Introduction of the 4,4,4-Trifluorobut-2-ene Chain Exploiting a Regioselective Tsuji–Trost Reaction Catalyzed by Palladium Nanoparticles

Abstract

A palladium-nanoparticle-catalyzed Tsuji-Trost reaction of 4,4,4-trifluorobut-2-en-1-yl acetate and ethyl(4,4,4-trifluorobut-2-en-1-yl)carbonate was accomplished with various nucleophiles including phenols, amines, and malonates. In the case of the phenols, isomerization of the double bond in the product (up to 20%) was observed as a side reaction. Further synthetic transformations including hydrogenation, the Diels-Alder reaction, and asymmetric dihydroxylation of a product were also examined.

Systematic study of the reactivity of (E)-4,4,4-trifluorobut-2-en-1-yl 4-methylbenzenesulfonate towards different classes of nucleophiles

“…This was a significant sidereaction in the palladium-catalyzed transformation [6]. In this case, isomerisation of the starting allylic tosylate was observed instead (10; 11% by NMR).…”

“…Increasing the number of equivalent of the malonate to 4 provided full conversion in 48 h. A better ratio in favor of 24a was obtained (83:17) and the desired product could be isolated in 72% yield. This product could not be obtained under the Tsuji-Trost reaction as 25 was the major product [6]. The reaction with dibenzyl methylmalonate proved to be slower and only 70% conversion was obtained after 96 h with 1.1 equivalent of the nucleophile.…”

“…Thiols have never been used as nucleophile in substitution reactions with reagent 1-3, and they did not behave well in our Tsuji-Trost reaction where they provided only trace amounts (up to 6%) of the desired products (13) along with the isomerized product (14) and various non-identified fluorinated side-products (7-15%) (Scheme 7) [6].…”

“…Page 12 of 25 A c c e p t e d M a n u s c r i p t 10 the use of a primary amine was not possible with the Tsuji-Trost system as a complex mixture was obtained [6].…”

“…Also, the use of other nucleophiles has not been really investigated [4,5]. We have recently explored an alternative strategy using a Tsuji-Trost reaction catalyzed by nanoparticles starting from either 4,4,4-trifluorobut-2-en-1-yl acetate (4) or ethyl (4,4,4-trifluorobut-2-en-1-yl)-carbonate (5) (Scheme 1) [6]. These conditions could be used to attach a 4,4,4-trifluorobut-2-ene chain not only to phenols, but also to secondary amines and malonates for the first time.…”