2-Thiophenecarbonyl chloride

CLEAR COLOURLESS TO YELLOW-GREY LIQUID

To a mixture of 2-acetylthiophene (0.108 ml, 1.0 mmol), pyridine (0.016 ml, 0.20 mmol), and chlorobenzene (0.35 ml) was added SA mixture of 2-acetylthiophene (0.108 ml, 1.0 mmol), 3-picoline (0.010 ml, 0.1 mmol), and thionyl chloride (0.363 ml, 5.0 mmol) was stirred at 70°C for 3 h 45 min, and then at 140°C for 14 h. The mixture was diluted with CDCI3 (1.5 ml), an internal standard was added (1BU3PO4, 0.0552 ml, 0.20 mmol), and the mixture was analyzed. 1H NMR indicated that mainly 2-thiophene carbonyl chloride (72percent yield) had been formed.A mixture of 2-acetylthiophene (0.108 ml, 1.0 mmol), pyridine (0.008 ml, 0.1 mmol), anddisulfur dichloride (0.320 ml, 4.0 mmol) was stirred at 70 °C for 3.5 h. Then it was stirred at137 °C for 18 h. The mixture was diluted with CDC13 (2 ml), an internal standard was added(iBu3PO4, 0.0552 ml, 0.20 mmol), and the mixture was analyzed. 1H NMR indicated that2-thiophene carbonyl chloride (86percent yield) had been formed.In this experiment, the 2-thiophenecarboxylic acid was the combined solids from Experiments 13.2 and 13.3 of Example 13. [0187] The combined solids of 2-thiophenecarboxylic acid (63.1 g, 493 mmol) was dissolved in ethyl acetate (208 g) in a 3-neck round-bottom flask equipped with a thermocouple, a reflux condenser, and an additional funnel and the system was purged with nitrogen. The reflux condenser outlet was connected to a chilled receiver containing aq. NaOH (20percent, 250 g). A catalytic amount of dimethylformamide (DMF) (0.2 mL, 0.005 eq.) was added and the resulting reaction mixture was heated to 65°C with stirring, followed by a slow addition of thionyl chloride (67.2, 565 mmol, 1.15 eq.). During the addition, gases such as sulfur dioxide (S02) and hydrogen chloride (HC1) were released and the reaction temperature dropped to about 58°C. The reaction completed in 2.5 hours with no detectable unreacted 2-thiophenecarboxylic acid by GC/MS.[0188] After cooling, the flask was fitted with a distillation head and 4-Methoxyphenol (8.9 mg) was added as a stabilizer during the distillation. By vacuum distillation (short path), ethyl acetate and thionyl chloride were distilled from the mixture first under a lower vacuum (approximately 60 to 125 mmHg). The remaining mixture was cooled to room temperature and switched to a higher vacuum. Distillation (short path, approximately 4 mmHg) at a vapor temperature of approximately 63°C afforded 2-thiophenecarbonyl chloride as a clear pale yellow oil (56.5 g, 81percent). GC-FID confirmed that the obtained material was 2-thiophenecarbonyl chloride with a purity of > 98 areapercent.According to Scheme 1 Step 1 : Thiophene-2-carboxylic acid (31.2 mmol, 4.00 g) was slowly added to a solution of thionyl chloride (56.2 mmol, 4.08 mL). The reaction mixture was stirred at room temperature for 1 hour. After evaporation of the thionyl chloride, the crude product was purified by bulb-to-bulb distillation (85DEVICEO: piston pump 260D from ISCO TeledyneDEVICE 1: tubular reactor with a length of 6 m, with an internal volume of 96.16 mL and an outer diameter of 0.25 inchDEVICE3: pressure control valve Swagelok BPV-SS-07 A mixture MIX1 containing 90 wtpercent of a mixture MIX2 of oxalyl chloride and thiophene witha molar ratio of 2 : 1, and 10 wtpercent sulfolane, the wtpercent being based on the total weight of theMlxi, was fed by DEVICEO with a rate of 2.14 mL/min through DEVICE 1 at an averagePRESS 1 of 80 bar which was adjusted and held by the means of DEVICE3. DEVICE 1 was maintained at a temperature of 200°C by means of a heating fluid. The residence time TIME1 of the mixture in DEVICE 1 was 45 mm. A liquid sample of the reaction mixture was collected and analyzed by 1H NMR with the internal standard dioxane, yield of thiophene-2- carbonyl chloride was 93 percent based on thiophene.

2-Thiophenecarbonyl Chloride is used in the synthesis of substituted pyridines as selective and highly effective GPR119 agonists. It is also seen in the preparation of diuretics.

Molecular Weight:146.60
XLogP3:2.6
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:145.9593136
Monoisotopic Mass:145.9593136
Topological Polar Surface Area:45.3
Heavy Atom Count:8
Complexity:105
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes