A Dichotomy in Cross-Coupling Site Selectivity in a Dihalogenated Heteroarene: Influence of Mononuclear Pd, Pd Clusters, and Pd Nanoparticles-the Case for Exploiting Pd Catalyst Speciation

Abstract

Site-selective dihalogenated heteroarene cross-coupling with organometallic reagents usually occurs at the halogen proximal to the heteroatom, enabled by intrinsic relative electrophilicity, particularly in strongly polarized systems. An archetypical example is the Suzuki-Miyaura cross-coupling (SMCC) of 2,4-dibromopyridine with organoboron species, which typically exhibit C2-arylation site-selectivity using mononuclear Pd (pre)catalysts. Given that Pd speciation, particularly aggregation, is known to lead to the formation of catalytically competent multinuclear Pd_n species, the influence of these species on cross-coupling site-selectivity remains largely unknown. Herein, we disclose that multinuclear Pd species, in the form of Pd₃-type clusters and nanoparticles, switch arylation site-selectivity from C2 to C4, in 2,4-dibromopyridine cross-couplings with both organoboronic acids (SMCC reactions) and Grignard reagents (Kumada-type reactions). The Pd/ligand ratio and the presence of suitable stabilizing salts were found to be critically important in switching the site-selectivity. More generally, this study provides experimental evidence that aggregated Pd catalyst species not only are catalytically competent but also alter reaction outcomes through changes in product selectivity.

Scheme 1. Site-Selectivity in Suzuki–Miyaura Cross-Couplings of Heteroarenes, Exemplified by Dihalogenated Pyridines and Related Derivatives

A guiding example, for which many catalyst systems/reaction conditions have been investigated, is given, showing high C2 site-selectivity.

Scheme 2. Benchmark SMCC of 1 with p-Fluoro-phenylboronic Acid 2a To Give Typical Product 3a_C2-Ar, Atypical Product 3a_C4-Ar, and Diarylated Product 3a_diaryl [1]; the Proposed Equilibrium for 2a and n-Bu₄NOH, Which Is Expected to Lie to the Right-Hand Side Is Shown in [2]

Figure 1

Summarizing Pd catalyst efficacy under different precatalytic Pd:PPh₃ regimes, showing reaction conversions of which product selectivities for the SMCC (Scheme 2) of 1 with p-fluoro-phenylboronic acid 2a to give typical product 3a_C2–Ar and atypical product 3a_C4–Ar and bis-arylated product 3a_diaryl.

Scheme 3. Testing Additive and Base Effects for the SMCC between 1 and 2b

Scheme 4. Conditions, Reagents, and Catalysts Used for Kinetic Product Distribution Analysis in SMCC Reactions of 1

Figure 2

Product distribution of 3b_C4–Ar, 3b_C2–Ar, and 3b_diaryl as functions of time in the SMCC reaction between 1 and 2b. Using (A) Pd₃Cl₂ and (B) Pd(OAc)₂/2PPh₃ as the precatalyst.

Scheme 5. Conditions for the Kumada Cross-Coupling of 1 with Phenylmagnesium Bromide 5

Variables changed are highlighted in bold.

Figure 3

Effect of product selectivities in SMCC reactions as a function of catalyst system employed and para-substituent on the phenylboronic acid substrate. (A) Using Pd₂(dba)₃·CHCl₃/2PPh₃. (B) Pd₃Cl₂. (C) Pd(OAc)₂/1PPh₃.

Scheme 6. Conditions, Reagents, and Catalysts Used for para-Substituent Analysis of Site-Selective SMCC Reactions at 1

Determined by ¹H NMR analysis of the crude reaction mixture, after 1 h.

Figure 4

Plot of ΔΔG^‡ against σ_P for para-substituent changes in SMCC reactions of 1 with p-Z-C₆H₄-B(OH)₂ (2a–f).

Scheme 7. Conditions and Reagents Used for Determining the Effects of a Variety of P-Ligands on Site-Selective SMCC Reactions at 1

Figure 5

Performance of phosphorus-containing Pd precatalysts systems in site-selective Suzuki–Miyaura cross-coupling of 1.

Figure 6

Confirmation of mechanistic reasoning for C₂–Br site-selectivity in the reaction of Pd⁰(PPh₃)₄ with 1 at 23 °C.

Figure 7

Analysis of the THF-d₈. solution arising from the mixture of Pd(OAc)₂/1PPh₃. (A) XRD structure of a single crystal of 4 is shown (selected atoms). (B) ¹H NMR analysis, confirming solution presence of 4 ca. 10 min after mixing at 25 °C. (C. i. and ii.) ³¹P NMR spectral data and reaction speciation, showing the decay of 4 and growth of multiple P-containing species over 12 h, 25 °C.

Scheme 8. Dichotomy in Site-Selectivity at 1: Different Pd Species Arising from Different Ratios of Pd(OAc)₂/nPPh₃ Result in Different Cross-Coupling Selectivities under Cross-Coupling Conditions

Scheme 9. Mechanistic Hypotheses: (A) Catalytic Cycle Involving Mononuclear Pd Species, via Classical Pd Intermediates or Alternative Route Involving a S_NAr-Type Mechanism; (B) Catalyst Cycle Based on That Evidenced by Li et al. Involving Pd₃ Cluster Species; (C) Proposed Involvement of Higher Order Pd Agglomerates (Note: Only Details of Key Steps Are Shown – trans–cis Isomerizations and Ligand Dissociation/Association Are Involved)

Note: (P) = PPh₂; P = PPh₃; X = anion, e.g. Br or OH.