Reactions fluoromethylation

Fluoromethyl sulfides are converted to fluoromethanesulfonyl chlorides by reaction with chlorine in waters at low temperatures, intermediate sulfoxides can be isolated [109] (equation 100)... 

The preparation of a tnflate salt may include the decomposition of tnflyl azide by azide ion Tnflyl azide can be prepared by the reaction of the azide ion with tnfluoromethanesulfonyl fluonde or tnfluoromethanesulfomc anhydnde [18] (equauonlS) Anotherone stepprocedureusesaquatemaryammoniumcountenon [J9] (equation 15) This tnflate can react with primary halides to form tn fluoromethyl sulfones [19 (equation 16) (Table 7)... 

Convenient syntheses of vinyl fluorides are of synthetic interest, fhe conjugate base of fluoromethyl phenyl sulfone reacts with carbonyl compounds to provide P-tluoro alcohols, which are used to prepare terminal vinyl fluorides [25] (equation 23) (Table 9) This reaction offers an alternative to the Winig reaction, which may be very sensitive to reaction conditions. 

The photochemical or thermal reaction between petfluoroalkyl iodides and mercury-cadmium amalgams has been used for the synthesis of perfluoro-alkylmercury compounds [150] Functionalized analogues have been prepared similarly via this route [151, 152] (equation 117), and the preparation of bis(tri-fluoromethyl)mercury has been described [153]... 

Aryl bromides were also perfluoroethylated under these conditions [205] The key to improved yields was the azeotropic removal of water from the sodium perfluoroalkylcarboxylate [205] Partial success was achieved with sodium hepta-fluorobutyrate [204] Related work with halonaphthalene and anthracenes has been reported [206 207] The main limitation of this sodium perfluoroalkylcarboxylate methodology is the need for 2 to 4 equivalents of the salt to achieve reasonable yields A trifluoromethylcopper solution can be prepared by the reaction of bis(tri-fluoromethyl)mercury with copper powder in /V-methylpyrrolidone (NMP) at 140 °C [208] (equation 138) or by the reaction of N-trifluoromethyl-A-nitro-sotnfluoromethane sulfonamide with activated copper in dipolar aprotic solvents [209] This trifluoromethylcopper solution can be used to trifluoromethylate aro matic [209], benzylic [209], and heterocyclic halides [209]... 

Alkynes substituted with one or two trifluoromethyl groups are also highly reactive dienophiles [9] Indeed, hexafluoro-2-butyne is used increasingly as a definitive acetylenic dienophile in "difficult Diels-Alder reactions. It was used, for example, to prepare novel inside-outside bicycloalkanes via its reaction with cir,trnns -l,3-undecadiene [74] (equation 67) and to do a tandem Diels-Alder reaction with a l,l-bis(pyrrole)methane [75] (equation 68) Indeed, its reactions with pyrrole derivatives and furan have been used in the syntheses of 3,4-bis(tri-fluoromethyl)pyrrole [76, 77] (equation 69) and ],4-bis(trifluoromethyl)benzene-2,3-oxide [78] (equation 70), respectively. 

Allenes carrying trifluoromethyl groups, such as l,l-dichloro-3,3-bis(tn fluoromethyl)allene, undergo facile, room-temperature Diels-Alder reactions with cyclopentadiene (87%) and furan (95%) [94]... 

A mixture of 2.0 g (0.064 mol) of 2-fluoromethyl-3-(o-tolyl)-6-nitro-4(3H)-qulnazolinone, Oi g of 5% palladium-carbon and 100 ml of acetic acid is shaken for 30 minutes in hydrogen gas. The initial pressure of hydrogen gas is adjusted to 46 lb and the mixture is heated with an infrared lamp during the reaction. After 30 minutes of this reaction, the pressure of hydrogen gas decreases to 6 lb. After the mixture is cooled, the mixture is filtered to remove the catalyst. The filtrate is evaporated to remove acetic acid, and the residue is dissolved in chloroform. The chloroform solution is washed with 5% aqueous sodium hydroxide and water, successively. Then, the solution is dried and evaporated to remove solvent. The oily residue thus obtained is dissolved in 2 ml of chloroform, and the chloroform solution is passed through a column of 200 g of silica gel. The silica gel column is eluted with ethyl acetate-benzene (1 1). Then, the eluate is evaporated to remove solvent. The crude crystal obtained is washed with isopropylether and recrystallized from isopropanol. 0.95 g of 2-fluoromethyl-3-(o-tolyl)-6-amino-4(3H)-quinazolinone Is obtained. Yield 52.5% MP 195°-196°C. 

