Thiophenes, acylation hydrogenation

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... 

Acetylthiophene reacts with synthesis gas to give 2-ethylthiophene. If the reaction is carried to completion, 2-ethylthiacyclopentane is secured. Acylated thiophenes are readily secured by the Friedel-Crafts reaction and their hydrogenation by hydrogen-carbon monoxide mixtures opens up a new synthetic route to the alkylthiophenes. and their tetra-hydro analogs. The evidence seems to indicate that the conversion of a substituted thiophene to the reduced thiacyclopentane is a stepwise process which with 2-thiophenecarboxyaldehyde may be represented as follows ... 

Stable 2H-thiophenium ions formed on acylation of thiophene and its homologs with aluminum chloride (due to hydrogen chloride originating during the reaction) essentially lower the yields of ketones. The formation of such cr-complexes, a-C-protonation products, does not take place on preparation of ketones under the usual conditions of acylation in thiophene series, namely, in the presence of tin tetrachloride with... 

A wide variety of substituents are tolerated. The group R can be alkyl, halogen, alkoxy, -amido, azi-domethyl, ester, aryl, aryloxy and aryloyl, and at least one ortho substituent is permissible with no loss in yield. TTie aromatic ring can also be 2-naphthyl, 9,10-dihydro-2-phenanthryl, 3-pyridyl, thiophen-2-yl or pyrrol-3-yl. The group R can be hydrogen, yl, acyl or acetic acid. Beyond Ae antiinflammatory targets, successful reaction substrates include the methyl ketones of a binaphthyl crown ether, a morphinane and a polyaromatic hydrocarbon. The preparation of ibuprofen methyl ester (38) is shown in equation (37) as a typical example. ... 

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. ... 

These substitutions are facilitated by electron release from the heteroatom pyrroles are more reactive than furans, which are in turn more reactive than thiophenes. Quantitative comparisons of the relative reactivities of the three heterocycles vary from electrophile to electrophile, but for trifluoroacetylation, for example, the pyrrole furan thiophene ratio is 5 x 10 1.5 x 10 I " in formylation, furan is 12 times more reactive than thiophene, and for acetylation, the value is 9.3. In hydrogen exchange (deuteriodeproton-ation), the partial rate factors for the a and p positions of A-methylpyrrole are 3.9 x 10 ° and 2.0 x 10 ° respectively for this same process, the values for furan are 1.6 x 10 and 3.2 x l(f and for thiophene, 3.9 X 10 and 1.0 x 10 respectively, and in a study of thiophene, a P ratios ranging from 100 1 to 1000 1 were found for different electrophiles. Relative substrate reactivity parallels positional selectivity i.e. the a P ratio decreases in the order furan > thiophene > pyrrole. ° Nice illustrations of these relative reactivities are found in acylations of compounds containing two different systems linked together. ... 

A good and comprehensive review of catalytic electrophilic acylation was published by Pearson and Buehler.i Only the catalysts most widely used were considered, with special attention to iron trichloride, zinc chloride, iodine, and elemental iron. The substrates that can be acylated using small amounts of catalysts include alkylarenes, aryl ethers, biphenyls, naphthalenes, acenaphthenes, fluorene, furans, and thiophenes. Aromatic acyl chlorides lead to better yields than aliphatic ones, reaching a maximum of 96% and a minimum of 34%. In general, fhe reactions are performed af relatively high temperatures (from 50°C to 200°C) af which hydrogen chloride evolution is fairly rapid. 

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... 

---