Acetylation of thiophene

Acetylthiophene Is prepared by the acetylation of thiophene with acetic anhydride In the presence of orthophosphoric acid ... 

Ketene thioacetals 7 have been used to synthesize thiophene with a carbonyl in the 3-position 8 (Scheme 2) <03X1557, 03X2631>. In the reported procedure <03X2631> a-oxoketene dithioacetal is converted to the substituted thiophene 9 upon reaction with diiodomethane in the presence of Zn-Cu. Simple formylation or acetylation of thiophenes only produces the 2- or 5-derivatives and, hence, this is a useful technique to produce the 3- or 4- derivatives. Xhis method also has been studied to synthesize substituted selenophenes 10 <03SL855>. 

In addition to the methods of preparation given in connection with the procedure for the acetylation of thiophene with acetyl chloride in the presence of stannic chloride, 2-acetothienone has been prepared from thiophene and either acetyl chloride or acetic anhydride in the presence of iodine, hydriodic acid, silica-metal oxides, zinc chloride, or inorganic oxyacids. It has also been prepared from thiophene and acetic acid in the presence of hydrogen fluoride or phosphorus pentoxide. The acylation in the presence of phosphorus pentoxide is particularly useful with higher aliphatic acids. ... 

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. 

Manufacture of 2-acetylthiophenes involves direct reaction of thiophene or alkylthiophene with acetic anhydride or acetyl chloride. Preferred systems use acetic anhydride and have involved iodine or orthophosphoric acid as catalysts. The former catalyst leads to simpler workup, but has the disadvantage of leading to a higher level of 3-isomer in the product. Processes claiming very low levels of 3-isomer operate with catalysts that are proprietary, though levels of less than 0.5% are not easily attained. 

In the reactions of 2,5-disubstituted thiophenes elimination of an a-substituent occurs to a much greater extent than in the benzene series. The Friedel-Crafts acetylation of 5-bromo-2-ethylthiophene in the presence of SnCE gives 2-ethyl-5-acetyIthiophene. Elimination of an a-bromine occurs also in the chloromethylation of 2,5-di-bromothiophene, leading to a mixture of 2-bromo-5-chloromethyIthio-phene and 2,5-dibromo-3-chloromethyIthiophene. Bromine atoms at both the and -position are exchanged for chlorine in the... 

Two different sets of experimental conditions have been used. Buu-Hoi et al. and Hansen have employed the method introduced by Papa et using Raney nickel alloy directly for the desulfurization in an alkaline medium. Under these conditions most functional groups are removed and this method is most convenient for the preparation of aliphatic acids. The other method uses Raney nickel catalysts of different reactivity in various solvents such as aqueous ammonia, alcohol, ether, or acetone. The solvent and activity of the catalyst can have an appreciable influence on yields and types of compounds formed, but have not yet been investigated in detail. In acetic anhydride, for instance, desulfurization of thiophenes does not occur and these reaction conditions have been employed for reductive acetylation of nitrothiophenes. Even under the mildest conditions, all double bonds are hydrogenated and all halogens removed. Nitro and oxime groups are reduced to amines. 

In a 500-cc. round-bottomed, three-necked flask provided with a thermometer, dropping funnel, a liquid-sealed stirrer, and calcium chloride tube are placed 16.8 g. (0.2 mole) of thiophene (Org. Syn. 12, 72), 15.6 g. (0.2 mole) of acetyl chloride, and 200 cc. of dry benzene. The solution is cooled to o°, and 52 g. (23 cc., 0.2 mole) of freshly distilled stannic chloride is added dropwise, with efficient stirring, during the course of about forty minutes. The reaction mixture assumes a purple color when the first drops of stannic chloride are added, and soon a purple solid precipitates. 

Additional acylation studies were also reported (24), (26). In the first case it is claimed that acylation of thiophene is achieved by means of HC104 and acetic anhydride affording a 65 % yield of 2-acetylthiophene. In the second paper Levine and coworkers reported that while 2,5-dimethylthiophene could be readily acetylated, 2,5-dichlorothiophene acetylated sluggishly. This is, however, readily explained, since the presence of chlorine atoms on the thiophene ring decreased its reactivity in electrophilic substitution reactions. In the case of methyl substitution, however, the 3 and 4 positions of the ring are activated toward electrophilic substitution by the inductive and hyperconjugative effects. Thus 2,5-dimethylthiophene was successfully acylated by the boron fluoride etherate method in high yield with three aliphatic anhydrides. 

