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CAS No. : | 272-49-1 | MDL No. : | MFCD00971977 |
Formula : | C7H6N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XWIYUCRMWCHYJR-UHFFFAOYSA-N |
M.W : | 118.14 | Pubchem ID : | 9226 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 36.09 |
TPSA : | 28.68 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.26 cm/s |
Log Po/w (iLOGP) : | 1.12 |
Log Po/w (XLOGP3) : | 1.07 |
Log Po/w (WLOGP) : | 1.56 |
Log Po/w (MLOGP) : | 0.58 |
Log Po/w (SILICOS-IT) : | 2.15 |
Consensus Log Po/w : | 1.3 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.99 |
Solubility : | 1.22 mg/ml ; 0.0103 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.26 |
Solubility : | 6.44 mg/ml ; 0.0545 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.86 |
Solubility : | 0.163 mg/ml ; 0.00138 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.29 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-Bromosuccinimide In N,N-dimethyl-formamide at 0℃; for 0.5 h; | (R)-3-Pyrrolidin-2-ylmethyl-1H-pyrrolo[3,2-b]pyridine.(Compound 88) 4.6 g (25.8 mmol) NBS was added to 3.05 g (25.8 mmol) 4-azaindole in 40 ml of DMF (0° C.).). The mixture was stirred for 30 minutes at 0° C. MeOH was added and the mixture was filtrated over SCX-2, followed by flash chromatography (ethyl acetate followed by MeOH) afforded 3-bromo-1H-[3,2-b]pyridine (86) as a solid. mp 241° C. (4.52 g, 89percent). 1H-NMR (400 MHz, D6DMSO) δ 11.7 (bs, 1H), 8.39 (dd, J=5 Hz, 2 Hz, 1H), 7.85 (s, 1H), 7.82 (dd, J=8 Hz, 2 Hz, 1H), 7.19 (dd, J=8 Hz, 5 Hz, 1H). |
76% | Stage #1: With copper(ll) bromide In acetonitrile at 17 - 20℃; Cooling Stage #2: With ammonia In methanol; acetonitrile at 10℃; |
Example 3 3-Bromo-4-Azaindole[00147] solution of 0.9707g (8.21 mmol) of 4-azaindole in 50 ml. of acetonitrile was placed in a 250 ml. three-neck round-bottom flask equipped with a magnetic stirrer, thermocouple, nitrogen bleed, and cooling ice bath. A total of 5.5187g (24.7 mmol, 3 eq.) of solid CuBr2 was added portion-wise to the flask at 170C in 10 minutes. The resulting green suspension stirred at room temperature until no starting material was observed by TLC (approximately 1-2 hours). The reaction mixture was cooled to 1 O0C and then was slowly quenched by addition of 7Λ/ ammonia in methanol solution (6OmL). The resulting blue solution was concentrated on rotavap at room temperature, and the residue was extracted with ethyl acetate (3 x 80 mL). The organic extract was dried over Na2SO4, filtered, and concentrated on rotavap to give 1.4g of off-white solid. This residue was suspended in 100 mL of hexane, filtered and dried under suction to give 1.225g (76percent yield) of 3-bromo-4-azaindole as white solid. |
67% | With N-Bromosuccinimide In N,N-dimethyl-formamide at 0℃; for 1 h; Inert atmosphere; Schlenk technique | To a stirredsolution of 1H-pyrrolo[3,2-b]pyridine(1.0 g, 8.47 mmol) in dry DMF (10 ml) was added N-bromosuccinimide(1.51 g, 8.48 mmol) at 0 °C and the resultant mixture was stirredfor 1 h at the same temperature. The reaction mixture was dilutedwith saturated sodium bicarbonate solution (50 ml) and extracted withethyl acetate (2 x 150 ml). The combined organic layers were washedwith brine (50 ml) and dried (Na2SO4).The residue obtained after evaporation of the solvent was purified bysilica gel column chromatography using3percent methanol in chloroformm toyield 1.12 g (67percent) of product as a white solid. 1HNMR (300 MHz, DMSO-d6)7.19 (dd, J= 5.1, 4.8 Hz, 1H), 7.81 (d, J= 1.5 Hz, 1H), 7.82 (d, J= 3.0 Hz, 1H), 8.37 (d, J= 4.8 Hz, 1H), 11.69 (br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | for 4 h; Reflux | A mixture of 4-azaindole (0.500 g; 4.223 mmol), hexamethylenetetramine (0.890 g; 6.348 mmol) and acetic acid (3.630 mL; 63.45 mmol) in water (9 mL) was refluxed for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (2percent to 4percent) in dichloromethane furnished 0.550 g (89percent) of 1 /-/-pyrrolo[3,2-£>]pyridine-3-carbaldehyde. ESI/APCI(+): 147 (M+H). ESI/APCI(-): 145 (M-H). |
56% | With acetic acid In water for 4 h; Heating / reflux | A mixture of 1H-pyrrolo[3,2-b]pyridine (947 mg, 8.02 mmol), hexamethylenetetramine (1.7 g, 12 mmol) and acetic acid (7.5 mL) in water (14 mL) was refluxed under N2 for 4 hours. The reaction mixture was cooled to RT, concentrated, and the residue was purified via flash chromatography (DCM/MeOH/NH4OH) affording 1H-Pyrrolo[3,2-b]pyridin-3-carbaldehyde as a white solid (660 mg, 56percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-iodo-succinimide In tetrahydrofuran at 20℃; | To a solution of lH-pyrrolo[3,2-b]pyridine (1.94 g, 16.4 mmol) in THF (10 mL) is added N- iodosuccimide (4.06 g, 18.1 mmol). Preciptation occurs after a few minutes. The reaction is continued to stri at rt overnight. The preciptate is collected by filtration and is washed with a smalll amount of THF and heptane. The resultin white solid is dried in vacuo. The yeild of the reaction is 4.1 g (quantitative). 1H NMR (OMSO-d6, 300 MHz) δ 8.40 (s, 1H), 7.90-7.70 (m, 2H), 7.15 (d, 1H). LC 0.41 min; MS m/z 245 (M+l). |
93.5% | With N-iodo-succinimide In tetrahydrofuran at 20℃; | To a solution of lH-pyrrolo[3,2-b]pyridine (3.0 g, 25.4 mmol, 1.0 eq) in THF (20 mL) was added NIS (6.3 g, 27.9 mmol, 1.1 eq). Precipitation occurred after a few minutes. The stirring was continued at rt overnight. The precipitate was collected by filtration and washed with a small amount of THF. The resulting solid was dried in vacuum to give 3- iodo-lH-pyrrolo[3,2-b]pyridine (5.8 g, 93.5percent). |
9.18 g | With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 1.08333 h; Inert atmosphere | To a mixture of 1H-pyrrolo[3,2-b]pyridine (Purchased from Combi Blocks Inc.), (5 g) and DMF (100 mL) stirred under nitrogen at room temperature was added potassium hydroxide (9.02 g) followed by iodine (12.89 g) and the resulting mixture was stirred at room temperature for 1 h 5 min., then poured onto a mixture of Na2S2O5.5H2O (4.25 g), water (635 mL), and 28-30percent ammonium hydroxide (43 mL). The resultant mixture was cooled in an ice bath for 20 min, and the precipitate thus produced was filtered and washed with ice water then dried under vacuum to give the title compound (9.18 g). LCMS: m/z 245.39 [M+H]+. 1H NMR (400 MHz, DMSO-d6) ppm 7.17 (dd, J=8.1, 4.5 Hz, 1H) 7.72-7.87 (m, 2H) 8.38 (d, J=4.4 Hz, 1H) 11.74 (br. s., 1H) |
9.18 g | With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 1.08333 h; Inert atmosphere | To a mixture of 1H-pyrrolo[3,2-b]pyridine (Purchased from Combi Blocks Inc.), (5 g) and DMF (100 mL) stirred under nitrogen at room temperature was added potassium hydroxide (9.02 g) followed by iodine (12.89 g) and the resulting mixture was stirred at room temperature for 1 h 5 min., then poured onto a mixture of Na2S2O5.5H2O (4.25 g), water (635 mL), and 28-30percent ammonium hydroxide (43 mL). The resultant mixture was cooled in an ice bath for 20 min, and the precipitate thus produced was filtered and washed with ice water then dried under vacuum to give the title compound (9.18 g). LCMS: m/z 245.39 [M+H]+. 1H NMR (400 MHz, DMSO-d6) ppm 7.17 (dd, J=8.1, 4.5 Hz, 1H) 7.72-7.87 (m, 2H) 8.38 (d, J=4.4 Hz, 1H) 11.74 (br. s., 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With hydrogen | |
71% | With formic acid; palladium 10% on activated carbon In methanol for 4h; Inert atmosphere; | |
With hydrogenchloride; iron In 1,4-dioxane; methanol at 80℃; for 3h; | 45.4 Into a 5000 niL three-necked roundbottom flask, was placed a solution of N,N-dimethyl-2-(3- nitropyridin-2-yl)ethenamine (100 g, 517.60 mmol) in 1,4-dioxane (1.4 L). To this was added HCl(IN) (283 rnL). To the mixture was added CH3OH(347.5 rnL). To the above was added Fe (232 g, 4.14 mol) in several batches, while warming to a temperature of 80 °C. The resulting solution was allowed to react, with stirring, for 3 hours while the temperature was maintained at 80 °C. The reaction progress was monitored by TLC (CH2Cl2ICH3OH = 15:1). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The resulting solution was diluted with 1000 mL of H2O. The resulting solution was extracted 4 times with 4000 mL of EtOAc and the organic layers combined and concentrated by evaporation under vacuum using a rotary evaporator. The resulting solution was decolorized by the addition of active carbon. The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The resulting mixture was washed once with 500 mL of EtOEt and 1 time with 500 mL of PE, gave 1H-pyrrolo[3,2-b]pyridine. |
15 mg | With palladium 10% on activated carbon; hydrogen In ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.5% | With sodium ethanolate In ethanol for 1h; Heating / reflux; | S.4 Preparation Example S-4. 1H-Pyrrolo[3, 2-b]pyridine (2-Trimethylsilanylethynyl-pyridin-3-yl)carbamic acid ethyl ester described in Preparation Example S-3 (0.42g, 1.6mmol) was dissolved in ethanol (8mL), sodium ethoxide (204mg, 3mmol) was added thereto, followed by stirring for 1 hour under reflux. After the reaction was completed, the reaction mixture was poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then evaporated, the resulting solid was washed with solvent (diethylether: hexane = 1: 2), and the title compound (0.12g, 1 mmol, 63.5%) was obtained. 1H-NMR Spectrum (DMSO-d6) δ (ppm): 6.50-6.54 (1 H, m), 7.06 (1 H, dd, J=4.8, 8.4Hz), 7.58-7.62 (1 H, m), 7.72-7.76 (1 H, m), 8.26-8.30 (1 H, m), 11.2 (1 H, brs). |
63.5% | With sodium ethanolate In ethanol for 1h; Heating / reflux; | S.4 (2- Trimethylsilanylethynyl-pyridin-3-yl)carbamic acid ethyl ester described in Preparation Example S-3 (0.42g, 1.6mmol) was dissolved in ethanol (8mL), sodium ethoxide (204mg, 3mmol) was added thereto, followed by stirring for 1 hour under reflux. After the reaction was completed, the reaction mixture was poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then evaporated, the resulting solid was washed with solvent (diethylether : hexane = 1 : 2), and the title compound (0.12g, 1 mmol, 63.5%) was obtained. 1H-NMR Spectrum (DMSO-d6) δ(ppm) : 6.50-6.54 (1H, m), 7.06 (1H, dd, J=4.8, 8.4Hz), 7.58-7.62 (1 H, m), 7.72-7.76 (1 H, m), 8.26-8.30 (1 H, m), 11.2 (1 H, brs). |
With sodium ethanolate In ethanol Heating; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0℃; for 0.5h; | (R)-3-Pyrrolidin-2-ylmethyl-1H-pyrrolo[3,2-b]pyridine.(Compound 88) 4.6 g (25.8 mmol) NBS was added to 3.05 g (25.8 mmol) 4-azaindole in 40 ml of DMF (0° C.).). The mixture was stirred for 30 minutes at 0° C. MeOH was added and the mixture was filtrated over SCX-2, followed by flash chromatography (ethyl acetate followed by MeOH) afforded 3-bromo-1H-[3,2-b]pyridine (86) as a solid. mp 241° C. (4.52 g, 89percent). 1H-NMR (400 MHz, D6DMSO) delta 11.7 (bs, 1H), 8.39 (dd, J=5 Hz, 2 Hz, 1H), 7.85 (s, 1H), 7.82 (dd, J=8 Hz, 2 Hz, 1H), 7.19 (dd, J=8 Hz, 5 Hz, 1H). |
76% | Example 3 3-Bromo-4-Azaindole[00147] solution of 0.9707g (8.21 mmol) of 4-azaindole in 50 ml. of acetonitrile was placed in a 250 ml. three-neck round-bottom flask equipped with a magnetic stirrer, thermocouple, nitrogen bleed, and cooling ice bath. A total of 5.5187g (24.7 mmol, 3 eq.) of solid CuBr2 was added portion-wise to the flask at 170C in 10 minutes. The resulting green suspension stirred at room temperature until no starting material was observed by TLC (approximately 1-2 hours). The reaction mixture was cooled to 1 O0C and then was slowly quenched by addition of 7Lambda/ ammonia in methanol solution (6OmL). The resulting blue solution was concentrated on rotavap at room temperature, and the residue was extracted with ethyl acetate (3 x 80 mL). The organic extract was dried over Na2SO4, filtered, and concentrated on rotavap to give 1.4g of off-white solid. This residue was suspended in 100 mL of hexane, filtered and dried under suction to give 1.225g (76percent yield) of 3-bromo-4-azaindole as white solid. | |
67% | With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0℃; for 1h;Inert atmosphere; Schlenk technique; | To a stirredsolution of 1H-pyrrolo[3,2-b]pyridine(1.0 g, 8.47 mmol) in dry DMF (10 ml) was added N-bromosuccinimide(1.51 g, 8.48 mmol) at 0 °C and the resultant mixture was stirredfor 1 h at the same temperature. The reaction mixture was dilutedwith saturated sodium bicarbonate solution (50 ml) and extracted withethyl acetate (2 x 150 ml). The combined organic layers were washedwith brine (50 ml) and dried (Na2SO4).The residue obtained after evaporation of the solvent was purified bysilica gel column chromatography using3percent methanol in chloroformm toyield 1.12 g (67percent) of product as a white solid. 1HNMR (300 MHz, DMSO-d6)7.19 (dd, J= 5.1, 4.8 Hz, 1H), 7.81 (d, J= 1.5 Hz, 1H), 7.82 (d, J= 3.0 Hz, 1H), 8.37 (d, J= 4.8 Hz, 1H), 11.69 (br s, 1H). |
