1-Methyl-1,3-dihydroindol-2-one

Light-Yellow Solid

To 5 L 4-neck flask (equipped with a mechanical stirrer, condenser and N2 inlet) was charged with 2 L water and 50percent sodium hydroxide (NAOH) (2.52 mol, 201.6 g, 2.25 equiv) followed by oxindol (1.12 mol, 150 g, 1 equiv) and the reaction mixture was heated TO-40° C. Dimethylsulfate (1.68 mol, 211.7 g (159 mL), 1.5 equiv) was added slowly via syringe. The addition was slightly exothermic with temperature rising to 53° C. When addition was complete, the reaction mixture was heated to- 100° C and held for 15 minutes (min). The reaction mixture was cooled TO-600 C, and a second portion of dimethylsulfate (0.476 mol, 60 g (45 mL), 0.425 equiv) was added. The reaction mixture was heated TO ~ 100° C and held 15 min. TLC (heptane/ethyl acetate (EtOAc), 1: 1) show methylation was essentially complete. The reaction mixture was cooled TO-50° C and the pH adjusted to-7 with concentrated HCI. The reaction mixture was seeded, cooled to room temperature and allowed to stand overnight. The solids were collected, wash with water (4X) and dried overnight in a vacuum over AT-40° C to give 110.7 g (67percent) of 1-methyl-1, 3-dihydroindol-2-one as a pink solid, mp 84-86° C.A stirred mixture of sodium hydride (60percent, 31g, 0.79 mol) in dry xylene (500 mL), under a nitrogen atmosphere, was heated to reflux for 30 min. l, 3-Dihydro-indol-2-one 16a (100 g, 0.75 mol) was then slowly added via an addition funnel and stirred at reflux for 1.5 hrs. Dimethyl sulfate (104 g, 0.83 mol) was added drop-wise, whereupon the resulting homogeneous solution was refluxed for an additional 2 hrs. After cooling to room temperature, the reaction mixture was washed with water, dried over Na2SC>4, and concentrated under reduced pressure to afford l-methyl-l, 3-dihydro-indol-2-one 16b (74 g, 67.3percent). General procedure: Isatin (0.1 mol, 14.7 g) was dissolved in DMF (60 mL) and finely ground anhydrous K2CO3 (0.15 mol, 20.7 g) was added under stirring. RX (0.15 mol) was added dropwise and mixture was heated at 60–70°C for 3 h (as alkylation reagent RX were used Me2SO4, EtI, n-PrBr, AmBr, BnCl, PMBCl, respectively). After cooling to room temperature mixture was poured into ice water (200 mL).Precipitated orange solid was filtereted, washed with water and recrystallized from ethanol (95percent) togive N-alkylated isatins as red crystalls in 37–92percent yield. The purity of obtained compounds weredetermined by melting points, which corresponded to those published in the literature (ref. 2–4).N-Substituted isatin (10 mmol) was mixed with 16 M N2H4·H2O (15 mL). The suspension was heatedat reflux 3 h (caution: rapid gas evolution), then it was cooled to room temperature, diluted with waterS4(40 mL) and extracted with EtOAc (3 x 25 mL). Organic phase was washed with water (25 mL), brine (25 mL), then it was dried over Na2SO4 and evaporated under reduced pressure to give the desired product. The latter was recrystallized from hexane and small amount of EtOAc to give N-substituted indolin-2-one as yellow solid in 47–96percent yield. The purity of obtained compounds were determined by melting points and 1H NMR spectra data, which corresponded to those published in the literature (ref. 5, 6).N-Substituted indolin-2-one (2 mmol) were dissolved in dry DMF (5 mL) and NaH (60percent dispersion in mineral oil, 6 mmol, 240 mg) was portionwise added carefully at a temperature of –15 °C. When the rapid evolution of H2 stops, the mixture allowed to stir for 10 min. Then solution of 1, 2-dibromoethane (508 mg, 2.7 mmol) in dry DMF (3 mL) was added to the mixture. The latter was warmed to room temperature and stirred overnight. Then it was cooled with ice, diluted with water (20 mL) and extracted with PhMe (2 x 15 mL). Organic phase was washed with water (2 x 15 mL), brine (15 mL) and then it was dried over Na2SO4. Evaporation under reduced pressure gave the desired product. The latter was washed with hexane to remove mineral oil or purified by flash column chromatography (eluent: hexane/CH2Cl2). The