Friedel-Crafts acylation of thiophene

The acylation of thiophenes has been reviewed (86HC(44/3)309). The best catalyst for the Friedel-Crafts acylation of thiophene, using free carboxylic acids, appears to be 2-(trifhioromethylsulfonyloxy)pyridine (84) in conjunction with TFA. 2-Acylthiophene is formed in quantitative yield, without any evidence of the thiophene dimerizing. The reaction might be mediated by the mixed anhydride (85) (Scheme 15) (88BCJ455) (cf. (84CHEC-(4)74l)). 

The first three reactions are all electrophilic substitution a bromination of a pyrrole, the nitration quinoline, and a Friedel-Crafts acylation of thiophene. Bromination occurs on the pyrrole at only remaining site. Nitration of quinoline occurs on the benzene rather than the quinoline r-fi (actually giving a mixture of 5- and 8-nitroquinolines, but don t worry if you didn t see t- Mi p. 1174), and the acylation would occur next to sulfur. 

CAMEO failed to predict the formation of 2-benzoylthiophene (12) via Friedel-Crafts acylation of thiophene (13) with benzoyl chloride (14) in the presence of a Lewis acid (e.g., stannic chloride) using the Electrophilic Aromatic module. Thiophene is highly reactive under these conditions and would have been expected to undergo acylation readily, as previously reported (71) (Scheme 4). Instead, CAMEO predicted that stannic chloride (the catalyst) would replace a hydrogen in either the 2- or 3-position of... 

The Friedel-Crafts acylation of thiophenes is a much-used reaction and proceeds generally to give good yields under controlled conditions, despite the fact that aluminium chloride reacts with thiophene to generate tars this problem can be avoided by adding catalyst to the thiophene and the acylating agent tin tetrachloride has been used most frequently. Almost exclusive a-substitution is observed, but where both a-positions are substituted, P-substitution occurs easily. 

In the next section, the progress of Friedel-Crafts acylation of thiophene, including different acylating agents, different Lewis acids as well as catalytic and enantioselective variants, is shown. 

Reactions leading to a ring closure are always of interest. Two 5,6,7,8-tetrahydro-4//-cyclohepta[6]thiophen-4-ones were synthesised as intermediates for new cytotoxic agents [51] using two successive Friedel-Crafts reactions, the last intramolecular. Friedel-Crafts acylation of thiophene or 2-methylthiophene with glutaric anhydride in the presence of AICI3 gave 5-(thien-2-yl)-5-oxopentanoic acid 27a (R=H) and 5-(5-methylthien-2-yl)-5-oxopentanoic acid 27b (R=Me),... 

Dithien-3-yI diketones 42 (Scheme 46) are the key intermediates for the synthesis of l,2-di(thien-3-yl)ethenes through McMurry reactions. Friedel-Crafts acylation of thiophenes with a dicarboxylic dichloride is a simple and direct route to the di(thien-3-yl) diketones 42 [63]. 

Friedel-Crafts acylation of fluorobenzene with thiophene-l-carboxylic acid gives the ketone 7. Nitration proceeds ortho to the fluoro group to give the intermediate Nucleophilic displacement by means of... 

Octahydrodibenzothiophene (73) has been prepared by the following sequence. Friedel-Crafts acylation of 4,5,6,7-tetra-hydrobenzo[6]thiophene with succinic anhydride (87%) or with the ester chloride of succinic acid followed by hydrolysis (80%), yields the keto acid (74). Huang-Minlon reduction of 74 followed by cyclization of the derived acid chloride with stannic chloride yields l-keto-1,2,3,4,6,7,-8,9-octahydrodibenzothiophene (53) (Section V,A). Reduction of 53 gives 73 as a solid (overall yield 32%). 

Thiophenes have served as important four-carbon templates for molecular elaboration. Both functionalized cyclic and acyclic chains can be generated by carrying out conventional reactions on the thiophene nucleus and then performing a Raney nickel desulfurization at or near the very end of the scheme. Thus, the major constituent (279) of the Panamanian ant, Atta columbica, was made by Friedel-Crafts acylation of the thiophene derivative (277), followed by Grignard addition to the carbonyl group of (278), dehydration, and reductive desulfurization (Scheme 57) (60JOC1754). 

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). 

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>. 

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

Friedel-Crafts acylation of 2,3-dihydrobenzo[6]thiophene using succinic anhydride 426 or acetyl chloride 427 affords the 5-substituted... 

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). 

Friedel-Crafts acylation of halobenzo[6]thiophenes has been much less extensively studied. Acetylation of 5-bromo-,76,144 5-chloro-,144 and 4,5,6,7-tetrafiuorobenzo[6]thiophene103 gives mainly the 3-acetyl compound in each case, together with less than 10% of the 2-isomer in some cases.103,144 2,3-Dibromobenzo[6]thiophene affords mainly the... 

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... 

Synthesis of standards. Friedel-Crafts acylation of 2,3-dimethylthiophene with hexadecanoic acid and a subsequent reduction of the ketone with LiAlD4 yielded the 2,3-dimethyl-5-(l ,l -d2-hexadecyl)thiophene (II, Table II). Experimental details of these reactions have been reported elsewhere (10). Ionic hydrogenation of the 2,3-dimethyl-5-(l ,l -d2-hexadecyl)thiophene in trifluoroacetic acid using triethylsilane and BF3.etherate as catalyst yielded 2,3-dimethyl-5-(l ,l -d2-hexadecyl)thiolane (IV, Table II). For... 

A -Butylpyridinium tetrafluoroborate, containing dissolved phosphorus pentachloride, allows catalytic Beckmann rearrangement of cyclohexanone oxime giving e-caprolactam with good conversion and selectivity <2001TL403>. The same ionic liquid containing dissolved ytterbium(m) trifluoromethanesulfonate was used to perform Friedel-Crafts acylation of furan and thiophene <2005JIG398>. 

Iodine in trace amounts has been used as catalyst in Friedel-Crafts acylations of furane and thiophene and of more active members of the benzene series such as anisole and acetanilide. " Oddly enough, it is not effective for benzoylation of anthracene.""... 

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. 

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