Trifluoromethyl-substituted alkynes

Trifluoromethyl-substituted pyrazoles are easily obtained using trifluoromethyl-alkynes as dipolarophiles (Table 8.2, entry 9). Thus, treatment of 4,4,4-trifluorobut-2-ynoic acid with excess diazomethane gave methyl 4-(trifluoromethyl)pyrazole-4-carboxylate (45%) accompanied by its N - (32%) and -methylated (6.5%) derivatives (267). Another convenient route to CF3-substituted pyrazoles involves dipolar cycloaddition of appropriately CF3-substituted alkenes followed by eliminative aromatization (76,77,268). For example, the reaction of alkenes such as (CF3)2C=C(H)COAr with ethyl diazoacetate gave 4-aroyl-5-trifluoromethylpyra-zole-3-carboxylates (268). 

Alkynes continue to be used as a reactive functionality in quinoline synthesis. The readily available thiocarba-mates, thioamides, and thioureas allow intramolecular cyclization of pendant alkynes to give modest to good yields of the quinolines (Equation 118) <20030L1765>. An intermolecular reaction involving a zinc-mediated alkynylation-cyclization provides an efficient route to 4-trifluoromethyl-substituted quinolines (Equation 119) <2002JOC9449>. 

The highly regio- and stereoselective carbocupration of the trifluoromethyl-substituted alkyne 211 was recently used by Konno and co-workers154 in a short synthesis of the antiestrogenic drug panomifene 213. The initial product 212 was transformed into the target molecule by Suzuki coupling and elaboration of the side chain (Scheme 52). 

The indazolines themselves may be regarded as masked azomethine ylides and therefore are susceptible to further [3 + 2] cycloaddition reactions (59JOC582). (V-Methyl-A -(2-perfluoropropenyl)trifluoroacetamide exists in a valence tautomeric equilibrium with a cyclic azomethine ylide, which can be trapped with various dipolarophiles. The [3 -I- 2] cycloadducts with alkynes rearomatize on cycloelimination of fluorophosgene to give trifluoromethyl-substituted pyrroles (89BAUI325) (Scheme 61). 

A preparatively and mechanistically interesting synthesis of trifluoromethyl-substituted thiadiazoles from trifluoromethyl-substituted alkynes and tetrasulfur tetranitride has been described [87JCS(PI)1579, 87JCS(P1)1585] (Scheme 73). 

Trifluoromethyl-substituted alkynes are good dienophiles. 3,3,3-Trifluoropropync itself reacts with the electron-rich 2,3-diniethylbuta-l,3-diene to give the cyclohexa-1.4-diene 1. ... 

Trifluoromethyl-substituted dienes are generally electron poor and react with various dieno-philcs, alkenes. and alkynes, and even with electron-deficient alkenes. 

Cycloadditions of Trifluoromethyl-Substituted Alkenes or Alkynes with... 

Trifluoromethyl-substituted alkynes can also react with nitrones, leading to rearranged cycloadducts. The cycloaddition of ethyl 4,4,4-trifluorobut-2-ynoate and hexafluorobut-2-yne " with C,A -diphenyl nitrone is a route to trifluoromethyl-substituted indoles. 

Some examples are known of 1,3-dipolar cycloaddition reactions of trifluoromethyl-substituted alkenes and alkynes with other dipoles (see Table 12), such as diazomethane.nitrile imines, " " nitronates," and munchones." Depending on reaction conditions, cycloadditions may occur via a two-step process. 

I.I.6.2.3.2. 3 + 2] Cycloadditions of Alkenes or Alkynes with Trifluoromethyl-Substituted... 

Cycloaddition reactions with trifluoromethyl-substituted alkynes provide good access to trifluoromethyl-substituted aromatic compounds,32"34 e.g. formation of 5.32... 

Examples of cycloadditions of nitrile oxides with trifluoromethyl-substituted alkynes arc also known. Yields of isoxazoles are high when there is a second electron-withdrawing substituent, such as an ester.91 a substituted phenyl group.92 or a phosphate.9 ... 

Ru3(CO)i2 coordinated with 2-(diphenylphosphino)benzonitrile catalysed the regioselective 2 + 2 + 2-cyclotrimerization of trifluoromethyl-substituted aryl alkynes in high yields and with a high regio-selectivity4 The alkyne 2 + 2 + 2-cyclotrimerization reaction has been applied to the synthesis of the central 4,5,6-tricyclic core (94) of 4,5,6-trinems (Scheme 30)4 The NbC /DMI-catalysed intermolecular 2 + 2 + 2-cycloadditions of terminal alkynes, internal alkynes, and alkenes produced 1,3,4,5-tetrasubstituted 1,3-cyclohexadienes in excellent yields and with high chemo- and regio-selectivities. ... 

Trifluoromethyl-substituted alkynes were found to give good yields of the hydroary-lation products in superacid (Scheme 21). ° i For example, the propyne derivative (91) gives a nearly quantitative yield of the addition product (92) by reaction in triflic acid. Protonation initially leads to the resonance-stabilized vinyl cation (93), which reacts with benzene. The diarylalkyl cation (94) is generated by a second protonation - its presence confirmed through direct observation by NMR - and this yields the olefin (92) upon workup of the reaction. 

In 2013, a C-H activation route to dibenzopentalenes was discovered by the Itami group (Scheme 2.16) [49]. Through a series of electrophilic palladations and insertions, the diphenyldibenzopentalene 14i was constructed in 52% yield. Notably, this method obviates the need for ortho-functionalized precursors as in prior examples. Over the course of a mechanistic study, it was found that the first C-H palladation event was sensitive to the electronic nature of the substrate and the subsequent alkyne insertion proceeded irrespective of it. Electron-poor / -trifluoromethyl-substituted tolans were excellent substrates (14m, 79% yield), and /w-substituted tolans were decent as well (14n, 53% yield 14o, 66% yield) however, / -methoxy-substituted tolans provided no product. 

The RhCls/amine system catalyzed [2 + 2 + 2] cycloaddition of symmetric internal alkynes with trifluoromethyl-substituted unsymmetric internal alkynes, although the chemo- and regioselectivities observed were moderate to low (Scheme 4.7) [18]. 

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. 

Halogen atoms. The introduction of side-chains on 9-trifluoromethyl-paullone 409 can be accomplished applying a Stille coupling (Scheme 86, Section 5.2.1.1 (2005EJM655)). Similarly, a Heck reaction of iodo 409 with terminal alkenes under standard conditions affords 2-substituted paullones 413 exclusively as E-isomers. The reaction of terminal alkynes with 409 in the presence of cuprous iodide and a palladium catalyst in triethylamine furnishes the 2-alkynyl-paullones 412 (2000BMCL567). 

Alkyl(aryl)-2-(trifluoromethyl)-5(277)-oxazolones have been used as intermediates to prepare 2-(trifluoromethyl)pyrroles interesting compounds frequently used as insecticides and acaricides. The oxazolones react with electron-dehcient unsaturated compounds in the presence of a base. Reaction of 5(277)-oxazolones, usually with a substituted aryl ring at C-4, with a wide variety of alkynes and alkenes has given rise to numerous 2-(trifluoromethyl)pyrroles 56. For example,... 

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