Phenoxythiazoline (FTz)‐Cobalt(II) Precatalysts Enable C(sp²)–C(sp³) Bond‐Formation for Key Intermediates in the Synthesis of Toll‐like Receptor 7/8 Antagonists**

Abstract

Evaluation of the relative rates of the cobalt‐catalyzed C(sp2)–C(sp3) Suzuki–Miyaura cross‐coupling between the neopentylglycol ester of 4‐fluorophenylboronic acid and N‐Boc‐4‐bromopiperidine established that decreasing the size of the N‐alkyl substituents on the phenoxyimine (FI) supporting ligand accelerated the overall rate of the reaction. This trend inspired the design of optimal cobalt catalysts with phenoxyoxazoline (FOx) and phenoxythiazoline (FTz) ligands. An air‐stable cobalt(II) precatalyst, (FTz)CoBr(py)3 was synthesized and applied to the cross‐coupling of an indole‐5‐boronic ester nucleophile with a piperidine‐4‐bromide electrophile that is relevant to the synthesis of reported toll‐like receptor (TLR) 7/8 antagonist molecules including afimetoran. Addition of excess KOMe•B(OiPr)3 improved catalyst lifetime due to attenuation of alkoxide basicity that otherwise resulted in demetallation of the FI chelate. Determination of the experimental rate law established a first‐order dependence on the cobalt precatalyst and a saturation regime in heterogeneous potassium aryl boronate (apparent zeroth order), supporting turnover‐limiting transmetalation and the origin of the observed trends in N‐imine substitution. The optimized cobalt precatalyst and reaction conditions were applied to the multigram‐scale synthesis of an intermediate used in both the discovery and process routes for toll‐like receptor (TLR) 7/8 antagonist molecules.

(Phenoxyimine)nickel-Catalyzed C(sp2)–C(sp3) Suzuki–Miyaura Cross-Coupling: Evidence for a Recovering Radical Chain Mechanism

“…The solution concentration of (FI)nickel(II)−aryl ( 20) is proportional to the rate of product formation (5) such that the alkyl radical capture is the turnover-limiting step for product formation. Radical capture yields (FI)nickel(III) intermediate 26, 63 which presumably undergoes C(sp 2 )−C(sp 3 ) bond-forming reductive elimination, 64 yielding cross-coupled product (5) and a putative (FI)nickel(I) intermediate (18) (20). It should be emphasized that product-forming propagation occurs in excess of ten times per rate-limiting initiation event, such that the rate of product formation is not proportional to a single turnoverlimiting step in the classical sense.…”

“…From the potassium isopropoxide (FI)nickel(II)−aryl complex (21), β-hydride elimination and C−H reductive elimination releases arene (24) and generates potassium (FI)nickel(0)ate−acetone complex (13). Potassium (FI)nickel(0)ate ( 13) readily activates alkyl bromide (4), forming an alkyl radical (25) and a putative (FI)nickel(I) intermediate (18), completing radical (re)initiation.…”

“…15 The (FI)cobalt-catalyzed methods have so far proven more synthetically versatile, 16 and identification of turnover-limiting transmetalation 17 enabled the synthesis of next-generation catalysts bearing phenoxythiazoline (FTz) chelates that expanded the scope of the reaction to include preparation of the core of the TLR7/8 antagonist afimetoran. 18 A commonality between phenoxyimine iron and cobalt catalysts is the persistence of high-spin, tetrahedral intermediates that enables radical activation of the alkyl bromide electrophile partner (Scheme 2). 19,20 Specific advantages of the phenoxyimine ligands in cobalt-catalyzed cross coupling include straightforward preparation and modularity of the supporting ligand, accelerated alkyl radical capture as compared to catalysts supported by L 2 -type ligands, 17 and, notably, fidelity of the catalyst in the presence of stoichiometric alkoxide bases.…”

“…In the process of radical capture and C−C bond formation, the (FI)nickel(I) intermediate ( 18) is generated. This reduced (FI)nickel species (18) activates another molecule of alkyl bromide (4b) generating (FI)nickel(II) monobromide ( 19) 52 and an additional equivalent of alkyl radical (17). In this fashion, autocatalytic radical propagation results in C−C bond-forming events in excess of the number of initiation events.…”

“…The solution concentration of (FI)nickel(II)−aryl ( 20) is proportional to the rate of product formation (5) such that the alkyl radical capture is the turnover-limiting step for product formation. Radical capture yields (FI)nickel(III) intermediate 26, 63 which presumably undergoes C(sp 2 )−C(sp 3 ) bond-forming reductive elimination, 64 yielding cross-coupled product (5) and a putative (FI)nickel(I) intermediate (18)…”