Hydrogen-Free Alkene Reduction in Continuous Flow

The first continuous hydrogenation that requires neither H₂ nor metal catalysis generates diimide by a novel reagent combination. The simple flow reactor employed minimizes residence time by enabling safe operation at elevated temperature

Diisobutylaluminum Hydride Reductions Revitalized: A Fast, Robust, and Selective Continuous Flow System for Aldehyde Synthesis

A continuous flow system for the multiparameter (flow rate, temperature, residence time, stoichiometry) optimization of the DIBALH reduction of esters to aldehydes is described. Incorporating an in-line quench (MeOH), these transformations are generally complete in fewer than 60 s. Mixing of the DIBALH and ester solutions was observed to be an exceptionally critical parameter for optimum results. This system thus provides general guidelines based on the structure of the ester for selective reduction of an ester without overreduction

Simplifying Nickel(0) Catalysis: An Air-Stable Nickel Precatalyst for the Internally Selective Benzylation of Terminal Alkenes

The synthesis and characterization of the air-stable nickel­(II) complex <i>trans</i>-(PCy₂Ph)₂Ni­(<i>o</i>-tolyl)Cl is described in conjunction with an investigation of its use for the Mizoroki–Heck-type, room temperature, internally selective coupling of substituted benzyl chlorides with terminal alkenes. This reaction, which employs a terminal alkene as an alkenylmetal equivalent, provides rapid, convergent access to substituted allylbenzene derivatives in high yield and with regioselectivity greater than 95:5 in nearly all cases. The reaction is operationally simple, can be carried out on the benchtop with no purification or degassing of solvents or reagents, and requires no exclusion of air or water during setup. Synthesis of the precatalyst is accomplished through a straightforward procedure that employs inexpensive, commercially available reagents, requires no purification steps, and proceeds in high yield

Simplifying Nickel(0) Catalysis: An Air-Stable Nickel Precatalyst for the Internally Selective Benzylation of Terminal Alkenes

The synthesis and characterization of the air-stable nickel­(II) complex <i>trans</i>-(PCy₂Ph)₂Ni­(<i>o</i>-tolyl)Cl is described in conjunction with an investigation of its use for the Mizoroki–Heck-type, room temperature, internally selective coupling of substituted benzyl chlorides with terminal alkenes. This reaction, which employs a terminal alkene as an alkenylmetal equivalent, provides rapid, convergent access to substituted allylbenzene derivatives in high yield and with regioselectivity greater than 95:5 in nearly all cases. The reaction is operationally simple, can be carried out on the benchtop with no purification or degassing of solvents or reagents, and requires no exclusion of air or water during setup. Synthesis of the precatalyst is accomplished through a straightforward procedure that employs inexpensive, commercially available reagents, requires no purification steps, and proceeds in high yield

Continuous Flow Oxidation of Alcohols and Aldehydes Utilizing Bleach and Catalytic Tetrabutylammonium Bromide

We report a method for the oxidation of a range of alcohols and aldehydes utilizing a simple flow system of alcohols in EtOAc with a stream of 12.5% NaOCl and catalytic Bu₄NBr. Secondary alcohols are oxidized to ketones, aldehydes are oxidized directly to methyl esters in the presence of methanol, and benzylic alcohols are oxidized to either benzaldehydes or methyl esters, depending on the conditions used. The reaction conditions are mild and generally provide complete conversion in 5–30 min

Hydroxyl-Substituted Ladder Polyethers via Selective Tandem Epoxidation/Cyclization Sequence

A new and highly selective method for the synthesis of hydroxyl-substituted tetrahydropyrans is described. This method utilizes titanium­(IV) isopropoxide and diethyl tartrate to perform a diastereoselective epoxidation followed by in situ epoxide activation and highly selective <i>endo</i>-cyclization to form the desired tetrahydropyran ring. The <i>HIJ</i> ring fragment of the marine ladder polyether yessotoxin was synthesized using this two-stage tactic that proceeds with high efficiency and excellent regioselectivity

Direct β‑Selective Hydrocarboxylation of Styrenes with CO₂ Enabled by Continuous Flow Photoredox Catalysis

The direct β-selective hydrocarboxylation of styrenes under atmospheric pressure of CO₂ has been developed using photoredox catalysis in continuous flow. The scope of this methodology was demonstrated with a range of functionalized terminal styrenes, as well as α-substituted and β-substituted styrenes

Continuous Flow Total Synthesis of Rufinamide

Small molecules bearing 1,2,3-triazole functionalities are important intermediates and pharmaceuticals. Common methods to access the triazole moiety generally require the generation and isolation of organic azide intermediates. Continuous flow synthesis provides the opportunity to synthesize and consume the energetic organoazides, without accumulation thereof. In this report, we described a continuous synthesis of the antiseizure medication rufinamide. This route is convergent and features copper tubing reactor-catalyzed cycloaddition reaction. Each of the three chemical steps enjoys significant benefits and has several advantages by being conducted in flow. The total average residence time of the synthesis is approximately 11 min, and rufinamide is obtained in 92% overall yield

Selective Lewis Acid Catalyzed Assembly of Phosphonomethyl Ethers: Three-Step Synthesis of Tenofovir

Described herein is a novel Lewis acid catalyzed rearrangement–coupling of oxygen heterocycles and bis­(diethyl­amino)­chlorophos­phine that provides direct formation of the phosphono­methyl ether functionality found in several important antiretroviral agents. A wide range of dioxolanes and 1,3-dioxanes may be employed, furnishing the desired products in good yield. The utility of this method is demonstrated in a novel synthesis of tenofovir, an antiretroviral drug used in the treatment of HIV/AIDS and hepatitis B

Bench-Stable Nickel Precatalysts with Heck-type Activation

Herein, we report the synthesis and characterization of a new class of air- and moisture-stable phosphine-containing nickel­(II) precatalysts, which activate through a Heck-type mechanism. The activities of the precatalysts are demonstrated with a carbonyl–ene coupling reaction