(Het)aryl Difluoromethyl‐Substituted β‐Alkoxyenones: Synthesis and Heterocyclizations

Abstract

An efficient approach to the preparation of β‐alkoxyenones bearing (het)aryl difluoromethyl substituents is described. The method included acylation of acyclic or cyclic vinyl ethers with (het)aryl difluoroacetyl chlorides. The method worked well for most substrates, except aryl‐substituted derivatives bearing electron‐donating groups in o‐ or p‐positions, and heteroaromatic compounds bearing sufficiently basic nitrogen atom. Synthetic utility of (het)aryl difluoromethyl‐substituted β‐alkoxyenones as CCC bis‐electrophiles was demonstrated by heterocyclizations with common 1,2‐ and 1,3‐bis‐nucleophiles leading to compounds with (het)aryl–CF2–(het)aryl motif, in particular (het)aryl difluoromethyl‐substituted pyrazoles, isoxazoles, and pyrimidines – promising chemotypes for drug discovery.

Haloacetylated Enol Ethers: a Way Out for the Regioselective Synthesis of Biologically Active Heterocycles

“…Despite the fact that cyclic enones 4 (acylated 3,4‐dihydro‐2 H ‐pyrans) have been used in heterocyclic synthesis for quite some time, [81–84] the introduction of a methoxy or ethoxy group at the 2‐position furnishes a building block with an additional acetal reactive center [85] . The main advantage of this is that, during the ring opening reaction, the acetal moiety, which is easily hydrolyzed, [86,87] may suffer the nucleophilic addition of another portion of the nucleophile (in this case, amines).…”

Synthesis of Fused Pyridine Carboxylates by Reaction of β-Alkoxyvinyl Glyoxylates with Amino Heterocycles

“…Besides increased stability and possibility for preparation of the simplest representatives, improved regioselectivity and increased yields of the condensation products were observed with these building blocks. 17,[40][41][42][43] To the best of our knowledge, synthetic utility of alkoxyvinyl glyoxylates for the construction of fused pyridines was not demonstrated to date. In continuation of our work in the field of pyridine chemistry, [44][45][46][47][48][49][50] we have now aimed at the study of the low-molecular-weight alkoxyvinyl glyoxylates 11a-c as CCC bis-electrophiles in the reactions with common NCC binucleophiles 9 (Scheme 1).…”

A convenient synthetic approach to a novel class of aryldifluoromethyl pyrimidine derivatives containing strobilurin motif as insecticidal agents

“…To the best of our knowledge, there are only a few methods for the synthesis of difuoromethylene‐containing compounds. To date, there are only two examples for the preparation of aryldifluoromethyl pyrimidine (Figure 3): (i) gem‐difuluorination‐deoxofluorination of diarylketones [13,16,32] and (ii) applications of fluorinated building blocks‐(Het)aryl difluoromethyl‐substituted β ‐alkoxyenones by [3 + 3] cycloadditions [33]. Thus, there is an urgent need to develop more efficient and accessible new methods to construct aryldifluoromethyl pyrimidine.…”