Distal γ‐C(sp³)−H Olefination of Ketone Derivatives and Free Carboxylic Acids

Abstract

Reported herein is the distal γ‐C(sp3)−H olefination of ketone derivatives and free carboxylic acids. Fine tuning of a previously reported imino‐acid directing group and using the ligand combination of a mono‐N‐protected amino acid (MPAA) and an electron‐deficient 2‐pyridone were critical for the γ‐C(sp3)−H olefination of ketone substrates. In addition, MPAAs enabled the γ‐C(sp3)−H olefination of free carboxylic acids to form diverse six‐membered lactones. Besides alkyl carboxylic acids, benzylic C(sp3)−H bonds also could be functionalized to form 3,4‐dihydroisocoumarin structures in a single step from 2‐methyl benzoic acid derivatives. The utility of these protocols was demonstrated in large scale reactions and diversification of the γ‐C(sp3)−H olefinated products.

Access to Unsaturated Bicyclic Lactones by Overriding Conventional C(sp3)-H Site Selectivity

“…All of these results further spurred us to inspect the effectiveness of the protocol for the lactonization of macro rings such as 12, and 15 membered rings. There are no straightforward routes in the literature to prepare bicyclic lactones like [12,5], [15,5] fused lactones in an efficient manner. Gratifyingly, employing our method, we successfully formed such macro bicyclic lactones in synthetically useful yields (Fig.…”

“…1c). [12][13][14][15][16] However, C−H activation was carried out mostly at the terminal methyl group. Reports of -methylene activation in alkyl monocarboxylic acids is yet not known in the literature.…”

Remote C(sp3)—H insertion into non-activated bonds: rapid construction of an added-value molecular diverse library

“…However, the selective functionalization of specific positions within the sidechain of these molecules is not always trivial. Thus, while the functionalization of the α and the β position is well developed (10-16), the selective functionalization of C-H bonds placed at more distant positions with respect to the oxidized functional group usually requires the introduction of a suitable directing group, that must then be cleaved (17,18).…”

Nickel-catalyzed reductive coupling of homoenolates and their higher homologues with unactivated alkyl bromides

“…Early routes for stoichiometric generation of homoenolates include (a) β-deprotonation of camphenilone with KOtBu by Nickon and Lambert 9 ; (b) TiCl 4 -mediated ring opening of silyloxycyclopropanes by Nakamura and Kuwajima 10 ; (c) Brønsted base-mediated metalation of allyl carbamates 11 ; and (d) directed β-metalation of N,N-diisopropyl amides by Beak and colleagues 12,13 , among others [14][15][16][17][18][19][20] . The generation and reactions of γ-metallocarbonyls, however, remains relatively unexplored 21 .…”

“…This method employed 3,3-disubstituted butyric acid derivatives to circumvent the β-C-H functionalization pathway (Fig. 1c) 21,37 . To the best of our knowledge, the use of inexpensive nickel catalysts for the generation and functionalization of β-, or γ-bound carboxylic acid derivatives remains underdeveloped, especially related to coupling of these intermediates with alkyl groups 38,39 .…”