HFIP in Organic Synthesis

Abstract

1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) is a polar, strongly hydrogen bond-donating solvent that has found numerous uses in organic synthesis due to its ability to stabilize ionic species, transfer protons, and engage in a range of other intermolecular interactions. The use of this solvent has exponentially increased in the past decade and has become a solvent of choice in some areas, such as C–H functionalization chemistry. In this review, following a brief history of HFIP in organic synthesis and an overview of its physical properties, literature examples of organic reactions using HFIP as a solvent or an additive are presented, emphasizing the effect of solvent of each reaction.

A General Strategy to Install Amidine Functional Groups Along the Peptide Backbone

“…Other fluorinated alcohols like the more expensive hexafluoroisopropanol (HFIP) were found to have similar results as TFE. The beneficial effects of TFE obviously extend beyond simple solubility, wherein the strong hydrogen-bond donor ability of fluoroalcohols may help to meditate the shuttling of protons during the reaction. , …”

Synthesis of alpha-pyrones and chromen-2-ones by transition-metal catalyzed annulations of sulfoxonium and iodonium ylides withcis-stilbene acids

“…The fluorinated solvents, especially HFIP, marked their presence by their varied utilities in the C–H activation strategy. 12 Delightfully, the reaction in HFIP delivered 80% yield of desired product 3a (entry 11, Table 1), which galvanized us to explore the combination of HFIP : H 2 O (1 : 1), but unfortunately the stated combination failed to reproduce or improve the result (entry 12, Table 1). Subsequently, ethanol and trifluoroethanol (TFE) were also explored as the solvent for the stated reaction only to produce inferior or no results (entries 13 and 14, Table 1).…”

Selective Synthesis of α‐Alkoxy Enones by α‐Addition of Alcohols to Alkynones Using 1,1,1,3,3,3‐Hexafluoroisopropanol and PPh3 as Co‐catalysts

“…Some commonly used solvents were also screened. In tetrahydrofuran (THF) or CHCl 3, it just gave moderate yields (entries [15][16], and the reaction in THF consumed longer time. With CH 3 CN as solvent, only 9 % product was detected.…”

“…Thus, HFIP is often used to solve problems in the realms of homogeneous catalysis. [15] After an extensive screening of "acid", it was delighted to find that the employment of HFIP as an additive can improve the selectivity of the addition.…”