Overcoming Limitations in Decarboxylative Arylation via Ag-Ni Electrocatalysis

Abstract

A useful protocol for achieving decarboxylative cross coupling (DCC) of redox-active esters (RAE, isolated or generated in situ) and halo(hetero)arenes is reported. This pragmatically focused study employs a unique Ag-Ni electrocatalytic platform to overcome numerous limitations that have plagued this strategically powerful transformation. In its optimized form coupling partners can be combined in a surprisingly simple way: open to the air, technical grade solvents, an inexpensive ligand and Ni source, substoichiometric AgNO3, proceeding at room temperature with a simple commercial potentiostat. Most importantly all of the results are placed into context by benchmarking with state-of-the-art methods. Applications are presented that simplify synthesis and rapidly enable access to challenging chemical space. Finally, adaptation to multiple scale regimes, ranging from parallel mg-based synthesis to decagram recirculating flow is presented

Control of Redox‐Active Ester Reactivity Enables a General Cross‐Electrophile Approach to Access Arylated Strained Rings**

“…We envision that further ligand design and NHP ester tuning will enable the use of even less reactive coupling partners in the future, expanding the utility of redox active esters as a tool for C−C bond formation. We note that, while this manuscript was in review, the Baran group in collaboration with several pharmaceutical companies reported a complementary approach to tuning NHP ester reactivity under electrochemical conditions by doping the nickel cathode with silver; [38] we imagine that combining new ligands, tuned NHP esters, and electrochemistry could be particularly fruitful.…”

Decarboxylative Cross-Coupling: A Radical Tool in Medicinal Chemistry

“…In this case, the use of Ag-Ni electrocatalysis is singularly successful among all methods evaluated (when free phenols and heterocycles are employed). 31 Thus, the DCC approach is attractive in terms of ideality, scalability, and rapid access to diversity. Another emblematic approach to such molecules utilizes reliable C(sp 2 )−C(sp 2 ) Suzuki−Miyaura couplings followed by hydrogenation.…”

“…49 Alternatively, the acidbearing saturated heterocycle 5 can be purchased and directly coupled with an arene of interest through DCC in a single, diversity-incorporating step. 31 Another compelling example of the simplifying effect that decarboxylative approaches can have on synthetic planning can be found in their application to the antipsychotic drug Asenapine (Saphris) 6. This substituted chiral pyrrolidine bears two contiguous stereocenters that only differ by the placement of a chlorine atom on the aryl ring substituents.…”

“…This often requires the practitioner to synthesize bespoke organometallic reagents for more structurally complex cross-coupling partners, which undoubtedly adds additional concession steps to any synthesis. To this end, several reports have emerged that leverage an exogenous reductant (Zn, − Hantzsch ester under photochemical activation, , dual photoredox/Ni-catalysis, or electrochemical reduction − ) and C­(sp 2 )–electrophile equivalents to mimic the overall transformations achieved in the organometallic approach but under milder reaction conditions. Further, this approach leverages more commercially available and benchtop stable C­(sp 2 )–halides and pseudohalides.…”

“…In contrast, the same product can be obtained with a reductive DCC starting from the RAE of the amino acid and the desired aryl halide partner. In this case, the use of Ag-Ni electrocatalysis is singularly successful among all methods evaluated (when free phenols and heterocycles are employed) . Thus, the DCC approach is attractive in terms of ideality, scalability, and rapid access to diversity.…”