Copper trifluoromethyl derivatives

Burton and co-workers, as part of a series of ground-breaking studies on fluorinated organometallic systems [14], have established that trifluoromethyl derivatives may be obtained by reaction of halofluoromethanes with copper and other metals. The process involves electron transfer from the metal, with subsequent loss of halogen to form difluorocarbene which, in turn, generates very active fluoride ion by reaction with the solvent. The full process is indicated in Figure 10.60. 

Similarly, adenosine, inosine and 2 -deoxyinosine have been converted into their 8-trifluoromethyl derivatives by reaction with the copper complex formed from trifluoromethyl iodide and copper in hexamethylphosphorotriamide (80JCS(P1)2755). iV -Trifluoromethyl-purine riboside was also produced from 6-chloropurine riboside. Recently, guanosine has been shown to give the C (8)-substituted derivative (148) by reaction with a benz[a]anthracene 5,6-dioxide at pH 9.5 over 4 days at 37 °C (80CC82). 

G. Trifluoromethyl Derivatives of Group 11 Metals 1. Copper Trifluoromethyl Compounds... 

Trifluoromethyl copper has been shown to react with a 5-iodo-dioxinone (25) in the presence of HMPA to give the corresponding 5-trifluoromethyl derivative in 65% yield through an addition-elimination pathway (Equation (10)) <91CC1241>. 

The copper-catalyzed trifluoromethylation of iV-phenyl-2-iodoimidazole and A-methyl-2-iodobenzimidazole using 5 -(trifluoromethyl)diphenyl iodonium triflate afforded the corresponding C-2 trifluoromethylated derivatives in 85-90 % yields (Scheme 1) [8], Interestingly, the trifluoromethylation of iV-tritylimidazole failed, even at 80 °C, presumably due to the steric effect of the trityl group. 

Aromatic perfluoroaLkylation can be effected by fluorinated aUphatics via different techniques. One category features copper-assisted coupling of aryl hahdes with perfluoroalkyl iodides (eg, CF I) (111,112) or difluoromethane derivatives such as CF2Br2 (Burton s reagent) (113,114), as well as electrochemical trifluoromethylation using CF Br with a sacrificial copper anode (115). Extmsion of spacer groups attached to the fluoroalkyl moiety, eg,... 

A/,A/ -3,5-Bis(trifluoromethyl)phenylboronic Acid Derivative, 594 A/-[Phenyl(pentacarbonylchromium- or-tungsten)]carbenyl, 595 A/-Copper or A/-Zinc Chelate, 595 18-Crown-6 Derivative, 596... 

A second reaction which is very often used for the preparation of phthalonitriles, although the yields are usually not reproducible, is the Rosenmund-von Braun reaction (see Houben-Weyl, Vol. E5, p 1460).106 107 Herein, a benzene derivative with a 1,2-dibromidc or 1,2-dich-loride unit is treated with copper(I) cyanide in dimethylformamidc or pyridine. During this reaction the formation of the respective copper phthalocyanine often occurs. This can be used as an easy procedure for the exclusive synthesis of copper phthalocyanines (see Section 2.1.1.7.),1 os-109 but can also lead to problems if the phthalonitrile is required as the product. For example, if l,2-dibromo-4-trifluoromethyl-benzene is subjected to a Rosenmund-von Braun reaction no 4-trifluoromethylphthalonitrile but only copper tetra(tri-fluoromethyljphthalocyanine is isolated.110... 

Due to the poor efficiency of trifluoromethylated organometaUic derivatives as trifluoromethylating reagents, nucleophilic trifluoromethylation has remained unattractive for a long time. Indeed, in the absence of stabilization, the trifluoromethyl anion is very unstable and is quickly transformed into difluorocarbene (cf. Chapter 1). When the carbon-metal bond is relatively covalent, the organometaUic species becomes more stable but it is then less reactive toward an electrophile. On the synthetic level, only zinc and copper derivatives have found real applications in... 

Trifluoromethylation of aryl iodides was carried out by the fluoride ion in duced cross-coupling reaction of aromatic iodides with trifluoromethyltnalkyl-silanes in the presence of copper salts [219] (equation 147) Some pentafluoro- ethyl derivative was also formed This methodology was extended to pentafluoroethyl-and heptafluoropropyltnethylsilanes [219]... 

Trifluoromethyl)copper reagents have a tendency to thermally decompose by oligomerization which is formally an a-elimination route. This pathway has been employed synthetically for the preparation of perfluoro(arylethyl) derivatives (Sections 2.1.1.3.3. and 2.1.1.3.5.). 

A remarkable double insertion of difluorocarbene, derived from trifluoromethyl copper, has been reported [227] (Figure 9.87). 

Many types of trifluoromethylated nucleosides have been synthesized by trifluoromethylation of halogenated nucleoside derivatives with trifluoroiodomethane in the presence of copper, e.g. formation of 10. ... 

A-9-Borabicyclononane, 837 A-Difluoroborinic Acid, 838 3,5-Bis(trifluoromethyl)phenylboronic Acid, 838 A-[Phenyl(pentacarbonylchromiuin- or-tungsten)]carbenyl, 839 A-Copper or A-Zinc Chelate, 840 18-Crown-6 Derivative, 840... 

Germanium.— The microwave spectrum of (trifluoromethyl)germane, prepared in < 5 % yield by adding bromotrifluoromethane to a cold solution of the potassium derivative KGeHg in hexamethylphosphoramide, has been examined. The spectrum of a sample which was left in a copper waveguide for over 2 weeks remained very intense, so little or no decomposition (CFs GeHs FGeHa + CFa) appears to have occurred. 

The trifluoromethylation of aryl iodides has been achieved using the reaction with (trifluoromethyl)-trimethoxyborate and a copper(I)/phenanthroline catalyst." A copper chloride/phenanthroline catalyst has also been used together with (TMP2Zn), zinc bis-tetramethylpiperidide, in the reaction of aryl iodides with perfluoroalkyl derivatives to yield arylperfluoroalkanes. The mechanism is thought to involve initial formation of bis(perfluoroalkyl)zinc species followed by rate-limiting transmetalation with copper halide and reaction with the aryl iodide to give the coupled product." ... 

Shimizu R, Egami H, Nagi T, Chae J, Hamashima Y, Sodeoka M (2010) Direct C2-trifluoromethylation of indole derivatives catalyzed by copper acetate. Tetrahedron Lett 51 5947-5949. doi 10.1016/j.tetlet.2010.09.027... 

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