Photoinduced Cobalt(III)-Trifluoromethyl Bond Activation Enables Arene C-H Trifluoromethylation.

Visible-light capture activates a thermodynamically inert CoIII -CF3 bond for direct C-H trifluoromethylation of arenes and heteroarenes. New trifluoromethylcobalt(III) complexes supported by a redox-active [OCO] pincer ligand were prepared. Coordinating solvents, such as MeCN, afford green, quasi-octahedral [(S OCO)CoIII (CF3 )(MeCN)2 ] (2), but in non-coordinating solvents the complex is red, square pyramidal [(S OCO)CoIII (CF3 )(MeCN)] (3). Both are thermally stable, and 2 is stable in light. But exposure of 3 to low-energy light results in facile homolysis of the CoIII -CF3 bond, releasing . CF3 radical, which is efficiently trapped by TEMPO. or (hetero)arenes. The homolytic aromatic substitution reactions do not require a sacrificial or substrate-derived oxidant because the CoII by-product of CoIII -CF3 homolysis produces H2 . The photophysical properties of 2 and 3 provide a rationale for the disparate light stability.

Spectroscopic and Structural Elucidation of Uranium Dioxophenoxazine Complexes.

Uranium derivatives of a redox-active, dioxophenoxazine ligand, (DOPO(q))2UO2, (DOPO(sq))UI2(THF)2, (DOPO(cat))UI(THF)2, and Cp*U(DOPO(cat))(THF)2 (DOPO = 2,4,6,8-tetra-tert-butyl-1-oxo-1H-phenoxazin-9-olate), have been synthesized from U(VI) and U(III) starting materials. Full characterization of these species show uranium complexes bearing ligands in three different oxidation states. The electronic structures of these complexes have been explored using (1)H NMR and electronic absorption spectroscopies, and where possible, X-ray crystallography and SQUID magnetometry.

Catalytic C-H Trifluoromethylation of Arenes and Heteroarenes via Visible Light Photoexcitation of a Co(III)-CF3 Complex.

A cobalt photocatalyst for direct trifluoromethylation of (hetero)arene C(sp2)-H bonds is described and shown to operate via visible light activation of a Co-CF3 intermediate, which functions as a combined chromophore and organometallic reaction center. Chemical oxidations of previously reported (OCO)Co complexes containing a redox-active [OCO] pincer ligand afford a Co-CF3 complex two oxidation states above Co(II). Computational and spectroscopic studies are consistent with formulation of the product as [(OCO•)CoIII(CF3)(THF)(OTf)] (II) containing an open-shell [OCO•]1- radical ligand bound to a S = 0 Co(III) center. II is thermodynamically stable, but exposure to blue (440 nm) light induces Co-CF3 bond homolysis and release of •CF3, which is trapped by radical acceptors including TEMPO•, (hetero)arenes, or the radical [OCO•] ligand in II. The latter comprises a competitive degradation pathway, which is overcome under catalytic conditions by using excess substrate. Accordingly, generation of II from the reaction of [(OCO)CoIIL] (III) (L = THF, MeCN) with Umemoto's dibenzothiophenium trifluoromethylating reagent (1) followed by photolytic Co-CF3 bond activation completes a photoredox catalytic cycle for C-H (hetero)arene trifluoromethylation utilizing visible light. Electronic structure and photophysical studies, including time-dependent density functional theory (TDDFT) calculations, suggest that Co-CF3 bond homolysis at II occurs via an ligand-to-metal charge-transfer (LMCT) (OCO0)CoII(CF3) state, revealing ligand redox activity as a critical design feature and establishing design principles for the use of base metal chromophores for selectivity in photoredox bond activations occurring via free radical intermediates.

Practical and Scalable Two-Step Process for 6-(2-Fluoro-4-nitrophenyl)-2-oxa-6-azaspiro[3.3]heptane: A Key Intermediate of the Potent Antibiotic Drug Candidate TBI-223.

A low-cost, protecting group-free route to 6-(2-fluoro-4-nitrophenyl)-2-oxa-6-azaspiro[3.3]heptane (1), the starting material for the in-development tuberculosis treatment TBI-223, is described. The key bond forming step in this route is the creation of the azetidine ring through a hydroxide-facilitated alkylation of 2-fluoro-4-nitroaniline (2) with 3,3-bis(bromomethyl)oxetane (BBMO, 3). After optimization, this ring formation reaction was demonstrated at 100 g scale with isolated yield of 87% and final product purity of >99%. The alkylating agent 3 was synthesized using an optimized procedure that starts from tribromoneopentyl alcohol (TBNPA, 4), a commercially available flame retardant. Treatment of 4 with sodium hydroxide under Schotten-Baumann conditions closed the oxetane ring, and after distillation, 3 was recovered in 72% yield and >95% purity. This new approach to compound 1 avoids the previous drawbacks associated with the synthesis of 2-oxa-6-azaspiro[3,3]heptane (5), the major cost driver used in previous routes to TBI-223. The optimization and multigram scale-up results for this new route are reported herein.