Synthesis of pyrrolidines and piperidines from ω-azidoalkylboronic esters. Stereocontrolled access to chiral nonracemic 2-and 3-substituted derivatives

The conversion of ω-azidoalkylboronic esters 1 into the corresponding pyrrolidines or piperidines was achieved by oxidation with hydrogen peroxide followed by successive mesylation and catalytic hydrogénation. Homologation reactions were used as key steps of the syntheses of a chiral non-racemic 2-substituted pyrrolidine and a 3-substituted piperidine.     

On the scope of Pd-catalyzed carboamination reactions—synthesis of 2,4-disubstituted pyrrolidines and 2-substituted piperidines and morpholines

The scope of the palladium-catalyzed carboamination reaction for the synthesis of 2-substituted pyrrolidines, piperidines, and morpholines was investigated. Formation of a 2,4-disubstituted pyrrolidine proceeded in high yield but with a diastereoisomeric ratio of only 2:5, favoring the cis-isomer. The diastereoselectivity is hence significantly smaller than that observed previously in the formation of 2,3- and 2,5-disubstituted pyrrolidines. The yields of substituted piperidines and morpholines were lowered by competing Heck arylation reactions. Both the N-substituent and the choice of phosphine ligand for the palladium-catalyzed reaction were determining for the outcome.     

Opposite CD curves in chromophoric derivatives of 3-substituted 5-and 6-membered cyclic amines

Absolute configuration was assigned to 3-isopropylpyrrolidine by chemical correlation with R-3-isopropylsuccinic acid. The comparison between CD curves of 3-substituted piperidines, morpholines and pyrrolidine having the same chirality shows that the chiroptical properties of these five and six-membered cyclic amine derivatives are opposite.     

Development of a [3+3] cycloaddition strategy toward functionalized piperidines

This paper describes a novel route to functionalized piperidines via a formal [3+3] cycloaddition reaction of activated aziridines and palladium-trimethylenemethane (Pd-TMM) complexes. The cycloaddition reaction generally proceeds enantiospecifically with ring opening at the least hindered site of the aziridine. Therefore, readily available enantiomerically pure 2-substituted aziridines can be utilized to prepare enantiomerically pure 2-substituted piperidines in good to excellent yield. The N-substituent on the aziridine proved to be crucial to the success of this reaction with only 4-toluenesulfonyl (Ts) and 4-methoxybenzenesulfonyl (PMBS) aziridines permitting smooth cycloaddition to take place. Additionally, spirocyclic aziridines have been found to participate in the [3+3] cycloaddition reaction, whereas 2,3-disubstituted aziridines can be applied to provide fused bicyclic piperidines, albeit in low yield.     

Cyclopolymerization. IV. Low Molecular Weight Products for the Reactions of Allylamines and Diallylamines with Azobisisobutyronitrile

The azobisisobutyronitrile-initiated polymerization of various N-substituted diallylammonium, N-ethyldimethallylammonium, and triallylammonium chlorides yielded as the respective major by-products 2-substituted 6, 6-dimethylperhydro-5-isoindolones, 2-ethyl-3a, 6,6,7a-tetramethylperhydro-5-isoindolone, and 2-allyl-6,6-dimethylperhydro-5-isoindolone. These isoindolones are formed from pyrrolidylmethylene radical precursors and indicate that, in agreement with recent ESR studies, radical addition to diallylamines results in the formation of pyrrolidine derivatives and not piperidines as previously supposed. The reactions of azobisisobutyronitrile and azobisis-obutyramidine dihydrochloride with the models, N,N-dimethylallylammonium and N,N,2-trimethylallylammonium chlorides, are also described.     

Synthesis of enantiopure substituted piperidines via an aziridinium ring expansion

Herein we report a novel methodology for the asymmetric synthesis of 3-substituted piperidines from readily available chiral building blocks. This method, which features a novel irreversible dihydropyrole-tetrahydropyridine ring expansion, allows the introduction of a large variety of substituents at the 3-position and permits substitution at the 2- and 6-position giving mono-, di-, or trisubstituted piperidines with high diastereocontrol.     

A flexible method for the synthesis of 2-substituted 1,2,5,6-tetrahydropyridines and piperidines from chloro-containing propargylamines

A general approach for the stereoselective synthesis of 2-substituted 1,2,5,6-tetrahydropyridines and piperidines is described. The addition of 4-chloro-1-butyne to Ellman sulfinimines to produce chloro-containing propargylamines, reduction with Lindlar catalyst, and cyclization using LHMDS provides efficient, stereoselective access to diverse 2-substituted 1,2,5,6-tetrahydropyridines. For substrates incompatible with the LHMDS cyclization reaction conditions removal of the sulfinamide moiety and cyclization with Cs₂CO₃ allows the preparation of the corresponding 2-substituted 1,2,5,6-tetrahydropyridines. This method can be extended to the synthesis of 2-substituted piperidines through reduction of the chloro-containing propargylamine with PtO₂.     

C-H Bond Functionalization via Hydride Transfer: Formation of α-Arylated Piperidines and 1,2,3,4-Tetrahydroisoquinolines via Stereoselective Intramolecular Amination of Benzylic C-H Bonds

We here report a study of the intramolecular amination of sp(3) C-H bonds via the hydride transfer cyclization of N-tosylimines (HT-amination). In this transformation, 5-aryl aldehydes are subjected to N-toluenesulfonamide in the presence of BF(3)·OEt(2) to effect imine formation and HT-cyclization, leading to 2-arylpiperidines and 3-aryl-1,2,3,4-tetrahydroisoquinolines in a one-pot procedure. We examined the reactivity of a range of aldehyde substrates as a function of their conformational flexibility. Substrates of higher conformational rigidity were more reactive, giving higher yields of the desired products. However, a single substituent on the alkyl chain linking the N-tosylimine and the benzylic sp(3) C-H bonds was sufficient for HT-cyclization to occur. In addition, an examination of various arenes revealed that the electronic character of the hydridic C-H bonds dramatically affects the efficiency of the reaction. We also found that this transformation is highly stereoselective; 2-substituted aldehydes yield cis-2,5-disubstituted piperidines, while 3-substituted aldehydes afford trans-2,4-disubstituted piperidines. The stereoselectivity is a consequence of thermodynamic control. The pseudoallylic strain between the arene and tosyl group on the piperidine ring is proposed to rationalize the greater stability of the isomer with the aryl ring in the axial position. This preferential placement of the arene is proposed to affect the observed stereoselectivity.     

Nitropyridines as 2π-Partners in 1,3-Dipolar Cycloadditions with N-Methyl Azomethine Ylide: An Easy Access to Condensed Pyrrolines

1,3-Dipolar cycloaddition reactions of 2-substituted 5-R-3-nitropyridines and isomeric 3-R-5-nitropyridines with N-methyl azomethine ylide were studied. The effect of the substituent at positions 2 and 5 of the pyridine ring on the possibility of the [3+2]-cycloaddition process was revealed. A number of new derivatives of pyrroline and pyrrolidine condensed with a pyridine ring were synthesized.     

Asymmetric carbon-carbon bond formations in conjugate additions of lithiated N-Boc allylic and benzylic amines to nitroalkenes: enantioselective synthesis of substituted piperidines,pyrrolidines, and pyrimidinones

(-)-Sparteine mediated lithiations of N-Boc-allylic and benzylic amines provide configurationally stable intermediates which on conjugate additions to nitroalkenes provide highly enantioenriched enecarbamate products in good yields, and with high diastereoselectivities. Straightforward transformations of these adducts offer general routes to substituted 3,4-substituted piperidines, 3,4-substituted pyrrolidines, and 4,5-substituted pyrimidinones. Diastereoselective substitutions of intermediate lactams followed by reduction provide 3,4,5-substituted piperidines and 3,4-trisubstituted pyrrolidines. Lithiation adjacent to nitrogen of 3,4-substituted piperidines and pyrrolidines followed by diastereoselective substitution opens a route to 2,4,5- and 2,4,5,6-substituted piperidines as well as 2,3,4- and 2,3,4,5-substituted pyrrolidines. The enantiomers of the enecarbamate and 3,4-substituted piperidine products may be accessed by stannylation/transmetalation sequences as well as by further manipulation of 4-substituted piperidones. The methodology is used to synthesize both enantiomers of an aspartic peptidase inhibitor intermediate, 3-hydroxy-4-phenylpiperidine, as well as the antidepressant (+)-femoxetine.     

Chiroptical properties of cyclic amines

Chiroptical properties of several 2 or 3 monosubstituted azetidines, pyrrolidines and piperidines as free bases and N-[2-pyridyl N-oxide] derivatives has been examined. The absolute configuration can be unambiguously established, independently on the nature of the substituent and the size of the ring, only for 2-substituted N-[2-pyridyl N-oxide]amine derivatives. This behaviour is explained in terms of limited rotational freedom in these compounds.     

Chiroptical properties of 2-substituted piperidines : A simple helicity rule

The CD spectra of fifteen 2-substituted piperidines 2 and their N-methylated derivatives 1 have been determined. The sign of the Cotton effect observed for the n→σ^* transition of nitrogen is shown to be correlated, for a given absolute configuration, with the axial or equatorial orientation of the nitrogen lone pair, and to be determined by the screw sense of the helicity between the nitrogen lone pair and the 2-substituent R in 1 and 2: for compounds of the absolute D configuration, a positive helicity gives a positive CD and vice versa.     

Novel diastereoselective synthesis of bicyclic beta-lactams through radical cyclization and their reduction toward 2-(1-alkoxy-2-hydroxyethyl)piperidines and 2-(1-alkoxy-2-hydroxyethyl)azepanes

1-Allyl- and 1-(3-phenylallyl)-substituted 4-(2-bromo-1,1-dimethylethyl)azetidin-2-ones were transformed into 3-substituted 7-alkoxy-5,5-dimethyl-1-azabicyclo[4.2.0]octane-8-ones through radical cyclization by means of n-tributyltin hydride and AIBN in toluene with excellent diastereocontrol (>or=99%). The radical cyclization of 4-(2-bromo-1,1-dimethylethyl)-1-(2-methylallyl)azetidin-2-ones afforded 8-alkoxy-3,6,6-trimethyl-1-azabicyclo[5.2.0]nonan-9-ones in good diastereomeric excess (75-78%). The reductive ring opening of 1-azabicyclo[4.2.0]octane-8-ones and 1-azabicyclo[5.2.0]nonan-9-ones with lithium aluminum hydride resulted in novel 2-(1-alkoxy-2-hydroxyethyl)piperidines and -azepanes, which were isolated as single isomers.     

Reactions of 6-(Dimethylamino)fulvene with diazoazoles and arene- and azolediazonium salts

6-(Dimethylamino)fulvene reacted with 3- and 4-substituted 5-diazoazoles, as well as with 4-substituted benzene- and pyrazole-5-diazonium salts, in an aprotic solvent with high regioselectivity at an extremely high rate to give acyclic coupling products at the α-carbon atom of the cyclopenta-1,3-diene fragment. The nature of the diazo component did not affect the reaction direction, rate, or yield. Hydrolysis of the azo compounds obtained from arenediazonium salts involved elimination of the dimethylamino group with formation of aldehydes, and their reaction with pyrrolidine resulted in replacement of the dimethylamino group by pyrrolidine ring.     

1-Substituted 2-Azaspiro[3.3]heptanes: Overlooked Motifs for Drug Discovery

The 2-substituted piperidine core is found in drugs (18 FDA-approved drugs), however, their spirocyclic analogues remain unknown. Described here is the synthesis of spirocyclic analogues for 2-substituted piperidines and a demonstration of their validation in drug discovery.     

Stereoselective synthesis of N-heterocycles: application of the asymmetric Cu-catalyzed addition of Et2Zn to functionalized alkyl and aryl imines

The preparation of N-heterocycles from alkyl- and aryl-substituted imines is described. The key step involves a copper-catalyzed addition of diethylzinc to functionalized alkyl-substituted imines that were generated in situ from the sulfinic acid adducts. The nucleophilic addition products were then converted to 2-substituted pyrrolidines and piperidines. Aryl-substituted imines were transformed into enantioenriched 1- and 1,4-substituted tetrahydroisoquinolines.     

New method of preparation of C2F5Li and its reactions with cyclic imines and lactims: Synthesis of α-pentafluoroethyl proline

Addition of pentafluoroethyllithium to cyclic imines leads to pentafluoroethyl substituted pyrrolidines, piperidines and azepanes while reaction of cyclic lactims gives rise to 2-pentafluoroethyl imines. Oxidative cleavage of 2-furyl-2-pentafluoroethyl pyrrolidine has been found to be an effective method for the preparation of a racemic α-pentafluoroethyl proline.     

Cyclohydrocarbonylation-based strategy toward poly-substituted piperidines

Convenient accesses to enantiomerically pure 2-, 2,3-, 2,6-, 2,3,6-substituted piperidines and 1,4-substituted indolizine are described. At first, indium-mediated aminoallylation and -crotylation of aldehydes with (R)-phenylglycinol or (1R,2S)-1-amino-2-indanol gave homoallylamines with high stereocontrol. Then, these products, submitted to a Rh(I)-catalyzed hydroformylative cyclohydrocarbonylation, afforded perhydrooxazolo[3,2-a]piridines whose oxazolidines are opened with nucleophiles. Finally, the removal of the chiral auxiliaries delivered the enantiomerically pure piperidines.     

Rapid access to CF3-containing heterocycles

The silyl-Prins and aza-silyl-Prins reactions have been employed for the preparation of 6-CF₃-substituted dihydropyrans and 6-CF₃-substituted tetrahydropyridines. The product heterocycles have been further elaborated to a number of products, including CF₃-substituted pipecolates and hydroxylated pyrans and piperidines.     

A highly enantioselective approach towards 2-substituted 3-bromopyrrolidines

A facile and highly enantioselective approach towards 2-substituted 3-bromopyrrolidines has been developed. The process involves an amino-thiocarbamate catalyzed bromoaminocyclization of 1,2-disubstituted olefinic amides. The pyrrolidine products could readily be converted into other useful building blocks including a dihydropyrrole and a 2-substituted pyrrolidine.