Cycloaddition of alkynyl ketones with N-tosylimines catalyzed by Bu3P and DMAP: synthesis of highly functionalized pyrrolidines and azetidines

Cycloadditions of alkynyl ketones with N-tosylimines catalyzed by Lewis bases to synthesize azetidines and pyrrolidines were systematically described. In the reaction of alkynyl ketones with N-tosylimines catalyzed by Bu3P at room temperature in toluene, highly functionalized pyrrolidines were formed in good to excellent yields. When DMAP was used in place of Bu3P as catalyst to facilitate the cycloaddition, completely substituted azetidines were produced in moderate to good yields in CH2Cl2. Both cyclization reactions proceeded smoothly with complete stereoselectivity. The scope and limitations of these cycloaddition reactions were also investigated.     

A smooth rearrangement of N-p-toluenesulfonyl 2-tert-butyldiphenylsilylmethyl-substituted azetidines into N-p-toluenesulfonyl 3-tert-butyldiphenylsilyl-substituted pyrrolidines

The rearrangement of N-p-toluenesulfonyl 2-tert-butyldiphenylsilylmethyl-substituted azetidines into 3-tert-butyldiphenylsilyl-substituted pyrrolidines under Lewis acid conditions in dichloromethane involves 1,2-migration of silicon through a siliranium ion. The formation of siliranium ion was discovered not to be in concert with σ(C-N) cleavage from stereochemical analysis of the pyrrolidine products formed from 3- and 4-substituted-2-tert-butyldiphenylsilylmethyl azetidines and also from the optical rotation data and chiral HPLC analysis of the pyrrolidine product formed from N-p-toluenesulfonyl 2(R)-tert-butyldiphenylsilylmethyl azetidine. The formation of sterically less hindered siliranium ion is followed by its S(N)2 opening by the internal nitrogen nucleophile. Oxidative cleavage of σ(C-Si) bond leads to the formation of 3-hydroxypyrrolidines.     

Azacycloalkanes from epoxides and aziridines

Methods of preparation of azetidines, pyrrolidines, and piperidines from epoxides and aziridines were analyzed. The possibility of epoxides conversion into aziridines was considered. The examples of application of azacycloalkanes in the medical and organic chemistry as biologically active substances and synthons for their preparation were calculated.     

Rapid Assembly of Saturated Nitrogen Heterocycles in One‐Pot: Diazo‐Heterocycle “Stitching” by N–H Insertion and Cyclization

Methods that provide rapid access to new heterocyclic structures in biologically relevant chemical space provide important opportunities in drug discovery. Here, a strategy is described for the preparation of 2,2‐disubstituted azetidines, pyrrolidines, piperidines, and azepanes bearing ester and diverse aryl substituents. A one‐pot rhodium catalyzed N–H insertion and cyclization sequence uses diazo compounds to stitch together linear 1,m‐haloamines (m=2–5) to rapidly assemble 4 ‐, 5 ‐, 6 ‐, and 7 ‐membered saturated nitrogen heterocycles in excellent yields. Over fifty examples are demonstrated, including examples with diazo compounds derived from biologically active compounds. The products can be functionalized to afford α,α‐disubstituted amino acids and applied to fragment synthesis.     

Asymmetric synthesis of 2-substituted cyclic amines

Cyanomethylenetributylphosphorane-mediated ring closure for the asymmetric synthesis of 2-substituted cyclic amines such as azetidines, pyrrolidines and a piperidine is reported. The desired stereochemistry at the 2-position was fixed using (S)-tert-butyl sulfinamide as a chiral auxiliary.     

Stereoselective synthesis of pyrrolidines from N-allyl oxazolidines via hydrozirconation-cyclization

[reaction: see text] A new diastereoselective synthesis of pyrrolidines from readily available chiral N-allyl oxazolidines is presented. The construction of the pyrrolidine ring is achieved via a tandem hydrozirconation-stereoselective Lewis acid mediated cyclization sequence.     

