Asymmetric synthesis of 1-(2- and 3-haloalkyl)azetidin-2-ones as precursors for novel piperazine, morpholine, and 1,4-diazepane annulated beta-lactams

A high-yielding, asymmetric synthesis of novel 4-formyl-1-(2- and 3-haloalkyl)azetidin-2-ones was developed as valuable starting materials for the synthesis of different enantiomerically enriched bicyclic azetidin-2-ones, such as piperazine, morpholine, and 1,4-diazepane annulated beta-lactam derivatives. Especially the hydride reduction of 4-imidoyl-1-(2- and 3-haloalkyl)azetidin-2-ones turned out to be an efficient and straightforward method for the preparation 2-substituted piperazines and 1,4-diazepanes.     

Reactivity of N-(omega-haloalkyl)-beta-lactams with regard to lithium aluminium hydride: novel synthesis of 1-(1-aryl-3-hydroxypropyl)aziridines and 3-aryl-3-(N-propylamino)propan-1-ols

The reactivity of 4-aryl-1-(2-chloroethyl)azetidin-2-ones and 4-aryl-1-(3-bromopropyl)azetidin-2-ones with regard to lithium aluminium hydride has been evaluated for the first time. 4-Aryl-1-(2-chloroethyl)azetidin-2-ones were transformed into novel 1-(1-aryl-3-hydroxypropyl)aziridines through an unprecedented conversion of beta-lactams into 2,3-unsubstituted aziridine derivatives. Unexpectedly, 4-aryl-1-(3-bromopropyl)azetidin-2-ones underwent dehalogenation towards 3-aryl-3-(N-propylamino)propan-1-ols upon treatment with LiAlH(4). 1-(1-Aryl-3-hydroxypropyl)aziridines were further elaborated by means of ring opening reactions using benzyl bromide in acetonitrile towards 3-aryl-3-[N-benzyl-N-(2-bromoethyl)amino]propan-1-ols and using aluminium(iii) chloride in diethyl ether, affording 3-aryl-3-[N-(2-chloroethyl)amino]propan-1-ols.     

Facile radical mediated synthesis of azetidin-2,3-diones: potential synthons for biologically active compounds

Abstract  

An operationally simple and efficient approach for the synthesis of azetidin-2,3-diones is described. The starting substrate 2-(2-bromobenzyloxy)ethanoyl chloride was treated with appropriate Schiff’s bases in triethylamine and dichloromethane to afford 3-(2-bromobenzyloxy)azetidin-2-ones. The synthesis of azetidin-2,3-diones was successfully achieved via radical mediated rearrangement of appropriately substituted 3-(2-bromobenzyloxy)azetidin-2-ones using n-tributyltin hydride and AIBN in refluxing dry benzene.     

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).     

Spectroscopic characterization of the 1-substituted 3,3-diphenyl-4-(2'-hydroxyphenyl)azetidin-2-ones: application of (13)C NMR, (1)H-(13)C COSY NMR and mass spectroscopy

The article deals with spectroscopic characterization of azetidin-2-ones. The presence of substituents like hydroxyl, fluoro, methoxy and benzhydryl, etc., on the azetidin-2-one ring significantly affects the IR absorption and (13)C NMR frequencies of the carbonyl group present in these compounds. The presence of an ester carbonyl group or too many methine protons in the molecule has been observed to limit the scope of IR and (1)H NMR spectroscopy in unambiguous assignment of the structure. The application of (13)C NMR, 2D NMR ((1)H-(13)C COSY) and mass spectroscopy in characterization of complex azetidin-2-ones is discussed. An application of the latter two techniques is described in deciding unequivocally between an azetidin-2-one ring and chroman-2-one ring structure for the product obtained by treatment of the 1-substituted 3,3-diphenyl-4-[2'-(O-diphenylacyl)hydroxyphenyl]-2-azetidinones with ethanolic sodium hydroxide at room temperature.     

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.     

