A2-Piperideine

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... 

The iminium ions produced by the C- alkylation of A2-piperideines can have synthetic utility for the formation of additional carbon-carbon bonds. This concept is illustrated (Scheme 12) by the synthesis of vincamone and its epimer from piperideine (120). Treatment of enamine (120) with ethyl iodoacetate gave iminium ion (121) which cyclized to (122) under the reaction conditions. Completion of the synthesis was accomplished by base followed by acid treatment (82TL177). 

The reaction of A2-piperideine (115) with methyl vinyl ketone to give (124) is another example of how initial electrophilic attack on the enamine double bond can be used in heterocyclic synthesis (77ACR193). This overall process is an enamine analog of the Robinson annelation and is a useful approach to the perhydroquinoline ring system. 

The addition of acid to Az-piperideine results in an iminium ion that readily reacts with nucleophilic species. This reaction has been particularly useful for the formation of carbon-carbon bonds in alkaloid total synthesis. For example, key steps in the total synthesis of ( )-porantherine (equation 36) (74JA6517), coccinelidine (equation 37) (77H(7)685) and eburnamonine (equation 38) (65JA1580) were acid-catalyzed ring closures between A2-piperideine derivatives and ends. Even the weakly nucleophilic carbon-carbon double bond can participate in this type of reaction (80JA5955), as has been demonstrated by a recent total synthesis of a morphinan derivative (Scheme 13). 

The reactions shown in equations (49)-(51) are reminiscent of the Mannich reaction. An example of where this approach was used to great advantage for the synthesis of lycopodine (82JA1054) is illustrated in Scheme 35. In this sequence the A2-piperideine was not isolated but was prepared as a reactive intermediate. 

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). 

The A2-piperideines are capable of behaving as dehydrosecodine analogs in alkaloid synthesis. One of the first successful applications of this approach is provided by the total synthesis of the aspidosperma alkaloid minovine (234 Scheme 41) (73JA7146). 

A closer analogy to dehydrosecodine (228) has been developed using A2-piperideines (e.g. 236). These compounds are not isolated but are produced by the fragmentation of salt (235). This elegant method is illustrated in Scheme 42 by the synthesis of racemic pandoline (237) and its C2o epimer. This reaction has provided an efficient route to a number of aspidosperma alkaloids (80JOC3259). 

The intramolecular cycloaddition reaction of enamides has recently been exploited in alkaloid synthesis (81JOC3763). Application of A2-piperideine derivatives resulted in the... 

It was suggested in the discussion of Section 2.07.5.1 that an intramolecular Diels-Alder reaction between a dihydropyridine and a-indolyl acrylate could be an efficient route to indole alkaloids. Although this has proven to be a successful reaction with A2-piperideines (Section 2.07.5.1), all attempts, most of which have not been reported in the literature, to apply this concept to dihydropyridines have been unsuccessful (81JOC3293). 

From the preparative standpoint, 1-methyl-A2-piperideines are best prepared by the partial hydrogenation of quaternary pyridine salts in alkaline media [140, 141]. 

Tetrahydro compounds still contain one ring double bond and thus can exist in several tautomeric forms (cf. Section 2.2.5.2). Little systematic work is available regarding the position of such equilibria, but 1-methyl-A2-piperideine is more stable than the A3-isomer by 16 kJ mol 1 (Equation 12). 

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-... 

Moreover, a reaction of the Mannich type has been observed with heterocyclic enamines, e.g. in the treatment of 1,2-dimethyl-A2-piperideine with formaldehyde as described by Lipp and Widn-mann.350 In the condensation, the ring-opened form, viz. 1-methyl-amino-5-hexanone, is presumably involved. Recrystallization of the intermediate Y-hydroxy methyl derivative then gives the final 1-methyl-3-acetylpiperidine (121). 

Reduction of quaternary pyridine salts with sodium amalgam afford the 1,2-dihydro whereas sodium hydrosulphite gives the 1,4-dihydro derivative, respectively362. From a preparative point of view, partial hydrogenation of quaternary pyridinium salts in alkaline media to give substituted 1-methyl-A2-piperideines is very important363,364. 

Two interesting approaches for the stereospecific oxidation of the enamine bond of A2-piperideine have been reported in connection with studies on the synthesis of vinblastine derivatives (Scheme 14) (79JA2243). 

The bromination of A2-piperideine (131) has been reported to give iminium ion (132). Treatment of this ion with triethylamine gave the bromoenamine (133), while treatment with hydroxide ion resulted in a rearrangement to give the pyrrolidine (134 Scheme 15) (76TL2437). The presence of the 2-aryl substituent undoubtedly stabilized the iminium ion facilitating these reactions. 

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