Structure of 73568-41-9
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| CAS No. : | 73568-41-9 |
| Formula : | C10H5Cl2NO |
| M.W : | 226.06 |
| SMILES Code : | O=CC1=CC2=CC(Cl)=CC=C2N=C1Cl |
| English Name : | 2,6-Dichloroquinoline-3-carbaldehyde |
| MDL No. : | MFCD06202347 |
* 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 |
|---|---|---|
| 87% | With hydrogenchloride Heating; | |
| With acetic acid Reflux; | ||
| With hydrogenchloride In water Reflux; |
| With water; acetic acid Reflux; | ||
| With acetic acid Reflux; | ||
| With water; acetic acid Reflux; | ||
| With acetic acid In water Reflux; | General procedure for the synthesis of N-methyl, N-phenyl and thiosemicarbazone derivatives (5a-o) General procedure: The substituted 2-chloroquinoline-3-carbaldehydes (3a-e)(1 mmol) was heated under reflux with 70% acetic acid (10 mL) for 4-6 h and upon cooling the product preciptated out of solution to form (4a-e). The thiosemicarbazone derivatives were then formed according to the method in Bisceglie et al.[31] Substituted thiosemicarbazides, 4-methylthiosemicarbazides or 4-phenylthiosemicarbazides(1.0 mmol) dissolved in methanol (80 mL) were added to an equivalent amount of 4a-e (200 mg; 1.0 mmol) and the solution stirred at room temperature for 24 h. Upon completion, the flask was placed in an ice bath, where a solid formed, which was filtered, washed with ethanol and dried. | |
| With acetic acid | ||
| With acetic acid Reflux; | ||
| 10 g | With acetic acid In water at 95℃; | 77 Preparation 77.6-Chloro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (P1.72) A solution of P1.71 (24 g, 106 mmol, 1.0 eq) in a solution of 70% AcOH in H2O (530 mL) was stirred at 95°C overnight. The mixture was cooled to rt. The resulting solid was collected by filtered and washed with H2O. The solid was dissolved in MeOH. The solution was dried over MgSO4, filtered, and concentrated to give the desire product P1.72 as a pale-yellow solid (10 g) which was directly used for next step without further purification.1H NMR (400 MHz, DMSO-d6), δ: 12.3 (br. s, 1H), 10.2 (s, 1H), 8.48 (s, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.68 (dd, J = 8.8, 2.4 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H). |
| 10 g | With acetic acid In water at 95℃; | 77 Preparation 77.6-Chloro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (P1.72) A solution of P1.71 (24 g, 106 mmol, 1.0 eq) in a solution of 70% AcOH in H2O (530 mL) was stirred at 95°C overnight. The mixture was cooled to rt. The resulting solid was collected by filtered and washed with H2O. The solid was dissolved in MeOH. The solution was dried over MgSO4, filtered, and concentrated to give the desire product P1.72 as a pale-yellow solid (10 g) which was directly used for next step without further purification.1H NMR (400 MHz, DMSO-d6), δ: 12.3 (br. s, 1H), 10.2 (s, 1H), 8.48 (s, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.68 (dd, J = 8.8, 2.4 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H). |
| 1847 mg | With water; acetic acid at 95℃; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With sodium tetrahydroborate In methanol for 0.5h; Ambient temperature; | ||
| With methanol; sodium tetrahydroborate at 20℃; | ||
| With sodium tetrahydroborate In methanol at 20℃; |
