General and Scalable Approach to Trifluoromethyl-Substituted Cyclopropanes

Abstract

CF3-cyclopropanes with aliphatic, aromatic, and even heteroaromatic substituents were prepared on a multigram scale by deoxyfluorination of cyclopropane carboxylic acids or their salts with sulfur tetrafluoride. For labile α-pyridine acetic acids, only the use of their potassium salts allowed to obtain the needed products. Derivatization of CF3-cyclopropanes into building blocks ready for direct use in medicinal chemistry was performed.

Carbon Monoxide as C1 Building Block in Fine Chemical Synthesis†

“…Conveniently substituted cyclopropanes are commonly found in many pharmaceuticals, and may act as intermediates in organic synthesis. [ 148 ] In this regard, Wu [ 149 ] reported an innovative synthesis of diborylated cyclopropanes via a copper‐catalyzed carbonylation process using copper(II) triflate/dppp as catalyst, followed by cyclopropanation (Scheme 83). This reaction was effectively carried out using both internal or terminal aryl olefins, which allowed to prepare in moderate yields (34%—57%), a family of cyclopropyl bis(boronates) (18 examples), with a completely defined stereochemistry.…”

Efficient synthesis of functionalized trifluoromethyl cyclopropanes via cyclopropanation of α-trifluoromethyl styrenes with chloroacetonitrile and ethyl chloroacetate

“…2 It has been estimated that more than five thousand bioactive compounds containing the (trifluoromethyl)cyclopropyl group have appeared in patent literature. 3 In addition, 1,1-disubstituted trifluoromethyl cyclopropanes could be considered as a bioisostere of the tert-butyl group. 4 As a consequence, numerous methods for the synthesis of trifluoromethyl cyclopropanes have been developed.…”

Sulfur Tetrafluoride (SF4) as a Deoxyfluorination Reagent for Organic Synthesis in Continuous Flow Mode

“…Interestingly, SF 4 itself was identified as the first deoxyfluorinating agent in 1959 at Dupont’s Experimental Station (Wilmington, DE). SF 4 can convert alcohols, aldehydes, ketones, and carboxylic acids to the corresponding –F, −CHF 2 , −CF 2 –, and −CF 3 or −COF groups, respectively. − In recent years, there were many advances made in the use of SF 4 as a reagent for organic chemistry, , in particular by Enamine Ltd. − Nevertheless, SF 4 reactions in batch require special measures due to its gaseous (bp −38 °C) and highly hazardous nature, and are typically performed in autoclaves with a large excess of both SF 4 (3–6 equiv) and HF (10–30 equiv or as a solvent) . In this context, the advantages of continuous manufacturing are clear: (1) avoid gas headspace by solubilizing the gas into the reaction mixture using pressure; (2) process intensification to drastically increase space-time-yield (through the reduction of reactor volume); and (3) intrinsically safer configuration with an inline quench to destroy any remaining reactive gas .…”