Science: Professor Stephenson of the University of Michigan reports on the photocatalysis of the reactions of arylsulfonylacetamide with olefins by smiles truth

Arylethylamine structural units are widely found in dopamine, serotonin and many opioid receptor drugs used to regulate pain sensation and treat neurobehavioral disorders Therefore, the development of arylethylamines has become a hot research The conventional synthesis of arylethylamine requires multi-step homologation and reductive amination The alkenes derived from anethole and other bioactive compounds can be directly constructed by amino arylation Therefore, it is of great significance to develop two new C-C and C-N bond synthesis methods for the development of novel arylethylamines Transition metals such as palladium, copper, nickel and gold can activate alkenes and produce stereoselective cycloamination and arylation to form arylethylamine framework These transition metals, while controlling stereoselectivity and activating olefins, can inhibit the process of demetallization or β - hydrogen elimination that hinders the formation of C-C bonds Because amides and amines are more nucleophilic than alkenes, these reactions usually require high temperature Due to the limitation of the reaction between the guiding group and the intramolecular reaction, only pyrrolidine and piperidine can be produced In the bifunctionalization of olefins, photocatalysis and free radical chemistry have similar characteristics Among them, meerwein aminoaromatization is the simplest strategy, which follows the addition rule of Markovian, but has no stereoselectivity Using photocatalysis, Knowles and niewicz developed a regioselective hydrogen (carbon) amination of olefins However, the challenge of n-radical-mediated olefin addition is that addition and allylic hydrogen capture are competitive, so excessive olefins or intramolecular cyclization are needed Recently, Professor Corey R J Stephenson, University of Michigan, developed a photocatalysis free radical mediated smiles truth reaction They prepared a series of arylethylamines (Fig 1D) by using arylsulfonylacetamide as a bifunctional reagent for amino arylation of alkenes The smiles truth reaction has complete anti martensitic regioselectivity, excellent non enantioselectivity and extensive functional group tolerance Relevant research results were published on Science (Science, 2018, 361, 1369-1373) (source: Science) the author said the inspiration for the study came from the smiles truth reaction The traditional smiles rearrangement is a nucleophilic aryl substitution reaction, which is suitable for the ortho substitution of aromatic sulfide, sulfoxide, sulfone and amide Although Pennell and Motherwell have further developed the aryl radical mediated rearrangement of smiles and achieved some results, there are still many limitations in the atomic economy, reaction conditions and substrate design (Fig 1c) Therefore, the author hopes to develop a kind of photocatalysis of smiles truth reaction and realize the bifunctionalization of olefins by using arylsulfonylacetamide The catalytic cycle envisaged by the authors is shown in Fig 2A: olefins are first oxidized by the excited state of * IR III and react with arylsulfonylacetamide (II) to obtain β - amino alkyl radical intermediate (III); III generates intermediate IV through regioselective cyclization; IV can be desulfonylated through two reasonable ways, and finally amino arylation product VII can be obtained (source: Science) firstly, the reaction conditions were optimized with anethole (1) and naphthalene sulfonyl acetamide (2) as substrates (Fig 2b) With [IR (CF 3ppy) 2) (5,5 '- CF 3-bpy)] pf 6 (3) as photocatalyst, potassium benzoate as base and DMF as solvent, the substrate can react at room temperature under blue LED irradiation for 16 hours, and the yield of target product 4 can be 41%, and the reaction does not need to use excessive arylsulfonylacetamide and base Through the screening of amino groups, the author found that acetyl group is the best one (Fig 3a, 4 - 7) When 1,2-disubstituted p-methoxyarylalkenes are used, the reaction yield increases The aryl substituents in the arylsulfonylacetamide substrate can all undergo free radical migration, including 1-naphthyl (4-10, 21, 22), 2-naphthyl (11), 3-thiophene (12, 13), 2-thiophene (14, 15, 18) , 2-furanyl (16), 8-quinoline (17), 2-benzothiazole (19) and β - styrene (20), and the D.R values of the reactions were greater than 20:1 (Fig 3a) X-ray crystallographic analysis of compound 15 showed that there was a cis configuration between 5-bromothiophene and acetamide Ring (E) - olefins can be used to prepare corresponding ring aromatic ethylamines (23-26), while ring (z) - olefins can be used to prepare CIS diastereomers 27 (Fig 3b) (source: Science) further, the mechanism of the reaction was studied The authors hypothesized that the acyclic (z) - and (E) - alkenes would be transformed into trans aminoarylated diastereomers due to the rotation of the bond As shown in fig.4a, (z) - and (E) - anethole can react with 2 in similar yield and selectivity to obtain 9, and no enantiomer 9 'is observed in the reaction The reaction of (z) - anethole was monitored by 1H NMR It was found that (E) - anethole was formed in the reaction process On the basis of this observation, the isomerization rate and photostability of each anisole isomer under light condition were examined The results show that the ratio of Z: e is 1.4:1 in light stable state At first, (z) - anethole isomerized much faster than (E) - anethole At the beginning of the reaction, the consumption rate of olefins was slower than that of (z) - anisole isomerization These data indicate that the non enantioselectivity may be due to two factors: 1) the formation of (E) - anethole free radical cation is advantageous in kinetics; 2) in thermodynamics, the methoxyphenyl (PMP) and methyl substituent of the intermediate III of free radical preferentially adopt trans cross conformation Another possibility is that the reaction rate of (E) - anethole radical cation with 2 is faster than that of (z) - anethole (source: Science) conclusion: the team of Professor Corey R J Stephenson, University of Michigan, U.S.A prepared a series of arylethylamines through the amino arylation of arylsulfonylacetamide and olefins mediated by photocatalysis free radicals The reaction has complete anti martensitic regioselectivity, excellent non enantioselectivity and extensive functional group tolerance.