Argentic oxide mediated N-dearylation of β-lactams

A method is described for the N-dearylation of N-(4-methoxy- or 4-ethoxyphenyl)-2-azetidinones with argentic oxide. The yields are good-to-excellent and the reaction is simple, efficient, and fast.     

Synthesis and reactivity against Cp2TiCl of 4-isoprenyl-β-lactams. Trapping of N-titanoimidoyl radicals from cyanoformyl-2-azetidinones

A Staudinger reaction between methoxyketene and two different imines formed from citral afforded, after chemical transformation, the (E/Z)-4-alkenylepoxy-2-azetidinones 2, 3 and 4. These compounds, by reaction with Cp₂TiCl, did not cyclize to afford the expected polycyclic β-lactams, but the corresponding allylic alcohols 12, 13 and 15 were obtained instead. Unexpectedly, the treatment of cyanoepoxide (E)-3 with Cp₂TiCl also gave the hydroxyl aldehyde (E)-14 whose formation suggests to us that a possible radical reduction of the cyano group might have occurred, and we lastly succeeded in the capture of the N-titanoimidoyl radicals. The behaviour observed for the isoprenoid side chain in the Staudinger reaction, the reactions with Cp₂TiCl, as well as the trapping of N-titanoimidoyl radicals generated from benzocyanoformyl-2-azetidinones with the Ti(III) reagent, are discussed.     

Easy access to orthogonally protected α-alkyl aspartic acid and α-alkyl asparagine derivatives by controlled opening of β-lactams

The controlled opening of the N1C2 bond in 1-carbamate-substituted 2-azetidinones derived from amino acids by O- and N-nucleophiles provided a straightforward access to orthogonally protected α-alkyl aspartic acid and asparagine derivatives. The use of DBU or sodium azide as additive is essential for expedient cleavage by amino acids to the corresponding β-aspartic acid dipeptides.     

DMF-dimethyl sulfate as a new reagent for the synthesis of β-lactams

A number of 2-azetidinones were synthesized in good to excellent yields by a novel reaction between Schiff bases, substituted acetic acids and alkoxymethylene-N,N-dimethyliminium salts, the adduct formed from DMF and O-alkylating agents. The advantages of this new method are mild reaction conditions, low cost, avoiding the use of chlorinating agents and easy purification of the products. The best results were obtained when DMF and dimethyl sulfate were used at room temperature.     

Synthesis of 4-aryl-substituted β-lactam enantiomers by enzyme-catalyzed kinetic resolution

Enantiopure 4-phenyl- and 4-(p-tolyl)-2-azetidinones 3a, 3b, 4a and 4b (with e.e.s of ≥96%) were prepared through lipase-catalyzed asymmetric butyrylation of the primary OH group of N-hydroxymethylated β-lactams (±)-5 and (±)-6 at the (R)-stereogenic centre or by lipase-catalyzed asymmetric debutyrylation of O-butyryloxymethyl-2-azetidinones (±)-7 and (±)-8 at the (R)-stereogenic centre. The ring-opening of lactams 5a, 5b, 6b and 8a with HCl/EtOH afforded the corresponding β-amino ester enantiomers 9a, 9b, 10a and 10b with e.e.s of ≥92%.     

Facile conversion of 2-azetidinones to 2-piperidones: application to a formal synthesis of Prosopis and Cassia alkaloids

Nonracemic 5,6-disubstituted 2-piperidones were prepared from readily accessible 3,4-disubstituted-2-azetidinones having pre-installed substituents by reductive ring opening of 2-azetidinones followed by stereoselective installation of Z-α,β-unsaturated ester and lactam formation. For the synthetic application to the naturally occurring piperidine alkaloids, such as Prosopis and Cassia alkaloids, 5-hydroxy-2-piperidones (+)-13 and (−)-24 were prepared from 2-azetidinones (−)-6b and (+)-18 via two-carbon ring homologation.     

A convenient synthesis of α-amino-β-lactams

A safe and convenient method is described for the synthesis of α-amido-β-lactams starting with glycine and an azomethine. The amino group of glycine is protected by reaction with a β-dicarbonyl compound following the method of Dane etal. and the carboxyl group is activated through the formation of a mixed anhydride or an active ester. Condensation between these glycine derivatives and acyclic or cyclic imino compounds (including thioimidates) in presence of triethylamine leads to stereospecific synthesis of 3-(β-carbonyl-vinylamino)-2-azetidinones in 40–60% yield. The vinylamino side chain can be hydrolyzed under mild acid conditions to form 3-amino-2-azetidinones which can be acylated to α-amido-β-lactams. Alternatively, the vinylamino side chain can be converted to an amido side chain by ozonolysis. The molecular parameters of a 3-(β-carbonyl-vinylamino)-2-azetidinone were determined by X-ray crystallography. Usefulness of this α-amido-β-lactam synthesis is illustrated by the preparation of isotopelabeled β-lactams and intermediates for some β-lactam antibiotics.     

Dicarboxylic Acid Monoesters in β- and δ-Lactam Synthesis

A N-(2-methoxy-2-oxoethyl)-N-(phenylsulfonyl)glycine monomethyl ester of the respective dicarboxylic acid was involved in a reaction with imines promoted by acetic anhydride at an elevated temperature. Instead of the initially expected δ-lactam products of the Castagnoli–Cushman-type reaction, medicinally important 3-amino-2-azetidinones were obtained as the result of cyclization, involving a methylene group adjacent to an acid moiety. In contrast, replacing alcohol residue with hexafluoroisopropyl in the same substrate made another methylene group (adjacent to the ester moiety) more reactive to furnishing the desired δ-lactam in the Castagnoli–Cushman fashion.     

Preparation of 3-Oxo- and 3-Ethylideneazetidine Derivatives

The preparation of 3-azetidinones with different N-substituents and their transformation to 3-ethylideneazetidines has been studied in relation with a projected synthesis of 3-ethylideneazetidine-2-carboxylic acid (= polyoximic acid; 1 ). The stable crystalline 3-azetidinone hydrochloride ( 18 ), obtained by hydrogenolysis of the known 1-(diphenylmethyl)-3-azetidenone ( 4 ), is described for the first time, From this key intermediate, 3-oxoazetidine-derived amides, exemplified by benzamide 12 ,urethanes (e.g. 17 ), and ureas (e.g. 20 ) can be prepared in good yield (Scheme 3). The olefination of 3-azetidinones with alkylidene(triphenyl)phosphoranes is a perparatively useful process only for derivatives with a pyramidal N-atom, e.g. the diphenylmethyl derivative 4 , and not for the amide 12 or the urethane 17 (Scheme 4). 3-Alkylidene-azetidines with an amide N-atom should, therefore, be prepared by exchange of the N-substituent after the introduction of the double bond.     

Regio- and π-facial selective Lewis acid interceded Diels-Alder reactions of α-dienyl-β-lactams: an indepth analysis

The regio-, diastereo-, and π-facial selective Lewis acid mediated Diels-Alder reactions of cis/trans-3-butadienyl-2-azetidinones with unsymmetrical dienophiles viz. methyl acrylate, dimethyl fumarate, and acrolein leading to the synthesis of diastereomerically pure and biologically potent 1,3,4-trisubstituted-2-azetidinones are reported. Theoretical calculations at HF/6-31G^∗∗ and 6-31G^∗∗/DFT levels have been performed to support the observed π-facial selectivity. The formation of diastereomerically pure ‘endo’ adducts is supported by the X-ray diffraction studies.     

Nitrilimine cycloaddition onto 2-azetidinones bearing alkenyl dipolarophile(s)

Silver acetate-promoted nitrilimines cycloaddition onto 3(R*)-phenyl-4(R*)-cinnamoyl-2-azetidinone 1 were highly stereoselective giving 4-(4,5-dihydropyrazol-5-yl) carbonyl-2-azetidinones 5 as the major products and regioisomeric 4-(4,5-dihydropyrazol-4-yl) carbonyl-2-azetidinones 6 as the minor one. When the same protocol was applied to the novel 3(R*)-phenyl-4(S*)-(4-benzoyl-E,E-1,3-butadienyl)-2-azetidinone 2 it resulted in site- and regioselective but not stereoselective cycloaddition, involving the formation of the four cycloadducts 10-13.     

