Disposable cartridge concept for the on-demand synthesis of turbo Grignards, Knochel-Hauser amides, and magnesium alkoxides.

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.

Photolysis of Tertiary Amines in the Presence of CO2: The Paths to Formic Acid, α-Amino Acids, and 1,2-Diamines.

The photolysis of triethylamine (1a) in the presence of carbon dioxide leads to the hydrogenation of CO2, the α-C-C coupling of 1a, and the CO2 insertion into the α-C-H σ-bond of amine 1a. This reaction is proposed to proceed through the radical ion pair [R3N•+·CO2•-] generated by the photoionization of amine 1a and the electron capture by CO2. The presence of lithium tetrafluoroborate in the reaction medium promotes the efficient and stereoselective α-C-C coupling of 1a by enhancing the production of α-dialkylamino radicals and the isomerization of N,N,N',N'-tetraethylbutane-2,3-diamine (4a).

Reactivity of Lithium ß-Ketocarboxylates: The Role of Lithium Salts.

Lithium ß-ketocarboxylates 1(COOLi), prepared by the reaction of lithium enolates 2(Li+) with carbon dioxide, readily undergo decarboxylative disproportionation in THF solution unless in the presence of lithium salts, in which case they are indefinitely stable at room temperature in inert atmosphere. The availability of stable THF solutions of lithium ß-ketocarboxylates 1(COOLi) in the absence of carbon dioxide allowed reactions to take place with nitrogen bases and alkyl halides 3 to give α-alkyl ketones 1(R) after acidic hydrolysis. The sequence thus represents the use of carbon dioxide as a removable directing group for the selective monoalkylation of lithium enolates 2(Li+). The roles of lithium salts in preventing the disproportionation of lithium ß-ketocarboxylates 1(COOLi) and in determining the course of the reaction with bases and alkyl halides 3 are discussed.

A Continuous Flow Sulfuryl Chloride-Based Reaction-Synthesis of a Key Intermediate in a New Route toward Emtricitabine and Lamivudine.

We demonstrate a continuous two-step sequence in which sulfenyl chloride is formed, trapped by vinyl acetate, and chlorinated further via a Pummerer rearrangement. These reactions produce a key intermediate in our new approach to the oxathiolane core used to prepare the antiretroviral medicines emtricitabine and lamivudine. During batch scale-up to tens of grams, we found that the sequence featured a strong exotherm and evolution of hydrogen chloride and sulfur dioxide. Keeping gaseous byproducts in solution and controlling the temperature led to better outcomes. These reactions are ideal candidates for implementation in a continuous mesoscale system for the sake of superior control. In addition, we found that fast reagent additions at controlled temperatures decreased byproduct formation. Herein we discuss the flow implementation and the final reactor design that led to a system with a 141 g/h throughput.

On-demand synthesis of organozinc halides under continuous flow conditions.

Organozinc reagents are versatile building blocks for introducing C(sp2)-C(sp3) and C(sp3)-C(sp3) 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.

Iodide-Photocatalyzed Reduction of Carbon Dioxide to Formic Acid with Thiols and Hydrogen Sulfide.

The photolysis of iodide anions promotes the reaction of carbon dioxide with hydrogen sulfide or thiols to quantitatively yield formic acid and sulfur or disulfides. The reaction proceeds in acetonitrile and aqueous solutions, at atmospheric pressure and room temperature by irradiation using a low-pressure mercury lamp. This transition-metal-free photocatalytic process for CO2 capture coupled with H2 S removal may have been relevant as a prebiotic carbon dioxide fixation.