A practical and catalyst-free trifluoroethylation reaction of amines using trifluoroacetic acid

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作者：
Keith G. Andrews
Radmila Faizova
Ross M. Denton
机构：
[1] School of Chemistry,
[2] University Park,undefined
[3] University of Nottingham,undefined
来源：
Nature Communications | / 8卷
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摘要：
Amines are a fundamentally important class of biologically active compounds and the ability to manipulate their physicochemical properties through the introduction of fluorine is of paramount importance in medicinal chemistry. Current synthesis methods for the construction of fluorinated amines rely on air and moisture sensitive reagents that require special handling or harsh reductants that limit functionality. Here we report practical, catalyst-free, reductive trifluoroethylation reactions of free amines exhibiting remarkable functional group tolerance. The reactions proceed in conventional glassware without rigorous exclusion of either moisture or oxygen, and use trifluoroacetic acid as a stable and inexpensive fluorine source. The new methods provide access to a wide range of medicinally relevant functionalized tertiary β-fluoroalkylamine cores, either through direct trifluoroethylation of secondary amines or via a three-component coupling of primary amines, aldehydes and trifluoroacetic acid. A reduction of in situ-generated silyl ester species is proposed to account for the reductive selectivity observed.
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[31]  
Doyle AG(2001)Fluorination patterning: a study of structural motifs that impact physicochemical properties of relevance to drug discovery Bioorg. Med. Chem. Lett. 11 2867-6146
[32]  
Beatty JW(2006)Asymmetric synthesis of telcagepant, a CGRP receptor antagonist for the treatment of migraine J. Med. Chem. 49 6143-7658
[33]  
Douglas JJ(2016)Pyrimidinylimidazole inhibitors of p38: cyclic N-1 imidazole substituents enhance p38 kinase inhibition and oral activity Org. Biomol. Chem. 14 7654-99
[34]  
Cole KP(2012)Discovery of 6-N,N -Bis(2,2,2-trifluoroethyl)amino- 4-trifluoromethylquinolin-2(1 H )-one as a novel selective androgen receptor modulator # Nature 492 95-1047
[35]  
Stephenson CRJ(2013)Pd-catalyzed divergent trifluoroethylation and arylation of arylboronic acids by aryl(2,2,2-trifluoroethyl)iodonium triflates Nat. Protoc. 8 1042-1992
[36]  
Fujimoto T(2016)Practical and innate carbon–hydrogen functionalization of heterocycles Angew. Chemie Int. Ed. 55 1988-1637
[37]  
Ritter T(2013)Preparation and purification of zinc sulfinate reagents for drug discovery Org. Lett. 15 1634-2480
[38]  
Sather AC(2014)Mild and efficient palladium-catalyzed direct trifluoroethylation of aromatic systems by C–H activation Angew. Chemie Int. Ed. 53 2477-14507
[39]  
Nagib DA(2015)Photocatalytic synthesis of allylic trifluoromethyl substituted styrene derivatives in batch and flow Angew. Chemie Int. Ed. 54 14503-236
[40]  
MacMillan DWC(1986)Nickel-catalyzed C–H alkylations: direct secondary alkylations and trifluoroethylations of arenes J. Fluor. Chem. 31 231-8925
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