Regioselective Arene C−H Alkylation Enabled by Organic Photoredox Catalysis

Abstract

Expanding the toolbox of C À H functionalization reactions applicable to the late-stage modification of complex molecules is of interest in medicinal chemistry, wherein the preparation of structural variants of known pharmacophores is a key strategy for drug development. One manifold for the functionalization of aromatic molecules utilizes diazo compounds and a transition-metal catalyst to generate a metallocarbene species, which is capable of direct insertion into an aromatic CÀH bond. However, these high-energy intermediates can often require directing groups or a large excess of substrate to achieve efficient and selective reactivity. Herein, we report that arene cation radicals generated by organic photoredox catalysis engage in formal C À H functionalization reactions with diazoacetate derivatives, furnishing sp 2 -sp 3 coupled products with moderate-to-good regioselectivity. In contrast to previous methods utilizing metallocarbene intermediates, this transformation does not proceed via a carbene intermediate, nor does it require the presence of a transitionmetal catalyst.Metallocarbenes are reactive organometallic species that may be generated by using a transition-metal precursor and diazoacetate derivatives. [1][2][3] The resulting carbene intermediate may then undergo CÀH insertion with reactive CÀH bonds (often aryl or alkyl), affording the corresponding alkylated adducts. However, owing to the high reactivity of metallocarbenes, aromatic substrates are often required to be present in excess for efficient reactivity.Among methodologies based on metallocarbene CÀH insertion that do not use a several-fold excess of arene, directing groups are often required. The groups of Fox [4] and Wang [5] have reported ortho-selective C À H functionalization of heterocycles by using diazoacetates. In addition, other directing groups, such as purines, [6] azacycles, [7] disubstituted anilines, [8] and phenols, [9] have been utilized in metallocarbene CÀH alkylation reactions. Collectively, these directing groups limit the synthetic applicability of metallocarbene C À H alkylation reactions.Recently, Suero and co-workers reported the synthesis of aryl diazoacetate derivatives under photoredox conditions. [10]

Across the Board: Yang Li on Visible‐Light Photoredox Catalysis

“…The powerful oxidative ability upon photoexcitation is retained ( E * red =+2.15 V vs. SCE) with a fluorescence lifetime of 14.4 ns . Owing to higher stability, PC 2 has also been used in various transformations …”

“…Followed by a SET, 3 is reduced to the ground‐state 4 . In the previous reported pathways, ground‐state 4 undergoes another oxidative SET to regenerate PC 2 . Notably, different to the typical pathway, ground‐state 4 is excited by 390 nm light to generate a combination of a highly reducing lower‐energy doublet and a TICT 5 .…”

Process analytical technology (PAT) as a versatile tool for real-time monitoring and kinetic evaluation of photocatalytic reactions

“…13 In particular, photoredox catalysis in the visible range is a fast growing field due to the possible utilisation of sunlight. [14][15][16] While tremendous research efforts focus on challenging C-H activations 17,18 or enantioselective synthesis, 19,20 an evaluation of the underlying reaction kinetics is rarely performed. Nevertheless, detailed knowledge about the interdependence of process parameters like catalyst concentration and light intensity is indispensable for reaction modelling and further industrial application.…”

Organophotocatalytic Regioselective C−H Alkylation of Electron‐Rich Arenes Using Activated and Unactivated Alkenes

“…[19] In 2020, Nicewicz developed a visible-light induced CÀ H alkylation of arenes with diazoacetates with moderate to good regioselectivity (Scheme 1b, bottom). [20] The reaction undergoes a distonic cationic aryl radical induced cationic aromatic cyclopropanation/oxidative ring opening mechanism (Scheme 1b, bottom). Collectively, methodologies using diazo radicals as the alkylating reagents restricted to scope of alkylating group as well as incompatibility of certain functional groups due to the reactive nature of diazo compounds.…”