Trifluoromethyl preparation

Geranyl acetoacetate (685) is converted into geranylacetone (686). On the other hand, a mixture of E- and Z-isomers of 688 is obtained from neryl acetoacetate (687). The decarboxylation and allylation of the allyl malonate or cyanoacetate 689 affords the o-allylated acetate or nitriie[447]. The trifluoromethyl ketone 691 is prepared from cinnamyl 4.4,4-trifluoroacetoace-tate (690)[448],... 

The main preparative techniques used to make all seven trifluoromethyl-quiaoline isomers iaclude copper-assisted coupliag of the haloquiaoliae with trifluoromethyl iodide (112) quiaoliaecarboxyhc acid with sulfur tetrafluoride—hydrogea fluoride (434,445) and aminoben2otrifluoride and glycerol... 

Trifluridine, C2qH22F2N20, (5-trifluoromethyl-2 -deoxyuridine [70-00-8] F TdU, 14) was first prepared (30) in 1962. It is used for topical therapy of herpes vims-infected eyes. It is especially usefiil for treating infections that are resistant to IdU therapy. Like IdU, trifluridine is incorporated into DNA in place of thymidine in both infected and uninfected cells. But it is 10 times more potent than IdU against herpes keratitis in rabbits and 10 times more soluble in water. Trifluridine is also usefiil in treating human cytomegalovims (HCMV), but its toxicity to bone marrow may limit its clinical use. 

Cyclic and Polymeric Substances Containing Arsenic—Arsenic Bonds. A number of organoarsenic compounds containing rings of four, five, or six arsenic atoms have been prepared (cycHc polyarsines). The first such four-membered ring compound to be adequately characterized, tetrakis (trifluoromethyl) tetrarsetane [7547-15-17, was obtained by the interaction of a diiodoarsine and mercury (107,108) ... 

The Tcrom ester is prepared from the cesium salt of an N-protected amino acid by reaction with 2-(trifluoromethyl)-6-chromylmethyl bromide (DMF, 25°, 4 h, 53-89% yield). Cleavage of the Tcrom group is effected by brief treatment with n-propylamine (2 min, 25°, 96% yield). It is stable to HCl/dioxane, used to cleave a BOC group. ... 

This dialkoxydiphenylsulfurane has been prepared by the reaction of diphenyl sulfide, 2,2,2-trifluoro-l-phenyl-l-(trifluoromethyl)ethyl hypochlorite, and potassium l,l,l,3,3,3-hexafluoro-2-phenyl-2-propanolate and by the reaction of diphenyl sulfide with 1 equivalent of chlorine and 2 equivalents of potassium 1,1,1,3,3,3-hexafluoro-2-phenyl-2-propanolate in diethyl ether. ... 

Although fluonnation of peroxoanions [S2] has been examined, the major emphasis in the fluonnation of oxygenated material is the preparation offhioroxy compounds The simplest, trifluoromethyl hypofluorite, can be prepared almost quantitatively by the action of fluorine on carbonyl fluoride (fluorophosgene) in the presence of various catalysts [Si, 84] Addition of fluorine to trifluoroacetic acid [S5] or its sodium salt [S6] gives rise to FjCF(OF)2 Long-chain fluoroxy compounds can also... 

Tetrakis(trifluoromethyl)dithietane is generated by dimerization of hexa-fluorothioaeetone which is prepared in situ from hexafluoiopropylene with potassium fluoride and sulfur [189] or with sulfur and antimony pentafluoride [190] (equation 27)... 

Alkyl fluorides are more reactive than other alkyl halides under Friedel-Crafts conditions, whereas trifluoromethyl groups are less reactive than other trihalomethyl groups Thus, a bromoindane is prepared from 1-bromo-l-fluoro-2,2,3,3-tetramethylcyclopropane and benzene [5] (equation 8) whereas 3-tnfluo romethylphenyldiphenylchloromethane is obtained from 3-trifluoromethyl-benzotrichloride and benzene [9] (equation 9)... 

