Thiophenes, acylation alkylation

Benzo[6]thiophene, 2-acetyl-3-hydroxy-synthesis, 4, 892 Benzo[6]thiophene, 2-acyl-synthesis, 4, 918 Benzo[6]thiophene, 3-acyl-synthesis, 4, 918- 19 Benzo[6]thiophene, acylamino-synthesis, 4, 815 Benzo[6]thiophene, alkenyl-synthesis, 4, 917 Benzo[6]thiophene, 2-alkoxy-synthesis, 4, 929 Benzo[6]thiophene, 3-alkoxy-synthesis, 4, 929 Benzo[6]thiophene, 4-alkoxy-synthesis, 4, 930 Benzo[6]thiophene, 2-alkyl-synthesis, 4, 877-878 Benzo[6]thiophene, 2-alkylthio-synthesis, 4, 931 Benzo[6]thiophene, 2-amino-diazotization, 4, 810 reactivity, 4, 797 stability, 4, 810 synthesis, 4, 869, 924-925 tautomerism, 4, 38 Benzo[6]thiophene, 3-amino-cycloaddition reactions, 4, 68 synthesis, 4, 109, 881, 925 Benzo[6]thiophene, 4-amino-synthesis, 4, 925 Benzo[6]thiophene, 5-amino-synthesis, 4, 925 Benzo[6]thiophene, 7-amino-synthesis, 4, 925 Benzo[6]thiophene, 3-t-amyl-synthesis, 4, 915 Benzo[6]thiophene, 2-aryl-synthesis, 4, 881... 

Beckmann rearrangement, 4, 809 reactions, 4, 809 toxicity, 1, 136 Thiophene, 2-acyl-alkylation, 4, 777 synthesis, 4, 917 transacylations, 4, 760 Thiophene, 3-acyl-synthesis, 4, 918... 

In the second class of synthesis two thiophene rings become joined through a carbon atom that is already a substituent of one of them by this means symmetrically and unsymmetrically substituted products in the 2,2, 2,3, and 3,3 series are available. Three main reaction types have been employed in this approach. In one of these a thiophene is alkylated with a thenyl halide (Eq. 3). Friedel-Crafts acylation of a thiophene by a thenoyl chloride or thenoic acid followed by reduction of the resulting dithienyl ketone provides a second route in this category. The last and most versatile synthesis in this class involves reaction of a thienyllithium (or Grignard reagent) with a thienylaldehyde or thienyl ketone reduction of the carbinol (see Eq. 2) then gives the dithienylalkane. 

Both thiophene acylation (Scheme 19) and alkylation (see Sect. 2.2.3) [39] were achieved by application of benzotriazole derivatives as active reagents. Thus,... 

Sulfonated styrene—divinylbensene cross-linked polymers have been appHed in many of the previously mentioned reactions and also in the acylation of thiophene with acetic anhydride and acetyl chloride (209). Resins of this type (Dowex 50, Amherljte IR-112, and Permutit Q) are particularly effective catalysts in the alkylation of phenols with olefins (such as propylene, isobutylene, diisobutylene), alkyl haUdes, and alcohols (210) (see Ion exchange). Superacids. 

All lation. Thiophenes can be alkylated in the 2-position using alkyl halides, alcohols, and olefins. Choice of catalyst is important the weaker Friedel-Crafts catalysts, eg, ZnCl2 and SnCl, are preferred. It is often preferable to use the more readily accompHshed acylation reactions of thiophene to give the required alkyl derivatives on reduction. Alternatively, metalation or Grignard reactions, on halothiophenes or halomethylthiophenes, can be utilized. 

Acyl-pyrroles, -furans and -thiophenes in general have a similar pattern of reactivity to benzenoid ketones. Acyl groups in 2,5-disubstituted derivatives are sometimes displaced during the course of electrophilic substitution reactions. iV-Alkyl-2-acylpyrroles are converted by strong anhydrous acid to A-alkyl-3-acylpyrroles. Similar treatment of N-unsubstituted 2- or 3-acyIpyrroles yields an equilibrium mixture of 2- and 3-acylpyrroles pyrrolecarbaldehydes also afford isomeric mixtures 81JOC839). The probable mechanism of these rearrangements is shown in Scheme 65. A similar mechanism has been proposed for the isomerization of acetylindoles. 

The thenyl cyanides are of great importance for the preparation of thiophene derivatives. Because of the acidifying effects of both the thienyl and of the cyano groups, carbanions are easily obtained through the reaction with sodamide or sodium ethoxide, which can be alkylated with halides, carbethoxylated with ethyl carbonate, or acylated by Claisen condensation with ethyl... 

