Difluoromethyl

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). 

Enflura.ne, Enflurane or Ethrane, 2-chloro-l,l,2-tri luoroethyl difluoromethyl 3838-16-9] was synthesized in 1963. This agent is a mildly... 

The reaction of the ethynylestradiol derivative (50) with difluorocarbene represents an equally fascinating series of reactions. The major product obtained in 48% yield is the difluorocyclopropene (51). The latter is hydrolyzed to the cyclopropenone (53), and is readily alkylated at C-21 to (54), which is also obtained by difluoromethylation of the propynyl derivative (57). The cyclopropenone (53) loses carbon monoxide at elevated temperature to... 

At 320 °C, cesium tetrafluorocobaltate converts benzotrifluoride to /n-fluo-robenzotrifluoride, 2f/-heptafluorotoluene, octafluorotoluene, pertluoro-l -meth-ylcyclohexene, and perfluoromethylcyclohexane [29] l,3-Bis(trifluoromethyl)-benzene is convened at 420 °C to 4,5,6-trifluoro-l,3-bis(trifluoroethyl)bcnzene, perfluoro-l,3-dimethylbenzene, and perfluoro-l,3-dimethylcyclohexane [29], p-Xylene gives at 350 °C l,4-bis(difluoromethyl)tetrafluorobenzene, 1-di-fluoromethyl-3-trifluoromethyltetrafluorobenzene, perfluoro-1,3-dimethyl-benzene, and perfluoro-1,3-dimethyloyclohexane... 

Unsaturated and some aromatic aldehydes reaet cleanly with sulfur tetrafluo-ride in the presence of potassium fluoride (a hydrogen fluoride scavenger) to give reasonable to good yields of the corresponding difluoromethyl derivatives [f 72] (equation 87)... 

The difluoromethyl group in chlorofluoroalkanes can be oxidized into a carboxylic group by a mixture of chlorine and dinitrogen tetroxide at high temperatures [2] (equation 1)... 

The monofluoromethylene group and difluoromethyl group m 1H perfluoro-alkanes and -cycloalkanes are oxidized at the C-H bond to perfluoroalkyl and perfluorocycloalkyl fluorosulfates by anodic oxidation m fluorosulfonic acid [J, 4] Two modifications of the method are used ox idation by fluorosulfonyl peroxide generated pnor to the reaction [J] (equation 2A) and direct electrolysis m the acid [i, 4] (equabons 2B and 3)... 

Difluoroalkenyl boranes, which are prepared in situ, are converted to difluoromethyl ketones by oxidation with hydrogen peroxide m alkaline media [720] (equation 107)... 

Trifluoromethyl thiirane is formed by the action of tris(diethylamino)-phosphineon l-chloromethyl-2,2,2-trifluoroethyldisulfide [S2] (equation 73) Difluoromethyl phenyl selenide is prepared by treatment of lithium phenyl-selemde with chlorodifluoroniethane via a carbene mechanism [Si] (equation 44) Bis(2,2,2-trifluoroethyl)diselenide is formed in the reaction of 2,2,2-trifluoroethyl mesylate with lithium diselenide [84] (equation 74). 

Table 1. gem-Difluorocyclopropanes from Bromo(difluoromethyl)-triphenylphosphonium Bromide... 

A peculiar dehydrofluorination occurs when tnfluoromethyl dihydropyndine derivatives are treated with organic bases A double-bond shift and a hydrogen migration convert one tnfluoromethyl group to a difluoromethyl group and aromatize the ring [22] (equation 20)... 

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]. 

Reaction of 2 equiv of 2-aminopyridines with 2-hydropolyfluoroalk-2-anoates 351 in MeCN in the presence of NEts at 90 °C for 50 h afforded a mixture of the isomeric 2-oxo-2H- and 4-oxo-4//-pyrido[l,2-n]pyrimidines 110 and 111. Reaction of 3 equiv of 2-amino-pyridines and 2-hydropoly-fluoroalk-2-enoates 351 in MeCN in the presence K2CO3 could be accelerated by ultrasonic irradiation (125W). 2-Amino-6-methylpyridine yielded only 2-substituted 6-methyl-4//-pyrido[l,2-n]pyrimidin-4-ones 111 (R = 6-Me), whereas 2-amino-5-bromopyridine gave a mixture of 7-bromo-4//-pyrido[l,2-n]pyrimidin-4-one (111, R = 7-Br, R = CF2C1) and 2-(chlor-o,difluoromethyl)-6-bromoimidazo[l, 2-n]pyrimidine-3-carboxylate in 44 and 8% yields, respectively (97JCS(P 1)981). Reactions in the presence of K2CO3 in MeCN at 90°C for 60h afforded only imidazo[l,2-n]pyrimidine-3-carboxylates. 

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

CN (6/ -ci.r)-7-[[[(difluoromethyl)thio]acetyl]amino]-3-[[[l-(2-hydroxyethyl)-lH-tetrazol-5-yl]thio]methyl]-... 

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