康 · 学术 | Reaction of the Day No. 1772

Photochemical Aminomethylation of C(sp3)–H Bonds via Hydrogen Atom Transfer

Merve Akdeniz1, Lorenzo Di Terlizzi1, Jonas Djossou1, Timothy Noel

Flow Chemistry Group, Van ’t Hoff Institute for Molecular Sciences (HIMS), University of Amsterdam

—10.26434/chemrxiv.15010233/v1

Recommended by Qifei Hu _ SC

KEY WORDS: Aminomethylation, photo chemistry, C-H activation, Flow Chemistry (反应类型),Csp3-Csp3, Csp3-N (成键类型),α-amino C–H bonds, α-oxy C–H bonds, α-thio C–H bonds, Formaldehyde(原料), sulfonamides, 1,2-diamines, amino alcohols, α-amino carbonyl compounds(产物)

ABSTRACT:Direct installation of an aminomethyl group onto aliphatic C–H bonds provides an attractive route to valuable amine-containing building blocks but remains challenging with conventional polar approaches. Here, we report a photochemical aminomethylation of C(sp3)–H bonds enabled by hydrogen atom transfer (HAT). Photoexcited benzophenone directly abstracts hydrogen from α-amino, α-oxy, and α-thio C–H bonds, generating carbon-centered radicals that are intercepted by an in situ-formed N-protected formimine. This strategy provides direct access to protected vicinal diamines, amino alcohol derivatives, and related aminomethylatedproducts without requiring prefunctionalization of the C–H donor. Notably, the C–H substrate can be employed as the limiting reagent, while selective radical generation suppresses overfunctionalization. Translation to continuous flow reduces reaction times from 20 h to 3 h, while improving yields for the investigated substrates, and enables scalable synthesis. Subsequent deprotection and functionalization further demonstrate the synthetic utility of the resulting aminomethylatedproducts.

Substrate Scope: N-containing H-donors (selected examples)

Substrate Scope: O- containing H-donors (selected examples) 

Generality of the amidomethylation of non-acidic C-H positions (selected examples) 

Flow scale-up for the synthesis of selected compounds

Downstream synthetic applications

Proposed Mechanism

Summary and Comments

Recently, Prof. Timothy Noel and his group developed a direct photochemical strategy for the aminomethylation of C(sp3)–H bonds through hydrogen atom transfer. By coupling HAT-based radical generation with in situ-formed formimines, α-amino, α-oxy, and α-thio C–H bonds can be converted into valuable aminomethylatedproducts without prior functionalization of the carbon partner and with the C–H substrate as the limiting reagent. The resulting products provide versatile entry points to 1,2-diamines, amino alcohols, and α-amino carbonyl compounds, while continuous-flow processing enables substantial process intensification and a scalable synthesis. Overall, this approach extends aminomethylation beyond classical polar disconnections by directly exploiting C–H bonds as latent carbon nucleophiles.