Copper catalyzed remote C (SP3) - H Alkynylation of o-acyloxime ester with terminal alkynes

Alkynes are important functional groups in organic synthesis and exist in many natural products and drugs Among many synthesis methods, Sonogashira reaction is one of the most effective conversion of alkynes The coupling of terminal alkynes with aryl / vinyl (pseudo) halides in the presence of palladium / copper or copper was initially developed, which was also extended to the alkylbromide / iodide reaction catalyzed by Pd / Cu, Ni / Cu and Cu / h V (Fig 1a) Another method is to oxidize n, N-dimethylaniline derivatives in situ to corresponding ammonium sulfite, and then add them with copper acetylene nucleophilic to synthesize propargylamine (Fig 1b) However, up to now, there is no report about the direct Alkynylation of SP 3 carbon by terminal alkynes Only WASER group reported the ring opening Alkynylation of naphthenic ketoxime ether and ebx reagent Recently, Zhu Jieping, Professor of the Federal Institute of technology in Lausanne, Switzerland, solved this challenge by developing a long-distance SP 3 carbinylation method of alkanone oxime ester 1 and 2 and terminal alkyne 3 catalyzed by Cu (I) salt and tridentate ligand (tbu3 terpy), and preparing a series of γ - and δ - alkynylnitriles and γ - alkynone derivatives (Fig 1F) Relevant research results were published in NAT Commun (DOI: 10.1038/s41467-020-14292-2) (source: Nat Commun.) the reaction mechanism of this strategy is shown in Fig 1E The reduction of o-acyoxime 1 (ring) or 2 (chain) to Cu (II) intermediate B and ammonia free radical C by acetylene copper a formed in situ from terminal alkyne 3 and Cu (I) species After β - fracture or 1,5-hat, the carbon center free radical D was formed, which was oxidized with B to form Cu (III) species E The intermediate e was eliminated by reduction to obtain Alkynylation product 3, and Cu (I) catalytic species were regenerated at the same time At the beginning of the study, the feasibility of Alkynylation was studied by using cyclobutanone oxime ester and phenylacetylene 3A as model substrate Through the systematic screening of ester, copper source, ligand and base, the author found that the best reaction conditions were: using Cui as catalyst, tbu3 terpy as ligand, potassium carbonate as base, 1a and 3a reacted in acetonitrile at 60 ° C, and the target product 4A could be obtained in 76% yield It is suggested that tbu3-terpy is the key to the success of the reaction After determining the best reaction, the author investigated the application scope of the substrate (Fig 2) A variety of aryl or heteroaryl acetylene with electron donor and electron acceptor groups can obtain γ - alkynylnitriles (4a - 4U) in good yields Aliphatic alkynes are also suitable substrates (4O - 4W) and compatible with a series of functional groups, such as esters, amides, sulfonamides, etc (source: Nat Commun.) then, the author investigated the application scope of various oxime esters (Fig 3) The cyclobutanone oxime ester derived from C-3 can undergo Alkynylation successfully, and the corresponding γ - alkynylated nitrile (4V - 4AF) can be obtained C 2-substituted asymmetric cyclobutanone derivatives were β - broken at more substituents, and alkynylated products (4ag-4ai and 4al-4am) were obtained in good yields 2,3,3-trisubstituted oxime ester 1aj is also suitable for this reaction system (source: Nat Commun.) then, the author investigated the universality of the chain oxime ester substrate By optimizing the reaction conditions, the author found that under the catalysis of Cu (OTF) 2 · C6H6 and tbu3 terpy, 2 A and 3 a can obtain the internal alkyne 5A in 76% yield Various oximes and ethynes with different electrical properties can be successfully acetylated with γ - C (SP 3) - H, and the corresponding γ - alkynone can be obtained in high yield Terminal alkynes (5T), nitriles (5S), thioethers (5ae), Alkylchlorides (5AC) and heteroarenes (5u - 5W) are all well tolerated (source: Nat Commun.) to sum up: the author has developed an efficient strategy for the synthesis of γ - and δ - alkynylnitriles and γ - alkynones from o-acyoximes and terminal alkynes catalyzed by copper The strategy was carried out by a series reaction of domino, including the reduction of imino group, the formation of carbon center radicals by β - cleavage or 1,5-hat translocation, and the coupling of copper catalyzed C - (SP 3) radicals with terminal alkynes.