Piperidin-4-ones, substituted

The often potent biological properties of piperidine derivatives underlie their vast use in pharmaceuticals, agrochemicals, and natural products. It is for this reason that there exists a myriad of synthetic routes to variously functionalized and substituted piperidine derivatives, which will be highlighted in the subsequent section. In the past year there have been two reviews highlighting two approaches to the synthesis of piperidines. One review focused on the use of aziridines in parallel and solid-phase synthesis of substituted piperidine derivatives as well as other scaffolds <07EJO1717>. The other review covered the synthesis of 3-arylpiperidines by radical 1,4- and 1,2-aryl migration <07T7187>. 

A novel and efficient synthesis of 2,5-substituted-l,2,4-triazol-3-ones where various alkyl, aryl, and heterocyclic groups can be introduced successfully at both the N2 and C5 positions has been described <05TL7993>. A practical synthesis of piperidine-/tropane-substituted 1,2,4-triazoles has been reported <05SL1133>. Novel isonucleosides with 1,2,4-triazole-3-earboxamide attaehments were prepared from D-ribose and D-xylose <05SC2653>. 

Substituent-dependent keto enol tautomerism was also observed for 4-piperidin-ones 21 (91ZN(B)1237). When R1 = H, Me, the ketones 21a are more stable than enols 21b, and 2,6-czx-substituted ketones are more stable than 2,6-tranx-substituted ketones. The introduction of an ester group into the 3-position shifts the keto enol equilibrium toward the enol form. 

Halo-substituted 3-hydroxypyridazin-6(lFf)-ones react in some instances by cine substitution. For example, 4-chloro-l-methyl-2-phenylpyridazin-6(lFf)-one, when treated with piperidine, yields a mixture of the corresponding 4- and 5-piperidino isomers in nearly equal amounts. 

The halogens of halothiophenes are more labile than those of the corresponding benzenes in accordance with theoretical considera-tions which indicate that thiophenes should also undergo nucleophilic substitutions more rapidly than benzenes. Hurd and Kreuz" found that in qualitative experiments 3,5-dinitro-2-chlorothiophene was more reactive toward piperidine and methanolic potassium hydroxide than 2,4-dinitrochlorobenzene. A quantitative study on the reaction of the six isomeric bromonitrothiophenes with piperidine (Table V) shows that the thiophenes react about one thousand times... 

Enantiopure (7 )-3-alkylpiperidines (38, R = Me, Et) were obtained when perhydropyrido[2,l-Z)][l,3]benzoxazin-9-ones (37, R = H, Me) were treated first with an excess of AIH3, then with PCC, followed by a 2.5 N solution of KOH (99TL2421). Treatment of optically active perhydropyr-ido[2,l-Z)][l,3]benzoxazines 39 and 40 with LAH in the presence of AICI3 and DIBALH (if R = COOEt) yielded 3-substituted piperidines 41 (00TA2809). 

Oxidative cyclization of 1 -[(2 -aminocarbonyl)phenyl]piperidine and its 4 -substituted derivatives with Hg(OAc)2-EDTA reagent afforded 1,2,3,4-tet-rahydro-6//-pyrido[2,l-Z)]quinazolin-6-one and its 3-substituted derivatives in 36-82% yields (99ZN(B)1577). Similarly, ( )-2-(piperidin-2-yl)benzal-doximes gave 2,3,4,4u-tetrahydro-l//-pyrido[l,2-u]quinazolin-5-oxide and... 

Substituted perhydropyrido[l,2-c][l,3]oxazines 83 were obtained by the cyclization of l-(/er/-butoxycarbonyl)-2-(2-hydroxyalkyl)piperidines 104 in pyridine on the action of MeS02Cl at room temperature (96CJC2434). Cyclization of c/5-2,6-H- l-(methoxycarbonyl)-2-(2-acetoxyhexyl)-9-methox-ypiperidines 105 and 106 in THF in the presence of KO/-Bu yielded 3-butyl-9-methoxyperhydropyrido[l,2-6 ][l,3]oxazin-l-ones 94. Treatment of l-(/erc-butoxycarbonyl)-2-[2-hydroxy-2,2-di(2-propyl)ethyl]piperidine with NaH in boiling THF yielded 3,3-di(2-propyl)perhydropyrido[l,2-c][l,3] oxazin-l-one (01JA315). 

Substitution of an alicyclic ring for one of the aromatic rings in the amino alcohols such as 32 or 39 produces a series of useful antispasmodic agents that have found some use in the treatment of the symptoms of Parkinson s disease. Mannich reaction of acetophenone with formaldehyde and piperidine affords the amino-ketone, 44a. Reaction of the ketone with cyclohexylmagnesium... 

A somewhat more complex scheme is required for the preparation of benzimidazolones in which one of the nitrogen atoms is substituted by a 4-pi peridyl group. The sequence starts with aromatic nucleophilic substitution on dichlorobenzene by protected amino-piperidine derivative to give Reduction of the... 

