Benzo thiophenes acylation

Italian authors227 found the following order of decreasing reactivity in halogenation and acylation a-position in thiophene > /3-position in benzo[ ]thiophene > a-position in benzo[6]thiophene > /3-position in thiophene. 

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... 

Benzo[b]thiophene-2,3-quinone, 5-chloro-oxidation, 4, 824 Benzothiophenes, 4, 863-934 biological activity, 4, 911-913 intramolecular acylation, 4, 761 mass spectrometry, 4, 739 metabolism, 1, 242 phosphorescence, 4, 16 reactivity, 4, 741-861 spectroscopy, 4, 713-740 structure, 4, 713-740 substituents reactivity, 4, 796-839... 

The electron-rich thiophene ring system can be elaborated into complex, fused thiophenes by acid-mediated intramolecular annelation reactions. For example, treatment of alcohol 96 with trimethylsilyl triflate promoted a Friedel-Crafts acylation and subsequent dehydration giving benzo[b]thiophene 97, a potential analgesic <00JMC765>. Treatment of ketone 98 with p-toluenesulfonic acid resulted in the formation of fused benzo[b]thiophene 99 <00T8153>. Another variant involved the cyclization of epoxide 100 to fused benzo[f>]thiophene 101 mediated by boron trifluoride-etherate . 

Cagniant and Cagniant have reported that succinoylation of benzo[6]thiophene under Friedel-Crafts conditions yields a separable mixture of the y-ketobutyric acids 42a and 43a in a ratio of 9 1 (combined yield 85%). Huang-Minlon reduction of 42a to the butyric acid (90%) followed by cyclization of the derived acid chloride (90%) was reported to yield 4-keto-l,2,3,4-tetrahydrodibenzothiophene (44a) (69% overall). Likewise, acylation of benzo[6]thiophene with the ester chloride of succinic acid in carbon disulfide-aluminum chloride gave a separable mixture (80%) of the 2- and 3-y-ketobutyric esters. Two alternative... 

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 most direct synthesis of 2-acylbenzo[6]thiophenes involves reaction of the readily available 2-lithio derivative with acylating agents, such as nitriles, acid anhydrides, etc. (equation 19). Benzo[f>]thiophene-2-carboxylic acids are available by a variety of cyclization reactions (Section 3.15.9.2.4) and the acid chlorides or esters can be used to synthesize 2-acyl derivatives by conventional means. 

Friedel-Crafts acylation of benzo[6]thiophene using a variety of catalysts gives a mixture of isomers, in which the 3-isomer predominates in a ratio of about 4 1. The milder catalysts, such as boron trifluoride etherate or iodine, give the best yields, since there is less destruction of the ring. While aluminum chloride gives the 3-isomer in about 9 1 ratio over the 2-isomer, the total yield is only 38%, as contrasted to yields over 70% with milder catalysts (70AHC(11)177). 

Acetylbenzo[6]tellurophene is also formed in isolable quantities. Benzo[6]selenophene is converted into 2-acyl derivatives by reaction with acid chlorides in the presence of aluminum chloride, whereas similar Friedel-Crafts acylation of benzo[6]thiophene yields 3-substituted products. When the 2-position is blocked, formylation can be directed into the 3-position. Thus treatment of 2-bromobenzo[6]selenophene with dichloromethyl butyl ether (Cl2CHOBu) and titanium tetrachloride yields the 3-formyl derivative (72BSF3955). If the 2- and 3-positions of benzo[6]selenophene are blocked with methyl groups, acylation under Friedel-Crafts conditions occurs in the 6-position (78CR(C)(287)333>. 

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... 

Monosubstitution (e.g., chlorination, bromination, and Friedel-Crafts acylation) of benzo[6]thiophene usually gives a mixture of... 

Disubstituted Benzo[b]thiophenes 2,3-I)ibromobenzo[6]thiophene undergoes Friedel-Crafts acylation in the 6-position,77 but gives a mixture of the 4- and 6-nitro isomer on nitration.101 Similarly, 2,3-dimethylbenzo[b]thiophene undergoes Friedel-Crafts acetylation82,136,418 and bromination81 mainly in... 

The earlier observations 655 that Friedel-Crafts acylation of benzo[6]thiophene yields a mixture of the 2- and 3-ketone, in which the 3-isomer predominates, has been confirmed by reaction of benzo-[6]thiophene with a variety of acid chlorides,132,464,4fi5,485,501-502, 512,650,656-658 es er chlorides,135,4 9,50o,659 an(j aci(j anhydrides439, 500, 620, 660, 661 (Tab]e XIH). 

ITuedel Cuafts Acylation op Alkyl, Alkoxy, Halo, and Hydro Benzo[6]thiophenes ... 

For convenience, the acylation of benzo[6]thiophene is omitted from this table. References are given in Section VI,L, 2. 

Friedel-Crafts acylation of benzo[6]thiophene and its derivatives with succinic anhydride132,439,662,663 or the ester chloride of succinic acid614, 618, 650,662 gives a y-keto acid (or ester), which is reduced to the corresponding y-(benzo[6]thienyl)butyric acid by the Huang Minion or Clemmensen method. y-(Benzo[6]thienyl)butyric acids may alternatively be prepared by the diethyl malonate synthesis on the appropriate halide,439,499 by the Arndt-Eistert reaction on the corresponding propionyl chloride,409,618 or by cyclization.347,618 The ketones (317 R = Hor OMe)347 have been prepared by cyclization... 

The formation of naphtho[6c]thiophene-3-ones 106 takes place on acylation of 2-substituted benzo[b]thiophenes 103 with cinnamoyl chloride (78AP710, 78LA627 79LA965). Interestingly, the aromatization of the intermediate 105 occurs with elimination of benzene. Chalcone 104 also may be obtained on acetylation of benzo[fe]thiophene 103, followed by condensation of benzaldehyde with the methyl group of the 3-acetylbenzo[b]thiophene intermediate (79LA965). 

Naphtho[ >c]thiophenones 108 can be synthesized in one step on acylation of 2-substituted benzo[6]thiophenes 107 with malonic acid... 

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