With N-Bromosuccinimide; In tetrahydrofuran; at -78℃; | Example 1 : 2-ri-(2,6-Dichloro-4-trifluoromethyl-phenyl)-1 /-/-pyrrolor3,2-fc)1pyridin-3-yl1-1 ,1 ,1- trifluoro-propan-2-ol; a); To a solution of 4-azaindole (400 mg) in dry THF (10 ml.) cooled to -78°C is added N- bromosuccinimide (783 mg) in one portion. The reaction mixture is stirred for 2 at -78°C and allowed to warm up to room temperature. It is then poured on a 5OmL cartridge containing 7g of Isolute.(R). HM-N sorbent (column packed with diatomaceous earth support) and eluted with CH2CI2 followed by acetone. The acetone fractions are evaporated under vacuum to give 4- aza-3-bromoindole as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With sodium hydride In N,N-dimethyl-formamide at 90 - 95℃; for 11h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With formic acid; palladium 10% on activated carbon In methanol for 4h; Inert atmosphere; | E.d (d) 0.2 g of 10% Pd/C was flashed with nitrogen before 10 ml of a mixture of 8.8 % formic acid in methanol was added cautiously. The crude (E)-N,N-Dimethyl-2-(3-nitropyridin-2-yl)ethenamine obtained as a red oil (0.69 g, 3.6 mmol) was also dissolved in 10 ml of a mixture of 8.8 % formic acid in methanol before it was added to the reaction. |
37% | With hydrogen | |
0.31 g | With formic acid In methanol for 4h; |
With formic acid In methanol for 4h; Inert atmosphere; | 12.d A modified procedure of Cash et al. (Org. Biomol. Chem. 2005, 3. 3701-3706) was used. 0.2 g of 10%) Pd/C was flashed with nitrogen before 10 ml of a mixture of 8.8 % formic acid in methanol was added cautiously. The crude (E)-N,N-Dimethyl-2-(3-nitropyridin-2- yl)ethenamine obtained as a red oil (0.69 g, 3.6 mmol) was also dissolved in 10 ml of a mixture of 8.8 % formic acid in methanol before it was added to the reaction. The reaction was stirred for 4 h until the red color completely disappeared. The Pd catalyst was removed by iltration through Celite , the filtrate was concentrated. After sitting over night, the product, 4-azaindole, crystallized (0.21g, 1.8 mmol, 71%). NMR (300 MHz, CDC13) 9.00 (bs; IH; NH); 8.48 (pdd; 4J = 1 Hz; J = 4.6 Hz; IH; H-5); 7.70 (pdd; 4J = 1 Hz; 3J = 8.2 Hz; IH; H-7); 7.48 (pt; J = 2.9 Hz; IH; H-2); 7.12 (pdd; 3J = 4.6 Hz; 3J = 8.2 Hz; IH; H-6); 6.76 (m; IH; H- 3). | |
With iron(III) chloride; hydrazine hydrate In methanol; water at 25 - 70℃; | 2 Step 2: Step 2: 1H-pyrrolo[3.2-b]pyridine To a dry round-bottom flask was added hydrazine hydrate (0.3 L), the product of Step 1 (0.1 kg, 0.5 mol), followed by water (0.3 L). A solution of FeCl3 (0.01 kg, 0.06 mol) in MeOH (0.3 L) was prepared and added dropwise to the reaction mixture, maintaining the temperature between 25-70 °C. The resulting reaction mixture was stirred at a temperature between 65-70 °C for approximately 12-15 hours before being cooled to 50-60 °C. MeOH was then removed by distillation at 50-60 °C and the resulting aqueous mixture was cooled to 25-30 °C and extracted with DCM (0.3 L, then again using 0.1 L). The combined organic washings were dried over sodium sulfate, filtered and concentrated in vacuo to afford a crude material. To this crude material was added hexanes (0.3 L) and the slurry was stirred for 30 minutes. The solids were then filtered, rinsing the filter cake with additional hexanes (0.05 L) to afford the desired 15 product after drying under vacuum at 50-60 °C. LRMS (EI) calc'd for C7H6N2 [M], 118; found 118. 1H NMR (500 MHz, DMSO-D6) δ 11.28 (br s, 1H), 8.28 (d, 1 H), 7.74 (d, 1H), 7.61 (t, 1H), 7.06 (q, 1H), 6.52 (br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate In 1,4-dioxane at 150℃; for 2.5h; Microwave irradiation; | 52 Example 52; 1-f4-n-f6-methylDyridin-3-yl)-4-fpyridin-2-v»-1H-imidazol-2-ylbhenv»-1H-pynOlor3.2- bipvridine; A mixture of 2-(2-(4-iodophenyl)-1-(6-methylpyridin-3-yI)-1H-imidazol-4-yl)pyridine(200 mg, 0.45 mmol), 1 H-pyrrolo[3,2-b]pyridine (Chem. Pharm. Bull. 1987, 35(5) 1823-28, 53 mg, 0.45 mmol, CuI (5 mg, 0.026 mmol), K3PO4 (209 mg, 1 mmol) and N,N-dimethyl-fraϖs- 1,2-cyclohexanediamine (7 mg, 0.049 mmol) in p-dioxane (1 mL) was heated by microwave at 150 0C for 2.5h, diluted with DCM, filtered, and concentrated and the residue purified by SGC (1%-4% MeOH in DCM, 0.5 % NH4OH) giving a yellow solid. Yield 35 mg. 1H NMR (CDCI3) δ 8.59 (d, 1H, J = 4.5 Hz), 8.52 (m, 2H)1 8.15 (d, 1H1 J = 7.9 Hz), 7.95 (br. 1H)1 7.90 (d, 1H1 J = 8.3 Hz), 7.80 (dt, 1H, J = 1, 8 Hz), 7.65-7.62 (m, 3H), 7.57 (dd, 1H1 J = 2.7, 8.1 Hz)1 7.43 (m, 2H)1 7.27 (d, 1H, J = 8.3 Hz)1 7.24-7.20 (m, 2H), 6.98 (d, 1H1 J = 3 Hz)1 2.64 (s, 3H). HPLCMS 2.91 min, m/e 429 (MH+). IC50 = 9.32 nM |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium <i>tert</i>-butylate In tetrahydrofuran; acetonitrile at 20℃; for 2h; | 8.1 Preparation of 4-azaindole 1a Product 25 7 (1.96 g, 10.3 mtnol, 1 eq.) was subjected to a cyclization reaction in the presence of a 1M 28 THF solution 29 potassium-tert-butoxide (10.3 ml, 10.3 mmol, 1 eq.) in 30 CH3CN (15 ml) at room temperature for 2 hours. The mixture was then diluted with ethyl acetate and hydrolyzed with water. After decantation, the organic phase was washed with saturated aqueous NaCl solution, dried over MgSO4 and concentrated under reduced pressure. 22 4-azaindole was isolated by flash column chromatography on silicagel (ethyl acetate/petroleum ether=1/1) with a yield of 97% |
70% | With potassium <i>tert</i>-butylate In 1-methyl-pyrrolidin-2-one at 20℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium hydroxide In methanol Heating / reflux; | 45.5 Into a 2000 mL roundbottom flask, was placed a solution of 1H-pyrrolo[3,2-b]pyridine (80 g, 644.07 mmol, 1.00 equiv, 95%) in CH3OH (1500 mL). To this was added tert-butyl 4-oxopiperidine-1- carboxylate (136 g, 683.42 mmol, 1.00 equiv). To the mixture was added KOH (114 g, 2.04 mol, 3.00 equiv). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (CH2Cl2/Me0H = 15:1). The product was precipitated by the addition of H2O. A filtration was performed. The filter cake was washed with 1000 mL of H2O and washed with 400 mL of PE. The solid was dried in an oven under reduced pressure. This resulted in 190 g (98%) of tert-butyl 4-(1H-pyrrolo[3,2-b]pyridin-3-yl)-5,6- dihydropyridine-l(2H)-carboxylate. Data: 1HNMR^OOMHZ, CDCl3) δ: 1.46 (3H,t), 2.60 (2H, s), 3.70 (2H,m), 4.19 (2H, d), 7.13 (1H, d), 7.16 (1H, d), 7.38 (1H,d), 7.69 (1H, d), 8.63 (1H, d). LCMS [M+H]+ calcd for C17H22N3O2 300, found 300. |
With potassium hydroxide In methanol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With hydrogen In methanol at 20℃; for 24h; | |
85% | With palladium 10% on activated carbon; hydrogen at 20℃; for 24h; | Synthesis of 1H-pyrrolo[3,2-b]pyridines (14a,b). General procedure: To a solution of suitable derivatives 13a,b (12.9 mmol) in ethanol or methanol (40 mL) a catalytic amount of 10% palladium on carbon was added and the mixture was hydrogenated in a Paar apparatus at room temperature for 24 h. The catalyst was filtered off and the solvent was removed under reduced pressure. The residue was purified by column chromatography using dichloromethane/ethyl acetate (95/5) (for compound 14a) or (6/4) (for compound 14b) as eluent. |
68% | With hydrogen; sodium hydrogencarbonate In ethanol; water; acetic acid | 1.3 Step 3. Step 3. Preparation of 4-Azaindole A mixture of (3-nitropyridin-2-yl)acetonitrile (4.89 g, 30.0 mmol) and 10% palladium on carbon (0.50 g) in ethanol (100 mL) and glacial acetic acid (6.0 mL) is hydrogenated under 55 psi of hydrogen in a Parr apparatus for 24 h. The reaction is filtered through Celite and concentrated in vacuo to a green oil which is treated with water (25 mL) and NaHCO3 (~10 g). The resulting mixture is extracted with CH2Cl2 The combined extracts are dried over MgSO4 and concentrated in vacuo. Chromatography (silica gel, ethyl acetate)of the resultant residue affords the title azaindole compound as a pale pink solid, 2.40 g (68% yield), mp 126-128° C., identified by NMR and mass spectral analyses. |
68% | With palladium 10% on activated carbon; hydrogen; acetic acid In ethanol at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 8h; Heating / reflux; | 38 A mixture of (2-bromopyridin-3-yl) carbamic acid tert-butyl ester (1.09 mg, 4.00 mmol), (trimethylsilyl) acetylene (2.83 mL, 20.0 mmol), Cul (75.8 mg, 0.400 MMOL), and dichlorobis (triphenylphosphine) palladium (II) (141 mg, 0.200 mmol) in a mixture of 12 mL of triethylamine and 3.0 ML of anhydrous DMF were stirred at room temperature overnight. The reaction was diluted with 50 ML OF diethyl ether and quenched with 50 mL of saturated aqueous ammonium chloride solution. The organic layer was washed with 20 mL of saturated aqueous ammonium chloride solution and the combined aqueous layers were extracted with three 20 mL portions of diethyl ether. The combined organic layers were then washed with 20 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SI02 (20% to 30% ethyl acetate in hexanes, gradient) gave 500 mg of (2- trimethylsilanylethynylpyridin-3-yl) carbamic acid ter-butyl ester (43% yield). A mixture of (2-TRIMETHYLSILANYLETHYNYLPYRIDIN-3-YL) carbamic acid tert-butyl ester (500 mg, 1.72 mmol) in 5 mL of THF was treated with TBAF (1 M in THF, 10.3 mL) at room temperature. The mixture was heated at reflux for 8 hours, cooled to room temperature, diluted with 100 mL of diethyl ether, and quenched with 100 mL of water. The aqueous layer was extracted with three 50 mL portions of diethyl ether, and the combined organic layers were washed with 500 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SI02 (100% CH2CI2 to 10% MeOH in CH2C12, gradient) gave 160 mg of the title product as tan solid (79% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With triethylamine; paraformaldehyde In water; butan-1-ol | 1.4 Step 4. Step 4. Preparation of N,N-Dimethyl-(1H-pyrrolo[3,2-b]pyridin-3-yl)methylamine A solution of 4-azaindole (0.880 g, 7.45 mmol), dimethylamine hydrochloride (0.67 g, 8.19 mmol) and paraformaldehyde (0.25 g, 8.19 mmol eq.) in 1-butanol is heated at reflux temperature for 3 h, cooled, concentrated in vacuo, treated with water and saturated aqueous NaHCO3 and extracted with 4:1 CH2Cl2:ethanol. The combined extracts are dried over MgSO4 and concentrated in vacuo. The resultant residue is chromatographed (silica gel, ethyl acetate, followed by 5:95 triethylamine:ethanol as eluent) to afford the title compound as a tan solid, 0.838 g (64% yield), identified by NMR analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; ammonium hydroxide; methyl magnesium iodide; ammonia In 1,4-dioxane; acetonitrile | 2.5 Step 5. Step 5. Preparation of 2-Oxo-2-(1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide A solution of 4-azaindole (1.0 eq.) in ether is treated with methyl magnesium iodide (1.1 eq.) at room temperature, stirred for 1 h, treated with zinc chloride (1.2 eq.), stirred for a further 1 h, treated with oxalyl chloride (10 eq.), stirred for 10 h and concentrated in vacuo to give a residue. The residue is dissolved in acetonitrile and pyridine (1.6 eq.), treated with ammonia (2 eq., solution in dioxane), stirred for 1 h and concentrated in vacuo. The concentrate is purified by chromatography [silica gel, CH2Cl2/methanol (containing 5% ammonium hydroxide) as eluent] to afford the title acetamide compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With water; acetic acid; for 4h;Reflux; | A mixture of 4-azaindole (0.500 g; 4.223 mmol), hexamethylenetetramine (0.890 g; 6.348 mmol) and acetic acid (3.630 mL; 63.45 mmol) in water (9 mL) was refluxed for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of methanol (2% to 4%) in dichloromethane furnished 0.550 g (89%) of 1 /-/-pyrrolo[3,2-£>]pyridine-3-carbaldehyde. ESI/APCI(+): 147 (M+H). ESI/APCI(-): 145 (M-H). |
79% | With water; acetic acid; for 6h;Reflux; | To a stirred mixture of compound (1) (20 g, 169.2 mmol) and hexamethylenetetramine (HMTA) (72 g, 507.8 mmol) in 80 mL acetic acid, 160 mL of H2O and was heated to reflux for 6 hours. After completion of the reaction, the reaction mass was cooled to room temperature, a large number of solid precipitations were filtered and then the filter cake was washed with water and dried to give a white solid. The crude compound obtained was recrystallized from hexane to get the pure compound 3, 19.6 g with 79% in yield. |
56% | With acetic acid; In water; for 4h;Heating / reflux; | A mixture of 1H-pyrrolo[3,2-b]pyridine (947 mg, 8.02 mmol), hexamethylenetetramine (1.7 g, 12 mmol) and acetic acid (7.5 mL) in water (14 mL) was refluxed under N2 for 4 hours. The reaction mixture was cooled to RT, concentrated, and the residue was purified via flash chromatography (DCM/MeOH/NH4OH) affording 1H-Pyrrolo[3,2-b]pyridin-3-carbaldehyde as a white solid (660 mg, 56% yield). |
With water; acetic acid;Inert atmosphere; Reflux; | To a stirred solution containing 1.50 g (12.7 mmol) of 1H-pyrrolo[3,2-b]pyridine in 20 mL of 1:1 AcOH/H2O was added 2.67 g (19.0 mmol) of hexamethylenetetramine (HMTA). The reaction mixture was heated at reflux overnight under argon. The reaction mixture was cooled to 0 C and the formed precipitate was filtered and dried under vacuum. 1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde (12) was obtained as a colorless solid and was used directly in the next step without further purification. To a stirred solution containing 487 mg (3.33 mmol) of 1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde (12) in 20 mL of anhydrous DMF at 0 C was added 119 mg (4.99 mmol) of NaH. The reaction mixture was stirred at 0 C for 10 min under argon and then 954 mg (4.99 mmol) of p-TsCl was added. The reaction mixture was stirred at 0 C under argon for 3 h, diluted with 100 mL of NaHCO3 and extracted with two 50-mL portions of EtOAc. The combined organic phase was dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (10 × 4 cm). Elution with 4:1 hexanes/ethyl acetate gave 1-tosyl-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde (13) as an off-white solid: yield 691 mg (23% for two steps). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap In acetonitrile at 20℃; for 3h; Inert atmosphere; | |
