Diaryl ether synthesis in supercritical carbon dioxide in batch and continuous flow modes

Abstract

A high yielding, batch mode synthesis of diaryl ethers and sulfides by an S(N)Ar fluoride-mediated process in scCO(2) has been developed; the use of a polymer-supported imidazolium fluoride reagent in batch mode led to the development of a fixed-bed continuous flow process, with high conversions.

Future Trends for Green Chemistry in the Pharmaceutical Industry

“…An interesting use of SC -CO 2 to remove solvents from waste water streams has recently been published by Merck [51] . Metalcatalyzed Heck, Suzuki, and diaryl ether formation reactions [52] and hydrogenation in SC -CO 2 [53] are probably the most studied applications in the synthesis of pharmaceutical intermediates (Figure 16.5 ), but are still a long way from being adopted at large scale.…”

Translation of microwave methodology to continuous flow for the efficient synthesis of diaryl ethers via a base-mediated SNAr reaction

“…Until recently, the nucleophilic substitution of aromatic halides to phenolic substrates has been largely overlooked, with Ueno and coworkers [ 13 ] reporting the use of triethylsilane and a phosphazene “super base”, Holmes [ 14 ] describing the use of scCO 2 , and Moseley et al [ 15 ] employing microwave irradiation as a means of efficiently heating the reaction mixture in order to significantly reduce reaction times ( Scheme 1 ). Although microwaves have found widespread application in the research laboratory, their implementation at a large scale, whilst increasing, is not as well established, largely due to the challenges associated with the uniform irradiation of large reactor vessels [ 16 ].…”

Total Synthesis of Neomarchantin A: Key Bond Constructions Performed Using Continuous Flow Methods

“…The coupling of phenol 6 and aryl fluoride 11 occurred in 86% yield when performed under K 2 CO 3 /DMSO/130 °C reaction conditions. Various S N Ar reactions have been reported to provide high yields and short reaction times under continuous flow conditions, while the synthesis of biaryl ethers specifically has been shown to proceed when performed in supercritical CO 2 . Given the possibility to augment the process via continuous flow, the S N Ar synthesis of biaryl ether 4 was repeated using a heated column of K 2 CO 3 at 130 °C, affording the desired ether 4 in 71% yield but with a significantly shorter reaction time of 12 min .…”

“…Various S N Ar reactions have been reported to provide high yields and short reaction times under continuous flow conditions, 16 while the synthesis of biaryl ethers specifically has been shown to proceed when performed in supercritical CO 2 . 17 Given the possibility to augment the process via continuous flow, the S N Ar synthesis of biaryl ether 4 was repeated using a heated column of K 2 CO 3 at 130 °C, affording the desired ether 4 in 71% yield but with a significantly shorter reaction time of 12 min. 18 The synthesis of the ethano bridge between the two biaryl ethers was performed using Wittig chemistry (Scheme 2).…”