Azetidines as ligands in the Pd(II) complexes series

The preparation of palladium (II) complexes having sterically congested azetidines as ligands is described. Diastereomerically pure α-alkylamino and α-alkylimino azetidines react with Na₂PdCl₄ to afford the corresponding bidendate Pd(II) complexes, whereas 2-cyano azetidines can be used to access bidendate Pd(II) complexes containing an amino-imidate moiety. Preliminary study of the catalytic activity of these new complexes in the Suzuki cross-coupling reaction is presented.     

Selective Reductive Elimination at Alkyl Palladium(IV) by Dissociative Ligand Ionization: Catalytic C(sp3)−H Amination to Azetidines

A palladium(II)‐catalyzed γ‐C?H amination of cyclic alkyl amines to deliver highly substituted azetidines is reported. The use of a benziodoxole tosylate oxidant in combination with AgOAc was found to be crucial for controlling a selective reductive elimination pathway to the azetidines. The process is tolerant of a range of functional groups, including structural features derived from chiral α‐amino alcohols, and leads to the diastereoselective formation of enantiopure azetidines.     

N-phtalimidoazetioines par reactions d'isonitriles avec les N-phtalimidoazirioines,Ylures d'azomethine potentiels ; transposition en imines.

The reactions of isocyanides RNC with the 1-phtalimido 2-cyano 2-methoxycarbonyl 3-aryl aziridines gives N-phtalimido azetidines. Rearrangement of azetidines with R = tert-butyle or tert-octyle yields isomeric imines.     

Inhibition of nonmammalian glycosidases by azetidine iminosugars derived from stable 3,5-di-O-triflates of pentoses

Efficient ring closure of stable crystalline 3,5-di-O-triflates of pentofuranosides with amines to form azetidines allowed preliminary evaluation of four-ring iminosugars as glycosidase inhibitors; significant and specific inhibition of nonmammalian α-glucosidases is shown by L-xylo- and L-arabino-iminosugar azetidines.     

Synthesis of enantiopure azetidines: a route to new β-amino alcohols

β-Amino alcohols possessing an E vinylsilane moiety were cyclized in the presence of N-bromosuccinimide to afford diastereoisomerically pure polyfunctional azetidines. These azetidines were then transformed into enantiopure β-amino alcohols with a Z vinylic bromide moiety.     

Cation-Promoted Strain-Release-Driven Access to Functionalized Azetidines from Azabicyclo[1.1.0]butanes

Access to 1,3-functionalized azetidines through a diversity-oriented approach is highly sought-after for finding new applications in drug-discovery. To this goal, strain-release-driven functionalization of azabicyclo[1.1.0]-butane (ABB) has generated significant interest. Through appropriate N-activation, C3-substituted ABBs are shown to render tandem N/C3-fucntionalization/rearrangement, furnishing azetidines; although, modalities of such N-activation vis-à-vis N-functionalization remain limited to selected electrophiles. This work showcases a versatile cation-driven activation strategy of ABBs. And capitalizes on the use of Csp³ precursors amenable to forming reactive (aza)oxyallyl cations in situ. Herein, N-activation leads to formation of a congested C−N bond, and effective C3 activation. The concept was extended to formal [3+2] annulations involving (aza)oxyallyl cations and ABBs, leading to bridged bicyclic azetidines. Besides the fundamental appeal of this new activation paradigm, operational simplicity and remarkable diversity should engender its prompt use in synthetic and medicinal chemistry.     

Diastereoselective preparation of azetidines and pyrrolidines

Iodine-mediated cyclization of homoallyl amines at room temperature delivered cis-2,4-azetidine through a 4-exo trig cyclization. Isomerization of iodo-azetidines to cis-pyrrolidines could be achieved by heating, with complete stereocontrol. The relative stereochemistry of the iodo-azetidines and pyrrolidines was confirmed by NMR spectroscopy and X-ray crystallography. Further functionalization was achieved through nucleophilic displacement of iodine to deliver substituted azetidines and pyrrolidines. 1,2,3-Triazole-appended azetidines and pyrrolidines were also prepared.     

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.     

Synthesis of 1-alkyl-2-(trifluoromethyl)azetidines and their regiospecific ring opening toward diverse α-(trifluoromethyl)amines via intermediate azetidinium salts

A convenient approach toward nonactivated 1-alkyl-2-(trifluoromethyl)azetidines as a new class of constrained azaheterocycles was developed starting from ethyl 4,4,4-trifluoroacetoacetate via imination, hydride reduction, chlorination, and base-induced ring closure. Furthermore, the reactivity profile of these 2-CF(3)-azetidines was assessed by means of quaternization and subsequent regiospecific ring opening at C4 of the azetidinium intermediates by oxygen, nitrogen, carbon, sulfur, and halogen nucleophiles, pointing to a clear difference in reactivity compared to azetidines bearing other types of electron-withdrawing groups at C2.     

