Trifluoromethyl ethers synthesis

Leroux, F.R., Manteau, B., Vors, J.-P., and Pazenok, S. (2008) Trifluoromethyl ethers synthesis and properties of an imusual substituent. BeUstein Journal of Organic Chemistry, 4, 13. 

Both aromatic and aliphatic fluoroformates 7 can be readily prepared from phenols or alcohols and carbonyl difluoride and treated with sulfur tetrafluoride without isolation. Hydrogen fluoride evolved in the reaction of hydroxy compounds with carbonyl di fluoride serves as a catalyst for the consecutive reaction with sulfur tetrafluoride.15<)-162 This provides a general, convenient, direct synthesis of aryl and alkyl trifluoromethyl ethers 5 from phenols and alcohols. When the intermediate fluoroformate 7 is isolated prior to treatment with sulfur tetrafluoride, at least one mole equivalent of hydrogen fluoride is necessary to promote the fluorination reaction. 159 163 Representative examples of the conversion of hydroxy compounds 6 into trifluoromethyl ethers 5 via intermediate fluoroformates 7 are given (for other examples 7 -> 5, see Houben-Weyl, Vol. E4, pp 628. 629). 

Sosnovskikh, V. Y., Irgashev, R. A., Khalymbadzha, I. A. and Slepukhin, P. A. (2007) Stereoselective hetero-Diels-Alder reaction of 3-(trifluoroacetyl)chromones with cyclic enol ethers synthesis of 3-aroyl-2-(trifluoromethyl)pyridines with to-hydroxyalkyl groups. Tetrahedron Lett., 48, 6297-6300. 

Scheme A.10 Synthesis of trifluoromethyl ethers from xanthogenates [15].

Hojo, M. Masuda, R. Okada, D. A facile synthesis of 2,4-dialkoxy-, 2-alkoxy-4-phenoxy-and 2,4-diphenoxy-6-trifluoromethyl-3,4-dihydro-2/7-pyrans. Hetero-Diels-Alder reactions of tra i- 3-trifluoroacetylvinyl ethers with various vinyl ethers. Synthesis 1989, 215-216. 

Trifluoromethyl)allyltrimethylsilane results frwith aldehydes and ketones gives trifluoromethyl-ated alcohols and silyl ethers. Synthesis of allyl and allenyl-silanes is stereospecific from hydroalumination or hydroboration of... 

Various reviews have been published about this topic. Jeschke and Leroux [2] pubhshed about the medical apphcation of a-fluorinated ethers. Leroux and Pazenok [1] wrote about the synthesis and the properties of trifluoromethyl ethers. Leroux, Jeschke and Schlosser [3b] reviewed the properties of a-fluorinated ethers, thioethers and amines. The work of Boiko [4a] is dedicated to aromatic and heterocyclic perfluoralkyl sulfides. Vovk and Gakh [4b] gave a detailed review about trifluoro-methoxy containing azoles and azines. This review summarized the literature data on synthesis and biological activity of trifluoromethoxy, difluoromethoxy and a-fluorinated sulfides derivatives of five and six membered heterocycles. 

Another standard route to aromatic trifluoromethyl ethers is based on the treatment of phenolates with chlorodifluoromethane (CHFjCl) [27] or dibromodifluoromethane (CF2Br2> [27, 28] in the presence of a base, with subsequent introduction of the third fluorine atom. Leroux [25] et al. studied this approach for the synthesis of pyridine trifluoromethyl ethers. In this case the reactivity at the pyridine ring was also influenced by chlorine. When 3-hydroxypyridine and 2,6-dichloro-3-hydroxypyridine were treated with chlorodifluoromethane in a triphasic mixture of aqueous sodium hydroxide and dioxane, the difluoromethoxypyridine and 2,6-dichloro difluorometh-oxypyridine were obtained in 24 and 92 % yield (Scheme 2). The photochlorination of... 

Feiring AE (1979) Chemistry in hydrogen fluoride. 7. A novel synthesis of aryl trifluoromethyl ethers. J Org Chem 44 2907-2910. doi 10.1021/jo01330a017... 

Kuroboshi M, Suzuki K, Hiyama T (1992) Oxidative desulfurization-fluorination of xanthates. A convenient synthesis of trifluoromethyl ethers and difluoro(methylthio)methyl ethers. Tetrahedron Lett 33 4173 176. doi 10.1016/S0040-4039(00)74681-8... 

WITTIG OLEFINATION OF PERFLUOROALKYL CARBOXYLIC ESTERS SYNTHESIS OF 1,1,1-TRIFLUORO-2-ETHOXY-5-PHENYLPENT-2-ENE AND 1-PERFLUOROALKYL EPOXY ETHERS 1,1,1-TRIFLUORO-2-ETHOXY-2.3-EPOXY-5-PHENYLPENTANE (Oxirane, 2-ethoxy-3-(2-phenylethyl)-2-(trifluoromethyl)-, cis-(+)-)... 

In the presence of copper(I) chloride, FC-113a adds to silyl enol ethers affording adducts which can be transformed into the /1-chloro-/i-trifluoromethyl enones in moderate yields [100]. The carbon-carbon bond is formed via a free radical addition reaction (Eq. 28). Free radical addition mediated by iron pentacarbonyl was also described recently during a synthesis of a modified pyrethroid [101]. 

Dehydrobromination of bromotrifluoropropene affords the more expensive trifluoropropyne [237], which was metallated in situ and trapped with an aldehyde in the TIT group s [238]synthesis of 2,6-dideoxy-6,6,6-trifluorosugars (Eq. 77). Allylic alcohols derived from adducts of this type have been transformed into trifluoromethyl lactones via [3,3] -Claisen rearrangements and subsequent iodolactonisation [239]. Relatively weak bases such as hydroxide anion can be used to perform the dehydrobromination and when the alkyne is generated in the presence of nucleophilic species, addition usually follows. Trifluoromethyl enol ethers were prepared (stereoselectively) in this way (Eq. 78) the key intermediate is presumably a transient vinyl carbanion which protonates before defluorination can occur [240]. Palladium(II)-catalysed alkenylation or aryla-tion then proceeds [241]. 

Hojo et al. [218,308,309] described the trifluoroacetylation of alkenes activated by heteroatom donors such as vinyl ethers and ketene acetals (Eq. 116) the reaction occurs under mild conditions and can be used to prepare bis(trifluoro-acetyl) products from highly activated derivatives [310]. The main use of the products appears to be in the synthesis of trifluoromethyl heterocycles both... 

There have been some further examples of the use of the Conrad-Limpach reaction on substituted 5-aminoquinolines for the synthesis of 4-hydroxy-1,7-phenanthrolines, although the products (see Section IV,F,1) should properly be designated as phenanthrolinones.169 Hot diphenyl ether is often employed as the medium for ring closure.170 Ethyl trifluoro-acetoacetate has been used successfully in place of ethyl aceto-acetate, and this variation has allowed entry to 2-trifluoromethyl-substituted 1,7-phenanthrolines.96 Extensions of the Conrad-Limpach type of synthesis starting with m-phenylenediamine (20) and utilizing diethyl ethoxymethylene malonate or ethyl ethoxalylacetate, reagents frequently used in quinoline syntheses, have afforded, after hydrolysis,... 

In the abstract of a symposium paper22 Nakai and Co-workers briefly reported the synthesis of allyl 1-(trifluoromethyl)vinyl ethers 66 from the corresponding trifluoromethyl ketone enolates followed by Claisen rearrangement to trifluoromethyl ketones 67 under very mild conditions (40 C for 66a, 60 C for 66b22,24). 

The synthesis (Scheme 9) begins with the appropriate 1-trifluoromethyl-substituted enol ether 43, where R1 is an amino acid side chain or another appropriate carbon chain. The enol ether undergoes reaction with MCPBA in CH2C12 to give the corresponding epoxy ether 44. The epoxy ether is cleaved by reaction of a wide variety of secondary amines to give the a-amino trifluoromethylated ketone 45. Only a few compounds have been synthesized by this method. 35,36 ... 

A new, efficient and general synthesis of 4-amino-3-arylcinnolines has been described recently, starting from arylhydrazines and aryl trifluoromethyl ketones, and the following is a typical example. Addition of a THF solution of the hydrazone formed from phenylhydrazine and 2-trifluoroacetylthiophene to 5 equivalents of KHMDS in THF at -78°C, then slow warming of the mixture to room temperature and stirring at room temperature for several hours, gave 4-amino-3-(2-thienyl)cinnoline in 68% yield after work-up (quench with ether, then a wash with brine). 

Synthesis of 1,3-disubstituted naphthalenes is a non-trivial exercise. In an interesting approach to such compounds it was found that they could be assembled by a simple two-step operation as follows. Condensation of 2-(trifluoromethyl)benzaldehyde with pentan-3-one gave the expected aldol product as the (E)-isomer, treatment of which with lithium 4-methylpiperazide in ether at -10°C led directly to l-methylpiperazino-3-propionylnaphthalene in 30% yield. 

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