Piperidine trisubstituted

Unlike the pyrrolidine enamine of 2-methylcyclohexanone (7), which consists predominantly of the trisubstituted isomer, the morpholine and piperidine enamines of 2-methylcyclohexanone (20 and 21) were shown by... 

Reaction of the pyrrolidine enamine of cyclohexanone with phenyl vinyl sulfone afforded a 9 1 mixture of the tri- and tetrasubstituted isomers (2(5). The preference of the less substituted isomer in this case is in keeping with the greater overlap requirement between the n electrons of the double bond and the electron pair on the nitrogen atom, since the double bond exo to the five-membered ring is much more favored than the double bond exo to the six-membered ring. It is, however, hard to explain the formation of largely the trisubstituted isomer with the piperidine enamine of cyclohexanone, where both of the rings involved are six-membered. 

Tetrahydropyridines 103 undergo a Michael reaction to afford [ran.s-(2,3)-cis-(2,6)-trisubstituted piperidines 104 (97T9553). The reaction is stereoselective (a single stereoisomer was obtained) and provides a convenient route to the 5,8-disubstituted indolizidine 105 and 1,4-disubstituted quinolizidine system 106 (found in Dendrobates alkaloids) by introduction of various alkyl, alkenyl, or... 

Fewer procedures have been explored recently for the synthesis of simple six-membered heterocycles by microwave-assisted MCRs. Libraries of 3,5,6-trisubstituted 2-pyridones have been prepared by the rapid solution phase three-component condensation of CH-acidic carbonyl compounds 44, NJ -dimethylformamide dimethyl acetal 45 and methylene active nitriles 47 imder microwave irradiation [77]. In this one-pot, two-step process for the synthesis of simple pyridones, initial condensation between 44 and 45 under solvent-free conditions was facilitated in 5 -10 min at either ambient temperature or 100 ° C by microwave irradiation, depending upon the CH-acidic carbonyl compound 44 used, to give enamine intermediate 46 (Scheme 19). Addition of the nitrile 47 and catalytic piperidine, and irradiation at 100 °C for 5 min, gave a library of 2-pyridones 48 in reasonable overall yield and high individual purities. 

Aminonaphthalene (775) reacts with diethyl azodicarboxylate to give the trisubstituted hydrazine (776) which can be cyclized in wet piperidine to l,4-dihydro-3-oxonaphtho-[2,1 -e][ 1,2,4]triazine-1 -carboxylate (777) (21CB213). 

A very recent synthesis of ( )-pumiliotoxin C employed the nitrone cyclization product (29), obtained in 74% overall yield from the nitrone precursors.12b Reduction of (29) with zinc-acetic acid provided a trisubstituted piperidine which was converted in several steps to ( )-pumiliotoxin C. 

Chiral A-amidino-l,2,3,4-tetrahydropyridines undergo a stereoselective epoxidation-nucleophilic opening sequence with either alcohols or organozinc reagents to give 2,3,6-trisubstituted piperidines where the relationship between the 2- and 3-positions is cis (Equation 15) <2005OL2747>. 

A stereospecific route to enantiopure all-cis-2,3,6-trisubstituted piperidines relies on a cyclization step that is dependent upon temperature, and choice and quantity of base (Scheme 42) <2003TL3963>. Further intramolecular alkylation reactions reported include that of the chiral enaminone to the bicylic structure 35, a key intermediate toward the synthesis of lepadin alkaloids (Equation 80) <2004AGE4222>. 

The synthesis of 2,4,6-trisubstituted piperidines has been reported via the generation of a fused cyclic intermediate in a three-component reaction using typical palladium-based chemistry (Scheme 112) <20060L3813, 20060L3809>. Stereocontrol was observed and the same intermediate was used in the stereoselective synthesis of the indolizidine alkaloid (—)-dendroprimine. 

Risperidone 118 has been used to treat schizophrenia and bipolar disorder <1997WO042940>. Piperidine derivatives such as panamesine 119, a 1,4,4-trisubstituted piperidine, and preclamol 120, a 1,3-disubstituted piperidine, have also been used as antipsychotic agents . 

A three-component procedure for preparation of trisubstituted thiophenes involving the 5-aryldihydrothiophen-2-ones 49, pyrrolidine, and aldehydes has been developed, leading for example to the series 50 in moderate yields. A corresponding series of reactions involving piperidine gave similar products, albeit in lower yields <07TL6133>. 

A stereospecific route to enantiopure all-cjs-2,3,6-trisubstituted piperidines was described <03TL3963>. The cyclization step is dependent upon reaction temperature, choice and amount of base. 

---