An enantio- and diastereoselective approach to indoloquinolizidines in continuous flow.

Merging polymer-supported asymmetric organocatalysis with continuous flow in a packed bed reactor has been used as the key, enantiodetermining step in a short synthesis of indoloquinolizidines. Using this approach, a highly enantioselective, solvent-free and rapid conjugate addition of dimethyl malonate to a diverse family of cinnamaldehydes in continuous flow, allowing the preparation of relevant oxodiesters in multigram amounts has been developed. The obtained Michael adducts have been used to complete an expedient diastereoselective synthesis of indoloquinolizidine via cascade Pictet-Splengler cyclisation-lactamisation in continuous flow. The conversion of enantiopure Michael adducts into δ-lactones via telescoped reduction/cyclisation in continuous flow has also been explored.

Enantioselective Flow Synthesis of Rolipram Enabled by a Telescoped Asymmetric Conjugate Addition-Oxidative Aldehyde Esterification Sequence Using in Situ-Generated Persulfuric Acid as Oxidant.

A novel approach is reported for the enantioselective flow synthesis of rolipram comprising a telescoped asymmetric conjugate addition-oxidative aldehyde esterification sequence followed by trichlorosilane-mediated nitro group reduction and concomitant lactamization. The telescoped process takes advantage of a polystyrene-supported chiral organocatalyst along with in situ-generated persulfuric acid as a robust and scalable oxidant for direct aldehyde esterification. This approach demonstrates significantly improved productivity compared with earlier methodologies while ensuring environmentally benign metal-free conditions.

Shedding light on the nature of the catalytically active species in photocatalytic reactions using Bi2O3 semiconductor.

The importance of discovering the true catalytically active species involved in photocatalytic systems allows for a better and more general understanding of photocatalytic processes, which eventually may help to improve their efficiency. Bi2O3 has been used as a heterogeneous photocatalyst and is able to catalyze several synthetically important visible-light-driven organic transformations. However, insight into the operative catalyst involved in the photocatalytic process is hitherto missing. Herein, we show through a combination of theoretical and experimental studies that the perceived heterogeneous photocatalysis with Bi2O3 in the presence of alkyl bromides involves a homogeneous BinBrm species, which is the true photocatalyst operative in the reaction. Hence, Bi2O3 can be regarded as a precatalyst which is slowly converted in an active homogeneous photocatalyst. This work can also be of importance to mechanistic studies involving other semiconductor-based photocatalytic processes.

Telescoped Continuous Flow Synthesis of Optically Active γ-Nitrobutyric Acids as Key Intermediates of Baclofen, Phenibut, and Fluorophenibut.

The two-step flow asymmetric synthesis of chiral γ-nitrobutyric acids as key intermediates of the GABA analogues baclofen, phenibut, and fluorophenibut is reported on a multigram scale. The telescoped process comprises an enantioselective Michael-type addition facilitated by a polystyrene-supported heterogeneous organocatalyst under neat conditions followed by in situ-generated performic acid-mediated aldehyde oxidation. Simple access to valuable optically active substances is provided with key advances in terms of productivity and sustainability compared to those of previous batch approaches.

Organocatalytic Enantioselective Continuous-Flow Cyclopropanation.

A set of six solid-supported diarylprolinol catalysts (varying on the anchoring strategy and the type of polymeric support) has been prepared and applied to the enantioselective cyclopropanation reaction. The selected candidate allows implementation of a long flow experiment (48 h) and generates a library of 12 cyclopropanes by sequential flow experiments. The mildness and utility of the method have enabled a telescoped process in which the outstream is directly used in a Wittig flow reaction.

Key Non-Metal Ingredients for Cu-catalyzed "Click" Reactions in Glycerol: Nanoparticles as Efficient Forwarders.

The effect of long-alkyl-chain amines in CuI-assisted azide-alkyne cycloadditions of terminal alkynes with organic azides in glycerol and other environmentally benign solvents (water, ethanol) has been examined. The presence of these additives favors the in situ formation of CuI -based nanoparticles and results in an increase of the catalytic reactivity. In glycerol, liquid-phase transmission electron microscopy (TEM) analyses, enabled by the negligible vapor pressure of this solvent, proved that CuI nanoparticles are responsible for the observed catalytic activity. The wide variety of alkynes and azides of which this effect has been investigated (14 combinations) confirms the role played by these additives in Cu-catalyzed Huisgen cycloadditions.

Continuous-flow enantioselective α-aminoxylation of aldehydes catalyzed by a polystyrene-immobilized hydroxyproline.

The application of polystyrene-immobilized proline-based catalysts in packed-bed reactors for the continuous-flow, direct, enantioselective α-aminoxylation of aldehydes is described. The system allows the easy preparation of a series of ß-aminoxy alcohols (after a reductive workup) with excellent optical purity and with an effective catalyst loading of ca. 2.5% (four-fold reduction compared to the batch process) working at residence times of ca. 5 min.