Piperidines, /3-hydroxyalkyl

Treatment of perhydropyrido[l,2-c][l,3]oxazin-l-ones 83, 85, and 87 with 2M ethanolic KOH afforded 2-(2-hydroxyalkyl)piperidines 84, 86, and 88 (96CJC2434). (4-)-9-Epi-6-epipinidinol (90) was obtained similarly from 3,8-dimethylperhydropyrido[l,2-c][l,3]oxazin-l-one 89 (98T13505). 

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). 

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>. 

Oxidative reactions at carbon predominate in the biotransformation of cyclic amiiies, and an important consequence of this is often the cleavage of the carbon-nitrogen bond. For example, A-dealkylation of N- alkyl substituted pyrrolidine (or piperidine, morpholine, etc.) involves an initial oxidative attack at the a- alkyl carbon atom to yield an N hydroxyalkyl derivative (carbinolamine), which is then metabolized to a secondary amine and the corresponding aldehyde. The metabolic conversion of nicotine to nornicotine (30 see Scheme 3) probably involves this mechanism, although the iminium ion (31) has also been suggested as an intermediate in the biotransformation (76JMC1168). Carbinolamines are unstable intermediates and have been identified only in a few cases, e.g. A-hydroxymethylcarbazole... 

Based on the previous work of this group on the three-component aza[4+2]/ allylboration strategy to construct polysubstituted piperidines [62], Gao and Hall developed a catalytic enantioselective version [63] of the corresponding oxygeneous process to construct a-hydroxyalkylated pyrans from 3-boronoacrolein [64], This recent variant of a Vaultier-Lallemand one-pot three-component reaction (see Scheme 12.14) was successfully applied to a concise total synthesis of (5R,6S)-6-acetoxy-5-hexadecanolide 128 (Scheme 12.20), the oviposition attractant pheromone of the female Culex mosquito [65] capable of transmitting the West Nile virus. 

B. Carboni, L. Toupet, G. Dujardin, Chem. Commun. 2003, 276-277. A novel diastereoseleetive route to a-hydroxyalkyl dihydropyrans using an hetero Diels-Alder/allylboration sequence, (h) B. B. Toure, D. G. Hall, Angew. Chem. Int. Ed. 2004, 43, 2001-2004. Three-component sequential aza[4+2] cycloaddition/allylboration/retro-sulfinyl-ene reaetion a new stereocontrolled entry to palustrine alkaloids and other 2,6-disubstituted piperidines, (i) B. B. Toure, D. G. Hall, J. Org. Chem. 2004, 69, 8429-8436. Design of a nonreductive method for chemoselective cleavage of hydrazines in the presence of unsaturations application to a steieoconveigent three-component synthesis of (-)-methyl palustramate. 

Inspired by the pioneering work of Vaultier and co-workers on the two-step carbo-cyclic [4+2] cycloaddition/allylboration [78] and the one-pot variant by LaUemand [79], Tailor and HaU described the first tandem aza[4+2]cycloaddition/allylboration three-component reaction [129]. Thermal reaction between hydrazonobutadienes 91, N-substituted maleimides, and aldehydes provides polysubstituted a-hydroxyalkyl-piperidines 94 via the allylboronate intermediate 92 and the proposed allylboration transition structure 93 (Equation 48) [130], A variant of this process, an aza[4+2]cy-cloaddition/aUylboration/retro-sulfinyl-ene, has been applied to the total synthesis of palustrine alkaloids [131]. 

Tailor J, Hall, DG. Tandem aza[4+2]/allyboration a novel multicomponent reaction for the StereocontroUed synthesis of a-hydroxyalkyl piperidine derivatives. Org. Lett. 2000 2 3715-3718. 

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