Direct arylation of strong aliphatic C–H bonds

Abstract

Despite the widespread success of transition-metal-catalysed cross-coupling methodologies, considerable limitations still exist in reactions at sp-hybridized carbon atoms, with most approaches relying on prefunctionalized alkylmetal or bromide coupling partners. Although the use of native functional groups (for example, carboxylic acids, alkenes and alcohols) has improved the overall efficiency of such transformations by expanding the range of potential feedstocks, the direct functionalization of carbon-hydrogen (C-H) bonds-the most abundant moiety in organic molecules-represents a more ideal approach to molecular construction. In recent years, an impressive range of reactions that form C(sp)-heteroatom bonds from strong C-H bonds has been reported. Additionally, valuable technologies have been developed for the formation of carbon-carbon bonds from the corresponding C(sp)-H bonds via substrate-directed transition-metal C-H insertion, undirected C-H insertion by captodative rhodium carbenoid complexes, or hydrogen atom transfer from weak, hydridic C-H bonds by electrophilic open-shell species. Despite these advances, a mild and general platform for the coupling of strong, neutral C(sp)-H bonds with aryl electrophiles has not been realized. Here we describe a protocol for the direct C(sp) arylation of a diverse set of aliphatic, C-H bond-containing organic frameworks through the combination of light-driven, polyoxometalate-facilitated hydrogen atom transfer and nickel catalysis. This dual-catalytic manifold enables the generation of carbon-centred radicals from strong, neutral C-H bonds, which thereafter act as nucleophiles in nickel-mediated cross-coupling with aryl bromides to afford C(sp)-C(sp) cross-coupled products. This technology enables unprecedented, single-step access to a broad array of complex, medicinally relevant molecules directly from natural products and chemical feedstocks through functionalization at sites that are unreactive under traditional methods.

The Persistent Radical Effect in Organic Synthesis

“…[246] Thet hus generated Cradicals then engage in Ni-mediated cross-couplings according to the general mechanism depicted in Figure 39 a. Instead of quinuclidine,ketones, [247] aldehydes, [248] or adecatungstate complex (see also Section 4.3) [249] can be used as HATr eagents for Cradical generation in such C À Ha rylations (Figure 40 b). After excitation, these mediators abstract an Hatom at activated CÀHs ites in alkanes.A fter Habstraction, the mediators are regenerated by electron transfer and subsequent deprotonation.…”

Morpholine As a Scaffold in Medicinal Chemistry: An Update on Synthetic Strategies

“…In this approach, generation of the carbon‐centered radical is followed by a Ni‐catalyzed cross‐coupling reaction with an aryl bromide, resulting in C−C products with sp 3 hybridization. A representative example is depicted in Scheme A …”

“… A metallophotoredox catalysis of C−H functionalization ( A ) and tert‐butyl hydroperoxide radical based couplings toward morpholine functionalization ( B – D ). Reagents and conditions : a) Ni(dtbbpy)Br 2 (5 mol %), TBADT (1 mol %), K 3 PO 4 (1.1 equiv), ACN (0.1 M), 34 W 390 nm Kessil lamp, fan (yield: 48 %); b) TBHP (2 equiv), t ‐BuOK (10 mol %), MeCN, 110 °C, 24 h (yield: 44 %); c) TBHP (1.5 equiv), FeSO 4 ⋅ 7H 2 O (20 mol %), rt, 36 h (yield: 51 %); d) TBHP (10 mol %), Fe(OAc) 2 (10 mol %), DCE, N 2 atm, 80 °C, 3 h (yield: 51 %) . (TBADT: tetrabutylammonium decatungstate)…”

Alkyl‐C‐C‐Bindungsbildung durch Nickel/Photoredox‐Kreuzkupplung

“…[61] Ein alternativer Ansatz zur Durchführung einer durch HATausgelçsten, dualen katalytischen Kreuzkupplung ist die Verwendung eines Aminreagenzes,u me ine gezielte H- Atomabstraktion zu ermçglichen (Abbildung 4B). [65] 2.6. [62,63] Diese Strategie wurde auf die C-H-Arylierung freier Alkohole ausgedehnt.…”