A novel method for the synthesis of methylthiophenes from ketones containing an active methylene group

A method for the synthesis of methylthiophenes from various ketones has been elaborated. The target methylthiophenes were used for the synthesis of photochromic 1,2-dithienylethenes with heterocyclic bridges


Introduction
3][4] The most general and convenient method for the synthesis of methylthiophenes is the reduction of thiophene carboxaldehydes. 5The latter, however, are not always available, and for this reason the elaboration of novel methods for the synthesis of methylthiophenes is a problem.

Results and Discussion
We report a novel general three-step approach for the synthesis of the methylthiophenes 1 starting from active-methylene ketones.The first step in the scheme included heating the starting ketones 2 in POCl 3 /DMF at 40°C led to the chloro-aldehydes 3 in 50-99 % yields. 6Reaction of the compounds 3 with methyl thioglycolate in methanolic NaOMe proceeded readily to provide the methyl thiophenecarboxylates 4 in 60-80 % yields 7 (Scheme 1).We were interested in the transformation of the ester moiety into a methyl group.General methods of this kind are not present in the literature.Although there are a few examples of such a reduction, these methods are not sufficient.For example, pyrrole-3-carboxylic acid esters can be reduced to the corresponding 3-methylpyrroles by LiAlH 4 . 8,9Besides that, we have found three examples [10][11][12] of one-pot synthesis of methyl derivatives from methyl carboxylates.The first example 10 concerned the reduction of methyl anthranilate by LiAlH 4 to methylaniline in 96 % yield, but the process takes 20 days at room temperature.The second one 11 deals with the reduction of cinnamic acid esters by a mixture of LiAlH 4 and AlCl 3 .In this reaction, a mixture of the target compound and the product of allylic rearrangement was obtained in the ratio 2:1.The third example 12 of reduction applied to fused heterocyclic system containing thiophene ring.However, the outlined procedures are not general, and cannot be applied to the reduction of other esters.Therefore it was necessary to elaborate a reliable procedure for the reduction of the obtained esters, 4.
We have found that the esters 4 can be reduced by one-portion addition of LiAlH 4 to their AlCl 3 /Et 2 O solutions.Reaction proceeded smoothly at room temperature and was complete in 2 hours.Work-up of the reaction mixture produced the methylthiophenes 1 in good yields.However, when dealing with the thiophenecarboxylates 4f-g we found that under the conditions we used, additional reduction of the bromine atom in the benzene ring occurred (Scheme 1).
Thus we have elaborated a three-step method for the synthesis of methylthiophenes starting from various ketones containing an active-methylene moiety.The method allows the synthesis of various methylthiophenes (fused, substituted) in good overall yields, under mild conditions.The thiophene 1b was used for the synthesis of 1,2-dithienylethenes with heterocyclic bridged fragments.Previously, we suggested methods for the synthesis of 1,2-dithienylethenes with heterocyclic bridges (e.g., furan 13 and 1,3-dioxolan-2-one 14 ) using 2,5-dimethylthiophene as starting material.It is known 2 that the fatigue resistance of photochromic dithienylethenes is enhanced by the introduction of alkyl groups at position-4 of the thiophene ring.We supposed that 1,2-dithienylethenes based on thiophene 1b would possess improved photochromic properties.
The photochromic characteristics of compound 5 were examined in acetonitrile solution.As was supposed, the dioxol-2-one 5 exhibits photochromic properties.The characteristic spectrum of the photochrome 5 is shown in Fig. 1.The long-wavelength absorption band of the open form A of compound 5 is observed at 229 nm.The maximum of the first absorption band of the cyclic form of photochromic 1,3-dioxol-2-one 5 is observed at 453 nm.The cyclic form of compound 5 is thermally irreversible, i.e., form B does not transform to form A without irradiation.It should be noted that this compound exhibits low fatigue resistance and the optical density of the cyclic form is regained by no more than 80 % after three-to five-fold photochromic conversions.
To summarize, we have developed a procedure for the synthesis of substituted 2methylthiophenes which can be used for the preparation of photochromic dihetero-arylethenes.It was demonstrated that 1,3-dioxol-2-one 5 derived from 2-methyl-4,5,6,7-tetrahydrobenzo-[b]thiophene (1b) is the thermally irreversible photochromic compound.Experimental Section General Procedures.All reagents are commercially available (Aldrich, Acros) and were used without further purification.Column chromatography was performed on silica gel (Aldrich, grade 22, 60-200 mesh).Thin-layer chromatography (TLC, on aluminum plates coated with silica gel 60F 254 , 0.25 mm thickness, Merck) was used for monitoring the reactions; eluent hexane/ethyl acetate 6:1.Melting points (mp) were determined on a Kofler hot-stage microscope. 1 H NMR spectra were recorded with a Bruker AM-300 instrument (300.13MHz).The mass spectrum was measured on a Kratos MS-30 instrument with direct inlet of the sample into the ion source; the energy of the ionizing electrons was 70 eV.Absorption spectra were obtained with a Shimadzu UV-3100 spectrophotometer in acetonitrile (special purity grade) solution at room temperature.Chloroaldehydes 4 were prepared as described. 6,15Ketone 6 was prepared from the corresponding thiophene 1b according to the reported procedure. 3he photochromic characteristics of compound 5 were studied in a solution in MeCN (special purity grade).The cyclic form B was prepared by irradiation of the sample with a DRSh-500 mercury lamp using filters to separate lines of the Hg spectrum (313, 546 and 578 nm) and were then identified on the basis of λ max in the UV spectrum.The intensity of radiation of the Hg lamp was determined using a F4 photoelement calibrated against a ferrioxalate actinometer for λ = 313 nm and against an actinometer based on the Reinecke salt for λ = 546 and 578 nm.The absorption spectra were recorded on a Shimadzu UV-3100 spectrophotometer.

