of Piperidines to 4-Substituted and 3,4-Disubstituted 2-Piperidinones

Remote and multiple functionalization of piperidines without the use of transition-metal catalysts and elaborate directing groups is one of the major challenges in organic synthesis. Herein is reported an unprecedented two-step protocol that enables the multiple functionalization of piperidines to either 4-substituted or trans-3,4-disubstituted 2-piperidones. First, by exploiting the duality of TEMPO reactivity, which under oxidative and thermal conditions fluctuates between cationic and persistent-radical form, a novel multiple C(sp³)-H oxidation of piperidines to α,β-unsaturated 2-piperidones was developed. Second, the intrinsic low reactivity of the unsaturated piperidones toward conjugated Grignard additions was overcome by using trimethylsilyl chloride (TMSCl) as Lewis acid. Subsequently, conjugated Grignard addition/electrophilic trapping protocol provided substituted 2-piperidone intermediates, some of which were then transformed into pharmaceutical alkaloids.     

Esterification kinetics and mechanism of stereoisomers of substituted 4-hydroxypiperidines and cyclohexanols

Esterification rates of stereoisomeric substituted 4-hydroxypiperidines and cyclohexanols (in the presence of N-methylpiperidine) with benzoyl chloride in tetrachloroethylene at 25° are found to indicate intramolecular catalysis and intermolecular acylation, respectively. Isomers of 4-hydroxyperidines with an axial hydroxyl group undergo acylation four times as fast as their 4-equatorial hydroxyl epimers accounted for by higher stability of the resulting intermediate complex.     

Reaction of methyl tetronate with some amines. Synthesis of substituted 4-aminobut-2-enolides

A series of substituted 4-aminobut-2-enolide derivatives have been synthesized by reaction of a variety of substituted amines with methyl tetronate. The ¹H and ¹³C nmr spectral analysis of all compounds synthesized are given.     

13C Pulse fourier transform NMR of menthol stereoisomers and related compounds

¹³C NMR spectra of menthol stereoisomers have been determined. The correlations of chemical shifts of these ring carbons with those of stereoisomeric 2-isopropylcyclohexanols are examined. Observed chemical shifts of 1-Me carbons are compared with those predicted from the chemical shifts of stereoisomeric 1-methyl-4-t-butylcyclohexanes. ¹³C NMR spectra of menthyl acetates, and cis and trans p -menthanes have also been examined.     

Stereochemistry of the hydrocyanation of hydroxypiperidin-4-ones

Preparative methods have been developed for the preparation of stereoisomers of 3,4-dihydroxy-1,3-dimethyl-6-(4-chlorophenyl)-4-cyanopiperidin-4-ones. Products with the cyano group equatorial predominate in the equilibrium mixtures of the cyanohydrins synthesized.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 673–676, May, 1993.     

Synthesis of 4-isobutyl substituted thiophenes byGewald reaction

Summary TheGewald reaction of 4-methyl-2-pentanone with alkyl cyanoacetates was investigated. Alkyl 2-amino-4-isobutylthiophene-3-carboxylates (4) were formed, together withbis-(2-amino-3-alkoxycarbonyl-4-isobutyl-5-thienyl)-disulfides (5) and alkyl 2-amino-4-isobutyl-5-morpholinothiophene-3-carboxylates (6). The absence of any 4-methyl substituted aminothiophene in the product mixtures came up highly unexpected. The mechanism of the reaction is discussed with respect to previously reported suggestions.Dedicated to Professor Dr.Karl Gewald on the occasion of his 65^th birthday     

PMR studies of the deuteration and hydration of 4-piperidones

PMR spectra of substituted 4-piperidones in base and salt forms in D₂O, water and other solvents are reported, and spectral characteristics interpreted in terms of equilibria between free ketone and 4,4-dideuteroxy (or hydroxy) forms. It is shown that 1-mono and 1,3-disubstituted-4-piperidones exist extensively as the corresponding dideuteroxy (or hydrated) species in D₂O (or H₂O) provided the ring nitrogen atom is positively charged, and that 3-substituents decrease the population of these forms. The facile D/H exchange of α-protons in the piperidone bases is also demonstrated.     

A novel and concise synthetic access to chiral 2-substituted-4-piperidone

A novel and concise synthetic access to enantiopure chiral 2-aryl/alkyl substituted 4-piperidone has been demonstrated.This new route features two key steps:the highly diastereoselective conjugate addition of homochiral lithium amides to trans-β-substituted-α,β-unsaturated methyl esters guaranteed the enantiopurity at 2 position(de19:1)and the intramolecular attacking of carbanions to methyl esters led to the formation of the piperidone ring.A wide range of substrates,including chiral2-aryl and 2-alkyl-4-piperidones,were successfully synthesized with modest to high yield.Moreover,some non-chiral3-substituted-4-piperidones were also synthesized with enhanced ring-formation yield,implicating the versatility of this method in construction of various piperidine rings.     

Stereochemical aspects of pyrrole formation from substituted piperidin-4-one oximes and acetylene

Oxime derivatives of 1,2,5-trimethylpiperidin-4-one, 2-methyl-, and 2-(2-furyl)-4-ketodecahydroquinoline react with acetylene to form substituted pyrrolo[3,2-c]piperidines and their N-vinyl derivatives. During the course of pyrrolization the configuration at the 7-position is partially changed, resulting in the formation of two stereoisomeric pyrroles.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1365–1370, October, 1991.