3-Bromothiophene-2-carbaldehyde

Colorless to yellow liquid

Under a nitrogen atmosphere, diisopropylamine (51.6 Kg, 509.9 mol, 1 leq) and anhydrous THF (385.0 OKg) were added to a 1000 L autoclave. The temperature was lowered and maintained at 0-5 ° C. BuLi (131.4 Kg, 463.8 mol, 1.0 eq). After the addition was complete, stirring was continued for half an hour at 0-5 ° C. A solution of 3-bromothiophene (starting material 1) (75.0 Kg, 460. Omol, 1 Oeq) in THF (20.0 OKg) was added dropwise at 0-5 ° C. After the addition was complete, stirring was continued for half an hour at 0-5 ° C. A solution of DMF (35.3 kg, 473.3 mol, 1.0 eq) in THF (10Kg) was added dropwise at 0-5 ° C. After completion of the dropwise addition, the temperature was maintained at 0-5 ° C and stirring was continued for 3 hours. Aqueous 14percent NH4Cl (700.OKg) was added dropwise at 0-5 ° C. After completion of the addition, the mixture was stirred at 0 to 5 ° C for 15 minutes, allowed to stand for 15 minutes, and the organic phase was temporarily stored in a clean tetrafluoroethylene drum. The aqueous phase was pumped into the reaction kettle, methyl tert-butyl ether (150. OKg) was added, stirred for 15 minutes, allowed to stand for 15 minutes, phase separated and the upper organic phase taken. The above organic phases were combined, anhydrous sodium sulfate (85. OKg) was added, and dried for a few hours until moisture <1percent. After filtration, the filter cake was washed twice with methyl tert-butyl ether (20 mL) and concentrated under reduced pressure to remove the solvent to give 3-bromothiophene-2-carbaldehyde (Intermediate 2) (93.8 Kg, 100percent).To a stirred solution of iPr2NH (5.0 mL, 3.6 g, 35.3 mmol) in THF (30 mL) in a 100-mL 2-neckedflask under dry argon nBuLi (13.7 mL, 2.35 M in hexanes, 32.2 mmol) was added dropwise during 10 minutes at 0 °C. After stirring for an additional 20 minutes at 0°C, the mixture was cooled to −78 °C and a solution of 3-bromothiophene (5.0 g, 30.6 mmol) in THF (30 mL) was added dropwise during 20 minutes. After stirring for 1 hour at −78°C, the mixture was allowed to warm to −30 °C for 30 minutes before cooling again back to −78 °C. A solution of DMF (2.9 g, 40.0 mmol) in THF (10 mL) was then added dropwise over 10 minutes the mixture was allowed to gradually warm to room temperature with stirring for 6 hours. The mixture was poured into 1M HCl (100 mL) and EtOAc (100 mL) mixture. The organic layer was separated out and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (100 mL) then dried over Na2SO4, filtered, and concentrated in vacuo to give a brown oil. The residue was subjected to column chromatography on SiO2 (eluent EtOAc/hexane, 1/25 → 1/10) to give SI-1i (5.0 g, 26.2 mmol, 85percent) as colorless oil crystallizing in refrigerator.EXAMPLE l.AP. Preparation of 3-bromothiophene-2-carbaldehyde (1-53). I-53 [0202] To a solution of 3-bromothiophene (25 g, 153 mmol) in tetrahydrofuran (250 mL) was added 2 M Lithium diisopropylamide in tetrahydrofuran (77 mL, 154 mmol) at 0°C and the reaction mixture was stirred at 0°C for 1 h. N, N-dimethylformamide (12.2 g, 168 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for additional 2 h. Water (100 mL) was added and extracted with ethyl acetate (500 mLx 3) was performed. The combined organic layer were dried over anhydrous magnesium sulfate, solids were removed by filtration and the filtrate was concentrated by evaporation in vacuo. The residue was purified by silica gel chromatography (petrol ether/ethyl acetate = 10/1) to provide intermediate 1-53 (20 g, 68percent). MS (ESI): m/z 190 [M + H]A solution of 3-bromothiophene (30.0 g, 184 mmol) in THF (200 mL) cooled to 0 °C was added slowly to a 2.0 M solution of LDA in THF (92 mL, 184 mmol; Aldrich Chemicals). The orange solution was stirred at 0 °C for 30 min, then piperidine-1-carbaldehyde (20.4 mL, 184 mmol) was added. The mixture was stirred for a further1 h then diluted with Et2O (300 mL), washed with brine (100 mL), dried, and concentrated. The resulting orange oil was purifiedby chromatography (silica gel, heptane–EtOAc). Product containing fractions were combined and concentrated to give an orange liquid; 21 yield: 29.3 g (85percent).Commercially available lithium diisopropylamide (LDA) solution (2 M, 27 mL, 53.4 mmol) wasdiluted in THE (100 mL)solution at0 °C. A solution of compound 6d (5.0 mL, 53.4 mmol) in THE(5 mL) was added drop wise to the dilute LDA solution at 0 °C over 60 minutes using a droppingfunnel. The reaction mixture was allowed to stir at 0 °C for 30 minutes. After 30 mins, 1-formyl-piperidine was added drop-wise to the reaction mixture. The resultant mixture was gradually warmed to room temperature and stirred at room temperature for 2 hours. The reaction mixture was quenched with NH4CI (150 mL) and extracted with Et20 (3 x 100 mL). The combined organic layers were washed with brine and concentrated to give yellow oil, which was purified by col15 umn chromatography on silica gel using DCM: hexane (v/v 1:1)to yield compound 8a as a yellow oil (8.7 g, 85percent). 1H NMR (400 MHz, CDCI3) ö 9.99 (s, 1 H), 7.71 (d, 1 H, J = 5.2 Hz), 7.15 (d, 1H, J = 5.2 Hz).Experimental procedure3-Bromo-thiophene (6.523 g, 40 mmol) was dissolved under N[00174] To a solution of lithium diisopropylamide (31.6 mmol) in 50 mL of THF at -78 °C was added 3-bromothiophene (3.0 g, 31 mmol) (1). After stirring for 1 h, formylpiperidine (3.50 g, 31.6 mmol) (2) was added and the reaction was warmed to 0 °C. After 12 h, the reaction mixture was partitioned between DCM and sat. NHA round 500 mL flask was charged with tetrahydrofuran (200 mL) Cool to -78 ° C. Thereafter, 2.0 M LDA (55 mL, 0.11 mol) was added theretoAnd 3-bromothiophene (16.3 g, 0.1 mol) was added slowly.After stirring at the same temperature for 1 hourDimethyl formaldehyde(8.48 ml, 0.11 mol).Then, the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was fractionally distilled through ethyl acetate, The remaining water was removed with anhydrous magnesium sulfate, and the solvent was evaporated, Pure Compound A was obtained by column chromatography (18 g, 94percent).a) General procedure: To the solution of 1M NaHMDS (8.8 mL, 8.8 mmol) in THF was slowly added the substrate (6.8 mmol) at 0 Thieno[3, 2-b]thiophene-2-carboxamidine hydrochloride

Molecular Weight:191.05
XLogP3:2.1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:189.90880
Monoisotopic Mass:189.90880
Topological Polar Surface Area:45.3
Heavy Atom Count:8
Complexity:96.4
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes