Ritter-type amination of C(sp3)-H bonds enabled by electrochemistry with SO42−

Abstract

By merging electricity with sulfate, the Ritter-type amination of C(sp3)-H bonds is developed in an undivided cell under room temperature. This method features broad substrate generality (71 examples, up to 93% yields), high functional-group compatibility, facile scalability, excellent site-selectivity and mild conditions. Common alkanes and electron-deficient alkylbenzenes are viable substrates. It also provides a straightforward protocol for incorporating C-deuterated acetylamino group into C(sp3)-H sites. Application in the synthesis or modification of pharmaceuticals or their derivatives and gram-scale synthesis demonstrate the practicability of this method. Mechanistic experiments show that sulfate radical anion, formed by electrolysis of sulfate, served as hydrogen atom transfer agent to provide alkyl radical intermediate. This method paves a convenient and flexible pathway for realizing various synthetically useful transformations of C(sp3)-H bonds mediated by sulfate radical anion generated via electrochemistry.

Electrochemical Benzylic C(sp3)–H Amidation via Ritter-Type Reaction in the Absence of External Mediator and Oxidant

“…Compared with the above functionalized substrates, the direct amidation of alkanes or aryl alkanes has not been fully appreciated, probably due to the relatively low reactivity and poor selectivity of the C(sp 3 )−H bonds. Although transitionmetal catalytic chelation-assisted C(sp 3 )−H amidation has been achieved with excellent regioselectivity, the use of directing groups are difficult to avoid (Scheme 1a). 10 Some metal catalyst/oxidant systems such as CuBr/ t BuOOH and FeCl2/NBS were also used to the C(sp 3 )−H amidation of alkanes (Scheme 1b).…”

“…Although transitionmetal catalytic chelation-assisted C(sp 3 )−H amidation has been achieved with excellent regioselectivity, the use of directing groups are difficult to avoid (Scheme 1a). 10 Some metal catalyst/oxidant systems such as CuBr/ t BuOOH and FeCl2/NBS were also used to the C(sp 3 )−H amidation of alkanes (Scheme 1b). 11 An impressive work by Shi, et al uncovered that iodoarene-catalyzed stereospecific intramolecular C(sp 3 )−H amidation using m-CPBA as an oxidant under transition-metalfree conditions (Scheme 1c).…”

“…10 Some metal catalyst/oxidant systems such as CuBr/ t BuOOH and FeCl2/NBS were also used to the C(sp 3 )−H amidation of alkanes (Scheme 1b). 11 An impressive work by Shi, et al uncovered that iodoarene-catalyzed stereospecific intramolecular C(sp 3 )−H amidation using m-CPBA as an oxidant under transition-metalfree conditions (Scheme 1c). 12 In 2022, Wang, Pan and coworkers developed an efficient visible-light-mediated C(sp 3 )-H amination and amidation in the presence of tetrabutylammonium decatungstate (TBADT) and Ni(II) catalyst (Scheme 1d).…”

“…11 An impressive work by Shi, et al uncovered that iodoarene-catalyzed stereospecific intramolecular C(sp 3 )−H amidation using m-CPBA as an oxidant under transition-metalfree conditions (Scheme 1c). 12 In 2022, Wang, Pan and coworkers developed an efficient visible-light-mediated C(sp 3 )-H amination and amidation in the presence of tetrabutylammonium decatungstate (TBADT) and Ni(II) catalyst (Scheme 1d). 13 The Ritter reaction, which was first reported in 1948, provides an efficient way for the formation of Nalkylamides.…”

“…14 In this reaction, a carbocation generated in situ from an alkene or an alcohol under acidic conditions was trapped by a nitrile to produce a nitrilium intermediate. In 2012, Baran and co-workers reported CuBr2/F-TEDA-PF6 mediated Ritter-type C(sp 3 )-H amidation, in which a variety of hydrocarbons such as cycloalkanes were the suitable substrates and a carbocation intermediate could be generated in situ (Scheme 1e). 15 Liu, Chen et al reported an efficient photoredoxcatalysis strategy for the amidation of tertiary and benzylic C-H bonds, and nucleophilic trapping of a carbocation occurred in this process, either (Scheme 1f).…”