Recently, Uneyama reported that treatment of (R)-l-tosyl-2-trifTuoromethylazir-idine 76 (Scheme 3.24) with w-BuLi at -100 °C and subsequent trapping of the anion with electrophiles such as chloroformates produced aziridine-2-carboxylates 77 in good to excellent yields [71]. The retention of the configuration of the tri-fluoromethylated quaternary carbon center in the course of the reaction was confirmed by derivatization of the product and by X-ray studies. 

Table 1.7 Values of for the Cross-Reaction between Fluoromethyl and Ethyl Radicals (25 °C) 172174...

Subsequently, exchange with dimethylcadmium produces mixed fluoromethyl compounds, according to the following reaction 31). 

Two branched-chain sugars, methyl 3-azido-4,6-0-benzylidene-2,3,-dideoxy-3-C-(fluoromethyl)-a-D-flraZ)/ o-hexopyranoside and methyl 2-azido-4,6-0-benzylidene-2,3-dideoxy-2-C-(fluoromethyl)-) -D-r/to-hexo-pyranoside have been prepared through the usual displacement reactions. 

Treatment of a-dichloromethyl phenyl sulfoxide with lithium diisopropylamide in THF gave monolithiated derivative 122, which upon further treatment with aldehyde afforded the )S-hydroxy-a-dichlorosulfoxide 123. Thermolysis of 123 gave dichloroketone 124, by extruding benzenesulfenic acid as shown below . Similarly, in the reaction of lithio-a-fluoromethyl phenyl sulfoxide and aldehyde, fluoromethyl ketone 126 was obtained, after thermolysis of the hydroxy intermediate 125. Diethylphosphorylmethyl methyl sulfoxide was shown by Miko/ajczyk and coworkers to be lithiated with n-BuLi to intermediate 127, which upon treatment with carbonyl compounds afforded the corresponding a, -unsaturated sulfoxides 128 in good yields. 

Fluoromethyl)phosphonate ester anions react with CO2 or COS to yield esters of the type (161 Y=0 or S) which may be dealkylated to the free acid through the use of bromotrimethyl-silane, but the course of the reaction with CS2 depends on the individual ester thus, (162) yields (163), but (165) is formed from (164). 22... 

A solution of 10.5 g. (0.046 mol) of freshly distilled bis(tri-fluoromethyl)-l,2-dithiete (Note 2) in 200 ml. of n-pentane is cooled to —10° in a 1-1. round-bottomed flask equipped with an efficient reflux condenser and protected from moist air by a dry nitrogen blanket. A solution of 3.0 ml. (0.023 mol) of nickel carbonyl dissolved in 100 ml. of w-pentane is added down the condenser in one portion to this solution. The mixture is swirled to mix. An intense blue-violet color develops in about 15 to 20 seconds and after 1 to 2 minutes, vigorous evolution of carbon monoxide occurs. This evolution subsides in 10 minutes and the deep violet solution is allowed to warm to 0° during 2 hours to ensure complete reaction. Most of the pentane is removed by distillation at atmospheric pressure, the remaining 50 to 60 ml. is removed in vacuo (0.1 mm.), and the resultant crystalline mass is evacuated (0.1 mm.) at 50° for 4 hours. The crude product consists of shiny black-purple needles and weighs 11.8 g. (98%). Recrystallization from dry benzene (Note 3) gives shiny black crystals, m.p. 134 to 135° (sealed tube). The complex is air-stable but should be kept out of contact with moist air. 

Di-0-isopropylidene-a-D-rtbo-hexofuranos-3-ulose (100) was treated with (chlorofluoromethylene)triphenylphosphorane (prepared by reaction of triphenylphosphine on difluorocarbene generated in situ by reaction of potassium ferf-butoxide with dichloro-fluoromethane), to give cis- and rans-3-C-(chlorofluoromethylene)-3-deoxy-l,2 5,6-di-0-isopropylidene-a-D-ribo- (101 and 103) and -xyfo-hexofuranoses (105 and 107), which, on treatment with lithium aluminum hydride, gave cis- and frans-3-deoxy-3-C-(fluoromethyl)-1,2 5,6-di-O-isopropylidene-a-D-rtbo- (102 and 104) and -xyZo-hexofura-... 

