Stereoselective Organocatalytic Synthesis of α,α-Difluoro-γ,γ-Disubstituted Butenals

Abstract

A highly stereoselective reaction of α,α-difluoro-γ,γ-disubstituted butenals 2 bearing two different substituents at the γ position has been developed with an organocatalytic system of l-proline (30 mol %) and salicylic acid (60 mol %). This novel reaction demonstrated a wide substrate scope and excellent E stereoselectivity in most cases. The obtained difluorinated aldehyde 2a was applied as a useful synthetic precursor for constructing 3,3-disubstituted allylic difluoride moieties.

Cinchona-Based Primary Amine Catalyzed a Proximal Functionalization of Dienamines: Asymmetric α-Fluorination of α-Branched Enals

“…Control by steric hindrance of a substrate has sometimes been quite successful (see the top portion of Figure ). − Moreover, we applied this methodology for the regioselective and stereoselective synthesis of α,α-difluoro-γ,γ-disubstituted butenals, of which fluorination can proceed only at the α-position, because of the steric hindrance of the substrates on γ-position; however, it is inherently not possible to cause a reaction at a sterically hindered reaction site (for example, constructing a quaternary substituted carbon). The steric hindrance of catalysts has also been utilized to differentiate reaction sites, although the reaction has an electrophile size limitation (see the middle panel in Figure ); bulky electrophiles are required to attain excellent stereoselectivity .…”

One‐Pot l‐Proline‐Mediated Stereoselective α‐C(sp2)–H Fluorination of α,β‐Unsaturated Aldehydes through Methoxyfluorination–Elimination

“…Brenner-Moyer [15] reported an organocatalytic asymmetric olefin aminofluorination reaction to synthesize chiral α-fluoro-amino aldehydes (Scheme 1c). Arimitsu [16] reported the first highly regio-and stereoselective organocatalytic synthesis of α,α-difluoro-γ,γ-disubstituted butenals (Scheme 1d). However, the direct α-C(sp 2 )-H fluorination of α, -unsaturated aldehydes was not reported.…”

“…, entries[13][14][15][16][17][18]. When L-proline was not used, only trace amounts of the product were detected (Table 2, entry 19).…”

Stereoselective Synthesis of 4-Substituted 2,4-Dichloro-2-butenals by α- and γ-Regioselective Double Chlorination of Dienamine Catalysis

“…Recently, our group reported a highly stereoselective reaction of 2,2-difluoro-4,4-disubstituted 3-butenals using enolizable α,β-unsaturated aldehydes and N-fluorobenzenesulfonimide (NFSI) in the presence of L-proline as organocatalyst, 9 which can be applied in other halogenation reactions. In this context, herein, we wish to report the stereoselective organocatalytic synthesis of 2,4-dichloro-2butenals in one step from enolizable α,β-unsaturated aldehydes.…”

“…Moreover, neither α,α-nor γ,γ-dichlorinated products were observed in this reaction, which differs from a previous fluorination that gives only α,α-difluorinated products under similar conditions. 9 After determining the optimal conditions, the substrate scope was investigated with regard to the substituent R of aldehyde 1 (Table 2). Generally, aromatic substituents bearing electron-withdrawing groups at the para position resulted in similar reaction outcomes as an unsubstituted phenyl group, and the corresponding products 2 and 3 were obtained in moderate yields (Table 2, entries 2-4).…”