Oxidation of Difluorocarbene by Pyridine N‐Oxide and Ensuing Access to Carbamoyl Fluorides^†

Abstract

Comprehensive SummaryA practical one‐pot preparation of carbamoyl fluorides from easily obtained pyridine N‐oxide, commercially available secondary amines and synthetically versatile difluorocarbene precursors (Ruppert‐Prakash reagent or Chen's reagent) was developed herein, which dexterously resorted to the oxidation of difluorocarbene by external pyridine N‐oxide to produce the toxic and gaseous fluorophosgene in situ. Notable features of this method include nice functionality tolerance, late‐stage modification of drug molecules and the recovery and recycle of quinoline.This article is protected by copyright. All rights reserved.

eFluorination for the Rapid Synthesis of Carbamoyl Fluorides from Oxamic Acids

“… 42 Furthermore, the successful preparation of compound 2j in 72% yield confirms the compatibility of cyclopropanes, which are redox-active moieties, with the electrolytic conditions. Numerous other functional groups, such as esters ( 2o ), 34 sulfones ( 2p ), tetrahydropyrans (THPs, 2r ), trifluoromethyls ( 2t ), nitriles ( 2u ), and amides ( 2y ), were compatible and led to the formation of functionalized carbamoyl fluorides in average to excellent yields. Interestingly, Et 3 N·3HF is close to neutral and, therefore, did not deprotect the Boc carbamates, 38 allowing for the formation of compound 2q in 62% yield.…”

“…Fluorine has long held a special place in many areas of chemistry as a result of its ability to impart or enhance remarkable physical and chemical properties to a molecule when present in its framework. − Carbamoyl fluorides have attracted much attention for their use as insecticides and esterase inhibitors. − In addition, because carbamoyl fluorides exhibit greater stability and selectivity than carbamoyl chlorides, they represent exceptional building blocks in the synthesis of hydrazines, isocyanates, carbamates, thiocarbamates, ureas, and amides. − ,, Unfortunately, their synthesis can remain a challenge (Figure ). , The primary preparation method is to treat a carbamoyl chloride with nucleophilic sources of fluoride. , While this method seems straightforward, it still requires the preparation of the highly reactive and often unstable chloride analogue, which is usually produced using expensive and highly toxic phosgene derivatives. , The past decade has seen a rapid increase in the development of novel methods for preparing carbamoyl fluorides, confirming the growing interest of the synthetic community in this fluorinated motif. − However, most use impractical conditions, often combined with highly air- and water-sensitive, toxic, hazardous, and expensive reagents, such as carbonyl difluoride, ,− carbon disulfide, highly reactive and unstable carbamoyl chlorides, or explosive diethylaminosulfur trifluoride (DAST)-type reagents. , Some other methods need expensive Ag salts, significant excess of reagents leading to time-consuming chromatographic purifications, , or high temperatures . Although some early work has yielded the desired products in single-step reactions, using DAST and silver salts presents a significant challenge to scale up the reaction, especially under process-friendly conditions. ,− There is an urgent need to develop a novel, practical, sustainable, inexpensive, and milder way to access carbamoyl fluorides rapidly.…”

“… 21 − 24 However, most use impractical conditions, often combined with highly air- and water-sensitive, toxic, hazardous, and expensive reagents, such as carbonyl difluoride, 13 , 25 − 28 carbon disulfide, 29 highly reactive and unstable carbamoyl chlorides, 28 or explosive diethylaminosulfur trifluoride (DAST)-type reagents. 30 , 31 Some other methods need expensive Ag salts, 32 significant excess of reagents leading to time-consuming chromatographic purifications, 33 , 34 or high temperatures. 35 Although some early work has yielded the desired products in single-step reactions, using DAST and silver salts presents a significant challenge to scale up the reaction, especially under process-friendly conditions.…”

C–F bond functionalizations via fluorinated carbenes

“…This method features good functional group tolerance, late modification of drug molecules, and step economy. 45…”

Synthesis of N-substituted phthalimides via Pd-catalyzed [4+1] cycloaddition reaction

“…4 So far, a series of methods for the involvement of transition metals in the transfer of difluorocarbene have been developed. 5 In recent years, several successful trans-formations of [Pd]CF 2 have been reported, mostly limited to nucleophilic arylboronic acids and esters (Scheme 1a). 5 c ,6 The involvement of difluorocarbene as a carbonyl source has also been reported.…”