Β-keto Amides Research Articles

A Facile Pathway to Enantiomerically Enriched 3‐Hydroxy‐2‐Oxindoles: Asymmetric Intramolecular Arylation of α‐Keto Amides Catalyzed by a Palladium–DifluorPhos Complex

The method is applicable to aryl triflates bearing different aromatic and aliphatic substituents, as well as sterically hindered β-keto amide (XII).

Domino Ligand-Free Copper-Catalyzed Synthesis of Polysubstituted Indoles

The synthesis of polysubstituted indoles is described by the domino reaction of 2-haloanilines and 1,3-dicarbonyl compounds, 1,3-diketones, β-keto esters and β-keto amides, using copper catalysis under ligand-free conditions. The protocol provides a simple, general and atom economical process for the synthesis of substituted indoles at moderate temperature.

Bioinspired Total Synthesis and Human Proteasome Inhibitory Activity of (−)-Salinosporamide A, (−)-Homosalinosporamide A, and Derivatives Obtained via Organonucleophile Promoted Bis-cyclizations

A full account of concise, enantioselective syntheses of the anticancer agent (-)-salinosporamide A and derivatives, including (-)-homosalinosporamide, that was inspired by biosynthetic considerations is described. The brevity of the synthetic strategy stems from a key bis-cyclization of a β-keto tertiary amide, which retains optical purity enabled by A(1,3)-strain rendering slow epimerization relative to the rate of bis-cyclization. Optimization studies of the key bis-cyclization, enabled through byproduct isolation and characterization, are described that ultimately allowed for a gram scale synthesis of a versatile bicyclic core structure with a high degree of stereoretention. An optimized procedure for zincate generation by the method of Knochel, generally useful for the synthesis of salino A derivatives, led to dramatic improvements in side-chain attachment and a novel diastereomer of salino A. The versatility of the described strategy is demonstrated by the synthesis of designed derivatives including (-)-homosalinosporamide A. Inhibition of the human 20S and 26S proteasome by these derivatives using an enzymatic assay are also reported. The described total synthesis of salino A raises interesting questions regarding how biosynthetic enzymes leading to the salinosporamides proceeding via optically active β-keto secondary amides, are able to maintain the stereochemical integrity at the labile C2 stereocenter or if a dynamic kinetic resolution is operative.

ChemInform Abstract: Homochiral Amine Synthesis by Baker′s Yeast Resolution of a β- Keto Amide: 1-Phenylethylamine.

Abstract Preliminary investigation of the resolution potential of baker's yeast reduction of β-keto amides has been carried out with 1-phenylethylamine. Enantiomeric excess was determined by direct comparison of resolved enantiomers with derivatives prepared from commercially available (R)-(+)-1-phenylethylamine and was found to be 56–58.6% for the S enantiomer and 76–84.6% for the R enantiomer.

A Novel Synthesis of N-Unsubstituted β-Enamino Thioesters from 3-Arylisoxazoles and 3-Aryl-5-phenylthio-2-isoxazolines

A novel procedure for the synthesis of N-unsubstituted β-enamino thioesters, (Z)-S-phenyl 3-amino-3-arylprop-2-enethioates, from 3-arylisoxazoles or 3-aryl-5-phenylthio-2-isoxazolines is described and a plausible mechanism for the reaction is proposed. Some examples of conversion of one β-enamino thioester [(Z)-S-phenyl 3-amino-3-phenylprop-2-enethioate] into N-unsubstituted β-enaminoacyl derivatives (β-enamino esters, β-enamino amides, and β-keto amides) are also reported.

Ru-Catalyzed Dynamic Kinetic Resolution of β-Keto Amides via Transfer Hydrogenation

Ru-Catalyzed Dynamic Kinetic Resolution of β-Keto Amides via Transfer Hydrogenation

Enamine-Based Domino Strategy for C-Acylation/Deacetylation of Acetoacetamides: A Practical Synthesis of β-Keto Amides

A practical three-step route for C-acylation/deacetylation of acetoacetamides is described. Initial enamination of the acetoacetamides with Boc-monoprotected ethylenediamine provides β-enamino amides, which are acylated at the α-carbon with excellent selectivity. The C-acylated derivatives undergo domino fragmentation in acidic media to give the corresponding β-keto amides accompanied by 2-methyl-4,5-dihydro-1H-imidazole.

One-Carbon Bridge Stereocontrol in Robinson Annulations Leading to Bicyclo[3.3.1]nonanes

The one-carbon bridge stereochemistry of bicyclo[3.3.1]nonane products formed in the Robinson annulation reactions of 2-substituted cyclohex-2-enones was investigated. In contrast to previous reports, it was found that the major diastereomer formed places the one-carbon bridge substituent anti to the beta-keto ester/amide unit introduced in the Robinson annulation. This stereoselectivity appears to be kinetically controlled. In the case of a beta-keto amide product derived from carvone, it was demonstrated, through base-catalyzed epimerization, that thermodynamic control favors the syn isomer.

