One-carbon chain extension of esters to alpha-chloroketones: a safer route without diazomethane

The reaction of a variety of methyl esters with dimethylsulfoxonium methylide at 0-25 degrees C affords the chain-extended beta-keto dimethylsulfoxonium ylides. Subsequent treatment with hydrogen chloride in THF proceeds with loss of DMSO to afford the corresponding alpha-chloroketones. This sequence has been utilized to convert the methyl esters of CBZ-protected alanine and valine to the anti N-protected alpha-amino epoxides, which are important pharmaceutical intermediates. When the same protocol is applied to BOC-protected phenylalanine methyl ester, epimerization occurs so that the use of a more reactive aryl ester is required. This chemistry provides a practical route to alpha-chloroketones that avoids the use of toxic and explosive diazomethane.     

Reactive barium-promoted Reformatsky-type reaction of alpha-chloroketones with aldehydes

A Reformatsky-type aldol reaction of alpha-chloroketones with aldehydes has been achieved using reactive barium as a low-valent metal in THF; this one-pot process is more effective for obtaining the desired beta-hydroxy ketones in high yields than the stepwise process in which barium enolates are prepared prior to the reaction with aldehydes.     

Alkylation on graphite in the absence of Lewis acids

Graphite is introduced as a convenient catalyst for alkylation of aromatic compounds and alcohols by benzyl, tertiary alkyl, and secondary alkyl halides in the absence of strong Lewis acids. Primary alkyl halides are not active under the reaction conditions.     

Asymmetric Mannich reactions with in situ generation of carbamate-protected imines by an organic catalyst

The instability of carbamate-protected alkyl imines has greatly hampered the development of catalytic asymmetric Mannich reactions suitable for the synthesis of optically active carbamate-protected chiral alkyl amines. A highly enantioselective Mannich reaction with in situ generation of carbamate-protected imines from stable alpha-amido sulfones catalyzed by an organic catalyst was developed. This reaction provides a concise and highly enantioselective route converting aromatic and aliphatic aldehydes into optically active aryl and alkyl beta-amino acids. [reaction: see text].     

Ethylene polymerization with supported bis(triphenylsilyl) chromate catalysts

Bis(triphenylsilyl) chromate is an active catalyst for ethylene polymerization without further treatment or additives. Catalytic activity is markedly increased when the compound is deposited on silica–alumina and is further increased if it is deposited on silica and then treated with an aluminum alkyl. Polymer molecular weight can be controlled by reaction temperature, hydrogen addition, support type, and reducing agent structure to give polymers ranging in melt index from essentially zero to > 100. In the supported catalysts the bis(triphenylsilyl) chromate appears to be bound to the support and to undergo a reduction step either by reaction with ethylene or with aluminum alkyl prior to polymerization. The active site is envisioned as chromium alkyl, bound to the support, with propagation occurring by insertion of the monomer into a Cr? C bond. Chain termination is by chain transfer to monomer.     

异氰酸酯的反应

我们研究了芳基和烷基异氰酸酯在消耗性镁阳极存在下的有机电解反应。芳基异氰酸酯电解得N, N'-二取代脲, 烷基异氰酸酯则还原偶联为N, N'-二取代草酰胺。我们认为这是由于烷基异氰酸酯从阴极得到电子发生比分子偶联, 芳基异氰酸酯则是与阴极析出的高分散的活性镁起作用。     

异氰酸酯的反应≠

我们研究了芳基和烷基异氰酸酯在消耗性镁阳极存在下的有机电解反应。芳基异氰酸酯电解得N,N’-二取代脲,烷基异氰酸酯则还原偶联为N,N’-二取代草酰胺。我们认为这是由于烷基异氰酸酯从阴极得到电子发生双分子偶联,芳基异氰酸酯则是与阴极析出的高分散的活性镁起作用。     

Electron spin resonance studies on radiation graft copolymerization. I. Grafting initiated by alkyl radicals trapped in irradiated polyethylene

The behavior of trapped radicals in polyethylene which is irradiated in air at room temperature, under grafting of methylmechacrylate or butadiene has been studied by electron spin resonance. Part of the alkyl radicals are converted to allyl radicals by reaction with double bonds and the others disappear by recombination under vacuum. The active species of grafting are alkyl radicals when the vapor pressure of monomers is relatively high, while at low pressure allyl radicals also play a role as well as alkyl radicals. In the grafting at 20°C, the grafting yields depend mainly on the decay rate of alkyl radicals which come out of the crystalline regions of polyethylene. The decay rate of alkyl radicals and the rate of grafting at the initial stage increase with decreasing crystallite size of polyethylene.     

Copper‐Catalyzed Aerobic Oxidative C?C Bond Cleavage for C?N Bond Formation: From Ketones to Amides

A novel copper‐catalyzed aerobic oxidative C(CO) C(alkyl) bond cleavage reaction of aryl alkyl ketones for C N bond formation is described. A series of acetophenone derivatives as well as more challenging aryl ketones with long‐chain alkyl substituents could be selectively cleaved and converted into the corresponding amides, which are frequently found in biologically active compounds and pharmaceuticals.     

Copper‐Catalyzed Aerobic Oxidative CC Bond Cleavage for CN Bond Formation: From Ketones to Amides

A novel copper‐catalyzed aerobic oxidative C(CO)? C(alkyl) bond cleavage reaction of aryl alkyl ketones for C? N bond formation is described. A series of acetophenone derivatives as well as more challenging aryl ketones with long‐chain alkyl substituents could be selectively cleaved and converted into the corresponding amides, which are frequently found in biologically active compounds and pharmaceuticals.     

Decarboxylative Negishi Coupling of Redox‐Active Aliphatic Esters by Cobalt Catalysis

A cobalt‐catalyzed decarboxylative Negishi coupling reaction of redox‐active aliphatic esters with organozinc reagents was developed. The method enabled efficient alkyl–aryl, alkyl–alkenyl, and alkyl–alkynyl coupling reactions under mild reaction conditions with no external ligand or additive needed. The success of an in situ activation protocol and the facile synthesis of the drug molecule (±)‐preclamol highlight the synthetic potential of this method. Mechanistic studies indicated that a radical mechanism is involved.     

Studies on Ziegler-Natta catalysts. Part V. Stereospecificity of the active center

Experimental results on Ziegler-Natta catalysts, based on observations made with the electron microscope, and a qualitative comparison of the stereospecificity of various catalyst combinations are given. The polymerization of olefin in these experiments is performed in the gas phase on dry catalysts in the absence of solvent or excess aluminium alkyl. The crystallographic structure of the lateral faces of α-TiCl₃ is established by electron microscopy and electron diffraction. The electron micrographs of α-TiCl₃–AlMe₃ catalysts show that the active centers, which are revealed by the dotwise formation of polymer, are located along the growth spirals, on lateral faces, and on surface defects. These regions of the surface are the only regions in which the surface titanium atoms are incompletely coordinated. The presence of chlorine vacancies and exposed titanium atoms is therefore an essential condition for the formation of active centers. However, the number of active centers is small in comparison to the number of incompletely coordinated titanium atoms, and hence it is concluded that the normally occurring α-TiCl₃ sites with one vacancy do not yield active centers on reaction with aluminum alkyl. It is proposed that the reaction with aluminum alkyl on such sites leads ultimately to a bimetallic complex which fills the original vacancy on the titanium atom. That the complexation is reversible and that the deblocked alkylated site, which is of the type proposed by Cossee, is an active center is not excluded. Such a center would, however, give atactic polymer. Similar complex formation on a TiCl₃ site having originally two vacancies would leave one vacancy on the titanium atom. This is believed to be the center of stereospecific polymerization. A model of this active center and a mechanism of polymer growth on it are proposed.     

Electron spin resonance studies on Ziegler-Natta type catalyst systems

Electron spin resonance spectra of Ziegler-Natta type catalyst systems (titanium trichloride and alkyl aluminums) have been studied. When triethylaluminum was added to titanium trichloride, an absorption with a g value of 1.96 was observed from the solid phase of the system. The number of spins of this signal is equal to that of the active centers for propylene polymerization. The solid phase from the mixture of titanium trichloride and diethylaluminum chloride also gives the same signal, which suggests the identity of the action of two alkyl aluminums on titanium trichloride surface. The signals obtained from the liquid phase of the both systems are all ascribed to the reaction products of the reaction of alkyl aluminum with titanium tetrachloride occluded in solid.     

N-BROMOSUCCINIMIDE-CATALYSED TRANSESTERIFICATION AND RACEMIZATION OF SULPHINATES

Abstract

Both aliphatic and aromatic sulphinates undergo transesterification reaction in the presence of N-bromosuccinimide. Isopropanolysis of optically active alkyl arenesulphinates was found to give racemic isopropyl arenesulphinates. The rate of racemization of optically active isopropyl p-toluenesulphinate was found to be first order with respect to both N-bromosuccinimide and isopropyl alcohol, suggesting that the reaction is a bimolecular nucleophilic substitution at the sulphur atom. The para electrodonating substituents in the aromatic ring accelerate slightly the rate of racemization. At the same time the rate of racemization was found to be retarded by the increase of steric requirements of the substituent at the sulphinyl sulphur atom suggesting that the initial formation of bromoxonium salt is the rate-determining step. Completely nonstereospecific isopropanolysis of optically active alkyl p-toluenesulphinates suggests that a sulphurane is formed as an intermediate in the exchange step of the reaction.     

