1H-Pyrrole-2-carboxylic acid, 5-formyl-, methyl ester

Anhydrous DMF (7.0 mL, 90.4 mmol) was cooled to 5-10 degrees Centigrade under nitrogen. POCl3 (7.8 mL, 83.7 mmol) was added dropwise to the cooled DMF over a couple of minutes. Dry 1, 2-dichloroethane (25 mL) was then added and the solution was cooled to 0-5 degrees Centigrade during the addition of 2 (9.46 g, 75.6 mmol) in dry 1, 2-dichloroethane (25 mL). The mixture was then heated to reflux for 15 minutes. The reaction was cooled to room temperature, treated with a mixture of ethyl acetate (60 mL) and water (75 mL), poured into saturated NaHCO3 (350 mL), and separated. The aqueous layer was washed three times with ether, and the combined organic extracts were washed twice with aqueous saturated Na2CO3, dried over Na2SO4, and evaporated under vacuum. The resulting solid was sublimed under reduced pressure (20'10'3 torr) at 60 degrees Centigrade in 3-hour intervals to yield compound 3 (7.79 g, 50.1 mmol, 66percent). 1H-NMR (CDCl3): ' 10.57 (br s, 1H), 9.70 (s, 1H), 6.95 (m, 2H), 3.94 (s, 3H).Phosphorylchloride (4.39 mmol, 0.4 mL) was added dropwise to 0.34 mLDMF at 0 C. The reaction was allowed to reach room temperatureand 2.2 mL of dry CH2Cl2 were subsequently added. The mixturewas cooled again to 0 C and a solution of 6 (500 mg, 4 mmol)was added dropwise within 1 h. The reaction mixture was thenrefluxed for 4 h, cooled to 0 C and hydrolysed with a solution ofsodium acetate (1.8 g, 22 mmol) in water (5.5 mL). The phaseswere separated and the aqueous phase was extracted with ethylacetate. The combined organic extracts were dried with Na2SO4and concentrated. The residue was purified by flash chromatography(eluent; hexane/ethyl acetate = 5/1) to afford 387 mg of compound7 (yield = 63percent). Characterization was in agreement withliterature data.17 1H NMR (500 MHz, DMSO-d6) d 13.07 (s, 1H), 9.70 (s, 1H), 6.97 (d, J = 3.9 Hz, 1H), 6.90 (d, J = 3.9 Hz, 1H), 3.83(s, 3H).To the stirred solution of methyl 1H-pyrrole-2-carboxylate (0.9 g, 7.19 mmol) in DMF (4.2 g, 57.52 mmol) at 0 00, POOl3 (5.5 g, 35.96 mmol) was added. The reaction mixture was stirred at 10 00 for 30 mm at room temperature over night. The reaction mixture was quenched with sodium hydroxide solution and extracted using ethyl acetate dried over anhydrous Na2SO4. The crude mixture of products was purified by column chromatography to yield the title compound polar spot (0.53 g, 48.18percent) as a pale yellow solid. LCMS: (M-H) = 152.1; 1H NMR: (DMSO-d6, 300MHz) 6 12.73 (5, 1H), 7.76 (5, 1H), 7.82-7.83 (d, 1H), 7.14 (5, 2H), 3.81 (5, 3H). Intermediate 12a: Methyl 5-formyl-1H-pyrrole-2-carboxylate was formed along with11 a. Upon separation of 11 a and 1 2a, intermediate 1 2a obtained (0.5 g, 45.45percent) asa pale yellow solid. LOMS: (M-H) = 152.1To a solution of intermediate 1 2a (0.1 g, 0.7 mmol) in mixture of solvents methanol(i mL) and THF(i mL), NaOH (0.13 g, 3.25 mmol) was added and stirred at 0C for 3 h.The solvent was removed under reduced pressure; salt was washed with diethyl ether to remove impurities. It was acidified with 1 N HCI, extracted with ethyl acetate. The combined organic layer was dried and evaporated to yield title product (0.080 g, 88.0%) as beige solid. 