Metal‐Free Aryl Cross‐Coupling Directed by Traceless Linkers

Abstract

The metal‐free, highly selective synthesis of biaryls poses a major challenge in organic synthesis. The scope and mechanism of a promising new approach to (hetero)biaryls by the photochemical fusion of aryl substituents tethered to a traceless sulfonamide linker (photosplicing) are reported. Interrogating photosplicing with varying reaction conditions and comparison of diverse synthetic probes (40 examples, including a suite of heterocycles) showed that the reaction has a surprisingly broad scope and involves neither metals nor radicals. Quantum chemical calculations revealed that the C−C bond is formed by an intramolecular photochemical process that involves an excited singlet state and traversal of a five‐membered transition state, and thus consistent ipso–ipso coupling results. These results demonstrate that photosplicing is a unique aryl cross‐coupling method in the excited state that can be applied to synthesize a broad range of biaryls.

pysisyphus: Exploring potential energy surfaces in ground and excited states

“…The interested reader is referred to the original publication for the full discussion of the reaction mechanism. [167] The example presented here exemplifies that full reaction paths can be obtained in pysisyphus with minimal user intervention by using robust and efficient algorithms. Starting from the preoptimization and ending with the optimization of the IRC endpoints, all calculations took 9.6 hours on a desktop computer equipped with eight physical CPU cores (Ryzen 1700X CPU).…”

“…[157][158][159][160][161][162][163][164][165][166] Kloss recently reported a novel metal-free cross-coupling reaction, where two phenyl groups tethered by a sulfonamide linker can be fused in a single coupling product through irradiation by ultraviolet light with high regio-and chemoselectivity. [167,168] Haensch proposed an intramolecular photochemical mechanism involving a five-membered TS. Here, we present the calculation of a GS reaction coordinate for this photoreaction using pysisyphus as it is an example for a complex and computationally challenging reaction where three bonds are broken and one bond is formed.…”

“…Besides the already mentioned platinum complexes, pysisyphus was already successfully applied in our group to elucidate the reaction mechanisms of (metal-free) biaryl cross-couplings and iron(0)mediated (3 + 2) cycloaddition of thiochalcones. [167,186] Possible extensions of pysisyphus would be the generalization of ES tracking to arbitrary multiplicities and support for wavefunctions beyond CIS as they occur in complete active space self-consistent field (CASSCF) calculations. By combining the interpolation and ES optimization capabilities of pysisyphus, the automated calculation of rate constants, for example, in the scope of electron transfer processes using semiclassical Marcus theory, could be realized.…”

“…The interested reader is referred to the original publication for the full discussion of the reaction mechanism. [ 167 ]…”

“…Even though the true reaction coordinate involves ESs, the GS coordinate is a good approximation to it. We choose the unsubstituted N ‐benzyl‐benzenesulfonamide BBSA (compound 1 p in Reference [167]) as this allows all calculations to be performed in a timely manner—even on common desktop hardware.…”