Construction of Vicinal Tetrasubstituted Stereocenters with a C–F Bond through a Catalytic Enantioselective Detrifluoroacetylative Mannich Reaction

Abstract

An efficient asymmetric detrifluoroacetylative Mannich reaction of 2-fluoro-1,3-diketones/hydrates with isatin-derived ketimines catalyzed by a chiral copper(II)-diamine complex has been realized. The reaction afforded a series of 3-substituted 3-amino-2-oxindoles bearing fluorine-containing vicinal tetrasubstituted stereocenters in high yields (up to 99%) with excellent diastereoselectivities (up to >20:1 dr) and enantioselectivities (up to 94% ee).

Detrifluoroacetylative cascade reactions of bicyclic fluoro-enolates with ortho -phthalaldehyde: Aspects of reactivity, diastereo- and enantioselectivity

“…Consistent with our interest in the development of new reagents for asymmetric synthesis of fluoro-organic compounds [9], we recently reported a new brand of enolate precursors 3, designed as general reagents for installation of sterically constrained polycyclic moieties containing quaternary stereogenic C-F group [10]. We [10,11] and others [12] have assessed the original reactivity of enolate precursors 3 in asymmetric aldol and Mannich addition reactions.…”

Catalytic Enantioselective Michael Addition Reactions of Tertiary Enolates Generated by Detrifluoroacetylation

“…In the presence of organic base (usually triethylamine) and metal ions (usually LiBr) compounds 1–3 readily undergo in situ elimination of trifluoroacetic acid and generation of corresponding enolates 4 . Chemistry of these enolates has been studied on the examples of halogenation, aldol and Mannich addition reactions. While it is still premature to draw any definite conclusion about reactivity of these enolates generated in situ by detrifluoroacetylation, the available data point to the necessity to use highly electrophilic reaction partners.…”

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This work describes, for the first time, Michael additionr eactions of tertiary fluoro-enolates in situ generated by detrifluoroacetylation with 1-(1-(phenylsulfonyl) vinylsulfonyl)benzene. While it is still premature to draw any definite conclusion about reactivity of these enolates generated in situ by detrifluoroacetylation, the available data [11][12][13][14][15][16][17][18][19][20] point to the necessity to use highly electrophilic reaction partners.F or example, enolates 4 do not react at all with unactivated imines [16a] and ketones. These reactions show ac onsiderable degree of structuralg eneralitya nd allow the preparation of new types of biologically relevant molecules that contain quaternaryC ÀFstereogenic carbonatomsand feature five-, six-, or seven-membered rings as well as heterocyclic 3-fluoro-2,3-dihydrochromen-4-one moieties.

Development of new efficient methodsf or the synthesis of fluorine-containing compounds remainso ne of the central challenges of modern organic chemistry.

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“…Over the years, the fluorinatedb uilding-block approach was shown to be synthetically reliablea nd functional as ag roup-diverse strategyf or the preparation of structurally complex molecules of medicinal importance. [6,7] As presented in Scheme 1, three general structural types of enolate precursors 1, [6,8] 2, [9] and 3 [10] have been introduceds o far.I nt he presence of organic base (usually triethylamine) and metali ons (usually LiBr) compounds 1-3 readily undergo in situ elimination of trifluoroacetic acid and generationo fc orresponding enolates 4.C hemistry of these enolates has been studied on the examples of halogenation, [11] aldol [12][13][14][15] and Mannich [16][17][18][19][20] addition reactions. [5] One of the recent innovations in this chemistryw as the development of a detrifluoroacetylative approach fort he in situ generation of fluoro-enolates (Scheme 1).…”

“…[4] In this area, fluorine-containing enols are particularly attractive structural units displaying versatile reactivity and target molecular diversity. While it is still premature to draw any definite conclusion about reactivity of these enolates generated in situ by detrifluoroacetylation, the available data [11][12][13][14][15][16][17][18][19][20] point to the necessity to use highly electrophilic reaction partners.F or example, enolates 4 do not react at all with unactivated imines [16a] and ketones. [6,7] As presented in Scheme 1, three general structural types of enolate precursors 1, [6,8] 2, [9] and 3 [10] have been introduceds o far.I nt he presence of organic base (usually triethylamine) and metali ons (usually LiBr) compounds 1-3 readily undergo in situ elimination of trifluoroacetic acid and generationo fc orresponding enolates 4.C hemistry of these enolates has been studied on the examples of halogenation, [11] aldol [12][13][14][15] and Mannich [16][17][18][19][20] addition reactions.…”