The oxidation of ethylbenzene with hydrogen peroxide and molecular oxygen catalyzed by cobalt and bromide ions in acetic acid as solvent was studied. The oxidation of ethylbenzene with hydrogen peroxide provided a mixture of ethylbenzene hydroperoxide, acetophenone, 1-phenylethanol, and 1-phenylethyl acetate. After rapid initial oxidation, the reaction rate decreased steadily so that full conversion of ethylbenzene and reaction intermediates to acetophenone could not be achieved. In contrast, no catalyst deactivation was observed for oxidations using atmospheric oxygen. Ethylbenzene was oxidized to acetophenone in 74% selectivity after a reaction time of 150 min at 80 °C. The reaction conditions were translated to a continuous flow process using a tubular gas–liquid reactor. At temperatures of 110 to 120 °C and an oxygen pressure of ∼12 bar, the reaction time necessary for complete oxidation of ethylbenzene was reduced to 6 to 7 min. The acetophenone was formed in 80 to 84% selectivity, and virtually pure acetophenone was isolated in 66% product yield without the need for chromatography. Increasing the reaction time to 16 min at a reaction temperature of 150 °C led to benzoic acid as the final product in 71% yield.

The palladium-catalyzed N-demethylation of the opioid alkaloids oxymorphone 3,14-diacetate and 14-hydroxymorphinone 3,14-diacetate to their nor-derivatives with oxygen as the terminal oxidant has been investigated. Palladium­(II) acetate forms colloidal palladium(0) particles upon heating in N,N-dimethylacetamide. The palladium(0) particles are effective catalysts for the aerobic N-demethylation of these opiate alkaloids. Demethylation of 14-hydroxymorphinone 3,14-diacetate with pure oxygen as oxidant in a continuous flow reactor provided the demethylated product with excellent selectivity after residence times of only 10–20 min with 2.5–5 mol % palladium acetate as catalyst on a laboratory scale. Scale-up of the oxidation in a 100 mL flow reactor (combination of FlowPlate A6 and coiled tube to enhance the gas–liquid mass transfer), hydrogenation in a packed bed reactor, and subsequent hydrolysis afforded the desired noroxymorphone in high quality and good yield on a kg scale. The reaction sequence consumes only oxygen, hydrogen, and water as stoichiometric reagents.

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A major driving force for the intriguing developments in the field of total synthesis over the past century is the proficiency with which biological systems transform simple starting materials into complex molecular frameworks. Although necessary issues such as selectivity and synthetic efficiency to construct intricate biological structures can be addressed nowadays to a high degree, new aspects such as diversity and operational efficiency are becoming more important, because of the demand for making complex molecular architectures by effective and simple methodologies.[1] In this respect, catalytic cascade reactions involving two or more selective transformations in one pot are emerging as an attractive tool to overcome the operational limitations associated with traditional "Stop-and-Go" synthesis. [2] Organocatalysis has been shown to be a powerful tool for forming multiple stereocenters in a one-pot protocol by employing either a single catalyst [3a-k] or a combination of catalysts.[3i-l] We became interested in the 4,5-disubstituted isoxazoline-N-oxide motif, since it has the potential to serve as an important building block for diversity orientated total synthesis. Several approaches to isoxazoline-N-oxides are present in the literature either in a racemic fashion, [4] starting from enantiomerically pure compounds, [5] or by employing stoichiometric amounts of a chiral reagent.[6] We envisioned that 4,5-disubstituted isoxazoline-N-oxides having up to three stereocenters could be obtained through a highly stereoselective one-pot procedure using simple and commercially available starting materials in combination with one or two organocatalysts (Scheme 1).Herein, we report a new enantio-and diastereoselective one-pot protocol to access 4,5-disubstituted isoxazoline-Noxides, as well as demonstrate the use of this protocol for the de novo synthesis of b,g-dihydroxylated and b,g,d-trihydroxylated a-amino acid derivatives, phytosphingosines, and amino sugars.Recently, our group reported an efficient and highly enantioselective procedure for the formation of optically active a-bromo aldehydes. [7a,b] Encouraged by the size and leaving group ability of the bromine, we evaluated the possibility of an in situ entrapment, thereby, generating a new class of chiral 1,2-dielectrophiles to participate in multiple-bond-forming cascade sequences. To our delight, the chirality stored within this a-carbonyl sp 3 -carbon center, formed by the direct a-bromination of aldehydes 1 by the electrophilic bromination reagent 2 catalyzed by the TMSprotected diaryl-prolinol 3, is fully exploited by a basepromoted face-selective Henry addition of nitroacetates and subsequent stereospecific O-alkylation, furnishing the enantio-and diastereoselective synthesis of 4,5-disubstituted isoxazoline-N-oxides 4 in one pot (Table 1). The generality of this one-pot, three-step sequence was explored and the results are outlined in Table 1. It appears that b-branched aldehydes 1 a-c provided the 4,5-disubstituted isoxazoline-Noxides 4 a-c as s...

