2-Methyl-6-alkyl-1 -piperidein

Lukes studied the reaction of N-methyl lactams with Grignard reagents. With the five- (39-42) and six-membered (43-47) rings, 2,2-dialkylated bases (16, = 1,2) are formed as by-products in addition to the l-methyl-2-alkyl pyrrolines (15, = 1) or l-methyl-2-alkyl piperideines (15, =2). Aromatic Grignard reagents afford only the unsaturated bases, probably because of steric factors (48,49). Separation of enamines and 2,2-dialkylated amines from each other can be easily achieved since the perchlorates of the enamines and the picrates of 2,2-dialkylated bases crystallize readily. Therefore enamines can be isolated as crystalline perchlorates and the 2,2-dialkylated bases as crystalline picrates. Some authors who repeated the reactions isolated only pyrrolines (50,57) or, by contrast, 2,2-dialkylated bases (52). This can be explained by use of unsuitable isolation techniques by the authors. 

Reduction of l-methyl-2-alkyl-.d -pyrroline and l-methyl-2-alkyl-.d -piperideine perchlorates with complex hydrides prepared in situ by partial decomposition of lithium aluminum hydride with the optically active alcohols (—)-menthol and (—)-borneol affords partially optically active l-methyl-2-alkyl pyrrolidines (153, n = 1) and 1-methy 1-2-alkyl piperideines (153, n = 2), respectively (241,242). 

An explanation of the exclusive N methylation of 1,2-dimethyl-J -piperi-deine by means of methyliodide is more difficult. Pyrrolines and piperideines which are not alkylated on the nitrogen atom afford only quaternary ammonium salts on alkylation (203-205), for example 119. 

In a similar addition to l-methyl-2-alkyl-J -piperideines, l-methyl-8-alkyl-1,2,3,4-tetrahydroquinolines (134) were obtained (Scheme 10) (163). 

Venoms from the fire ants Solenopsis invicta and 5. geminata are free of detectable histamine but possess histamine-release activity. This activity can account for the edema, itch, redness, warmth, and possibly the pain and burning sensations resulting from fire ant stings. And it can be attributed to the piperidines which constitute the major component of the venom. It has actually been proved that 6-methyl-2-n-undecylpiperidines (Ic and Id), components of S. geminata, possess the histamine-release activity (75). Due to some of the above-mentioned various activities the piperidine alkaloids play roles as defensive compounds. In addition to 2-alkyl-6-methylpiperidines, their N-methyl derivatives (3) are found in S. pergandei, S. carolinensis, and S. conjurata, and 1-piperideine derivatives (6 and 7) in S. sp. A (Puerto Rico) and S. xyloni (Table I). 

In general, alkylations as well as some acylations of enamines using halides as the leaving group occur predominantly on carbon (B-69MI20700). For example, treatment of A2-piperideine (115) with methyl bromoacetate followed by sodium borohydride reduction... 

As expected, macroscale reduction gave products corresponding to those from reduction of the parent pyridine, that is, piperideines and piperidines. Electrolysis of a series of N-alkyl-substituted 2-pyridones, for example N-methyl-(79), yielded a mixture of A-methylpiperidine and -piperideine 80.126 Reduction of the methyl ether of 2-pyridone gave piperidine only.127... 

The apparently simple procedures of partial dehydrogenation of pyrrolidines and partial hydrogenation of pyrroles afford Zl1-pyr-rolines. However, the reaction is complex and is of little preparative value.97-98 A 1-Pyrrolines may be obtained by isomerization of A 3-pyrrolines.100 From the preparative point of view, partial hydrogenation of quaternary pyridine salts in strongly alkaline media to give 1-alkyl-id 2-piperideines is more important.101 Formation of heterocyclic enamines was observed in the reduction of i -methyl-pyrrolidone with lithium aluminum hydride,102 -alkylpiperidones with sodium in ethanol,103,104 and in the electrolytic reduction of N-methylglutarimide.106... 

Though l-methyl-2-alkyl-d2-piperideines react with acids to yield only the immonium salts, a mixture of the ammonium and immonium perchlorates is obtained from piperideines unsubstituted in position 21 (Eq. 4). 

When mesomerism is precluded sterically, enamines are alkylated solely on the nitrogen atom, cf. the methylation of neostrychnine with methyl iodide.229 Explanation of the exclusive A-methylation of 1<9)-dehydroquinolizidine (36)172 and 1,2-dimethyl-zl2-piperideine (68)229 is more difficult. 

Because of the conjugation of the free electron pair on the nitrogen atom with the double bond, enamines react very readily with double bonds activated by electronegative groups. Addition of acrolein to l-methyl-2-ethylidenepyrrolidine, followed by dehydrogenation, led to 1,7-dimethylindole.260 In a similar addition to l-methyl-2-alkyl-d2-piperideines, l-methyl-8-alkyl-l,2,3,4-tetrahydroquinolines (75) were obtained.38 In the reaction scheme, the starting bases are considered to react as the tautomeric l-methvl-2-alkvlidenepiperidines (74). 

Reduction of l-methyl-2-alkyl-J2-piperideine perchlorates with complex hydrides prepared in situ by partial decomposition of... 

Some l-alkyl-4-aryl-3-piperideines are obtained from a-methyl-styrene and its derivatives by the reaction with formaldehyde and hydrochloride of a primary amine, rearrangement of the resulting oxazine derivative (14) with sulfuric acid or hydrochloric acid to l-alkyl-4-aryl-4-piperidinol, and dehydration of the latter.13-15... 

Lukes and coworkers " developed a very simple and useful method for the preparation of heterocyclic enamines. A-M ethyl lactams with five- and six-membered rings (104, n = 1,2) give, with Grignard reagents, l-methyl-2-alkyI(aryl)-2-pyrrolines (105, n = 1) and l-methyl-2-alkyl(aryl)-2-piperideines (105, n = 2), respectively. 2,2-Dialky-lated bases (106, n = 1,2) are by-products of this reaction. Aromatic Grignard reagents afford only the unsaturated bases, probably because of steric factors " ". Some authors who repeated the reactions isolated only pyrrolines or, in other cases, 2,2-dialkylated bases . This can be ascribed to the use of unsuitable isolation technique by the authors. The reaction was also carried out with various substituted and non-methylated lactams . ... 

Electrolytic reductions ofN-methyl- and jV-ethyl-2-pyridone have given mainly 1-alkylpiperidine and some l-alkyl-3-piperideine. Both 1,3-dimethyl- (XII-652) and 1,6-dimethyl-2-pyridone give mainly the piperidine (e.g., XII-653) and equal but smaller amounts of the two isomeric piperideines (e.g., XII-654, XII-6S5). ... 

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