A3-Piperideine

The A3-piperideines are the most stable isomers of the tetrahydropiperidines. The nitrogen atom and the double bond are isolated by saturated carbon atoms and might be expected to have little influence on each other. This is particularly true of the nitrogen atom iV-alkylations and -acylations of A3-piperideines occur without difficulty. 

The nitrogen atom in A3-piperideines would be expected to influence the addition of... 

The double bond of A3-piperideines can be used to activate and control the functionalization of the six-membered ring. For example, studies on the synthesis of the benzomorphans require 2-benzyl-A3-piperideine derivatives. One approach to these compounds has been... 

Another example is provided by the application of the modified Polonovski reaction to A3-piperideines. Treatment of amine oxides (141) with trifluoroacetic anhydride results in the formation of iminium ion (142). These compounds can behave as useful synthetic intermediates, reacting with a number of nucleophiles such as cyanide ion (80JA1064). 

The acid-catalyzed cyclization of A3-piperideines has proven to be a valuable approach to the benzomorphans (equation 42) (77CRV1). This is a general reaction and, with simple alkyl substitution on the double bond, anti addition to the double bond gives the predominant if not exclusive product. This has led to speculation that the reaction occurs in a concerted fashion. 

The 7r-systems of the A2- and A3-piperideines are not reactive toward nucleophilic reagents. The A3-piperideine contains an isolated double bond whereas the A2-piperideine contains the electron-rich enamine functional group. However, treatment of either piperideine (10) or (11) with strong base (potassium t-butoxide) apparently does generate a small equilibrium concentration of the anion (217), as is evidenced by the equilibration of the A3-piperideine (10) to the more stable A2-isomer (11) (78T3027). The A2-piperideine is favored to such an extent that this reaction can be used preparatively (80JOC1336). 

A -Piperideine — see Pyridine, 2,3,4,5-tetrahydro-A2-Piperideine — see Pyridine, 1,2,3,4-tetrahydro-A3-Piperideine — see Pyridine, 1,2,3,6-tetrahydro-Piperideines — see Pyridines, tetrahydro-Piperidine, 1-acryloyl-polymers, 1, 284 Piperidine, N-acyl-... 

Reduction of aromatic heterocyclic bases and their quaternary salts is of particular interest. Reduction of pyridine with lithium aluminum hydride gives the unstable 1,2-dihydro derivative,403 whereas sodium in 95% ethanol yields 1,4-dihydropyridine. The latter is readily hydrolyzed with the formation of glutaric dialdehyde.404 Reduction of pyridine and its homologs with sodium in butanol affords a mixture of saturated and unsaturated bases d3-piperideines are formed405 only from those pyridine homologs which possess alkyl groups in positions 3 and 4. Electrolytic reduction always gives a mixture of both bases.406 A3-Piperideines have been obtained by reduction with a mixture of lithium aluminum hydride and aluminum chloride.407... 

The nitrogen atom in A3-piperideines would be expected to influence the addition of unsymmetrical reagents to the double bond. Although this effect has not been extensively studied, the results on the hydroboration-oxidation of a number of N- substituted A3-piperideines show a preference for the piperidin-3-ol (Scheme 16) (70JOC802). Initial coordination of borane with the nitrogen atom was proposed and the observed regiochemistry is believed to be the result of electronic factors (70TL1133). 

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