Benzoxazin-4-yl)methylenemalonate (138) was obtained in the reaction of 7,8-difluoro-3-fluoromethyl-l,4-benzoxazine and EMME at 130-140°C for 3 hr [86JAP(K)204188]. 

B. Fluoromethyl phenyl sulfone (2). To a 3-L, three-necked, round-bottomed flask, equipped with an overhead stirrer, thermometer, and 1-L addition funnel with sidearm are added Oxone (221.0 g, 0.36 mol) (Note 9) and water (700 mL). The mixture is cooled to 5°C and a solution of the crude fluoromethyl phenyl sulfide (1) in methanol (700 mL) is placed in the addition funnel and added in a slow stream to the stirring slurry. After addition of the sulfide, the reaction mixture is stirred at room temperature for 4 hr, (Note 10) and the methanol is removed on a rotary evaporator at 40°C. The remaining solution is extracted with methylene chloride (2 x 500 mL). The combined organic layers are dried over magnesium sulfate, concentrated to ca. 150 mL, filtered through a plug of silica gel (230-400 mesh, 300 mL, 10 x 6.5 cm), and washed with an additional 500 mL of methylene chloride (Note 11). The colorless filtrate is concentrated and the resulting oil or solid is dried under vacuum (0.1 mm) at room temperature to provide 29 g of crude fluoromethyl phenyl sulfone (2) as a solid... 

REACTION OF SULFOXIDES WITH DIETHYLAMINOSULFUR TRIFLUORIDE PREPARATION OF FLUOROMETHYL PHENYL SULFONE, A REAGENT FOR THE SYNTHESIS OF FLUOROALKENES (Benzene, [(fluoromethyl)sulfonyl]-)... 

In most oases, the fluoro Pummerer reaction can be carried out with 1.33 to 2.0 equiv of DAST and a "catalytic" amount of antimony trichloride in either refluxing methylene chloride or chloroform at room temperature or 50°C. In the synthesis of fluoromethyl phenyl sulfide, however, the induction period makes room temperature conditions the preferred method for large scale synthesis. 

A type iii-d reaction leads to the formation of (69). Trifluoromethyl radicals generated electrochemically from triflu-oroacetate can attack electron-deficient olefins leading to trifluoromethylated carbon radicals whose chemical and electrochemical follow-up reactions can be controlled by current density, reaction temperature, and substituents of the olefins. With fumaronitrile (86) at 50 °C the monotri-fluoromethylated compound (87) was obtained in 65% yield (Scheme 31) [110]. 

On the basis of encouraging work in the development of L-proline-DMSO and L-proline-ionic liquid systems for practical asymmetric aldol reactions, an aldolase antibody 38C2 was evaluated in the ionic liquid [BMIM]PF6 as a reusable aldolase-ionic liquid catalytic system for the aldol synthesis of oc-chloro- 3-hydroxy compounds (288). The biocatalytic process was followed by chemical catalysis using Et3N in the ionic liquid [BMIM]TfO at room temperature, which transformed the oc-chloro-(3-hydroxy compounds to the optically active (70% ee) oc, (3-epoxy carbonyl compounds. The aldolase antibody 38C2-ionic liquid system was also shown to be reusable for Michael additions and the reaction of fluoromethylated imines. 

Mono- and difluoromethylation involving the halogenofluoromethanes can be performed on malonic esters. A Curtius reaction, further performed on only one of the ester functions, leads to a-fluoromethyl amino acid (Figure 5.26). °... 

These compounds come from methylenation reactions of the corresponding carbonyl derivative by means of an ylide. Several experimental conditions have been described. In most cases, CF2Br2 and HMPT (hexamethyl phosphorotriamide) are employed. The reaction occurs with aldehydes as well as with ketones in the furanose and pyranose series. The reaction can also be performed with lactones the fluoromethyl group is then introduced in the anomeric position. With these substrates, the Julia olefmation, which uses difluoromethyl sulfone, has also been reported to be an efficient method. Some examples of these reactions are shown in Figure 6.24. 

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