Cyclometalated Iridium–PhanePhos Complexes Are Active Catalysts in Enantioselective Allene–Fluoral Reductive Coupling and Related Alcohol-Mediated Carbonyl Additions That Form Acyclic Quaternary Carbon Stereocenters

Abstract

Iridium complexes modified by PhanePhos catalyze the 2-propanol-mediated reductive coupling of diverse 1,1-disubstituted allenes 1a-1u with fluoral hydrate 2a to form CF 3-substituted secondary alcohols 3a-3u that incorporate acyclic quaternary carbon-containing stereodiads. By exploiting concentration-dependent stereoselectivity effects related to the interconversion of kinetic (Z)-and thermodynamic (E)-σ-allyliridium isomers, adducts 3a-3u are formed with complete levels of branched regioselectivity and high levels of anti-diastereoand enantioselectivity. The utility of this method for construction of CF 3-oxetanes and CF 3-azetidines is illustrated by the formation of 4a and 6a, respectively. Studies of the reaction mechanism aimed at illuminating the singular effectiveness of PhanePhos as a supporting ligand in this and related transformations have led to the identification of a chromatographically stable cyclometallated iridium-(R)-PhanePhos complex Ir-PP-I that is catalytically competent for allene-fluoral reductive coupling and previously reported transfer hydrogenative CC couplings of dienes or CF 3-allenes with methanol. Deuterium labelling studies, reaction progress kinetic analysis (RPKA) and computational studies corroborate a catalytic mechanism involving rapid allene hydrometalation followed by turnover-limiting carbonyl addition. A computationally determined stereochemical

Multilayer 3D Chirality and Its Synthetic Assembly

“…Even though multilayer chirality has existed in nature from the beginning of the living world, a strategy to mimic this functionality by using planar chirality has not been established yet to the best of our knowledge. So far, planar chirality has only been focused on two-layer arrangement which has been applied to a series of asymmetric reactions [25][26][27][28][29][30][31][32][33][34]. For example, Lautens and coworkers established a bulky and electron rich Qphos ligand for Pd-catalyzed cycloisomerization (carbohalogenation) reaction for the formation of versatile heterocycles in which the carbon iodine bond was regenerated at the end of the catalytic cycle [27][28][29][30].…”

“…It is interesting that, during this work, the synthesis of both -tosyl benzamide and enantioenriched potassium -amido trifluoroborates would be regarded as GAP (Group-Assisted Purification) since their special functional groups enabled their purification to be performed simply by washing. Very recently, Krische and coworkers launched chromatographically stable chiral Iridium-PhanePhos catalysts and successfully utilized them for various important reactions including allene-fluoral reductive coupling, C-C coupling of methanol with dienes, and CF 3 -allenes [32,33]. In the meanwhile, the two-layer chirality of imidazoline-based biaryl P,N-ligands has been elegantly designed for asymmetric alkyne conjugate addition and alkynylation reactions with excellent asymmetric induction [34].…”

Highly Enantioselective Synthesis of Indazoles with a C3-Quaternary Chiral Center Using CuH Catalysis

“…The hydrocupration of allene 2a with copper hydride 4 takes place via TS1 with a 15.9 kcal/mol activation energy (see the Supporting Information, Figure S1, for other less favorable hydrocupration pathways). This step leads to the irreversible formation of the Z-isomer of the terminal allylic copper species (5). Complex 5 can rapidly isomerize to form either diastereomers of the tertiary benzylic copper intermediate 6, which undergoes subsequent isomerization to afford the thermodynamically more stable E-isomer of the terminal allylic copper (7).…”

“…Allene synthesis: buta-2,3-dien-2-ylbenzene (1a), 2 1-(buta-2,3-dien-2-yl)-4methoxybenzene (1b), 2 1-(buta-2,3-dien-2-yl)-2-fluorobenzene (1c), 3 2-(buta-2,3-dien-2yl)furan (1d), 4 5-(buta-2,3-dien-2-yl)-2-methoxypyridine (1e), 5 1-bromo-4-(penta-1,2dien-3-yl)benzene (1g), 6 1-(buta-2,3-dien-2-yl)-4-(trifluoromethyl)benzene (1j), 2 1-(buta-2,3-dien-2-yl)-2-methylbenzene (1k) 4 are known compounds and were prepared by previously reported procedures. Allene 2-(buta-2,3-dien-2-yl)-1-tosyl-1H-pyrrole (1f), 1-(1-cyclopropylpropa-1,2-dien-1-yl)-4-methoxybenzene (1h), 6-chloro-4vinylidenechromane (1i) and (5-methylhexa-1,2-dien-3-yl)benzene (1l) are unknown compounds and were prepared by previously reported procedures.…”

“…Conventionally, indazoles are employed as nucleophiles in these transformations, and either the N1-or N2-isomer is formed, depending on the reaction conditions. 4,5 Direct C3-alkylation processes, however, are rare due to the lack of nucleophilicity at the C3-position, even when N1-or N2-position is protected ( Figure 1b). 6 Recently, we developed a method to prepare chiral alkylated indoles through a CuH-catalyzed nucleophilic alkylation reaction.…”