Wang Qingmin, Professor of Nankai University: light mediated Minisci C-H alkylation of non activated haloalkanes

Nitrogen containing aromatic rings are widely found in natural products, drug molecules, organic materials and ligands It is of great significance to modify the N-containing aromatic ring by the way of selective functionalization of hydrocarbon bonds Under the condition of acidity and oxidation, the addition reaction of free radicals to nitrogen-containing aromatic rings, i.e Minisci reaction, provides an efficient method for the synthesis of alkyl substituted nitrogen-containing aromatic rings However, there are few reports on the Minisci reaction of non activated haloalkanes as the source of alkyl radicals, which is mainly due to the low reduction potential of non activated haloalkanes, which is difficult to be reduced to produce alkyl radicals Recently, the research group of Professor Wang Qingmin of Nankai University has made a breakthrough in this field Under the condition of photocatalysis, the miniscic-h alkylation of non activated haloalkanes has been realized through the strategy that organosilicon free radical grabs halogen atom to produce alkyl free radical The relevant research results are shown in Chem SCI (DOI: 10.1039 / c8sc04892d) Brief introduction of Professor Wang Qingmin's research group The current research work of the research group includes: separation, identification, total synthesis and structural transformation of natural pesticides; molecular design, synthesis, biological activity and structure-activity relationship of new and efficient green chemical pesticides; total synthesis of natural products and efficient construction of heterocyclic molecular framework; free radical reaction under photocatalysis to build heterocyclic molecules Professor Wang Qingmin's cutting-edge scientific research achievements: it can be seen that the research team of Professor Wang Qingmin of Nankai University has done a series of pioneering work in the field of photocatalysis of heteroatom ortho radical reaction (org Lett 2016, 18, 4686; chem EUR J 2017, 23, 10871; ORG Lett 2018, 20, 5661 ; chem EUR J 2018, 24, 9269; chem EUR J 2018, 24, 11283; adv synth Catalyst 2018, 360, 287), relevant invitation review published in Chem EUR J (DOI: 10.1002/chem.201804873), and recently realized the Minisci reaction of heteroatom neighborhood under photocatalysis (ORG Lett 2018, 20, 5661) Under the condition of photocatalysis, peroxide, alcohol, carboxylic acid and boric acid can be used as the source of alkyl radicals to realize Minisci reaction However, there are few reports about Minisci reaction by using non activated haloalkanes as the source of alkyl radicals, which is mainly due to the low reduction potential of non activated haloalkanes, which is difficult to be reduced by photocatalysts to produce alkyl radicals In 2016, barriault group used strong reducing photocatalyst [Au 2 (DPPM) 2] Cl 2 to reduce brominated alkanes to generate alkyl radicals, and for the first time realized minsci reaction of brominated alkanes as the source of alkyl However, the use of 5 mol% expensive Au photocatalyst and the use of high-energy UV lamp as the light source limited the functional group compatibility, substrate application and the application in drugs and natural products Because of the difference between the BDE value of the silicon bromine bond (96 kcal / mol) and the BDE value of the carbon bromine bond (69 kcal / mol), it is easy to produce the alkyl radical by the process of the silicon radical grabbing the halogen atom of the haloalkane Based on this property, the Minisci C-H alkylation of non activated haloalkanes catalyzed by visible light has been realized (Fig 1) This method has the advantages of mild reaction conditions, good functional group compatibility, wide range of substrate application, and can be used for the late functional groups of various drugs and natural products Fig 1 Photocatalytic Minisci reaction (source: chem SCI.) the author optimized the reaction conditions with 4-methylquinoline and bromocyclohexane as raw materials The results showed that with IR [DF (CF 3) PPy] 2 (dtbbpy) pf 6 as photocatalyst, tris (trimethylsilyl) silane (ttms) as organosilicon reagent, trifluoroacetic acid (TFA) as acid, oxygen as oxidant, the substrate reacted for 24 hours under light, and the target product with separation yield of 82% was obtained (Fig 2) Figure 2 Optimization of reaction conditions (source: chem SCI.) after obtaining the best reaction conditions, the author