90% |
Stage #1: 5-chloroindole 2,3-dione With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Inert atmosphere;
Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; |
|
86% |
Stage #1: 5-chloroindole 2,3-dione With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.166667h;
Stage #2: benzyl bromide In N,N-dimethyl-formamide at 80℃; for 0.166667h; Microwave irradiation; |
Synthesis of Isatin Derivatives (1b-1f)
General procedure: A mixture ofisatin (5mmol) and potassium carbonate (8mmol) in DMF(10 mL) was stirred for 10minutes at roomtemperature. Alkylhalides (6mmol; benzyl bromide for preparation of 1c, 1d,and 1e; CH3I forpreparationof 1b; and1,3-dibromoethane forpreparation of 1f) were added dropwise to the reaction mixtureand then the reaction was microwave irradiated usinga multimode reactor (Synthos 3000, Anton Paar GmbH,Graz, Austria) (1,400W maximum magnetron). The vesselswere heated for 5 minutes at 80∘C and held at the sametemperature for a further 5 minutes (400 W). Cooling wasaccomplished by a fan (5 minutes). The final product wasdried and recrystallized from ethanol. All the spectral datafor the products obtained were in good agreement with thereported data. |
86% |
Stage #1: 5-chloroindole 2,3-dione With sodium hydride In N,N-dimethyl-formamide; paraffin oil at 0℃; for 1h; Inert atmosphere;
Stage #2: benzyl bromide In N,N-dimethyl-formamide; paraffin oil for 1h; Inert atmosphere; |
General procedure forthe synthesis of N-alkylindolin-2,3-diones
General procedure: To a stirring solution of indolin-2,3-dione (2.0g, 13.6 mmol, 1.0 equiv.) in anhydrous DMF, sodium hydride (60% suspension inparaffin oil, 0.65 g, 16.32 mmol, 1.2 equiv.) was slowly added at 0 oCunder inert atmosphere. After 1 h, benzyl bromide (1.78 mL, 14.96 mmol,1.1 equiv.) or prenyl bromide (1.73 mL, 14.96 mmol,1.1 equiv.) or methyl iodide ( 0.93 g, 14.96, 1.1equiv.) was added dropwise. Reaction mixture was stirred for another hour.Completion of the reaction was monitored by TLC. The reaction mixture was thenquenched with aq. NH4Cl, washed with water, extracted into ethylacetate. The ethyl acetate fraction was dried over anhydrous sodiumsulfate. It was evaporated under vacuumto give a solid compound which was purified by column chromatography on silicagel (60-120 mesh) using ethyl acetate-hexane (3:97) mixture as eluent. |
85% |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; |
|
84% |
Stage #1: 5-chloroindole 2,3-dione With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃;
Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 0℃; for 1h; |
4.2.1. 1-Benzylisatin 2a
General procedure: Isatin (6.14 g, 41.8 mmol) was placed in a 250 mL round bottom flask and dissolved in DMF (80 mL). The bright orange solution was cooled to 0 °C using an ice/water bath. Next, NaH (1.84 g, 46.0 mmol, 60 wt% in mineral oil) was added portionwise forming a deep purple solution. The resulting mixture was stirred until any effervescence had ceased. Then benzyl bromide (6 mL, 50.2 mmol) was added dropwise, and the resulting red-brown mixture was stirred for an additional 1 h at 0 °C. After being quenched by H2O (200 mL), the precipitated crude product was filtered and recrystallized from EtOH to give an orange solid (8.3 g, 84% yield). |
83.8% |
With tetrabutylammonium bromide; potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12h; |
N-substitution isatin derivatives 6j-p:
General procedure: In the presence of K2CO3 (1mol) and tetrabutylammonium bromide (1mol), isatin or substituted isatin 6a-i (0.5mol) was reacted with BnBr or CH3I (1mol) in DMF (6L) and the reaction mixture was stirred 12h at room temperature. Intermediates 6j-p were obtained by filtration and purified by recrystallization from acetic acid with high yield (72.7%-85.1%). |
78% |
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.333333h; |
|
72% |
Stage #1: 5-chloroindole 2,3-dione With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.166667h;
Stage #2: benzyl bromide In N,N-dimethyl-formamide for 12h; |
Synthesis of N-Benzyl Isatins 1g-n with Substituents on the PhenylRing; General Procedure
General procedure: To a round-bottomed flask was added isatin (5 mmol, 1 equiv), dimethylformamide(5 mL), and K2CO3 (6 mmol, 1.2 equiv), and thesolution was stirred at r.t. for ten minutes. The solution rapidly turneddark purple. Benzyl bromide, methyl iodide, allyl bromide, propargylbromide, or trityl chloride (5.5 mmol, 1.1 equiv) was added in oneportion. The reaction mixture rapidly changed color. After 12 h, water(10 mL) was added, then the suspension was vacuum filtered, and purifiedby column chromatography on silica gel to afford the product. |
66.84% |
Stage #1: 5-chloroindole 2,3-dione With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.25h;
Stage #2: benzyl bromide at 20℃; for 1h; |
Synthesis of 1-benzyl-5-chloro-isatin
