Enantioselective Synthesis of β-Fluoro-β-aryl-α-aminopentenamides by Organocatalytic [2,3]-Sigmatropic Rearrangement

Abstract

The tetramisole-promoted catalytic enantioselective [2,3]-sigmatropic rearrangement of quaternary ammonium salts bearing a (Z)-3-fluoro-3-arylprop-2-ene group generates, after addition of benzylamine, a range of β-fluoro-β-aryl-α-aminopentenamides containing a stereogenic tertiary fluorine substituent. Cyclic and acyclic nitrogen substituents as well as various aromatic substituents are tolerated, giving the β-fluoro-β-aryl-α-aminopentenamide products in up to 76% yield, 96:4 dr, and 98:2 er.

Effect of Fluorination on Skin Sensitization Potential and Fragrant Properties of Cinnamyl Compounds

“…[12] Reduction of ester 3b by LiBH 4 in tetrahydrofuran (THF) afforded the alcohol 2b in quantitative yield. [13] This latter compound was then oxidized by IBX (2-iodoxybenzoic acid) to give the desired 2-fluorocinnamaldehyde (1b) in 85% yield, as already published by Wheeler et al [14] Ethyl (Z)-3-fluoro-3-phenylacrylate (3c) was synthesized by the addition of silver fluoride to ethyl phenylpropiolate as reported by Jiang and co-workers, and is described in Scheme 2. [15] The fluorine addition proceeded in a regio-and stereoselective manner to afford exclusively the (Z)-configured product.…”

“…[11] [35] In an oven-dried three-neck flask equipped with a stir bar and flushed with argon, a solution of the benzaldehyde (1.1 g, 10.3 mmol.) [11] [13] In an oven dried three-neck flask equipped with a stir bar and flushed with argon, a solution of ester 3b (850 mg, 4.4 mmol) in dry THF (20 ml) was prepared. A solution of diethylzinc (42.4 mmol, 1 M in hexanes) was then added slowly through cannula at 0°C.…”

“…The biphasic mixture was then concentrated under reduced pressure and the residue extracted three times with Et 2 O. 13 After removal of the MgSO 4 and evaporation of the volatile materials under reduced pressure, the crude was purified by flash chromatography on silica gel (cyclohexane/AcOEt 9:1) to afford the expected ester 3b (1.2 g, 60% yield) as a colorless oil.…”

“…1 (2Z)-2-Fluoro-3-phenylprop-2-en-1-ol (2b). [11] [13] In an oven dried three-neck flask equipped with a stir bar and flushed with argon, a solution of ester 3b (850 mg, 4.4 mmol) in dry THF (20 ml) was prepared. The mixture was cooled to 0°C and lithium borohydride (670 mg, 30.8 mmol) was then added slowly.…”

“…1 H-NMR (400 MHz, CD 2 Cl 2 ) 10.17 (d, J = 7.6, 1 H); 7.76 -7.69 (m, 2 H); 7.59 -7.53 (m, 1 H); 7.53 -7.46 (m, 2 H); 6.10 (dd, J = 7.6, 34.0, 1 H). 13…”