3,5‐Bis(trifluoromethyl)phenyl Sulfones for the Highly Stereoselective Julia–Kocienski Synthesis of α,β‐Unsaturated Esters and Weinreb Amides

Abstract

The 3,5-bis(trifluoromethyl)phenyl (BTFP) sulfones tert-butyl α-(BTFPsulfonyl)acetate (4) and Weinreb α-(BTFPsulfonyl)-acetamide (5) have successfully been employed in the JuliaKocienski olefination of aldehydes with K 2 CO 3 as the base at 120°C in DMF under solid/liquid phase-transfer catalysis conditions to afford α,β-unsaturated esters and Weinreb amides, respectively. The corresponding products were obtained in good yields and with high E stereoselectivities (E/Z up to Ͼ99:1), especially in the case of the amides. A detailed computational study of the Julia-Kocienski olefination with BTFP sulfone 4 was carried out and confirmed the existence of an equilibrium in the initial addition of the sulfone enolate

Highly Efficient and Stereoselective Julia–Kocienski Protocol for the Synthesis of α‐Fluoro‐α,β‐unsaturated Esters and Weinreb Amides Employing 3,5‐Bis(trifluoromethyl)phenyl (BTFP) Sulfones

“…[22] As we have previously shown for the olefination of aromatic aldehydes with non-fluorinated sulfones 5 and 6, [15] the reaction proceeds through a two-step mechanism (Scheme 2). The first one (TS1) corresponds to the nucleophilic addition of enolate I to benzaldehyde and generating a high-in-energy alkoxy intermediate (II-type).…”

“…Evaporation of the solvent afforded the corresponding pure crude sulfones 5a, 5b, and 6 which were recrystallized in ether/hexane or purified by flash chromatography (hexane/EtOAc). Products 5b [15] and 6 [15] have been previously described and gave satisfactory spectroscopic and physical data. For compound 5a see Supporting Information.…”

“…Since previously studies with unfluorinated BTFP sulfones 5b and 6 [15] had shown K 2 CO 3 (9 equiv.) and TBAB (0.1 equiv.)…”

“…The obtained yields and Z/E ratios are displayed in Table 1 Under the optimized reaction conditions, the synthesis of a-fluoroacrylates through the modified Julia olefination with methyl and tert-butyl esters 3a and 3b was next investigated (Table 1, entries [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. As shown, the fluorinated BTFP sulfone reagents 3 were significantly more reactive than the non-fluorinated congeners 5 [15] probably due to the alpha effect of the fluorine atom. Condensation of BTFP sulfones 3a and 3b with selected aldehydes gave, in general, good yields of the corresponding a-fluoro-a,b-unsaturated esters 7a and 7b, respectively.…”

“…[14] Very recently, BTFP sulfones have also been successfully used for the stereoselective synthesis of a,b-unsaturated esters and Weinreb amides under solid-liquid PTC conditions. [15,16] Herein we report the synthesis of a-(BTFP sulfonyl)-a-fluoroacetates 3 and Weinreb amide 4 and their use as efficient reagents for a highly stereoselective synthesis of a-fluoro-a,b-unsaturated esters and Weinreb amides, respectively.…”