Abstract
The large number of reagents that have been developed for the synthesis of trifluoromethylated compounds is a testament to the importance of the CF3 group as well as the associated synthetic challenge. Current state-of-the-art reagents for appending the CF3 functionality directly are highly effective; however, their use on preparative scale has minimal precedent because they require multistep synthesis for their preparation, and/or are prohibitively expensive for large-scale application. For a scalable trifluoromethylation methodology, trifluoroacetic acid and its anhydride represent an attractive solution in terms of cost and availability; however, because of the exceedingly high oxidation potential of trifluoroacetate, previous endeavours to use this material as a CF3 source have required the use of highly forcing conditions. Here we report a strategy for the use of trifluoroacetic anhydride for a scalable and operationally simple trifluoromethylation reaction using pyridine N-oxide and photoredox catalysis to affect a facile decarboxylation to the CF3 radical.
Highlights
The large number of reagents that have been developed for the synthesis of trifluoromethylated compounds is a testament to the importance of the CF3 group as well as the associated synthetic challenge
We report a strategy for the use of trifluoroacetic anhydride for a scalable and operationally simple trifluoromethylation reaction using pyridine N-oxide and photoredox catalysis to effect decarboxylation to the CF3 radical
Trifluoroacetic acid (TFA) and its anhydride (TFAA) represent attractive sources of CF3 because of their ready availability and inexpensive nature (TFAA $35 per kg at 1,000 kg) but have seen minimal application towards this end. This dearth of methods is a direct result of the challenge associated with the decarboxylation of TFA (Fig. 1a)—a process that occurs in a polar manner only at high temperatures (4140 °C for copper trifluoroacetate)[20,21]
Summary
The large number of reagents that have been developed for the synthesis of trifluoromethylated compounds is a testament to the importance of the CF3 group as well as the associated synthetic challenge. The development of requisite methodologies for trifluoromethylation on preparative scale has become an increasingly important, yet challenging priority Compounding this issue, many reagents most commonly used for laboratory-scale trifluoromethylation are prohibitively expensive and/or unobtainable in the quantities required for scale-up (for a cost comparison, see Supplementary Note 1)[17]. Advancements in scalable, inexpensive and operationally simple protocols for fluorine incorporation are of the utmost importance for modern pharmaceutical[2], agrochemical[18] and specialty chemical production[19] To this end, we report a strategy for the use of trifluoroacetic anhydride for a scalable and operationally simple trifluoromethylation reaction using pyridine N-oxide and photoredox catalysis to effect decarboxylation to the CF3 radical. The reaction proceeds on a range of vinyl, aryl and heteroaryl substrates and has been demonstrated on a significant scale in both batch (100 g) and flow (20 g)
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