6-Methyl-2,3,4,5-tetrahydropyridine, deprotonation

The allylically activated chiral methanimidamides are more reactive and can be prepared from 2,5-dihydro-l//-pyrrole or 1,2,5,6-tetrahydropyridine by heating with a chiral auxiliary substituted methanimidamide in toluene. Deprotonation of the more acidic 1 -iminomethy 1-2,5-dihydro-1//-pyrrole with butyllithium was complete after a few minutes, even at — 100 °C41. Alkylation afforded a mixture of regioisomers, 2-alkylated 2,5-dihydro-l //-pyrrole 1 (n = 1) and 3-alkylated 2,3-dihydro-l//-pyrrole 2 (n = 1), the former strongly predominating (about 92 8). During hydrazinolysis of the 2-substituted 2,5-dihydro-1 //-pyrrole 1 (n = 1) the minor product decomposed, thus separation of the regioisomers was unnecessary. About 80-85% of the chiral auxiliary (S)-l- m-butoxy-3-methyl-2-butanamine was recovered after hydrazinolysis. 

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. 

The use of 6-methyl-2,3,4,5-tetrahydropyridine 163 has been widely reported in the synthesis of heterocycles due to its ability to be deprotonated selectively on the o -methyl group using lithium diisopropylamide (LDA). Deprotonation of tetrahydropyridine 163 with LDA followed by addition of a nitrile and propargyl bromide give tetrahydroindolizines 164 in moderate to high yields (Equation 12) <1996JOC2185>. 

IJnsymmetrical diketimines 168, which are widely used as bidentate metal ligands, can be synthesized by deprotonation of 6-methyl-2,3,4,5-tetrahydropyridine 163 followed by addition of imidoyl thioethers 167 (Equation 13) <2005JOC2075>. 

Methyl-2,3,4,5-tetrahydropyridine 558 can be deprotonated at the methyl group and thus utilized in heterocyclic ring synthesis, for example, to make 559 <1996JOC2185>. 

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