Trifluoromethyl substituted pyrrole

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). 

In the presence of triethylamine, enaminones 11 are synthesized in high yields from the corresponding amino ester or amino nitrite hydrochlorides and vinylogous esters 10, Scheme 4 (89TL6173, 92S533). The products are precursors for trifluoromethyl-substituted pyrroles and dihydropyrroles (Section V,C). 

Chlorfenapyr (52 1995, Pirate , ACC/BASF) [119], a potent uncoupler of mitochondrial oxidative phosphorylation [120], is based on a trifluoromethyl substituted pyrrole (Scheme 35.3). 

Hoffmann MG, Wenkert E (1993) Natural product synthesis in agricultural chemistry. 2. A new and efficient synthesis of 2-trifluoromethyl substituted pyrroles and ethyl-2,3-bis(ethoxycarbonyl)-lH-pyrrole-1-propionate. Tetrahedron 49 1057-1062... 

In a study being conducted at Case Western Reserve University under the direction of Dr. Lawrence Sayre, trifluoromethyl-substituted analogs of 2,5-hexanedione will be synthesized, compared with the parent compound in chemical model studies, and evaluated for neurotoxicity in rats. This is part of an effort to address how gamma-diketone-induced pyrrole formation at neurofilament-based lysine epsilon-amino groups leads to neurofilament accumulations. Nuclear magnetic resonance (NMR) studies will provide direct visualization of the nature of chemical modification. 

The adducts (92 R = PhCO or COOBu ") of perf luorobut-2-yne, CF CECCF, to N-substituted pyrroles have been degraded to 3,4-bis(trifluoromethyl)pyrroles (93) by two methods in the former, the adducts were first hydrogenated at the unsubstituted double bond and then heated to eliminate ethylene,while in the latter, the adducts were treated with mesitonitrile oxide, 2,4,6-Me C H2C=N -0, which removed the ethylene unit in the form of the isoxazole (94). 

Phenyl pyrrole shows only marginal antimicrobial activity. Several substitutions on the phenyl ring improved activity with m-trifluoromethyl phenyl pyrrole being most active. 

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. 

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,... 

Phase-transfer catalysis was found <1996CHEC-II(7)1> to be successful for N-substitution of the furo[3,2-/ ]pyrrole system. The reaction of 81a with methyl iodide or benzyl chloride gave 81b and 81c derivatives. Methyl 4-acetyl-2-[3-(trifluoromethyl)phenyl]furo[3,2-3]pyrrole-5-carboxylate 82 was obtained by reacting 81a in boiling acetic anhydride (Scheme 6) <2005CEC311>. 

Acetyl-2-[3-(trifluoromethyl)phenyl]furo[3,2- ]pyrrole 84 was obtained during heating in boiling acetic anhydride of 2-[3-(trifluoromethyl)phenyl]-42/-furo[3,2- ]pyrrole-5-carboxylic acid 83, and it was used for preparing parent compound 85a and the N-substituted compounds 8Sb and 85c (Scheme 7) <2005CEC311>. 

Several further experimental results lend support to the mechanisms postulated to explain the formation of the photoproducts. Thus irradiation of thiophene and substituted thiophenes in the presence of -propylamine leads to pyrroles, presumably via cyclopro-penylthiocarbonyl, or Dewar thiophene, intermediates (75T785). An extremely interesting development is the isolation of l,2,3,4-tetrakis(trifluoromethyl)-5-thiabicyclo[2.1.0]pent-2-ene, or perfluoro(tetramethyl Dewar thiophene) (2) by vapor-phase irradiation of perfluorotetramethylthiophene (81ACR76) the yield is about 58%. The half-life of thermal rearomatization of (2) at 160 °C is 5.1 h. The fluxional behaviour of the Dewar thiophene... 

Tetrafluorobenzyne, generally generated by the treatment of pentafluoro-benzene with butyllithium at -78 °C in ether in the presence of the substrate diene, is a versatile dienophile [9, 103, 104]. In an interesting study of the use of substituted benzynes to synthesize isoindoles, tetrafluorobenzyne, 4-fluorobenzyne, and 4-(trifluoromethyl)benzyne were shown to react in moderate yields with A7 (trimethylsiIyl)pyrroles, with the adducts being easily converted to the respective fluorinated isoindoles [705] (equation 87). 

The reactions of the l uro 3,2-9 Ipyrroles and their benzo derivatives with DMAD were described earlier [2] and it was stated that the reaction course is influenced by the ring substituents. Recently, it was found that the 4-acetyl-2-13-(trifluoromethyl (phenyl furo 3,2-9 Ipyrrolc 58 reacts in acetonitrile with DMAD at the a and a -positions of the pyrrole ring, giving [4 + 2] cycloadduct, which by subsequent 1,5-sigmatropic rearrangement gives the substituted benzo[9]furan 70 (Fig. 10) [18]. 

Dewar tetrakis(trifluoromethyl)thiophene, (59), has served as a dieneophile (dipolarophile) in several cycloadditions. Diels-Alder reaction of (59) with butadiene <8icci289> and pyrrole (82JA847) has served as the starting point for the synthesis of 1,2,3,8-tetrakis(trifluoromethyl)cyclooctatetraene (60) and tetrakis(trifluoromethyl)Dewar furan (61), respectively, as illustrated in Scheme 20. It is noteworthy that (61) was unattainable by direct photolysis of the substituted furan. Moreover, (59) served as a common precursor for the preparation of tetrakis- (80JA6633) and penta-<83JA3563> (trifluoromethyl)cyclopentadienides (64) and (65), respectively (Scheme 21). Accordingly, photolysis... 

Trifluroinetliyl pyrroles can be also synthesized by nucleophilic trilluoromethylation. In few works the ip o-substitution of iodide in compounds 49 by the trifluoromethyl group was reported using a mixture of FS02CF2C02Et and CuBr2 as the source of the unstable intermediale trifluoromethyl anion [26], No yields of compounds 50 were given. 

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