Fluorination of thiophenes

Fluorination of thiophene-2,5-dicarboxylic acitl with a sulfur tetrafluoritie-hydrogen fluoride mixture provides 2,5-bis(trifluoromethyl)thiophene in a 69% yield no fluorine addition to the thiophene ring occurs [229J. Also, imidazole mono- and dicarboxylic acids yield only the respective trifluo-romethyliinidazoles [230],... 

Neudorfer, J. Fluorination of Thiophene in the Vapor Phase. C. R. hebd. 

Schultz, J., and M. Hauptschein The Fluorination of Thiophene with Cobalt Trifluoride. J. Amer. chem. Soc. 74, 848 (1952). 

Addition of fluorine to the thiophene ring does not occur under any conditions fluorination of thiophene-2,5-dicarboxylic acid with the sulfur tetrafluoride/hydrogen fluoride reagent yields 2.5-bis(trifluoromethyl)thiophene (16) as the sole product.157... 

The product from the fluorination of thiophene over potassium tetrafluorocobaltate(III) varied, not surprisingly, with temperature.108 At 120 C, virtually the sole product was the dihydrothiophene 5, albeit in low yield (14%) this compound is obviously analogous to 2,2.5,5-tetra-fluoro-2,5-dihydrofuran from tetrahydrofuran and potassium tetrafluorocobaltate(IIl). At 350-370 °C, 5 is still a major product, but now seven others are also present, the main ones being 6-8 and the sulfur extruded product perfluorobutane. 

Fluorination of tetrachlorothiophene with potassium tetrafluorocobaltate(III) gave 3,4-dichlorotetrafluoro-3-thiolene (156). Similar fluorination of thiophene yielded the 3-thiolene (157) and the thiolan (158) <71JCS(C)346, 72T43). It has been suggested that the fluorination proceeds by initial oxidation of thiophene to the cation-radical by the metal ion, and subsequent quenching of this by atomic fluorine (Scheme 30). 

The direct fluorination of thiophene, 1-methylpyrrole, pyrrole, and furan with dilute elemental fluorine (5%) at low conversion (ca. 5%) has been reported.1-Methyldihydropyrrole and thiophene give mixtures of products substituted by fluorine at positions 2 and 3 for thiophene the 2-position and for 1-methylpyrrole the 3-position are favored. Furan undergoes addition reactions and pyrrole produces only tars, even at — 65 C. 

Fluorination of thiophene and derivatives and of 1,4-dithiane [241] with KC0F4 gives a series of fluorinated derivatives. Chlorine-fluorine exchange in sulphides is also possible in some cases [242] (Figure 8.86). 

Electrophilic fluorination of the thiophene derivatives was used for preparation of 2-fluorothiophenes but fluorination of thiophene by F2/He mixture leads to a mixture of two isomers, with 2-fluorothiophene being the major product. ° ... 

The methods of electophilic fluorination of thiophenes are more perspective for the synthesis of 3-fluorothiophenes. For example, thiophene fluorination by F2 affords 3-fluorothiophene in 34% yield,but the use of other electrophilic fluorinating agents gives much better results. 

Thiophenes Containing Two Fluorinated Substituents 2,5-Difluorothio-phene was obtained from 2,2,5,5-tetrafluoro-3-thiolen 151. Compound 151 is a major product in the fluorination of thiophene over potassium tetrafluorocobaltate. ... 

Crestoni ME, Fomarini S (1989) Direct fluorination of thiophene and N-methylpyrrole. Gazz Chim Ital 119 203-204... 

Direct fluorination of thiophene with molecular fluorine (F2) is inconvenient as it is not selective process, owing to the extreme reactivity of molecular fluorine. For example, the reaction of thiophene 1 with fluorine at -63 °C (5 % F2 in He) gave a mixture of 2- and 3-fluorothiophene 2 and 3 in a 2 1 ratio [10], The synthesis of 3-fluorothiophene 3 is challenging due to the higher reactivity of the 2-position of thiophene. When a tenfold excess of fluorine was used, the 3-sub-stituted isomer 3 (68 %) was three times more abundant then the 2-substituted product 2. 

Obtained in very low yield by fluorination of thiophen with CoF,... 

Unlike the nitrogen of pyrroles and the oxygen of furans, the sulfur of thiophenes does not significantly affect fluorine chemical shifts either inductively or as an electron donor. Thus, the fluorine chemical... 

Similarly, the fluorines of a trifluoromethyl group in the 3-position of thiophenes absorb at a higher field than those of one at the 2-position (Scheme 5.49). 

The use of organic polymers as conductors and semiconductors in the electronics industry has led to a huge research effort in poly(thiophenes), with a focus on the modification of their electronic properties so that they can behave as both hole and electron conductors. Casado and co-workers [60] have performed combined experimental and theoretical research using Raman spectroscopy on a variety of fluorinated molecules based on oligomers of thiophene, an example of one is shown in Figure 7. 

The first successful Diels-Alder addition of thiophene appears to have been with tetrafluorobenzyne (66CC143). The adduct apparently loses sulfur, resulting in the isolation of the tetrafluoronaphthalene in 40% yield (Scheme 78). Other thiophene derivatives (69T25) and fluorinated benzynes <71JCS(C)604) have been similarly reacted. Subsequently it was found (80H 14)647) that unsubstituted benzyne, generated from diphenyliodonium-2-carboxylate, could be trapped with thiophene to form naphthalene in 33% yield. The earlier failure to add thiophene to benzyne generated by other methods must have been due to intervention of side reactions. Thiophyne also has been similarly trapped to yield benzo[A]thiophene (see Section 3.14.2.2). 

Halogen Derivatives of Thiophenes and Benzo[6]thiophenes 3.15.9.6.1 Fluorine derivatives... 

Very little work has been done on fluoro derivatives of thiophenes. 2-Fluorothiophene was obtained in low yield from treatment of 2-iodothiophene with arsenic trifluoride. The action of fluoroboric acid on thiophenediazonium salts was unsuccessful. It may be useful for the preparation of 4-, 5-, 6- or 7-fluorobenzo[6]thiophenes from the appropriate amines. However, these are more conveniently prepared from fluorine-substituted benzenethiols by ring-closure reactions. For example 4,5,6,7-tetrafluorobenzo[6 Jthiophene was obtained by decarboxylation of the corresponding 2,3-dicarboxylic acid (equation 99) prepared by condensation of pentafluorobenzenethiol with diethyl acetylenedicarboxylate (Section 3.15.3.4.1). 2-Fluorothiophene has been prepared from 2-thienyllithium using perchloryl fluoride, and 2-fluorobenzo[ Jthiophene from the 2-lithio derivative in a similar manner (Section 3.14.3.9.1). 

Fluorination of benzo[6]thiophene in the vapor phase with cobalt trifluoride gives mainly perfluoroethylcyclohexane, formed by fission of the molecule, elimination of sulfur, and fluorination of the hydrocarbon fragment.480... 

Unlike the nitrogen of pyrroles and the oxygen of furans, the sulfur of thiophenes does not significantly affect fluorine chemical shifts either inductively or as an electron donor. Thus, the fluorine chemical shifts of fluorothiophenes are generally in the region of electron-rich fluo-robenzenes (Scheme 3.92). Moreover, in this heterocycle, fluorines at the 2-position are slightly shielded compared to those at the 3-position. 

Several 3-ai"yl-2-fluorobenzo[/ ]thiophenes have been prepared by fluorination of the 2-lithio derivatives using the electrophilic fluorinating reagent AT-fluorobenzenesulfonimide (Equation 110) <2005SL247>. The yields are fair to excellent. 

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