99% | In tetrahydrofuran at 20℃; for 48h; | |
95% | With dmap; triethylamine In dichloromethane at 20℃; | 6.1 To a solution of 1H-pyrrolo[3,2-b]pyridine 6a (2.00 g, 16.9 mmol) in 30 mL dichloromethane was added 4-dimethylaminopyridine (2.06 g, 16.9 mmol), triethylamine (2.05 g, 20.3 mmol) and di-tert-butyl dicarbonate (4.42 g, 20.3 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (20% EtOAc/PE) to give tert-butyl 1H-pyrrolo[3,2-b]pyridine-1-carboxylate 6b (3.5 g, white solid, yield: 95%). MS-ESI calc'd. [M+H]+ 219, found 219. |
In tetrahydrofuran at 23℃; for 17.25h; Inert atmosphere; | 16.A 4-azaindole (50.05 g, 426 mmol) as a red solid was dissolved in tetrahydrofuran(380 ml.) to give a deep red colored solution. The di-te/t butylcarbonate (95.24 g, 430 mmol) was dissolved in tetrahydrofuran (50 ml.) and was slowly added drop-wise by addition funnel over the time of 75 minutes to the solution of the azaindole. The flow rate was approximately 2 mL/min. The lengthy addition was used to regulate the carbon dioxide evolution. The addition caused the color of the reaction mixture to turn lighter and more orange in color. The mixture was stirred for 16 hours at room temperature before the reaction was concentrated to dryness under vacuum. The orange residue solidified to give a 93.84 g of a tan colored solid (MS ES+: 163.2 [M- tBu]). This material was used in the subsequent step without further purification. | |
With dmap; triethylamine In dichloromethane at 20℃; for 16h; | 3 Step 3: Step 3: tert-butyl 1H-pyrrolo[3,2-b]pyridine-1-carboxylate To a stirred solution of the product of Step 2 (1.97 g, 16.7 mmol), and DMAP (2.04 g, 16.7 mmol) in DCM (30 mL) was added TEA (2.33 mL, 16.7 mmol), followed by Boc2O (4.37 g, 20.0 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, diluted with a minimal amount of DCM and purified directly by column chromatography on silica gel, eluting with EtOAc/hexane (7-60%) to give the desired product as a yellow oil that solidified under high vacuum. LRMS (ESI) calc'd for C12H15N2O2 [M+H)+, 219; found 219. 1H NMR (500 MHz, DMSO-D6) δ 8.47 (d, 1H), 8.29 (d, 1H), 7.97 (d, 1H), 7.32 (q, 1H), 6.82 (d, 1H), 1.62 (s, 9H). | |
With dmap In acetonitrile at 20℃; for 3h; | 268.1 Step 1. tert-butyl lH-pyrrolor3.2-blpyridine-l-carboxylate To a stirred solution of lH-pyrrolo[3,2-b]pyridine (10 g, 85 mmol) in ACN (200 niL) were added DMAP (1.034 g, 8.46 mmol) and Boc20 (23.58 mL, 102 mmol) at RT. After the addition was finished, the reaction was stirred at 20 °C and the reaction was monitored by TLC (Petroleum ether/ EtOAc =1 : 1). After stirring at 20 °C for 3 h, the reaction was finished and the solvent was removed. The residue was purified by column chromatography on silica gel (Si02) (eluting with Petroleum ether/ethyl acetate 20: 1 to 10: 1) to give the title compound as a solid. MS (ESI) m/z: 219. [M + H+]. | |
In tetrahydrofuran; dichloromethane at 20℃; for 10h; | 12 Preparation of tert-butyl 1H-pyrrolo[3,2-b]pyridine-1-carboxylate To a mixture of 1H-pyrrolo[3,2-b]pyridine (1.0 g, 9.0 mmol) in THF (30 mL), was added a solution of di-tert-butyl dicarbonate (2.1 g, 9.4 mmol) in DCM (20 mL). The reaction mixture was stirred at RT for 10 h. It was then concentrated in vacuo to give tert-butyl 5- bromoindoline-1-carboxylate as a yellow oil (1.9 g, quantitative yield). LC-MS (ESI): m/z (M+1)+ = 209.23. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a cold solution of 14a,b (2 mmol) in anhydrous toluene (30 mL), potassium t-butoxide (0.31 g, 2.72 mmol) and tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1) (1 or 2 drops) were added. The reaction mixture was stirred at room temperature for 5 h and then iodomethane (0.1 mL, 2 mmol)was added. TLC analysis (dichloromethane) revealed that methylation was complete after 1 h (for compound 14c) or 24 h (for compound 14d). The solvent was evaporated under reduced pressure. The residue was treated with water, extracted with dichloromethane (3 x 20 mL), dried (Na2SO4), evaporated and purified by column chromatography using dichloromethane (for compound 14c) or dichloromethane/ethyl acetate (7/3) (for compound 14d) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: 1H-pyrrolo[3,2-b]pyridine With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: With chloroamine In diethyl ether; N,N-dimethyl-formamide at 20℃; for 3h; Stage #3: With water In diethyl ether; N,N-dimethyl-formamide | 118.1 Example 118; 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxyric acid pyrrolor3,2-b1pyridin-l-vlamide; Step 1 : A solution of pyrrolo[3,2-b]pyridine (1.64 mmol) and potassium tert-butoxide (3.29 mmol) in DMF (7.3 mL) is stirred at rt under N2 for 2 h. 0.15 M NH2CLm ether (16.3 mL) is added drop-wise at rt and the reaction mixture is stirred at rt for 3 h. The reaction mixture is quenched with 5 % Na2S2O3 aqueous solution (10 mL), and extracted with ether. The combined organic layer is washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with EtOAc to afford pyrrolon .2-blpyridin- 1 -ylamine (136 mg, 62%) as a solid. MS: 134 (M+H); 1H NMR (300 MHz, CDCl3): δ 4.89 (br, 2N-H), 6.61 (d, H), 7.16 (m, H), 7.38 (d, H), 7.76 (d, H), 8.47 (d, H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: 1H-pyrrolo[3,2-b]pyridine With sodium hydride Stage #2: benzyl bromide at 60℃; for 12h; | 43 INTERMEDIATE 43 1-BENZYL-1H-PYRROLO[3, 2-b]PYRIDINE INTERMEDIATE 43 [1-BENZYL-LH-PYRROLO] [3, 2-b]p [PYRIDINE] A solution of [LH-PYRROLO] [3, [2-B]] pyridine (1.30 g, 9.42 mmol) in DMF (15 ml) was treated with sodium hydride (60% in mineral oil, 434 mg, 11.3 mmol) at r. t. until effervescence ceased. After cooling to [0°C] benzyl bromide (1.68 ml, 14.1 mmol) was added and the reaction warmed at [60°C] overnight. The reaction mixture was partitioned between water and EtOAc (50 [ML] each) and extracted with EtOAc (50 ml). The combined organics were washed with brine (20 [ML),] dried [(MGS04),] filtered and concentrated in vacuo to give the title compound as a brown oil (1.20 g, 58%). [No.H] (CDC13) 8.39 [(1H,] d, [J4.] 4 Hz), 7.48 [(1H,] d, [J8.] 2 Hz), 7.30 [(1H,] d, J3.1 Hz), 7.26-7. 18 (3H, m), 7.04-6. 69 (3H, m), 6.67 [(1H,] d, J4.4 Hz), 5.11 (2H, s). LCMS [(ES+)] RT 1.56 min, 209 (M+H+). |
Stage #1: 1H-pyrrolo[3,2-b]pyridine With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide Stage #2: benzyl bromide In tetrahydrofuran; N,N-dimethyl-formamide Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: 1H-pyrrolo[3,2-b]pyridine With sodium hydride In dimethyl sulfoxide for 0.25h; Stage #2: benzenesulfonyl chloride for 0.5h; | 1 INTERMEDIATE 1 [1-BENZENESULFONYL-LH-PYRROLO [3, 2-B] PYRIDINE] INTERMEDIATE 1 [1-BENZENESULFONYL-LH-PYRROLO [3, 2-B] PYRIDINE] Sodium hydride (60% in mineral oil, 203 mg, 5.08 mmol) was washed twice with hexane, and the residue suspended in DMSO (5 ml). [LH-PYRROLOR3, 2-B] PYRIDINE (500] mg, 4.24 [RMNOL)] was added and the reaction stirred for 15 minutes. Benzenesulphonyl chloride (749 mg, 4.42 mmol) was added rapidly and the reaction stirred for 0.5 h. After quenching with water the product was extracted into EtOAc, dried [(NA2S04)] and concentrated in vacuo. Chromatography (EtOAc, silica) yielded the title compound as a white crystalline solid (903 mg, 83%). aH [(D6-DMSO)] 8.48 [(1H,] dd, [J0.] 8,3. 8 Hz), 8.31 (1H, m), 8.15 [(1H,] d, [J3.] 8 Hz), 8.04 (2H, m), 7.72 [(1H,] m, ), 7.61 (2H, m, ), 7. [36] [(1H, DD,] [J4.] 7,8. [4 HZ),] 6.98 [(LX DD, J0.] 8,3. 8 Hz). LCMS [(ES+)] [RT 3. 056 MINUTES,] 259 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 72h; | 47.1 Into a 1000 ml roundbottom flask, was placed 1H-pyrrolo[3,2-b]pyridine (15 g, 127.12 mmol, 1.00 equiv). To this was added mCPBA (39 g, 192.73 mmol, 1.50 equiv, 85%). To the mixture was added DCM (700 g). The resulting solution was allowed to react, with stirring, for 3 days while the temperature was maintained at room temperature. The residue was purified by eluting through a column with a 20:1 CH2C12/MeOH solvent system. The collected fractions were combined and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 17 g (100%) of 1H-pyrrolo[3,2-b]pyridine 4- oxide as a yellow solid. |
88% | With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; | 420.A Part A. JH-pyrrolo[3, 2-b]pyridine 4-oxide To a solution of 1H-pyrrolo[3,2-bjpyridine (0.85 g, 7.20 mmol) in DCM (20 mL) at 0 °C, was added rn-CPBA (2.71 g, 8.63 mmol) and the mixture was stirred overnight at RT. The solution was warmed to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% methanol in dichloromethane) to afford 1H-pyrrolo[3,2-bjpyridine 4-oxide (0.85 g,6.34 mmol, 88% yield) as a yellow solid, ‘H NMR (300 MI-Tz, DMSO-d6): ö 11.79 (bs, 1H), 8.03 (dd, J6.04, 0.76 Hz, 1H), 7.55 - 7.62 (m, 1H), 7.45 (d, J=7.93 Hz, 1H), 7.08 (dd, J=8.31, 6.04 Hz, 1H), 6.63 - 6.69 (m, 1H), ppm. |
70% | With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 16h; Inert atmosphere; |
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; Inert atmosphere; | 1 (1) Intermediate 5: 1H-Pyrrolo[3,2-b]pyridine 4-oxide To a mixture of 1H-pyrrolo[3,2-b]pyridine (25 g) in DCM (885 mL) stirred at rt under nitrogen was added a suspension of m-chloroperbenzoic acid (54.8 g) in DCM (885 mL). The reaction was stirred at rt overnight, at which point LC-MS indicated completion. The crude reaction was filtered and the residue was stirred as a slurry in Et2O (1 L) for 30 min, then filtered. The residue was again stirred as a slurry in 1 L Et2O and filtered. The residue was dried under vacuum to give the title compound, (27.9 g) which still contained traces of m-chlorobenzoic acid, but was used without further purification. LCMS: m/z 135.43 [M+H]+. 1H NMR (400 MHz, CD3OD) ppm 6.87 (d, J=3.2 Hz, 1H) 7.23-7.32 (m, 1H) 7.69 (s, 1H) 7.77 (d, J=8.3 Hz, 1H) 8.21 (d, J=6.4 Hz, 1H). |
|
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; Inert atmosphere; | 13.1 (1) Intermediate 5: 1H-Pyrrolo[3,2-b]pyridine 4-oxide To a mixture of 1H-pyrrolo[3,2-b]pyridine (25 g) in DCM (885 mL) stirred at rt under nitrogen was added a suspension of m-chloroperbenzoic acid (54.8 g) in DCM (885 mL). The reaction was stirred at rt overnight, at which point LC-MS indicated completion. The crude reaction was filtered and the residue was stirred as a slurry in Et2O (1 L) for 30 min, then filtered. The residue was again stirred as a slurry in 1 L Et2O and filtered. The residue was dried under vacuum to give the title compound, (27.9 g) which still contained traces of m-chlorobenzoic acid, but was used without further purification. LCMS: m/z 135.43 [M+H]+. 1H NMR (400 MHz, CD3OD) ppm 6.87 (d, J=3.2 Hz, 1H) 7.23-7.32 (m, 1H) 7.69 (s, 1H) 7.77 (d, J=8.3 Hz, 1H) 8.21 (d, J=6.4 Hz, 1H). |
|
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 16h; | 2.2B.2B.16 To a solution of 1H-pyrrolo[3,2-b]pyridine (1, 2.5 g, 21 mmol) in DCM (75 mL) at 0 °C is slowly added m-CPBA (5.69 g, 25.4 mmol). The mixture is stirred from 0 °C to rt. After 16 h the reaction is complete as judged by TLC (SiO2, 10 % MeOH/DCM). The mixture is concentrated and the residue purified by column chromatography (SiO2, 0-20 % MeOH/DCM). The product is isolated as a mixture with m-CBA (ratio ca.1:0.7 by 1H-NMR). The so-obtained material 1H-pyrrolo[3,2-b]pyridine 4-oxide (2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: 1H-pyrrolo[3,2-b]pyridine With sulfuric acid; nitric acid at 0℃; for 2h; Stage #2: With sodium hydroxide In water | II.29.2 2. Synthesis of 3-nitro-1H-pyrrolo[3,2-b]pyridine; Nitric acid (286 mmol) is added to a cold (0° C.) solution of 1H-pyrrolo[3,2-b]pyridine (254 mmol) in sulfuric acid (120 mL) and the reaction mixture is maintained for 2 h at 0° C. The reaction mixture is diluted with ice water (300 mL) and the pH is adjusted to 7-8 with 2 M sodium hydroxide. The precipitated solids are collected by filtration and dried to provide 3-nitro-1H-pyrrolo[3,2-b]pyridine in 89% yield as a yellow solid. |
89% | Stage #1: 1H-pyrrolo[3,2-b]pyridine With sulfuric acid; nitric acid at 0℃; for 2h; Stage #2: With sodium hydroxide In water | 46.2 2. Synthesis of 3-nitro-l//-pyrrolo[3,2-blpyridine.Nitric acid (286 mmol) is added to a cold (0 0C) solution of lH-pyrrolo[3,2-b]pyridine (254 mmol) in sulfuric acid (120 mL) and the reaction mixture is maintained for 2 h at 0 0C. The reaction mixture is diluted with ice water (300 mL) and the pH is adjusted to 7-8 with 2 M sodium hydroxide. The precipitated solids are collected by filtration and dried to provide 3-nitro-lH- pyrrolo[3,2-b]pyridine in 89% yield as a yellow solid. |
