JACS: chromium catalyzed selective C (SP2) - C (SP3) coupling reaction

Transition metal catalyzed C (SP 2) - C (SP 3) coupling reaction can be used to construct complex organic molecules, which is an important organic reaction Although PD and Ni catalysts are widely used, other "first row transition metals" (such as Fe, Co, etc.) are also widely used These metals are cheap and low toxic, and have certain advantages Recently, the low valent CR salt has attracted great attention due to its rich content and low toxicity (lower than Fe salt) The coupling reaction of aryl and heteroaryl halides with alkyl Grignard reagent has been realized by using low valent CR salt Zeng group also realized the C-O and C-N activation assisted by guiding group by using low-cost CR salt In 1977, Hiyama group realized the regioselective allylation of aldehydes with equivalent CR reagent In addition, the stereoselective 1,2-difunctionality of 1,3-dibutylene can also be realized by CR / Co catalyst Zhang and glorius team also reported the asymmetric allylation of aldehydes catalyzed by light / CR Despite these progress, Cr catalyzed regioselective and stereoselective C (SP 2) - C (SP 3) coupling reactions have not been realized The transition metal catalyzed Grignard reagent or organic zinc reagent and the second-order alkyl halide (alkyl bromine or alkyl iodine) can be realized by Fe, Co or Ni catalyst However, the regioselective coupling of transition metal catalyzed alkyl Grignard reagent or organic zinc reagent with alkenyl or heteroaryl iodide mainly depends on Pd catalyst On the other hand, the easily obtained phenol or enol derivatives are environmentally friendly electrophilic reagents, which can be coupled with organometallic reagents under the catalysis of 3d transition metal However, the use of alkenyl acetates with higher atom economy and better stability for similar reactions is rarely reported Gosmini group reported the reductive coupling reaction between vinyl acetate and aryl halides, but the substrate range was narrow Subsequently, the Ackermann group reported the co catalyzed C-H activation of alkenyl acetate The coupling reaction of alkenyl acetate was only recently reported by jacobivon wangelin and knochel group In addition, Frantz reported the Fe catalyzed stereoselective coupling reaction of enol carbamate with Grignard reagent Recently, Paul knockel group of the University of Munich, Germany, reported the CR catalyzed regioselective coupling reaction of aryl Grignard reagent with alkyl halides, and extended this system to the coupling reaction of alkenylacetate and alkylgrignard reagent The reaction conditions are mild and the regioselectivity is high Relevant research results were published in J am Chem SOC (DOI: 10.1021 / JACS 9b08586) (source: J am Chem SOC.) the author first used aryl magnesium bromide 1a and 1, 4-disubstituted cyclohexyl iodide 2a was used as the template substrate to optimize the conditions (Table 1) Through optimizing the ligand, temperature and the ratio of reactants, the optimal reaction conditions were determined as follows: crcl2 as catalyst, THF as solvent, reaction at 0 ~ 23 ℃ for 16 hours, the final substrate with 91% yield and 97:3 Dr value to the coupling product It is worth mentioning that the absence of ligands can promote the reaction (source: J am Chem SOC.) after determining the optimal reaction conditions, the author extended the range of substrates in the reaction (scheme 2) Phenyl and alkyl substituted 1,4-disubstituted cyclohexyl iodides can be used with corresponding Grignard reagents to obtain the target products OTBs, amino groups and other functional groups can also be compatible with the reaction conditions In addition, steroid derivatives (including deuterium derivatives) can also participate in the reaction, and the target product can be obtained in a medium to high yield (source: J am Chem SOC.) later, the author extended this system to the coupling of Grignard reagent and alkenylacetate, and realized the alkenylation of alkylgrignard reagent Among them, chromanone derivatives and acetoxycyclohexyl benzoate analogues can be obtained in good yield Importantly, the second-order Grignard reagent and tert butyl Grignard reagent can also participate in the reaction (scheme 3) Then, the author uses the acyclic alkenyl acetate for coupling reaction, and halogen, methoxy and other functional groups are compatible with the reaction conditions In addition, the olefins with (z) configuration and (E) configuration can obtain the target products Finally, the good regioselectivity (scheme 4) in the reaction was highlighted again by the comparison experiment with Fe catalyst (source: j.am Chem SOC.) (source: j.am Chem SOC.) finally, the author proposed that the coupling reaction of aryl Grignard reagent and alkyl halide is a single electron free radical mechanism, and the coupling of alkenyl acetate and alkyl Grignard reagent is a non free radical process Summary: Paul knochel group reported the CR catalyzed chemical and regioselective coupling reactions, without the participation of ligands, with high efficiency, mild conditions and high selectivity The later mechanism experiments showed that the low valent CR species formed in situ may be the active species in the catalytic reaction.