Access to enantiomerically enriched cis-2,3-disubstituted azetidines via diastereoselective hydrozirconation

An asymmetric variant of the hydrozirconation reaction has been established starting from Boc-protected chiral allylic amines. The resulting diastereoselectively formed N-functionalized organozirconiums can be considered as promising chirons. In this case, they have been transformed into enantiomerically enriched cis-2,3-disubstituted azetidines through a iodination/cyclization sequence.     

Microwave-assisted synthesis of azetidines in aqueous media

Simple azetidines are synthesized in good to excellent yields and high purity via cyclization of 3-(ammonio)propyl sulfates derived from primary amines and the cyclic sulfate of 1,3-propanediol. A feature of this methodology includes the accelerated synthesis of azetidines in water under the influence of microwave-assisted heating.     

N,N'-carbonyldiimidazole-mediated cyclization of amino alcohols to substituted azetidines and other N-heterocycles

Amino alcohols are important synthons for N-heterocycles. We have developed an efficient method to activate hydroxyl groups, which avoids the use of toxic reagents and tolerates a wide variety of functional groups. Our strategy has been applied to the synthesis of functionalized p-methoxyphenyl-protected azetidines, pyrrolidines, and piperidines. The required amino alcohols were synthesized according to an optimized proline-catalyzed Mannich protocol. An azetidine analogue of ezetimibe was synthesized to demonstrate the potential for the synthesis of drug-like molecules.     

Ring transformation of 2-(haloalkyl)azetidines into 3,4-disubstituted pyrrolidines and piperidines

[reaction: see text] Reduction of 4-(haloalkyl)azetidin-2-ones with chloroalane (AlH(2)Cl) afforded new 2-(haloalkyl)azetidines in high yields. The latter compounds proved to be very useful starting materials for rearrangements toward stereospecifically defined five- and six-membered azaheterocycles, such as 3,4-cis-disubstituted pyrrolidines and piperidines. During these reactions, bicyclic azetidinium intermediates were formed which were ring opened by a variety of nucleophiles. Hereby, reactions proceeding via 1-azoniabicyclo[2.2.0]hexanes are reported for the first time.     

A convenient synthesis of 1,2,4-trisubstituted azetidines by reductive cyclization of aza-Michael adducts of chalcones

Aza-Michael adducts of chalcones and diethyl N-arylphosphoramidates undergo reductive cyclization with sodium borohydride followed by sodium hydride to afford 1,2,4-trisubstituted azetidines diastereoselectively in a one-pot procedure and excellent yields.     

Reaction of Nitrogen‐Radicals with Organometallics Under Ni‐Catalysis: N‐Arylations and Amino‐Functionalization Cascades

Herein, we report a strategy for the generation of nitrogen‐radicals by ground‐state single electron transfer with organyl–Ni^I species. Depending on the philicity of the N‐radical, two types of processes have been developed. In the case of nucleophilic aminyl radicals direct N‐arylation with aryl organozinc, organoboron, and organosilicon reagents was achieved. In the case of electrophilic amidyl radicals, cascade processes involving intramolecular cyclization, followed by reaction with both aryl and alkyl organometallics have been developed. The N‐cyclization–alkylation cascade introduces a novel retrosynthetic disconnection for the assembly of substituted lactams and pyrrolidines with its potential demonstrated in the short total synthesis of four venom alkaloids.     

Synthesis of novel N-hydroxy heterocycles via intramolecular reductive cyclization of diketoximes by NaBH3CN

A simple and efficient protocol for the construction of substituted piperazines, piperidines, thiomorpholines, decahydroquinolines, perhydrocyclopenta[b]pyridine, and pyrrolidines bearing N-hydroxy substituents through intramolecular reductive cyclization of diketoximes using sodium cyanoborohydride is described.     

Asymmetric synthesis of 3-hydroxy-pyrrolidines via tin-lithium exchange and cyclization

We report a method for the synthesis of chiral pyrrolidines using tin-lithium exchange and cyclization reactions. The precursors are formed readily from simple starting materials and undergo tin-lithium exchange by treatment with n-butyllithium. Subsequent intramolecular carbolithiation is stereoselective to give highly enantiomerically enriched pyrrolidines in excellent yields.     