Facile stereoselective synthesis of 1,3-disubstituted-4-trichloromethyl azetidin-2-ones

The highly stereoselective synthesis of 1,3-disubstituted-4-trichloromethyl azetidin-2-ones by the [2+2] cycloaddition of ketenes with imines derived from chloral is described.     

Asymmetric synthesis of cis-2,4-disubstituted azetidin-3-ones from metal carbene chemistry

Several chiral cis-2,4-disubstituted azetidin-3-ones were prepared as single diastereoisomers from N-protected amino acids, employing a highly stereoselective copper carbenoid N–H insertion reaction of diazoketones. These azetidin-3-ones were then converted into fully substituted azetidines in a few steps in good to high yields.     

Pictet–Spengler reactions of oxetan-3-ones and related heterocycles

Pictet–Spengler reactions of oxetan-3-ones and azetidin-3-ones with tryptamine and tryptophan derivatives produce spirocyclic tetrahydro-β-carbolines in good yields. Molecular iodine (5 mol %) is an effective catalyst in most cases and high levels of diastereoselectivity are witnessed using 2-substituted oxetan-3-ones.     

Electrophile-induced ring expansions of beta-lactams toward gamma-Lactams

[reaction: see text] An efficient and straightforward route toward 3,4-cis-4-isopropenylazetidin-2-ones was developed from 4-(1-chloroalkyl)azetidin-2-ones. Starting from the latter beta-lactams, a new synthesis of pyrrolidin-2-ones was achieved. When 4-isopropenylazetidin-2-ones were treated with bromine in dichloromethane, diastereoselective electrophile-induced ring expansions toward 5-bromopyrrolidin-2-ones were performed. Further oxidation of 3-benzyloxypyrrolidin-2-ones with bromine toward 3-bromopyrrolidin-2-ones was also established. When 4-isopropenyl-beta-lactams were added to a mixture of NBS and TMSN(3), 5-azidopyrrolidin-2-ones were obtained in moderate to high yields.     

A facile Lewis acid-promoted allylation of azetidin-2-ones

Exposure of 3α-chloro-3-phenylthioazetidin-2-ones and allyltrimethylsilane to a Lewis acid promotes a remarkably facile and stereoselective C-3 allylation to give 3α-allyl-3-phenylthioazetidin-2-ones 4 in excellent yield. These allylated azetidin-2-ones undergo smooth desulphurization with tri-n-butyltin hydride or Raney-nickel producing cis-3-allyl- and cis-3-propylazetidin-2-ones.     

Asymmetric synthesis of 4-formyl-1-(ω-haloalkyl)-β-lactams and their transformation to functionalized piperazines and 1,4-diazepanes

Chiral piperazine and 1,4-diazepane annulated β-lactams, prepared from the corresponding (3R,4S)-4-imidoyl-1-(ω-haloalkyl)azetidin-2-ones through reduction with sodium borohydride in ethanol, were transformed into novel methyl (R)-alkoxy-[(S)-piperazin-2-yl]acetates and methyl (R)-alkoxy-[(S)-1,4-diazepan-2-yl]acetates upon treatment with hydrogen chloride in methanol. On the other hand, bromination of (3R,4R)-1-allyl-4-formyl-β-lactams and (3R,4S)-1-allyl-4-imidoyl-β-lactams in dichloromethane, followed by sodium borohydride reduction of the resulting dibrominated azetidin-2-ones in ethanol, did not afford the envisaged bicyclic β-lactams but unexpectedly furnished (3R,4S)-1-(2-bromo-2-propenyl)azetidin-2-ones instead.     

Synthesis of a new series of N-substituted-3-[l-alkyl(aryl)- 4-piperidyl]azetidin-2-ones as possible muscarinic agents

A new series of N-substituted-3-[1-alkyl(aryl)-4-piperidyl]azetidin-2-ones 2a-j structurally related to the previously reported 2,7-diazaspiro[3.5]nonan-1-ones 1 have been synthesized and tested for their activity as muscarinic agents, both in vitro and in vivo. Preliminary pharmacological results showed that compounds 2 are devoid of significant cholinergic properties.     