The first example of an organocatalytic enantioselective conjugate addition of cyclic beta-ketoesters and glycine imine derivatives to electron-deficient allenes is described. We disclose that the corresponding chiral beta,gamma-unsaturated carbonyl compounds are formed exclusively under phase-transfer conditions using either cinchona-alkaloid-derived or biphenyl-based chiral quaternary ammonium salts as catalysts. The scope of the reaction for beta-ketoesters is outlined for allenes having a ketone or ester motif as electron-withdrawing group as well as different substituents in the 3-position, giving the optically active products in high yields and excellent diastereo- and enantioselectivities (90-96% ee). The conjugate addition also proceeds for a number of cyclic beta-ketoesters having different ring sizes, ring systems, and substituents in high yields and enantioselectivities. Glycine imine derivatives also undergo the asymmetric conjugate addition to electron-deficient allenes in high yields and with enantioselectivities in the range of 60-88% ee, thus providing a rapid entry to optically active alpha-vinyl-substituted alpha-amino acid derivatives. It is shown that the enantioselectivity is strongly dependent on the size of the ester moiety of the nucleophile in combination with the catalytic system used. The high synthetic value of the chiral products arising from these new catalytic processes is demonstrated by two straightforward transformations leading in one case to optically active hexahydrobenzopyranones and in the other to substituted pyroglutamates (gamma-lactames).

Give me five! An organocatalyzed two‐component domino reaction has been developed in which two new CC bonds and five stereocenters are created in a one‐pot fashion (see scheme; DABCO=1,4‐diazabicyclo[2.2.2]octane, TMS=trimethylsilyl). The striking features of this transformation are the high preference for one diastereomer (out of 32 possible isomers) and enantioselectivities of up to 94 %.

The development of a continuous flow sulfoxide imidation protocol for a pharmaceutically relevant target molecule is described. Sulfoxide imidation is a key-step in the preparation of certain ATR kinase inhibitors. Reactions with NaN 3 or TMSN 3 and concentrated sulfuric acid under literature conditions provided slow reactions and poor selectivities. In contrast, reactions employing fuming sulfuric acid afforded the target sulfoximine with a selectivity of ~90% after a reaction time of only 10 to 15 min at 50 °C.The imidation reaction using TMSN 3 as reagent was successfully performed in a flow reactor utilizing CH 2 Cl 2 /H 2 SO 4 biphasic conditions. The mixture was subsequently quenched in-line with H 2 O. Phase separation, neutralization and re-extraction with an organic solvent furnished the product in excellent purity and good yields, albeit with loss of chirality.

A general synthesis of optically active gamma-butyrolactone autoregulators is developed by a two-step sequence to assemble 2,3-trans-disubstituted butyrolactones in high yields and enantioselectivities; the scope of this reaction was elaborated by setting up a library of alkyl-substituted butyrolactones and the synthesis of the autoregulators IM-2 and VB-D.