first investigated the application scope of brominated alkanes The primary, secondary and tertiary brominated alkanes are all suitable for this reaction Three bond, double bond, ester, acetal, ether, amine and other functional groups are compatible Then, the scope of application of iodoalkanes was also investigated The first, second and third order iodoalkanes are all suitable for this reaction (Fig 3) Fig 3 Application range of haloalkanes (source: chem SCI.) then, the author investigated the range of nitrogen heterocyclic substrates (Fig 4) Quinoline, isoquinoline, pyridine, phthalazine, quinazoline, imidazo [1,2-b] pyridazine, benzothiazole and common phenanthroline ligands are all suitable for this reaction Figure 4 Scope of nitrogen heterocyclic substrate (source: chem SCI.) Minisci reaction developed before has general compatibility with natural products and drugs due to the use of oxidants with strong oxidation In order to investigate the practicability of the reaction, the author carried out late functional modification on a variety of natural products and drugs (Fig 5) Figure 5 Functional study of natural products and drugs in the later stage (source: chem SCI.) in order to understand the mechanism of this reaction, the author conducted in-depth research (Figure 6) When tempo and 1,1-stilbene were added to the reaction system, the reaction was completely inhibited When benzyl acrylate was added to the reaction system, a silicon radical adduct with 5% yield was obtained, and cyclohexyl radical adduct was detected by high resolution mass spectrometry When 6-bromo-1-hexene was used as the substrate, the ring closing products and ring opening products were obtained in the ratio of 14:1 When bromomethylcyclopropane was used as substrate, only ring opening products were obtained When bromomethyl cyclobutane was used as the reaction substrate, the ring closing products and ring opening products were obtained in the ratio of 14:1 The light switch experiment shows that the reaction can only be carried out under light Figure 6 Mechanism study (source: chem SCI.) finally, the author proposed the possible reaction mechanism (Figure 7) When the photocatalyst is excited under light condition, the alkyl bromine in the system will produce a small amount of Br - - the trivalent photocatalyst in the excited state will oxidize Br - to br.. And get the bivalent photocatalyst at the same time The bromine radical grabs the hydrogen atom of silane to produce the silicon radical Because of the difference between the BDE value of the silicon bromine bond (96 kcal / mol) and the BDE value of the carbon bromine bond (69 kcal / mol), the silicon radical is easy to grab the bromine atom of the brominated alkane and produce the nucleophilic alkyl radical a The intermediate B is obtained by the addition of a to the nitrogenous aromatic ring Oxygen oxidizes the photocatalyst in the divalent state to complete the photocatalysis cycle At the same time, O 2 − ·, O 2 − · grabs the hydrogen atom of intermediate B to obtain the final product Figure 7 Possible mechanism (source: chem SCI.) this achievement was recently published in Chem SCI (DOI: 10.1039 / c8sc04892d) The first author of this paper is Dong Jianyang, a doctoral student of Nankai University, and the corresponding author is Professor Wang Qingmin of Nankai University The above research work was supported by National Natural Science Foundation of China (21732002, 21672117) and Tianjin Natural Science Foundation (16jczdjc32400) Review of previous reports: Wang Qingmin, Professor of Nankai University Research Group: silver copper synergistic catalytic intramolecular cyclization / de sulfonamide / dehydrogenation reaction for the efficient synthesis of substituted carbazole Today, science and technology elements are increasingly valued in economic life, China has ushered in the "node of science and technology explosion" Behind the progress of science and technology is the work of countless scientists In the field of chemistry, in the context of the pursuit of innovation driven, international cooperation has been strengthened, the influence of Returned Scholars in the field of R & D has become increasingly prominent, and many excellent research groups have emerged in China For this reason, CBG information adopts the 1 + X reporting mechanism CBG information, chembeangoapp, chembeango official microblog, CBG wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the domestic representative research group, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.