Piperideine reduction

The use of primary amines instead of ammonia affords l,2-dialkyl-/l -pyrrolines or l,2-dialkyl-/l -piperideines. Amino ketones with a primary amino group are intermediates in the reduction of y-nitropropylalkyl ketones (14,15) or S-nitrobutylalkyl ketones (16-18) by catalytic hydrogenation over Raney nickel or with zinc and hydrochloric acid (Scheme 1). 

Reduction of l-methyl-2-alkyl-.d -pyrroline and l-methyl-2-alkyl-.d -piperideine perchlorates with complex hydrides prepared in situ by partial decomposition of lithium aluminum hydride with the optically active alcohols (—)-menthol and (—)-borneol affords partially optically active l-methyl-2-alkyl pyrrolidines (153, n = 1) and 1-methy 1-2-alkyl piperideines (153, n = 2), respectively (241,242). 

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. 

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). 

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... 

An enzyme that catalyzes the reduction of A -piperidein-2-carboxylate to piperidine-2-car-boxylate (r-pipecolate) in the catabolism of o-lysine by Pseudomonas putida ATCC12633 is an NADPH-dependent representative of a large family of reductases that are distributed among bacteria and archaea (Muramatsu et al. 2005). It also catalyzes the reduction of A -pyrrolidine-2-carboxylate to L-proline. 

Corynantheidol (255) has been prepared by Hanaoka et al. (155), who started from piperideine derivative 268 and tryptophyl bromide (197). The key cyclization step, resulting in indolo[2,3-a]quinolizine 270 as the major product besides 271, was carried out by mercuric acetate oxidation in the presence of the disodium salt of ethylenediaminetetraacetic acid (EDTA), followed by sodium borohydride reduction. Finally, lithium aluminum hydride reduction of 270 provided ( )-corynantheidol in good yield (155). 

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... 

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 carbon-nitrogen double bond of A1-piperideines is susceptible to reduction. This can be useful for the stereospecific introduction of ring substituents. An illustration is the preparation of ds-2,6-disubstituted piperidines (211) by catalytic hydrogenation of the corresponding A1-piperideine (210) (77T1569). 

Few reports on the electrolytic reduction of pyridine mention the isolation of partially reduced products. The only one observed to date has been the 3-piperideine (5). Ferles attributed the presence of 5 to concurrent reduction mechanisms, one which led to this product and the other to piperidine (Scheme 2).3S Thus, if the first-formed intermediate was a 1,4-dihydro product, then full reduction to piperidine occurred, but if the intermediate was a 1,2-dihydro product, then the olefin was formed. The 3-piperideine (5) would not be further reduced under the conditions. The concept of competing pathways at an initial step in the reduction mechanism is probably sound, but the proposal of 1,2- versus 1,4-dihydro intermediates has not been fully substantiated. 

Ferles et al. have studied the reduction of alkylpyridines and reported the yields of piperidines and 3-piperideines. For instance, reduction of either 2-picoline (15) or 3-picoline (16) gave predominantly the respective piperidines it also gave significant amounts of the piperideines 17 and 18, respectively (Scheme 5) (Table I).3i Other isomeric piperideines were not formed, and the... 

Reduction of the isomeric lutidines was also studied (Scheme 6).34,46,47 In some cases the products were only cis as in reduction of 2,6-lutidine (20), and in other cases the products were mixtures of stereoisomers, as in 2,3-lutidine (21). When alkyl substituents were in the 3,4- or 3,5-positions, piperideine products were predominant (Table II). Reduction of the symmetrical collidine (13) gave various piperidine isomers of which the all-cis (22) was predominant48 However, the 3-olefin 23 was the major product. The theormodynamically less stable piperidines 24 and 25 were found in significant yield. 

Reduction of the three isomeric pyridylcarbinols (29-31) (Scheme 10) leads to products similar to reduction of the hydrocarbon parents 15, 16, and 19 (Scheme 5).58 One should note, however, that the product ratios are different (Table IV). In the case of the 3-isomer (30), the unsaturated product (32) is exocyclic in this report, whereas it is endocyclic (18) in a previous report of the reduction of -picoline (16). Ferles and Tesarova give IR evidence for 32 here and identify 18 by derivatization.35 The IR evidence would seem to be more valid. In contrast to 30, the 3-pyridylmethylcarbinol (33) gave endocyclic piperideines 34 and 35 (Scheme 11). For the pyridylmethylcarbinols 36 and 37, the product ratios were different and the 3-isomer (36) gave a mixture of exocyclic and endocylic piperideines, but mostly exo-(38) (Scheme 12). 

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... 

