Trifluoromethyl sources

Trifluoroacetaldehyde hydrate, F3C-CH(OH)2, has been used as a trifluoromethyl source for nucleophilic trifluoromethylation of aldehydes and ketones, including hindered cases such as adamantanone. Using DMF solvent at -50 C, potassium t-butoxide is used to form the dianion of the hydrate, delivering trifluoromethyl anion, with significant stabilization by the solvent. 

Trifluoromethylation of furans and benzofurans is less studied to compare with other aromatic heterocycles. Generally, it can be performed as radical, electrophilic or nucleophilic process depending on the nature of trifluoromethyl source and reaction conditions. Thus, treatment of 2-nonylfuran 67 with trifluoromethyl iodide in acetonitrile under irradiation afforded the a-trifluoromethylated product 68 in 51 % yield [49],... 

Sodium trifluoroacetate, in the presence of copper(l) iodide, was also used as trifluoromethyl source to replace halogen by trifluoromelhyl group in the thiophene system. Sodium trifluoroacetate was decarboxylated, forming fluoroform, when heated alone in aqueous N-methylpyrrolidin-2-one. The addition of copper(l) iodide increased the rate of decarboxylation dramatically. The mechanism of this process was explored and an intermediate [CFsCul] was proposed. Introduction of higher perfluoroalkyl groups from their corresponding sodium perfluoroalkane carboxyl-ates was also shown to be possible [58],... 

Other inexpensive, easy-to-handle trifluoromethyl sources are also of great interest. For example, trifluoroaeetate salts are potential trifluoromethylat-ing agents through decarboxylation, the only by-product being CO2. These salts are derived from trifluoroaeetie aeid, which is produced on an industrial scale by electrochemical fluorination of acetyl chloride with HF. After pioneering work by Chambers and Kondo ° in the 1980s on the trifluoromethylation of iodoarenes mediated by Cu, Duan has reported the... 

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)... 

Cheaper sources of tnfluoromelhyl groups have been the goal of several groups The use of sodium tnfluoroacetate and copper (1) iodide in dipolar aprotic solvents gave regiospecific trifluoromethylation of aromatic halides [202] (equation 136)... 

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 chalcogene heterocycles have been used as stable precursors for sulfur-said selenium-cantaining hetero-l,3-dienes in cycloaddition reactions 3//-l,2,4-Thiaselenazoles are a convenient source of 4,4-bis(trifluoromethyl)-l-thia-3-aza-buta-1,3-dienes, and 3//-diselenazoles are a convenient source of 4,4-bis(trifluoromethyl)-l-selena-3-azabuta-l,3-dienes as well as bis(tnfluoro-methyl)-substrtuted nitrile ylides [137]... 

Bis(trifluoromethyl)thiobut-2-yne is a source of CF3S-substituted five-and six-membered heterocycles through pyrolysis, photolysis, and 1,3-dipolar cycloaddition (88CB1833). 

Bis(trifluoromethyl)-substituted 1,3-heterodienes are a rich source of heterocycles through cycloadditions, for example, with ketenes (86CZ83) and azirines [89JFC(42)51] to give dioxazines and triazepines, respectively. 

The facile elimination of the methylene-like species (CF3)2Ge indicates that, under the appropriate conditions, (CF3>4Ge may well serve as a useful laboratory source of trifluoromethyl-substituted Ge(II). 

In our laboratory, we find that the plasma reaction of trifiuoro-methyl radicals with mercuric iodide is an excellent source of bis(tri-fluoromethyDmercury. For those laboratories that lack access to radiofrequency (rf) equipment (a 100-W, rf source can at present be purchased for less than 1,000), synthesis of bis(trifluoromethyl)mercury by the thermal decarboxylation of (CFgCOjlzHg is also a functional, and quite convenient, source of bis(trifiuoromethyl)mercury (23). 

As these results indicate, the reaction of (CF3)2Hg with germanium tetraiodide provides a convenient source of the (trifluoromethyl)ger-manium iodides in good to excellent yields, and these yields can be varied, to increase the proportion of a particular (trifluoromethyl) germa-... 

Previously, trifluorosilyl groups have been bound to phosphorus (40) and silicon via the SiF (g), fluorine-bond insertion-mechanism (41). The new compound HgCSiFs) is readily hydrolyzed, but it can be stored for long periods of time in an inert atmosphere. It is a volatile, white solid that is stable up to at least 80°C. The preparation of bis(trifluoro-silyDmercury, of course, raises the possibility of (a) synthesis of the complete series of trifluorosilyl, "silametallic compounds, as had previously been done for bis(trifluoromethyl)mercury by using conventional syntheses, and (b) transfer reactions similar to those in Section II, as well as (c) further exploration of the metal-vapor approach. The compound Hg(SiF.,)j appears also to be a convenient source of difluoro-silane upon thermal decomposition, analogous to bis(trifluoromethyl)-mercury ... 

When colloidal selenium was heated with mercuric trifluoroacetate or silver trifluoroacetate, bis(trifluoromethyl)diselenide was formed (43). Later work with selenium/silver carboxylate, RC02Ag (R = CF3, C2F5, or C3F7), mixtures at 280° C in a vacuum produced a mixture of the bis(perfluoroalkyl)selenide and the bis(perfluoroalkyl)diselenide (44). Formation of a polyselenium trifluoroacetate, which decarboxylates to produce the trifluoromethylselenides, was the proposed mechanism for R = CF3 (44). However, silver trifluoroacetate is a source of trifluoromethyl radicals when heated above 260° C (21), hence the trifluoromethylselenides may be formed by reaction of trifluoromethyl radicals with selenium, as in the reaction of CF3I with selenium [Eq. (34)] (45). 

