JACS: LiCl accelerated cross coupling between aryl chloride and aryl trifluoromethylsulfonate

Biaryl compounds are widely used in pharmaceutical, agricultural chemistry and materials industry, but the availability of aryl metal reagents is still limited Because of its low utilization, many active research fields (scheme 1a) have been stimulated, including the synthesis methods of aryl metal reagents, C-H arylation and decarboxylation cross coupling, etc The variety of aryl electrophilic reagents makes the cross Ullman reaction more attractive (scheme 1b), but nickel and palladium catalysts are not widely effective for aryl chlorides Aryl chlorides not only have low cost, but also have low reactivity, which can realize the sequential coupling in the later stage of drug discovery based on fragments or functional group of complex molecules At present, the cross coupling between neutral or electron rich aryl chlorides and other aryl electrophilic reagents has not been reported Ni catalyst can activate aryl bromide faster than aryl trifluoromethane, while Pd catalyst can activate aryl trifluoromethane faster than aryl bromide When enough electron deficient aryl chlorides are used instead of aryl bromides, the selectivity of the catalyst is maintained, while when the unactivated aryl chlorides are used, the selectivity of the catalyst is lost Recently, Daniel J weix group of University of Wisconsin Madison used a common polymetallic solution to realize the selective coupling between various aryl chlorides and aryl trifluoromethylsulfonates (scheme 1c) This achievement was published in j.am Chem SOC (DOI: 10.1021 / JACS 9b05461) (photo source: J am Chem SOC.) it can be seen from the mechanism of nickel / palladium co Catalysis (table 1a) The slow consumption of aryl chloride and aryl trifluoromethane sulfonate indicates that the formation of aryl nickel (II) is inhibited Without aryl nickel (II), aryl palladium (IV) will not consume aryl trifluoromethane sulfonate The inhibition may be attributed to slow oxidation addition (I → II) and reduction (III → I) or non cycle loss of nickel catalyst The reduction of (dtbbpy) Ni II x 2 complex III Cl and III OTF was studied by electrochemical and chemical methods CV study showed that there was no difference between III Cl and III OTF (table 1b), but it did not take into account the complex dynamic image of metal surface reduction In the presence or absence of additives, the reduction of complexes III OTF and III CL on zinc tablets shows that III OTF will not be reduced unless there is a chloride salt (table 1b and 1c) At the same time, there is a cation effect: Although LiCl accelerates the reduction rate of III OTF and III Cl, ZnCl2 does not In fact, ZnCl2 or Zn (OTF) 2 formed in the reaction can inhibit the reduction of (dtbbpy) niiicl2, but LiCl can overcome the inhibition of zinc and is the most effective additive Although zinc salt can inhibit the reduction of octyl bromide to octyl zinc bromide, the reduction rate of PD (II) phosphine complex to PD (0) is very fast under the condition of LiCl or Zn or not The above study shows that the low reactivity of coupling aryl chloride with aryl trifluoromethane sulfonate is due to its self inhibition: the zinc salt (ZnCl2 and Zn (OTF) 2) formed in the reaction of I produced by reduction of III inhibits the reduction of subsequent III Although it has been reported that halogen anions can accelerate the reduction of Nix 2 Intermediate on zinc surface, the inhibition of OTF -, BF 4 -, PF 6 -, and zinc salt has not been reported Optimization of reaction conditions (table1c): two kinds of metal catalysts work together to play a catalytic role: the reaction selectivity without palladium is poor, and the reaction without nickel does not consume raw materials Similar to other cross electrophilic coupling reactions, the tolerance of exogenous oxygen can be carried out in conventional environment Zn and Mn can be used as reducing agents, LiBr is better than LiCl / Mn Dtbbpy and dppb are the best ligands, but PCY 3 is also effective In addition, 6,6 '- dibromo-2,2' - bipyridine is effective for the coupling of electron deficient aryl chlorides (picture source: J Am Chem Soc.) under the optimized reaction conditions, the coupling of three fluoromethanesulphonates with different functional groups and steric hindrances with various aryl chlorides was investigated (Scheme 2) The fluorine-containing substrate without electron, neutral and electron rich substrate and some sensitive sensory energy groups such as BOC protected amines, aldehydes, alkyl bpin esters and phosphate esters have good tolerance More active aryl halides, such as aryl chlorine, heteroaryl halides or aryl bromines with strong electron absorbing groups, can be selectively coupled to aryl trifluoromethane sulfonate via a 6,6 '- dibromo-2,2-bipyridine ligand with large steric hindrance and electron deficiency Under these conditions, ortho substituted and 2,6-disubstituted aryl bromine and chlorine can also be coupled However, the coupling between electron rich aryl chlorine and electron deficient aryl trifluoromethylsulfonate has low selectivity Finally, the author also investigated the range of application of aryl trifluoromethylsulfonate ester (scheme 2), and found that the substrate containing electron donor and electron acceptor had good yield However, the coupling yield between electron deficient aryl trifluoromethylsulfonate and electron deficient aryl chloride is low In this case, the yield of 6,6 '- dibromo-2,2' - bipyridine was not increased In addition to its low cost and easy to obtain, the low reactivity of aryl chlorides can also realize the multi-step synthesis (scheme 2): under the condition of retaining C-Cl bond, cross coupling with alkyl bromide (5), C-H arylation (7) and reductive α - arylation (9) can be carried out simultaneously (photo source: J am Chem SOC.) conclusion: Daniel J weix team reported the first cross Ullman coupling between aryl chloride and aryltrifluoromethylsulfonate, which can tolerate various functional groups The combination of nickel and palladium catalyst overcomes the selective challenge of coupling of inert electrophilic reagent and active electrophilic reagent, and it is found that LiCl is essential for the coupling, which can accelerate the reduction of Ni (II) → Ni (0) and counteract the self inhibition of Zn (0) reduction by Zn (II) salt.