N-Methyl-4-piperidone

The search for opioid analgesics which show reduced addiction liability ha.s centered largely on benzomorphan and morphinan derivatives. Some research has, however, been devoted to derivatives of the structurally simpler meperidine series. The preparation of one such compound, picenadol (59), starts with the reaction of N-methyl-4-piperidone with the lithium derivative from m-methoxybromobenzene. Dehydration of the first formed carbinol 51 gives the intermediate 52. Deprotonation by means of butyl lithium gives an anion which can be depicted in the ambident form 53. In the event, treatment of the anion with propyl bromide gives the product 54 from reaction of the benzylic anion. Treatment of that product, which now contains an eneamine function. 

Tricyclic antihistamines as a rule carry aliphatic nitrogen as a substituent on a side chain attached to the central ring the side chain nitrogen may be part of a heteroaromatic ring. Conjugate addition of p-chloroaniline (49) to the substituted vinylpyridine 50 gives the alkylated aniline 51. Treatment of that intermediate with nitrous acid leads to N-nitroso intermediate 52 which is then reduced to the hydrazine (53). Reaction of 53 with N-methyl-4-piperidone... 

We now turn to the remaining two hydroxylamines that are N-hydroxylated derivatives of 2,2,6,6-tetramethyl-4-piperidone and -4-piperidinol. The enthalpies of formation of some simple 4-piperidones and their corresponding 4-piperidinols have recently been determined. The values of gaseous N-methyl-4-piperidone and Af-methyl-4-piperidinol are —160.7 1.7 and —226.8 1.8 kJmol (also see Reference 18). The difference between these contemporary values is — 66.1 2.5 kJmol while for the hydroxylated and methylated counterpart species the difference is —47.0 4.8 kJmoH. For comparison, the formal enthalpy of reduction of 3-hexanone to 3-hexanol is ca —54 kJmoH. As has been discussed earlier, reduction enthalpies are not necessarily constant . Relatedly, reaction 8 that exchanges N-methyl and N-hydroxy and parent and tetramethylpiperidines is endothermic by 19.1 5.4 kJmol . The deviation from thermoneutrality is more... 

A solution of N-methyl-lH-indole-5-ethanesulphonamide (1.0 g) in methanol (50 ml) containing potassium hydroxide (5.6 g) and N-methyl-4-piperidone (1.0 ml) was heated at reflux for 24 h, cooled, and the resulting solid filtered off (1.0 g). A sample of the solid (0.2 g) was dissolved in a hot methanolic solution of oxalic acid (0.06 g), the solution cooled, and the salt precipitated by adding ethyl acetate (20 ml) and dry ether (50 ml). The salt was filtered off, and dried in vacuo to give the title compound as a solid (0.12 g), m.p. 87°-90°C (shrinks). 

Veratrylamine and N-methyl-4-piperidone added with stirring to 1 iV HCl, then aq. KCN added, stirred overnight at room temp, and 2 hrs. at 60, the resulting crude intermediate dissolved in diloroform, added slowly to coned. H2SO4, whereupon the temp, rises to reflux, whidi is maintained for a further 15 min. 6,7-dimethoxy-l -methylspiro-[l,2,3,4-tetrahydroisoquinoline-3,4 -piperidin]-4-one. Y 82.5%. F.e. s. D. Berney and T. Jauner, Helv. 58, 74 (1975). 

N-Methyl-2-phenyl-A2-tetraJiydropyridine and similar compounds have previously been prepared by the hydrolysis and decarboxylation of a-benzoyl-N-methyl-2-piperidone3 and by the addition of phenyl Grignard reagents to N-methyl-2-piperidone followed by dehydration.4 Both of these methods require that a heterocyclic ring already be present in the system. In contrast, this procedure offers a new flexible route to the construction of five- or six-membered heterocyclic rings which may easily be incorporated into a larger polycyclic product. Several examples of this process that can be cited to demonstrate this utility are... 

N-Alkyl-4-piperidones. A mixture of l,3-dimethyl-4-piperidone methiodide, benzylamine, and water allowed to stand overnight at room temp. 1-benzyl-3-methyl-4-piperidone. Y 66%. F. e. s. E. A. Mistryukov, N. I. Aronova, and V. F. ... 

Epimerization studies on cis- trans-1,2,6-trimethyl-4-piperidone (138 139) gave a low conformational free energy (0.47 kcal mol-1 at 50°C) for the 2-methyl group,195 presumably due to interaction between the methyl group and the N-substituent. The 2-methyl group is axial in the preferred conformation of l-benzyl-cis-2,5-dimethyl-4-piperidone (140),196... 

The l-methyl-3-allyl congener of fentanyl was made by application of the routine synthesis to l-methyl-3-allyl-4-piperidone (p.267) while l-carbethoxy-3-allyl-4-piperidone served as intermediate for synthesis of the 3-allyl/propyl-N-phenethyl analogs (Scheme 8.1). Reduction of intermediate Schiff bases was highly stereoselective and the cis isomers were produced almost exclusively by both chemical and catalytic reduction procedures low yields of the 3-propyl... 

Figure 11. Correlation between d and If for H abstractions from amines (Table 4). 42-46 are [109] N-methyl-2-pyrrolidone, e-caprolactame, 2-piperidone, 2-pirro-lidone, 2-oxazolidone, with E = 84.8 kJ mol. ...

OzymethyI-tropan, Homotrraiin 21 1200. l-Butyl-piperidon-(4) 81II215. l-Ath -3-acetyI-piperidin 21, 244,1264. N-Methyl-conhy< inon 811260, II219. N-Methyl-isopelletierin 81, 246,1267,268,... 

A novel synthesis of 2-atyl-4-piperidones by Mannich cy-clization of imino acetals, initiated by methylation of the imine, has been described. MeOTf has been used in the generation of a munchnone for cycloaddition. Finally, methylation of 1-lithio-2-n-butyl-l,2-dihydropyridine with MeOTf gives 2-butyl-... 

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