When trifluoroacetaldehyde ethyl hemiacetal [F3CCH(OH)OEt] is treated with enamines in hexane at room temperature, it provides a source of the aldehyde under mild conditions. Subsequent reaction with the enamine can be used to prepare -hydroxy-/ -trifluoromethyl ketones, F3CCH(OH)CH2COR. The enamine plays successive roles as base, ammonium counterion, and then carbon nucleophile as the sequence proceeds. 

It has recently been shown that when the tetrahedral intermediate of the reaction is cyclic, it is a better donor of nucleophilic CF3. These cyclic intermediates can be generated intramolecularly from trifluoroacetamides or trifluorosulfmamides derived from (9-silylated ephedrine. These reagents are able to trifluoromethylate aldehydes and ketones, even in the case of enolizable substrates, as a strong base is not required (Figure 2.34). However, while the source of CF3 is chiral, there is no chirality transfer to the addition product, and the replacement of ephedrine by other chiral amino alcohols did not show any improvement. " Similar to asymmetric trifluoromethylation with the Ruppert reagent, only the use of a fluoride salt of cinchonine can increase the enantioselectivity. " " ... 

Other sources of radical CF3, much less expensive than CF3I, have been discovered. These are the anodic oxidation of sodium trifluoroacetate (the decomposition being initated by a hydroperoxide or ruthenium catalyst) and trifluoromethyl bromide (CF3Br) using sodium dithionite as initiating agent. ... 

Starting from Trifluoroacetic Acid Derivatives Trifluoroacetic acid and its derivatives (e.g., esters, anhydride, fluoral, trifluoroethanol) are the major channel of the organic fluorine industry. They are relatively inexpensive and, compared to halons, they do not exhibit major environmental problems. They are the main source for the synthesis of trifluoromethylated compounds. 

For the formation of 5-chloropyrimidines, AT-chlorosuccinimide is normally the reagent of choice, but several other electrophilic chlorine sources including chlorine gas or sulfuryl chloride can be used <1994HC(52)1>. For example, the chlorination of 4-(trifluoromethyl)-2(l//)-pyrimidinone 59 with ferric chloride and sulfuryl chloride in acetic acid gave the 5-chloro derivative 60 in 80% yield <2004EJ03714>. 

Due to the cost of trifluoromethyl iodide, other cheaper sources have been investigated for trifluoromethylation. Sodium trifluoroacetate reacted with aryl iodide in the presence of copper (I) iodide in NMP at 140 -160 °C to afford the corresponding coupling product [87]. No trifluoromethylation was observed without Cul. Under similar reaction conditions, sodium pentafluoropro-pionate worked well to give the pentafluoroethylated compounds [88, 89] (Scheme 28). 

Recently, analogues of nucleosides [60], natural products Huperzine-A [61] and Hydroartemisinin [62], and inhibitors of metallo-/ -lactamases have been synthesised [63]. With acylsilane electrophiles, the initial adducts undergo Brook rearrangement which is interrupted by -Si bond fission with loss of fluoride anion (Eq. 16), leading to the formation of extremely useful difluoro-enol silanes [64]. Of the various fluoride sources employed, the tetrabutylam-monium triphenyldifluorostannate described by Gingras appears to be particularly effective. The numerous other methods for trifluoromethylation formed the subject of an exhaustive review [65]. More recently, the Olah group described a chlorodifluoromethyl trimethylsilane which is expected to have a rich chemistry [66]. 

Adamantanecarboxylic acids with a carboxylic group at a bridgehead position, e.g. adaman-tane-1-carboxylic acid (8),111 react with sulfur tetrafluoride in the conventional way giving high yields of the corresponding trifluoromethyl-substituted adamantanes. l-(Trifluoromethyl)-adamantane (9) can also be formed in one step from adamantane by treatment with a mixture of sulfur tetrafluoride, hydrogen fluoride and formic acid the latter serves as a source of carbon monoxide. The reaction is believed to proceed via carbonylation of an intermediate carbocat-... 

The rate of reaction is highly variable depending on the UV source. The reaction is easily monitored by TLC on silica gel using ethyl acetate-hexane (1 1) as the eluent and p-anisaldehyde stain. The Rf values and staining colors ot starting materials and products follow 9-ethyl-3,6-dimethylcarbazole R = 0.95 (gray) 3, 5 -di-0-benzoyl-2 -0-((3-trifluoromethyl)benzoyl]-5-methyluridine R = 0.75 (pink-purple) 5 -0-benzoyl-3 -deoxythymidine Rf = 0.55 (aqua blue) 3 ,5 -di-0-benzoylthymidine Rf = 0.30 (brown-black). 

The trifluoromethanesulfonyl (triflyl group) is one of the strongest electron-withdrawing groups and therefore is a versatile functionality for organic synthesis Trifluoromethyl sulfones have been prepared by using an electrophilic tnflyl source such as triflic anhydride or by displacing primary halides with a inflate salt... 

---