Aroylation of 2-and 3-acetylthiophenes using benzoyl chloride, benzotrichloride, and their substituted derivatives

Aryldichlorocarbenium tetrachloroaluminates are shown to be preferable reagents for the aroylation of 2-acetylthiophene, while the usual ArCOCl·AlCl 3 complexes give better results in aroylation of 3-acetylthiophene. Scope and limitations of both aroylation procedures are discussed.


Introduction
Previously, the effect of complex formation with Lewis and Brønsted acids on the reactivity of carbonyl compounds of thiophene derivatives and, especially, on the orientation of the electrophilic attack at the thiophene ring has been studied by our group extensively (see reviews 1,2 ).It has been shown that in such complexes the reactivity of carbonyl compounds is suppressed and the orientation is changed: electrophiles do not enter the free α'-position as usual, but preferentially or even exclusively attack position 4 that upon complex formation is deactivated to the lesser extent.In particular, 2-acylthiophenes are acylated with acetyl and chloroacetyl chlorides in the presence of excess anhydrous aluminum chloride without a solvent at ca 100 ºC affording 2,4-diacylthiophenes with an admixture (6-8%) of the 2,5-isomer in 50-70% total yield with respect to the consumed ketone. 3,4The reaction of 2-acetylthiophene (1)  with benzoyl chloride under the conditions mentioned is complicated by transacylation, and therefore, results in a mixture of products containing 2-benzoylthiophene (yield ca 30%) as well as diacetyl-, acetylbenzoyl-(13% of the total products) and dibenzoylthiophenes (Scheme 1). 4 ; actually, this complex is an alkylating and not an acylating agent: the corresponding substituted arylhetaryldichloromethanes are the primary products. 5Thus, 2-acetylthiophene (1) and benzotrichloride with an excess of aluminum chloride (to form 1•AlCl 3 and [PhCCl 2 ] + [AlCl 4 ] -complexes) gave, at a reaction temperature of ca.80 ºC and after treatment of the reaction mixture with an acidic, aqueous alcohol solution, 2-acetyl-4-benzoylthiophene (2a) without admixture of the 2,5-isomer (as indicated by 1 H NMR; Scheme 2). 5

Scheme 2
The goal of the present work was the comparison of trichloromethylarenes and aroyl chlorides in the preparation of 2,4-diacylthiophenes.As starting materials for the generation of the aryldichlorocarbenium tetrachloroaluminates both benzotrichloride and some substituted benzotrichloride derivatives were employed; substituted benzoyl chlorides were used as well.2-Acetylthiophene (1) and 3-acetylthiophene (3) were the substrates selected for studying the scope and the limitations of reactions mentioned.

Results and Discussion
Taking into account the side reactions encountered by using benzoyl chloride with AlCl 3 in the benzoylation of 2-acetylthiophene (1), 4 aryldichlorocarbenium tetrachloro-aluminates can be suggested as the preferable reagents for the aroylation of 1. Particularly, we have shown 5 that in the presence of aluminum chloride, benzotrichloride reacts with 2-acetylthiophene selectively and at lower temperature than benzoyl chloride to give diketone 2a in a much higher yield (50% 5 instead of 13% 4 ).

Scheme 4
However, not all tested aroyl chlorides were sufficiently stable under the acylation conditions applied.Thus, we could not obtain any product from the reaction with 4-(trifluoromethyl)benzoyl chloride.In the case of 4-methoxybenzoyl chloride the main product was the demethylated 4-acetyl-2-(4-hydroxybenzoyl)thiophene (4d).4-Acetyl-2-(4methoxybenzoyl)thiophene (4e) could be obtained in low yield (15%) only after methylation with dimethyl sulfate of the primarily formed reaction mixture of 4d and 4e (Scheme 4).
In summary, aryldichlorocarbenium tetrachloroaluminates have been shown to be preferable

Experimental Section
General Procedures. 1 H NMR spectra of CDCl 3 solutions were recorded with a Bruker AC-200 instrument (200 MHz).The purity of the products was checked by TLC on Silufol UV-254 using petroleum ether/ethyl acetate mixtures (3:1 for 2b, 2:1 for 4e, 5:1 in all other cases) as eluents.Light petroleum ether refers to the fraction of boiling range 40-60 ºC, petroleum ether refers to the fraction of boiling range 60-80 ºC.All starting materials, ketones, benzotrichloride, and the aroyl chlorides, were commercially available reagents (Aldrich, Merck).2,4-Dimethylbenzotrichloride was prepared by trichloromethylation of m-xylene; 6 3-bromobenzotrichloride was obtained from 3-bromobenzotrifluoride with AlCl 3 and AcCl according to a known procedure; 7 2chlorobenzotrichloride and 4-chlorobenzotrichloride were prepared by side-chain chlorination of 2-and 4-chlorotoluene, respectively, following literature procedures. 8Acetyl-4-(4-chlorobenzoyl)thiophene (2b).To the mixture of 1 (5 g, 4.3 mL, 39.7 mmol) and AlCl 3 (15.88g, 119.0 mmol) was added dropwise with stirring 4-chlorobenzotrichloride (9.13 g, 6.1 mL, 39.7 mmol).The mixture was stirred at 70-85 ºC for 15 min until the evolution of hydrogen chloride ceased, and after cooling it was poured onto ice.The aqueous layer was extracted with chloroform, the extract was washed with water until neutral, dried over MgSO 4 , and the solvent was evaporated.The residue, a dark brown liquid (13.15 g), was dissolved in ethanol (50 mL) containing H 2 SO 4 (0.5 mL), and the solution was refluxed for 3.5 h.After cooling the solution, the crude semisolid precipitate (5.34 g) was filtered off.The filtrate was partially evaporated, diluted with chloroform, and the resulting solution was washed with water, then with an aqueous solution of Na 2 CO 3 followed by water, and dried over MgSO 4 .Upon evaporation of the solvent the residual oil (4.95 g) was boiled with petroleum ether and gave after recrystallization from light petroleum ether colorless crystals of the diketone 2b (4.09 g, 39%); mp 126-127 °С. 1

2-Acetyl-4-(3-bromobenzoyl)thiophene (2c).
To AlCl 3 (16 g, 120 mmol) was added in portions while cooling with cold water 1 (5 g, 40 mmol).To the liquid complex formed, 3bromobenzotrichloride (10.9 g, 40 mmol) was added dropwise with stirring.The reaction mixture was heated at 95-100 °С for 20 min and worked-up as described before.After evaporation of chloroform extract the oily residue was dissolved in i-PrOH (100 mL); conc.H 2 SO 4 (0.5 mL) was added, and the solution was refluxed for 1 h.The hot solution was decanted from a resinous lower layer.Upon cooling the solution, the separated diketone crystals were Upon addition of benzotrichloride (11.6 g, 8.4 mL, 59 mmol) the temperature of the mixture rose to 47 °С, and subsequently, the reaction temperature was maintained in the range 90-93 ºC for 30 min.After the HCl evolution has ceased, the reaction mixture was cooled, chloroform (60 mL) was added, and the mixture was poured onto ice.The organic layer was separated, and the aqueous layer was extracted with chloroform.The combined extracts were evaporated, dissolved in ethanol (90 mL), and after addition of H 2 SO 4 (1.5 mL) the solution was refluxed for 2 h.The treatment of the ethanolic solution as described above gave diketone 4a (6.41 g, 47%) as colorless crystals; mp 92-93 ºC (lit. 492-93 ºC).