In light of the present evidence the biogenesis of metacyclophane Ly-thraceae alkaloids required revision, since the only published proposal (9) was based on pelletierine. A new biogenetic scheme was proposed which invoked intermediacy of A piperideine and two C6-C4 units [derived from /i-kctoester (193)]. An intermediate disubstituted piperidine (194) would give rise to two types of metacyclophane alkaloids as a result of reduction and phenol coupling as well as Michael addition in the case of the quinoli-zidine bases (10). 

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... 

Reduction of l-methyl-2-alkyl-J2-piperideine perchlorates with complex hydrides prepared in situ by partial decomposition of... 

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-... 

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. 

The indolyldithiane dianion 83 reacted with piperidein-2-ones 84a and 84b to give, in 64—80% yield, a mixture of diastereoisomeric lactams trans-85/ds-86 and trans-871 as-88 in ratio 1 1.5 and 1 1.4, respectively. Partial reduction of lactams 85-88 afforded the corresponding iminium salts that spontaneously cyclized either on the indole nitrogen or indole 3-position. Thus, treatment of lactam 86 with an excess of Red-Al in THF yielded a 3 1 mixture of diazocinoindole 89a and 90a in excellent total yield. Under identical conditions, lactam 88 yielded diazocinoindole 89b as major product and small amounts of 90b and 91b (61%, ratio = 10 1 1). Treatment of lactam 85 with Red-Al gave no reaction, whereas with LiAlPU it gave only 91a. 

The acetyl derivative (30) may be converted by Wolff-Kishner reduction into l,4-dimethyl-3-ethyl-3-piperideine (31).26 The latter compound is obtained in 17% yield also by dehydration of 1,4-dimethyl-3-( l-hydroxyethyl)piperidine (32) by the xanthate method.28 On the other hand, dehydration of the carbinol (32) with phosphorus pentoxide in toluene or by heating in concentrated hydrochloric aoid gives a mixture of isomeric l,4-dimethyl-3-ethylidenepiperidines (33a, b).28... 

The Freund reaction of 3,4-dimethylpyridine methobromide and benzylmagnesium bromide affords a mixture of two isomeric di-hydropyridines (46a, b). The partial reduction of the latter isomer to l,3,4-trimethyl-6-benzyl-3-piperideine (47) was performed by hydrogenation (Pd/BaS04), or by the action of sodium borohydride, or on treatment of the perchlorate with lithium aluminum hydride.39... 

Piperideines unsubstituted at the nitrogen atom may be prepared from the corresponding pyridine compounds by partial reduction with sodium and boiling alcohols (the Ladenburg reduction), by electrolytic reduction, or, preferably, by reduction with aluminum hydride. l-Alkyl-3-piperideines are prepared by reduction of quaternary pyridinium salts with formic acid (the Lukes reduction) or with complex hydrides. 

Ethyl-3-piperideine (56) is also formed as a by-product in the reduction of 4-j8-hydroxyethylpyridine with sodium in boiling butanol.49... 

The Ladenburg reduction of 4-sec-butylpyridine gives a mixture of a saturated and an unsaturated base, the latter probably being 4-sec-butyl-3-piperideine.50... 

Reduction of 2-(4-pyridyl)propenol (60)51 with sodium in ethanol and the aluminum hydride reduction of 4-isopropylpyridine48 afford the same product, 4-isopropyl-3-piperideine (61). 

The parent 3-piperideine (3) was first prepared (in the form of its hydrochloride) by Ladenburg reduction of 4-pyridone, conversion of the resulting 4-piperidinol into 4-bromopiperidine, and dehydro-halogenation of the latter.52... 

Two 3-piperideines (63 and 64) and two piperidines (cis and trans isomers) are obtained by the Ladenburg reduction of 4-ethyl-3-methyl-pyridine, whereas only one tetrahydro base, namely, 4,6-dimethyl-3-piperideine (65), results from 2,4-dimethylpyridine, in addition to the piperidines.48... 

Ladenburg reduction of 2,4,6-trimethylpyridine affords a mixture of cis-2,4,6-trimethyl-3-piperideine (66) and all three isomeric 2,4,6-trimethylpiperidines.5 4... 

The tetrahydro bases have been mentioned as possible by-products of electrolytic reduction of pyridines in some papers.55,58 Davies and McGee87 isolated 3-piperideine by fractional distillation of crude piperidine obtained by electrolytic reduction of pyridine. Appreciable amounts of 3-piperideines were obtained on reduction of pyridine and its homologs at activated lead electrodes in dilute sulfuric acid.47 The following tetrahydro bases were isolated (in addition to the corresponding hexahydro bases) 3-piperideine47 from the reduction of... 

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