Piperideine formation

A -Piperideine-N-oxide was obtained along with a dimeric product by oxidation of N-hydroxypiperidines with mercuric acetate or potassium ferricyanide (107-109). 2l -Pyrroline-N-oxide is formed by oxidation of N-ethylpyrrolidine with hydrogen peroxide with simultaneous formation of ethylene (110). 

Five- (70, = 1) and six-membered (70, n = 2) enamines substituted in position 2 generally exist in the cyclic form. Lukes and co-workers observed that partial ring-opening occurs with the pyrroline 157) or piperideine 163,164) derivatives by atmospheric moisture. This leads to the formation... 

Reaction of 2-alkyl- -pyrrolines and 2-alkyl- -piperideines with acid chlorides leads to ring-opening and formation of N-acylated amino ketones (131, = 1, 2) (211-213). Ketene reacts with J -piperideine to form a tricyclic derivative (132) (214). 

The reaction of 2-(a-pyridyl)alkylmalonic acid with J -piperideine leading to formation of 3-((x-pyridyl)quinolizidine-l-carboxylic acid on decarboxylation, has been used by Van Tamelen and Foltz (316) for the syntheis of the alkaloid lupanine (Scheme 20). A very elegant synthesis of matrine has been accomplished by Bohlmann et al. (317). 

As predicted, l,2,3,4-13C-labeled acetone dicarboxylate (15) provided an intact three-carbon chain into lycopodine. It also helped to explain why two molecules of pelletierine (12) were not incorporated (Scheme 6.3) [12]. As before, lysine (6) is converted to piperideine (8) via a decarboxylation. Then a Mannich reaction of labeled 15 with 8 provides pelletierine 12. The other half of the molecule to be incorporated must be pelletierine-like (12-CC>2Na), still containing one of the carboxylates. An aldol reaction of the two pelletierine fragments and a series of transformations leads to phlegmarine 9. Oxidation of 9 involving imine formation between N-C5, isomerization to the enamine and then cyclization onto an imine (at N-C13), provides lycopodine 10. Phlegmarine 9 and lycopodine 10 are proposed as... 

Imine formation is an important reaction. It generates a C-N bond, and it is probably the most common way of forming heterocyclic rings containing nitrogen (see Section 11.10). Thns, cycliza-tion of 5-aminopentanal to A -piperideine is merely intramolecular imine formation. A further property of imines that is shared with carbonyl groups is their susceptibility to reduction via complex metal hydrides (see Section 7.5). This allows imines to be... 

Alkaloids with the piperidine nucleus, such as pelletierine (Punica grana-tum), lobelanine Lobelia inflata) and piperine Piper nigrum), have a typical biosynthesis pathway. It starts with L-lysine and continues via cadaverine (biogenic amine), A -piperideine and A -piperidinium cations and lobelanine, to be synthesized as lobeline. Piperine is synthesized from A -piperideine via piperidine (Figure 49). For the transformation from A -piperideine to A -piperideine cation, the residue from acetyl-CoA is needed, together with SAM activity in the transformation to lobelanine. Piperine is synthesized from piperidine through the formation of amide. 

The a is L-lysine, as in the case of piperidine, but the f3 is different. The /3 is a-aminoadipic acid 6-semialdehyde. The q> is L-pipecolic acid, which is synthesized in plants from piperideine-6-carboxylic acid. In the case of many other organisms, the obligatory intermedia (q>) is derived from the /3. The

ring structure. The indolizidine nucleus will be formed only in the synthesis of the x- The deep structmal change occms when

Claisen reaction with acetyl or malonyl CoA (Cra/mCoA) and the ring closme process (by amide or imine) to 1-indolizidinone, which is the x- The second obligatory intermedia ( k ) only has the indolizidine nucleus. 

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 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). 

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). 

Accepting the enthalpies of formation given by Jackman and Packam150 for all three imines results in a value of 40 14 kJ mol 1, considerably lower than experiment148. In principle, clarification of this discrepancy could be achieved by related studies on other 1-azacycloalkenes. However, except for an unsuccessful attempt148 for the corresponding 1-azacyclohexene (alternatively, A1-piperideine or 3,4,5,6-tetrahydropyridine) 65—its trimer fails to monomerize—we do not know of any such study. 

