Difluoromethyl ethers

The limitations of this reagent are several. It caimot be used to replace a single unactivated halogen atom with the exception of the chloromethyl ether (eq. 5) to form difluoromethyl fluoromethyl ether [461 -63-2]. It also caimot be used to replace a halogen attached to a carbon—carbon double bond. Fluorination of functional group compounds, eg, esters, sulfides, ketones, acids, and aldehydes, produces decomposition products caused by scission of the carbon chains. 

Difluoroethanol is prepared by the mercuric oxide cataly2ed hydrolysis of 2-bromo-l,l-difluoroethane with carboxyHc acid esters and alkaH metal hydroxides ia water (27). Its chemical reactions are similar to those of most alcohols. It can be oxidi2ed to difluoroacetic acid [381-73-7] (28) it forms alkoxides with alkaH and alkaline-earth metals (29) with alkoxides of other alcohols it forms mixed ethers such as 2,2-difluoroethyl methyl ether [461-57-4], bp 47°C, or 2,2-difluoroethyl ethyl ether [82907-09-3], bp 66°C (29). 2,2-Difluoroethyl difluoromethyl ether [32778-16-8], made from the alcohol and chlorodifluoromethane ia aqueous base, has been iavestigated as an inhalation anesthetic (30,31) as have several ethers made by addition of the alcohol to various fluoroalkenes (32,33). Methacrylate esters of the alcohol are useful as a sheathing material for polymers ia optical appHcations (34). The alcohol has also been reported to be useful as a working fluid ia heat pumps (35). The alcohol is available ia research quantities for ca 6/g (1992). 

Trifluoroethanol is also the starting material for the anesthetic Isoflurane (l-chloro-2,2,2-trifluoroethyl difluoromethyl ether [26675-46-7]) (55,56) and Desflurane (2-difluoromethoxy-l,l,l,2-tetrafluoroethane [57041-67-5]) (57). 

An isomer of enflurane named isoflurane (l-chloro-2,2,2-tnfluoroethyl difluoromethyl ether) does not produce uncontrolled movements, is nonflammable, and IS metabolized to an even lesser extent than enflurane [7] As of this wntmg, isoflurane is the fastest growing anesthebc m more economically developed coun tries, but because of cost, it has not overtaken halothane in the rest of the world... 

In a later version of the synthesis [9], the trifluoroethyl difluoromethyl ether IS made directly from tnlluoroethanol and chlorodifluoromethane (equation 2) and then chlorinated to give the final product. Again, the major problem is overchlorination, because all the hydrogens are readily replaced by chlorine. Separation of the overchlonnated by-products poses a special problem because of close boiling points. This problem can be solved by adding acetone to create a more easily separable azeotrope of acetone and isoflurane [10]. 

Chemical Name 1 -Chloro-2 2 2-trifluoroethyl difluoromethyl ether Common Name —... 

H and 13C NMR Data. The H chemical shifts of CF2H protons of difluoromethyl ethers lie between 6.00 and 6.3 ppm, with a significantly enhanced F—H two-bond coupling constant of around... 

Figure 7.1.9 The molecular structure of enflurane (enthrane or 2-chloro-1,1,2-trifluoroethyl difluoromethyl ether).

Figure 7.1.10 The molecular structure of isoflurane (forane, aerrane, or 1-chloro-2,2,2- trifluoroethyl difluoromethyl ether).

Figure 7.1.12 The molecular structure of desflurane (suprane or 1,2,2,2-tetrafluoroethyl difluoromethyl ether).

Silyl enol ethers have also been used as a trap for electrophilic radicals derived from a-haloesters [36] or perfluoroalkyl iodides [32]. They afford the a-alkylated ketones after acidic treatment of the intermediate silyl enol ethers (Scheme 19, Eq. 19a). Similarly, silyl ketene acetals are converted into o -pcriluoroalkyl esters upon treatment with per fluoro alkyl iodides [32, 47]. The Et3B/02-mediated diastereoselective trifluoromethylation [48,49] (Eq. 19b) and (ethoxycarbonyl)difluoromethylation [50,51] of lithium eno-lates derived from N-acyloxazolidinones have also been achieved. More recently, Mikami [52] succeeded in the trifluoromethylation of ketone enolates... 

Synonyms Ethrane 2-chloro-l,l,2-triflu-oro ethyl difluoromethyl ether... 

PEE-IV Inhibitors Selective inhibitors of phosphodiesterase IV (PDE4) are in development for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Two of them contain fluorine atoms roflumilast (preregistered) bears a difluoromethyl ether and AWD-12-281 (Phase II) has a single fluorine atom (Figure 8.51). 

The difluoromethyl ether AZD-7009 is in Phase II clinical trials as an atrial repolarization-delaying agent. 

Diethylene glycol monomethyl ether acetate Difluoromethyl fluoromethyl ether 162.21 -9 209.1 29.9 ... 

However, difluoromethylation occurs when nucleophiles intercept difluoro-carbene generated under basic conditions, providing a route to difluoromethyl-ethers of phenols [33] and thiophenols [34]. The reaction with phosphite anion leads to the corresponding difluoromethyl phosphonate (see Sect. 2.3.2) while nucleophilic carbanions such as alkynes [35] also undergo formal alkylation, as do malonates [36,37]. An -difluoromethylaziridine was reported in a reaction with a glycine imine [38]. The scope of the established chemistry is summarised in Fig. 1. Bromodifluoromethylation occurs with a similar range of nucleophiles [39,40], and also with carbonyl-stabilised carbanions such as malonates [41,42]. 

A powerful solvent effect occurs in the reaction of 4-nitrobenzaldehyde with sulfur tetrafluoride. The reaction conducted in a benzene solution gives the expected l-(difluoromethyl)-4-nitro-benzene (16), while without a solvent bis[fluoro(4-nitrophenyl)methyl] ether (17) is formed as the sole product and in high yield.79 Other benzaldehydcs do not give a-fluoro ethers under any conditions, probably because of instability of such ethers under acid conditions.79... 

Substitution of hydrogen by fluorine also occurs, albeit with difficulty, in the formyl group of formates ethyl formate reacts with sulfur tetrafluoride in the presence of potassium fluoride to give a mixture of difluoromethyl ethyl ether (14) and ethyl trifluoromethyl ether (15).175... 

A large number of fluorinations of partially fluorinated ethers have been successfully carried out. A few examples are fluorination of methyl 2,2,2-trifluoroethyl ether (12),85 1,1,2,2-tetrafluoroethyl 2,2,2-trifluoroethyl ether (13),85 2-(l,l,2,3,3,3-hexafluoropropyl)tetrahydro-furan (14),86 difluoromethyl 2,2,2-trifluoroethyl ether (15),10 and bis(2,2,2-trifluoroethyl) ether (16).10 Manganese(III) fluoride is more reactive than cobalt(III) fluoride in the last two fluorinations. 

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