5-Methylbenzo[b]thiophene

white low melting mass

12116] Step 112117] A mixture of 5.2 g ofbromoacetaldehyde diethylacetal and 10 ml of tetrahydrofuran was added to a mixture of 4.00 g of 4-methylbenzenethiol, 1.4 g of 60percent sodium hydride, and 35 ml of tetrahydroffiran. The reaction mixture was stirred for 15 hours at room temperature. Ten (10) ml of aqueous saturated ammonium chloride solution was added to the reaction mixture, and extraction was performed three times by using tert-butyl methyl ether. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were added to a mixture of 5 g of diphosphorus pentoxide and lOg ofphosphoric acid that had been stirred for 45 minutes at 175° C., and the residue was stirred for 5 minutes. The reaction mixture was poured into ice water, and extraction was performed three times by using tert-butyl methyl ethet The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel colunm chromatography, thereby obtaining 2.77 g of 5-methylbenzo[b] thiophene12116] Step 112117] A mixture of 5.2 g ofbromoacetaldehyde diethylacetal and 10 ml of tetrahydrofuran was added to a mixture of 4.00 g of 4-methylbenzenethiol, 1.4 g of 60percent sodium hydride, and 35 ml of tetrahydroffiran. The reaction mixture was stirred for 15 hours at room temperature. Ten (10) ml of aqueous saturated ammonium chloride solution was added to the reaction mixture, and extraction was performed three times by using tert-butyl methyl ether. The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were added to a mixture of 5 g of diphosphorus pentoxide and lOg ofphosphoric acid that had been stirred for 45 minutes at 175° C., and the residue was stirred for 5 minutes. The reaction mixture was poured into ice water, and extraction was performed three times by using tert-butyl methyl ethet The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel colunm chromatography, thereby obtaining 2.77 g of 5-methylbenzo[b] thiopheneGeneral procedure: Polyphosphoric acid (PPA, 15g, 0.044mol) and chlorobenzene (30 mL) were mixed in three flasks purged with argon three times and heated to 130C , plus, Dissolved in chlorobenzene (10 mL) of (2, 2-diethoxyethyl)(4-fluorophenyl)sulfane (Formula B4, 3.6g, 0.015mol), stirred for 4 hours, cooled. Cooling to room temperature, water (100ml), extracted with petroleum ether three times (50ml), washed once with saturated brine (50ml), dried over sodium sulfate, silica gel columnChromatography, eluted with petroleum ether to give an orange-red liquid (formula B5, 0.75g, 33%).B. 5-Methylbenzo[b]thiophene The title compound is prepared as described in EXAMPLE 5, Part B substituting 4-methyl-1-(2, 2-dimethoxy-ethyl-sulfanyl)-benzene for 1-chloro-3-(2, 2-dimethoxy-ethyl-sulfanyl)-benzene. The crude product is purified by column chromatography eluding with hexanes to afford the title compound as a white solid. 1 H NMR (CDCl3, 300 MHz) delta 7.78 (d, 1H), 7.62 (s, 1H), 7.39 (d, 1H), 7.23 (d, 1H), 7.17 (d, 1H), 2.50 (s, 3H).B. 5-Methylbenzo[b]thiophene The title compound is prepared as described in EXAMPLE 5, Part B substituting 4-methyl-1-(2, 2-dimethoxy-ethyl-sulfanyl)-benzene for 1-chloro-3-(2, 2-dimethoxy-ethyl-sulfanyl)-benzene. The crude product is purified by column chromatography eluding with hexanes to afford the title compound as a white solid. 1 H NMR (CDCl3, 300 MHz) delta7.78 (d, 1H), 7.62 (s, 1H), 7.39 (d, 1H), 7.23 (d, 1H), 7.17 (d, 1H), 2.50 (s, 3H).PREPARATION 2 5-Methylbenzo[b]thiophene Refer to Chart A (conversion of LXXXVI to LXXXVII). Using the procedures of Chapman, et al., J. Chem. Soc. 514 (1968), and starting with Preparation 1 the tilted compound is prepared, having a melting point of 37-38 C.Step 5 Production of 5-methylbenzo[b]thiophene 2.03 g (9.87 mmol) of the 2-carboxy-5-methylbenzo[b]thiophene obtained in Step 4 were dissolved in 10 ml of quinoline followed by the addition of 799.2 mg of copper powder and heating to 190 C. After 100 minutes, the solution was cooled followed by the addition of 40 ml of 0.5 M hydrochloric acid and extraction with ethyl acetate (40 ml*2). The organic phase was washed with 40 ml of water and then dried with magnesium sulfate. After concentrating the solvent under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 1.41 g (9.51 mmol) of the target compound (yield of the two steps from Step 4: 96%).b 5-Methylbenzo[b]thiophene 320 g of P2 O5 are mixed with 246 ml of orthophosphoric acid and heated at 130 C. (1 h) At 180 C., 92.9 g of the compound from a) are introduced by means of a capillary tube under the surface of the polyphosphoric acid at 5 mmHg. The product distils out. 26 g are obtained as an oil. MS (EI)=135 (M+)Step 5 Production of 5-methylbenzo[b]thiophene 2.03 g (9.87 mmol) of the 2-carboxy-5-methylbenzo[b]thiophene obtained in Step 4 were dissolvedin 10 ml of quinoline followed by the addition of 799.2 mg of copper powder and heating to 190C. After 100 minutes, the solution was cooled followed by the addition of 40 ml of 0.5 M hydrochloric acid and extraction with ethyl acetate (40 ml x 2). The organic phase was washed with 40 ml of water and then dried with magnesium sulfate. After concentrating the solvent under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate = 20:1) to obtain 1.41 g (9.51 mmol) of the target compound (yield of the two steps from Step 4: 96%).

Molecular Weight:148.23
XLogP3:3.3
Hydrogen Bond Acceptor Count:1
Exact Mass:148.03467143
Monoisotopic Mass:148.03467143
Topological Polar Surface Area:28.2
Heavy Atom Count:10
Complexity:122
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes