Tetrahydropyridines, from pyridine

The preparation of conjugated dienes from pyridines is exemplified by the transformation of 2-picoline into the sex pheromone (669) of Lobesia botrana, a major pest of vineyards (Scheme 154) (80TL67). Thus, the lithio salt of 2-picoline was alkylated by 2-(5-chloropentyl-oxy)tetrahydropyran, the resulting pyridine (665) N-methylated, and the pyridinium salt reduced by sodium borohydride. Quaternization of the 1,2,3,6-tetrahydropyridine (666) and Hofmann elimination gave the (7 , 9Z)-undecadien-l-ol (667) as the sole isomer. Protection of the alcohol and treatment of the corresponding ammonium salt (668) of the amine with lithium dimethylcuprate gave pure (669) after hydrolysis, acetylation and HPLC purification. 

Anabasine (3-(2-piperidinyl)-pyridine) from Mcotiana and Duboisia species (Solanaceae) is an nACh-R agonist used to discourage tobacco smoking as is the JV-methylated tricyclic piperidine (—)-lobeline from Lobelia species (Campanulaceae). Lobeline-related compounds from Lobelia species include the bicyclic jV methyltetrahydropyridines isolobinine and lobinine and the tricyclic jV-methylpiperidines lobelanine and lobelanidine. Anabasine-related compounds include anatabine (2-(3-pyridyl)-l,2,3,6-tetrahydropyridine) from M tabacum and (+)-ammodendrine (jV-acetyltetrahydroanabasine) from Ammodendron and Sophora species (Fabaceae). 

Santamaria et al [42] for synthesizing a-amino nitriles in the alkaloid field and also for preparing 6-cyano-l,2,3,6-tetrahydropyridine from corresponding pyridine nucleus. A similar approach has also been used by Sundberg et al. [43a,43b] for the cyanation of Catharanthine alkaloids. In situ trapping of the iminium cation (37) by allyltrimethylsilanes or silyl enol ethers is also shown [44] recently as a direct —C-C— bond formation methodology at the a-posi-tion of tertiary amines (Scheme 8). The success of this reaction is based on the comparative correlation of ion-pair yield with the AGg, values from amines and enol ethers. 

Finally, pyridine derivatives can be reduced by metals. Piperidine is obtained from pyridine with sodium in alcohols Ladenburg reaction) piperidines, as well as tetrahydropyridines, are obtained from 4-alkylpyridines. A -Alkylpyridinium ions are converted into 7V-alkylpiperidines by metals such as Zn or Sn in an acidic medium, or by electrochemical reduction (122 - 125, see p 293). 

The direct preparation of pyridinium salts (35) from acyclic starting materials 33 and 34 was reported by Adamczyk and co-workers <00TA2289>. Pyridinium salts have also been used to form other heterocyclic ring systems such as imidazolo[l,2-a]pyridines as reported by Katritzky <00JOC9201>. A final report worthy of comment is the preparation of chiral 2,6-disubstituted tetrahydropyridines via chiral pyridinium salts . 

Perhaps the strongest evidence in favour of episulfonium ion involvement comes from the isolation of the 4-substituted 1-acetyltetrahydropyridines (137) and (138). Product (138) arises by addition of another molecule of 2-methylpropanethiol to (135). 4-Ethyl-pyridine 1-oxide on reaction with 2-methylpropanethiol, acetic anhydride and TEA yields another type of tetrahydropyridine (137). In this case TEA promotes elimination by abstraction of an ethyl proton, before 2-methylpropanethiol can attack position 6. Conversely, tetrahydropyridines are formed when R=Me, Pr or Pr1, as 2-methylpropanethiol (Scheme 78) is a better nucleophile (at C-6) than TEA is a base (at the 4-substituent). A different tetrahydropyridine (139) is obtained if the starting TV-oxide has a vacant 4-position (Scheme 79). Structural determination of compounds of this type has been greatly facilitated by the availability of 13C NMR (78JHC785). It should be remembered that while 3-substitution... 

Pyridine 1-oxide and methyl analogues undergo thioalkylation at the a- and y-positions with alkanethiols in acetic anhydride (Scheme 19). Some (3-substitution occurs under these conditions probably via episulfonium intermediates, evidence for which comes from the isolation of tetrahydropyridines, e.g. (267). 

JOC2691). Analogously, in the reaction of chalcone (145) with the enaminonitrile 146, the intermediate dihydropyridine (147) can be detected only in trace amounts because it undergoes disproportionation with the formation of tetrahydropyridine (148) and pyridine derivatives (149) (92JOC7352). Fused 5,6-dihydropyridines (150) were obtained from cyclic... 

The formation of piperidines from the borohydride reduction of pyridine and picoline methiodides has been reported by Ferles.17 He assumed that this complete reduction arose from initial formation of the 1,4-dihydropyridine, and that the ratio of tetrahydropyridine to piperidine represented the ratio of attack of hydride at the 2-position to that at the 4-position. 

In the reaction of 3,5-dimethyl-2,6-diphenylpiperid-4-one oxime (10) with acetylene and RbOH-DMSO, migration of the 3a-Me group to the anionic nitrogen atom occurred, leading to 5,7-dimethyl-4,6-diphenyl-4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine (11) (04CHE326). The formation of the N-anion caused aromatization of the tetrahydropyridine ring. Tetrahydropyrrolo[l,2-c]pyrimidine 12 resulted from the decomposition of the intermediate 3H-pyrrole in a retro-Mannich reaction (Scheme 3). 

Many quinolizidine alkaloids have been obtained by way of substituted perhydro-isoxazolo[2,3- ]pyridines. Reaction between 3,4-dimethoxy-benzaldehyde and the phosphorane derived from allyltriphenylphos-phonium bromide gave an - and Z-isomer mixture of l-(3,4-dimethoxy-phenyl)butadiene, which reacted with 2,3,4,5-tetrahydropyridine 1-oxide in boiling toluene to give the corresponding isomers of the isoxazolidines (43-46). The formation of the trans- (H-2, H-3a) isomers was favored in... 

A novel rearrangement of suitably 2-substituted side-chain perhy-dro-isoxazolo[2,3-a]pyridines has been shown to afford indolizine and quinolizine derivatives (86TL1727). Thus, 2-spirocyclopropylperhydro-isoxazolo[2,3-a]pyridine (61), obtained as a mixture with the 3-spiro isomer from the reaction between 3,4,5,6-tetrahydropyridine-l-oxide and methylene cyclopropane, undergoes thermal rearrangement (400°C, 0.2 mmHg) to the quinolizidin-2-one (62). 

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