spiro[cyclopropane-1, 3'-indolin]-2'-ones 1 are yellow solids, except N-amyl substituted spiro[cyclopropane-1, 3'-indolin]-2'-one, which is brown liquid. The purity of obtained compounds were determined by 1H NMR spectra data. Corresponding cyclopropanes were previously known in the literature (ref. 7–11).General procedure: A mixture of substitutedisoindigo (0.2 mmol) and hydrazine hydrate (3 ml) in freshly distilled EtOH(3 ml) was heated at 45 C for 10 min. The solvent and volatiles wereevaporated to afford pure products as white solids which did not need to bespecially purified.N-methylaniline (20 mL, 186 mmol) was dissolved in toluene (250 mL), and chloroacetyl chloride (15.8 mL, 198 mmol) was added slowly. Then the mixture was refluxed for 2h. Water (50 mL) was added after the mixture was cooledto room temperature and the mixture was stirred for 3h to decompose the chloroacetylchloride. Toluene layer was washed first with 10percent K2CO3 in water solution. And it wascontinuously added with HCl (2M) before drying overnight with sodium sulfate. Aftertoluene was evaporated, AlCl3 (82 g) was added, and the mixture was stirred for 10 minat 70. Then the above mixture was stirred at 210 for 90 min. The reaction mixture wasslowly poured into ice water, and then concentrated HCl (50 mL) was added. The mixturewas extracted with chloroform and chloroform layer was dried over sodium sulfate. Afterevaporating chloroform, the solid was recrystallized with hexane. N-methyloxindole (16 g)was prepared in total yield 66.6percent of the two step. 1H-NMR (300MHz, CDCl3) δ(ppm) : 7.29–7.20 (m, 2H), 7.05–7.00 (t, 1H), 6.81–6.78(d, 1H), 3.47 (s, 2H), 3.18 (s, 3H).0.4 mL of 1, 4-dioxane was added to a 50 mL reaction tube at room temperature.Add 2mL of water, Stir and mix, Weighing 1-fluoro-1, 2-phenyliodohydrin-3-(1H)-one (175 mg, 0.66 mmol) was added to the reaction tube and stirred for 1 min.After the reaction tube was placed in a 140 ° C oil bath, Was added N- methylindole (78mg, 0.6mmol), And with a built-in condenser, react in a 140 ° C oil bath for 5 hours.The TLC dot plate showed complete reaction of the starting material.Take the reaction tube out of the oil bath and cool to room temperature.The reaction was quenched by the addition of 10 mL of saturated sodium bicarbonate.Extracted with 20 mL of ethyl acetate.The organic layer was combined, dried over anhydrous sodium sulfate and evaporated.The yellow solid N-methyl-2-indanone 79 mg was obtained by column chromatography to give a yield of 90percent.Add diethyl azodicarboxylate (DEAD, 8.0 g, 44.9 mmol) dropwise to a solution of indolin-2-one (4.0 g, 30.0 mmol), methanol (1.4 g, 44.9 mmol) and triphenylphosphine (12.0 g, 44.9 mmol) in THF (40 mL) at 0° C., stir the reaction at room temperature overnight. To a 10-mL oven-dried vial containing a magnetic stirring bar, isatin 2a (35.6 mg, 0.15 mmol), and PhCF3 (1.0 mL), was added a solution of diazo compound 1a (52.6mg, 0.3 mmol) in PhCF3 (1.0 mL) via a syringe pump in 50 min at 90 oC. After the addition, the reaction mixture was monitored by proton NMR after the solvent was evaporated in vacuo at different reaction times (the time including the 50 min for the addition of 1a)General procedure: An oven-dried 10 mL microwave vial was charged with R-BMIDA (0.1 mmol, 1 equiv) before the addition MeOH (4 mL). The vial was capped before the addition of KHF1, 3-Dimethyl-5-propylaminomethylenepyrimidine-2, 4, 6-trione (6a) (Method B) The mixture of 1-propylamine (0.17 mL, 2 mmol), 1, 3-dimethylbarbituric acid 2a 0.312 g, 2 mmol) and triethyl orthoformate (0.4 mL, 2.5 mmol) was refluxed for 15 min in EtOH (2.5 mL). Filtered residue of 6a was recrystallized from EtOH, to give 6a

1-Methyl-2-oxindole is used in the prevention and therapy of atherosclerotic degradation of arterial walls.

Molecular Weight:147.17
XLogP3:1
Hydrogen Bond Acceptor Count:1
Exact Mass:147.068413911
Monoisotopic Mass:147.068413911
Topological Polar Surface Area:20.3
Heavy Atom Count:11
Complexity:178
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes