* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With dmap In tetrahydrofuran at 20℃; for 0.5 h; Stage #2: for 2 h;
In a 100 mL round-bottom flask was placed 1H-INDOLE-5-CARBONITRILE (2.0 g, 14.07 MMOL) in 20 mL of anhydrous THF. To this solution was added DMAP (0.86 g, 7.03 MMOL) and the mixture was allowed to stir for 0.5 h at rt. At this point, BOC20 (3.07 g, 14.07 MMOL) was added and the reaction stirred for an additional 2 h. The reaction was then quenched with water and extracted twice with ethyl ether. The combined organic layers were washed successively with 1 N HCI, water, and brine, then dried over MGS04 and concentrated to provide 3.26 g (96percent) of the desired product as a white SOLID.APOS;H- NMR (DMSO-d6) 8 8.20-8. 14 (m, 2H), 7.83 (d, 1H), 7.70 (d, 1H), 6.80 (d, 1H), 1.63 (s, 9H).
96%
Stage #1: With dmap In tetrahydrofuran at 20℃; for 0.5 h; Stage #2: for 2 h;
In a 100 ml round-bottom flask was placed 1W-indole-5-carbonitrile (2.0 g, 14.07mmol) in 20 ml of anhydrous THF. To this solution was added DMAP (0.86 g, 7.03mmol) and the mixture was allowed to stir for 0.5 h at rt. At this point, BocaO (3.07 g,14.07 mmol) was added and the reaction stirred for an additional 2 h. The reaction wasthen quenched with water and extracted twice with ethyl ether. The combined organiclayers were washed successively with 1N HCI, water, and brine, then dried over MgSO4and concentrated to provide 3.26 g (96percent) of the desired product as a white solid. 1H-NMR (DMSO-c/e) 5 8.20-8.14 (m, 2H), 7.83 (d, 1H), 7.70 (d, 1H), 6.80 (d, 1H), 1.63 (s,9H).
90%
With dmap In acetonitrile at 20℃; for 0.5 h;
[0486] tert-butyl 5-cyano-l H-indole-1 -carboxylate (INT-65) [0487] To a flask containing 5-cyanoindole (500 mg, 3.52 mmol) in CH3CN (5 mL) was added Boc20 (920 mg, 4.22 mmol) and DMAP (42 mg, 0.35 mmol) and the mixture was stirred at room temperature for 0.5 h. The mixture was concentrated, redissolved in DCM and chromatographed (EtOAc / hexanes) to provide 766 mg (90percent) of tert-butyl 5-cyano-lH- indole-l-carboxylate INT -65 as a white solid. LCMS-ESI (m/z) calculated for C14H14N20 :242.27; found 243.1 [M+H]+, tR = 3.93 min.
Reference：
[1] Synthesis, 2009, # 21, p. 3617 - 3632
[2] Journal of Organic Chemistry, 2002, vol. 67, # 21, p. 7551 - 7552
[3] Patent: WO2004/43950, 2004, A1, . Location in patent: Page 134
[4] Patent: WO2005/51957, 2005, A1, . Location in patent: Page/Page column 54-55
[5] Patent: WO2011/60389, 2011, A1, . Location in patent: Page/Page column 98-99
[6] Synthesis, 2008, # 5, p. 707 - 710
[7] Synlett, 2008, # 2, p. 294 - 296
[8] Journal of Organic Chemistry, 2005, vol. 70, # 1, p. 175 - 178
[9] Journal of Organic Chemistry, 2007, vol. 72, # 14, p. 5046 - 5055
[10] Patent: US2004/242559, 2004, A1, . Location in patent: Page 18
[11] European Journal of Medicinal Chemistry, 2017, vol. 128, p. 70 - 78
2
[ 557-21-1 ]
[ 182344-70-3 ]
[ 475102-10-4 ]
Reference：
[1] Journal of Organic Chemistry, 2017, vol. 82, # 13, p. 7040 - 7044
3
[ 1259448-45-7 ]
[ 889676-34-0 ]
[ 475102-10-4 ]
Reference：
[1] Journal of the American Chemical Society, 2010, vol. 132, # 50, p. 17933 - 17944
4
[ 1259448-38-8 ]
[ 1233500-93-0 ]
[ 475102-10-4 ]
Reference：
[1] Journal of the American Chemical Society, 2010, vol. 132, # 50, p. 17933 - 17944
5
[ 24424-99-5 ]
[ 1259448-44-6 ]
[ 889676-34-0 ]
[ 475102-10-4 ]
Reference：
[1] Journal of the American Chemical Society, 2010, vol. 132, # 50, p. 17933 - 17944
6
[ 24424-99-5 ]
[ 1259448-37-7 ]
[ 1233500-93-0 ]
[ 475102-10-4 ]
Reference：
[1] Journal of the American Chemical Society, 2010, vol. 132, # 50, p. 17933 - 17944
In a 100 mL round-bottom flask was placed 1H-INDOLE-5-CARBONITRILE (2.0 g, 14.07 MMOL) in 20 mL of anhydrous THF. To this solution was added DMAP (0.86 g, 7.03 MMOL) and the mixture was allowed to stir for 0.5 h at rt. At this point, BOC20 (3.07 g, 14.07 MMOL) was added and the reaction stirred for an additional 2 h. The reaction was then quenched with water and extracted twice with ethyl ether. The combined organic layers were washed successively with 1 N HCI, water, and brine, then dried over MGS04 and concentrated to provide 3.26 g (96%) of the desired product as a white SOLID.'H- NMR (DMSO-d6) 8 8.20-8. 14 (m, 2H), 7.83 (d, 1H), 7.70 (d, 1H), 6.80 (d, 1H), 1.63 (s, 9H).
96%
In a 100 ml round-bottom flask was placed 1W-indole-5-carbonitrile (2.0 g, 14.07mmol) in 20 ml of anhydrous THF. To this solution was added DMAP (0.86 g, 7.03mmol) and the mixture was allowed to stir for 0.5 h at rt. At this point, BocaO (3.07 g,14.07 mmol) was added and the reaction stirred for an additional 2 h. The reaction wasthen quenched with water and extracted twice with ethyl ether. The combined organiclayers were washed successively with 1N HCI, water, and brine, then dried over MgSO4and concentrated to provide 3.26 g (96%) of the desired product as a white solid. 1H-NMR (DMSO-c/e) 5 8.20-8.14 (m, 2H), 7.83 (d, 1H), 7.70 (d, 1H), 6.80 (d, 1H), 1.63 (s,9H).
90%
With dmap; In acetonitrile; at 20℃; for 0.5h;
[0486] tert-butyl 5-cyano-l H-indole-1 -carboxylate (INT-65) [0487] To a flask containing 5-cyanoindole (500 mg, 3.52 mmol) in CH3CN (5 mL) was added Boc20 (920 mg, 4.22 mmol) and DMAP (42 mg, 0.35 mmol) and the mixture was stirred at room temperature for 0.5 h. The mixture was concentrated, redissolved in DCM and chromatographed (EtOAc / hexanes) to provide 766 mg (90%) of tert-butyl 5-cyano-lH- indole-l-carboxylate INT -65 as a white solid. LCMS-ESI (m/z) calculated for C14H14N20 :242.27; found 243.1 [M+H]+, tR = 3.93 min.
With triethylamine;dmap; In dichloromethane; at 0℃; for 2h;
After introducing 5-cyanoindole, Boc2O, dichloromethane and DMAP into a 100 ml round-bottomed flask, the reaction medium is stirred at 0 C. under nitrogen for 2 hours. After disappearance of the starting cyanoindole, the reaction medium is poured into water and extracted with EtOAc. After drying and evaporating off the solvent, 1.7191 g of N-Boc-5-cyanoindole are obtained in the form of a yellowish powder. Rf (silica)=0.61; 7/3 cyclohexane/EtOAc. LC/MS m/z=242.
With Triisopropyl borate; lithium diisopropyl amide; In tetrahydrofuran; cyclohexane; at 0 - 20℃; for 2.33333h;
The indole derivative in the THF is introduced into a 50 ml round-bottomed flask. The borate is added at room temperature under nitrogen, followed by dropwise addition over 20 minutes, at 0 C. under nitrogen, of the LDA. The mixture is stirred at 0 C. for 2 hours. The reaction medium is neutralized with 2N HCl and extracted with EtOAc. After drying and evaporating off the solvent, 829.3 mg of a brown foam containing 60% of the expected product, <strong>[475102-10-4]N-Boc-5-cyanoindole</strong>-2-boronic acid, and 40% of its Boc-free analogue, are obtained. This product is used without further purification for the coupling in Step 3.
With 1,1,1,3',3',3'-hexafluoro-propanol; at 150℃; for 0.0833333h;Microwave irradiation;Product distribution / selectivity;
EXAMPLE 2; Following the procedure set forth in Example 1 (A) above, indole derivatives were deprotected using TFE or HFIP in a microwave reactor at 150 C. as set forth in Table 1 below.
98%
With 2,2,2-trifluoroethanol; at 150℃; for 1h;Microwave irradiation;Product distribution / selectivity;
Example 1; (A) A solution of the N-Boc protected amine (1 mmol) in TFE (2,2,2-trifluoroethanol) or HFIP (hexafluoroisopropanol) (5 mL) was placed in a sealed microwave vial. The reaction mixture was heated (100C or 150C) in a Biotage - Initiator Sixty microwave reactor with stirring until the disappearance of the starting material was observed. After cooling to room temperature, the mixture was evaporated to dryness under reduced pressure. The crude product was purified by flash-column chromatography. 1H NMR and 13C NMR were measured on Bruker Avance DPX-300 NMR or Bruker Avance-300 NMR spectrometers, operating at a proton (1H) frequency of 300.13 MHz and carbon (13C) frequency of 75.43 MHz.Example 2 Following the procedure set forth in Example 1(A) above, indole derivatives were deprotected using TFE or HFIP in a microwave reactor at 150C as set forth in Table 1 below.