80% | With sulfuric acid at 0℃; for 4h; | 1 1. Synthesis of 3-nitro-l//-pyrrolo[3,2-b] pyridine lH-pyrrolo[3,2-b]pyridine (10 g, 84.7 mmol, 1.0 equiv) was dissolved in cone. H2SO4 (40 mL). KNO3 (10.3 g, 101.6 mmol, 1.2 equiv) was added in several portions at 0°C and stirred for 4 hours at 0 °C. After completion of the reaction, pH of the resulting solution was adjusted to 8.0 by dropwise addition of NaOH (1 mol/L) solution. The solid was collected by filtration and washed with water (200 mL x 5). 3-Nitro-lH-pyrrolo[3,2- bjpyridine (11 g, 80%) was obtained as a dark solid. LCMS: Method A, MS-ESI, 164.1 [M+H+] |
80% | With sulfuric acid; potassium nitrate at 0℃; for 4h; | 2 Synthesis of 3-nitro-1H-pyrrolo[3,2-b]pyridine 1H-pyrrolo[3,2-b]pyridine (10 g, 84.7 mmol, 1.0 equiv) was dissolved in conc. H2SO4 (40 mL). KNO3 (10.3 g, 101.6 mmol, 1.2 equiv) was added in several portions at 0°C. Upon stirring 4 hours at 0°C, the resulting solution pH was adjusted to 8 by dropwise adding NaOH (1 mol/L) solution. The solid was collected by filtration and washed with water (200mLx5).3-Nitro-1H-pyrrolo[3,2-b]pyridine(11g, 80%) was obtained as a dark solid. |
43.4% | With sulfuric acid; nitric acid at -10℃; for 5h; Inert atmosphere; | 25b 3-Nitro-1H-pyrrolo[3,2-b ]pyridine (25b) [0316] To a solution of compound 1 (5 g, 0.042 moles) incon.H2S04 (50 mL), con.HN03 (3 mL, 0.063 mole) wasadded at -1 oo C. At this temperature the reaction mixture wasstirred for 5 h. Then the mixture was poured into ice coldwater (100 mL), neutralized with aq. NaOH (10%) andextracted with ethylacetate (2x100 mL). The combinedorganic layer was washed with brine and the solvent wasevaporated under reduced pressure to yield 3-Nitro-1H-pyrrolo[3,2-b ]pyridine (25b) 3 g ( 43.4% ). |
Stage #1: 1H-pyrrolo[3,2-b]pyridine With sulfuric acid; nitric acid at 0 - 5℃; for 2h; Stage #2: With sodium hydrogencarbonate In water | 50.1 Into a 50 mL 3-necked roundbottom flask, was placed 1H-pyrrolo[3,2-b]pyridine (1 g, 8.47 mmol, 1.00 equiv) The temperature was cooled to 0 °C. To this was added H2SO4 (10 mL). To the mixture was added HNO3/H2SO4 (800 mg, 12.70 mmol, 1.50 equiv). The resulting solution was allowed to react, with stirring, for 2 hours while the temperature was maintained at 0-5 °C. The resulting solution was diluted with 500 mL of H2O/ice. Adjustment of the pH to 8 was accomplished by the addition ofNaHCO3. A filtration was performed and the filtrate cake washed with H2O. The solid was dried in an oven under 100 °C. | |
With sulfuric acid; potassium nitrate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: 1H-pyrrolo[3,2-b]pyridine With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.5h; Stage #2: p-toluenesulfonyl chloride In tetrahydrofuran; mineral oil at 0 - 20℃; for 4h; | Reaction step 1. Synthe [3, 2-b] pyridine Reaction step 1. Synthe [3, 2-b] pyridineTo a solution of NaH (60% suspension in mineral oil, 10.2 g, 254 mmol, 1.5 eq) in THF (200 mL), at 0 C, 1H-pyrrolo[3, 2-b]pyridine (20.0 g, 170 mmol, 1eq) was slowly added and the mixture was stirred at room temperature for 30 min. The mixture was again cooled to 0 C and a solution of p-TsCl (38.6 g, 204 mmol, 1.2 eq) in THF (100 mL) was added slowly at 0 C. Stirring was continued for 4 h at room temperature. After completion of the reaction (monitored by TLC, 50% ethyl acetate-hexane, Rf = 0.45), the reaction was quenched by adding ice cubes and was extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1-tosyl-1H- pyrrolo[3,2-b] pyridine (42.0 g, 91%) as a brown solid. LCMS purity: 99.67%; (ES+): m/z 273.02 (M+H+); tr =1.83 min. |
90% | With dmap; tetra(n-butyl)ammonium hydrogen sulfate; triethylamine In dichloromethane at 20℃; for 26h; | |
Stage #1: 1H-pyrrolo[3,2-b]pyridine With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: p-toluenesulfonyl chloride In tetrahydrofuran at 20℃; for 3.5h; | 46.1 Into a 1000 ml 3-necked roundbottom flask, was placed a solution of NaH (5.6 g, 140 mmol, 1.10 equiv, 60%) in THF (300 mL). To the above was added 1H-pyrrolo[3,2-b]pyridine (15 g, 127.12 mmol, 1.00 equiv) in several batches, while cooling to a temperature of O°C over a time period of 30 minutes. This was followed by the addition of a solution of 4-methylbenzene-1-sulfonyl chloride (24 g, 125.65 mmol, 1.00 equiv) in THF (200 mL). The resulting solution was allowed to react, with stirring, for 3.5 hours while the temperature was maintained at room temperature. The reaction mixture was then quenched by the adding 300 ml of H2O.The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The resulting solution was extracted three times with 300 ml of EtOAc and the organic layers combined and dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 35 g (crude) of l-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[3,2- b]pyridine as a yellow solid. |
Stage #1: 1H-pyrrolo[3,2-b]pyridine With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1.16667h; Inert atmosphere; Stage #2: p-toluenesulfonyl chloride In tetrahydrofuran for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With copper(l) iodide; caesium carbonate In N,N-dimethyl-formamide at 120℃; for 48h; Inert atmosphere; | 11 4.5 General procedure for N-arylation General procedure: To a solution of heteroaromatic compound (8.0mmol), copper iodide (20mol%), and cesium carbonate (11mmol) in DMF (11mL) was added aryl bromide (5.7mmol) under argon atmosphere, and the reaction mixture was stirred at room temperature for 30min prior to being refluxed for 48h. The reaction mixture was cooled down to room temperature and diluted with ethyl acetate. The subsequent mixture was filtered through a pad of silica gel. The filtrate was concentrated to give a residue, which was subjected to preparative thin layer chromatography eluting with 50% ethyl acetate in hexane. |
52% | With C24H22N6Ni; sodium t-butanolate In N,N-dimethyl-formamide; acetonitrile at 30℃; for 24h; Inert atmosphere; Schlenk technique; | |
28% | With copper(l) iodide; 8-quinolinol; potassium carbonate In dimethyl sulfoxide at 130℃; |
With potassium carbonate In dimethyl sulfoxide at 130℃; for 3h; | 1.1 To a mixture of 4-azaindole (1.20 g, 10.2 mmol), copper(l) iodide (290 mg, 1.53 mmol), 8-hydroxyquinoline (221 mg, 1.53 mmol) and potassium carbonate (1.55 g, 11.2 mmol) in DMSO (24 ml) was added iodobenzene (1.25 ml, 11.2 mmol). The reaction mixture was stirred at 130 0C for 3 h. The mixture was then cooled to room temperature and a solution of ammonium hydroxide (10 % in water) and EA were added. The organic layer was separated, washed twice with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. Column chromatography on silica gel (EA/HEP) gave 560 mg of the title compound. LC/MS (method LC4): m/z = 195 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: pyrrolo<3,2-b>pyridine With sodium hydride In tetrahydrofuran Stage #2: benzenesulfonyl chloride In tetrahydrofuran at 20℃; | 108 Preparation 108: l-(Benzenesulfonyl)pyrrolo[3,2-b]pyridine; [1033] Sodium hydride (0.74g, 16.9mmol) was dissolved in 3OmL of anhydrous tetrahy- drofuran. lH-pyrrolo[3,2-b]pyridine (Ig, 8.46mmol) dissolved in 1OmL of anhydrous tetrahydrofuran was slowly added in drops, and the mixture was stirred for 30 min. Benzenesulfonyl chloride (3g, 16.9mmol) dissolved in 1OmL of anhydrous tetrahydrofuran was slowly added in drops, and the mixture was stirred for 15 h at room temperature. The reaction solution was poured to 0.1 N hydrochloric acid, which was then controlled to basic using aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was collected, and distilled under reduced pressure. The remaining substance was purified by column chromatography to give 2.06g (8mmol, Yield 94%) of the title compound.[1034] NMR 1H-NMR(CDCl3) δ 8.54(1H, d), 8.27(1H, d), 7.87(2H, d), 7.80(1H, d), 7.57(1H, t), 7.47(2H, t), 7.24(1H, dd), 6.88(1H, d)[1035] Mass(EI): 259(M++1) |
90% | With sodium hydride In tetrahydrofuran at 20℃; for 2h; | |
57.7% | Stage #1: pyrrolo<3,2-b>pyridine With sodium hydride In tetrahydrofuran; mineral oil for 0.5h; Inert atmosphere; Stage #2: benzenesulfonyl chloride In tetrahydrofuran; mineral oil at 20℃; for 4.25h; | 2.1 Synthesis of Step 1 : 1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine Under nitrogen protection,Sodium hydride (mass fraction 60%, 0.8 g, 20 mmol, 2.0 eq) was added portion wise to dry THF (30 mL).1H-pyrrolo[3,2-b]pyridine (1.19 g, 10 mmol, 1.0 eq) was dissolved in dry THF (10 mL) and slowly added dropwise to the system.After the drop,The reaction was kept for 30 minutes.Phenylsulfonyl chloride (3.5 g, 20 mmol, 2.0 eq) was dissolved in THF (10 mL).It was slowly added dropwise to the system, and the addition was completed in 15 minutes, and the reaction was carried out at room temperature for 4 hours. The reaction was completed by LC-MS. The reaction was quenched by dropwise addition of 0.1 mol/L aqueous HCl solution (20 mL), water (30 mL), EA (50 mL×2), the organic phase was combined, washed with brine, dried and concentrated Column chromatography gave the product as a white solid (1.5 g, yield: 57.7%). |
With triethylamine In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: 1H-pyrrolo[3,2-b]pyridine With aluminum (III) chloride In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: Ethyl oxalyl chloride In dichloromethane | 12.e Aluminium chloride (3.1 g, 23 mmol) and 4-azaindole (0.38 g, 4.6 mmol) were stirred in 100 ml dry dichloromethane at room temperature under nitrogen atmosphere. After 30 min ethoxalylchloride (2.5 ml, 3.0 g, 23 mmol) was added dropwise. The reaction mixture was stirred over night and then carefully hydro lyzed with ethanol/ice. After addition of dichloromethane the organic layer was separated, washed with NaHC03 solution, dried over Na2SC>4, filtered and concentrated. After sitting over night ethyl-2-(4-azaindol-3-yl)-2-oxoacetate (0.5 g, 2.3 mmol, 50 %) crystallized as a pale yellow powder. 1H NMR (300 MHz, CDC13) 12.21 (bs; IH; NH); 8.58 (s; IH; H-2); 8.49 (pdd; 3J = 4.6 Hz; 4 J = 1.3 Hz; IH; H-5); 7.93 (pdd; 3J = 8.2 Hz; 4J = 1.3 Hz; IH; H-7); 7.27 (pdd; 3J = 8.2 Hz; J = 4.6 Hz; IH; H-6); 4.37 (q; 3J = 7.1 Hz; 2H; CH2); 1.31 (t; 3J = 7.1 Hz; 3H; CH3). |
50% | Stage #1: 1H-pyrrolo[3,2-b]pyridine With aluminum (III) chloride In dichloromethane at 0℃; for 0.5h; Inert atmosphere; Stage #2: Ethyl oxalyl chloride In dichloromethane at 0 - 20℃; Inert atmosphere; | |
50% | Stage #1: 1H-pyrrolo[3,2-b]pyridine With aluminum (III) chloride In dichloromethane for 0.5h; Inert atmosphere; Stage #2: Ethyl oxalyl chloride In dichloromethane | E.e (e) (e) Ethyl-2-(4-azaindol-3-yl)-2-oxoacetate Aluminium chloride (3.1 g, 23 mmol) and 4-azaindole (0.38 g, 4.6 mmol) were stirred in 100 ml dry dichloromethane at room temperature under nitrogen atmosphere. After 30 min ethoxalylchloride (2.5 ml, 3.0 g, 23 mmol) was added dropwise. The reaction mixture was stirred over night and then carefully hydrolyzed with ethanol/ice. After addition of dichloromethane the organic layer was separated, washed with NaHCO3 solution, dried over Na2SO4, filtered and concentrated. After sitting over night ethyl-2-(4-azaindol-3-yl)-2-oxoacetate (0.5 g, 2.3 mmol, 50 %) crystallized as a pale yellow powder. H NMR (300 MHz, CDCl3) 12.21 (bs; 1H; NH); 8.58 (s; 1H; H-2); 8.49 (pdd; 3J = 4.6 Hz; 4J = 1.3 Hz; 1H; H-5); 7.93 (pdd; 3J = 8.2 Hz; 4J = 1.3 Hz; 1H; H-7); 7.27 (pdd; 3J = 8.2 Hz; 3J = 4.6 Hz; 1H; H-6); 4.37 (q; 3J = 7.1 Hz; 2H; CH2); 1.31 (t; 3J = 7.1 Hz; 3H; CH3). |
32% | In dichloromethane at 20℃; for 16h; | 1 A solution of ethyl 2-chloro-2-oxoacetate (631 mmol) in dichloromethane (200 mL) was added dropwise to a mixture of 1H-pyrrolo[3,2-b]pyridine (212 mmol) and aluminum chloride (639 mmol) in dichloromethane (1.50 L) and the reaction mixture was maintained for 16 h at rt. The reaction mixture was then quenched with ethanol, filtered, and concentrated. The residue was purified by Flash chromatography (5/1 ethyl acetate/methanol) to provide ethyl 2-oxo-2-(1H-pyrrolo[3,2-b]pyridin-3-yl)acetate in 32% yield as a brown solid. |
7.6% | Stage #1: 1H-pyrrolo[3,2-b]pyridine With aluminum (III) chloride In dichloromethane at 0℃; for 0.5h; Inert atmosphere; Stage #2: Ethyl oxalyl chloride In dichloromethane at 20℃; | 1 Step 1: Azaindole (2.0 g, 16.93 mmol) was added to aluminum chloride (11.29 g, 85 mmol) in dry dichloromethane (85 mL) at 0 °C under argon atmosphere. After 30 mm ato °C, the mixture was warmed to room temperature and ethyl chlorooxoacetate (11.56 g,85 mmol) was added dropwise. The reaction mixture was stirred vigorously forovernight, then carefully ice was added. Adjust pH to 7 with 4 N NaOH then cold sat.NaHCO3 solution. The product was extracted with DCM 3 times, dried over Na2SO4,filtered, and concentrated to afford ethyl 2-oxo-2-(1H-pyrrolo[3,2-bjpyridin-3-yl)acetateas a yellow oily residue. After a washing with cold petroleum ether the title compound was obtained as a light yellow powder 280 mg (7.6%). ESI-MS(-): MS m/z 217.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: 1H-pyrrolo[3,2-b]pyridine With aluminum (III) chloride In dichloromethane at 20℃; for 1h; Stage #2: (R)-ethyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylate In dichloromethane at 0 - 20℃; | II.29.a.3 3. Aluminum chloride (707 mmol) was added to a solution of 1H-pyrrolo[3,2-b]pyridine (169 mmol) in dichloromethane (500 mL) and the reaction mixture was maintained at rt for 60 min. The reaction mixture was cooled at 0° C. and a solution of (R)-ethyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylate (527 mmol) in dichloromethane (150 L) was added dropwise over 40 min. The reaction mixture was allowed to warm to rt and was maintained for 16 h. Methanol (200 mL) was added to quench the reaction and the reaction mixture was concentrated. The residue was purified by Flash chromatography (100/1 to 10/1 dichloromethane/methanol) to provide (R)-ethyl 2-(1H-pyrrolo[3,2-b]pyridine-3-carbonyl)pyrrolidine-1-carboxylate in 64% yield as brown oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With tris-(dibenzylideneacetone)dipalladium(0); 1,10-Phenanthroline; carbon monoxide In acetonitrile at 120℃; for 42h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium hydroxide In methanol Reflux; Inert atmosphere; Schlenk technique; | Step1:3-(1,4-Dioxaspiro[4.5]dec-7-en-8-yl)-1H-pyrrolo[3,2-b]pyridine: To a stirredsolution of 1H-pyrrolo[3,2-b]pyridine(1.0 g, 8.47 mmol) and 1,4-dioxaspiro[4.5]decan-8-one (1.32 g, 8.47)in methanol (15 ml) was added potassium hydroxide (1.42 g, 25.41mmol) and the mixture was refluxed overnight. The reaction mixturewas cooled to room temperature and poured into ice-cold water (50ml). The solid precipitated out was filtered and washed with water.The solid was dried in air oven to yield 1.82 g (84%) of product as awhite solid. 1HNMR (300 MHz, CDCl3)1.98 (t, J= 6.3 Hz, 2H), 2.57 (br s, 2H), 2.70-2.78 (m, 2H), 4.03 (s, 4H),7.05-7.15 (m, 1H), 7.36 (d, J= 2.4 Hz, 1H), 7.62 (d, J= 8.4 Hz, 1H), 8.17 (br s, 1H), 8.51 (d, J= 3.3 Hz, 1H); ESI-MS(m/z)257 (M+H)+. |
With potassium hydroxide In methanol for 4h; Reflux; | 1 Intermediate 48: Synthesis of 3-(4-azetidin-l-ylcyclohex-l-en-l-yl)-li/-pyrrolo[3,2- b] pyridine1. Synthesis of 3-(l,4-dioxaspiro[4.51dec-7-en-8-yl)-lH-pyrrolo[3,2-blpyridine.Potassium hydroxide (41.0 mmol) was added to a mixture of 4-azaindole (13.5 mmol) and 1 ,4-cyclohexanedione monoethylene acetal (13.5 mmol) in methanol (30 mL) and the reaction mixture was heated at reflux for 4h. The reaction mixture was diluted with ice water(200 mL) and the precipitated solids were collected by filtration, washed with water, and air dried. The residue was purified by Flash chromatography (70/30 to 50/50 hexane/ethyl acetate) to provide 3-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-lH-pyrrolo[3,2-b]pyridine. Data: 1H NMR (CDCl3) 6 8.51 (dd, J= 4.7, 1.4, IH), 8.15 (br, IH), 7.63 (dd, J= 8.2, 1.4, IH), 7.36 (s, IH), 7.15(m, IH), 7.11 (dd, J = 8.2, 4.7, IH), 4.03 (s, 4H), 2.8-2.6 (m, 2H), 2.6-2.4 (m, 2H), 1.8-2.2 (m,2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium hydroxide In methanol for 16h; Reflux; | II. Indole PreparationsIntermediate 45: Synthesis of tørf-butyl [4-(lH-pyrroIo[3,2-b]pyridin-3-yl)cyclohex-3-en-l- yl] carbamate. Potassium hydroxide (41.0 mmol) was added to a mixture of 4-azaindole (13.5 mmol) and 1,1 -dimethyl ethyl (4-oxocyclohexyl)carbamate (1.35 mmol) in methanol (30 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was diluted with ice water (200 mL) and the precipitated solids were collected by filtration, washed with water, and air dried. The residue was purified by Flash chromatography (70/30 to 50/50 hexane/ethyl acetate) to provide tert-butyl [4-(lH-pyrrolo[3,2-b]pyridin-3-yl)cycl ohex-3 -en- 1-yl] carbamate in 52% yield. Data: 1H NMR (CDCl3) δ 8.75 (br, IH), 8.52 (dd, J = 4.6, 1.3, IH), 7.64 (dd, J= 8.2, 1.3, IH), 7.36 (s, IH), 7.18 (m, IH), 7.12 (dd, J= 8.2, 4.6, IH), 4.7 (m, IH), 3.9 (m, IH), 2.8-2.5 (m, 3H), 2.3-2.1 (m, IH), 2.1-2.0 (m, IH), 1.6-1.8 (m, IH), 1.47 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Example 2 4-Azaindole[00146] Referring now to the Scheme 1 as shown in Fig. 1 , a solution of 4.789g(22.99 mmol) of boc-3-amino-2-methylpyridine in 70 ml. of anhydrous tetrahydrofuran hexane was placed in a 250 ml. three-neck round-bottom flask equipped with a magnetic stirrer, thermocouple, nitrogen bleed, and cooling acetone/dry ice bath. A solution of n- butyl lithium (2.5M in hexane, 20.2 ml_, 50.5 mmol, 2.2 eq.) was slowly introduced into a flask at -150C within 10 min. The resulting yellow suspension was slowly brought to O0C and stirred for additional 50 minutes at this temperature. A total of 2.36g (32.28 mmol, 1.4 eq.) of DMF was added in one portion, and reaction mixture was allowed to warm up to room temperature. The reaction was quenched by slow addition to the 50 ml. of cold 6N HCI following by heating to 450C for 1 hour. The reaction was cooled to room temperature and pH was brought to 1 1 with 5Lambda/ NaOH. Resulting red-colored mixture was extracted with ethyl acetate (3 x 80 ml_), organic phase dried over Na2SO4 and concentrated on rotavap to give 2.8g of red oil. Obtained crude material was purified on CombiFlash (12Og column, ethyl acetate/methanol) to give 1.1 g (40% yield) of 4- azaindole as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-iodo-succinimide; In tetrahydrofuran; at 20℃; | To a solution of lH-pyrrolo[3,2-b]pyridine (1.94 g, 16.4 mmol) in THF (10 mL) is added N- iodosuccimide (4.06 g, 18.1 mmol). Preciptation occurs after a few minutes. The reaction is continued to stri at rt overnight. The preciptate is collected by filtration and is washed with a smalll amount of THF and heptane. The resultin white solid is dried in vacuo. The yeild of the reaction is 4.1 g (quantitative). 1H NMR (OMSO-d6, 300 MHz) delta 8.40 (s, 1H), 7.90-7.70 (m, 2H), 7.15 (d, 1H). LC 0.41 min; MS m/z 245 (M+l). |
93.5% | With N-iodo-succinimide; In tetrahydrofuran; at 20℃; | To a solution of lH-pyrrolo[3,2-b]pyridine (3.0 g, 25.4 mmol, 1.0 eq) in THF (20 mL) was added NIS (6.3 g, 27.9 mmol, 1.1 eq). Precipitation occurred after a few minutes. The stirring was continued at rt overnight. The precipitate was collected by filtration and washed with a small amount of THF. The resulting solid was dried in vacuum to give 3- iodo-lH-pyrrolo[3,2-b]pyridine (5.8 g, 93.5%). |
9.18 g | With iodine; potassium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 1.08333h;Inert atmosphere; | To a mixture of 1H-pyrrolo[3,2-b]pyridine (Purchased from Combi Blocks Inc.), (5 g) and DMF (100 mL) stirred under nitrogen at room temperature was added potassium hydroxide (9.02 g) followed by iodine (12.89 g) and the resulting mixture was stirred at room temperature for 1 h 5 min., then poured onto a mixture of Na2S2O5.5H2O (4.25 g), water (635 mL), and 28-30% ammonium hydroxide (43 mL). The resultant mixture was cooled in an ice bath for 20 min, and the precipitate thus produced was filtered and washed with ice water then dried under vacuum to give the title compound (9.18 g). LCMS: m/z 245.39 [M+H]+. 1H NMR (400 MHz, DMSO-d6) ppm 7.17 (dd, J=8.1, 4.5 Hz, 1H) 7.72-7.87 (m, 2H) 8.38 (d, J=4.4 Hz, 1H) 11.74 (br. s., 1H) |
9.18 g | With iodine; potassium hydroxide; In N,N-dimethyl-formamide; at 20℃; for 1.08333h;Inert atmosphere; | To a mixture of 1H-pyrrolo[3,2-b]pyridine (Purchased from Combi Blocks Inc.), (5 g) and DMF (100 mL) stirred under nitrogen at room temperature was added potassium hydroxide (9.02 g) followed by iodine (12.89 g) and the resulting mixture was stirred at room temperature for 1 h 5 min., then poured onto a mixture of Na2S2O5.5H2O (4.25 g), water (635 mL), and 28-30% ammonium hydroxide (43 mL). The resultant mixture was cooled in an ice bath for 20 min, and the precipitate thus produced was filtered and washed with ice water then dried under vacuum to give the title compound (9.18 g). LCMS: m/z 245.39 [M+H]+. 1H NMR (400 MHz, DMSO-d6) ppm 7.17 (dd, J=8.1, 4.5 Hz, 1H) 7.72-7.87 (m, 2H) 8.38 (d, J=4.4 Hz, 1H) 11.74 (br. s., 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | Stage #1: 1H-pyrrolo[3,2-b]pyridine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Stage #2: Bromodiphenylmethane In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; | 1.A PREPARATION 1; Synthesis of 1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1 ,4-benzodioxin-6-yl)-1 ,3- dihydro-2H-pyrrolo[3,2-ib]pyridin-2-one; A. Synthesis of 1-(diphenylmethyl)-1/-/-pyrrolor3,2-lpyridine; To a solution of 1H-pyrrolo[3,2-b]pyridine (10.0 g, 84.7 mmol) in N1N- dimethylformamide (100 ml.) was added sodium hydride (60% w/w dispersion in mineral oil, 2.24 g, 65.3 mmol) in small portions at 0 0C. The reaction mixture was stirred at ambient temperature for 1 h and a solution of bromodiphenylmethane (22.0 g, 88.9 mmol) in Λ/,Λ/-dimethylformamide (50 mL) was added dropwise at 0 °C. The reaction mixture was stirred at ambient temperature for 17 h and water (400 mL) was added at 0 °C. The mixture was filtered and the filter cake was washed with ethyl acetate (3 x 100 mL). The filtrate was transferred to a separatory funnel and the aqueous layer was extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography, and eluted with a 10% to 50% gradient of ethyl acetate in petroleum ether to afford 1-(diphenylmethyl)-1/-/-pyrrolo[3,2-b]pyridine (4.70 g, 20%) as a colorless solid: 1H NMR (400 MHz, CD3OD) £8.30-8.29 (m, 1 H), 7.70 (d, J = 6.3 Hz, 1 H), 7.37-7.04 (m, 13H), 6.62 (d, J = 2.4 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With borane-THF; In tetrahydrofuran; for 5.0h;Reflux; | 2.3-Dihvdro-lH-pyrrolor3.2-blpyridine (1-1) To a solution of lH-pyrrolo[3,2-b]pyridine (1.18 g, 10 mmol) in 100 mL of THF, was added borane tetrahydrofuran complex (60 mL of a 1 M solution, 6 eq) and the mixture was heated at reflux for 5h. After allowing the reaction to cool down to room temperature, water was added slowly and the solution was extracted with ethyl acetate twice. The combined extracts were washed with a saturated solution of sodium bicarbonate, dried over sodium sulfate and evaporated. The residue was purified on silica gel (eluent: 15% methanol in DCM) to give 0.17 g of 2,3-dihydro-lH-pyrrolo[3,2- b]pyridine 1-1. | |
With diborane; In tetrahydrofuran; for 6.0h;Reflux; | To a solution of 23a1 (Matrix, 8 g, 68 mmol) in anhydrous THF (68 ml), a 1M solution of BH3 inTHF (41 0 ml, 410 mmol) is added over the period of 15 min at RT. This mixture is stirred underreflux for 6 h. After cooling to RT, the reaction mixture is neutralized with addition of MeOH andconcentrated under reduced pressure. The residue is dissolved in MeOH and refluxedovernight. The mixture is concentrated. The residue is dissolved in EtOAc, washed with waterand brine, and dried over Na2S04. After filtration and evaporation of the solvent, the crudematerial is purified by flash column chromatography (silica gel 230-400 mesh; 0-3% gradient ofMeOH in EtOAc) to provide 23a2. | |
0.18 g | With hydrogen; In ethanol; water; at 95℃; under 75007.5 Torr; for 41.0h;Inert atmosphere; Autoclave; | 1.49 g of Raney nickel at 50% in water are added to a solution of 1.5 g of 4-azaindole in 45 ml of absolute ethanol, in an autoclave under argon. The mixture is hydrogenated under 100 bar of hydrogen at a temperature of 95 C. for 41 h. After a return to ambient temperature, the catalyst is filtered off through Clarcel and the filtrate is concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 70 g 15-40 mum silica cartridge, elution being carried out with pure dichloromethane and then with a 99/1 v/v mixture of dichloromethanemethanol with a flow rate of 80 ml/min, and then on a 30 g 15-40 mum silica cartridge, elution being carried out with pure dichloromethane with a flow rate of 30 ml/min. 0.18 g of 4-azaindoline is thus obtained in the form of a pale yellow solid which melts at 63 C. (Kofler bench). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In butan-1-ol for 3h; Reflux; | |
In water; butan-1-ol for 3h; Reflux; | 8.1 Step 1: N,N-Dimethyl-l-(lH-pyrrolo[3,2-b]pyridin-3-yl)methanamine (44) Step 1: N,N-Dimethyl-l-(lH-pyrrolo[3,2-b]pyridin-3-yl)methanamine (44) [00651] To a solution of 1,4-azaindole (8.7 g, 1.0 eq.) in n-butanol (100 niL) was added formaldehyde (6.6 g. 37% in water, 1.1 eq.) and dimethylamine hydrochloride salt (6.6 g, 1.1 eq.). The resulting mixture was heated at reflux for 3h. The mixture was cooled and the solvent was removed in vacuo. The mixture was diluted with 100 mL ethyl acetate, washed with saturated NaHC03, water and brine, dried over Na2S04 and concentrated in vacuo to provide compound 44 (13 g) which was used without further purification. | |