Synthesis of γ-Butyrolactams by Photoinduced PhSe Group Transfer Radical Cyclization and Formal Synthesis of (±)-Isocynometrine with Diphenyldiselenide as Promoter

We have developed a strategy for constructing nitrogen heterocycles by photoinduced PhSe group transfer radical cyclization. trans-Alpha,beta-disubstituted gamma-butyrolactams (2-pyrrolidinones) were prepared in good yields (38-73%) with high regioselectivity and stereoselectivity from N-alkenyl alpha-PhSe beta-keto amides. Reaction outcomes were modulated by the steric effect of the substituents on the nitrogen atom of the cyclization precursors and the stereoelectronic effect of the substrates. Diphenyldiselenide, as an additive, was found to promote ring closure. The advantage of this strategy in natural product synthesis is demonstrated by a formal synthesis of (+/-)-isocynometrine.

Diphenyllead(IV) thiosemicarbazonates and pyrazolonates: Synthesis and characterization

Cyclization of thiosemicarbazones derived from β-keto esters and β-keto amides (HTSC) in the presence of diphenyllead(IV) acetate was explored in methanol solution at room temperature and under reflux. All β-keto ester TSCs underwent cyclization to give the corresponding pyrazolone (HL), which, except in one case, deprotonated and coordinated the PbPh 2 2+ moiety to form homoleptic [PbPh 2(L) 2] or heteroleptic [PbPh 2(OAc)(L)] derivatives. Cyclization did not occur with β-keto amide TSCs and only [PbPh 2(TSC) 2] or [PbPh 2(OAc)(TSC)] thiosemicarbazonates were isolated. The complexes were characterized by IR spectroscopy in the solid state and by 1H, 13C and 207Pb NMR spectroscopy in DMSO– d 6 solution, in which they evolve and decompose with time. Additionally, crystals of p-acetoacetanisidide thiosemicarbazone (HTSC 10), [PbPh 2(OAc)(L 5)] · MeOH (HL 5 = 2,5-dihydro-3,4-dimethyl-5-oxo-1 H-pyrazolone-1-carbothioamide), [PbPh 2Cl(L 2)] (HL 2 = 2,5-dihydro-5-oxo-3-phenyl-1 H-pyrazolone-1-carbothioamide), [PbPh 2(OAc)(TSC 8)] · 2MeOH (HTSC 8 = acetoacetanilide thiosemicarbazone), [PbPh 2(OAc)(TSC 10)] · H 2O and [PbPh 2(OAc)(TSC 11)] · 0.75MeOH (HTSC 11 = o-acetoacetotoluidide) were studied by X-ray crystallography. The complexes, monomers or dimers with almost linear C–Pb–C moieties, are compared with the corresponding derivatives of Pb(II).

Solvent-Free Synthesis of Hydrazine-Substituted Enaminones via a One-Pot Four-Component Reaction

A four-component reaction for the synthesis of hydrazine-substituted enaminones is illustrated. In situ generation of a β-keto ester or β-keto amide from diketene and ROH or RNH2 and then reaction with a primary amine to produce enaminones, followed by functionalization of the adduct by C-N bond formation through reaction with diisopropyl diazodicarboxylate, are performed under solvent-free conditions in one pot to obtain the title compound in good yield.

Direct Carbon−Carbon Bond Formation via Chemoselective Soft Enolization of Thioesters: A Remarkably Simple and Versatile Crossed-Claisen Reaction Applied to the Synthesis of LY294002

Thioesters undergo chemoselective soft enolization and acylation by N-acylbenzotriazoles on treatment with MgBr2 x OEt2 and i-Pr2NEt to give beta-keto thioesters. Prior enolate formation is not required, and the reaction is conducted using untreated CH2Cl2 open to the air. The coupled products are stable synthetic equivalents of beta-keto acids and can be converted directly into beta-keto esters, beta-keto amides, and beta-diketones under mild conditions. The utility of this carbon-carbon bond-forming method is shown through the synthesis of the PI3-K inhibitor LY294002.

Preliminary investigation of the yeast-mediated reduction of β-keto amides derived from cyclic amines as potential resolution methodology

2-Methylpiperidine and 2-cyclohexylpiperidine were converted to their respective β-keto amides by treatment with diketene. Several strains of yeast were used to reduce the racemic β-keto amides. The unreacted enantiomers were separated from the β-hydroxy amides, the amides cleaved, and the extent of resolution was determined for the cyclic amines. Detailed experimental and spectral data are provided for all compounds.

Facile Access to Polysubstituted Indoles via a Cascade Cu-Catalyzed Arylation−Condensation Process

Cu(I)/L-proline-catalyzed cross-coupling of 2-halotrifluoroacetanilides with beta-keto esters and amides followed by in situ acidic hydrolysis delivered 2,3-disubstituted indoles. The halides bearing a strong electron-withdrawing group in the 4-position can undergo in situ basic hydrolysis to provide the corresponding indoles. Polysubstituted indoles can be prepared from substituted 2-halotrifluoroacetanilides with high regioselectivity.

New lead(II) complexes with N,S-ligands, including a lead pyrazolonate with unusual packing flexibility

The reaction of lead(II) acetate in methanol with thiosemicarbazones derived from β-keto esters and β-keto amides (HTSCs) afforded two lead(II) thiosemicarbazonates and numerous homoleptic ([PbL 2]) and/or heteroleptic ([Pb(OAc)L]) complexes containing deprotonated pyrazolones L − formed by metal-induced cyclization of the starting HTSC ligands. All the complexes isolated were characterized by IR spectroscopy in the solid state and by 1H and 13C NMR spectroscopy in DMSO solution; in addition, crystals containing [Pb(L 6) 2] and [Pb(L 7) 2] were examined by X-ray crystallography. [Pb(L 6) 2] · 0.5H 2O · 0.3MeOH (HL 6 = 4-ethyl-2,5-dihydro-3-methyl-5-oxo-1 H-pyrazole-1-carbothiamide) showed three types of molecule with significant structural differences that appear to be determined by packing interactions. In all three molecules the Pb⋯Pb distances are very short [3.6096(8)–3.7562(8) Å], but density-functional-theoretic calculations at the B3LYP level do not support the existence of Pb–Pb bonds. In [Pb(L 7) 2] (HL 7 = N-ethyl-2,5-dihydro-3-methyl-5-oxo-1 H-pyrazole-1-carbothiamide) all the molecules are of a single type, and they are linked in a three-dimensional network by weak intermolecular Pb⋯O bonds.

Tautomeric equilibria in the reaction products of asymmetric 1,3-diamines with β-dicarbonyl compounds

The reaction products of 1,3-butanediamine and 2-methyl-2,4-pentanediamine with β-keto aldehydes were shown by 1H and 13C NMR spectroscopy to exist as tautomeric mixtures in solutions, comprising one cyclic and two open-chain forms due to the non-equivalence of the amino groups. The chain products exist as Z- and E-isomers. After equilibration, the products from 1,3-butanediamine contain relatively less of the cyclic form than those from 2-methyl-2,4-pentanediamine. The products of 2-methyl-2,4-pentanediamine with p-substituted aroylacetaldehydes, exhibit a linear correlation between log K of the ring–chain equilibria and Hammett's σ values of the aromatic ring substituents. α-Substitution of β-keto aldehydes notably increased the relative amounts of the chain E-isomers in their condensation products and also resulted in the formation of two diastereomers for each of the cyclic products. No ring–chain equilibria were observed in the products of 1,3-butanediamine and 2-methyl-2,4-pentanediamine with β-diketones, β-keto esters, or β-keto amides.

Ru‐SYNPHOS® and Ru‐DIFLUORPHOS®: Highly Efficient Catalysts for Practical Preparation of β‐Hydroxy Amides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Aerobic Oxidative Cyclization under Pd(II) Catalysis: A Regioselective Approach to Heterocycles

[chemical reaction: see text]. An efficient Yb(OTf)3-promoted palladium-catalyzed oxidative cyclization of gamma-heteroalkenyl beta-keto amides has been developed. Under simple aerobic condition, a variety of six-, seven-, and eight-membered-ring N- and O-heterocycles were obtained regioselectively in excellent yield.

Efficient and Reusable PdCl2(MeCN)2/CuCl2/PEG‐400 System for Cyclization of Alkenyl β‐Keto Esters and Amides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Efficient and Reusable PdCl2(MeCN)2/CuCl2/PEG-400 System for Cyclization of Alkenyl β-Keto Esters and Amides

PEG-400 [poly(ethylene glycol-400)] was found as an effective medium for the PdCl(2)(MeCN)(2)-catalyzed hydroalkylation cyclization of alkenyl beta-keto esters and amides. In PEG-400, no additives such as Me(3)SiCl and Ln(OTf)(3) were required for the complete conversion of alkenyl beta-keto esters. The results also showed that CuCl(2) could promote the reaction. In the presence of PdCl(2)(MeCN)(2), CuCl(2), and PEG-400, various alkenyl beta-keto esters and amides underwent a selective cyclization reaction to give good to excellent yields of the desired six-membered-ring carbocycles. Furthermore, the PdCl(2)(MeCN)(2)/CuCl(2)/PEG-400 system could be recycled and reused five times without any loss of catalytic activity.