Nature chem.: a new way of free radical formation photocatalysis + SN2 nucleophilic substitution

Free radical chemistry is widely used in materials science, drug research and development, agricultural chemistry and other disciplines In general, diazo compounds or peroxides can induce C-H or C-X bonds to form free radicals under high temperature or photoinitiation conditions (Fig 1a), but this method needs to break through the bond dissociation energy (BDE) of chemical bonds Another method is to use oxidant / reductant or electrochemistry to promote the single electron transfer of substrate to obtain free radicals (Fig 1b) While these classic strategies do work, they require relatively stringent reaction conditions, including hazardous and toxic reagents, high temperature or ultraviolet radiation This limits the selectivity of free radicals and the tolerance of functional groups to some extent Free radical precursors and reactants with thiofunctional groups can initiate free radical reactions under milder conditions, but such reactions still depend on specially designed stoichiometric reagents (source: nature chem.) recently, professor Paolo melchiorre of the Catalan Institute of chemistry in Spain reported a new strategy of photocatalytic free radical generation, which uses different physical properties of substrates to produce carbon free radicals Using the nucleophilic dithiocarbamate anion as catalyst, the alkylelectrophilic reagent was activated by the S N 2 pathway The intermediate II was split to provide free radicals under visible light (Fig 1c) The mild reaction conditions and high functional group tolerance enable the method to be applied to the preparation of drug molecules, the post modification of biological related compounds and enantioselective free radical catalysis Relevant research results were published on nature chem (DOI: 10.1038/s41557-018-0173-x) Firstly, the author designed a catalytic cycle (Fig 2a): dithiocarbonyl anion 1 attacks alkylelectrophilic reagent 2 to get intermediate II, whose C-S bond can be split to get free radicals III and IV; intermediate III adds electron deficient olefin 3 to get intermediate V, V from 1,4-cyclohexadiene (1, 4-chd) to extract hydrogen atoms to form product 4 and cyclohexadiene radical VI (source: nature chem.) then, the reaction conditions were screened with Chlorobenzyl 2a and dimethyl fumarate 3A as model substrates (Fig 2b) The cheaper and more stable γ - Terpinene was chosen as the substitute of 1,4-chd, and acetonitrile (CH3CN) was chosen as the reaction solvent When using potassium ethyl xanthate 1A as a nucleophilic catalyst (10 mol%) and the model reaction was carried out under 400 nm irradiation, the yield of 4A was 19% This result proves the feasibility of the photocatalysis strategy The yield of the target product can be further increased to 90% by changing the light source to 465 nm and using the thiocarbamate 1C containing indole as catalyst The reaction can tolerate oxygen without degassing the solvent, and water can be used as a cosolvent The solvent can be selected according to the solubility of different substrates When the reaction was carried out in various media (such as ethyl acetate, dichloroethane, toluene and tetrahydrofuran), no significant differences were observed Furthermore, the synthesis potential of this strategy was evaluated (Fig 3) A variety of benzyl electrophilic reagents with electron rich and electron deficient aryl substituents are all effective substrates (2G - J) The strategy can introduce oxazolidinone, protected secondary amines or primary amines with easily obtained precursor 2m - O as substrate The reaction showed high tolerance to nitrogen heterocycles, including thiazole (2P), isoxazole (2q), pyrazole (2R) and triazole (2S) Alkenes with various electron absorbing groups (such as esters, nitriles, sulfones and imides) can obtain the adduct 5A - E in good yields Good functional group tolerance creates opportunities for product diversification A series of different substituted indolones 7 were obtained by radical addition / cyclization of aromatic acrylamide 6 promoted by catalyst 1C Similarly, Alkylchlorides can be functionalized directly by free radicals with electron rich (hetero) aromatic compounds to obtain substituted (hetero) aromatic compounds 8 Various reactive functional groups such as aldehydes, SEC amides and free alcohols can be tolerated in the reaction (source: nature chem.) in order to demonstrate the synthesis effect of the strategy, pyrrole derivatives were prepared by flow synthesis and gram reaction for 8h, respectively The compounds are intermediates for the synthesis of nonsteroidal anti-inflammatory drug tometine This method can introduce pyrrole and indole ketone into the methanesulfonate derivative 9, which is a practical late modification strategy Base analogues 13 and 16 can be obtained by the reaction of uracil 12 and adenine 14, respectively (source: nature chem.) finally, the stereoselective intermolecular α - alkylation of Alkylchlorides and aldehydes was studied Under the action of catalyst 1C, various easily obtained Alkylchlorides can be directly enantioselective alkylated with aldehydes 17 to obtain corresponding α - alkylation products 20 - 22 (source: nature chem.) conclusion: professor Paolo melchiorre, Institute of chemistry, Catalonia, Spain, reported a photochemical free radical generation strategy, which uses the SN2 process to generate free radical intermediates from various electrophilic substrates, which is different from the traditional free radical generation strategy These reactions are highly functional group tolerant and can be used in the late modification and enantioselective catalysis of complex molecules.