Catalytic alkylation of remote C–H bonds enabled by proton-coupled electron transfer

Abstract

Despite significant advances in hydrogen atom transfer (HAT) catalysis,1–5 there are currently no molecular HAT catalysts capable of homolyzing the strong N-H bonds of N-alkyl amides (Figure 1a). The motivation to develop amide homolysis protocols stems from the synthetic utility of the resulting amidyl radicals, which engage in a variety of synthetically useful transformations, including olefin amination6–11 and directed C-H bond functionalization.12–16 The latter process, a subset of the well-known Hofmann-Löffler-Freytag (HLF) reaction, relies on a favorable bond strength differential to enable amidyls to abstract H• from unactivated aliphatic C-H bonds (Figure 1b).17–21 While powerful, these transforms typically require oxidative N-prefunctionalization of the amide starting materials to achieve efficient amidyl generation. Moreover, as these N-activating groups are often incorporated into the final products, these methods are generally not amenable to the direct construction of C-C bonds. Here we report a new approach that overcomes these limitations by homolyzing the N-H bonds of N-alkyl amides through a proton-coupled electron transfer (PCET) event. In this protocol, an excited state iridium photocatalyst and a weak phosphate base cooperatively serve to remove both a proton and an electron from an amide substrate in a concerted elementary step. The resulting amidyl radical intermediates are shown to be competent to promote subsequent C-H abstraction and radical alkylation steps (Figure 1c). As such, this C-H alkylation represents a novel catalytic variant of the HLF reaction that makes use of simple, unfunctionalized amides to direct the formation of new C-C bonds. Given the prevalence of amides in pharmaceuticals and natural products, we anticipate that this method will simplify the synthesis and structural elaboration of amine-containing targets. Moreover, these studies further demonstrate that concerted PCET can enable homolytic activation of common organic functional groups that are energetically inaccessible using traditional HAT-based approaches.

Complementary Strategies for Directed C(sp3)−H Functionalization: A Comparison of Transition‐Metal‐Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene Transfer

“…More recent studies incorporate photoredox catalysis into the oxidation of NÀHb onds.T he groups of Rovis [129] and Knowles [130] simultaneously and independently disclosed the remote alkylation of unactivated C(sp 3 )ÀHbonds directed by an amide (Scheme 47). In the system developed by Chu and Rovis,t rifluoroacetamide 263 undergoes alkylation at the tertiary C À Hb ond with methyl methacrylate (264)t of orm amide 265.S imilarly,a lkylated product 271 can be obtained from amide 269 with methyl vinyl ketone (270)b yu sing the procedure developed by Knowles and co-workers.I nt he proposed catalytic cycle of these two reactions,t he excited photocatalyst oxidizes amide 258 to yield nitrogen radical 259 in the presence of abase.A1,5-HATand trapping of the alkyl radical 260 with the electrophilic alkene generates aradical in the a-position to an electron-withdrawing group (261).…”

“…[169] Theh igher electron density of tertiary alkyl radicals accelerates their trapping with electron-deficient radical partners,t hereby suppressing undesired side reactions.Secondary and primary CÀHb onds are less reactive than their tertiary counterparts, but also can give reasonable yields.U nfortunately,t he functionalization of primary CÀHb onds with hydrogen atom transfer was not demonstrated in the most recent research with photoredox catalysis. [129,130,137] …”

Komplementäre Strategien für die dirigierte C(sp3)‐H‐Funktionalisierung: ein Vergleich von übergangsmetallkatalysierter Aktivierung, Wasserstoffatomtransfer und Carben‐ oder Nitrentransfer

“…[121] In dem postulierten Katalysezyklus reduziert der Kupfer(I) [122] Die N-Cl-Bindung des Sulfonamids 233 wird durch den angeregten Photokatalysator [Ir(ppy) 2 Neuere Forschungen binden die Photoredoxkatalyse in die Oxidation von N-H-Bindungen ein. Rovis [129] und Knowles [130] …”

“…Leider wurde die Funktionalisierung primärer C-H-Bindungen durch Wasserstoffatomtransfer mittels Photoredoxkatalyse bisher nicht demonstriert. [129,130,137] …”

“…Aktuelle Berichte von Rovis [129] und Knowles [130] sorgten jedoch fürF ortschritte in diesem Punkt (Schema 47 [206] die die Verwendung von Bu 3 SnH umgehen und eine Lçsung bieten kçnnten, um den begrenzten Anwendungsbereich der C(sp 3 )-H-Funktionalisierung mit Arylradikalen zu erweitern.…”