Preparation of 2-azetidinones by cyclocondensation of carboxylic acids and imines via diphosphorustetraiodide

One-pot mild synthesis of 2-azetidinones was carried out by the reaction of imines and carboxylic acids in dry dichloromethane at room temperature using diphosphorus tetraiodide. It was also applied for synthesis of 3-spiro-2-azetidinones. The synthesized compounds were characterized by analytical and spectral (infrared, ¹H NMR, ¹³C NMR, and elemental analysis) data.     

Eco-friendly synthesis of 2-azetidinone analogs of isonicotinic acid hydrazide

Abstract

2-Azetidinones possess broad and potent activity due to presence of β-lactam ring and has been established as one of the biologically important scaffolds. The synthesis of N-(4-aryl-2-oxoazetidinone)-isonicotinamide by novel methods of stirring and sonication are described. The conventional method for synthesis of 2-azetidinones involves use of Dean–Stark water separator for the removal of water from the reaction with long reaction time (12–16 h reflux) at a very low temperature (?70 to ?90°C). The microwave method reported requires inert atmosphere of nitrogen gas for the synthesis of 2-azetidinones. We report herein the synthesis of 2-azetidinone analogs of isonicotinic acid hydrazide by novel green route methods of sonication and stirring using molecular sieves. Results indicate that higher yields and shorter reaction times can be achieved by employing novel green route methods of synthesis.     

Preparation of a Sulfoalkylbetaine-Based Zwitterionic Monolith with Enhanced Hydrophilicity for Capillary Electrochromatography Separation Applications

A novel monolithic stationary phase based on in situ copolymerization of zwitterionic monomer N,N-dimethyl-N-methacryloxyethyl-N-(3-sulfopropyl) ammonium betaine (DMMSA), pentaerythritol triacrylate (PETA), either methacrylatoethyl trimethyl ammonium chloride (META) or sodium 2-methylpropene-1-sulfonate (MPS) was designed as a multifunctional separation column for hydrophilic interaction capillary electrochromatography (HI-CEC). A significantly enhanced hydrophilicity was obtained on the poly(DMMSA-co-PETA-co-META or MPS) monolith, which was contributed by the high percentage of DMMSA in the polymerization mixture. A column efficiency of 200,000 plates/m was obtained and the monolithic column also displayed a satisfactory repeatability in terms of migration time with RSD values less than 1.1% (intra-day, n = 5) and 2.0% (inter-day, n = 3). Most importantly, the column was successfully applied to separation of a pool of neurotransmitters which are not well separated on commercial HILIC packing materials. A baseline separation of the 12 model components was obtained with good selectivity, symmetrical peak shape and high column efficiency with BGE consisting of 20 mM ammonium formate (pH 3.0) in ACN/H₂O (80/20, v/v).     

Synthesis of new 2,5-diamino-1,3-thiazole and 2-thiohydantoin derivatives by condensation of N-(2-Aryl-1-chloro-2-oxoethyl) carboxamides with thioureas

N-(2-Aryl-1-chloro-2-oxoethyl) carboxamides react under mild conditions with thiourea, N-alkyl-and N-arylthioureas, and various N,N′-disubstituted thioureas, following the Hantzsch reaction scheme. The reactions are selective, and the resulting 2,5-diamino-1,3-thiazole derivatives undergo recyclization acid followed by hydrolysis to give substituted 2-thiohydantoins on heating with hydrochloric acid in ethanol.     

Reversed-phase ion-pair partition liquid chromatography of chelates with 2-(3,5-dibromo-2-pyridylazo)-5-[N-ethyl-N-(3-sulphopropyl) amino] phenol and analogues

The ion-pair reversed-phase chromatography of some transition metal chelates with 2-(3,5-dibromo-2-pyridylazo)-5-[N-ethyl-N-(3-sulphopropyl)amino]phenol (3,5-diBr-PAESPAP) was studied. 3,5-DiBr-PAESPAP and its V(V), Cr(III), Fe(II), Co(III) and Ni(II) chelates were retained on and the copper (II), zinc(II) and cadmium(II) chelates dissociated in an ODS column using acetonitrile/water (37+63, v/v) (pH 7.0) containing 0.01 M acetate, 0.01 M 3-(N-morpholino)propanesulphonate buffer (pH 7.0) and 0.05 M Na⁺ as mobile phase. The chromatograms of 3,5-diBr-PAESPAP chelates were compared with those of the chelates with 2-(3,5-dibromo- 2-pyridylazo)-5-[N-(3-sulphopropyl)amino]phenol (3,5-diBr-PASPAP),2-(5-bromo-2- pyridylazo)-5-[N-(3-sulphopropyl)amino]phenol and 2-(5-bromo-2-pyridylazo)-5-[N-propyl-N- (3-sulphopropyl)amino] phenol. With 3,5-diBr-PAESPAP the Fe(II) and Ni(II) chelates were not resolved, but resolution was achieved with 3,5-diBr-PASPAP. The calibration graphs were linear over the ranges 2.0–10.0 ng (10-μl injection) of Fe, Ni and Co and for 20–100 ng (10-μl injection) for V with 3,5-diBr-PAESPAP and 3,5-diBr-PASPAP.     

