An expedient synthesis of thienylacetic acids using the Willgerodt-Kindler reaction under PTC conditions

Novel (5-aryl-2-methylthiophen-3-yl)acetic acids were synthesized starting from 3-aryl-3-chloroacrylaldehydes via corresponding thienylcarbaldehydes and thienylethanones using Willgerodt-Kindler reaction under phase-transfer conditions. Their structures were established based on the data of 1 H, 13 C NMR, IR spectroscopy and mass-spectrometry.


Introduction
Derivatives of 3-thienylacetic acids are important intermediates in the synthesis of drugs, 1 pesticides 2 and multifunctional photochromic molecular systems possessing fluorescent, [3][4][5] magnetic 6 and complexing properties. 7The basic methods used for the synthesis of these compounds are based on hydrolysis of the corresponding nitriles, 8 the reduction of ketoacids, 9 Arndt-Eistert 10 and Willgerodt-Kindler 11 reactions.The Willgerodt-Kindler reaction is usually applied for the preparation of (thio)amides, carboxylic acids, and heterocycles. 12At the same time because of the low yields of the targeted compounds and formation of complex reaction mixtures 13 this reaction has not been more widely employed in organic synthesis.Only a few papers have been published on application of this method for the synthesis of arylacetic acids performed under conditions of the phase-transfer catalysts (PTC). 14Herein we report an expedient procedure for the synthesis of 5-arylsubstituted 3-thienylacetic acids starting from 3-aryl-3-chloroacrylaldehydes via corresponding thienylcarbaldehydes and thienylethanones based on the Willgerodt-Kindler reaction under PTC conditions.

Results and Discussion
6][17][18][19] Aldehyde 1a was previously synthesized by the Vilsmeier formylation of 5-(4-chlorophenyl)thiophene, 16 but no spectral data on the prepared compound were presented.The usually used Suzuki cross-coupling reaction of thienylboronic acids with bromothienyl compounds requires an inert gas atmosphere, palladium catalyst Pd(PPh3)4 and takes a long reaction time. 20Thus, this reaction for the synthesis of aldehyde 1b proceeds in 47 h (yield 31%).Our approach to the synthesis of 5-arylthiophene-2-carbaldehydes involves interaction of 3-chloro-3-arylacrylaldehydes with sodium sulfide and chloroacetaldehyde in DMF to give the compounds 1a,b in 44-59% yields (Scheme 1).The reaction time of the general procedure for preparation of 1a,b has been shortened to 6.5 hours.2-Methyl-5-(4-chlorophenyl)thiophene 2a was previously obtained by the treatment of 2methyl-5-(4-chlorophenyl)furan with hydrogen sulfide under conditions of acid catalysis. 21The reaction time was 48.5 h and the yield 54%.A significant drawback of this reaction is the presence in the reaction mixture of products of hydrolytic cleavage of the furans.We reduced aldehydes 1a,b by hydrazine hydrate via Kishner-Wolff reaction which led to 2-methyl-5-arylthiophenes 2a,b in 30-40% yields after 3h reflux of diethylene glycol solution.Acylation of 2a,b with acetic anhydride in toluene in the presence of SnCl4 gave rise to 1-(2-methyl-5-(arylthiophen-3yl)ethanones 3a,b in 41-84% yields.Then these compounds were exposed to the Willgerodt-Kindler reaction with sulfur and morpholine followed by the treatment of aqueous sodium hydroxide in the presence of a phase-transfer catalyst (benzyltriethylammonium chloride, TEBA) which produced 2-(2-methyl-5-(4-chlorophenyl)thiophen-3-yl)acetic acids 4a,b in moderate 53-64% yields.The described synthetic protocol (Scheme 1) allows preparation of various functionalized 5-aryl substituted thienylacetic acids starting from the corresponding 3-aryl-3chloroacrylaldehydes.

Conclusions
We report on the expedient synthetic protocol which allows to prepare various novel 5arylsubstituted 3-thienylacetic acids starting from 3-aryl-3-chloroacrylaldehydes via corresponding thienylcarbaldehydes and thienylethanones under phase-transfer conditions.

Experimental Section
General.The 1 H and 13 C NMR spectra in CDCl3 were recorded on a Bruker DPX-250 (250 MHz for 1 H, 62.9 MHz for 13C) spectrometer, the signals were referred with respect to the signals of residual protons of deutero-solvent (7.24 ppm), δ values were measured with precision 0.01 ppm.The IR spectra were recorded on a Varian Excalibur 3100 FT-IR instrument using the attenuated total internal reflection technique (ZnSe crystal).Mass spectra were recorded on a Shimadzu GCMS-QP2010SE instrument with direct sample entry into the ion source (EI, 70 eV).Elemental analysis was performed on a KOVO CHN-analyzer.Melting points were determined on a PTP (M) instrument.
General procedure for the synthesis of 1a,b.A solution of 3-chloro-3-(4chlorophenyl)acrylaldehyde (32 mmol, 6.5 g) or 3-([1,1'-biphenyl]-4-yl)-3-chloroacrylaldehyde (32 mmol, 7.8 g) in 100 mL of dry DMF was added dropwise with stirring to a suspension of Na2S .9H2O (33 mmol, 7.9 g) in 40 mL of dry DMF at 60 o С within 1 h.The reaction mixture was stirred for 2 h at 60 o С. 50% aqueous chloroacetaldehyde (36 mmol, 6 mL) was added dropwise and the reaction mixture was stirred for 3 h at 60 o С.A solution of K2CO3 (60 mmol, 8.3 g) in 10 mL of water was added and the stirring at the same temperature was continued for 0.5 h.The reaction mixture was then poured into 1000 mL of water.The precipitate was filtered, washed with water, dried and recrystallized from ethanol with the charcoal.General procedure for the synthesis of 2a,b.A mixture of 1a (10 mmol, 2.2 g) or 1b (10 mmol, 2.6 g), 85% hydrazine hydrate (135 mmol, 6.75 g) and KOH (75 mmol, 4.2 g) in 50 mL of diethylene glycol was stirred at reflux for 3 h.The solution was then diluted with water (150 mL).The crude product was filtered, dried and recrystallized from ethanol.General procedure for the synthesis of 3a,b.A solution of 2а (10 mmol, 2.1 g) or 2b (10 mmol, 2.5 g) in 75 mL of dry toluene was cooled to 0-5 °C.Acetic anhydride (20 mmol, 2.0 g) and then SnCl4 (20 mmol, 5.2 g) were added under stirring at this temperature.The reaction mixture was heated to 20°С, stirred for 4 h and then acidified with 10% aqueous HCl (100 mL).The organic layer was separated and dried (Na2SO4).The solvent was removed using a rotary evaporator to give a crude residue which was recrystallized from ethanol.