Replacement of one of the benzene rings in a fenamic acid by pyridine interestingly leads to a compound which exhibits antiliypertensive rather than antiinflammatory activity. Preparation of this agent starts with nucleophilic aroniatic substitution of anthranilic acid (8) on 4-chloropyri-dine. The product (9) is converted to its acid chloride (10), and this is condensed with piperidine. There is thus obtained ofornine (11) f31. 

If one limits the consideration to only that limited number of reactions which clearly belong to the category of nucleophilic aromatic substitutions presently under discussion, only a few experimental observations are pertinent. Bunnett and Bernasconi30 and Hart and Bourns40 have studied the deuterium solvent isotope effect and its dependence on hydroxide ion concentration for the reaction of 2,4-dinitrophenyl phenyl ether with piperidine in dioxan-water. In both studies it was found that the solvent isotope effect decreased with increasing concentration of hydroxide ion, and Hart and Bourns were able to estimate that fc 1/ for conversion of intermediate to product was approximately 1.8. Also, Pietra and Vitali41 have reported that in the reaction of piperidine with cyclohexyl 2,4-dinitrophenyl ether in benzene, the reaction becomes 1.5 times slower on substitution of the N-deuteriated amine at the highest amine concentration studied. 

When enamines are treated with alkyl halides, an alkylation occurs that is analogous to the first step of 12-14. Hydrolysis of the imine salt gives a ketone. Since the enamine is normally formed from a ketone (16-12), the net result is alkylation of the ketone at the a position. The method, known as the Stork enamine reaction is an alternative to the ketone alkylation considered at 10-105. The Stork method has the advantage that it generally leads almost exclusively to monoalkylation of the ketone, while 10-105, when applied to ketones, is difficult to stop with the introduction of just one alkyl group. Alkylation usually takes place on the less substituted side of the original ketone. The most commonly used amines are the cyclic amines piperidine, morpholine, and pyrrolidine. 

The hindered secondary amines can be highly effective photostabilizers for various polymers (]+.,5.,.6) Various hindered amines have been shown to retard oxidation, but most share the common feature of being secondary or tertiary amines with the a-carbons fully substituted. The most widely exploited representatives of this class are based on 2,2,6,6-tetramethylpiperidine either in the form of relatively simple low molecular weight compounds, or more recently as backbone or pendant groups on quite high molecular weight additives ( i.,5.,6). The more successful commercial hindered amines contain two or more piperidine groups per molecule. Photo-protection by tetra-methylpiperidines (near UV transparent) must result from the interruption of one or more of the reactions 1 to 3. Relatively recent results from our own laboratories, and in the open literature will be outlined in this context. 

Flash vacuum thermolysis (FVP) at 600°C or microwave excitation of 1-substituted perhydropyrido[l,2-f][l,3]oxa-zines afforded 1-substituted 1,4,5,6-tetrahydropyridines <2005TL5451>. Perhydropyrido[l,2-f][l,3]oxazin-l-ones were hydrolyzed with 2M ethanolic KOH to 2-(2-hydroxyalkyl)piperidines <1996CJC2434, 2005EJ01378>. (+)-9- />z -6-Epipinidinol 102 was similarly obtained from 3,8-dimethylperhydropyrido[l,2-f][l,3]oxazin-l-one 101 (Equation 16) <1998T13505>. 

Allylpiperidines were formed from 3-iodomethylperhydropyrido[l,2-f][l,3]oxazin-l-ones by treatment with Zn in AcOH <2002OL3459>. l-Methyl-2-(2-hydroxyalkyl)piperidines were prepared from 3-substituted perhydropyr-ido[l,2-tf][l,3]oxazin-l-ones with lithium aluminium hydride (LAH) in boiling THF and EtzO <2005T1595>. Reaction of 8-methylperhydropyrido[ 1,2-r [ 1.3 ]oxazine-1,3-dione 103 with PhCH2NH2, then PhCOCl and 4-meth-oxyphenol afforded ring-opened products 104 and 105, respectively (Scheme 8) <2000JA11009>. 

Treatment of tert-butyl (2/. )-2-(2-propcny lidene (piperidine-1-carboxylate with McjSil and PhOH yielded 3-substituted-3,4,7,8-tetrahydro-l//,6//-pyrido[l,2-c][l,3]oxazin-l-ones <2005T1595>. Reaction of l-(benzoxycarbonyl)2-styrylpiperidin-4-one with I2 resulted in the formation of r-3,4a-//-/ra r-4-//-4-iodo-3-phenylperhydropyrido[l,2-d-[l,3]oxazine-l,6-dione <2002JOC1972>. A diastereomeric mixture of 3-iodomethylperhydropyrido[ 1,2 z [ 1,3]oxazin-l-ones (e.g., 178) was obtained by intramolecular iodocarbamation of l-(alkoxycarbonyl)-2-allylpiperidines (e.g., 177) with I2 (Equation 34) <1999JOC8402, 2002OL3459>. 

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