The photochemical reactions of N,N-dialkyl α,β-unsaturated amides

Upon benzene-sensitized irradiation N,N-dibenzyl α,β-unsaturated amides 1a-1c cyclized to the corresponding 2-azetidinones 2a-2c in good yields via intramolecular hydrogen abstraction by the β-C atom. Under the same conditions N,N-diisopropyl amides 1e and 1f were found to undergo a novel photoreaction to give N-isopropyl saturated amides via the abstraction. Irradiation of N,N-diethyl and dimethyl amides gave neither 2-azetidinones nor N-monosubstituted amides.     

Microwave-assisted synthesis of N,N-bis-(2-pyridylmethyl)amine derivatives. Useful ligands in coordination chemistry

Microwave-assisted synthesis of the ligands N,N-bis-(2-pyridylmethyl)amine (BMPA), N-(methylpropanoate)-N,N-bis-(2-pyridylmethyl)amine (MPBMPA), N-(propanamide)-N,N-bis-(2-pyridylmethyl)amine (PABMPA), PNBMPA (N-(3-propionitrile)-N,N-bis-(2-pyridylmethyl)amine), N-(3-aminopropyl)-N,N-bis-(2-pyridylmethyl)amine (APBMPA), and lithium N-(proponoate)-N,N-bis-(2-pyridylmethyl)amine (LiPBMPA) are reported. High yields and short reaction time were obtained for condensation and Michael addition.     

Novel asymmetric total syntheses of (R)-(−)-pyridindolol, (R)-(−)-pyridindolol K1, and (R)-(−)-pyridindolol K2 via a mild one-pot aromatization of N-tosyl-tetrahydro-β-carboline with (S)-2,3-O-isopropylidene-l-glyceraldehyde as the source of chirality

Novel total syntheses of (R)-(?)-pyridindolol 1, (R)-(?)-pyridindolol K1 2, and (R)-(?)-pyridindolol K2 3 are described. By using l-tryptophan methyl ester and (S)-2,3-O-isopropylidene-l-glyceraldehyde as the starting materials, (R)-(?)-pyridindolol 1, (R)-(?)-pyridindolol K1 2, and (R)-(?)-pyridindolol K2 3 were synthesized in 5–7 steps in 66%, 41%, and 55% overall yields, respectively. The characteristic step of the total syntheses is a mild one-pot aromatization of N-tosyl-1,2,3,4-tetrahydro-β-carboline (N-Ts-THBC), which was obtained via Pictet–Spengler reaction of l-tryptophan methyl ester with (S)-2,3-O-isopropylidene-l-glyceraldehyde, and subsequent N-tosylation.     

Separation of alkaline earth elements by cation-exchange chromatography in ammonium malonate media

Be(II), Mg(II), Ca(II), Sr(II) and Ba(II) can be separated by elution from a cation-exchange column in the ammonium form with increasing concentrations of ammonium malonate. A typical elution sequence for a 60-ml column (volume in H⁺-form) of AG₅₀-X8 resin is: 200 ml of 0.20 N ammonium malonate plus 0.10 N malonic acid for Be(II); 300 ml of 0.50 N, 450 ml of 0.70 N, 350 ml of 1.10 N ammonium malonate for Mg(II), Ca(II) and Sr(II), respectively, and 200 ml of 3.0 N nitric acid for Ba(II). Separations are sharp and quantitative for element pairs in weight ratios from 1:1000 to 1000:1. Distribution coefficients, elution curves and quantitative separations are presented.