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With boron tribromide In dichloromethane at -10 - 20℃; for 1.5 h; Inert atmosphere
To a solution of Example 20a (1.5 g, 9.14 mmol, 1.0 eq) in DCM (20 mL) was added dropwise BBr3 (36.6 ml, 36.6 mmol, 4.0 eq, 1M in DCM) at -10°C under N2. The mixture was stirred at this temperature for 30 min, and then warmed to r.t. for 1 h. The reaction was quenched with MeOH at - 5°C. The mixture was extracted with DCM (50 mL) and water. The organic layer was washed with aq.NaHC03, dried over Na2S04 and concentrated. The residue was purified by flash column chromatography (PE:EA=4: 1) to give the desired product(Example 20b, 1 g, yield 73percent, as a yellow solid). MS [M+1]+=151.0
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 8, p. 2948 - 2950
[2] Patent: WO2017/218960, 2017, A1, . Location in patent: Paragraph 00463; 00466
[3] Journal of Heterocyclic Chemistry, 2001, vol. 38, # 5, p. 1025 - 1030
[4] Journal of the American Chemical Society, 2013, vol. 135, # 20, p. 7450 - 7453
[5] Patent: US2010/279983, 2010, A1, . Location in patent: Page/Page column 24
[6] Patent: WO2012/138776, 2012, A1, . Location in patent: Page/Page column 166
[7] Patent: WO2007/139729, 2007, A1, . Location in patent: Page/Page column 32
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[ 4923-87-9 ]
[ 19301-35-0 ]
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[2] Angewandte Chemie - International Edition, 2018, vol. 57, # 7, p. 1968 - 1972[3] Angew. Chem., 2018, vol. 130, p. 1986 - 1990,5
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[ 19301-35-0 ]
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[2] Journal of the American Chemical Society, 1956, vol. 78, p. 5351,5354
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[ 20532-28-9 ]
[ 19301-35-0 ]
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[4] Justus Liebigs Annalen der Chemie, 1937, vol. 527, p. 83,101
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[ 6345-55-7 ]
[ 19301-35-0 ]
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[1] Synthetic Communications, 1991, vol. 21, # 7, p. 959 - 964
[2] Justus Liebigs Annalen der Chemie, 1937, vol. 527, p. 83,101
[3] Journal of the American Chemical Society, 1956, vol. 78, p. 5351,5354
[4] Journal of the American Chemical Society, 1956, vol. 78, p. 5351,5354
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[ 6361-21-3 ]
[ 19301-35-0 ]
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[1] Synthetic Communications, 1991, vol. 21, # 7, p. 959 - 964
[2] Justus Liebigs Annalen der Chemie, 1937, vol. 527, p. 83,101
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[1] Justus Liebigs Annalen der Chemie, 1937, vol. 527, p. 83,101
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[3] Journal of the American Chemical Society, 1956, vol. 78, p. 5351,5354
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[1] Journal of Heterocyclic Chemistry, 2001, vol. 38, # 5, p. 1025 - 1030
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 8, p. 2948 - 2950
[3] Journal of the American Chemical Society, 2013, vol. 135, # 20, p. 7450 - 7453
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[2] Journal of the American Chemical Society, 2013, vol. 135, # 20, p. 7450 - 7453
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With boron tribromide-dimethyl sulfide complex; In dichloromethane; chlorobenzene; at 0 - 120℃;Inert atmosphere;
General procedure: To a solution of 14a (or 14b) (2 mmol) in anhydrous chlorobenzene (20 mL) a solution of BBr3SMe2 1M in CH2Cl2 (4 mL, 4 mmol) was added dropwise at 0C and under Ar atmosphere. The reaction was kept stirring at reflux for 10h. After cooling down, the reaction was quenched with water and extracted with CH2Cl2 (three times). The organic layers were collected, dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The crude was purified on silica gel to afford compounds 9a (or 9b) with 80% (or 81%) yield. 1H and 13C spectra of compounds 9a-b were in agreement with literature data.[1]
73%
With boron tribromide; In dichloromethane; at -10 - 20℃; for 1.5h;Inert atmosphere;
To a solution of Example 20a (1.5 g, 9.14 mmol, 1.0 eq) in DCM (20 mL) was added dropwise BBr3 (36.6 ml, 36.6 mmol, 4.0 eq, 1M in DCM) at -10C under N2. The mixture was stirred at this temperature for 30 min, and then warmed to r.t. for 1 h. The reaction was quenched with MeOH at - 5C. The mixture was extracted with DCM (50 mL) and water. The organic layer was washed with aq.NaHC03, dried over Na2S04 and concentrated. The residue was purified by flash column chromatography (PE:EA=4: 1) to give the desired product(Example 20b, 1 g, yield 73%, as a yellow solid). MS [M+1]+=151.0
With pyridine hydrochloride; at 190℃; for 3.5h;Sealed tube;
METHOD B. 5-HYDROXY-1-BENZOTHIOPHENE5-methoxy-1-benzothiophene (6.37 g, 38.8 mmol) was combined with pyridine hydrochloride (13.5 g, 116.4 mmol) in a sealed tube and heated to 190 C. for 3.5 hrs. The reaction was cooled to room temperature and the resulting residue was dissolved in 2:1 EtOAc-H2O with sonication. The organic layer was washed with water, brine, dried over anhydrous Na2SO4, and filtered. The filtrate was evaporated in vacuo. The crude residue was purified by silica gel chromatography using 20% EtOAc-hexanes to give 5-hydroxy-1-benzothiophene.1H NMR (500 MHz, acetone-d6) delta (ppm): 8.32 (s, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.56 (d, J=5.5 Hz, 1H), 7.28 (d, J=2.3 Hz, 1H), 7.25 (d, J=5.3 Hz, 1H), 6.96 (dd, J=2.3 Hz, 1H).