A novel tunable aromatic bromination method using alkyl bromides and sodium hydride in DMSO

Aromatic bromination on various aromatic systems with different substitutions was performed in the presence of alkyl bromide and sodium hydride in DMSO. Mono-bromination on a wide range of substrates was achieved by selecting proper alkyl bromides and controlling its amount. Further bromination could happen with more active alkyl bromides and additional amount of bromides and sodium hydride. The yields ranged from moderate to excellent. In addition, reaction mechanism was postulated to explain our observations.     

3+2] versus [4+2] cycloadditions of quinone monoimide with azadienes: a Lewis acid-free access to 5-amino-2,3-dihydrobenzofuranes

The reaction between p-quinone monoimide 1a and various azadienes 2 is described in the absence of a Lewis acid promoter. When alpha,beta-unsaturated hydrazones are substituted by proton or alkyl groups, 2,3-dihydrobenzofuranes 4, a motif that is present in numerous biologically active products, are obtained in moderate to excellent yields. The regio- and stereoselectivity of this reaction has been proved by a complete NMR study, including 1H-15N correlations.     

Direct Regiospecific and Highly Enantioselective Intermolecular α‐Allylic Alkylation of Aldehydes by a Combination of Transition‐Metal and Chiral Amine Catalysts

The first direct intermolecular regiospecific and highly enantioselective α‐allylic alkylation of linear aldehydes by a combination of achiral bench‐stable Pd⁰ complexes and simple chiral amines as co‐catalysts is disclosed. The co‐catalytic asymmetric chemoselective and regiospecific α‐allylic alkylation reaction is linked in tandem with in situ reduction to give the corresponding 2‐alkyl alcohols with high enantiomeric ratios (up to 98:2 e.r.; e.r.=enantiomeric ratio). It is also an expeditious entry to valuable 2‐alkyl substituted hemiacetals, 2‐alkyl‐butane‐1,4‐diols, and amines. The concise co‐catalytic asymmetric total syntheses of biologically active natural products (e.g., Arundic acid) are disclosed.     

A new approach for generic screening and quantitation of potential genotoxic alkylation compounds by pre-column derivatization and LC-MS/MS analysis

A generic LC-MS/MS method was developed for the analysis of potentially genotoxic alkyl halides. A broad selection of alkyl halides were derivatized using 4-dimethylaminopyridine in acetonitrile. The reaction conditions for derivatization, i.e., solvent, reaction time, temperature and concentration of alkyl halide, active pharmaceutical ingredient (API), and reagent, were optimized for sensitivity and robustness. The interference of the matrix and the API and the presence of water on the derivatization reaction were investigated for a model drug product (paracetamol/caffeine tablets). Hydrophilic interaction liquid chromatography was used to allow a quantitative determination of the derivatives by tandem mass spectrometry. The derivatization reaction was shown to be selective for alkyl halides, although some reactivity was also observed for an aromatic sulfonate, which is also genotoxic. Even though differences in reaction efficiencies have been observed, the enhanced sensitivity obtained by the derivatization allows the majority of the alkyl halides to be detected by MS/MS at relevant levels for genotoxic impurity evaluation, i.e., 10 mg kg(-1). Another key advantage is that for the majority of derivatives, reagent-related fragments are produced, which allows low-level screening for alkyl halides. Highly specific MS detection can be performed using neutral loss and precursor ion scan experiments. The applicability of a generic screening method will make the genotox evaluation less dependent on the quality of assessments based on predictions only, and it will provide essential information during the development of new chemical entities. In addition to screening, target analysis in the low milligrams per kilogram range can be performed. A similar response of the derivatized compounds was obtained in the range of 1-100 mg kg(-1) with a reproducibility better than 10%, which is sufficient for the determination of alkyl halides in APIs and drug products.     

Organosulphur compounds : XLVII Alkylation of sulphinic acids by o-alkylisoureas: o-versus s-reactivity and asymmetric synthesis of alkyl sulphinates

The reaction of 0-alkylisoureas with sulphinic acids was found to produce the corresponding sulphones and sulphinates, the latter being predominantly formed. The sulphinate to sulphone ratio is strongly influenced by the kind of alkyl groups in the 0-alkylisourea and appeared to be also dependent on the solvent used. A few optically active sulphinates (e.e. up to 8.1%.) were prepared in the reaction between benzenesulphinic acid and a series of 0-alkylisoureas bearing optically active substituents at the nitrogen atom. A possible reaction mechanism is discussed.     

Cobalt(diamine)-catalyzed cross-coupling reaction of alkyl halides with arylmagnesium reagents: stereoselective constructions of arylated asymmetric carbons and application to total synthesis of AH13205

A cobalt-diamine complex catalyzes the cross-coupling reactions of primary and secondary alkyl halides with aryl Grignard reagents. It is confirmed that oxidative addition of alkyl halide to cobalt proceeds via a radical process. Optically pure Ueno-Stork halo acetals undergo diastereoselective cross-coupling reactions, the products of which are transformed into optically active THF derivatives. A sequential radical cyclization/arylation reaction under cobalt catalysis provides extremely short access to a synthetic prostaglandin AH13205.