Pyridyl-1,2,3,6-tetrahydropyridine

Two polymorphic forms of 3- 2-[4-(6-fluorobenzisoxazol-3-yl)-l,2,3,6-tetrahydropyridin-l-yl]ethyl -2-methyl-6,7,8,9-tetrahydro-4//-pyrido[l,2-n] pyrimidin-4-one (137 R = H) were prepared (99MIP1). Racemic 9-hydroxy-2-methyl-3- 2-[4-(6-fluorobenzo[r/ isoxazol-3-yl)-l,2,3,6-tetrahydro-l-pyridyl] ethyl -6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidin-4-one was resolved into its (R)- and (5)-isomers (OOMIPIO). 

Diastereoselectivities of up to 90% were observed for the cycloadditions of jV-galaclosy-limines 108 (Piv = pivalyl R = 2-furyl, 2-thienyl-, 4-FC6H4, 4-ClC6f or 3-pyridyl) to isoprene in the presence of zinc chloride to form the tetrahydropyridines 109 and 110 (equation 62)55. 

The reductive cleavage of the C—O bond in 2- and 4-substituted hydroxy-methylpyridines was mentioned in Part I. The optically active l-(4-pyridyl)-alkanols are reduced in good yield to the optically inactive alkylpyridine, whereas the 2-substituted derivatives were reduced in lower yield to the optically active alkylpyridine (and some tetrahydropyridine derivatives).384,385 The difference in behavior was explained by orientation of the adsorbed pro-tonated pyridine, allowing contact between the electrode and the 2-substituent, but not the 4-substituent. This model was used in later work however, not excluded was the possibility that the higher stability of the p-quinonoid dihydropyridine intermediate, compared to the o-quinonoid dihydropyridine, played a role in the relative ease of reduction of the 4- and 2-substi-tuted pyridines. 

The quaternary salts of ketals of 4-pyridyl alkyl and aryl ketones undergo reduction with sodium borohydride to give the expected 1,2,3,6-tetrahydropyridines.47" Reduction of an analogous ketal of a quaternary salt of a 3-pyridyl ketone led to rupture of the ketal ring.476... 

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). 

Hydrogenations of acetylpyridines were carried out similarly, and yielded various products depending on the reaction conditions and especially on the catalyst used. Thus 4-acetylpyridine was hydrogenated over palladium oxide to form the corresponding alcohol, 4-(l-hydroxyethyl)pyridine, with a small amount of the pinacol (4), but it was converted mainly to the pinacol using palladium on charcoal or rhodium on alumina. However, under different conditions, the pyridyl ring of 3-acetylpyridine was reduced to a mixture of 3-acetyl-l, 4,5,6-tetrahydropyridine and 3-acetylpiperidine. 

A number of other aryl-cyclic amine functionalities were examined as replacements for the 1,2,3,6-tetrahydro-4-phenylpiperidine of 36 (Table 6). Thiophene analogue 41 was found to have somewhat weaker DA D2 receptor affinity. In the 1,4-cyclohexenyl series 2-pyridylpiperazine attached to the phenyl cyclohexene produced potent compounds. The 1,5-cyclohexenyl analogue 42 having a 2-pyridylpiperazine group was also an interesting compound. However, the parent tetrahydropyridine 36 caused greater decreases in DA synthesis than piperazine 42. Replacement of the 2-pyridyl group with phenyl (43) or 2-pyrimidyl (44) resulted in compounds with decreased receptor affinity and in vivo activity. 

The synthesis of isoquinolinone carboxylates by Diels-Alder reaction was carried out by using arecoline (or its isomer methyl tetrahydropyridine carboxylate) with Danishefsky s diene under thermal and microwave conditions. It was found that with microwave technique, higher yields of the adduct were achieved as well as a new a, P-unsaturated pyridyl ketone was also formed (Jankowski et al., 2001). 

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