Another way to prepare fluorinated sulfides is the photochemical alkylation of sulfides or disulfides by perfluoroalkyl iodides [69, 70, 71] (equations 62-64). Reaction of trifluoromethyl bromide with alkyl or aryl disulfides in the presence of a sulfur dioxide radical anion precursor, such as sodium hydroxymethanesulfi-nate, affords trifluoromethyl sulfides [72] (equation 65). 

Fluorinated sulflnates are prepared from sodium dithionite and liquid per-fluoroalkyl halides [74] (equation 67). For the transformation of the gaseous and poorly reactive trifluoromethyl bromide, it is necessary to use moderate pressure [75] (equation 68) These reactions are interpreted by a SET between the intermediate sulfur dioxide radical anion and the halide The sodium trifluorometh-anesulfinate thus obtained is an intermediate for a chemical synthesis of triflic acid. 

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). 

Azido-2-phenyl-4-trifluoromethyl-l, 3-azole is prepared from 5-fluoro-4-trifluoromethyl-1,3-azole [109] (equation 95)... 

Recently developed trifluoromethylatmg agents capable of transferring the trifluoromethyl group as a cation to strongly nucleophilic compounds such as carbanions and sulfur and phosphorus nucleophiles are prepared from o-biphenyl trifluoromethyl sulfoxide [164] and are shown in equation 141... 

The preparation of trifluoromethyl trifluoromethanesulfonate was reported by Olah and Ohyama [29]. In this safe and practical method, trifluoromethanesulfonic acid and fluorosulfonic acid are used [29] (equation 27). 

The bond between the trifluoromethyl group and boron is difficult to form Preparation of trifluoromethyl aminohoranes was successfully achieved by transfer of trifluoromethyl group from reagent 2, which was prepared in situ [107] (equation 85)... 

Knorr condensation of ethyl trifluoroacetylacetate with a variety of partners serves as a facile route to the preparation of a variety of trifluoromethylated pyrroles [25, 26] (equation 15)... 

Fluoroolefins may he prepared by the reaction of Wittig reagents and other pho sphorus-containtng y tides with fluorinated carbonyl compounds. (A discussion of the fluorinated Wittig reagents or other fluonnated phosphorus reagents with nonfluorinated carbonyl compounds is on page 581.) Tnphenylphosphoranes, derived from alkyltriphenyl phosphonium salts, react with 1,1,1-trifluoroacetone [3/] or other trifluoromethyl ketones [32, iJ] (equation 26) (Table 10). 

Ligand exchange reactions can be used to prepare perfluoroalkylzinc compounds Solvated trifluoromethylzinc compounds can be synthesized via the reaction of dialkylzincs with bis(trifluoromethyl)mercury [36] (equation 27) A similar exchange process with bis(trif]uorometliyl)cadinium and diraethylzinc gives a mixture of tnfluoromethylcadmium and zinc compounds [77]... 

Tnfluoromethanesulfinate can be prepared from the reaction of trifluoromethyl bromide with sulfur dioxide and zinc [50] (equation 41) Similar insertion occurs when perfluoroalkyl iodides are used as precursors (equations 41 and 42)... 

Dialkylcadmium reagents are often useful alternatives to the more reactive Gngnard reagents in the preparation of ketones from acyl halides However, bis(trifluotomethyl)cadmium glyme is decomposed by acyl halides and does not give trifluoromethyl ketones [, 124] Nevertheless, this reaction can be used as a low-temperature source of difluorocarbene [S, 124] (equation 102)... 

The reaction of trifluoromethyl radicals, generated in a radio-frequency discharge process, with elemental mercury f/7i], mercury halides [174], dime-thylmercuiy [24], or HgO [175] has been used for the preparation of CFjHgX and (CF3)2Hg. Direct fluorination of dimethylmercury with elemental fluorine gives (CF3)2Hg [176],... 

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]... 

Reactions offluorinated dipoles. In recent years, much effort has been devoted to the preparation of tnfluoromethyl-substituted 1,3-dipoles with the goal of using them to introduce trifluoromethyl groups into five-membered nng heterocycles Fluorinated diazoalkanes were the first such 1,3-dipoles to be prepared and used in synthesis A number of reports of cycloadditions of mono- and bis(tnfluo-romethyl)diazomethane appeared prior to 1972 [9] Other types of fluonne-substi-tuted 1,3-dipoles were virtually unknown until only recently However, largely because of the efforts of Tanaka s group, a broad knowledge of the chemistry of tnfluoromethyl-substituted nitrile oxides, nitnle imines, nitnle ylides, and nitrones has been accumulated recently... 

Nitrones are among the most highly studied and useful reagents for the synthesis of five-membered-nng heterocycles. The first fluonnated nitrone, N-methyl-C-(trifluoromethyl)nitrone, was prepared recently and used to introduce Irifluoromethyl groups into such heterocycles... 

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. 

Perfluoroalkyl groups adjacent to multiple bond systems lower the frontier molecular orbitals (FMOs) Therefore, cycloaddition reactions preferentially occur with electron-rich multiple-bond systems The preference of bis(trifluoromethyl)-substituted hetero-l,3-dienes for polar reacuons makes them excellent model compounds for developing new types of diene reactions deviating from the well documented Diels-Alder scheme (pathway 1) A systematic study of the reactions of diene (1 =2-3=4)-dienophile (5=6) combinations reveals new synthetic possibilities that have not yet been fully exploited as tools for preparative organic cherrustry (equation 25)... 

Of all known [4+1] cycloadducts, the ttn heterocycles exhtbit the most interesting preparative potential [I33 On heating they are transformed into 5-fluoro-4-tnfluoromethyl-l,3 azoles [132, 133] The fluorine atom at C-5 can be replaced by various nucleophiles By this route, the 4-trifluoromethyl-l 3-azole moiety can be introduced into many compounds of biological interest (equation 31)... 

Trifluoromethyl-substituted diazonium betaines [176]. Synthetic routes to trifluoromethyl-substituted diazo alkanes, such as 2,2,2-trifluorodiazoethane [ 177, 7 78, 179] and alkyl 3,3,3-trifluoro-2-diazopropionates [24], have been developed Rhodium-catalyzed decomposition of 3,3,3-tnfluoro-2-diazopropionates offers a simple preparative route to highly reactive carbene complexes, which have an enormous synthetic potential [24] [3-1-2] Cycloaddition reactions were observed on reaction with nitnles to give 5-alkoxy-4-tnfluoromethyloxazoles [750] (equation 41)... 

Trifluoromethyl-substituted nitrones have been prepared [184, 185, 186] and used for [3+2] cycloaddition reactions [iS5, 186] (equation 42). 

Certain trifluoromethyl-substituted 1,2,4,5 tetrazines [260, 26i] and 1,2,4 triazines [i06] can be used as cyclic hetero-1,3-dienes and provide efficient preparative routes to partially fluorinated heterocycles (equations 55 and 56)... 

Trifluoromethyl-l-oxa-2-aza-l,3-butadienes can be prepared in situ by 1,4-HBr elimination from the corresponding a-bromo oxime on treatment with base, and provide an interesting and versatile four-skeleton-atom building block [262] (equation 57). 

Perfluorotetramethylthiadiphosphanorbornadiene and bis(trifluoromethyl) thiadiphosphole can be prepared by thermolysis of an adduct of methanol and hexakis(trifluoromethyl)-l,4-diphosphabarrelene with sulfur [113] (equation 23) Pyrolysis of the adduct of hexafluorinated Dewar benzene and phenyl azide results in ring expansion giving azepine, which photochemically yields an intramolecular 2-1-2 adduct, a good dienophile for the Diels-Alder reaction [114, //5] (equation 24) Thermolysis of fluonnated derivatives of 1,5-diazabicyclo-... 

Secondary aziridines bearing a trifluoromethyl group were prepared via the Hoch-Campbell reaction of Grignard reagents and oximes bearing a trifluoromethyl... 

Tetraalkylfurans can be prepared via the Paal-Knorr reaction. For example, Muramatsu synthesized 2,5-diethy]-3,4-bis(trifluoromethyl)furan (72) in 94% yield by treatment of dione 71 with sulfuric acid." ... 

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