Trifluoromethyl building blocks

Yamauchi, Y., Kawate, T., Itahashi, H., Katagiri, T., and Uneyama, K., (2003) Tetrahedron Lett. 44, 

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Nocentini T, Brule C, BottiUon JP, Gorrault-Birormeau S, Portella C (2007) Fluoride-induced coupling of perlluoroketene dithioacetals with silyl alkynes a way towards new polyfunc-tionalized trifluoromethyl building blocks. J Fluor Chem 128 13(X)-1305... 

Ethyl 5-trifluoromethylpyrazole-3-carboxylate was quantitatively prepared in a 1,3-dipolar cycloaddition between ethyl diazoacetate and sulphur (or bromo) derivatives of 3,3,3-trifluoropropene that act as easier to handle synthetic equivalents of 3,3,3-trifluoropropyne [35]. On top of all these studies, the most common strategy for the preparation of 3- and 5-trifluoromethylpyrazoles entails the [3 + 2] heterocy-clization of trifluoromethyl building blocks derived from p-(amino/aIkoxy/thioxy) vinylketones and 1,3-dicarbonyl with monosubstituted hydrazines. Mixtures of regioisomers are often obtained depending on the substrate, the substituent of the hydrazine, and the reaction conditions [36]. 

W-(Methoxycarbonyl)triphenylphosphine imide reacts with methyl trifluoro-pyruvate to form methyl A -methoxycarbonyl 2 immo-3,3,3 trifluoropropionate m 95% yield This convenient building block easily adds nucleophiles such as Gngnard reagents without competing side reactions at the ester group to form trifluoromethylated amino acids [J.S] (equation 31)... 

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). 

Fluorinated heterocycles have many uses and the following are some typical examples. Trifluoromethyl pyridines are useful building blocks for agrochemicals (91MI1). Fluorinated quinolones have evoked considerable interest in the last 10 years as antibacterial agents (90MI1, 90MI2). The... 

The a-methoxylated products are highly useful building blocks for the construction of a carbon-carbon bond a to the trifluoromethyl and diflu-oromethyl groups, which is difficult to obtain by other methods, as shown in Scheme 6.15. Thus, a-tri and a-difluoromethylated a-aminonitriles, which are precursors to the corresponding fluorinated a-amino acids, have been prepared in good yields, and flourinated homoallyanilines have been also successfully prepared [44]. in addition, tri- and difluoromethylated tetra- and dihydroquinoline derivatives can be prepared by cationic polar cycloaddition in high yields [45]. 

Sulfenimines are versatile building blocks for the preparation of secondary and tertiary amines. Therefore, fluoroalkylated sulfenimines should be promising building blocks for the preparation of N-fluoroalkylamino compounds. In fact, very recently, trifluoromethylated sulfenimines have been easily prepared in... 

The sulfenimines have been shown to be highly useful building blocks for the preparation of trifluoromethylated amines, aminoketones, and aminoalkano-ates as illustrated in Scheme 6.19. 

Kolbe electrolysis of trilfuoromethylated carboxylic acids has been shown to be a versatile method for providing useful building blocks having a CF3 group. Seebach and Renaud have prepared new types of trifluoromethylated chiral building blocks from enantiomerically pure 3-hydroxy-4,4,4-trifluorobutyric acid (Scheme 7.6) [76]. 

Both enantiomers of l-[3,5-bis(trifluoromethyl)phenyl]ethan-2-ol are of importance in the pharmaceutical industry, and so considerable effort has been expended in their asymmetric synthesis. The (7 )-enantiomer is a building block for aprepitant, a neurokinin-1 (NK-1) antagonist used for the treatment of chemotherapy-induced nausea (Figure 1.11). ... 

The compounds obtained in these reactions, especially enol ethers, are interesting building blocks they can give rise to many other trifluoromethyl molecules. For... 

The higher homologue of fluoral, pentafluoropropionaldehyde, prepared by reduction of ethyl pentafluoropropionate, is a precursor of diethyl tetrafluoroketene dithioacetal, which is a versatile building block for the synthesis of trifluoromethyl-substimted functional compounds, such as trifluoromethyl lactones, lactams, and heterocyclics, as exemplified in the Figure 2.53. ... 

Two approaches to the synthesis of molecules which contain either one or two fluorine atoms or a trifluoromethyl group are the reaction of fluorine with a precursor which then gives the required molecule directly, and the introduction of fluorine into small molecules which are subsequently used as building blocks in the synthesis of more complex products [2,4, 5, 8,117-120]. Direct reaction between a substrate, or a simple derivative of a substrate, and elemental fluorine has a role to play in both of these approaches. Preparation of fluorina-ting agents by the reaction of fluorine with various molecules will be discussed but further chemistry of the derived reagents themselves will not be described. 

Building blocks derived from microbial transformations are usually employed as the key units of fluorinated analogs of appropriate natural products or synthetic biologically active materials [42-45]. Among such useful compounds, trifluoromethylated carbohydrates constitute one of the most interesting fields for intensive study. Novel and efficient routes to access a variety of chiral... 

Trifluoroacetic acid is a most useful building block for a wide range of tri-fluorocompounds, particularly trifluoromethyl ketones [206]. Esters are useful... 

Semicarbazide hydrochloride [705] and amidrazones [106] react with trifluoropyruvates to give six-membered heterocycles A variety of trifluoromethyl substituted heterocyclic systems is available, starting from the hydrate of trifluoropy-ruvicacid, a versatile 1,2-bielectrophilic building block (reaction type 2, equation 10) [107] (equation 24). 

The Henry nitro-aldol condensation involves the use of P-amino alcohols as the building blocks of fluoromethyl ketones. Although this method has been used extensively in the synthesis of monofluoropeptides (Table 2),19-121 it is more widely utilized as a method for synthesizing trifluoromethyl ketones and the details of the reaction will be discussed in Section 15.1.4.3.2. 

Pyridyldimethylsilane 24 is a reagent for the metal-catalyzed hydrosilylation of alkynes and alkenes <2004EROS1>. 4-(Trifluoromethyl)pyridine 25 has been used as a building block in heterocycle synthesis <2005EROS1>. 

Hexafluoroacetone was shown to be an extremely versatile (1,2 ne) building block for the introduction of a geminal pair of trifluoromethyl groups as well as a single trifluoromethyl group into flve-membered heterocyclic systems (87MI2). 

Polyfluorinated target molecules are obtained when both building blocks are fluorinated and/or perfluoroalkylated. A typical example for this type of condensation is the synthesis of a tris(trifluoromethyl)-substituted 1,3,4-triazole from 3,5-bis(trifluoromethyl)benzhydrazide and trifluoroaceta-midine (78BRP1510647). 

Trifluoromethyl-substituted nitrones have been prepared [78JFC-(12)153 88JFC(39)39, 88MI2 89JHC381] and used as building blocks for five-membered ring synthesis (Scheme 66). 

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