Acetylation of ester (58) followed by treatment similar to that shown above resulted in 5-ethyl-3-methylthieno[3,2-6]thiophene (27). ... 

Thus, methyl (5-acetyl-2-thienyIthio)acetate (62) was prepared by acetylation of 61. Addition of a second acetyl group in the presence of excess AlClj led to methyl (3,5-diacetyl-2-thienylthio)acetate (63), which, on heating in ethanolic sodium ethoxide yielded about 95% of 5-acetyl-3-methylthieno[2,3-6]thiophene-2-carboxylic acid (64) reduction of acid 64 resulted in 5-ethyl-3-methylthieno[2,3-6] ophene 2-carboxylic add (65), identical with the acid obtained by cyclization of methyl (3-acetyl-5-ethyl-2-thienylthio)acetate. Decarboxylation of acid 64 gave 5-acetyl-3-methylthieno[2,3-6]thiophene (66) [Eq. (25)1. 

Similarly, acetylation of thieno[3,2-6]thiophene (2) afforded 2-acetyl-thieno[3,2-6]thiophene, which was converted into methyl n-hexyl ketone by desulfurization with Raney nickel. Oxidation of 2-acetylthieno-[3,2-i]thiophene followed by nitration gave 5-nitrothieno[3,2-6]-thiophene-2-carboxylic acid. Decarboxylation of the latter furnished 2-nitrothieno[3,2-ft]thiophene identical with the compound obtained by direct nitration of thienothiophene 2 [Eq. (60)]. 

Direct nitration of thiophene, using a mild nitrating system at low temperature, gives 2-nitrothiophene in excellent yield. Acetyl nitrate, benzoyl nitrate or copper(I) nitrate in acetic anhydride or acetic acid is commonly used, and only traces of 3-nitrothiophene and 2,5-dinitrothiophene are formed. Slow addition of thiophene dissolved in acetic anhydride to a solution of nitric acid in glacial acetic acid, maintaining the temperature at 10°C, is reported to be the optimum procedure (Section 3.14.2.4.8). 

Both thienothiophenes (3) and (7) were subjected to competitive electrophilic substitution reactions with thiophene. The fused heterocycles were always more reactive than thiophene in acetylation, Vilsmeier formylation and chlorination with NCS. While acetylation of both (3) and (7) occurrred at a comparable rate, formylation and chlorination occurred faster in the [3,2-6]-fused isomer (3) than in the [2,3-6] isomer (7). 

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... 

Acylation of 2- or 3-methoxybenzo[6]thiophene in the presence of boron trifluoride takes place in the free thiophene position183 concomitant demethylation may occur in the presence of aluminum chloride.272,666 Attempted acetylation of 3-bromo-2-methoxybenzo-... 

In 2-alkyl-substituted thienothiophenes I and 2 the free a-position is attacked.44,57 7,219 However, acetylation of 2-ethylthieno[2,3-61-thiophene (20) produced, together with 2-acetyl-5-ethylthieno[2,3-61-thiophene, small quantities of some other compound which was ascribed219 the structure of 3-acetyl-2-ethylthieno[2,3-61thiophene by analogy with the acetylation products of 2-ethylthiophene.24 Acetylation of 2,5-dialkylthienothiophenes 1 and 2, like 2,5-dialkyl-thiophenes,247 proceeds easily in the presence of stannic chloride. For example 2,5-diethylthieno[2,3-6]thiophene (with AcCl/SnCl/QH ) forms 3-acetyl-2,5-diethylthieno[2,3-6]thiophene in 80% yield. 7... 

Acetylation of 3-ethylthieno[2,3-6]thiophene (21) gives 2-acetyl-3-ethylthieno[2,3-6]thiophene,2 and acetylation of 3-methylthieno[3,2-61-thiophene (27) proceeds similarly (92% yield), while 2-ethyl-6-methyl-thieno[3,2-6]thiophene is converted into 2-acetyl-5-ethyl-3-methyl-thieno[3,2-6]thiophene (73%).43... 

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). 

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