Diastereoselective synthesis of trifluoromethylated 1,3-dioxanes by intramolecular oxa-Michael reaction

Abstract

A highly diastereoselective synthesis of trifluoromethylated 1,3-dioxanes is described. The reaction proceeds by an addition/oxa-Michael sequence and works efficiently under mild reaction conditions, with a good substrate scope and acceptable to good yields.

An intramolecular oxa-Michael reaction on α,β-unsaturated α-amino-δ-hydroxycarboxylic acid esters. Synthesis of functionalized 1,3-dioxanes

“…The results shown in table 1 prompted us to optimise the reaction conditions and to use other electrophilic reagents. We have recently reported the use of trifluoroacetophenone (TFAP) in addition/oxa-Michael sequences 5 using simple substrates, so we decided to use this ketone as the electrophile in the optimisation process. Table 2 shows the results obtained in this field.…”

“…This motif is present in some interesting molecules, because of its biological properties and structures ( Figure 1); in consequence, straightforward methods to synthesize this fragment are particularly desirable. Traditionally, the 1-amino-2,4-diols have been synthesized by long reaction sequences where the three stereocenters are created by independent steps, 4 thus making the addition/oxa-Michael sequence applied to the correctly functionalized substrates an interesting alternative to synthesize the previously mentioned functionalized diols; nonetheless, there is only one example in literature for the application of this sequence to a Michael acceptor substituted in α position to the electron withdrawing group by a nitrogen 5 and very few examples where the substitution is with an oxygen in the same position.…”

Synthesis of Nitrile-Bearing Quaternary Centers via an Equilibrium-Driven Transnitrilation and Anion-Relay Strategy

“…Procedure based on literature precedent. [5] In a flame-dried round bottom flask equipped with a stir bar, hydrocinnamaldehyde (1.10 mL, 10.0 mmol, 1.00 equiv) and activated zinc powder (990 mg, 15.0 mmol, 1.50 equiv) were added to saturated solution of aq. NH4Cl (8.0 mL) and THF (2.0 mL).…”

“…[4] Of particular interest are reactions that avoid the use or generation of cyanide ions. [5] Herein, we report a method for the generation of all-carbon quaternary centers bearing a nitrile group from secondary alkyl lithiums (or halides) using a one-pot transnitrilation, anion-relay [6] and electrophile-trapping strategy (Scheme 1c). This method uses 2-methyl-2-phenylpropanenitrile as a non-toxic electrophilic CN source, avoiding the use of cyanide salts that are typically involved in the synthesis of alkylnitriles from alkyl halides.…”

Water‐Compatible Synthesis of 2‐Trifluoromethyl‐1,3‐Dioxanes

“…We recently described the preparation of trifluoromethylated 1,3‐dioxanes using trifluoroacetophenones with α,β‐unsaturated‐δ‐hydroxy Michael acceptors and we expanded the reaction scope to the use α,β‐unsaturated α‐amino‐δ‐hydroxycarboxylic acid esters (Scheme a) . The method is based on the in situ generation of a hemiacetal anion that reacts in a Michael addition.…”