General method for the synthesis of ketones (2f-g)
To a suspension of AlCl 3 (31.5 mmol) in CH 2 Cl 2 (70 ml) was added propionyl chloride (33 mmol).The resulting mixture was stirred until the precipitate dissolved.Then the solution of the appropriate biphenyl (30 mmol) in CH 2 Cl 2 was added.The reaction mixture was stirred for 48 h, and poured onto ice (250 ml).The organic layer was separated, washed with water (2x50 ml), NaHCO 3 (5% sol., 2x50 ml) and dried over MgSO 4 .After evaporation of the solvent the residue was crystallized from EtOH (40 ml).

General procedure for the synthesis of methylthiophene carboxylates (4)
Sodium (1.2 g, 0.052 mol) was dissolved in anhydrous MeOH (50 ml).Methyl thioglycolate (2.7 ml, 0.030 mol) was added to this solution and stirred for 15 min.Then aldehyde 3 (0.026 mol) was added over 30 min.A water bath was used to maintain the reaction mixture at about 20-25 °C.The mixture was then stirred overnight.Work-up in the cases a-c: The reaction mixture was diluted with water (200 ml) and extracted with ether (3x100 ml).The ether layer was washed with water (3x100), dried over MgSO 4 and evaporated.The crude esters were distilled in vacuum (4b-c) or recrystallized from hexane (4a).Work-up for cases d-g: The reaction mixture was filtered and the residue washed with a large amount of water.The crude esters were recrystallized from MeOH (30 ml) to give the pure compounds 4.

General procedure for the synthesis of thiophenes (1a-e)
To a solution of AlCl 3 (3.0g, 0.022 mol) in anhydrous Et 2 O (100 ml) was added the corresponding ester 4 (0.005 mol).LiAlH 4 (1.5 g, 0.038 mol) was added to the solution in one portion.This was stirred for 2 hours, benzene (100 ml) was added and the reaction mixture was carefully quenched with water (50 ml).The organic layer was separated, washed with water (3x100 ml), dried over MgSO 4 and evaporated.The resulting thiophenes 1 were either distilled in vacuum (1a-c) or purified on a column (1d, e).