5-Chloro isatin (0.5 g, 0.002 mol) was dissolved in DMF(3 mL) and the solution was cooled to 0 °C. NaH (0.167 g,0.006 mol) was added and the mixture stirred for 15 min at 0°C and then benzyl bromide (0.7 mL, 0.005 mol) was addeddropwise to the reaction mixture and stirred for 1 hour atroom temperature. It was diluted with water and extractedwith EtOAc (3x50 mL). The combined organic phase driedover anhydrous Na2SO4. Evaporation of the solvent gavecrude compounds, which were purified by column chromatography(hexane/ethylacetate 9:1) to give 1b (0.5 g,66.84%, M.p.: 123 °C, MS (ESI): m/z, 272.26 [M+1]+). |
|
With potassium carbonate In N,N-dimethyl-formamide at 20℃; |
|
|
Stage #1: 5-chloroindole 2,3-dione With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; Inert atmosphere;
Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil for 1h; Inert atmosphere; |
|
|
Stage #1: 5-chloroindole 2,3-dione With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃;
Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25h; |
|
|
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25h; |
|
|
Stage #1: 5-chloroindole 2,3-dione With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 1h;
Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; for 72h; |
Synthesis of N-benzyl isatin and N-benzyl-5-chloro isatin
General procedure: Isatin and 5-chloro isatin (0.03 mol) was dissolved in DMF (6 ml) and the solution was cooled to 0°C. NaH (0.09 mol) was added and the mixture stirred for 15 min at 0°C and then 45 min at room temperature. Benzyl bromide (0.07 mol) was added dropwise to the rection mixture and stirred for 72h at room temperature. It was diluted with water and extracted with EtOAc (3x50 ml). The combined organic phase was dried over anhydrous Na2SO4. Evaporation of the solvent gave crude compounds, which were purified by column chromatography using hexane: ethyl acetate (9.5:0.5) and following EtOH crystallization. |
|
With potassium carbonate In acetonitrile for 24h; Reflux; |
Protection of Isatin (6)
General procedure: To a mixture of the protecting reagent RBr (0.2 mmol) and K2CO3 (0.138 g) in MeCN (10 mL), isatin (6) was added (0.147 g) at room temperature. After that, the reaction mixture was stirred 24 h at reflux. Then, the solvent was evaporated under vacuum, and the reaction crude was purified by column chromatography (SiO2, Hex:EtOAc 8:2), giving rise to the corresponding product 7. |
|
Stage #1: 5-chloroindole 2,3-dione With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃;
Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; |
|
|
With sodium hydride In N,N-dimethyl-formamide at 20℃; |
|
|
With potassium carbonate In N,N-dimethyl-formamide for 3h; Reflux; |
|
|
With potassium carbonate In N,N-dimethyl-formamide at 25℃; |
|
|
With sodium hydride In N,N-dimethyl-formamide Reflux; |
|
|
With potassium carbonate In acetonitrile Heating; |
General procedure for the synthesis of N-benzyl isatins
General procedure: Isatin (1 mmol), corresponding benzyl bromide (1 mmol) and K2CO3 (3 mmol) were heated in acetonitrile for 1-2 h. After completion of the reaction, solvent was removed under vacuum and the product was extracted using ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated. The product obtained was used for next step without further purification. |
|
With potassium carbonate In acetonitrile for 3h; Reflux; |
|
|
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; |
4.1.7 General procedure for synthesis of N-substituted isatins 13a-d
General procedure: To a mixture of isatins 12a,c (3mmol) and anhydrous potassium carbonate (1.24g, 9mmol) in dry DMF (15mL), bromomethane 9a or benzyl bromide 9b (6mmol) was added. The mixture was stirred at room temperature for 24h. The reaction mixture was poured into ice water. The formed precipitate was filtered off and washed with water and petroleum ether and recrystallized from ethanol to afford compounds 13a-d [29,30]. |
|
With potassium carbonate; potassium iodide for 3h; Reflux; |
4.1.3. Synthesis of N-substituted isatin derivatives 4a-f and 8a-l
General procedure: Isatin derivatives 1a-c (0.005 mol) were stirred in acetonitrile(20 mL) with (0.007 mol) of the appropriate methyl iodide 2, propyliodide 3 or benzyl bromide 7a-d in the presence of catalytic amountof potassium iodide with (0.010 mol) of dry potassium carbonate atreflux temperature. The reaction was monitored with TLC. Aftercomplete of reaction, the mixture was poured into ice-water, theformed solid was collected, washed with water and recrystallizedfrom ethanol-water to furnish the final compounds 4a-f and 8a-l[58-61]. |
|
Stage #1: 5-chloroindole 2,3-dione With potassium carbonate In N,N-dimethyl-formamide for 0.5h;
Stage #2: benzyl bromide In N,N-dimethyl-formamide |
2.1.General procedure for the synthesis of N1-alkylated-isatin/N1-alkylated-5-chloroisatinderivatives (3 or 4)
General procedure: The isatin/5-chloroisatin1(1 equiv.) and solid K2CO3 (1.2 equiv.) were taken ina 100 ml round bottom flask containing DMF (30 ml) as the solvent and thereaction was stirred for half-an-hour.The appropriate alkyl/benzyl bromide 2(1.2 equiv.) was added to the reaction mixture and stirred continuously for10-12 h until the starting material was consumed (monitored by TLC). Thereaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 ×50 mL). The organic layer was washed with brine (2 × 50 mL), dried over anhydrousNa2SO4 and filtered. The filtrate was evaporated and thecrude product was purified by using silica gel column chromatography (EtOAc:hexane = 3:7; Rf 0.7), as the red solid products (3 and 4) in 70-80% yields. The structures were established on the basisof their spectroscopic data and these were identical in all respects to thosereported earlier.[1,2] |
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With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; |
|
|
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide for 3h; Reflux; |
5.1.3. Preparation of N-alkyl/benzyl isatin derivatives 6a-o
General procedure: To a stirred mixture of isatins 3a-c (3.4 mmol), potassium carbonate(0.94 g, 6.8 mmol) and catalytic amount of potassium iodidein dry DMF (10 mL), the appropriate alkyl halide 5a-d (3.7 mmol) or benzyl bromide 5e (0.63 g, 3.7 mmol) was added, and the mixture was heated under reflux for 3 h. Then, the reaction mixture was poured into ice-water, the obtained solid was collected, washed several times with water, and recrystallized from ethyl alcohol to afford the N-substituted isatin derivatives 6a-o [27]. |
|
Stage #1: 5-chloroindole 2,3-dione With sodium hydride In N,N-dimethyl-formamide; mineral oil Cooling with ice;
Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.25h; Cooling with ice; |
|
|
Stage #1: 5-chloroindole 2,3-dione With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25h;
Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25h; |
|
|
With Cs2CO3 In N,N-dimethyl-formamide at 24.84℃; for 12h; |
2.1. Synthesis and crystallization
Isatins (A) (see Scheme 1), where X = H or Cl, wereconverted to the corresponding N-alkyl analogues (B) byreaction with the appropriate alkyl bromide in dimethylformamide solution in the presence of solid caesium carbonateacting as a weak base, giving yields in excess of 90% after areaction time of 12 h at 298 K. For the synthesis of the 3-hydroxyindolin-2-ones, (I) (see Scheme 1), a mixture of an N-alkylisatin,(B) (1.0 mmol), the appropriate aryl methylketone (1.0 mmol) and piperidine (0.2 mmol) in ethanol(10 ml) was stirred at 298 K for 6 h [24 h in the case of compound (Id)], after which time the starting materials were no longer detectable using thin-layer chromatography (TLC).The resulting solid products were collected by filtration, washed with cold ethanol (2 ml) and dried in air to give the products of type (I). |
|
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8h; Inert atmosphere; |
2.0 General procedure for the synthesis of N-protected isatins1 1 (GP-1)
General procedure: Commercially available isatins S1 were treated with different alkyl halides to prepare Nalkylatedwith in the presence of K2CO3 in DMF at room temperature for 8 h. To a stirredsolution of isatin S1 (1.0 g, 6.8 mmol, 1.0 equiv) and K2CO3 (2.3 g, 17.0 mmol, 3 equiv) in DMFwas added 1.5 equiv. of alkyl halide (MeI or BnBr or allyl bromide) and stirred for 8 h at roomtemperature. The reaction mixture was quenched with water and extracted with ethyl acetate (3 x20 mL). The combined organic fractions were washed with brine, dried over anhydrous Na2SO4,filtered and concentrated in vacuo. The crude residue was then purified by columnchromatography on silica gel with ethyl acetate-hexane (10/90 to 20/80) to provide compounds 1. |
|
Stage #1: 5-chloroindole 2,3-dione With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.333333h;
Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.333333h; |
|
|
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; |
|
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With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; |
|
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With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 6h; |
|
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With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; |
|
|
Stage #1: 5-chloroindole 2,3-dione With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h;
Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0 - 20℃; |
|
|
With potassium carbonate In N,N-dimethyl-formamide for 12h; Reflux; |
|
|
With potassium carbonate In acetonitrile for 4h; Reflux; |
|
|
Stage #1: 5-chloroindole 2,3-dione With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h;
Stage #2: benzyl bromide With potassium iodide In N,N-dimethyl-formamide Heating; |
|
|
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 0.75h; |
|