Piperideine reactions

Alkyl-/l -pyrrolines (8, n = 1) and 2-alkyl-/l -piperideines (8, n = 2) are readily formed by the methods used to prepare y- and S-amino ketones (3-6). The reaction of corresponding halogeno ketones with ammonia belongs to the classical reactions of this type. 

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. 

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). 

Addition to 1,2-dimethyl- -piperideine or 1,2-dimethyl- -pyrroline is followed by intramolecular alkylation by the ester group as a side reaction to give 140 and 141 ( = 1, 2), respectively. Cyclization products 142 and... 

Heterocyclic enamines A -pyrroline and A -piperideine are the precursors of compounds containing the pyrrolidine or piperidine rings in the molecule. Such compounds and their N-methylated analogs are believed to originate from arginine and lysine (291) by metabolic conversion. Under cellular conditions the proper reaction with an active methylene compound proceeds via an aldehyde ammonia, which is in equilibrium with other possible tautomeric forms. It is necessary to admit the involvement of the corresponding a-ketoacid (12,292) instead of an enamine. The a-ketoacid constitutes an intermediate state in the degradation of an amino acid to an aldehyde. a-Ketoacids or suitably substituted aromatic compounds may function as components in active methylene reactions (Scheme 17). 

Isotripiperideine and a-tripiperideine structures differ from each other in a new C—C bond formed in is otripiperideine by an aldol reaction (296, 297). In aqueous media at pH 2-13, two molecules of -piperideine yield tetrahydroanabasine (297). 

The last isomer, the so-called aldotripiperideine (185), is obtained by the action of acid catalysts on a-tripiperideine at its boiling point (298,299), or in aqueous solution at pH 9.2 and 100°C. Further aldol reaction between tetrahydroanabasine and A -piperideine obviously occurs. Hydrogenolysis of this compound gives dihydroaldotripiperideine (186) which is convertible into matridine (187), a reduction product of the alkaloid matrine. 

Curiously, neither J -piperideine nor tetrahydroanabasine undergo aldolization in strongly acidic or strongly alkaline media the reaction occurs only at pH 2-13, when both the free base and its salt are present (295). This relation between the rate of aldolization and pH indicates that aldolization occurs by condensation of the methylene group of the immonium salt with the free base. 

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). 

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). 

Tetrahydrocarboline derivatives have recently been synthesized from 2-o-nitroarylated cyclohexanone derivatives. Thus, reductive cyclization of 3-(2,4-dinitrophenyl)-l-methyl-4-piperidone (68) (prepared by the reaction of 2,4-dinitrochlorobenzene with l-methyl-4-A-pyrrolidmo-3-piperideine) gave 7-amino-2-methyl-l,2,3,4-tetrahydro-y-carboline (69). Neither catalytic nor chemical reduction of the... 

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... 

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. 

Piperidines can also be functionalized via the N-chloro derivatives. These are known to give imines when treated with base (76S745). Although there is little regiochemical control, the reaction provides a useful entry into the simple A1 -piperideines (Scheme 6) (80JOC1515). 

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 bromination of Az-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. 

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 A1-piperideines, in contrast to the A2- and A3-isomers, are usually very reactive toward nucleophilic reagents. Depending upon the nature of the nucleophile, two reaction pathways are possible (equation 48). The nucleophile can add to the inline carbon or the nucleophile can abstract the a-hydrogen. Since both of the resulting anions can undergo further reactions, A1-piperideines have potential for the synthesis of complex six-membered ring heterocycles. 

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). 

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... 

The Diels-Alder reaction using the double bond of a A -piperideine as the dienophile is relatively rare. The potential of this reaction is illustrated by the synthesis of lupinine (242) <79H(12)949), where the quinolizidine ring was formally constructed by a Diels-Alder reaction involving A1-piperideine and the ester (240 Scheme 43). 

The double bond of A piperideines is known to participate in [2+2] cycloaddition reactions, particularly with electron rich ir-systems (Scheme 44) (70CB573). 

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). 

The triazole ring can be synthesized by reaction between a suitable pyridine (or piperideine) and an azide. Thus 5-nitro-2-pyridone (or N-substituted pyridones) and sodium azide give a 5-oxotriazolo[4,5-b]pyridine (94)182-184 whereas the enamine 95 reacts with p-nitrophenyl azide to give the hexahydro-l//-triazolo[4,5-c]pyridine 96.185,186... 

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