A key stage in the biosynthesis of piperidine alkaloids is reached with the formation of A -piperideine. For the elaboration of diverse alkaloids, this intermediate undergoes condensation with a variety of nucleophiles, commonly a /3-keto-acid. (A similar situation is found for pyrrolidine alkaloid biosynthesis see, e.g., Scheme l).1,2 Existing evidence on Lythraceae alkaloid biosynthesis, taken up again below, indicated that condensation occurred in this case between A piperideine (17) and acetoacetic acid to give pelletierine (26), further elaboration yielding alkaloids like (22). In the event, however, labelled pelletierine was found not to be a precursor for (22) or (23).8 Negative evidence is always difficult to interpret, but is here made persuasive by the fact that other precursors that were fed concurrently were incorporated. Conclusive support for these results depended on others outlined below. 

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... 

The reactivity of the a-methylene group in lactams allows Claisen condensation with esters of formic, oxalic, and arylcarboxylic acids. Treatment of ethyl formate with A-methylpiperidone, followed by acidification, yields a salt of 1 -methyl- J2-piperideine, whereas in an alkaline medium its dimer was isolated.34- 158 With oxalic acid ester as the condensing reagent, 1-methyl-J2-pyrroline-2-carboxylic acid159 and l-methyl-d2-piperideine-2-carboxylic acid160 were obtained (Scheme 4). 

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... 

Reduction of both the free bases and their quaternary salts proceeds by similar mechanisms. In pyridine and its quaternary salts, a hydride ion, or its equivalent, attacks a position of a low electron density, i.e. the 2- or 4-position. The mechanism of the reduction of quaternary salts of pyridine and its homologs (LukeS and Ferles414) has been elucidated using deuterated formic acid.415 The hydride ion attack in position 2 is followed by addition of a proton to the enamine grouping with the formation of A 3-piperideines (124). If the reduction commences with attack in the 4-position, a saturated base (125) is the final product. In agreement, a-picoline methobromide yields 1,2-dimethyl-... 

The oxime of l-methyl-4-phenyl-4-benzoylpiperidine (25) was found to decompose by the action of thionyl chloride with formation of l-methyl-4-phenyl-3-piperideine and benzonitrile.19... 

Reduction of quaternary pyridinium halides (or, more precisely, formates) with formic acid in the presence of potassium formate at about 150°C is usually referred to as the Lukes reduction.80-95 Instead of potassium formate, triethylamine may be used, especially with quaternary pyridinium iodides.85,86 Mixtures of l-alkyl-3-piperideines (77) and 1-alkylpiperidines (78) are usually obtained. Formation of piperideines (77) might be explained by analogy with the Ladenburg reduction of pyridine bases the double bond at position 3 is resistant toward further reduction by formic acid or by... 

According to their proposal, the reduction is effected by hydride ion transfer from the formate anion which, as a nucleophile, reacts at positions 2, 4, or 6 where the electron density is lowest (cf. calculations by the HMO method90 97) to give the 1,2-dihydro and 1,4-dihydro intermediates. Further reduction of the 1,2-dihydro compound leads to the 3-piperideine (92), whereas the hexahydro derivative (93) is obtained from the 1,4-dihydro intermediate. 

Evaporation of an acetic acid solution of l-methyl-3,4-dibromo-4-phenylpiperidine hydrobromide (130) (obtained from 127 by addition of bromine in acetic acid) was unexpectedly accompanied by dehydro-bromination, with the formation of l-methyl-4-phenyl-5-bromo-3-piperideine hydrobromide (131).115... 

Demethylation of 1-methyl-3-piperideines may be accomplished with the use of the von Braun cyanogen bromide procedure.60,128 A certain drawback of this method consists in loss of half of the tertiary amine in formation of a quaternary salt (e.g., 146), in addition to the required 1-cyano derivative (e.g., 147), which is then hydrolyzed to the required secondary amine. 3-Piperideine was obtained by this procedure in the form of a stable free base.128... 

A mixture of 1-methyl-2-p-methoxybenzyl-3,4-diethyl-3-piperi-deine (156), 1 - methyl- 3,4-diethyl - 4 -p- metho xybenzyl- 2-piperideine (157), and 1-methyl- 2-(2-methyI-5-methoxyphenyl)-3,4-diethyl-3-piperideine (158) was obtained from 1-methyl- 1-p-methoxybenzyl-3,4-diethyl-3-piperideinium chloride (155). Compounds 156 and 157 were formed by the Stevens rearrangement, whereas the formation of compound 158 was due to the Sommelet rearrangement.1296... 

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. 

Piperideines. Desilylative condensation of this reagent with HCHO and a primary amine (CF3COOH promotion) results in the heterocycle formation. 

Following upon closely related earlier work, it has been found that photolysis of the iV-chloroamine (3) leads to loss of the piperidine ring as 5-methyl-A -piperideine and formation of the C-20 diastereoisomeric derivatives (4). 

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