JACS: Montgomery group constructs tetrasubstituted olefins by nickel catalyzed electrophilic cross coupling

Reduction coupling (electrophilic cross coupling) using two different electrophilic components is a common strategy to construct C-C bond, the most common one is to construct csp2-csp3 bond (scheme1a) The formation of Ni (II) heterocyclic intermediate by oxidation and cyclization of two kinds of Ni (0) complexes with different π components is the basis of various catalytic processes The metal heterocyclic intermediates obtained usually undergo further functionalization through σ bond decomposition, metal transfer or migration insertion Recently, the John Montgomery group of the University of Michigan reported on j.am Chem SOC The synthesis of tetrasubstituted alkenes by series metal cyclization / electrophilic cross coupling (DOI: 10.1021 / JACS 8b04637) In this reaction, the metal heterocyclic intermediate is produced by the oxidation and cyclization of alkynes and aldehydes, and then the intermediate is electrophilically cross coupled with alkyl halides to obtain the addition product A new C-C bond (scheme 1b) is formed in each of the two processes (photo source: J am Chem SOC.) the synthesis of polysubstituted allylic alcohol via aldehyde alkyne coupling is common in the synthesis of natural products In this process, alkyl metal reagents such as dialkyl zinc and trialkyl aluminum are often used as reducing agents Alkyl metal reagent can be used as reducing agent, or an alkyl can be directly introduced at the end of alkyne However, it is difficult to introduce functionalized alkyl segments into the method, which limits its application scope and requires highly active organometallic reagents In order to solve this limitation, the author tried to cyclize alkynaldehyde with butylhalogen as electrophilic substrate and manganese as terminal reductant under the catalysis of nickel (0) in order to prepare tetrasubstituted alkene products However, the expected products were not obtained It is suggested that scheme 1b with ring framework and Ni-O bond is quite different from other Ni (II) halides in the process of free radical addition Therefore, the author tried to add tescl in order to convert metal ring 2 into alkenyl nickel halide (II), which is more similar to the oxidation addition product of vinyl halide precursor and nickel (0) Firstly, the author optimized the reaction conditions (Table 1) When commercial NIBR 2 · DME catalyst and 2,2 '- bipyridine (bipy) ligand were used as catalyst system, 28% yield was obtained The results show that manganese is the best reductant, DMF is the best solvent, and 2,2 '- bipyridine is the best ligand The one component catalyst (2,2' - bipyridine) nickel (II) is NIBR 2 · DME and 2, An effective substitute for 2 '- bipyridine, the selectivity of product e isomer can be improved when the reaction concentration is increased to 1.0m (photo source: J am Chem SOC.) after determining the best reaction conditions, the author screened the application scope of alkyl bromide substrate (scheme 2) The experimental results show that all kinds of alkyl bromides containing alcohols and amides with protective groups are well tolerated and tetrasubstituted alkenes with high functionalization can be obtained; the yield of product 8 is good when tmscl is used instead of tescl, but the E / Z ratio is slightly reduced, and most other reactions can obtain good e / Z selectivity The target product can be obtained from the alkyl halides containing β - branched chain, but the selectivity of E / Z is significantly reduced The reaction results of alkyne substituent show that the cyclization reaction has chemical selectivity (photo source: J am Chem SOC.) after determining the substrate range of alkyl halide part, the author turned his attention to the substrate expansion of alkynaldehyde (scheme 3) The results showed that both electron rich and electron deficient alkynaldehyde were well tolerated in the reaction Among them, the substrate containing p-ome aromatics is more effective at lower catalyst loading (1 mol%) In other nickel catalytic conversion, substrates containing arylborates and arylchlorides can be successfully coupled without other competitive reactions The electrophilic functional groups such as ketone, ester and nitrile have good tolerance Thiophene, protected indole and uracil can be tolerated in the reaction The reaction is not limited to aryl substituted alkynaldehydes, and alkylated or propargyl ether containing substrates can also be successfully reacted Alkynaldehyde and alkynaldehyde with different skeletons can also be cyclized successfully The product of exoalkenyl tetrahydrofuran is obtained from oxyalkynaldehyde, and the compound derived from malonic acid is exocyclopentene The nitrogen-containing substrate can be used to synthesize pyrrolidine, and the alkyl halides with acidic N-H can be coupled The results show that the z-isomer is the main product of the reaction (photo source: J am Chem SOC.) finally, the author proposed the possible reaction mechanism of alkylation and cyclization (scheme 4) Under the catalysis of nickel (0), alkynaldehyde is oxidized and cyclized to form nickel ring 35, and then the nickel oxygen bond is cracked by tescl to produce vinyl nickel (II) intermediate 36 The next reaction may go through two ways: one is to add 36 to form nickel (III) intermediate 38 (path a); the other is to generate nickel (I) intermediate 37 through manganese (0) mediated reduction of 36, and then generate nickel (III) intermediate 38 (path B) through oxidative addition of alkyl halides Since the oxidation addition of Ni (I) by alkyl halides is carried out through a single electron transfer pathway, pathway a and B ultimately involve the addition of Ni (II) radicals The product and Ni (I) intermediate 39 were obtained by rapid reduction and elimination of intermediate 38, which was further reduced by Mn (0) to complete the catalytic cycle Subsequent experiments with stoichiometric nickel (0) catalyst showed that the product would not form without reducing agent, which supported path B (photo source: J am Chem SOC.) conclusion: in recent years, nickel catalyzed cross electrophilic coupling has become an efficient method for the construction of C-C bond Montgomery group has developed a new method for the synthesis of tetrasubstituted olefins by combining the method with π - π coupling This method can not only synthesize highly substituted allyl alcohol derivatives, but also avoid the need for stoichiometric organometallic nucleophiles Compared with the previously developed method, the new method extends the application scope of substrate and improves the tolerance of functional groups Professor John Montgomery