4-hydroxy-4-phenylpiperidines

A mixture of 750 grams of 1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine and 2,500 cc of 48% hydrobromic acid is refluxed for about 20 minutes. It is then poured into 8 liters of water. An oily precipitate appears which on standing crystallizes. It is filtered and crystallized from about 3.5 liters of alcohol. 2-Methyl-9-phenyl-2,3-dihydro-1-pyridindene hydrobromide, MP 201°-203°C, is obtained. 

Diethyl A-(4-hydroxy-4-phenylpiperidin-1 -yl)methylenemalonate did not react with ketene in acetone to give a cyclobutanone derivative (64JMC68). 

Transition metals (iron, copper, nickel and cobalt) catalyse oxidation by shortening the induction period, and by promoting free radical formation [60]. Hong et al. [61] reported on the oxidation of a substimted a-hydroxyamine in an intravenous formulation. The kinetic investigations showed that the molecule underwent a one-electron transfer oxidative mechanism, which was catalysed by transition metals. This yielded two oxidative degradants 4-hydroxybenzalde-hyde and 4-hydroxy-4-phenylpiperidine. It has been previously shown that a-hydroxyamines are good metal ion chelators [62], and that this can induce oxidative attack on the a-hydroxy functionality. 

Figure 11.2 Plot of calculated logP values against log(ll ECS0) values for a series of propafenones modified at the nitrogen atom ( ) IV-alkyl derivatives, ( ) IV-aryl derivatives, (t) fV-diphenylalkyl derivatives, and ( ) 4-hydroxy-4-phenylpiperidine derivatives.

H19N3, (2,6-cis-Dimethylpiperidyl)diazobenzene, 44B, 214 3H20CINO, 1,2-Dimethyl-4-hydroxy-4-phenylpiperidine hydrochloride, 40B, 230... 

Similarly, fV-BOC-aminoalcohols can be subjected to Mitsunobu reaction conditions to yield the piperidine structure 10 (Equation 26) <2004JOC2229>, which is an intermediate in the synthesis of galactohomonojirimycin (BOC = /-butoxycarbonyl). Cyclization of an iV-BOC derivative of an aminoalcohol mesylate was reported in the synthesis of enantiopure 3-hydroxy-4-phenylpiperidine derivatives starting from L-phenylglycine <2004TL987>. 

Oxidation of JV-hydroxypiperidine with cupric acetate or potassium ferricyanide gives J1-piperideine 1-oxide (30) in addition to a dimer or trimer.184,185 Dehydrogenation of l-hydroxy-2-phenylpiperidine takes a similar course.189... 

The catalytic asymmetric synthesis of (2S,3S)-3-hydroxy-2-phenylpiperidine was developed by J. Lee et al. using an intramolecular epoxide opening 5-exo-tet) followed by ring expansion. The acyclic c/s-epoxide substrate was prepared in good yield and in greater than 94% ee by the Jacobsen epoxidation from the corresponding (Z)-alkene. ... 

Cyclization of the A -Boc derivative of an aminoalcohol mesylate was used in a synthesis of enantiopure 3-hydroxy-4-phenylpiperidine derivatives from i-phenylglycine <04TL987>. Alternatively, such 77-Boc-aminoalcohol derivatives may be subjected to Mitsunobu reaction conditions, as in the preparation of 142, an intermediate in a route to 1-deoxy-D-galactohomonojirimycin <04JOC2229>. 

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