Suzuki–Miyaura Cross-Coupling of 2-Pyridyl Trimethylammonium Salts by N–C Activation Catalyzed by Air- and Moisture-Stable Pd–NHC Precatalysts: Application to the Discovery of Agrochemicals

Abstract

We report the first Suzuki−Miyaura cross-coupling of 2-pyridyl ammonium salts by highly selective N−C activation catalyzed by air-and moisture-stable Pd(II)−NHC (NHC = Nheterocyclic carbene) precatalysts. The use of well-defined and highly reactive [Pd(IPr)(3-CF 3 -An)Cl 2 ] (An = aniline) or [Pd(IPr)(cin)Cl] (cin = cinnamyl) Pd(II)−NHC catalysts permits an exceptionally broad scope of the cross-coupling to furnish valuable biaryl and heterobiarylpyridines that are ubiquitous in medicinal chemistry and agrochemistry research. The overall process leverages the Chichibabin C−H amination of pyridines with N−C activation to enable an attractive strategy to the 2-pyridyl problem. The utility of the method to the discovery of potent agrochemicals is presented. Considering the importance of 2-pyridines and the versatility of N−C activation methods, we envision that this new C−H/N−C activation strategy will find broad application.

Full-color emission of fluorinated benzothiadiazole-based D–A–D fluorophores and their bioimaging applications

“…When the molar ratio of 1a and 2m was controlled as 1 : 1, the monosubstituted compound 3p was obtained by the Sonogashira reaction. Importantly, the molecular structure and purity of all obtained 3a–3p were well demonstrated by 1 H, 19 F, 13 C NMR, 27,28 HRMS (Fig. S1–S62, ESI†) and single-crystal X-ray diffraction analysis (for compounds 3e , 3f , 3m and 3p , Tables S1–S4, Fig.…”

Pd–NHC (NHC = N-Heterocyclic Carbene)-Catalyzed B-Alkyl Suzuki Cross-Coupling of 2-Pyridyl Ammonium Salts by N–C Activation: Application to the Discovery of Agrochemical Molecular Hybrids

“…However, in contrast to the synthesis of 2-arylpyridines, which are readily synthesized by the biaryl Suzuki cross-coupling of appropriate precursors, the synthesis of 2-alkylpyridines remains a significant challenge due β-hydride elimination degrading the organometallic reagent and slower transmetalation step. , Critically, the presence of the basic pyridine nitrogen often coordinates to the metal and slows down the already challenging alkylative catalytic cycle . Further, the competing β-hydride elimination of alkyl organometallics leads to the formation of olefins, which undergo reinsertion, resulting in regioselectivity issues .…”

“…Preliminary selectivity studies to gain insight into the reaction mechanism were conducted (Scheme ). (1) Intermolecular competition experiments using differently substituted organoboranes showed that electron-rich nucleophiles are more reactive ( n -C 10 H 21 : n -(CH 2 ) 3 C 6 F 5 > 95:5), which is consistent with faster transmetalation. , (2) Interestingly, competition experiments using alkyl vs Ar nucleophiles showed that alkyl organoboron reagents are more reactive under these conditions ( n -C 10 H 21 :Ph = 64:36), which bodes well for the future development of Pd(II)–NHC-catalyzed alkylative Suzuki cross-couplings of unconventional electrophiles. Mechanistically, it should be noted that the pyridine nitrogen is likely involved in assisting oxidative addition.…”

“…4a Further examples include the synthesis of interlocked catenanes and C2-alkyl-functionalized ligands for Pd(II)-catalysis. 5 However, in contrast to the synthesis of 2-arylpyridines, which are readily synthesized by the biaryl Suzuki crosscoupling of appropriate precursors, 6 the synthesis of 2alkylpyridines remains a significant challenge due β-hydride elimination degrading the organometallic reagent and slower transmetalation step. 3c,7 Critically, the presence of the basic pyridine nitrogen often coordinates to the metal and slows down the already challenging alkylative catalytic cycle.…”

“…Further, the competing β-hydride elimination of alkyl organometallics leads to the formation of olefins, which undergo reinsertion, resulting in regioselectivity issues . Previously, we reported the biaryl Suzuki cross-coupling of 2-pyridinium ammonium salts . This approach leverages the valuable C–H Chichibabin amination of pyridines to access 2-pyridinium ammonium electrophiles, which can be engaged in a generic C–N activation, thus obviating the need for prefunctionalized or highly reactive substrates (Figure B). − Considering the importance of 2-alkylpyridines and the urgent need to develop new methods for the synthesis of this privileged scaffold, − we questioned whether the significantly more challenging alkylative C–N Suzuki cross-coupling could be achieved by leveraging the versatile Pd­(II)–NHC catalysts to overcome the difficulties poised by C–N oxidative addition and transmetalation with alkyl organoboranes. − Notably, we recognized that B-alkyl Suzuki cross-coupling with quaternary ammonium salts has not been previously reported in any fashion.…”