Organocatalytic Decarboxylative Cyanomethylation of Difluoromethyl and Trifluoromethyl Ketones

Abstract

An efficient organocatalytic method for the synthesis of difluoromethyl and trifluoromethyl substituted β-hydroxynitriles is introduced. The decarboxylative cyanomethylation of fluorinated ketones with readily available cyanoacetic acid gives a variety of tertiary alcohols in high yields and without concomitant water elimination. The reaction occurs in the presence of catalytic amounts of triethylamine, can be upscaled and applied to chlorofluoromethyl ketones and difluoromethyl ketimines.

Selective Csp3–F Bond Functionalization with Lithium Iodide

“…R f = 0.2 (hexanes/EtOAc, 4:1). The spectroscopic data of N-butyl-N-(4-cyanobenzyl)butan-1-amine (38) are in accordance with the literature.…”

“…Having established a profound interest in organofluorine chemistry, 32 33 34 35 36 37 38 39 40 including C–F bond activation methodology and synthetic or chiroptical sensing applications thereof, 19,21 , 41–43 we decided to investigate the possibility of practical alkyl fluoride to iodide conversion, which would also enable subsequent nucleophilic displacements or other reactions. Hilmersson and co-workers showed that this is possible with YbI 3 (THF) 3 , which has to be prepared from expensive ytterbium(II) iodide (Scheme 1 ).…”

Enantioseparation and racemization of α‐aryl‐α‐fluoroacetonitriles

“…Based on our longstanding interest in fluorinated compounds, 7,9–20 we decided to screen a variety of chiral stationary phases (CSPs) to separate the enantiomers of the 2‐aryl‐2‐fluoroacetonitriles 1 – 10 by liquid chromatography, Figure 1. It was expected that the development of high performance liquid chromatography (HPLC) conditions that allow baseline separation of 1 – 10 would not be a simple task and most likely be achieved with some of the most frequently used CSPs originally introduced by Pirkle and Okamoto who without a doubt have been the most influential inventors of broadly useful chiral HPLC columns 21–27 .…”

A computational study for the reaction mechanism of metal-free cyanomethylation of aryl alkynoates with acetonitrile

“…[1][2][3] In addition, cyanomethyl moieties obtained via cyanomethylation are found as versatile motifs in some important bioactive natural products and drugs. 4,5 A variety of protocols have been reported, including transition-metalcatalyzed methods [6][7][8][9][10][11][12][13][14][15][16] and metal-free catalyzed methods [17][18][19][20][21][22] for the synthesis of cyanomethyl-containing compounds. Compared to the toxic metal used, metal-free catalyzed methods used acetonitrile [9][10][11][12]17,18 and its analogs such as bromoacetonitrile, [13][14][15][16] cyanoacetic acid 19,20 and ethyl cyanoacetate 5 have drawn considerable attention due to its inexpensive and environmental-friendly properties.…”

“… 4,5 A variety of protocols have been reported, including transition-metal-catalyzed methods 6–16 and metal-free catalyzed methods 17–22 for the synthesis of cyanomethyl-containing compounds. Compared to the toxic metal used, metal-free catalyzed methods used acetonitrile 9–12,17,18 and its analogs such as bromoacetonitrile, 13–16 cyanoacetic acid 19,20 and ethyl cyanoacetate 5 have drawn considerable attention due to its inexpensive and environmental-friendly properties. In recent years, metal-free cyanomethylation using of acetonitrile as a cyanomethyl source in the synthesis of the cyano-containing compounds was reported.…”