Rapid and Mild Metal-Free Reduction of Epoxides to Primary Alcohols Mediated by HFIP

Abstract

The reduction of epoxides is a powerful tool to access anti-Markovnikov alcohols, but reported methods are poorly compatible with strongly electronically deactivated substrates. Here, we describe a general method for the linear-selective reduction of styryl oxides incorporating strong electron-withdrawing groups. The method remains compatible with more traditional epoxide motifs, such as aliphatic and electron-rich styrene oxides. Other (hetero)cycles such as oxetanes, tetrahydrofurans, aziridines and cyclopropanes can also be reductively opened. This user-friendly reaction relies on the combination of a Brønsted acid catalyst and hexafluoroisopropanol as a solvent and thus, in contrast to existing epoxide reduction methods, does not require anhydrous reagents or an inert atmosphere. The generated primary alcohols can be conveniently functionalized in situ by a dehydrative Friedel-Crafts arylation without pre-activation.

Synthesis of functionalised isochromans: epoxides as aldehyde surrogates in hexafluoroisopropanol

“…We then explored post-functionalization pathways. First, driven by the serendipitous formation of 2au and our recent study on the reduction of epoxides in HFIP, 4 the reductive ring-opening of isochroman 2e ring was achieved, using triethylsilane in HFIP in the presence of TfOH (Scheme 5A). The resulting alcohol 4a was obtained in 74% yield and further reacted with mesitylene to afford Friedel–Crafts product 4b in 91% yield, again using HFIP and TfOH at 80 °C.…”

“…During our recent work on epoxide reduction using hexafluoroisopropanol (HFIP), 2 we found that the mechanism involved an initial Meinwald rearrangement, 3 in which epoxides were first converted in situ into the corresponding aldehydes before reacting further. 4 This observation triggered our interest, as aldehydes, particularly the aliphatic ones that are enolizable, are notoriously prone to side-reactions such as self-condensation, which render them unstable and difficult to store in pure form. As a result, some commercially available aldehyde derivatives are expensive and must be freshly purified before use.…”

Total Syntheses of Favolasins A, E, G and K, Polyketides Isolated from Cultures of the Basidiomycetes Fungi Favolaschia sp. BCC 18686 and Favolaschia caloceraBCC 36684

“…A range of conditions was then explored in an effort to effect the efficient 7‐ endo ‐tet cyclization of compound 30 into isomer 8 [4b,10] but inevitably if this was formed at all then it was accompanied by significant quantities of the 6‐ exo ‐tet product 31 or the isomeric and related compounds 32 — 35 as shown in Figure 4. After considerable experimentation (Table 1), and by following a protocol for reductive epoxide ring‐cleavage reported by Leboeuf, [ 11 ] when substrate 30 was treated with methanesulfonic acid and triethylsilane in hexafluoroisopropyl alcohol (HFIPA) at ambient temperatures for 12 h then, as shown in Entry 11, Table 1 and Scheme 5, a 1 : 1 and chromatographically separable mixture of two major products, namely compounds 8 and 31 (26% yield of each), was obtained.…”

Tandem Cooperative Friedel-Crafts Reaction of Aldehydes with Electron Deficient Arenes Through Catalyst-Activation via Hydrogen Bonding Network

“…In fact, the need to develop an atom economic process under environmentally benign conditions is considered one of the primary focus of research in this field 3 . Recent developments in FC reaction focuses on using other electrophiles such as epoxides [4][5] , benzyl alcohols [6][7][8][9][10] & their derivatives 11 , benzyl fluorides 12 , aldehydes and ketones etc [13][14][15][16][17][18] . For example, in a seminal work by Hall and coworkers a ferrocenium boronic acid catalyst was developed for the FC arylation of deactivated benzylic alcohols 6 .…”