Asymmetric α-Functionalization of 2-Alkyl Azaarenes: Synthesis of Tertiary Fluorides Having Vicinal Stereogenic Centers

Abstract

An enantioselective approach for synthesizing fluorinated azaarenes containing vicinal quaternary−tertiary stereocenters is summarized. The chiral copper(I)−phosphine complex binds with the azaarenes followed by Michael addition to unsaturated acyl imidazoles, resulting in α-functionalized products with an excellent level of enantioselectivities (up to 99%), diastereoselectivities (>20:1), and yields (up to 97%). Furthermore, post-functionalization of the acyl imidazole part has also been demonstrated.

Enantioselective Vinylogous Mukaiyama‐Michael Reaction of Silyl Ketene Acetals to α,β‐Unsaturated 2‐Acyl Imidazoles to Construct 1,7‐dioxo Compounds

“…Subsequently, the effects of solvent on the enantioselectivity of 3 aa were also investigated. Solvent screening revealed that the outcomes in DCM, DCE, THF and toluene were inferior compared to CHCl 3 (Table 1, entries [13][14][15][16].…”

“…[12] As a result, novel enantioselective approaches have been devised by employing α,β-unsaturated 2acyl imidazoles as a favored substrate. [13] In this context, our research group recently described enantioselective reports on α,β-unsaturated 2-acyl imidazoles to generate vicinal stereocenters, [14] and to synthesize different core moieties such as substituted pyrrolidines, [15] and 1-pyrrolines. [16] Herein, we disclose the first Sc(III)-pybox catalyzed enantioselective vinylogous Mukaiyama-Michael reaction (VMMcR) of vinyl ketene silyl acetals with α,β-unsaturated 2-acyl imidazoles to construct enantioenriched 1,7-dioxo compounds (Scheme 1c).…”

Enantioselective Conjugate Addition of Boronic Acids to α,β-Unsaturated 2-Acyl Imidazoles Catalyzed by Chiral Diols

“…Over the past few decades, the conjugate addition reactions of organoboron compounds to α,β-unsaturated carbonyl compounds have been successfully achieved, using transition metal catalysts, such as rhodium, palladium, copper, nickel, and so on, which offer a broad substrate scope and functional group tolerance . α,β-Unsaturated 2-acyl imidazoles represent an important class of substrates for asymmetric reactions, and the 2-acylimidazolyl moiety can be transformed into various carboxylic functional groups . In 2012, Ohmiya and Sawamura reported the first enantioselective conjugate addition of alkylboranes (alkyl-9-BBN) to imidazole-2-yl α,β-unsaturated ketones catalyzed by a copper- N -heterocyclic carbene complex (Scheme a) .…”

Asymmetric Construction of Carbon–Fluorine Quaternary Stereogenic Centers via Synergistic Pd/Cu Catalysis

“…7 Addi-tionally, Singh and co-workers also reported a highly enantioselective method for the synthesis of tertiary fluorides bearing vicinal quaternary−tertiary stereocenters. 8 These approaches suggest that the construction of tertiary alkyl fluorides with high enantioselectivity can be efficiently accomplished with α-fluoro pyridinyl acetates. However, in all of the examples, products were furnished with two chiral vicinal stereocenters using identical ligand L1 (Scheme 1, 1a− 1c).…”

“…Afterward, He and co-workers reported Pd- and Cu-catalyzed asymmetric cross-coupling of conjugated enyne with α-fluoro pyridinyl acetates, giving allenes bearing carbon–fluorine quaternary stereogenic centers in high yield with high enantioselectivities and diastereoselectivities . Additionally, Singh and co-workers also reported a highly enantioselective method for the synthesis of tertiary fluorides bearing vicinal quaternary–tertiary stereocenters . These approaches suggest that the construction of tertiary alkyl fluorides with high enantioselectivity can be efficiently accomplished with α-fluoro pyridinyl acetates.…”