2-(Pyridin-2-yl)isopropyl (PIP) Amine: An Enabling Directing Group for Divergent and Asymmetric Functionalization of Unactivated Methylene C(sp³)–H Bonds

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: Directing group (DG) assistance provides a good solution to the problems of reactivity and selectivity, two of the fundamental challenges in C(sp 3 )−H activation. However, the activation of unbiased methylene C(sp 3 )−H bonds remains challenging due to the high heterolytic bond dissociation energy and substantial steric hindrance. Two main strategies have been developed thus far, that is, use of a strongly coordinating bidentate DG pioneered by Daugulis and use of a weakly coordinating monodentate DG accelerated by pyridine-type ligands, as disclosed by Yu. The seminal work by Daugulis sparked significant interest in the application of the monoanionic bidentate auxiliary in aliphatic C−H activation reactions. Our research has focused on enabling the divergent functionalization and enantiotopic differentiation of unactivated methylene C−H bonds. Inspired by the structure of bidentate 8-aminoquinoline and the accelerating effect of the gem-dimethyl moiety in cyclometalations, we developed a strongly coordinating bidentate 2-(pyridine-yl)isopropyl (PIP) amine DG consisting of a pyridyl group, a gem-dimethyl moiety, and an amino group, which enabled the divergent functionalization of unactivated β-methylene C(sp 3)−H bonds to forge C−O, C−N, C−C, and C−F bonds with palladium catalysts. The exclusive βselectivity was ascribed to the preferential formation of kinetically favored [5,5]-bicyclic palladacycle intermediates. DFT calculations revealed that the well-designed gem-dimethyl group was responsible for the lowered energy and compressed bite angle of the key transition state related to C−H cleavage.More recently, the combination of PIP amine with axially chiral ligands was found to promote asymmetric functionalization of unbiased methylene C(sp 3 )−H bonds, a challenging research topic in the area of C−H activation that remains to be addressed. Two different types of axially chiral ligands, namely, non-C 2 -symmetric chiral phosphoric acids (CPAs) and 3,3′-disubstituted BINOLs, have been developed. The former enabled Pd(II)-catalyzed inter-and intramolecular arylation of unbiased methylene C(sp 3 )−H bonds with high enantioselectivity, whereas the latter promoted a series of asymmetric functionalization reactions, such as alkynylation, arylation, alkenylation/aza-Wacker cyclization, and intramolecular amidation. The unexpectedly high stereocontrol compared with other bidentate DGs might be attributable to steric communication between the ligand and gem-dimethyl moiety of PIP amine. Thus far, the combination of PIP amine DG with 3,3′-disubstituted BINOL ligands is arguably the most general strategy for asymmetric functionalization of unbiased methylene C(sp 3 )−H bonds. Finally, the ease of installation and removal of PIP under mild conditions and synthetic applications are described.

Modification of [2.2]paracyclophane through cobalt-catalyzed ortho-C–H allylation and acyloxylation

“…To overcome these preparative challenges, transition metal-catalysed coordination-assisted C–H activation reactions were investigated to streamline the synthesis of ortho -disubstituted [2.2]paracyclophanes. 4,5 Bolm and co-workers reported the first palladium-catalysed ortho -C–H acetoxylation of [2,2]paracyclophanes tailored with a range of N -chelate directing groups (Scheme 1B). 5 a Later in 2013, Bräse and co-workers developed a methyloxime-directed palladium-catalysed C–H halogenation of [2,2]paracyclophanes, allowing the synthesis of ortho -brominated and iodinated aldehydes as key intermediates for the modular synthesis of 4,5-disubstituted [2,2]paracyclophanes (Scheme 1B, top).…”

Copper-catalyzed monoselective C–H amination of ferrocenes with alkylamines

“…We initiated our study by investigating the C-H amination of ferrocene carboxylic amide 1a with morpholine (2a) using 8-amonoquinoline as directing group [51][52][53][54][55][56]. The ortho- aminated ferrocenylamide 3a was isolated in 11% yield in the presence of CuI, N-methylmorpholine N-oxide (NMO) and K 2 CO 3 in DMF (Table 1, entry 1).…”

Atroposelective Synthesis of Conjugated Diene-Based Axially Chiral Styrenes via Pd(II)-Catalyzed Thioether-Directed Alkenyl C–H Olefination

“…However, the strong π-coordinating ability of alkenes might inhibit the reactivity and enantioselectivity. As our long-standing efforts in the construction of chiral molecules via asymmetric C–H activation, herein, we report the highly atroposelective synthesis of atropisomeric styrenes with a conjugated 1,3-diene scaffold by Pd­(II)-catalyzed alkenyl C–H olefination using chiral spiro phosphoric acid as the chiral ligand (Scheme d). A broad range of axially chiral styrenes were obtained with complete Z -selectivity and excellent yields and enantioselectivities (69 examples, up to 99% yield and 99% ee).…”