3,3-Dibromo-2-trifluoromethyl acrylic acid ethyl ester: a versatile platform for the stereoselective preparation of functionalized-α-trifluoromethyl α,β-unsaturated lactones and trifluoromethyl pyrazolinones

Abstract

We herein describe a method for the synthetic routes to multi-functionalized-α-trifluoromethyl α,β-unsaturated lactones and trifluoromethyl pyrazolinones. This involves tandem stereoselective functionalization of 3,3-dibromo-2-trifluoromethyl acrylic acid ethyl ester and intramolecular cyclization reaction to afford precursors for a Suzuki-Miyaura cross-coupling reaction with arylboronic acids.

Synthesis of Trifluoromethyl‐α,β‐unsaturated Lactones and Pyrazolinones and Discovery of Influenza Virus Polymerase Inhibitors

“…We recently developed a novel synthetic method for assessing various multi‐functionalized α‐trifluoromethyl‐α,β‐unsaturated lactones and trifluoromethyl pyrazolinones from 3,3‐dibromo‐2‐trifluoromethyl‐acrylic acid ethyl ester 1 a as a single precursor . The synthetic routes are outlined in Scheme .…”

“…To effectively obtain diverse compounds of functionalized‐α‐trifluoromethyl‐α,β‐unsaturated lactones C and trifluoromethyl pyrazolinones D , further transformation using a Suzuki–Miyaura cross‐coupling reaction with various arylboronic acids can be employed. All compounds shown in Figure have already been reported in our recent work . These compounds were screened in anti‐influenza tests to determine the potency of their inhibitory activity.…”

“…Thin‐layer chromatography was performed on TLC Silica gel 60 F 254 aluminum sheets (Merck, Ltd.) and silica gel F 254 glass plates (Merck). For chemical experiments, α‐trifluoromethyl‐α,β‐unsaturated lactones ( 3 a – e , 4 a , b , 5 a – g , 6 a , b , 7 a , b , and 8 – 10 ) and trifluoromethyl pyrazolinones ( 11 a , b , 12 a – e , 13 , and 14 a , b ) which were previously synthesized, were used for biological tests. NMR spectral information and physical data are shown in Supporting Information (Chemistry and NMR spectral information).…”

“…To effectively obtain an array of trifluoromethyl heterocycles, divergent synthesis for drug discovery using a simple and readily available CF 3 ‐containing precursor to convert into a diverse set of trifluoromethyl heterocyclic compounds is one of the straightforward strategies. We recently reported a method for the efficient synthesis of α‐trifluoromethyl‐α,β‐unsaturated lactones and trifluoromethyl pyrazolinones . These two structural motifs of trifluoromethyl heterocycles were synthesized by following a synthetic pathway that includes tandem stereoselective functionalization of a key precursor, 3,3‐dibromo‐2‐trifluoromethyl acrylic acid ethyl ester.…”

“…In particular, γ‐lactone as an important core unit is found in a large number of biological compounds possessing biological activities such as antiviral, antitumor, antiulcer, cardiotonic, antihelmintic, antiallergic, contraceptive, and immunomodulation activities . Thus, α‐trifluoromethyl‐α,β‐unsaturated lactones and trifluoromethyl pyrazolinones which have been synthesized previously may be used as new biological agents. With the aim to explore their potential biological activities, we have performed preliminary screening for testing antiviral, antibacterial and antitumor activities of the γ‐lactone compounds using influenza virus, Escherichia coli , and HeLa (human carcinoma cell line), respectively.…”