Angelw: cross coupling reaction of benzothiophene s-oxide with styrene without metal catalysis

1,3-dienes are widely found in natural products, bioactive compounds and precursors of organic materials Therefore, the development of synthesis methods of asymmetric substituted 1,3-dienes has always been the goal of chemists and has made good progress, but the synthesis of asymmetric substituted 1,3-dienes is still facing great challenges The stereoselectivity of ligand coupling reaction of high valence thioalkanes is not easy to be controlled, so the intermediate of high valence thioalkanes is seldom used in synthesis reaction Inspired by the two aryl methanes reported by the Stockman group, the asymmetric ligand coupling reaction between the sulfinic alkane intermediates was induced The David J Procter research team of University of Manchester, UK, envisaged that two olefin ligand coupling agents could generate high valent sulphur intermediates, and then selective C (SP 2) -C (SP 2) coupling reaction was formed The key point of this idea is that organic lithium or organic magnesium can trigger the intermolecular reaction between sulfoxide and olefin coupling agent, and benzothiophene s-oxide can be used as the precursor of Z-type olefin Based on the above background research, the author reported the first strategy of one pot synthesis of (E, z) - 1,3-diene without metal catalysis Benzothiophene s-oxide can react with styrene in an interrupted pummer Then, organic lithium / magnesium will trigger the formation of the intermediate I of high valence thioalkane, and then a ligand coupling reaction will take place to selectively remove the benzothiophene group order to obtain substituted (E, z) - 1,3-diene compounds (scheme 1) Relevant research results were published in angelw Chem Int ed (DOI: 10.1002 / anie 201902903) (picture source: angelw Chem Int ed.) used 2-methylbenzothiophene s-oxide 1a and 2-fluorophenylethylene 2A as template substrates The reaction conditions were screened repeatedly Under the optimal reaction conditions, the (E, z) - 1,3-diene compound 3A can be obtained in 86% yield, and there is no other product (scheme 2) (picture source: angelw Chem Int ed.) under the optimal reaction conditions, the author investigated the substrate range (scheme 3) of styrene and benzothiophene s-oxide All kinds of substituted styrene (especially the functional group substituted styrene which is usually incompatible with organometallic reagents) can be well adapted to the reaction conditions, and the target product can be obtained in good yield It is gratifying that all kinds of 2-substituted benzothiophene s-oxides can also adapt to the reaction conditions well On the contrary, if C 2 - substituted benzothiophene s - oxide is replaced, 2 - stilbene can be obtained (image source: angelw Chem Int ed.) using methyl benzothiophene s-oxide 1a and 2-fluorostyrene 2A as template substrates, the author investigated the range of organometallic reagents (scheme 4) It has been proved that organic magnesium reagent and LiCl additive can effectively promote the reaction, and all kinds of substituted Grignard reagents can adapt to the reaction conditions well, and can get the corresponding products in a good yield Interestingly, alkenyl and aryl substituted organomagnesium reagents can also yield diene in good yield (image source: angel Chem Int ed.) then, under the optimal conditions, the author further investigated the substrate range of Dibenzothiophene s-oxide and styrene (scheme 5) All kinds of substituted styrene and dibenzothiophene s-oxide can be well adapted to the reaction conditions, and the corresponding products can be obtained in medium to good yields In particular, 4-substituted dibenzothiophene s-oxide, a substrate with high steric hindrance, can also obtain the corresponding products in high yield (image source: angelw Chem Int ed.) based on previous literature reports and controlled trials, the author proposed a possible mechanism (scheme 6) Benzothiophene s-oxide 1 is converted into matte oxide III intermediate under the action of TF 2O, and then, III and styrene 2 undergo an interrupted Pummerer reaction to form e-alkenyl matte II (scheme 6a) Organometallic reagents trigger II to convert to scheme 6B The SP 2 hybrid orbital overlaps in the optimal form, and then the ligand coupling reaction takes place to obtain the corresponding diene products For 2-substituted benzothiophene sulfonium salt II, it will attack the ligand reagent from the back of heterocyclic C 2-s bond to generate ia intermediate, and then generate (E, z) - diene compound 3 through ligand coupling reaction If the sulfonium salt II of benzothiophene is replaced by C2, the nucleophilic addition will take place on the back of c7a-s bond to form IB intermediate, and then the ligand coupling reaction will take place to form compound 4 At the same time, steric hindrance has a great influence on the stereoselectivity of 4-substituted dibenzothiophene IV (scheme 6c) (image source: angelw Chem Int ed.) in order to prove the utility value of the reaction, the author also carried out gram level reaction and derivative reaction The gram reaction can be carried out smoothly, and the target product can be obtained with high yield, and the stoichiometric ratio of the substrate has little effect on the yield of the reaction (scheme 7a) Diene 3A can be selectively oxidized to corresponding sulfoxide imines 7, 8 and 9 8 can be further converted into various 1,3-dienes (10a, 10B and 10c) (photo source: Angew Chem Int Ed.) Summary: the David J Procter research group of University of Manchester reported the first strategy without the need of metal catalyzed one pot synthesis of E Z -1,3- dienes Benzothiophene s-oxide can react with styrene in an interrupted Pummerer reaction Next, organic lithium / magnesium will trigger the formation of the intermediate I of high valent thioalkane, and then a ligand coupling reaction will take place to selectively remove the benzothiophene skeleton to obtain a substituted (E, z) - 1,3-diene compound.