Trifluoromethylated furans synthesis

The reaction conditions of the classical Paal-Knorr furan synthesis can be too harsh, when labile functionality has to be preserved. In the synthesis of the 3-oxa guaianolide 4, a five-step detour proved to be more efficient than direct cyclization (Scheme 4) <2000T6331>. Cyclic carbinol amides yield a-trifluoromethyl-sulfonamido furans upon treatment with triflic anhydride (Equation 7) <20030L189>. 

The methods of synthesis for bis(perfluoroalkyl)furans are more developed. For example, 2-methyl-3,4-bis(trifluoromethyl)furan can be synthesized by the reaction of 2-methyl-furan-3,4-dicarboxylic with sulfur tetrafluoride. However, the main synthetic methods rely on the use of unsaturated fluorine-containing acyclic compounds. So, 3-trifluoromethylfurans 57 were prepared from p,p-bis(trifluoro-methyl)a,p-unsaturated ketones and tin(II) chloride. ... 

Lithio-3,4-bis(trifluoromethyl)furan easily prepared from 3,4-bis(trifluoromethyl) furan and BuLi was used for the synthesis of a wide variety of derivatives by the reactions with appropriate electrofile. ... 

Also noteworthy is the synthesis of trifluoromethylated furans 37 from propargylic alcohols 35 and methyl 4,4,4-trifluorobut-2-ynoate 36 with l,4-diazabicyclo[2.2.2]octane as catalyst (Scheme 13) (14JOC2105). The trifluoromethylated furans were isolated in good yields under mild conditions. 

Bouillon J-P, Henin B, Knot J-F, PorteUa C (2002) Fluorinated ketene dithioacetals 8 l,l-bis(ethylsulfanyl)perfluorobut-l-ene as starting material for the synthesis of substituted 2-(trifluoromethyl)furans and -pyrroles. Eur J Oig Chem 1556-1561... 

Diels-Alder reaction/retro-Diels-Alder sequence can be applied to the synthesis of furans with unusual substitution pattern. For example, the reaction of furan 69 and 2-methylfuran 83 with hexafluorobut-2-yne 84 afforded 7-oxanorbomadienes 85, which were further transformed into 3,4-bis(trifluoromethyl)furans 87 through the intermediate 86 [72-75], Temperature of retro-Diels-Alder reaction should be relatively high in this case. However, this drawback can be circumvented by the addition of tetrazine 88. It was shown that reaction of 85a with this reagent proceeds at room temperature giving rise to 3,4-bis(trifluoromethyl)furan 87a through the Diels-Alder cycloaddition and double retro-Diels-Alder reaction [76]. 

Similarly, Diels-Alder/retro-Diels-Alder sequence was utilized to the synthesis of ethyl 4-(trifluoromethyl)furan-3-carboxylate 92 starting from furan and ethyl trifluorobut-2-ynoate via intermediate products 90 and 91 [78], Cycloadduct 90 was also transformed into 92 by two-step procedure including its Diels-Alder reaction with tetracyclone and thermolysis of adduct 93 [79]. 

Other common approach towards trifluoromethylated furans is based on a cyclization of the corresponding 1,4-diketones [85]. Various methods were used for the synthesis of starting trifluoromethyl-substituted 1,4-diketones. Thus, alkylation of ethyl 4,4,4-trifluoroacetate 103 with chloroacetone produced 1,4-diketone derivative 104. The latter underwent cyclizations either directly [86] or after decarboxylation [87] yielding furans 105-107. 

The inoeased ability of polyfluorinated compounds to undergo fluorine substitution was used for the synthesis of trifluoromethyl-substituted furans. Reaction of perfluorobut-2-ene 131 with acetylacetone or acetoacetic ester furnished 2,3-bis(trifluoromethyl)furans 132 through two sequential fluorine substitutions [97]. Similarly, fluoride-ion catalyzed reaction of fluorinated enol phosphates 133 led to dihydrofurans 134 which treatment with a base produced furans 135 in 44-56 % yields [98]. 

Other methods were also used for the synthesis of trifluoromethylfurans. Thus, flash vacuum thermolysis of silyl enol ether of 1,3-diketone 148 at 800 °C afforded furan 69 (70 %) via intermediate allenic ketone 149 [110], Another synthesis of trifluoromethylated furan from 1,3-diketone comprised reaction of diazomethane with 2-(trifluoroacetyl)dimedone 150. This approach produced dihydrofuran 152 in a mixture with methylated product 151. Compound 151 underwent aromatiza-tion into 153 under heating withp-toluenesulfonic acid [111]. 

