Trifluoromethylated Pyrazoles via Sequential (3 + 2)-Cycloaddition of Fluorinated Nitrile Imines with Chalcones and Solvent-Dependent Deacylative Oxidation Reactions

Abstract

A general approach for preparation of two types of polyfunctionalized 3-trifluoromethylpyrazoles is reported. The protocol comprises (3 + 2)-cycloaddition of the in situ generated trifluoroacetonitrile imines with enones leading to trans -configured 5-acyl-pyrazolines in a fully regio- and diastereoselective manner. Initially formed cycloadducts were aromatized by treatment with manganese dioxide. Depending on the solvent used, the oxidation step either led to fully substituted pyrazoles (DMSO) or proceeded via a deacylative pathway to afford 1,3,4-trisubstituted derivatives (hexane) with excellent selectivity.

An automated method for graph‐based chemical space exploration and transition state finding

“…Using our method, we have been able to obtain reaction networks containing the expected reaction mechanism for the five chemical systems with the above‐mentioned involved intermediates. The reaction mechanisms are in good agreement with those reported in previous studies 64–69 . By inspecting activation energies in paths connecting the reactant and the product for the chemical systems shown in Figure 4 in their respective reaction networks, we have found that the minimum energy paths agree with the expected ones described above.…”

“…The reaction mechanisms are in good agreement with those reported in previous studies. [64][65][66][67][68][69] By inspecting activation energies in paths connecting the reactant and the product for the chemical systems shown in Figure 4 in their respective reaction networks, we have found that the minimum energy paths agree with the expected ones described to allow for posterior successful optimizations of transition states with the higher DFT-B3LYP level of theory.…”

Base-Promoted (3 + 2) Cycloaddition of Trifluoroacetohydrazonoyl Chlorides with Imidates En Route to Trifluoromethyl-1,2,4-Triazoles

“…In 1982, Tanaka’s research group disclosed an elegant cycloaddition of trifluoromethyl nitrile imines with terminal alkynes, albeit with poor regioselectivity . Subsequently, the utility of trifluoromethyl nitrile imines was further showcased in the cycloaddition with enamines, enol ethers, arynes, and alkenes (nitroalkenes, chalcones, and cyano-alkenes), thus providing a diverse set of trifluoromethylated pyrazoles (Scheme a). Aside from unsaturated carbon–carbon bonds, a few substrates containing unsaturated carbon-heteroatom bonds could also proceed the (3 + 2) cycloaddition reaction with trifluoromethyl nitrile imines.…”

Fluorinated and Non-Fluorinated 1,4-Diarylpyrazoles via MnO2-Mediated Mechanochemical Deacylative Oxidation of 5-Acylpyrazolines

“…Exemplary reactions leading to polysubstituted pyrazoles 2 – 4 and bicyclic analogues 5 (indazoles) are depicted in Scheme 1 a. More recently, we disclosed a general two-step protocol for two types of multi-substituted 3-trifluoromethylpyrazoles comprising (3 + 2)-cycloaddition of in situ generated nitrile imines 1 with chalcones, followed by MnO 2 -mediated aromatization of the first 5-acylpyrazolines 6 formed [ 42 ]. Remarkably, depending on the solvent used, the oxidation step preferentially afforded fully substituted pyrazoles 7 (in polar solvents such as DMF or DMSO) or proceeded via a deacylative pathway (in non-polar solvents, e.g., in hexane), leading to 1,3,4-trisubstituted pyrazoles 8 as major products ( Scheme 1 b).…”