98%
With 1,1,1,3',3',3'-hexafluoro-propanol; at 150℃; for 0.0833333h;Microwave irradiation;Product distribution / selectivity;
Example 1; (A) A solution of the N-Boc protected amine (1 mmol) in TFE (2,2,2-trifluoroethanol) or HFIP (hexafluoroisopropanol) (5 mL) was placed in a sealed microwave vial. The reaction mixture was heated (100C or 150C) in a Biotage - Initiator Sixty microwave reactor with stirring until the disappearance of the starting material was observed. After cooling to room temperature, the mixture was evaporated to dryness under reduced pressure. The crude product was purified by flash-column chromatography. 1H NMR and 13C NMR were measured on Bruker Avance DPX-300 NMR or Bruker Avance-300 NMR spectrometers, operating at a proton (1H) frequency of 300.13 MHz and carbon (13C) frequency of 75.43 MHz.Example 2 Following the procedure set forth in Example 1(A) above, indole derivatives were deprotected using TFE or HFIP in a microwave reactor at 150C as set forth in Table 1 below.
In a 100 mL round-bottom flask was placed 2.0 g (8.26 mmol, 1 equiv) of tert-butyl 5-cyano-1W-indole-1-carboxylate (step 1) in 25 ml of THF. The mixture was cooledto -78 C and 1.1 equiv (5.34 mL, 1.7 M in pentane) of f-BuLi was added dropwise.The mixture was allowed to stir for 1 h and 2.14 g (18.16 mmol, 2.2 equiv) of dimethyloxalate in 5 ml of THF was added quickly in one portion. The reaction was then allowedto warm to 0 C and stirred until complete, as monitored by TLC (about 2 h). The mixturewas diluted with 30 mL of water and transferred to a separatory funnel where it wasextracted with EtOAc (3 x 100 mL). The combined organic extract was washed withbrine, dried (Na2SO4), filtered, and evaporated to give a brown residue. To the residue was added MeOH (10 ml) to give an insoluble yellow solid, which was filtered, washedwith MeOH, dried, and purified to provide 0.44 g (24%) of the desired product as a yellowsolid. 1H-NMR (DMSO- c/6l) 5 12.63 (s, 1H), 8.40 (s, 1H), 7.77 (s, 1H), 7.65 (d, 1H), 7.60(d, 1H), 3.93(s, 3H).
23.6%
In a 100 mL round-bottom flask was placed 2.0 g (8.26 mmol, 1 equiv) of tert-butyl 5-CYANO-1H-INDOLE-1-CARBOXYLATE (step 1) in 25 mL of THF. The mixture was cooled to- 78 C and 1.1 equiv (5.34 mL, 1.7 M in pentane) of t-BuLi was added dropwise. The mixture was allowed to stir for 1 h and 2.14 g (18.16 mmol, 2.2 equiv) of dimethyl oxalate in 5 mL of THF was added quickly in one portion. The reaction was then allowed to warm to 0 C and stirred until complete, as monitored by TLC (about 2 h). The mixture as diluted with 30 mL of water and transferred to a separatory funnel where it was extracted with EtOAc (3 x 100 mL). The combined organic extract was washed with brine, dried (NA2SO4), filtered, and evaporated to give a brown residue. To the residue was added MeOH (10 mL) to give an insoluble yellow solid, which was filtered, washed with MeOH, dried, and purified to provide 444.3 mg (23.6%) of the desired product as a yellow solid. 1H-NMR (DMSO-D6) 6 12. 63 (s, 1H), 8.40 (s, 1H), 7.77 (s, 1H), 7.65 (d, 1H), 7.60 (d, 1H), 3.93 (s, 3H).
With hydroxylamine hydrochloride; sodium carbonate; In ethanol; at 75℃;
[0488] tert-butyl 5-(N-hydroxycarbamimidoyl)-lH-indole-l-carboxylate (INT -66)[0489] Prepared using General Procedure 1. To a flask containing tert-butyl 5-cyano-lH- indole-l-carboxylate INT-65 (200 mg, 0.73 mmol) was added EtOH (6 mL), hydroxylamine hydrochloride (177 mg, 2.54 mmol) and Na2C03 (154 mg, 1.45 mmol). The mixture was stirred at 75C overnight then concentrated, re-dissolved in DCM and washed with NaHC03. The combined organic layers were dried over Na2S04 and concentrated to provide 222 mg of crude tert-butyl 5-(N-hydroxycarbamimidoyl)-lH-indole-l-carboxylate INT-66 as a white solid which was used directly in the next experiment. LCMS-ESI (m/z) calculated for C14H17N303: 275.3; found 276.1 [M+H]+, tR = 2.25 min.
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