A solvent-free, base-catalyzed domino reaction towards trifluoromethylated benzenes from bio-based methyl coumalate

Abstract

A novel, efficient, and environmentally compatible method for CF3-substituted benzene production is reported. It sources a bio-based feedstock, employs tBuOK as catalyst, and is solvent-free. This regioselective approach provides various trifluoromethyl benzenes in good to excellent yields, without extra oxidant or special care. CO2 and water are the only byproducts of this process, and reaction conditions can scale up to gram quantities. The transformation involves an unprecedented tBuOK-catalyzed domino process, and features Michael addition / 6π-electrocyclic ring opening / [1,5]-H shift / carba-6π-electrocyclic ring closure / decarboxylative aromatization reactions.

2‐Pyrone – A Privileged Heterocycle and Widespread Motif in Nature

“…Expanding this approach, a cascade reaction of coumalate 191, with carbonyl compounds (198 and 199) being further activated by electron-withdrawing groups (EWG) was developed (Scheme 41). [70,71] By applying nucleophiles like 198, highly substituted pyrans 203 and 204 containing diverse functional Scheme 37. Nucleophilic ring opening of 2-pyrone (1).…”

“…[70] Moving to triflouroacetyl compounds 199, benzenes 207 were obtained in excellent yields under mild conditions with a great tolerance of electron-neutral, electronpoor and electron-rich groups (Scheme 41). [71] Concerning the mechanism, the authors propose that both reactions start with a 1,6-conjugated addition of deprotonated 198/199 to pyrone 191, leading to intermediate 200 which undergoes a fast 6-πelectrocyclic ring opening to 201. From here, a [1,5]-H shift to 202 occurs in the case of nucleophiles 198, followed by a second rapid 6π electrocyclization /decarboxylation sequences, giving rise to pyrans 203 or 204.…”

The bio-based methyl coumalate involved Morita–Baylis–Hillman reaction

“…[29][30][31][32][33][34][35][36] We recently discovered that MC can serve as 1,6-Michael acceptor, in the presence of certain nucleophiles. [37][38][39] Inspired by these findings, we began studying the nucleophilicity of the zwitterionic intermediates in the MBH catalytic pathway ( Figure 1). We encoutered challenges in trapping pyran intermediates with electrophiles without side reaction competition (i.e.…”

A general strategy for the synthesis of α-trifluoromethyl- and α-perfluoroalkyl-β-lactams via palladium-catalyzed carbonylation

“…Among the established synthetic toolbox for incorporation of fluorine-containing units, in particular processes for introducing CF 3 -groups are important. Notable examples include trifluoromethylated arenes, 7 olefins, 8,9 ethers, 10 and allylic compounds. 11 In addition, especially trifluoromethylated heterocycles 11,12 are emerging as promising building blocks for many life science and material applications.…”