Unlocking Tertiary Acids for Metallaphotoredox C(sp2)-C(sp3) Decarboxylative Cross-Couplings

Abstract

Dual nickel photoredox catalysis conditions have been developed for the decarboxylative cross-coupling of aryl halides and carboxylic acids containing fully substituted alpha carbons, a valuable but challenging substrate class for C(sp2)–C(sp3) bond-forming reactions. High-throughput experimentation identified Ni(TMHD)2 as the optimal precatalyst for this reaction in contrast to the nickel-bipyridyl complexes typically employed in decarboxylative couplings, which predominantly furnished undesired C–O products. Computational work provides insight into the potential mechanistic underpinnings for the C–C vs. C–O selectivity for the nickel-diketonate complex.

Ni-Electrocatalytic Decarboxylative Arylation to Access Quaternary Centers

“…In the final optimized conditions, the amount of BINAP could be reduced to 5 mol% along with 25 mol % Ni (Table 1, entry 14 and 15). Basic control studies confirmed the essential nature of the Ni, Ag, BINAP, and pyridine additives as well as electricity (Table 1, entries [16][17][18][19][20]. The final set of conditions are as practically trivial to setup as our previous disclosure (dump and stir) with no precautions taken to remove air or moisture.…”

“…[11][12][13][14] Whereas the scope of such couplings is broad when primary and secondary acids and their redoxactive esters (RAEs) are employed, extending that reactivity to tertiary acids has been a vexing problem. [15][16][17][18] For instance, the simple coupling of RAE/acid 1a-b with pyrimidine 2 fails under the most modern of conditions (chemical, photochemical, electrochemical), delivering at most 9% yield. Although the published scope of these methods generally tolerates numerous types of arenes, the only competent alkyl coupling partners involve systems that form radicals which are part of a strained ring system or stabilized by the presence of an -heteroatom (as listed in Figure 1B).…”

“…Although the published scope of these methods generally tolerates numerous types of arenes, the only competent alkyl coupling partners involve systems that form radicals which are part of a strained ring system or stabilized by the presence of an -heteroatom (as listed in Figure 1B). [15][16][17][18] In this initial disclosure, a step towards solving this issue is presented by building upon the Ag-functionalized electrode Ni-electrocatalytic method reported previously. 18 This newly invented protocol can, for example, achieve the coupling of 1a and 2 in 45% isolated yield (along with 3% of the undesired isomer) and is general across a range of substrates that have proven challenging with all published methods to date.…”

“…In order to place these results in the proper context, comparisons to the original Ag/Ni conditions are shown in addition to recent photochemical conditions that were optimized for hindered couplings (9 out of 52 arylations in that study formed quaternary centers with the remainder being fully substituted centers with an adjacent heteroatom). 17 Three photochemical reports show that tertiary alkyl radicals precursors can be cross-coupled with aryl halides, and Ni(TMHD)2 complex is the only effective catalyst in those three photochemical reports. 16,17,31 While effective at promoting the formation of quaternary centers, a noticeable drawback of Ni(TMHD)2 complex in those cross-couplings is its incompatibility with ligating substrates such as bromopyridine and other simple (hetero)aryl halides; doping experiments showed that pyridine and other heterocycles inhibit the active Ni-species.…”

“…17 Three photochemical reports show that tertiary alkyl radicals precursors can be cross-coupled with aryl halides, and Ni(TMHD)2 complex is the only effective catalyst in those three photochemical reports. 16,17,31 While effective at promoting the formation of quaternary centers, a noticeable drawback of Ni(TMHD)2 complex in those cross-couplings is its incompatibility with ligating substrates such as bromopyridine and other simple (hetero)aryl halides; doping experiments showed that pyridine and other heterocycles inhibit the active Ni-species. 33 In contrast, the electrochemical method presented in this report overcomes these limitations, as exemplified by compounds 16, 21, and 26.…”