4.5.6- Trisubstituted 1,4,5,6-tetrahydropyridines

Tetrahydropyridines 103 undergo a Michael reaction to afford [ran.s-(2,3)-cis-(2,6)-trisubstituted piperidines 104 (97T9553). The reaction is stereoselective (a single stereoisomer was obtained) and provides a convenient route to the 5,8-disubstituted indolizidine 105 and 1,4-disubstituted quinolizidine system 106 (found in Dendrobates alkaloids) by introduction of various alkyl, alkenyl, or... 

Michael addition of (benzotriazol-l-yl)acetonitrile 557 to a,[)-unsatu rated ketones followed by heterocyclization provides new means for preparation of 2,4,5-trisubstituted pyridines. The reaction is catalyzed by bases. In the presence of secondary amines, a nucleophilic attack of amine on the CN group in adduct 556 initiates the cyclization to tetrahydropyridine 558 that subsequently eliminates water and benzotriazole to give pyridine 559. Analogously, in the presence of NaOH, pyridone 560 forms, via intermediate 561 (Scheme 88) <1997JOC6210>. 

There has been extensive research into electrophilic additions to 3-substituted-l,4-dihydropyridines, such as N-methyl-3-cyano-l,4-dihydropyridine 138, which readily undergoes addition across the more reactive enamine-like 5,6-alkene to give 2,3,5-trisubstituted-l,2,3,4-tetrahydropyridines (Scheme 38) <1998JOC2728, 2000CEJ1763, 2003TL8449>. In an unusual example, the reaction with sulfinyl chlorides and triethylamine results in the formation of the 1,4-dihydropyridine sulfoxide 139, where in the absence of an additional nucleophile, the iminium intermediate is deprotonated to yield the monosubstituted 1,4-dihydropyridine product 139. 

Chiral A-amidino-l,2,3,4-tetrahydropyridines undergo a stereoselective epoxidation-nucleophilic opening sequence with either alcohols or organozinc reagents to give 2,3,6-trisubstituted piperidines where the relationship between the 2- and 3-positions is cis (Equation 15) <2005OL2747>. 

The reduction of tri- and polysubstituted pyridinium ions has not received extensive attention, and generalizations are not available. A 1,2,4-trisubstituted pyridinium ion has been shown to form a 1,2,3,6-tetrahydropyridine,15 and 1,3,4-trisubstituted pyridinium salts (49) are reported to give 1,2,5,6-tetrahydropyridines (50) which were useful as intermediates in the synthesis of benzomorphans (51).40-43 As discussed above, those pyridinium ions having substituents on both the 3- and 5-positions usually lead to stable dihydro-pyridines on reduction with sodium borohydride.43 ... 

A .A -Dialkyl enamines yield alkyl 2-dialkylaminocyclopropane-l-carboxylates in low yield only, or, more typically, not at all. In contrast, less nucleophilic enamines, such as 77-acyl enamines (see Houben-Weyl, Vol. El9b, p 1153), A-acyl-2,3-dihydropyrroles, 77-acyl-l,2,3,4-tetrahydropyridines and A W-bis(trimethylsilyl) enamine 15, are cyclopropanated by diazoacetic esters without problems, e.g. formation of 16. In contrast to ( )-15, the Z-isomer and related trisubstituted enamines are cyclopropanated only in low yield (5-10%). ... 

The catalytic asymmetric /-selective Diels-Alder annulation of a, -unsaturated /-butyrolactams with enones provided a synthesis of, y-functionalized bridged bi-or tri-cyclic dihydropyranopyrrolidin-2-ones in one step (up to 98% yield, >20 1 dr, and 99% ee) The inverse-electron-demand aza-Diels-Alder cycloaddition 0 of A-aryl-a,/0-unsaturated ketimines with enecarbamates in the presence of chiral bifunctional phosphoric acids produced 4,5,6-trisubstituted 1,4,5,6-tetrahydropyridines having three contiguous stereogenic centres in up to 84% yield, 95 5 dr, and 95% 5-Alkenylthiazoles react as in-out dienes with e-poor dienophiles in polar 44-2- 0 cycloaddition reactions. The cycloadditions are site selective. The mechanism is thought to lie between a concerted but highly asynchronous process and a stepwise process. 

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