A General Access to Propargylic Ethers through Brønsted Acid Catalyzed Alkynylation of Acetals and Ketals with Trifluoroborates

Abstract

A general Brønsted acid catalyzed methodology for the alkynylation of acetals and ketals with alkynyltrifluoroborate salts has been developed. The reaction proceeds rapidly to afford valuable synthetic building block propargylic ethers in good to excellent yields. Unlike Lewis acid catalyzed transformations of trifluoroborates, this approach does not proceed via unstable organodifluoroborane intermediate. As a result, the developed methodology features excellent functional group tolerance and good atom economy.

Brønsted Acid-Catalyzed Direct Substitution of 2-Ethoxytetrahydrofuran with Trifluoroborate Salts

“…Previously, we discovered that tetrafluoroboric acid (HBF4) is an effective catalyst for the reactions of trifluoroborate salts [4,5]. To investigate the efficiency of the HBF4 as a Brønsted acidcatalyst towards the substitution of 2-ethoxytetrahydrofuran, we first looked at using unsubstituted potassium phenylacetylenetrifluoroborate salt (S1) as a model substrate (Table 1).…”

“…Attempts to use an alternative acid such as trifluoroacetic acid, which has a pK a similar to that of HBF 4 , only resulted in trace amounts of product formation (Table 1, entry 2). Our previous studies indicated that increasing the amounts of trifluoroborate salt and HBF 4¨O Et 2 to 1.5 equivalents resulted in a higher yield for the alkynylation of ketals [5]. We then looked to apply these reaction conditions to the direct functionalization of 2-ethoxytetrahydrofuran.…”

“…To our delight, product 1a was obtained in an excellent 92% yield (Table 1, entry 3). Other reaction conditions, such as reaction temperature and solvent, were not directly explored since both conditions were already extensively studied in our previously described set of novel Brønsted acid-catalyzed reactions [4,5].…”

“…In addition to phenylacetylenetrifluoroborates, hexynyltrifluoroborate salt reacted with 2-ethoxytetrahydrofuran to afford product 1h in 64% yield. as reaction temperature and solvent, were not directly explored since both conditions were already extensively studied in our previously described set of novel Brønsted acid-catalyzed reactions [4,5].…”

“…Direct substitution at the 2-position of 2-ethoxytetrahydrofuran occurs in the presence of a Brønsted acid catalyst. Recently, our group has discovered that Brønsted acid-catalyzed reactions of benzhydryl alcohols [4] and acetals/ketals [5] with organotrifluoroborates proceed with excellent functional group tolerance. Previously, organotrifluoroborate salts have been shown to act as shelf-stable equivalents of boronic acids [6].…”