[organic] angelw: palladium catalyzed efficient carbon sequestration direct synthesis of bis (trifluoromethyl) methanol derivatives

The introduction of fluorine into bioactive molecules is a powerful tool to change their chemical and biological properties α α - bis (trifluoromethyl) methanol derivatives are widely used in biochemistry, pharmacology and other multidisciplinary fields (scheme 1a) At present, these compounds have been proved to have a variety of biological activities, such as anti-tumor, diabetes, hepatitis C, dyslipidemia and inflammation Due to the large amount of fluorine atoms in the fragments of these compounds, they also become a potential contrast agent for 19 f-MRI In addition, polymers containing α, α - bis (trifluoromethyl) methanol group also show excellent material properties, high thermal stability and good flame retardancy Hexafluoroisopropanol group also plays a role in ligand design due to its strong electron absorption and large volume In addition, the polymer can also be used for the detection of nerve agents and the synthesis of precursor of Martin spirosilane (source: angelw Chem Int ed.) the synthesis of bis (trifluoromethyl) methanol derivatives reported in the literature is very limited Its preparation mainly depends on Grignard reaction of hexafluoroacetone, aromatic electrophilic substitution reaction and nucleophilic addition of carboxylic acid derivatives with CF 3 (scheme
1b) However, these methods have some limitations, such as the poor tolerance of functional groups, the toxicity of required reagents or the need for additional steps to pre activate functional groups Recently, the team of troelsskrydstrup, University of Aarhus, Denmark, reported a method (scheme
1c) for direct conversion of bromide or aryl fluorosulfate to (hetero) aryl α, α - bis (trifluoromethyl) methanol by palladium catalyzed carbonylation strategy This method can also be used for direct or later 13 C isotope labeling of compounds (angel Chem Int ed 2018, DOI: 10.1002/anie.201802647) Using coware as the reaction vessel, 4-Bromoanisole (1a) as the substrate and tmscf3 as the nucleophile, the reaction conditions were screened (Table 1) It was found that the target compound 2A could be obtained by adding 3 mol% PD (OAC) 2, 4.5 mol% xantphos, 1.2 equivalent CO and 3.5 equivalent KF into the reaction system and heating in DMF for 18 hours (source: angelw Chem Int ed.) after determining the optimal reaction conditions, the author investigated the applicability of the substrate (scheme 2) Aryl bromides containing electron donor or electron acceptor groups can be effectively converted into α, α - bis (trifluoromethyl) methanol derivatives When the substituent is in the ortho position of the aromatic ring, there is no adverse effect on the reaction (2C) Halogen (including chlorine and fluorine) can also be tolerated in the reaction, which provides the possibility for further modification of the target product In addition, the brominated aromatic heterocyclic compounds of pyridine, indole, pyrimidine, quinoline and benzothiophene can also be used for such conversion (2h-k, 2n and 2S) Even heterocycles as substituents or fused with benzene rings are tolerable (2L, 2m, 2O and 2P) It is worth noting that the conversion can achieve gram scale preparation (2L) At last, the author also tried to prepare 2E with aryl chloride as the substrate, and got a good yield (66%), but the temperature should be increased to 120 ℃ Then, we prepared two kinds of bioactive molecules: hepatitis C virus inhibitor 2T and liver X receptor agonist T0901317 (2U) by using this reaction We also used 13C CO to label the two compounds It is worth noting that the introduction of isotopes did not have a significant impact on the yield of the products (source: angelw Chem Int ed.) aryl fluorosulfates can be easily prepared from phenol derivatives (scheme 3), which has attracted more and more attention in recent years because it can be used as a linker or a leaving group of sufex click chemistry It is found that aryl fluorosulfates can also be used to prepare derivatives containing one or two α, α - bis (trifluoromethyl) methanol The bis (trifluoromethyl) carbinol 2Z derived from estrone was prepared by using this electrophilic reagent and labeled by a specific 13C source (source: angelw Chem Int ed.) then, the author compared the activity difference of palladium aryl bromide and fluorosulfate in carbonylation (scheme 4a) The author put equal amount of 1b and 4B into the standard system for reaction The results show that the fluorosulfate has higher conversion rate in the same time, which proves that it has stronger reaction activity Pentafluoroethyl carbinol derivatives can also be prepared under the reaction conditions, and the yield can reach 83% (scheme 4b) It is found that if CO2 is used as the carbonyl source, 4Z can also be converted into the corresponding target compound 2Z by reducing it to CO in situ, with a yield of 68% (scheme 4C) (source: angelw Chem Int ed.) conclusion: through palladium catalyzed carbonylation, the team of troelsskrydstrup, University of Aarhus, Denmark, has realized the direct conversion of aryl bromide and fluorosulfate to (hetero) aryl α, α - bis (trifluoromethyl) methanol derivatives This method is easy to operate and has very good functional group tolerance, which provides an effective method for the introduction of bis (trifluoromethyl) methanol unit into drug molecules.