Piperideines, examples

The piperideine derivatives have not been studied as extensively as the analogous pyrrolines (151,152). The imino structure has been established, for example, for the alkaloid y-coniceine (146) (46). The great influence of conjugation on the structure is seen with l-(a-picolyl)-6,7-methylenedioxy-3,4-dihydroisoquinoline (47), possessing an enamine structure, whereas the analogous 1-methyl derivative (48) possesses an imine structure according to infrared spectra (152,153). 

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. 

The dimer of 1-methyl- -pyrroline (39) was obtained by reduction of N-methylpyrrole with zinc and hydrochloric acid (132) and, together with the trimer, by mercuric acetate dehydrogenation of N-methylpyrrolidine (131). J -Pyrroline-N-oxides form dimers in a similar manner (302). Treatment of 1,2-dimethyl-zl -piperideine with formaldehyde, producing l-methyl-3-acetylpiperidine (603), serves as an example of a mixed aldol reaction (Scheme 18). 

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 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 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 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. 

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... 

Instead of methylenebiscarbamates, acylated aldehyde aminals may be used in some cases. Thus, for example, the reaction of 2,3-dimethyl-1,3-butadiene and benzalbisacetamide has been reported to afford l-acetyl-3,4-dimethyl-6-phenyl-3-piperideine (42).34... 

Nonreductive syntheses of 3-piperideines from pyridine derivatives are not numerous. For example, treatment of 3-methylpyridine with o-tolyllithium was reported to give a mixture of 2-o-tolyl-3-methyl-3-piperideine (45) and three isomeric methyl o-tolylpyridines, formed by disproportionation of the dihydro intermediates.38... 

Preparation of secondary (or tertiary) carbinols from pyridines and an aldehyde (or a ketone) in the presence of magnesium or aluminum and mercuric chloride is known in pyridine chemistry as the Emmert reaction. 7 70 For example, dimethyl-2-pyridylcarbinol is obtained in this way from pyridine and acetone. When a mixture of pyridine and acetone is subjected to an electrolytic reduction in dilute sulfuric acid at lead electrodes, a mixture of two main products results, namely, 2-(2-hydroxy-2-propyl)-3-piperideine and 4-(2-hydroxy-2-propyl)piperidine. Analogous compounds are obtained with the use of methyl ethyl ketone as the reactant. The mixed electrolytic reduction of 2-methylpyridine and acetone affords 2-(2-hydroxy-2-propyl)-6-methyl-3-piper ideine (74) and 2-methyl-4-(2-hydroxy-2-propyl)-piperidine.71... 

Formations of 6-dimethylamino-2,4-hexadiene (163) from 1,6-dimethyl-3-piperideine,87 5-dimethylamino-4-methyl-1,3-pen tadiene (164) from l,3-dimethyl-3-piperideine,82 5-dimethylamino-3-methyl-1,3-pentadiene (165) from l,4-dimethyl-3-piperideine,83 and 6-di-methylamino-2,4-heptadiene (166) from l,2,6-trimethyl-3-piperi-deine94 may serve as further examples of the Hofmann exhaustive methylation in the 3-piperideine series. 

Boyer and co-workers studied the sulphuric acid-catalysed decomposition of three secondary cyclic azides cyclopentyl, cyclohexyl and cycloheptyl, and found that ring expansion, i.e. alkyl migration, competes quite favourably with hydrogen migration. For example, cyclopentyl azide in chloroform, gave cyclopentanone (as its 2,4-dinitrophenylhydrazone, 2-2%) and piperideine (5) (79 8%), on... 

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