Titanium‐Mediated Synthesis of Spirocyclic NH‐Azetidines from Oxime Ethers

The Ti^IV‐mediated synthesis of spirocyclic NH‐azetidines from oxime ethers using either an alkyl Grignard reagent or terminal olefin ligand exchange coupling partner is described. Through a proposed Kulinkovich‐type mechanism, a titanacyclopropane intermediate forms and serves as a 1,2‐aliphatic dianion equivalent, inserting into the 1,2‐dielectrophilc oxime ether to ultimately give rise to the desired N‐heterocyclic four‐membered ring. This transformation proceeds in moderate yield to furnish previously unreported and structurally diverse NH‐azetidines in a single step.     

Mechanistic insights into the rearrangement of azetidine N-oxides to isoxazolidines

Various functionalized azetidines were oxidized with mCPBA or hydrogen peroxide, to produce the corresponding N-oxide and study its fate in the [1,2] Meisenheimer rearrangement. This ring expansion leading to isoxazolidines occurs readily, without trapping of the transient N-oxide. Starting with azetidines bearing a nitrile or an ester group at C-2, the rearrangement is regioselective. However, a varying amount of epimerization on the migrating radical is observed, which can also be observed with the related [1,2] Stevens rearrangement.     

Synthesis of enantiopure azetidine 2-carboxylic acids and their incorporation into peptides

Enantiopure azetidine 2-carboxylic acids were prepared by hydrolysis of the corresponding 2-cyano azetidines, without ring cleavage of the azetidine or epimerization. The produced amino acids, which are conformationally constrained analogues of phenylalanine, can be cleanly debenzylated and used for the synthesis of tripeptides. In the course of the synthesis of new enantiopure 2-cyano azetidines through intramolecular alkylation of a metallated amino nitrile, it was found that the involved anionic cyclisation can be thermodynamically controlled, thus enhancing its diastereoselectivity.     

Azetidine iminosugars from the cyclization of 3,5-di-O-triflates of α-furanosides and of 2,4-di-O-triflates of β-pyranosides derived from glucose

Primary amines with either 3,5-di-O-ditriflates of α-furanosides or 2,4-di-O-triflates of β-pyranosides form bicyclic azetidines in high yield.     

Carbohydrate derived bicyclic azetidin-3-ones as scaffolds for highly functionalized azetidines

Bicyclic azetidin-3-ones with no acidic α-hydrogens, prepared in good yields via cis-2,4-di-O-triflates of pyranosides, are stable divergent intermediates for the synthesis of highly substituted azetidines, as illustrated by the synthesis of (2R,3R,4R)-3-hydroxy-4-(hydroxymethyl)-3-methylazetidine-2-carboxylic acids. Preliminary studies on the reactions of bicyclic azetidinones indicate their potential as scaffolds for novel complex azetidines.     

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.     

Reduction of 4-(haloalkyl)azetidin-2-ones with LiAlH4 as a powerful method for the synthesis of stereodefined aziridines and azetidines

[reaction: see text] A new synthesis of stereodefined aziridines and azetidines, starting from 4-(1- or 2-haloalkyl)azetidin-2-ones, is described. Treatment of the latter compounds with LiAlH(4) gave 1,2-fission of the beta-lactam, followed by an intramolecular nucleophilic substitution of the halogen, giving rise to the formation of 2-(1-alkoxy-2-hydroxyethyl)aziridines in the case of 4-(1-haloalkyl)azetidin-2-ones and of 2-(1-alkoxy-2-hydroxyethyl)azetidines in the case of 4-(2-haloalkyl)azetidin-2-ones. The resulting 2-(1-alkoxy-2-hydroxyethyl)aziridines were transformed into the corresponding trans-3,4-substituted oxolanes via an intramolecular nucleophilic ring opening, triggered by AlCl(3).     

Addition of 1,4 - diphenyl - 1 - azabutadiene to allenic esters

Reactions of 1,4-diphenyl-1-azabutadiene with allenic esters (1,2) in refluxing benzene furnish the respective cyclohexenone derivatives (3,4) as major products, and presumably proceed via azetidines (B).     

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.     

Synthesis of spirocyclopropyl γ-lactams by tandem intramolecular azetidine ring-opening/closing cascade reaction: synthetic and mechanistic aspects

The scope and limitations of a novel intramolecular azetidine ring-opening/closing cascade reaction affording spirocyclopropyl γ-lactams from azetidines in high regio- and stereoselectivity is reported. The key step of the process is a S_N2-type ring-opening of TMSOTf-activated azetidine rings by silyl ketene acetals generated by treatment with TMSOTf and TEA. This study is a very rare example of nucleophilic ring-opening of azetidines that does not require formation of quaternary azetidinium salts by N-alkylation or the use of N-electron-withdrawing groups. Application of this process to 2-azetidinone system led to a complete change in reactivity and provide 6-aza-bicyclo[3.2.0]heptane derivatives via an unprecedented Mukaiyama aldol-like reaction involving an ester acceptor and a silyl imidate.     

Stereocontrolled synthesis of substituted N-arenesulfonyl azetidines from gamma-(phenylseleno)alkyl arylsulfonamides

Different synthetic methodologies for the stereocontrolled synthesis of substituted azetidines are reported. The approach utilizes an optimized oxidation reaction of gamma-(phenylseleno)alkyl arylsulfonamides, followed by the intramolecular substitution of the resulting phenylselenonyl group by the nitrogen atom.