Trifluoromethylation methods

While Yu et al. [15] reported the palladium-catalyzed ortho trifluoromethylation of arenes with an electrophilic trifluoromethylation reagent (Scheme 19.9), Liu and coworkers [69] developed a nondirected C-H trifluoromethylation method using the nucleophilic Ruppert-Prakash (TMSCFj) reagent (Scheme 19.43). Thus, indoles underwent trifluoromethylation in moderate yields at the C-2 position or, when the C-3 position was free, at the C-3 position in the presence of a Pd /bis-oxazoline catalyst, cesium fluoride, PhI(OAc)2 as the stoichiometric oxidant, and TEMPO as a radical trap. Similar to Yu s method, the mechanism was proposed to involve the formation of an Ar-Ph -CEj intermediate that reductively eliminates to form the Ar-CFj bond. 

There have been several reports of the formation of tertiary bismuthines by the action of free radicals on metallic bismuth. One method of generating the radicals iavolves cleavage of ethane or hexafluoroethane ia a radiofrequeacy glow discharge apparatus the radicals thus formed are allowed to oxidize the metal at — 196°C (53). Trimethylbismuthiae and tris(trifluoromethyl)bismuthine [5863-80-9], C BiF, have been obtained by this procedure. 

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). 

Among the many methods of generating difluorocarbene, the treatment of bromodifluoromethylphosphonium bromides with potassium or cesium fluoride is particularly useful at room temperature or below [II, 12 13] The sodium iodide promoted decomposition of phenyl(trifluoromethyl)mercury is very effective at moderate temperatures [S, 14] Hexafluoropropylene oxide [/5] and chlorodifluo-roacetate salts [7] are excellent higher temperature sources of difluorocarbene... 

The phosphonium salt method works best with nucleophilic olefins [//, 12, 16, 17, 18, 19] (Table 1 and equations 1-3) and has been used m mechanistically important studies of difluorocarbene additions to norbornadienes [20 21, 22, 23] that provided the first example of a concerted homo-l,4-addition (equation 4) A recent modification uses catalytic 1,4,7,10,13,16 hexaoxacyclooctadecane (18-crown-6) to shorten reaction times and increase yields with less nucleophilic olefins [12] (Table 1) Neither procedure, however, compares with the use of phenyl(tri-f1uoromethyl)mercury or (trifluoromethyl)trimethyltin reagents [efficient reactions with less nucleophilic olefins (equations 3 and 5) and cyclic dienes [24, 25] (equations 6 and 7)... 

Tnfluoromethyl-substUuted 1,3-dipoles of the propargyl-allenyl type and trifluoromethyl-substituted nitrilium betaines. Tnfluoromethyl- [164, 765] and bis(trifluoromethy])-substituted [166, 167] nitrile ylides have been generated by different methods and trapped with various dipolarophiles to yield [3+2] [768] and [3+1] cycloadducts [769], respectively... 

Previous extended Hiickel calculations on the bis(trifluoromethyl) derivative 6 show the favored isomer to be 6b, while the CNDO/2 method favors 6a [75JCS(P2)559]. More recent ab initio calculations for different R substituents show that electron-releasing substituents favor the ring-opened dithione (6b), whereas electron-withdrawing substituents favor the cyclic structure (6a) (80JA6687). These conclusions are supported by electron diffraction (ED) (76JA899) and photoelectron (PE) spectral data... 

An unusual method for the preparation of 3-(trifluoromethyl)-4-aryl-furazans 49a,b in 47-77% yield has been reported (99H627) (Scheme 19). Thus, dehydration of l,l,l-trifluoroalkane-2,3-dione dioximes 48a,b was accomplished on heating with silica gel. If, as in 48b, Ar was an electron-withdrawing moiety, the conversion proceeded more smoothly. The dehydration of the same dioximes using traditional methods failed. 

Methods for synthesis of a,(3-unsaturated trifluoromethyl ketones and their use in the synthesis of trifluoromethyl-substituted heterocycles 99UK483. 

Fluorination. Direct fluorination of quinoline was accompanied by extensive fragmentation of the heteroring, but trifluoromethyl hypofluorite in trichlorofluoromethane at -70°C converted 5-fluoro-8-hydroxyquino-line into the 5,7-difluoro-8-hydroxy product (72JMC987). Quinoline, itself, was perfluorinated by fluorine and cobalt(III) fluoride (56JCS783), whereas cesium tetrafluorocobaltate at around 350°C converted it into a mixture of saturated polyfluoro compounds (82JFC413). It is much more satisfactory to introduce fluorine by nucleophilic methods. 

Bromo-Ar,Ar-dimethyl-3-(trifluoromethyl)aniline has been prepared by the methylation of 4-bromo-3-(trifhioromethvl)aniline with trimethyl phosphate in 70-80% yield.3 The present method, which effectively uses 3-(trifluoroinethyl)aniline as starting material, offers advantages in cost, yield, and ease of purification. 

Although there are several reports in the literature on boron-mediated amide formations, the boron reagents had to be used in stoichiometric amounts.1-4-5-6-7-8-9 Recently, Yamamoto et al. presented the first truly catalytic method allowing for a direct amide formation from free carboxylic acids and amines as the reaction partners.10-1112 Best results were obtained by using phenylboronic acids bearing electron withdrawing substituents in the meta- and/or para-positions such as 3,4,5-trifluorophenylboronic acid or 3,5-bis(trifluoromethyl)boronic acid as the catalysts. 

The state of the synthetic art in this area, in 1979, is much more satisfactory. During the past decade, several new synthetic developments have occurred such that we are closer to the point where the limitations upon synthesis of trifluoromethyl compounds are related more to stability problems in isolated cases, and are not nearly so much due to lack of widely applicable synthetic techniques. We find ourselves, for example, in a position in 1979 where the germanium compound, Ge(CF3)4, which in the past decade, was considered by many workers to be of insufficient stability to permit isolation, has been prepared by four independent methods and is known to be stable to over 100°C. Many of these new synthetic techniques have emerged from studies conducted in our laboratory at the University of Texas and previously... 

A quite surprising development, even to experienced workers in elemental-fluorine chemistry, has been the synthesis of trifluoromethyl organometallic compounds by direct fluorination of metal alkyls (25). Even more surprising is the fact that, for certain metal and metalloid systems, such as the reaction of elemental fluorine with tetramethyl-germane, this t5rpe of low-temperature synthesis is a practical method 26) for the laboratory preparation of the perfluoro analog. 

It is quite probable that, were this reaction to be repeated, yields much higher than the 6.8% yield reported (25) could be obtained. In fact, it is even possible that this method, too, could eventually be developed into a practical synthesis for bis(trifluoromethyl)mercury. 

Analytical methods for fortified soils were developed for the simultaneous quantitation of the trifluralin metabolites, 2,6-dinitro-A-propyl-4-(trifluoromethyl)-benzenamine (1) and 2,4-dinitro-A,A-dipropyl-6-(trifluoromethyl)benzenamine (2) (Figure 2). The SFE method developed as described in Section 2.2.1 was extended to the determination of these metabolites. From soil fortified with 0.5-2.5 mg kg each of trifluralin, (1) and (2), the compounds were efficiently extracted by this procedure. Trifluralin and its metabolites (1) and (2) are characterized by absorbance bands in both the ultraviolet (UV) and visible ranges for HPLC however. 

Arguably the most challenging aspect for the preparation of 1 was construction of the unsymmetrically substituted sec-sec chiral bis(trifluoromethyl)benzylic ether functionality with careful control of the relative and absolute stereochemistry [21], The original chemistry route to ether intermediate 18 involved an unselective etherification of chiral alcohol 10 with racemic imidate 17 and separation of a nearly 1 1 mixture of diastereomers, as shown in Scheme 7.3. Carbon-oxygen single bond forming reactions leading directly to chiral acyclic sec-sec ethers are particularly rare since known reactions are typically nonstereospecific. While notable exceptions have surfaced [22], each method provides ethers with particular substitution patterns which are not broadly applicable. 

Arylgold(I) compounds can be similarly prepared to alkyl derivatives via the organolithium or the Gridnard route. These methods have been used to prepare pentachlorophenyl,1641 4,4 -octa-fluorobiphenyl (Equation (27)),2109 2,4,6-tris(trifluoromethyl)phenyl,1 2,21 0 triphenylar-... 

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