Fluorinated Alcohols: Magic Reaction Medium and Promoters for Organic Synthesis

Abstract

Fluorinated alcohols have been widely used in the synthetic organic chemistry over the past decades. The unique properties such as the strong hydrogen‐bonding donor ability and low nucleophilicity allow them to promote organic reactions in the absence of any catalyst. These approaches have distinct advantages in terms of operational simplicity, practicability and environmental friendliness. Reactions promoted by fluorinated alcohols, including nucleophilic substitution reactions, annulation reactions, electrophilic reactions, dearomatization reactions, functionalization of multiple bond, epoxidation reactions and miscellaneous reactions have been summarized in this account.

HFIP-Promoted Synthesis of Substituted Tetrahydrofurans by Reaction of Epoxides with Electron-Rich Alkenes

“…This sharp contrast in the performance of both fluorinated alcohols in this transformation can be explained by their different properties. Thus, HFIP has higher acidity (p K a (TFE) = 12.37, p K a (HFIP) = 9.30); higher hydrogen bond ability (α TFE = 1.51, α HFIP = 1.96), which can facilitate the activation of epoxide ring; and much lower nucleophilicity ( N TFE = −2.78, N HFIP = −4.23) [ 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. This last parameter would explain the obtention of fluoroalkyl ether 5 as major product when TFE was essayed.…”

“…In the last years, our research group has become interested in the use of fluorinated alcohols as solvents and promoters of organic reactions [ 14 , 15 ]. The unique chemical and physical properties that fluoroalkyl alcohols have in comparison with their non-fluorinated analogues, such as their high hydrogen bond donor ability, high polarity and ionizing power, and low nucleophilicity values together with the slightly acidic character, make them perfect candidates as promoters of reactions involving ionic processes [ 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. On the other hand, fluorinated alcohols have already proven to be efficient promoters in the ring-opening reaction of epoxides with different nucleophiles [ 23 , 24 , 25 , 26 ].…”

Electrosynthesis 2.0 in 1,1,1,3,3,3‐Hexafluoroisopropanol/Amine Mixtures

“…[6][7][8] This is illustrated by their use as solvents, co-solvents or promoters in organic syntheses. [2,5,9,10] Several examples have showcased the utility of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) in transition metal-catalyzed, [10,11] and metal-free reactions. [12] In combination with bases, HFIP promotes unusual transformations like the generation of aza-oxyallyl cationic intermediates from α-haloamides [13] or HFIP-promoted nucleophilic substitutions [9,14] .…”

“…[2,5,9,10] Several examples have showcased the utility of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) in transition metal-catalyzed, [10,11] and metal-free reactions. [12] In combination with bases, HFIP promotes unusual transformations like the generation of aza-oxyallyl cationic intermediates from α-haloamides [13] or HFIP-promoted nucleophilic substitutions [9,14] . These unique features of HFIP make it particularly well-suited as a solvent for electrochemical reactions, especially its ability to stabilize radical intermediates.…”

Chemo‐ and Stereoselective Synthesis of Fluorinated Amino Alcohols through One‐pot Reactions using Alcohol Dehydrogenases and Amine Transaminases

“…Thus, bienzymatic synthesis combining transketolases, [7] pyruvate aldolases, [8] pyruvate decarboxylases [9] or alcohol dehydrogenases (ADHs) [10] with amine transaminases (ATAs) have provided efficient and selective access to amino alcohol diastereoisomers, and even the possibility of using three enzymes (epoxide hydrolases, ADHs and ATAs) in a linear cascade set-up has been successfully reported. [11] The synthesis of various families of fluorinecontaining compounds has attracted great attention in recent decades [12] due to the importance of organofluorinated compounds in medicinal chemistry [13] and asymmetric catalysis. [14] For that reason, we decided to explore the potential of biocatalysis for the production of chiral fluorinated amino alcohols, attempting onepot bioreduction and biotransamination reactions (Scheme 1).…”