（来源：康龙化成）
转自：康龙化成
Aminative Suzuki–Miyaura Coupling Tackling Alkyl Nucleophiles and Addressing the Viability of the Electrophile-First Mechanism
Sophia Z. Li and Richard Y. Liu*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford St., Cambridge, MA 02138, USA;
—Angew. Chem. Int. Ed., 2025,10.1002/anie.202518260
Recommended by Xuemei Yao_MC3
KEY WORDS:Pd catalysis, Aminative Suzuki–Miyaura Coupling (反应类型), aryl bromides, aryl triflates, alkyl pinacol boronic ester, DPPH (原料), aromatic anilines (产物), Csp2-N, Csp3-N(成键类型)
ABSTRACT:Insertive cross-coupling reactions provide the option of repurposing widely available coupling partners for the formation of new linkages. By confronting a major limitation of the aminative Suzuki–Miyaura methods we recently reported, we achieve a general method for the Pd-catalyzed aminative coupling of primary and secondary alkyl boronic esters with aryl (pseudo)halides. Introducing a formal nitrene insertion into this Suzuki–Miyaura reaction diverts the outcome from the traditional C(sp2)─C(sp3) products to the C(sp2)─NH─C(sp3) analogues (N-aryl anilines). DFT calculations and experimental mechanistic studies indicate that C─N bond formation from the electrophilic aryl component occurs first, providing further evidence for this previously hypothetical pathway. By comparison of several transition state structures, we find that C─N bond formation likely takes place through an unusual dyotropic rearrangement of a LPd(Ar)NHX complex (X = OPOPh2).
Repurposing cross-coupling partners to increase directly accessible chemical space
Aminative B-alkyl Suzuki–Miyaura cross-coupling
Substrate (selected examples)
Synthetic applications
Proposed Mechanism
Sophia Z. Li and Prof. Richard Y. Liu reported an aminative cross-coupling reaction of alkyl pinacol boronic esters and aryl (pseudo)halides, providing a complementary strategy to conventional C─N cross-coupling methods. The transformation tolerates a wide range of functional groups, accommodates both primary and secondary alkyl nucleophiles, and proceeds without erosion of enantiomeric excess when chiral boronates are employed. This modular and stereoretentive three-component coupling proceeds via an “electrophile-first” mechanism, wherein C(aryl)─N bond formation precedes alkyl transmetalation. This proposal also rationalizes the major competing pathway: undesired formation of homodiarylamine products when the Pd(II) arylamidointermediate is subject to hydrolysis. Further work on insertivecatalytic processes with the potential to access unconventional cross-coupling products is ongoing in our laboratories.