The synthesis of N-(tetrazol-5-yl)azetidin-2-ones

A series of N-(tetrazol-5-yl)azetidin-2-ones have been prepared from serine and threonine and evaluated as antibiotics against a range of bacteria.     

Lewis acid mediated functionalization of β-lactams: mechanistic study and synthesis of C-3 unsymmetrically disubstituted azetidin-2-ones

A convenient and efficient route to novel unsymmetrically disubstituted azetidin-2-ones is described. β-Lactam carbocation equivalents of type 1 and active aromatic substrates in the presence of a Lewis acid promote a facile and stereoselective C-3 substitution to provide monosubstituted β-lactams (3,4) and symmetrically disubstituted β-lactams (5). cis-3-(4′-Methoxyphenyl)-3-phenylthioazetidin-2-ones (4) undergo further substitution with active aromatic substrates mediated by a Lewis acid to afford unsymmetrically disubstituted azetidin-2-ones (7).     

Selective ring contraction of 5-spirocyclopropane isoxazolidines mediated by acids

Thermolysis of 3,4-cis ring-fused 5-spirocyclopropane isoxazolidines 16, 18-21, 33, 34, 38a, and 61, in the presence of a protic acid at 70-110 degrees C, yielded 3,4-cis ring-fused azetidin-2-ones 22-26,41, 42, 46, and 62 with concomitant extrusion of ethylene, in good yields. So far, the collected evidences strongly support a mechanism started by a homolytic cleavage of the protonated N-O bond for the rearrangement of 5-spirocyclopropane isoxazolidines to beta-lactams. Some different competitive pathways can then follow depending on the stability or the stereoelectronic properties of cationic diradical intermediates. The two-step process, intramolecular 1,3-dipolar cycloaddition/thermal rearrangement under acidic conditions, represents a general synthesis of a new class of 3,4-cis-fused bicyclic azetidin-2-ones starting from easily available compounds such as amino acids, hydroxy acids, and dicarbonyl or amino alcohol derivatives.     

Synthesis of Enantiopure Dehydropiperidinones from α-Amino Acids and Alkynes via Azetidin-3-ones

Chiral dehydropiperidinones were synthesized in enantiopure form from α-amino acids and alkynes via azetidin-3-ones.     

Synthesis of Azetidin-2-Ones from Imines and Acids Using Trichloroacetonitrile-Triphenylphosphine Reagent

A one step synthesis of azetidin-2-ones (3a-j) has been described by the reaction of imines (1) with acids (2) in presence of trichloroacetonitrile, triphenylphosphine and triethylamine.     

Diastereoselective construction of azetidin-2-ones by electrochemical intramolecular C-C bond forming reaction

A convenient method for synthesis of optically active azetidin-2-ones using electrochemical oxidation has been exploited. The method consists of a diastereoselective intramolecular C-C bond forming reaction between active methylene and methyne groups through an electrochemical system in which positive iodine species acted as mediators under mild conditions.     

Stereoselective synthesis of bicyclic tetrahydrofuran-fused β-lactams and their conversion into methyl cis-3-aminotetrahydrofuran-2-carboxylates

cis-3-Benzyloxy-4-(2-mesyloxyethyl)azetidin-2-ones were shown to be useful starting products for the synthesis of cis-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones in high overall yields and purity upon hydrogenolysis of the benzyl ether substituent followed by intramolecular nucleophilic substitution using sodium hydride in THF. These unconventionally C-fused bicyclic β-lactams were easily converted into the corresponding methyl cis-3-aminotetrahydrofuran-2-carboxylates via acidic methanolysis. This methodology constitutes a convenient alternative for the known preparation of cis-4,4-dimethyl-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones and methyl cis-3-amino-4,4-dimethyltetrahydrofuran-2-carboxylates, as their 4,4-nor-dimethyl variants are usually considered to be more promising compounds within the field of drug design.