Organozinc reagents are versatile building blocks for introducing C(sp)-C(sp) and C(sp)-C(sp) bonds into organic structures. However, despite their ample synthetic versatility and broad functional group tolerance, the use of organozinc reagents in the laboratory is limited because of their instability, exothermicity and water sensitivity, as well as their labor-intensive preparation. Herein, we describe an on-demand synthesis of these useful reagents under continuous flow conditions, overcoming these primary limitations and supporting widespread adoption of these reagents in synthetic organic chemistry. To exemplify this procedure, a solution of ethyl zincbromoacetate is prepared by flowing ethyl bromoacetate through a column containing metallic zinc. The temperature of the column is controlled by a heating jacket and a thermocouple in close contact with it. Advice on how to perform the procedure using alternative equipment is also given to allow a wider access to the methodology. Here we describe the preparation of 50 ml of solution, which takes 1 h 40 min, although up to 250-300 ml can be prepared with the same column setup at a rate of 30 ml per h. The procedure provides the reagent as a clean solution with reproducible concentration. Organozinc solutions generated in flow can be coupled to a second flow reactor to perform a Reformatsky reaction or can be collected over a flask containing the required reagents for a batch Negishi reaction.
The application of Reformatsky and Blaise reactions for the preparation of a diverse set of valuable intermediates and heterocycles in a one-pot protocol is described.
Magnesium organometallic reagents occupy a central position in organic synthesis. The freshness of these compounds is the key for achieving a high conversion and reproducible results. Common methods for the synthesis of Grignard reagents from metallic magnesium present safety issues and exhibit a batch-to-batch variability. Tubular reactors of solid reagents combined with solution-phase reagents enable the continuous-flow preparation of organomagnesium reagents. The use of stratified packed-bed columns of magnesium metal and lithium chloride for the synthesis of highly concentrated turbo Grignards is reported. A low-cost pod-style synthesizer prototype, which incorporates single-use prepacked perfluorinated cartridges and bags of reagents for the automated on-demand lab-scale synthesis of carbon, nitrogen, and oxygen turbo magnesium bases is presented. This concept will provide access to fresh organomagnesium reagents on a discovery scale and will do so independent from the operator’s experience in flow and/or organometallic chemistry.
A sustainable synthesis of isothiazoles has been developed using an α-amino-oxy acid auxiliary and applying photoredox catalysis. This simple strategy features mild conditions, broad scope and wide functional group tolerance...
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