Trifluoromethyl groups have found a use in medicinal chemistry for many reasons which include lowering the basicity of a molecule and increase the metabolic stability of alkyl groups.
A recent paper by Altman et al. expanded on the previous work of Chen in which he published a method for the decarboxylative trifluoromethylation of benzyl bromodifluoroacetates.
Altman noticed that there are currently methods for accessing trifluoroethylarenes via nucleophilic trifluoromethylation of benzyl electrophiles but there were no catalytic methods for this transformation on electron-deficient or heterocyclic substrates.
The current systems for benzylic trifluoromethylation require either stoichiometric copper (1), exclusive transformation of electron-neutral (2) or electron-rich substrates (3)(scheme 1)
The benefits of Chen’s work was the easy access to substrates derived from benzylic alcohols and the benign and easily separable by-products (CO2 and KBr). This method was not shown to convert a wide variety of substrates which Altman believes is related to the reaction mechanism described by Chen (scheme 2).
Chen’s mechanism postulates a free CF3 anion, generated by an outer-sphere decarboxylation, which could react with sensitive carbonyl groups or deprotonate acidic sites. Altman hoped that he could refine the reaction so that an inner-sphere decarboxylation took place which generated Cu-CF3 and therefore making the reaction more tolerant of functional groups.
In this paper Altman investigated the reaction solvent, the catalytic copper source, additives and total quantity of iodide present on the reaction yield and by-product profile (table 1).
The optimised reaction conditions, 0.2 eq CuI, 0.25 eq KI, 0.4 eq MeO2CCF2Br and 4 eq KF in 1:1 DMF/MeCN, were then used to test if substrates containing a broad range sensitive groups and heterocycles could by trifluoromethylated in reasonable yields (table 2).
As can be seen from table 2 these reaction conditions tolerated a range of functionalities. The reaction was also conducted on a gram scale (2b) without a decrease in yield. Due to this functional group compatibility with amide (2c) and carbonyls Altman suggested that free CF3 anion (pKa = 27 in water) was not in existence in solution. To reflect the observations from this series of experiments, and previous work, including the absence of the CF3 anion and the importance of iodide in the reaction mixture Altman suggested the reaction sequence in figure 1.
To demonstrate the utility of this reaction an intermediate of fluorinated tebufenpyrad was synthesised in fewer steps and higher yield compared with a published route and also without the use of manganese or tin (scheme 3).
This paper has taken a previously published useful reaction for the transformation of benzylic alcohols into trifluoroethylarenes and further optimised it. The reaction can now be used to form trifluoroethylarenes from reagents that contain unactivated electrophiles, reactive carbonyls, acidic protons and heterocycles.
Blog written by Lewis Pennicott