γ-Lactam-containing peptidomimetics

Protected diaminoalcohols obtained through allyl addition to α-amino acid-derived imines and subsequent hydroboration were used for the preparation of pyrrolidinones and pyrrolidines. Pyrrolidinones were synthesized with moderate yields by oxidation of the hydroxy function with tetrapropylammonium perruthenate/N-methylmorpholine-N-oxide and concomitant cyclization while pyrrolidines were synthesized in good yields by tosylation of the hydroxy group and subsequent intramolecular nucleophilic substitution. Thus accessible substrates were transferred into peptidomimetics by attachment of amino acid moieties at both termini using conventional peptide coupling strategies. Molecular mechanics optimizations suggest that these substrates preferentially adopt a turn conformation.     

Acid-catalyzed cyclization of vinylsilanes bearing an amino group. Stereoselective synthesis of pyrrolidines

[reaction: see text] In the presence of an acid catalyst, vinylsilanes 1 bearing an amino group protected by an electron-withdrawing group were smoothly cyclized to 2-(silylmethyl)pyrrolidines 2. This cyclization was utilized for the stereoselective synthesis of 2,n-disubstituted pyrrolidines (n = 3-5). The cyclized products could be converted to the corresponding alcohols by oxidative cleavage of the carbon-silicon bond with TBAF and H2O2.     

Aqueous N-heterocyclization of primary amines and hydrazines with dihalides: microwave-assisted syntheses of N-azacycloalkanes, isoindole, pyrazole, pyrazolidine, and phthalazine derivatives

[reactions: see text] The synthesis of nitrogen-containing heterocycles from alkyl dihalides (ditosylates) and primary amines and hydrazines via a simple and efficient cyclocondensation in an alkaline aqueous medium that occurs under microwave irradiation is described. This improved greener synthetic methodology provides a simple and straightforward one-pot approach to the synthesis of a variety of heterocycles, such as substituted azetidines, pyrrolidines, piperidines, azepanes, N-substituted 2,3-dihydro-1H-isoindoles, 4,5-dihydropyrazoles, pyrazolidines, and 1,2-dihydrophthalazines.     

Highly stereoselective ring expansion of enantiopure α-hydroxyalkyl azetidines

Stereodefined α-hydroxyalkyl azetidines, prepared in a few steps from enantiopure β-amino alcohols, are chlorinated or transformed into methanesulfonyloxymethyl derivatives in good yields. Heating of these compounds in chloroform or dimethylformamide induces a stereospecific ring enlargement to give 3-chloro or 3-methanesulfonyloxy pyrrolidines. The ease of this rearrangement depends on the nature of the migrating group (Cl⁻ or MsO⁻), of the class of the starting alcohol (primary or secondary) and of the relative stereochemistry of the starting material.     

Intramolecular Metalloamination of N,N‐Dimethylhydrazinoalkenes: A Versatile Method to Access Functionalized Piperidines and Pyrrolidines

Highly diastereoselective metalloamination/cyclization reactions of zinc(II) hydrazides obtained through reaction of diethylzinc with N,N‐dimethylhydrazinoalkenes are described. The resulting organozinc intermediates undergo facile allylation and acylation, in situ, to provide the corresponding functionalized piperidines and pyrrolidines.     

Les α et β-Cetophosphonates,des Precurseurs de Pyrrolidines et de Quinoleines Phosphonatees

The condensation of primary amines on α- or β-ketophosphonates affords the corresponding iminophosphonates. The reaction was found to be highly stereoselective, affording the E isomer exclusively. These phosphonylimines were then treated in basic media to give pyrrolidines and quinolines through intramolecular cyclization. The structures of all obtained products were confirmed by NMR spectroscopy (¹H, ³¹P, ¹³C), and in some cases by mass spectrometry.