Inhibition of (dppf)nickel-catalysed Suzuki-Miyaura cross-coupling reactions by α-halo-N-heterocycles

Abstract

A nickel/dppf catalyst system was found to successfully achieve the Suzuki-Miyaura cross-coupling reactions of 3- and 4-chloropyridine and of 6-chloroquinoline but not of 2-chloropyridine or of other α-halo-N-heterocycles. Further investigations revealed that chloropyridines undergo rapid oxidative addition to [Ni(COD)(dppf)] but that α-halo-N-heterocycles lead to the formation of stable dimeric nickel species that are catalytically inactive in Suzuki-Miyaura cross-coupling reactions. However, the corresponding Kumada-Tamao-Corriu reactions all proceed readily, which is attributed to more rapid transmetalation of Grignard reagents.

Scheme 1. Literature examples of Suzuki–Miyaura cross-coupling reactions of 2-chloropyridine substrates (E = CH or N; Ch = O or S).

Scheme 2. Initial attempts at the Suzuki–Miyaura reaction of chloroheteroarenes. Results are quoted as conversion to product as determined by calibrated GC-FID analysis. ^aSubstrate was used as the hydrochloride salt, so 4 equiv. K₃PO₄ were used.

Scheme 3. Synthesis of dimeric nickel(ii) complexes.

Fig. 1. Molecular structures of 3-Cl (left), 3-Br (middle), and 5 (right) determined by single crystal X-ray diffraction analysis. Solvent molecules and hydrogen atoms are omitted for clarity.

Scheme 4. (a) Complex 3-Cl is does not catalyse Suzuki–Miyaura cross-coupling reactions. (b) Alternative catalysts do not catalyse these reactions. (c) Complex 3-Cl does not react with base and boronic acid. (d) Complex 3-Cl does not react with PhSn(n-Bu)₃. (e) Complex 3-Cl reacts with PhMgCl.

Scheme 5. Kumada–Tamao–Corriu reactions of chloroheteroarenes. Results are quoted as conversion to product as determined by calibrated GC-FID analysis. ^aUsing 3 equiv. of PhMgCl for 4 h. ^bUsing 5 mol% 3-Cl as a catalyst. ^cUsing 5 mol% 3-Cl as a catalyst with 5 mol% of additional dppf. ^dUsed as the hydrochloride salt with 2.1 equiv. PhMgCl.

Fig. 2. Free energy profiles for the reactions of chlorobenzene, 3-chloropyridine, and 4-chloropyridine with 2. Images of A, TS-A-B, and B are provided for the representative example of the oxidative addition reaction of chlorobenzene.

Fig. 3. Structures for the reaction of 2-chloropyridine with 2via (a) an η²(CC) complex and (b) an η²(CN) complex, and (c) free energy profiles for these reactions.

Fig. 4. Molecular structure of the cation of 6 determined by single crystal X-ray diffraction analysis. Hydrogen atoms and the outer-sphere triflate counter ion are omitted for clarity.

Fig. 5. QTAIM analyses for oxidative addition transition states TS-A2-B′ for 2-chloropyridine (left), TS-A1-B for 2-chloropyridine (middle), and TS-A-B for chlorobenzene (right). Red points represent bond critical points, while coloured spheres represent atomic positions (white = H; grey = C; light orange = P; light green = Cl; dark green = Ni; dark orange = Fe).

Fig. 6. Proposed reaction mechanism for the formation of 3-Cl from B. Energies are free energies in kcal mol⁻¹ with respect to 2, and are obtained from M06/6-311+G(d,p) single point calculations in benzene solvent (SMD) using B3LYP-D3/6-31G(d)+LANL2TZ(f) geometries.