In water; butan-1-ol at 120℃; for 3h; | 17.1 Step 1 : N,N-Dimethyl-1-(1H-pyrrolo[3,2-6]pyridin-3-yl)methanamine To a solution of 1H-pyrrolo[3,2-b]pyridine (500 mg, 4.23 mmol, 1 eq) in n-BuOH (5 mL) was added HCHO (377.65 mg, 4.65 mmol, 346.47 uL, 37% in water, 1.1 eq) and N- methylmethanamine (379.43 mg, 4.65 mmol, 1.1 eq, HC1 salt). The mixture was stirred at 120 °C for 3 h. LC-MS showed starting material was consumed completely and one main peak with desired MS was detected. The reaction mixture was concentrated under reduced pressure to give N,N-dimethyl-l-(lH-pyrrolo[3,2-]pyridin-3-yl)methanamine (559.7 mg, crude) as a yellow solid which was used in the next step without further purification. MR (400 MHz, CD3OD) δ ppm 8.32 (dd, J = 1.1, 4.6 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.56 (s, 1H), 7.16 (dd, J = 4.8, 8.3 Hz, 1H), 3.80 (s, 2H), 2.28 (s, 6H); ES-LCMS m/z 176.1 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 43.1 Example 43: 2-(5-(6,7-dichloro-3-(1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline-2-ylthio)-1H-tetrazole-1-yl)-N,N-dimethylethanamine [537] Step 1: Preparation of 2,6,7-trichloro-3-(1H-pyrrolo[3,2-b]pyridine-1-yl) quinoxaline [538] 1.6797 mmol of 2,3,6,7-tetrachloroquinoxaline, 2.0 mmol of 4-azaindole, and 6.7 mmol of K2CO3 were dissolved in 9.0 ml of dimethylformamide and stirred all night at room temperature. After reaction, it was extracted by ethylacetate, adding water. Water was removed from the organic solvents using magnesiumsulfat anhydrous, and ethylacetate was removed by filtration and decompression. 2,6,7-trichloro-3-(1H-pyrrolo[3,2-b]pyridine-1-yl)quinoxaline was synthesized by using the condensed rudiment applying to silica gel chromatography (EtOAc : Hexane = 1 : 5). [539] [540] 1H NMR (CDCl3, 400MHz) 8.64(d, 1H, J=5.2Hz), 8.46~8.54(br, 1H), 8.30~8.34(br, 1H), 8.27(s, 1H), 8.23(s, 1H), 7.54~7.60(br, 1H), 7.40~7.45(br, 1H) |
Yield | Reaction Conditions | Operation in experiment |
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With 3-chloro-benzenecarboperoxoic acid In 1,2-dimethoxyethane at 20℃; for 2h; Cooling with ice; | 55 PREPARATION 55 1 H-Pyrrolo[2,3-b]pyridine 7-oxide PREPARATION 55 1 H-Pyrrolo[2,3-b]pyridine 7-oxide 1 /-/-Pyrrolo[2,3fc>]pyridine (9.2 g, 78 mmol) was dissolved in 260 ml dimethoxyethane and the solution was cooled in an ice-bath. 3-Chloroperbenzoic acid (77% purity, 31 g, 138 mmol) was added portion-wise and the mixture was stirred at room temperature for 2 h. The solvent volume was reduced to half under reduced pressure and the precipitate formed was collected by filtration and washed with ether. The solid was suspended in 150 ml water, the aqueous basifed to pH 9 with saturated potassium carbonate solution and left in the refrigerator overnight. The precipitate was collected by filtration, washed with hexane and dried in vacuo to obtain 7.0 g (52 mmol, 68%) of the title compound as a white solid. Purity 98%. 1 H N MR (300 MHz, DMSO-d) δ ppm 8.13 (d, J=5.28 Hz, 1 H), 7.65 (d, J=8.22 Hz, 1 H), 7.46 (d, J=2.93 Hz, 1 H), 7.01 - 7.13 (m, 1 H), 6.58 (d, J=2.93 Hz, 1 H). UPLC/MS (3 min) retention time 0.61 min. LRMS: m/z 135 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; for 16h; | To a solution of lH-Pyrrolo[3,2-]pyridine (35 mg, 0.3 mmol) and mesitylsulfonyl chloride (88 mg, 0.4 mmol) in 4 mL of THF was added 60% NaH (16 mg, 0.4 mmol) at 0 C. The resulting mixture was stirred at r.t. for 16 h. The solution was diluted with EtOAc (50 mL), washed with 1 N HC1 (aq.) (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2S04 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane/EtOAc = 1/1) to give the desired product as a white solid (86 mg, 96%). H NMR (600 MHz, CDC13) delta 8.48 (d, 1H, J = 3.6 Hz), 7.74-7.75 (m, 1H), 7.71 (d, 1H, J = 8.4 Hz), 7.09-7.11 (m, 1H), 6.94 (s, 2H), 6.81 (d, 1H, J = 3.0 Hz), 2.50 (s, 6H), 2.25 (s, 3H). 13C NMR (150 MHz, CDC13) delta 148.1, 145.8, 144.7, 140.4, 132.6, 132.5, 129.6, 128.3, 119.8, 118.7, 107.8, 22.7, 21.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.60 g | With caesium carbonate In N,N-dimethyl-formamide at 20 - 80℃; | 13 Reference Example 13 4-(3-Cyanopyrrolo[3, 2-b]pyridine-1-yl)-2-methoxymethoxy benzoic acid ethyl ester To a solution of 1H-pyrrolo[3, 2-b]pyridine (0.4 g) in N, N-dimethylformamide (6 mL) were added 4-fluoro-2-methoxymethoxy benzoic acid ethyl ester (0.85 g) and cesium carbonate (2.21 g) at room temperature, and the mixture was stirred at 80°C overnight. To the mixture was added water, and the resulting mixture was extracted with dichloromethane. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give 2-methoxymethoxy-4-pyrrolo[3, 2-b]pyridine-1-yl-benzoic acid ethyl ester (0.60 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With iron(III) chloride In nitromethane at 50℃; for 1h; | I-11.40 Synthesis of 3-[1-(4-iodophenyl)-1,2-dimethyl-propyl]-1H-indole (Intermediate 11) General procedure: Method 8 Synthesis of 3-[1-(4-iodophenyl)-1,2-dimethyl-propyl]-1H-indole (Intermediate 11) To a solution of I-7 (800 mg, 2.76 mmol) and indole (323 mg, 2.76 mmol) in nitromethane (8 mL) is added anhydrous FeCl3 (45 mg, 0.28 mmol) and the resultant solution stirred at room temperature for 1 h. The suspension is concentrated in vacuo and purified by flash chromatography (SiO2, 10% EtOAc in heptane) to give the title intermediate I-11 (972 mg, 90%) m/z 390.0 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With copper(l) iodide; trans-1,2-Diaminocyclohexane; potassium carbonate In N,N-dimethyl-formamide at 115℃; for 18h; Inert atmosphere; | 23 PROPANE-2-SULFONIC ACID [2-(4PYRROLO[3,2-B]PYRIDIN-1-YLPHENYL)PROPYL]AMIDE(FIJC-2-29) To a solution of HJC-1-2 (184 mg, 0.5 mmol) and 4-azaindole (59 mg, 0.5 mmol) in DMF (5 mL) was added K2C03 (138 mg, 1.0 mmol), trans- 1 ,2-diaminocyclohexane (11 mg, 0.1 mmol) and then Cul (10 mg, 0.01 mmol). The resulting mixture was deoxygenated via five vacuum/N2-refill cycles. The mixture was stirred at 115 °C for 18 h, and was then partitioned between EtOAc (100 mL) and H20 (30 mL). The organic layer was separated and washed with brine (10 mL), dried over anhydrous Na2S04, filtered and concentrated to give an oil residue. This residue was purified with silica gel column (Hexane/EtOAc = 1/1) to obtain HJC-2-29 (30 mg, 40%) as a pale yellow oil and the recovered 4-azaindole (34 mg). 1H NMR (600 MHz, CDC13) δ 8.49 (s, 1H), 7.80 (d, 1H, J = 9.0 Hz), 7.54 (s, 1H), 7.41 (d, 2H, J = 7.8 Hz), 7.38 (d, 2H, J= 7.2 Hz), 7.12-7.14 (m, 1H), 6.87 (s, 1H), 4.37 (t, 1H, J= 6.0 Hz), 3.37-3.42 (m, 1H), 3.28-3.32 (m, 1H), 3.06-3.13 (m, 2H), 1.30-1.37 (m, 9H). 13C NMR (150 MHz, CDC13) δ 147.6, 144.1, 144.1, 142.3, 137.9, 131.0, 128.9, 124.5, 117.8, 117.2, 104.7, 53.7, 50.5, 40.7, 19.2, 16.8, 16.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | Stage #1: 1H-pyrrolo[3,2-b]pyridine With n-butyllithium In tetrahydrofuran at -70℃; for 1h; Stage #2: With carbon dioxide In tetrahydrofuran at -70℃; for 0.333333h; Further stages; | S.1 S.1 2-Chloro-4-[(6-chloro-3-pyridyl)methyl]pyrrolo[3,2-b]pyridine To a solution of 1 H-pyrrolo[3,2-b]pyridine (3.54 g, 0.03 mol) in THF (60 mL) was added slowly n- butyllithium (12 mL, 0.03 mol) at -70 °C and the mixture was stirred for 1 hour at -70 °C. The gaseous CO2 was bubbled through the solution for 20 min, then the mixture was evaporated at 0 °C. The residue was dissolved in THF (60 mL) and t-butyllithium (24 ml, 0.03 mol) was added at -70 °C, then the mixture was stirred for 1 hour at -70 °C. A solution of C2CI6 (7.1 1 g, 0.03 mol) in THF was added to the mixture and the mixture was stirred for 12 h at room temperature. Water was added and the mixture was extracted with ethyl acetate, dried and evaporated, the residue was purified by column (eluent: CH2CI2) to give the desired 2-chloro-1 H-pyrrolo[3,2- b]pyridine (200 mg, yield 4%). H NMR (400 MHz, MeOH): 8.29 (d, 1 H, J=4.8), 7.76 (d, 1 H, J=8.0), 7.17-7.20 (dd, 1 H, J=4.8 and J=8.0), 6.53 (s, 1 H). To a solution of 2-chloro-1 H-pyrrolo[3,2-b]pyridine (140 mg, 0.92 mmol) in anhydrous DMF (20 ml.) was added 2-chloro-5-(chloromethyl)pyridine (150 mg, 0.92 mmol) and the mixture was stirred for 12 h at at 100 0C. Then the mixture was evaporated and the residue was purified by p-TLC to give compound example E1.1 (70 mg, yield: 28%). 1H NMR (400 MHz, CDC ): 8.45 (d, 1 H, J=2.0), 8.17 (d, 1 H, J=6.8), 8.03 (d, 1 H, J=7.6), 7.72- 7.74 (dd. 1 H, J=2.0 and J=8.0), 7.46 (d, 1 H, J=8.0), 7.15-7.19 (m, 1 H), 6.49 (s, 1 H), 5.74 (s, 2H). LC-MS: 278.2 [M+H]+; tR = 0.82 min*>. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; 3,4,7,8-Tetramethyl-o-phenanthrolin In tetrahydrofuran at 80℃; for 4h; Inert atmosphere; Glovebox; regioselective reaction; | |
11% | Stage #1: 1H-pyrrolo[3,2-b]pyridine; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane With triethylamine In tetrahydrofuran at 80℃; for 0.333333h; Schlenk technique; Inert atmosphere; Stage #2: With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; 3,4,7,8-Tetramethyl-o-phenanthrolin at 80℃; for 4h; Schlenk technique; Inert atmosphere; | General procedure A: Iridium-catalyzed borylation of indoles General procedure: A procedure similar to Preshlock’s report was followed.[1] Indole (1.0 equiv.) was added to a flame-dried Schlenk tube (tube A), the system was capped with a septum and flushed with argon by means of a balloon. Next, degassed, anhydrous THF (indole concentration: 1 M), degassed triethylamine (1.0 equiv.) and pinacolborane (2.1 equiv.) were added sequentially through a syringe. Then, the reaction mixture was heated at 80 °C for 20 min. In the meantime, a second flame-dried Schlenk tube (tube B) was charged with [Ir(OMe)(COD)]2 (2.5 mol%) and 3,4,7,8-tetramethyl-1,10-phenanthroline (1.0 mol%) and brought under an argon atmosphere. After the aforementioned 20 min., tube A was allowed to cool to room temperature and then its content was transferred to tube B. Subsequently, tube B was stirred at 80 °C for 4 h. Afterwards, the mixture was exposed to air and diluted with MeOH (to cleave the -Bpin directing group on the indole nitrogen). The volatiles were removed under reduced pressure and the crude mixture was purified via MPLC (heptane/ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1H-pyrrolo[3,2-b]pyridine With aluminum (III) chloride In dichloromethane at 20℃; Stage #2: 2-Bromoacetyl bromide In dichloromethane Reflux; | Synthesis of 2-bromo-1-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethanones (15a-d) General procedure: To a solution of 14a-d (2.5 mmol) in anhydrous dichloromethane (10 mL) anhydrous aluminum chloride (1.2 g, 8.8 mmol) was slowly added. The reaction mixture was stirred at room temperature (in the case of 15b) or heated under reflux for 10 min (in the case of 15a,c,d) and bromoacetyl bromide (0.2 mL, 2.5 mmol) in dichloromethane (2 mL) was added dropwise. The resulting solution was allowed to stir under reflux for 15-40 min. After cooling, water and ice were slowly added and the obtained precipitate was filtered off and purified by column chromatography using ethyl acetate (for compounds 15a, c) or dichloromethane/ethyl acetate (95/5) (for compound 15b,d) as eluent. For compounds 15b-d see supplementary material. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.4% | With potassium phosphate; copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane In toluene at 110℃; for 24h; Microwave irradiation; Inert atmosphere; Sealed tube; | General procedure: To a microwave vial was added 18(100mg,0.194mmol),CuI(2mg,0.01mmol), the 4-azaindole (28mg,0.23 mmol), andK3PO4(83mg,0.39 mmol), and the reaction vessel was fitted with arubber septum. The vessel was evacuated and back-filledwith argon and thisevacuation/back-fill procedure was repeated one additional time. Toluene (3 mL) and (1R,2R)-N,N'-Dimethyl-1,2-cyclohexanediamine (6μL,0.039mmol) were then successively added under a stream of argon. Thereaction tube was quickly sealed and the contents were stirredwhile heating in an oil bath at110°C for 24h. The reaction mixture was cooled toambient temperature, diluted with ethyl acetate, and filtered through a plug ofsilica gel, eluting with additional ethyl acetate. The filtrate was concentrated and the resultingresidue was purified by column chromatography(20:1 DCM/MeOH) to provide the product (2,4-bis(benzyloxy)-5-(1H-pyrrolo[3,2-b]pyridin-1-yl)ph-enyl)(isoindolin-2-yl)methanoneS18 as a light yellow oil(38mg,35.4%).1H NMR (400 MHz, Chloroform-d)δ 8.52 (s, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.51-7.31 (m, 11H), 7.28-7.27(m, 2H), 7.18 (d, J = 7.1 Hz, 1H), 7.15-7.06 (m, 3H), 6.88 (s, 1H), 6.80(s, 1H), 5.18 (s, 2H), 5.01 (s, 2H), 5.00 (s, 2H), 4.74 (s, 2H).MS (ESI) : m/z 552.2(M+H)+.Retention timeof 3.38 min, >90% pure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium phosphate; copper In dimethyl sulfoxide at 80℃; for 5h; Inert atmosphere; | General procedure for Cu-NP catalyzed N-arylations of azoles with aryl halides General procedure: An oven dried two-necked round bottom flask was charged with aryl halide (1mmol) and K3PO4 (2mmol), evacuated and backfilled with argon. The azole compound (1mmol) and 2mL of DMSO were added under argon. After that Cu-NP (1.6mmol) was added and the flask was again backfilled with argon. The flask was then immersed in a preheated oil bath at 80°C until the conversion was completed (detected by TLC). The cooled mixture was partitioned between ethyl acetate (10mL) and saturated NH4Cl (10mL). The aqueous layer was extracted with ethyl acetate (2×10mL), the organic layer was washed with brine (20mL), dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography on silica gel using ethyl acetate in hexane (1.5-10%) as eluent to afford the desired product. All the products have been characterized by 1H NMR, 13C NMR, and mass spectroscopy. For new products, FTIR data were also recorded. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With 18-crown-6 ether; potassium <i>tert</i>-butylate In N,N-dimethyl-formamide for 5h; Reflux; | 1-[2,2-Dimethoxy-3-(4-octylphenoxy)propyl]-1H-4-azaindole A solution of compound 23 (100 mg, 0.26 mmol), 4-azaindole(40 mg, 0.34 mmol), potassium tert-butylate (294 mg, 2.62 mmol)and 18-crown-6 (40 mg, 0.15 mmol) in dry DMF (20 mL) washeated under reflux for 5 h. The reaction mixture was diluted withwater (30 mL) and extracted twice with ethyl acetate (50 mL). Thecombined organic layers were dried (Na2SO4) and concentrated.The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate, 9:1 to ethyl acetate) to yield 24 as an oil(109 mg, 99%); 1H NMR (600 MHz, CDCl3): d 0.88 (t, J = 7.0 Hz,3H), 1.21-1.33 (m, 10H), 1.56 (d, J = 7.1 Hz, 2H), 2.47-2.55 (m,2H), 3.41 (s, 6H), 3.60 (s, 2H), 4.42 (s, 2H), 6.73-6.67 (m, 3H),6.90 (dd, J = 8.3 Hz and 4.6 Hz, 1H), 7.00-7.05 (m, 2H), 7.35 (d,J = 3.4 Hz, 1H), 7.68 (dt, J = 8.3 and 1.1 Hz, 1H), 8.35 (d, J = 4.7 Hzand 1.4 Hz, 1H); HRMS (APCI, direct probe) m/z [M+H]+ calculated:425.2799, found: 425.2782. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In acetonitrile for 6h; Reflux; | 4-(Cyanomethyl)-1H-pyrrolo[3,2-b]pyridin-4-ium Chloride (3) To a solution of 4-azaindole (1 g, 8.5 mmol) in MeCN (5 mL) was added chloroacetonitrile (0.8 mL, 12.75 mmol). The reaction mixture was stirred under reflux for 6 h. The precipitate was collected by filtration, washed with MeCN (3 ×) and dried under air to give a beige solid; yield: 1.358 g (83%); mp 226-228 °C. IR (KBr): 3013-2573, 1637, 1583, 1462, 1384, 1342, 1286, 1237,1168, 1131, 900, 822, 796, 764, 598 cm-1. 1H NMR (600 MHz, DMSO-d6): δ = 6.34 (s, 2 H), 7.21 (d, J = 3.1 Hz, 1H), 7.78 (dd, J = 6.2, 1.5 Hz, 1 H), 8.46 (d, J = 3.1 Hz, 1 H), 8.74 (d, J = 7.6 Hz, 1 H), 9.00 (d, J = 6.2 Hz, 1 H). 13C NMR (150 MHz, DMSO-d6): δ = 43.9, 96.2, 114.3, 117.2, 129.4, 132.7, 137.0, 138.3, 138.4. ESI-MS: m/z = 158 [M - Cl]+. Anal. Calcd for C9H8ClN3 (193.63): C, 55.83; H, 4.16; N, 21.70. Found: C, 55.95; H, 4.06; N, 21.75. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: 1H-pyrrolo[3,2-b]pyridine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.25h; Inert atmosphere; Stage #2: 5-(bromomethyl)thiophene-3-carbonitrile In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil at 0℃; for 1.5h; | 15.1 Step 1: 5-(1H-Pyrrolo j3,2-bJ pyridin- 1-ylmethyl)thiophene-3-carbonitrile To a solution of 1H-pyrrolo[3,2-b]pyridine (0.59 g, 5.00 mmol) in anhydrous dimethylformamide (10 mL) was added sodium hydride (60% suspension in mineral oil, 0.29 g, 7.25 mmol) at 0 °C in small portions under nitrogen. After the addition, the mixture was stirred for 10 minutes at 0 °C and then at room temperature for 10 minutes, cooled to 0 °C and was added 5-(bromomethyl)thiophene-3-carbonitrile (1.11 g, 5.50 mmol) in anhydrous tetrahydrofuran (10 mL) dropwise. After the addition, the reaction mixture was stirred at 0 °C for 1.5 h, quenched with ice-water (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography using DCM: MeOH (92:8) as eluent to afford 5-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)thiophene-3-carbonitrile (1.0 g, 80%) as a brown solid.‘HNMR (400 1VIHz, CDC13): 5.47 (s, 2H), 6.79 (d, 1H, J= 4.0 Hz), 7.10 (s, 1H), 7.12 (m, 1H), 7.36 (d, 1H, J 3.6 Hz), 7.58 (d, 1H, J 10.4 Hz), 7.82 (s, 1H), 8.50 (d, 1H, J= 6.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1H-pyrrolo[3,2-b]pyridine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 2,6-Dichloropyrimidine In N,N-dimethyl-formamide; mineral oil at 15℃; for 12h; | A81. 2-chloro-4-(pyrrolo[3,2-b]pyrid-1-yl)pyrimidine. To a solution of pyrrolo[3.2-b]pyridine (2.54 g, 21.5 mmol) in DMF (60 mL) is added NaH (60% in mineral oil,1.03 g, 25.78 mmol) portionwise at 0 °C. After stirring at 0 °C for 30 min.2,4-dichloropyrimidine (3.20 g, 21.5 mmol) is added, and the mixture is allowed to stir at 15 °C for 12 hrs. The resulting mixture is quenched with water (200 mL) and the mixture is extracted with EtOAc (100 mL x 3), and washed with water (100 mL x 4), dried with Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (petroleum ether: EtOAc =10:1), to give 2-chloro-4-(pyrrolo[3.2-b]pyrid-1-ylpyrimidine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1H-pyrrolo[3,2-b]pyridine With sodium hydride In N,N-dimethyl-formamide; mineral oil Stage #2: 6-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-sulfonyl chloride In N,N-dimethyl-formamide; mineral oil at 20℃; | General procedure for the syntheses of 5-19 General procedure: NaH (10.3 mg, 0.258 mmol) was first dissolved in 1 mL of anhydrous DMF. Imidazole (10.5mg, 0.155 mmol) dissolved in 1 mL of anhydrous DMF was slowly added dropwise, and the mixture was stirred for 30 min. Compound 35 (40 mg, 0.129 mmol) dissolved in 1 mL of anhydrous DMF was slowly added dropwise, and the mixture was stirred for 3 h at room temperature. The reaction solution was poured into 0.1 mol/L hydrochloric acid, which was then turned basic using an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was collected, and distilled under reduced pressure. The residue was purified by flash chromatography to afford compound 5 (26 mg, 60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With copper(l) iodide; caesium carbonate In N,N-dimethyl-formamide at 120℃; for 48h; Inert atmosphere; | 12 4.5 General procedure for N-arylation General procedure: To a solution of heteroaromatic compound (8.0mmol), copper iodide (20mol%), and cesium carbonate (11mmol) in DMF (11mL) was added aryl bromide (5.7mmol) under argon atmosphere, and the reaction mixture was stirred at room temperature for 30min prior to being refluxed for 48h. The reaction mixture was cooled down to room temperature and diluted with ethyl acetate. The subsequent mixture was filtered through a pad of silica gel. The filtrate was concentrated to give a residue, which was subjected to preparative thin layer chromatography eluting with 50% ethyl acetate in hexane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With copper(l) iodide; caesium carbonate In N,N-dimethyl-formamide at 120℃; for 48h; Inert atmosphere; | 13 4.5 General procedure for N-arylation General procedure: To a solution of heteroaromatic compound (8.0mmol), copper iodide (20mol%), and cesium carbonate (11mmol) in DMF (11mL) was added aryl bromide (5.7mmol) under argon atmosphere, and the reaction mixture was stirred at room temperature for 30min prior to being refluxed for 48h. The reaction mixture was cooled down to room temperature and diluted with ethyl acetate. The subsequent mixture was filtered through a pad of silica gel. The filtrate was concentrated to give a residue, which was subjected to preparative thin layer chromatography eluting with 50% ethyl acetate in hexane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: 1H-pyrrolo[3,2-b]pyridine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Stage #2: 3-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester In N,N-dimethyl-formamide; mineral oil at 20℃; | PREPARATION OF INTERMEDIATE 68 Sodium hydride (19.1 mg, 0.48 mmol, 60%> dispersion in mineral oil) was added portionwise to a solution of 4-azaindole (CAS: 272-49-1; 52 mg, 0.44 mmol) in DMF (4.12 mL) at rt. The resulting mixture was stirred at rt for 30 min. Then tert-butyl 3-(((methylsulfonyl)oxy)methyl)piperidine-l-carboxylate (CAS: 162166-99-6; 0.1 g, 0.34 mmol) was added and the mixture was further stirred at rt overnight. The mixture was poured in to ice and EtOAc was added. The organic layer was separated, washed with brine, dried over MgS04, filtered and concentrated in vacuo. The residue thus obtained was purified by flash column chromatography (silica; MeOH in DCM, 0/100 to 10/90) and the desired fractions were concentrated in vacuo to yield intermediate 68 as colorless oil (63 mg, 58% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With caesium carbonate In N,N-dimethyl-formamide at 27℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: 1H-pyrrolo[3,2-b]pyridine With aluminum (III) chloride In dichloromethane for 1h; Inert atmosphere; Stage #2: chloroacetyl chloride In dichloromethane at 20℃; Inert atmosphere; | Synthesis of 2-chloro-1-(1H-pyrrolo[3,2-b]pyridin-3-yl)ethanone (14) and 2-chloro-1-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone (21) General procedure: Under an atmosphere of nitrogen, a suspension of azaindole (1.0 equiv) and AlCl3 (5 equiv) was stirred in dry DCM (c = 0.2 M) for 1 h. Afterwards a solution of chloroacetyl chloride (5 eq.) in dry DCM (c = 2.5 M) was added slowly and the mixture was stirred at rt overnight. The solvent was removed and the residue was dissolved in water and basified carefully with saturated Na2CO3 solution until pH 9 and extracted three times with EtOAc. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure to give title compounds as slightly yellow solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In methanol at 20℃; for 2h; | Complex cis-[Pt(4aza)2I2] (1) The solution of K2[PtCl4](0.2 mmol, 83 mg) in 1 mL of deionized water was heated to 50 °C and 5 molar equiv. of KI was added (166 mg).The reaction mixture was stirred at 50 °C for 10 min, providingthe solution of K2[PtI4]. After that, the solutionwas cooled to ambient temperature and the stoichiometricamount of 4aza (0.4 mmol, 47 mg) dissolved in 1 mLof MeOH was poured in. The obtained yellow suspensionwas stirred for 2 h, then the solid was collected by filtrationand washed with water (2 × 0.5 mL), MeOH (2 × 0.5 mL),and DEE (2 × 1 mL). The yellow solid product was driedin desiccator under the reduced pressure (30 min) andthe yield was ca. 75% (calculated to K2[PtCl4]). Anal.Calc. for PtC14H12N4I2:C, 24.5; H, 1.8; N, 8.2; Found:C, 24.9; H, 1.7; N, 8.0%. ESI+ MS (MeOH, m/z): 707.8(calc. 708.9; 30%; [Pt(4aza)2I2] + Na}+), 675.9 (calc.676.0; 40%; [Pt(4aza)3I]+), 558.0 (calc. 558.0; 100%;[Pt(4aza)2I]+), 430.1 (calc. 430.1; 20%; [Pt(4aza)2]-H}+), 119.2 (calc. 119.0; 40%; {(4aza) + H}+). ESI- MS(MeOH, m/z): 811.9 (calc. 811.8; 100%; [Pt(4aza)2I3]-),693.8 (calc. 693.7; 10%; [Pt(4aza)I3]-), 683.9 (calc.683.9; 10%; [Pt(4aza)2I2]-H}-), 576.0 (calc. 575.7;20%; [PtI3]-), 566.0 (calc. 565.8; 25%; [Pt(4aza)I2]-H}-). 1H NMR (DMF-d7, 25 °C, ppm): 11.89 (s, N1-H),8.94 (d, J = 5.5 Hz, C5-H), 7.93 (s, C2-H), 7.88 (d,J = 8.3 Hz, C7-H), 7.52 (s, C3-H), 7.14 (s, C6-H). 13CNMR (DMF-d7, 25 °C, ppm): 146.4 (C7a), 144.5 (C5),131.1 (C2), 130.6 (C3a), 121.0 (C7), 117.4 (C6), 103.6(C3). 15N NMR (DMF-d7, 25 °C, ppm): 200.6 (N4), N1-not detected. 195Pt NMR (DMF-d7, 60 °C, ppm): -3186.FTIR (νATR cm-1): 3284s, 3071m, 2894w, 2706w, 1569w,1496w, 1480m, 1417vs, 1273vs, 1353s, 1327s, 1209m,1131w, 1095w, 1059m, 888w, 792w, 760vs, 625w. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1H-pyrrolo[3,2-b]pyridine With sodium hydride In tetrahydrofuran at -20℃; for 0.25h; Inert atmosphere; Stage #2: isopropyl bromide In tetrahydrofuran at 150℃; for 1h; | N1-isopropyl-4-azaindole (ip4aza) NaH (1.2 mmol, 48 mg) and 4aza (1.0 mmol, 118 mg) werepoured into the reaction flask, which was closed with a rubberseptum and repeatedly evacuated and filled with nitrogengas. After that, 5 mL of THF was slowly poured in to startthe reaction (- 20 °C). After 15 min of stirring at - 20 °C,2-bromopropane (1.5 mmol, 183 μL) was added to this mixture,which reacted in microwave synthesizer at 150 °C for1 h. After cooling to ambient temperature, the mixture wascentrifuged to separate NaBr and supernatant, which wasdried (MgSO4), filtered, and evaporated on a rotary evaporator.The obtained brown oily product was purified usingflash silica gel chromatography with the mixture of ethylacetate and NH3(100:1, v/v) and using the thin-layer chromatography(TLC) control. The product (ip4aza; Fig. 1) wasobtained as brown-yellow oil after evaporation of solventson a rotary evaporator. 1H NMR (CDCl3, 25 °C, ppm): 8.46(d, J = 4.4 Hz, C5-H), 7.81 (d, J = 8.1 Hz, C7-H), 7.55 (d,J = 2.9 Hz, C2-H), 7.20 (dd, J = 8.4, 4.8 Hz, C6-H), 6.83(d, J = 2.9 Hz, C3-H), 4.70 (sep, J = 6.6 Hz, C8-H), 1.58 (d,J = 7.3 Hz, C9-H6). 13C NMR (CDCl3, 25 °C, ppm): 144.6(C7a), 140.8 (C5), 129.2 (C2), 128.7 (C3a), 118.4 (C7),115.9 (C6), 101.3 (C3), 47.9 (C8), 22.7 (C9). 15N NMR(CDCl3, 25 °C, ppm): 293.2 (N4), 124.9 (N1). ESI+ MS(MeOH): 161.2 (calc. 161.1 for {(ip4aza) + H}+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In neat (no solvent) at 100℃; for 2h; Microwave irradiation; | For method B the mixture of the cyclic imine 3,4-dihydroisoquinoline (66 mg, 0.50 mmol);6,7-dihydrothieno[3,2-c]pyridine (51 mg, 0.38 mmol); 3,4-dihydro--carboline (63 mg, 0.38 mmol) or4,5-dihydro-3H-benz[c]azepine (55.3 mg, 0.38 mmol); and the electron-rich aromatic compound (7-, 6-,4-, or 5-azaindole (30 mg, 0.25 mmol)) were placed in a 10 mL pressurized reaction vial and heated ina microwave reactor, under the conditions given in Tables 1-3. In the case of 5-azaindole, 10 mol % ofp-TSA (4.3 mg, 0.025 mmol) as a catalyst was also added. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | In neat (no solvent) at 100℃; for 2.5h; Microwave irradiation; | For method B the mixture of the cyclic imine 3,4-dihydroisoquinoline (66 mg, 0.50 mmol);6,7-dihydrothieno[3,2-c]pyridine (51 mg, 0.38 mmol); 3,4-dihydro--carboline (63 mg, 0.38 mmol) or4,5-dihydro-3H-benz[c]azepine (55.3 mg, 0.38 mmol); and the electron-rich aromatic compound (7-, 6-,4-, or 5-azaindole (30 mg, 0.25 mmol)) were placed in a 10 mL pressurized reaction vial and heated ina microwave reactor, under the conditions given in Tables 1-3. In the case of 5-azaindole, 10 mol % ofp-TSA (4.3 mg, 0.025 mmol) as a catalyst was also added. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In neat (no solvent) at 100℃; for 2h; Microwave irradiation; | For method B the mixture of the cyclic imine 3,4-dihydroisoquinoline (66 mg, 0.50 mmol);6,7-dihydrothieno[3,2-c]pyridine (51 mg, 0.38 mmol); 3,4-dihydro--carboline (63 mg, 0.38 mmol) or4,5-dihydro-3H-benz[c]azepine (55.3 mg, 0.38 mmol); and the electron-rich aromatic compound (7-, 6-,4-, or 5-azaindole (30 mg, 0.25 mmol)) were placed in a 10 mL pressurized reaction vial and heated ina microwave reactor, under the conditions given in Tables 1-3. In the case of 5-azaindole, 10 mol % ofp-TSA (4.3 mg, 0.025 mmol) as a catalyst was also added. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | In neat (no solvent) at 100℃; for 3h; Microwave irradiation; | For method B the mixture of the cyclic imine 3,4-dihydroisoquinoline (66 mg, 0.50 mmol);6,7-dihydrothieno[3,2-c]pyridine (51 mg, 0.38 mmol); 3,4-dihydro--carboline (63 mg, 0.38 mmol) or4,5-dihydro-3H-benz[c]azepine (55.3 mg, 0.38 mmol); and the electron-rich aromatic compound (7-, 6-,4-, or 5-azaindole (30 mg, 0.25 mmol)) were placed in a 10 mL pressurized reaction vial and heated ina microwave reactor, under the conditions given in Tables 1-3. In the case of 5-azaindole, 10 mol % ofp-TSA (4.3 mg, 0.025 mmol) as a catalyst was also added. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium acetate; copper diacetate In dimethyl sulfoxide at 80℃; for 12h; Schlenk technique; Sealed tube; | 31 Example 31 Aromatic substrates 1b (0.1 mmol), 4-azaindole 2c (0.15 mmol), copper acetate (0.1 mmol), potassium acetate (0.2 mmol), DMSO (1.0 mL) were added to 15 mL of Schlenk in an air atmosphere, respectively. Into the tube, and then directly seal the tube at 80 ° C for 12h. After the reaction was completed, the mixture was cooled to room temperature, and a small amount of ethyl acetate and ammonia were added to quench the reaction. The ethyl acetate was repeatedly extracted. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the solvent was evaporated under reduced pressure. The crude product was separated and purified by a preparative plate (DCM: MeOH = 35: 1) to obtain 3bc as a white solid, 32.4 mg, with a yield of 82%. |
82% | With copper diacetate; sodium carbonate In dimethyl sulfoxide at 90℃; for 3.5h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium acetate; copper diacetate at 80℃; for 12h; Schlenk technique; Sealed tube; | 27 Example 27 Aromatic heterocyclic substrates 1z (0.1mmol), 4azaindole 2c (0.15mmol), copper acetate (0.1mmol), potassium acetate (0.2mmol), DMPU (1.0mL) were added to 15mL in an air atmosphere. In a Schlenk tube, and then directly sealed at 80 ° C for 12h. After the reaction was completed, the mixture was cooled to room temperature, and a small amount of ethyl acetate and ammonia were added to quench the reaction. The ethyl acetate was repeatedly extracted. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the solvent was distilled off under reduced pressure. The crude product was separated and purified on a preparative plate (DCM: MeOH = 35: 1) to give 3zc as a white solid, 33.7 mg, with a yield of 85%. |
85% | With copper diacetate; sodium carbonate In dimethyl sulfoxide at 80℃; for 2h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With tetrabutyl phosphonium bromide; potassium carbonate In water at 20℃; for 12h; regioselective reaction; | General procedures for the Synthesis of 3a-I, 3m-o General procedure: The solution of 5-methoxyindole (1a, 3.4 mmol) and 2,2,2-trifluoro-1-phenylethan-1-one (2a, 3.70 mmol) was prepared in water (5 mL) and allowed it to stir at room temperature. To the solution, K2CO3 (0.5 mmol) and n-Bu4PBr (0.5 mmol) were added. Initially, the mixture wasallowed to stir vigorously due to the formation product in sticky mass. After keep stirring for a long time, the sticky mass was turned to be solid, which can be filtered through glass filter (pore size 5, 50 mL) and washed with 5% ethyl acetate in petroleum ether (boiling in the range 35- 60 °C). The product was dried at 40 °C in a heating oven for further spectroscopic and physical characterizations. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33.5 g | Stage #1: 1H-pyrrolo[3,2-b]pyridine; di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran at 0 - 20℃; for 18.7h; Stage #2: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 1.5h; | A-8.1 (Step 1) tert-Butyl 1H-pyrrolo[3,2-b]pyridine-1-carboxylate 4-oxide A solution of 1H-pyrrolo[3,2-b]pyridine (24.9 g)in tetrahydrofuran (400 mL)was allowed to cool to 0°C, di-tert-butyl dicarbonate (48.3 g)was added to the solution, and the mixture was stirred at room temperature for 18.7 hours. The solvent was distilled off, the resultant was dissolved in dichloromethane (400 mL), and the resultant solution was allowed to cool to 0°C. To the solution, 3-chloroperbenzoic acid (purity ≤77%, 54.6 g)was added, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate (30 g)were then added, and the mixture was stirred and then extracted with dichloromethane and chloroform. The organic layer obtained was washed with a saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was formed into a slurry with diisopropyl ether and then filtered off to obtain the title compound (33.5 g)as a solid. 1H-NMR (CDCl3)δ: 1.69 (9H, s), 7.07 (1H, d, J = 3.6 Hz), 7.17 (1H, dd, J = 8.5, 6.0 Hz), 7.75 (1H, d, J = 4.2 Hz), 8.02-8.09 (1H, m), 8.21 (1H, d, J = 6.7 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.045 g | With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 12h; | 5 Example 5 Preparation of 1-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-1H-pyrrolo[3,2-b]pyridine (Compound 136) A mixture of 3-[4-(chloromethyl)phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole (i.e. the product of Example 1, Step B) (0.3 g, 1.1 mmol), 1H-pyrrolo[3,2-b]pyridine (0.14 g, 1.1 mmol) and cesium carbonate (0.56 g, 1.7 mmol) in N,N-dimethylformamide (2.5 ml) was stirred at room temperature for 12 h. The reaction mixture was partitioned between ethyl acetate (25 ml) and water (5 ml). The organic layer was separated and washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel chromatography (eluting with a gradient of 5 to 50% ethyl acetate in hexanes) to provide the title compound, a compound of the present invention, as a solid (0.045 g). 1H NMR (CDCl3): δ 5.42 (m, 2H), 6.79-6.88 (m, 1H), 7.06-7.15 (m, 1H), 7.23 (m, 2H), 7.41 (d, 1H), 7.54 (d, 1H), 8.07 (d, 2H), 8.49 (br d, 1H). 19F NMR (CDCl3): δ -65.40. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.5% | Stage #1: 1H-pyrrolo[3,2-b]pyridine; 2,4-dichloro-1,3,5-triazine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: 5-(N-acrylamido)-4-((N,1-(2-(N,N-dimethylamino)ethyl)-N,1-methyl)amino)-2-methoxyaniline With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 25℃; for 20h; | 2 Synthetic Route: Compound B2 (202 mg, 1.70 mmol) and diisopropylethylamine (234 mg, 1.80 mmol) are added to a solution of 2,4-dichloro-1,3,5-triazine (257 mg, 1.70 mmol) in DMF (12 mL) at 0°C, then stirring for 0.5 hour. Intermediate III (500 mg, 1.70 mmol) and diisopropylethylamine (234 mg, 1.80 mmol) are sequentially added to the reaction solution at 0°C. The reaction mixture is stirred at 25°C for 20 hours. TLC (petroleum ether: ethyl acetate = 1: 2, Rf = 0.35) detection indicates complete reaction of the reactants. The reaction mixture is purified by prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water(10mM NH4HCO3)-ACN]; B%: 18%-48%, 10min) to give Compound 6 (37.5mg , yield: 4.5%) as a bright yellow solid. 1H NMR:(ES6045-14-P1A, CDCl3, 400MHz)δ10.21 (br s, 1H), 9.01 (d, J = 8.0 Hz, 1H), 8.65 (s, 1H), 8.52 (d, J = 2.8 Hz, 1H), 7.87 (s, 1H), 7.20-7.28 (m, 1H), 6.95 (s, 1H), 6.84 (s, 1H), 6.50 (d, J = 16.0 Hz, 1H), 6.37-6.33 (m, 1H), 5.75 (d, J = 10.0 Hz, 1H), 3.92 (s, 3H), 2.91 (s, 2H), 2.75 (s, 3H), 2.33 (d, J = 4.0 Hz, 2H), 2.18 (s. 6H). LCMS: 488.1 [M+H]+, Rt = 3.615. HPLC: 98.31% purity (220 nm), Rt = 3.52. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: 2-phenylacrylic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 3h; Stage #2: 1H-pyrrolo[3,2-b]pyridine With dmap; triethylamine In dichloromethane Cooling with ice; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 1H-pyrrolo[3,2-b]pyridine With aluminum (III) chloride In dichloromethane at 20℃; for 1h; Inert atmosphere; Stage #2: acetyl chloride In dichloromethane at 20℃; Inert atmosphere; | (ii) General procedure: To a suspension of AlCl3 (5.0 equiv.) in anhydrous DCM(100 mMin azaindole) under N2 was added an azaindole (1.0equiv.). The reaction mixture was stirred at room temperaturefor 1 h, and acetyl chloride (5.0 equiv.) was addeddropwise. The reaction mixture was stirred at room temperatureovernight, cooled down on an ice bath for 15 min,quenched by slow addition of CH3OH (150 mL), stirred atroom temperature for 1 h, and concentrated under reducedpressure. The residue was dissolved in H2O (50 mL), basifiedto pH 12 with 2 M NaOH, and extracted with EtOAc(3 200 mL) and DCM (3 200 mL). The organic extractswere combined and concentrated under reduced pressure,and the residue was purified by flash column chromatography(silica gel, DCM ramping to DCM:CH3OH 92:8) togive the desired 3-acetylazaindole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With caesium carbonate In dimethyl sulfoxide at 80℃; Inert atmosphere; | 11.1 Step 1. Synthesis of tert-butyl (2R)-2-[[(4-methylpyridin-2-yl)oxy]methyl]pyrrolidine-1- carboxylate To a mixture of tert-butyl (2R)-2-[[(4-methylbenzenesulfonyl)oxy]methyl]pyrrolidine-1-carboxylate (200 mg, 0.56 mmol, 1.0 equiv) and 4-azaindole (133 mg, 1.13 mmol, 2.0 equiv) in DMSO (2.0 mL) was added Cs2CO3 (550 mg, 1.69 mmol, 3.0 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C overnight under nitrogen atmosphere. The reaction was quenched by the addition of water (1 mL) at 0 °C. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in w ater, 5% to 95% gradient in 30 min; detector, UV 254 nm and UV 220 nm. This resulted in tert-butyl (2R)-2-[[(4-methylpyridin-2-yl)oxy]methyl]pyrrolidine-1-carboxylate (100 mg, 59% yield). LCMS (ESI) [M+H]+: 302.1 S |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With Graphene oxide In 1,2-dichloro-ethane at 20℃; for 12h; Irradiation; Schlenk technique; Green chemistry; | 3.2. General Procedure of the Products 6 General procedure: In a 10 mL Schlenk tube, indole (0.3 mmol), GO (17.6 mg), and thiol (0.36 mmol) werestirred in DCE (1 mL) for 12 h at room temperature under an air atmosphere irradiated byblue LEDs. The reaction mixture was concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel (eluent: EtOAc/PE = 1:10) to yield thecorresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium iodide In acetonitrile at 35℃; for 4h; Electrochemical reaction; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With copper (I) iodide; Cs2CO3 In N,N-dimethyl-formamide at 120℃; for 16h; Inert atmosphere; | D Intermediate 170. 4-Bromo-2-(1H-pyrrolo[3,2-b]pyridin-1-yl)thiazole 1H-Pyrrolo[3,2-b]pyridine (1.0 g, 8.5 mmol) was added to a mixture of 2,4- dibromothiazole (2.5 g, 10 mmol), Cs2CO3 (6.9 g, 21 mmol), and DMF (25 ml). The resultant mixture was sparged with N2 for 5 minutes and then treated with Cul (1 .6 g, 8.4 mmol). The resultant mixture was sparged with N2 for another 5 minutes and then heated at 120 °C for 16 hours. After this time, the mixture was cooled to room temperature and filtered. The filtrate was diluted with saturated NH4CI (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the product, which was purified by FCC (eluent: petroleum ether: ethyl acetate = 1 :0 to 1 :1 ) to afford the title compound (900 mg, 30%) as a white solid. LCMS (ESI): mass calcd. for C10H6BrN3S 278.95 m/z, found 281.8 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.72% | In acetonitrile at 80℃; for 8h; | 1.1 Then 388mg (1mmol) intermediate products, 590mg (5mmol) 4-azaindole and 50mL acetonitrile were added to a 100mL round-bottom flask, stirred at 80 °C for 8h, stopped the reaction, cooled to room temperature and put into a -20 °C refrigerator, precipitated orange-yellow solids, filtered pure product 211.8mg, yield 49.72%. |
Tags: 272-49-1 synthesis path| 272-49-1 SDS| 272-49-1 COA| 272-49-1 purity| 272-49-1 application| 272-49-1 NMR| 272-49-1 COA| 272-49-1 structure
[ 4943-67-3 ]
5-Methyl-1H-pyrrolo[3,2-b]pyridine
Similarity: 0.92
[ 887570-96-9 ]
5-Fluoro-1H-pyrrolo[3,2-b]pyridine
Similarity: 0.82
[ 183586-34-7 ]
6-Methyl-1H-pyrrolo[3,2-c]pyridine
Similarity: 0.77
[ 1190320-15-0 ]
6-Methyl-1H-pyrrolo[3,2-c]pyridin-3-amine
Similarity: 0.75
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P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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