Palladium-catalyzed reaction of 5-aryl-2-(trifluoromethyl)furan-3-carbonyl chloride 263 with phenylacetylene afforded derivative 264 which is a convenient precursor for synthesis of pyrazoles, pyrimidines, and other heterocyclic systems bearing trifluoromethylated furan as substituent [154]. 

Smith JO, Mandal BK, Filler R, Beery JW (1997) Reaction of ethyl 4,4,4-trifluoroacetate enolate with 3-bromo-l,l,l-trifluoroacetone synthesis of 2,4-bis(trifluoromethyl)furan. J Fluor Chem 81 123-128... 

Buiger K, Helmreich B, Hennig L, Spengler J, Albericio F, Fuchs A (2007) Partially fluori-nated heterocycles from 4,4-bis(trifluoromethyl)-hetero-l, 3-dienes via C-F bond activation -synthesis of 2-fluoro-3-(trifluoromethyl)furans. Monatsh Chem 138 227-236... 

Wang Y, Luo Y-C, Hu X-Q, Xu P-F (2011) A powerful cascade approach for expeditious synthesis of trifluoromethylated furans. Org Lett 13 5346-5349... 

Irgashev RA, Sosnovskikh VY, KaUnovich N, Kazakova O, Roschenthaler G-V (2009) Methyl 2-methoxytetrafluoropropionate as a synthetic equivalent of methyl trifluoropy-ruvate in the Claisen condensation. The first synthesis of 2-(trifluoroacetyl)chro-mones and 5-aryl-2-hydroxy-2-(trifluoromethyl)furan-3(2H)-ones. Tetrahedron Lett 50 4903-4905... 

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... 

So far, the formation of valence-bond isomers by photolysis has mainly been discussed. Tetrakis(trifluoromethyl) Dewar thiophene is stable at room temperature and was used for the synthesis of Dewar pyrroles, a Dewar furan, and other interesting compounds from the standpoint of the structural chemistry. In this section, some of these reactions will be discussed. 

The fast fade rate shown by 2-(4-trifluoromethyl)-2-phenyl-5-trifluorophenyl-[l]benzofuran[2,3-(]naphtho[l,2-6]pyran is attributable to the bulky 5-substituent rather than to the fused benzofuran ring <01WOP36424>. Its synthesis follows from the preparation of 9-hydroxy-7-trifluoromethylbenzo[6]naphtho[ f]furan from 4-chloromethyldibenzofuran (Scheme 18). 

As in case of furan derivatives, the methods for the synthesis of bis(polyfluoroaIkyl thiophenes are more studied. Huorination of 2,5-thiophendicarboxylic acid with sulfur tetrafluoride leads to the formation of 2,5-bis(trifluoromethyl)thiophen." Fluorination of perchlorinated thiophen 154 with AgF gives thiophene 155 and replacement of the p-chlorine atoms by fluorine could not be achieved in this reaction. 

Abstract Synthesis, reactions, and application of furans and benzofurans bearing a fluorine atom and a trifluoromethyl group are reviewed. 

Methods for the synthesis of trifluoromethyl-substituted furans and benzofurans can be divided into several groups direct trifluoromethylation of heterocycle, transformation of functional groups of hetarene into trifluoromethyl substituent, Diels-Alder/retro-Diels-Alder sequence, and various methods for the furan ring formation from precursors bearing trifluoromethyl moiety. 

Other systems for generation of electrophilic perfluoroalkyl radicals were also applied to the synthesis of perfluoroalkylfurans. Thus, trifluoromethylation of furan and benzofuran with trifluoromethyl iodide in DMSO afforded the 2-trifluoromethyl derivatives in 16 and 30 % yield correspondingly [51], Better results were reported for the photocatalytic Ru(bpy)3Cl2-TMEDA system. Trifluoromethylation of... 

The section highlights synthesis of compounds demonstrated physiological activities using fluoro- or trifluoromethyl-substituted furans as starting compounds. Acylation of aniline 287 with 5-fluorofuran-2-carbonyl chloride gave amide 288 which inhibited c-jun A-terminal kinase at submicromolar level [162],... 

Davydov DV, Beletskaya IP (2(X)4) Synthesis of naphtho[2,3-h]furan-4,9-diones having a trifluoromethyl group under conditions of phase-transfer catalysis. Russ JOrg Chem 40 134-136 (Zh Oig Khim 40 143-145)... 

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