Intramolecular Nitrone Cycloaddition of α-(Trifluoromethyl)styrenes. Role of the CF₃Group in the Regioselectivity

Abstract

The intramolecular 1,3-dipolar cycloaddition of ortho-substituted 1,1,1-trifluoromethylstyrene-derived nitrones is described. Tricyclic fused isoxazolidines were obtained as major or exclusive products, in contrast to the case for nonfluorinated substrates, which rendered the bridged derivatives. This change in the regioselectivity was attributed to the electronic and, particularly, steric requirements of the trifluoromethyl group in comparison to the methyl group. It is worth mentioning that trifluoromethylstyrenes have been employed for the first time as dipolarophiles in a 1,3-dipolar intramolecular cycloaddition reaction, leading to the corresponding isoxazolidines bearing a quaternary trifluoromethyl moiety. Finally, the synthetic utility of the developed methodology has been illustrated with the synthesis of a family of bicyclic fluorinated 1,3-amino alcohols.

Organocatalytic Enantioselective Synthesis of Trifluoromethyl‐Containing Tetralin Derivatives by Sequential (Hetero)Michael Reaction–Intramolecular Nitrone Cycloaddition

“…Very recently we disclosed the utility of α‐trifluoromethylstyrenes as suitable dipolarophiles for the intramolecular nitrone cycloaddition reaction (INCR). In this work, we found that the CF 3 acts as a directing group in controlling the regiochemistry of the cyclization process, affording preferentially or exclusively the corresponding fused tricyclic cycloadducts . The next step in our study was directed towards the enantioselective version of this transformation.…”

“…With these precedents, and inspired by our interest in organofluorine chemistry, we envisioned the possibility of employing cinnamaldehydes, substituted at the ortho position with a 1‐trifluoromethylalkene moiety, as starting substrates to carry out an organocatalytic nucleophilic conjugate addition followed by INCR. By means of this sequence, that employs the almost unprecedented 1‐trifluoromethylalkene as dipolarophile, a novel family of fluorinated tetralins bearing an all‐carbon CF 3 ‐containing quaternary stereocenter will be obtained [Scheme , Eq. (2)].…”

Fluoroalkyl N-sulfonyl hydrazones: An efficient reagent for the synthesis of fluoroalkylated compounds

“…Later, the Valdés group [26] discovered that the Pd-catalyzed crosscoupling of aryl bromides with N-tosyl hydrazones ( 16) derived from 1,1,1-trifluoroacetone yielded high yields of 3,3,3-trifluoromethylstyrenes (17). They are valuable synthetic intermediates used to synthesize a variety of fluoroalkylated benzo-fused bicyclic allylic amines [49], tetralins [50], tricyclic fused isoxazolidines [51], and polycyclic Scheme 2 Synthesis of fluoroalkylated pyrazolines from TFHz-Ts (color online).…”

Synthesis of 1-Trifluorometylindanes and Close Structures: A Mini Review

“…Intramolecular radical cyclization has been used in the stereoselective synthesis of 1-CF3-indane 44 from compound 43 in the presence of (n-Bu)3SnH and AIBN (Scheme 25) [41]. Pozo, Fustero et al have used intramolecular 1,3-dipolar nitrone cycloaddition to construct a 1-CF 3 -indane core from compounds 45 (Scheme 26) [42]. The reaction of the aldehyde group of substrates 45 with N-alkylhydroxylamines gives rise to the intermediate formation of the corresponding nitrones, which are spontaneously cyclized into isoxazolidines 46 adjacent to the trifluoromethylindane fragment.…”