Fatty acids are prepared by acylating thiophene with acid chlorides and reducing the ketones (218) to alkylthiophenes according to Wolff-Kishner or Clemmensen. The latter are then acetylated and oxidized by hypochlorite to 5-alkyl-2-thiophenecarboxylic acids, > ... 

In glatter Reaktion werden Formyl- bzw. Acyl-thiophene mit Triathyl-siliciumhydrid in Trifluoressigsaure zu Alkyl-tetrahydro-thiophenen reduziert (s, S. 99). 

Fig. 29 Microwave-promoted multicomponent synthesis of polysubstituted thiophenes on soluble PEG support. Reagents and conditions a NCCH2OOH, DCC, DMAP, CHCI3, MW 130 W, 5 min b RCOCH2R, S8, diisopropylethylamine, MW 130 W, 15 min c R"COCl, di-isopropylethylamine, 0 °C to rt, 3 h d 1% KCN in CH3OH, o.n. R = H or alkyl R = alkyl or acyl R" = CH3, Ph...

FC acylation and alkylation As pyrroles and furans are not stable in the presence of Lewis acids, which are necessary for FC alkylations and acylations, only thiophene, which is stable in Lewis acids, can undergo these reactions. Thiophene reacts with benzoyl chloride in the presence of aluminium chloride to produce phenyl 2-thienyl ketone. 

Alkylation of thiophene by alkenes, catalyzed by H2SO4, is not as efficient a reaction as acylation polymerization often occurs, resulting in lower yields of desired products. Moreover, the reagent is not selective, since mixtures of 2- and 3-alkylthiophenes result (63AHC(l)l). Various alcohols have been used as the carbenium ion source, in the presence of SnCl4. Thus 7-butanol gives 2,5-di-f-butylthiophene. 

Methyl- or 2-ethyl-benzo[Z> ]thiophenes are conveniently prepared by treatment of 2-benzo[6]thienyllithium with the appropriate alkyl sulfate <70AHC(11)177). Clemmensen or Wolff-Kishner reductions of the 2-acylbenzo[Z>]thiophenes are useful, but since acylation produces a mixture of the 2- and 3-acyl isomers (Section 3.14.2.4), these must be separated. Cyclization of phenyl phenacyl sulfide with hydrofluoric acid leads exclusively to 2-phenyl-benzo[6]thiophene, and 3-phenylbenzo[6]thiophene can be rearranged to the 2-isomer in hydrofluoric acid (Section 3.15.2.3.2). Aromatization of 2-cycIohexenylbenzo[6]thiophene, obtained by condensation of the 2-lithio reagent with cyclohexanone, gives 2-phenyl-benzo[6]thiophene, and the reaction is adaptable to the 2-(l-naphthyl) derivative also. 

The 3-acylbenzo[6]thiophenes, separated from the mixture obtained on acylation of benzo[6]thiophene (Section 3.14.2.4), are readily reduced to 3-alkylbenzo[6]thiophenes. 3-Benzo[6 ]thienyllithium can be prepared from 3-bromobenzo[6]thiophene at -70 °C (68JCS2733) and this may serve as a source of 3-acylbenzo[Z>]thiophenes. In certain instances, Friedel-Crafts alkylation gives the 3-substituted benzo[6]thiophenes nearly exclusively. For example, 3-t-amylbenzo[6]thiophene was the exclusive product of alkylation of benzo[6 Jthiophene with t-amyl alcohol in the presence of tin(IV) chloride <70AHC(11)177). 

Friedel-Crafts acylation of benzo[6]thiophene usually gives a mixture of 2- and 3-substituted isomers, in which the 3-isomer predominates (Section 3.14.2.4). However, various electron-releasing groups elsewhere on the ring system may favor 2-acylation. Certainly 3-alkyl- or 3-methoxy-benzo[h]thiophenes are acylated exclusively in the 2-position, and 5,6-dimethoxy-, 5,6-methylenedioxy- and 6-ethoxy-benzo[f>]thiophenes are acylated predominantly in the 2-position (70AHC(11)177). 

The use of modern physical methods (NMR, UV, and IR spectroscopy, mass spectrometry, and gas-liquid (GLC) and thin-layer (TLC) chromatography is becoming increasingly noticeable. By 19522 few systematic studies of the preparation of derivatives of benzo [6]thiophene had been undertaken, no attempt had been made to alkylate benzo[6]thiophene by means of the Friedel-Crafts reaction, and Friedel-Crafts acylation had been little studied. Halogenation of benzo[6]thiophene had only been superficially investigated and... 

The synthesis of 3-alkyl- and 3-arylbenzo[6]thiophenes, developed by an Italian group,329-334 involves the cyclization of o-acyl-S-... 

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