Angelw, carreira group: palladium catalyzed C-H bond Alkynylation of non activated olefins

Conjugated 1,3-enynes are widely found in natural products, drug molecules and functional materials The synthesis methods of this structure include alkyne dimerization, Sonogashira and Suzuki miyaara coupling reaction Although palladium catalyzed cross coupling reactions have good stereoselectivity, the stereoselectivity of these structures, especially of trisubstituted and tetrasubstituted olefins, is still difficult to control Palladium catalyzed C-H bond functionalization is a kind of efficient method for Alkynylation Most of the work is focused on aromatic substrate, and some breakthroughs have been made in saturated hydrocarbon substrate recently The Alkynylation of 1,3-alkyne is mainly limited to the active substrate, especially the alkene ketone and acrylamide (scheme 2a) However, the selective C-H bond Alkynylation of non activated alkenes has rarely been reported, mainly due to the increased difficulty of other reaction pathways, such as E / Z isomerization of alkenes, allylic functionalization and intramolecular nucleophilic palladization In the aromatics substrates previously reported, Zhao Yingsheng and Sarpong team reported two Alkynylation reactions of simple olefin substrates respectively, but still did not solve the problem of E / Z isomerization The substrate limits the rotation of the single bond via a 6-endo-ring metal intermediate However, the process of C-H bond Alkynylation via 6-exo-palladium intermediate has not been reported, and the structural stability of the intermediate is also a difficulty (scheme 2b) (photo source: angelw Chem Int ed.) recently, Professor Erick M carreira of the Federal Institute of technology in Zurich, Switzerland, reported the palladium catalyzed c-h-linked Alkynylation of non activated olefins, which uses pyridylamide as the guiding group to promote the formation of 6-exo-cyclopalladium, ensuring excellent stereoselectivity and regioselectivity Related results were recently published in angew Chem Int ed (DOI: 10.1002 / anie 202000935) (photo source: angew Chem Int ed.) Firstly, the author used CIS alkene (1a) and tips protected bromoalkyne (3) as model substrate for condition investigation (Table 1 ）The effects of different catalysts, additives and solvents on the yield and regioselectivity were investigated The optimum reaction conditions were determined as follows: palladium acetate as catalyst, potassium carbonate as base, adamantane formic acid as additive, substrate reacted in acetonitrile at 100 ℃ for 6 hours (picture source: angel Chem Int ed.) then, the author investigated the range of substrates (scheme 3) First, the influence of substituents on olefins was investigated The substituents of aryls can be compatible with fluorine, chlorine, bromine, trifluoromethyl and ether (2A-2E) and other functional groups The yield can be increased when the substituents of aromatic (2g-2h) are in the neighborhood, and the yield of diene (2I) and alkyl (2j-2k) is better The substitution of acyclic alkenes for cyclic alkenes can also give the target products 2R is a special product, which may be formed through 5-exo-pd intermediate (image source: angelw Chem Int ed.) then, in order to expand the type of substrate via endo palladium intermediate, the author investigated the cyclohexene ethylamine derivatives The product 2S - 2W can be obtained in a medium to good yield (scheme 4) (photo source: Angew Chem Int Ed.) previously reported C-H Alkynylation of aromatics is mainly limited by the type of alkyne substrate, usually limited to TIPS- protected brominated alkynes The substituents on alkynes can be extended to tert butyl, cyclohexanol derivatives, dichloroaromatics and so on (4 - 10) It is worth noting that the bioactive molecule (11) can also be used in this reaction, which provides a method for later modification of bioactive molecules (scheme 5) (image source: angelw Chem Int ed.) finally, the author carried out a series of substrate derivatization experiments (scheme 6) on product 2 The pyridylamide guiding group of 2 can be reduced by zinc powder to obtain free amino product 12; the tips protecting group of TBAF to remove 2 can quantitatively obtain terminal alkyne product 13; 2 can obtain product 14 through the epoxidation of mcpba; 2 can obtain product 15 through the coupling of Sonogashira after the desilication protecting agent (photo source: angelw Chem Int ed.) Summary: erickm Carreira team reported palladium catalyzed C-H bond Alkynylation of nonactivated olefins, which promoted the formation of 6-exo-cyclopalladium with pyridinamide as the guiding group, ensuring excellent stereoselectivity and regioselectivity, and the reaction has a good substrate range The product molecules are easy to be functionalized in the later stage, and the author has successfully applied the reaction to the later stage modification of bioactive molecules.