Organic letters: (Me4N) ScF3 reagent for direct and rapid acylation of carboxylic acids

Like acyl chloride, acyl fluoride, a carboxylic acid derivative, can be directly synthesized into a series of high-value compounds, such as amides and esters, through nucleophilic substitution reactions Compared with the active intermediate of acyl chloride, acyl fluoride is easier to separate, stable in silica gel and milder in reaction with nucleophiles The electrophilicity of acyl fluoride is similar to that of active ester, but there is no effect of steric hindrance In addition, when reacting with amines with obvious steric hindrance or dense functional groups, the by-products of acyl fluoride reaction are significantly less than those of acyl chloride, anhydrides and other active reagents Although acyl fluoride has so many advantages, acyl chloride is more commonly used in organic synthesis due to the lack of safe, direct and selective synthesis methods In the past, the synthesis of acyl fluoride was limited For example, the use of toxic cyanuric fluoride as a fluorination reagent, a major disadvantage of this method is that the functional compatibility is not good Special reagents such as DAST, deoxo fluor or xtalfuor can also be used These reagents are all derivatives of sulfur tetrafluoride There are problems of stability and side reactions in the reaction In addition, the use of urea cationic fluorination reagent can avoid unnecessary by-products, but the urea by-products from the reaction are difficult to be removed by general separation methods Fig 1 Source of synthesis method of acyl fluoride: Recently, Franziska schoenebeck research team from the Institute of organic chemistry, Aachen University of technology, Germany, used (me 4N) SCF 3 as acyl fluorination reagent to convert carboxylic acid into acyl fluoride directly and efficiently without any other side reactions In this study, the author found that solid (me 4N) SCF 3 can rapidly convert 1-adamantanic acid to acyl fluoride at room temperature The reaction is carried out in DCM After the reaction is completed, a small amount of low polar solvent, such as pentane or hexane, is added The by-product (Me4N) HF 2 in the system will become precipitated and precipitated, and the remaining acyl fluoride product in the organic phase is easy to be separated After discovering the fluorination of (me 4N) SCF 3 reagent, the author explored its application range, and the experimental results are shown in Figure 2 Aromatic formic acid, fatty acid and unsaturated acid all have good reactivity, and the yield of acyl fluoride products is good to excellent Moreover, halogen, cyano, nitro, ether bond, amide, heterocycle and other functional groups can be compatible with this reaction In addition, primary amines and secondary amines can be functionalized simultaneously in the reaction, for example, 4-amino-2-methoxybenzoic acid can be converted into isothiocyanate 17 under the action of (me 4N) SCF 3, and 4-methylaminobenzoic acid can be converted into thiocarbamoyl fluoride 18 Figure 2 Source of substrate expansion: in order to confirm the application prospect of this method in later functionalization, the author tried the acylation of complex molecules and amino acid molecules It can be seen that the yield of acyl fluorination of drug analogues 19-21 is very high (Fig 3a) In addition, when vitamin B7 reacts with (me 4N) SCF 3 reagent and adamantamide is added directly, adamantamide product can be obtained in one pot, and the yield can reach 84% (Fig 3b) The reactivity of N-protected amino acids is also very good, the protective group can be kept intact in the reaction, and the yield of acyl fluoride product is considerable (Fig 3C) Fig 3 Application source of functionalization of acylation in the later stage: at last, the author uses FTIR spectrum to monitor the reaction, so as to explore the reaction mechanism See Fig 4 for the mechanism of reactir experiment and proposal Figure 4 Reactir experiment and reaction mechanism source: summary of organic letters: Franziska schoenebeck research team has developed a method to convert carboxylic acid into acyl fluoride directly and rapidly In the reaction, SCF 3 (me 4N) is used as fluorination reagent, and by-product (me 4N) HF 2 is easy to remove The new method has a wide range of application, and provides a new choice for the later functionalization of drug molecules Paper link: http://pubs.acs.org/doi/10.1021/acs.orglett.7b02516 schoenebeck research group: http://www.schoenebeck.oc.rwth-aachen.de/our-team schoenebeck research group