1H NMR: (DMSO-d6, 300MHz) 6 13.08(5, iH), i2.89(s, iH), 9.69(s, 1 H), 6.94(s 1 H), 6.84(s 1 H).To a solution of intermediate 12a (0.1 g, 0.7 mmol) in mixture of solvents methanol(i mL) and THF (1 mL), NaOH (0.13 g, 3.25 mmol) was added and stirred at 0 00 for 3h. The solvent was removed under reduced pressure; salt was washed with diethyl ether to remove impurities. It was acidified with 1 N HCI, extracted with ethyl acetate. The combined organic layer was dried and evaporated to yield title product (0.080 g, 88.0%) as beige solid. 1H NMR: (DMSO-d6, 300MHz) 6 13.08(s, 1H), 12.89(s, 1H), 9.69(s, 1 H), 6.94(s 1 H), 6.84(s 1 H).General procedure: To the stirred solution of methyl 1H-pyrrole-2-carboxylate (0.9 g, 7.19 mmol) in DMF(4.2 g, 57.52 mmol) at 000, POOl3 (5.5 g, 35.96 mmol) was added. The reaction mixture was stirred at 10 00 for 30 mm and at room temperature over night. The reaction mixture was quenched with sodium hydroxide solution and extracted usingethyl acetate dried over anhydrous Na2SO4. The crude product was purified by column chromatography to yield the title compound polar spot (0.53 g, 48.18%) as a pale yellow solid. LCMS: (M-H) = 152.1; 1H NMR: (DMSO-d6, 300MHz) 6 12.73 (5, 1H), 7.76 (5, 1H), 7.82-7.83 (d, 1H), 7.14 (5, 2H), 3.81 (5, 3H).Compound 1F (1 g, 2.6 mmol) obtained in the previous step was added to EtOH (30 ml) and the mixture was stirred until completely dissolved.Then To a stirred solution of above pyrrole (3.50 g, 23.0 mmol) in DMSO (25 mL) was added a solution of monosodium phosphate (21.4 g, 137 mmol) in water (30 mL). A solution of sodium chlorite (7.44 g, 67.0 mmol) in water (15 mL) was added dropwise over 20 min and the resulting solution stirred at ambient temperature for 3 h. The reaction was quenched by addition of sat. aq. NaHCO3 (50 mL), water (100 mL) was added, and the mixture washed consecutively with Et2O (50 mL) and EtOAc (50 mL). The mixture was acidified to pH = 1 with 1M aq. HCl and extracted with EtOAc (3x 50 mL). The combined organics were washed with brine (3x 50 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford 16 as white solid (2.51 g, 65%). Experimental data as per literature. ADDIN EN.CITE Ranganath2016171117117125Ranganath, M. J. R.Madhavan, G. R.Shanmugam, P.Spiro-Substituted Oxindole Derivatives Having AMPK ActivityUnited States Patent ApplicationUnited States Patent Application2016United States1 1H NMR (500 MHz, DMSO-d6): delta 3.77 (s, 3H), 6.75 (d, J = 3.9 Hz, 1H), 6.80 (d, J = 3.9 Hz, 1H), 12.45 (s, 1H), 12.80 (br s, 1H). 13C NMR (125 MHz DMSO-d6): delta 51.6, 115.3, 115.5, 126.2, 128.1, 160.5, 161.4.To asolution of aldehyde 7 (50 mg, 0.326 mmol) in 10 mL acetonewas added dropwise a solution of KMnO4 (155 mg, 1 mmol) in10 mL of acetone:water (1:1). After 3 h, the reaction was quenchedwith a solution of 10% NaHSO3 and acidified with 1 N HC1. Thesolution was extracted several times with ethyl acetate(10 3 mL). The combined organic extracts were dried with Na2-SO4 and concentrated. The residue was used to the next step withoutfurther purification. Characterization was in agreement withliterature data.18 S1: 1H NMR (300 MHz, DMSO-d6) d 12.28 (s, 1H), 6.80 (d, J = 3.9 Hz, 1H), 6.75 (d, J = 3.9 Hz, 1H), 3.78 (s, 3H).

Molecular Weight:153.14
XLogP3:0.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:153.042593085
Monoisotopic Mass:153.042593085
Topological Polar Surface Area:59.2
Heavy Atom Count:11
Complexity:169
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes