When is an Imine Directing Group a Transient Imine Directing Group in C-H Functionalization?

'Transient' C-H functionalization has emerged in recent years to describe the use of a dynamic linkage, often an imine, to direct cyclometallation and subsequent functionalization. As the field continues to grow in popularity, we consider the features that make an imine directing group transient. A transient imine should be i) formed dynamically in situ, ii) avoid discrete introduction or cleavage steps, and iii) offer the potential for catalysis in both the directing group and metal. This concept article contrasts transient imines with pioneering early studies of imines as directing groups for the formation of metallacycles and the use of preformed imines in C-H functionalization. Leading developments in the use of catalytic additives to form transient directing groups (as aldehyde or amine) are covered including selected highlights of the most recent examples of catalytic imine directed C-H functionalization with transition metals.

eHydrogenation: Hydrogen-free Electrochemical Hydrogenation.

Hydrogenation reactions are staple transformations commonly used across scientific fields to synthesise pharmaceuticals, natural products, and various functional materials. However, the vast majority of these reactions require the use of a toxic and costly catalyst leading to unpractical, hazardous and often functionally limited conditions. Herein, we report a new, general, practical, efficient, mild and high-yielding hydrogen-free electrochemical method for the reduction of alkene, alkyne, nitro and azido groups. Finally, this method has been applied to deuterium labelling.

Dual Copper- and Aldehyde-Catalyzed Transient C-H Sulfonylation of Benzylamines.

This study reports the first example of using a dual catalytic system with copper(II) acetate and 2-hydroxynicotinaldehyde to achieve transient C(sp2)-H sulfonylation of benzylamines with sulfinate salts via a dynamically formed imine directing group. Manganese(IV) oxide was identified as an effective oxidant and base. Computational density functional theory investigations suggest that the transient directing group lowers the energy barrier for an acetate-mediated, turnover-limiting C-H activation step and subsequent combination of the cupracycle with a RSO2 radical.

Amine-Catalyzed Copper-Mediated C-H Sulfonylation of Benzaldehydes via a Transient Imine Directing Group.

Transient directing groups (TDGs) can provide a powerful means for C-H functionalization without requiring additional steps for directing group introduction and removal. We report the first use of a TDG in combination with copper to effect C-H functionalization. The regioselective copper mediated ß-C(sp2 )-H sulfonylation of aldehydes with sulfinate salts is accomplished using catalytic ß-alanine to form a transient imine. A broad range of sulfonylated benzaldehydes are prepared using copper fluoride as both copper source and oxidant, involving a [5,6] cupracyclic intermediate. γ-(peri)-Sulfonylation of napthyl and phenanthrenyl carboxaldehydes is achieved through [6,6] cupracyclic intermediates. Further derivatisation of the aldehyde products is demonstrated. Kinetic experiments and Hammett analysis suggest the turnover limiting step to be a concerted asynchronous C-H cleavage via a dearomative Wheland-type transition state.

Transient imine directing groups for the C-H functionalisation of aldehydes, ketones and amines: an update 2018-2020.

The use of pre-installed directing groups has become a popular and powerful strategy to control site selectivity in transition metal catalysed C-H functionalisation reactions. However, the necessity for directing group installation and removal reduces the efficiency of a directed C-H functionalisation method. To overcome this limitation, taking inspiration from organocatalytic methodologies, the use of transient directing groups has arisen. These methods allow for a transient ligand to be used, potentially in catalytic quantities, without the need for discrete installation or removal steps, enabling the discovery of more efficient, and mechanistically intriguing, dual catalytic methods. This review summarises recent developments in this fast moving field covering >70 new methodologies, highlighting new directing group designs and advances in mechanistic understanding. It covers progress since 2018, providing an update to our previous review of the field.

Copper catalysed oxidative α-sulfonylation of branched aldehydes using the acid enhanced reactivity of manganese(iv) oxide.

The oxidative coupling of secondary aldehydes and sulfinate salts is achieved using copper catalysis to form α-sulfonyl aldehydes. The use of an acidic co-solvent is important to adjust the oxidation potential of MnO2 as an oxidant. A broad range of sulfonylated aldehydes is prepared, and their further functionalisation is demonstrated. A dual ionic/radical pathway mechanism is proposed.

Dihalohydration of Alkynols: A Versatile Approach to Diverse Halogenated Molecules.

In this paper we outline how dihalohydration reactions of propargylic alcohols can be used to access a wide variety of useful halogenated building blocks. A novel procedure for dibromohydration of alkynes has been developed, and a selection of dichloro and dibromo diols and cyclic ethers were synthesized. The dihalohydration of homo-propargylic alcohols provides a useful route to 3-halofurans, which were shown to readily undergo cycloaddition reactions under mild conditions. Finally, a novel ring expansion of propargylic alcohols containing a cyclopropylalkyne provides access to halogenated alkenylcyclobutanes.