Diastereoselective Synthesis of Enantioenriched Trifluoromethylated Ethylenediamines and Isoindolines Containing Two Stereogenic Carbon Centers by Nucleophilic Trifluoromethylation Using HFC-23

Abstract

Fluoroform, HFC-23, is an industrial byproduct from the synthesis of polytetrafluoroethylene and is a vastly underused resource; however, its physicochemical properties have hindered progress toward synthetic uses. Herein, we describe the use of HFC-23 as a cheap trifluoromethylating agent in two reactions for the highly diastereoselective synthesis of medicinally attractive chiral amines with two stereogenic carbon centers: a base-dependent, stereodivergent nucleophilic addition to synthesize enantioenriched vicinal diamines and a tandem nucleophilic addition/aza-Michael sequence toward enantioenriched isoindolines.

Organic Superbases in Recent Synthetic Methodology Research

“…The use of KHMDS conditions developed by Prakash promotes addition to the opposite face of the imine compared to use of P 4 ‐ t Bu, a result explained through a chelated or non‐chelated addition transition state, respectively. An example of this methodology to access two diastereomers of a chiral diamine is shown in Figure 9 b [47b] …”

Synthesis of trifluoromethyl ketones by nucleophilic trifluoromethylation of esters under a fluoroform/KHMDS/triglyme system

“…Rather than decomposing CF 3 compounds, it would be better to maximize the efficiency of their use [16][17][18]. However, taming HCF 3 as a trifluoromethylation agent is a challenge in organic chemistry [19][20][21][22][23][24][25][26][27][28], although recent rapid progress in the chemistry of HCF 3 by Grushin (for CuCF 3 ) [29][30][31][32][33][34][35][36][37], Prakash (for KCF 3 ) [38], and others [39][40][41][42][43][44], including our group [45][46][47][48][49][50], has dramatically improved the prospects. One of the problems facing the treatment of HCF 3 for nucleophilic trifluoromethylation reactions is the low stability of the directly generated CF 3 anion (CF 3 − ) for decomposing to difluorocarbene (:CF 2 ) and fluoride (F − ) (Scheme 1a).…”

“…However, the preparation of NaDA was rather complicated and required pre-mixing of diisopropylamine, tetramethylethylenediamine (TMEDA), isoprene, and even more tedious "dispersion sodium" in n-heptane at 25°C for 4 h, before the reaction of esters with HCF 3 at −60 °C. We herein extend our glyme strategy [50] shown in Scheme 1d, the HCF 3 /KHMDS/triglyme system, for the synthesis of trifluoromethyl ketones from esters (Scheme 2e). The combination of HCF 3 and KHMDS in triglyme at −40 °C was found to be effective for this transformation, with good yields as high as 92%.…”

A study on selective transformation of norbornadiene into fluorinated cyclopentane-fused isoxazolines

“…In order to prepare a certain fluorinated organic molecule, two common approaches are used: i) late-stage fluorination, when the fluorine atom is incorporated in the final step of the synthetic protocol (e.g., deoxofluorinations) or ii) application of various commercial fluorine-containing scaffolds (e.g., fluorine-containing amines, fluorine-containing alkenes etc.) [49][50][51][52][53][54][55][56][57][58]. It is to be noted that a recent review has been devoted to the synthesis of various fluorine-containing derivatives through various metathesis techniques by the application of versatile fluorinated substrates [59].…”