Step 1. A 5.0 mL reaction vial was charged with 5-methoxy-l- benzothiophene (0.64 g, 3.9 mmol, Small Molecules, Hoboken, NJ) and pyridine hydrochloride (1.3 g, 12 mmol, Acros, Waltham, MA), and then the reaction mixture was heated at 190 C for 3.5 h. After that time, the reaction mixture was cooled to room temperature, partitioned between ethyl acetate (100 mL) water (50 mL), the layers were separated, the organic material was washed with brine (25 mL), dried (magnesium sulfate), filtered, and the filtrate was concentrated. The isolated material (0.64 g) was used in the next step of the synthesis without purification.
With pyridine hydrochloride; at 190℃; for 3.5h;Sealed tube; Neat (no solvent);
PREPARATIVE EXAMPLE 23 GENERAL PREPARATION OF BENZOTHI OPHENESMETHOD A. 5-HYDROXY-l -BENZOTHIOPHENE5-Methoxy-l -benzothiophene (6.37 g, 38.8 mmol) was combined with pyridine hydrochloride (13.5 g5 1 16.4 mmol) in a sealed tube and heated to 19O0C for 3.5 hrs. The reaction was cooled to room temperature and the resulting residue was dissolved in 2:1 EtOAc-H2O with sonication. The organic layer was washed with water, brine, dried over anhydrous Na2SO4, and filtered. The filtrate was evaporated in vacuo. The crude residue was purified by silica gel chromatography using 20% EtOAc-hexanes to give 5-hydroxy-l -benzothiophene.1H NMR (500 MHz, acetone-d6) deltappm): 8.32 (s, IH), 7.43 (d, J=8.8 Hz, IH), 7.56 (d, J=5.5 Hz, IH), 7.28 :d, J=2.3 Hz, IH), 7.25 (d, J=5.3 Hz5 IH); 6.96 (dd, J=2.3 Hz5 I H).
Stage #1: With di-isopropyl azodicarboxylate In dichloromethane at 0℃; for 0.166667h;
Stage #2: benzo[b]thiophen-5-ol; N-(tert-butoxycarbonyl)-L-prolinol With triethylamine; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 16h;
165.i
Polymer supported triphenyl phosphine (5.12 g, 13.32 mmol, 2.6 mmol/g loading) was suspended in dichloromethane (15 mL) cooled to 00C in an ice / water bath. Diisopropyl azodicarboxylate (2.69 g, 13.3 mmol, 2.6 mL) was added dropwise and the mixture was stirred for 10 min. A solution of benzo[b]thiophen-5-ol (1.20 g, 7.99 mmol) and (S)-tert- butyl-2-(hydroxymethyl)pyrrolidine-l-carboxylate (1.34 g, 6.66 mmol) dissolved in dichloromethane (20 mL) was added dropwise at 00C. The cooling bath was removed, triethylamine (1.35 g, 13.3 mmol) was added, and the mixture was stirred for 16 h. The polymer bound triphenylphosphine was removed by filtration and washed with dichloromethane (3x 10 mL). The organic layer was separated, dried over sodium sulfate (200 mg), filtered through a coarse frit (to remove the sodium sulfate), and condensed in vacuo to give a white solid (2.3 g). The crude product was purified by flash chromatography (EtOAc / hexane 1:1) to yield the title compound as a white solid (1.95 g, 55%). MS (M+H)+ 334.
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