| With sodium tetrahydroborate In methanol at 20℃; | Preparation of 3-azidomethyl-2-chloro-6/7/8-substituted quinoline (7c-i) General procedure: To a well stirred mixture of 2-chloroquinoline-3-carbaldehyde (2c-i) (0.01 mol) in methanol (10 ml), NaBH4 (0.01 mol) was added in small portions and the mixture was stirred at room temperature for 15-20 min. The completion of the reaction was monitored by TLC and the reaction mixture was concentrated under vacuum. The mixture was poured into ice cold water and the (2-chloroquinolin-3-yl) methanol separated as solid was filtered off and recrystallised from ethyl acetate. (2-Chloroquinolin-3-yl) methanol (0.01 mol) was further dissolved in DCM (10-15 ml) at 5°C and stirred well. After 10-15 min, PBr3 (0.06 mol) was added drop wise and stirred at room temperature for 1 h. After completion of the reaction, DCM was removed under vacuum and the mixture was poured into ice and neutralized by adding a saturated solution of NaHCO3. The precipitate of 3-(bromomethyl)-2-chloroquinoline was filtered and dried. The so formed 3-(bromomethyl)-2-chloro quinoline (0.010 mole) was taken in acetone (20 ml) in a round-bottom flaskamnd to this sodium azide (0.012 mole) in water (3.00 ml) was added drop wise with stirring, which was continued for 10 hr. The reaction mixture was then poured into ice-cold water. 3-Azidomethyl-2-chloro-6/7/8-substituted-quinoline 7c-i separated as solid was filtered and recrystallized using ethanol. | |
| With sodium tetrahydroborate In methanol at 20℃; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 88% | With sodium dodecyl-sulfate; trichlorophosphate In acetonitrile for 1.5h; Heating; | |
| 65% | With trichlorophosphate In 1,2-dichloro-ethane at 40℃; for 1h; ultrasound irradiation; | |
| 45% | With trichlorophosphate at 85℃; for 24h; |
| 36% | With trichlorophosphate at 80 - 90℃; for 16h; | |
| 36% | Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0 - 5℃; for 1h; Stage #2: 4-Chloroacetanilide at 0 - 80℃; Inert atmosphere; | 1.1 General procedure for synthesis of 2-chloroquinoline-3-carbaldehydes (13-18) General procedure: A round bottom flask charged with N, N-dimethylformamide (7.0 mol) was placed on an ice bath and the temperature kept at 0-5 °C. To this flask, phosphorus oxychloride (12.0 mol) was added dropwise and the reaction mixture was stirred for 1 h at 0-5 °C. The appropriate N-phenylacetamide (1.0 mol) was then added and stirred for a further 30 min followed by heating under reflux for 5-4 h under N2 atmosphere. After the reaction was completed (TLC monitoring), the mixture was poured into 200 g of crushed ice under constant stirring. The precipitate obtained was vacuum filtered, washed with water (2 × 30 mL), air-dried and recrystallised from EtOAc to give the relevant compounds in 36-84% yields. |
| With trichlorophosphate 1.) 0 deg C, 0.5 h, 2.) 70 deg C, 16 h; Multistep reaction; | ||
| With trichlorophosphate at 5 - 75℃; for 4h; | 25 2,6-Dichloroquinoline-3-carbaldehyde POCl3 (31.1 g, 210 mmol) was added to DMF (6.5 g, 90 mmol) while keeping the temperature below 5° C. 4-Chloroacetanilide (5.07 g, 30 mmol) was added in one portion and the reaction mixture was heated to 75° C. for 4 hours. The reaction mixture was cooled to room temperature and poured onto ice. The separated crystals were filtered and dried. Yield 220 mg. M.p. 188-190° C. | |
| With trichlorophosphate | ||
| With trichlorophosphate at 0 - 75℃; for 6h; | ||
| With trichlorophosphate | ||
| With trichlorophosphate | ||
| Stage #1: N,N-dimethyl-formamide With trichlorophosphate Stage #2: 4-Chloroacetanilide | ||
| With trichlorophosphate Heating; | ||
| With trichlorophosphate at 0℃; Reflux; | General procedure for the synthesis of 6-substituted-2-chloroquinoline-3-carbaldehydes 2a-d (Meth-Cohnet al., 1981) General procedure: Dimethylformamide 9.6 mL (0.125 mol)was cooled to 0 C, and phosphoryl chloride 32.2 mL(0.35 mol) was added drop-wise with stirring. To thissolution was added substituted acetanilide 1a-d (0.05 mol)and the reaction mixture was refluxed for 16-17 h. Reactioncompletion was monitored by TLC. The reactionmixture was poured into ice water (300 mL) and stirred for30 min at 0-10 °C. The resulting suspension was filteredand washed with water to give the intermediates 2a-d. | |
| With trichlorophosphate at 80 - 100℃; | Step II Preparation of 2-chloro-3-formylquinoline CFQ 8, 9 General procedure: To a s o l u t i o n o f a c e t a n i l i d e(N-phenylacetamide) (5 mmoles) in dry DMF (15mmoles) at 0-5oC POCl3 (60 mmoles) was addeddropwise with stirring and the mixture was thenstirred at 80 - 100oC for time ranging between 4-16hr. The mixture was poured on to crush ice, stirredfor 5 minutes and the resulting solid fltered, washedwell with water and dried. The compounds wererecrystallized from ethyl acetate. Phosphoryl chloride(commonly called phosphorus oxychloride) is acolorless liquid with the formula POCl3. It hydrolysesin moist air to phosphoric acid to release choking fumes of hydrogen chloride. It is manufacturedindustrially on a large scale from phosphorustrichloride and oxygen or phosphorus pentoxide. Itis mainly used to make phospha (Table 1). | |
| With trichlorophosphate | ||
| Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; Stage #2: 4-Chloroacetanilide at 80℃; for 18h; | ||
| With trichlorophosphate at 0 - 82℃; for 24h; Inert atmosphere; | ||
| With trichlorophosphate for 24h; Heating; | ||
| With trichlorophosphate at 80 - 90℃; | ||
| With trichlorophosphate at 0℃; for 16h; Reflux; | 2.3.1 General procedure for the synthesis of 6/7/8-substituted-2-chloro quinoline-3-carbaldehydes (2) General procedure: Dimethyl formamide (9.13g, 9.9ml, and 0.125mole)wasfrozento 0°C in a flask along with a drying tube and phosphoryl chloride (53.7g, 32.2ml. 0.35mole) was mixed drop wise with stirring. The substituted acetanilide (1) (6.55g, 0.05mole) was added to the mixture and the mixture was heated under reflux for 16h. The product obtained was added into ice cold water and stirred for 30min at 0-10°C. 6/7/8-Substituted-2-chloro quinoline-3-carbaldehyde (2) separated as yellow precipitate. It was filtered, washed with water and recrystallized from ethyl acetate. | |
| With trichlorophosphate at 70 - 80℃; for 16h; | Preparation of 2-chloroquinolin-3-carbaldehyde (6c-i) General procedure: Vilsmeir-Haack adduct was prepared by adding phosphorous oxychloride (0.35 mol) drop wise to the cold solution of DMF (0.125 mol) with constant stirring. To this adduct, substituted acetanilide (0.05 mol) was added slowly and stirred well for 15-20 min. The mixture was then refluxed for 16 h at 70-80°C. After completion of the reaction, the contents were poured into ice water and stirred for 30 min. The 2-chloroquinoline-3-carbaldehyde 6c-i precipitated out was filtered and washed well with water. Dried and recrystallized from ethyl acetate. | |
| Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; for 0.25h; Stage #2: 4-Chloroacetanilide at 80℃; for 8h; | ||
| With trichlorophosphate for 6h; Reflux; | ||
| With trichlorophosphate at 0℃; Reflux; Heating; | General procedure for the synthesis of N’-substituted-2-chloroquinoline-3-carbaldehydes2(a-e) and N’-substituted-2-methoxyquinoline-3-carbaldehydes 5(a-e) General procedure: Dimethylformamide 9.6 mL (0.125 mol) was takenin round bottom flask equipped with drying tube and phosphorus oxychloride 32.2 mL (0.35 mol) was added drop wise with continuous stirring at 0°C. To above solution different aryl acetanilide 1(a-e) (0.05 mol) were added and after 5 min the solution is heated under reflux for 16-17 h. The completion of the reaction was monitored by TLC, reaction contents were decanted into crushed ice with constant stirring. The settled solid was sieved, washed with water, dried and purified by recrystallization using ethyl acetate to afford final pure product 2(a-e) in good yield. | |
| With trichlorophosphate at 0 - 90℃; | General procedure for the synthesis of 6-substituted-2-chloro-3-formyl quinolines, 2 General procedure: To a solution of substituted acetanilide (5 mmol) indry dimethyl formamide (15 mmol) at 0-5°C withstirring POCl3 (60 mmol) was added drop-wise andthe mixture stirred at 80-90°C for time rangingbetween 4-16 h. The product obtained was pouredinto crushed ice, stirred for 5 min and the resultingsolid mass was filtered, washed well with water anddried. The compounds were recrystallized from ethylacetate. | |
| With trichlorophosphate at 80 - 90℃; | Synthesis of substituted quinoline-3-carbaldehydes (1a, b) General procedure: 6-substituted-2-chloro-quinoline-3-carbaldehydes (1a-b) were prepared by Vilsmeier-Haack reaction from substituted acetanilide using DMF and POCl3 as per the reported protocol. The reported melting points of compounds 1a and 1b are 146-148°C and 188-192°C, respectively, and the observed melting points of these intermediates were found to be 146-150°C and 188-190°C, respectively. | |
| With trichlorophosphate at 0℃; Reflux; | ||
| With trichlorophosphate at 0 - 90℃; | 4.2.2. General procedure for synthesis of compound 3 General procedure: DMF (42 mmol) was added dropwise to a solution of compound 2(16.7 mmol) in POCl3 (116.7 mmol) at 0 C, after completion, the icewaterbath was removed, the solution was heated to 90 C and stirredfor 6 h (monitored by TLC, VEA/VPE = 1/2). The solution was allowed tocool to room temperature, poured into ice water (200 mL) and theresulting mixture was stirred for 30 min. The precipitate was filtered andwashed with saturated sodium bicarbonate solution and afforded 3 as ayellow solid. Yield 40 % ~ 70 %. The crude 3 was used directly in thenext step without further purification. | |
| With trichlorophosphate at 0 - 90℃; | 4.2.2. General procedure for synthesis of compound 3 General procedure: DMF (42 mmol) was added dropwise to a solution of compound 2(16.7 mmol) in POCl3 (116.7 mmol) at 0 C, after completion, the icewaterbath was removed, the solution was heated to 90 C and stirredfor 6 h (monitored by TLC, VEA/VPE = 1/2). The solution was allowed tocool to room temperature, poured into ice water (200 mL) and theresulting mixture was stirred for 30 min. The precipitate was filtered andwashed with saturated sodium bicarbonate solution and afforded 3 as ayellow solid. Yield 40 % ~ 70 %. The crude 3 was used directly in thenext step without further purification. | |
| 24 g | Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0 - 20℃; Stage #2: 4-Chloroacetanilide at 0 - 90℃; | 76 Preparation 76.2,6-Dichloroquinoline-3-carbaldehyde (P1.71) A solution of POCl3(150 mL, 1.59 mol, 9.0 eq) in DMF (28 mL) was stirred at 0°C for 10 min and then at rt for 15 min. To the solution was added N-(4-chlorophenyl)acetamide (30 g, 177.48 mmol, 1.0 eq) at 0 °C in one portion. After the solution was stirred at 90°C overnight, the reaction mixture was diluted with H2O (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic layers were washed with brine solution, dried over MgSO4, filtered, and concentrated to give P1.71 as a brown solid (24 g) which was used for the next step without further purification.1H NMR (400 MHz, CDCl3), δ: 10.52 (s, 1H), 8.67 (s, 1H), 8.03- 8.00 (m, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.83-7.78 (m, 1H). |
| 24 g | Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0 - 20℃; Stage #2: 4-Chloroacetanilide at 0 - 90℃; | 76 Preparation 76.2,6-Dichloroquinoline-3-carbaldehyde (P1.71) A solution of POCl3(150 mL, 1.59 mol, 9.0 eq) in DMF (28 mL) was stirred at 0°C for 10 min and then at rt for 15 min. To the solution was added N-(4-chlorophenyl)acetamide (30 g, 177.48 mmol, 1.0 eq) at 0 °C in one portion. After the solution was stirred at 90°C overnight, the reaction mixture was diluted with H2O (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic layers were washed with brine solution, dried over MgSO4, filtered, and concentrated to give P1.71 as a brown solid (24 g) which was used for the next step without further purification.1H NMR (400 MHz, CDCl3), δ: 10.52 (s, 1H), 8.67 (s, 1H), 8.03- 8.00 (m, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.83-7.78 (m, 1H). |
| 65 % | Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; Stage #2: 4-Chloroacetanilide at 70℃; | General procedure for the synthesis of 2-chloro-3-formylquinoline (4 a-b) General procedure: To N, N-dimethylformamide (4.55 mL, 58.0 mmol, 4equiv.), phosphorous oxychloride (13 mL 0.000147 mmol,10 Equiv.) was added dropwise and stirred at 0 °C for30 min to get Vilsmeier reagent. The substituted acetanilide(2 g, 14.7 mmol, 1 equiv.) was added in the in situ preparedVilsmeier reagent at 70 °C. After completion of the reaction,the reaction mixture was cooled and poured overcrushed ice. Precipitate was filtered, washed with water, anddried to get a yellow crude product. The desired productwas isolated with column chromatography (100-200 meshsize silica) in 10% ethyl acetate in hexane as amobile phase. |
| With trichlorophosphate at 70℃; for 12h; | ||
| Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; for 0.166667h; Inert atmosphere; Stage #2: 4-Chloroacetanilide for 8h; Inert atmosphere; | ||
| With trichlorophosphate at 85℃; for 18h; | ||
| With trichlorophosphate at 0℃; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 61% | With sodium hydride In dimethyl sulfoxide at 90℃; for 2h; | 4.2. General procedure for the preparation of 2-arylthioquinoline-3-carbaldehyde 2 General procedure: To a mixture of thiophenol (11 mmol), NaH (20 mmol), and DMSO (20 mL) was added 2-chloro-3-formylquinolines 1 (10 mmol) and the mixture was heated at 90 °C for the given time. Then the reaction was quenched with water (60 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic layer was washed with brine solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The desired products 2 were obtained by flash column chromatography on silica (n-hexane/EtOAc, 10:1→6:1, v/v). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 85% | With piperidine In ethanol Reflux; | 6.1.1.4. 2-Amino-4-(2,6-dichloro(3-quinolyl))-7,7-dimethyl-5-oxo-1-phenylamino-1,4,6,7,8,-pentahydro quinoline-3-carbonitrile (5d) General procedure: A 100 mL round bottomed flask, fitted with a reflux condenser, was charged with a mixture of 2-chloro-3-formyl quinolines 2a-d (1 mmol), malononitrile (1 mmol), enhydrazinoketones 4a-f (1 mmol), and a catalytic amount of piperidine in ethanol (10 mL). The mixture was heated under reflux for 2-3 h and the progress of the reaction was monitored by TLC. After the completion of reaction (as evidenced by TLC), the reaction mixture was cooled to room temperature and stirred magnetically for further 20 min, the solid mass separated was collected by filtration, washed well with ethanol (10 mL) and purified by leaching in equal volume ratio of chloroform and methanol (10 mL) to obtain pure solid sample. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 86% | With hydrogen; sodium acetate; palladium dichloride In methanol at 35℃; for 2h; | Typical procedures: 6-bromonicotinaldehyde (930 mg, 5.0 mmol), NaOAc (820 mg, 10.0 mmol), MeOH (30 mL), and PdCl2 (45 mg) were mixed in a glass bottle capped with a balloon filled with hydrogen. After stirred at 35 °C for 4 h, the mixture was filtered and washed with MeOH. The solvent was removed and the residue was dissolved in water, neutralized with solid NaHCO3, and extracted with ethyl acetate. The organic phase was dried over anhyd Na2SO4, and then filtered. The solvent was removed and the residue was subjected to chromatography to yield pyridin-3-ylmethanol (428 mg, 78%). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 92% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide for 0.0666667h; Microwave irradiation; | General microwave procedure for the synthesis of substituted 2-hydrazino[1,3,4]thiadiazepino[7,6-b]quinolines (2a-h) General procedure: To a mixture of substituted quinoline 1a (0.764g, 0.004 mol) and carbidimide (0.530g, 0.005mol), catalytic amount of p-TsOH and anhydrous dimethylformamide (8 ml) were added and the contents were irradiated under microwave oven for about 4 minutes at an interval of 1 min at 160 W. The completion of reaction was monitored by TLC, the product 2a was poured into ice-cold water, stirred well, filtered, dried and recrystallised from aqueous DMF. The same procedure was used for the synthesis of (2b-h) |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 79% | With potassium hydroxide at 100 - 110℃; for 3h; | General procedure for the synthesis of 6-substituted-2-methoxyquinoline-3-carbaldehydes 3a-d General procedure: To a solutionof potassium hydroxide (1 g, 0.00178 mol) in 50 mL ofmethanol was added 6-substituted-2-chloroquinoline-3-carbaldehydes 2a-d (0.0131 mol). The mixture washeated cautiously at 100-110 °C for 3 h. After completionof the reaction, the resulting mixture was then cooled andpoured onto 200 g of crushed ice. The solid productobtained was filtered, washed with water, dried and purifiedby column chromatography (Pet. ether/Ethyl acetate 8:2). |
| 74% | With potassium hydroxide at 20 - 80℃; for 3h; | 16.2 Step-2: Synthesis of 6-chloro-2-methoxyquinoline-3-carbaldehyde To a stirred solution of 2,6-dichloroquinoline-3-carbaldehyde (1.6 g, 7.07 mmol, 1.0 eq.) in MeOH (30 mL) was added KOH (0.513 g, 7.74 mmol, 1.1 eq.) at RT. The resulting mixture was heated to 80° C. and stirred for 3 h at same temperature. Following this, reaction mixture diluted with ice cold water (10 mL) and stirred for 1 h. Filtered the solid and under vacuum to get title compound (1.12 g 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (s, 1H) 8.75 (s, 1H) 8.26 (d, J=2.19 Hz, 1H) 7.80-7.88 (m, 2H) 4.12 (s, 3H) |
| 42% | With potassium hydroxide at 60℃; | 1.1 General procedure for the synthesis of 2-methoxyquinoline-3-carbaldehydes (19-24) General procedure: To a solution of KOH (75.7 mmol) in MeOH (100 mL) was added the corresponding 2-chloro-3-quinolinecarbaldehyde (52.2 mmol) with constant stirring. The mixture was heated under reflux for 2.5-6 h and then cooled to room temperature. The product was precipitated out by adding water (300 mL) and then collected by vacuum filtration. The dried crude was recrystalised in DCM to afford compounds in yields ranging from 42-89%. |
| With potassium hydroxide at 100℃; | General procedure for the synthesis of N’-substituted-2-chloroquinoline-3-carbaldehydes2(a-e) and N’-substituted-2-methoxyquinoline-3-carbaldehydes 5(a-e) General procedure: Dimethylformamide 9.6 mL (0.125 mol) was takenin round bottom flask equipped with drying tube and phosphorus oxychloride 32.2 mL (0.35 mol) was added drop wise with continuous stirring at 0°C. To above solution different aryl acetanilide 1(a-e) (0.05 mol) were added and after 5 min the solution is heated under reflux for 16-17 h. The completion of the reaction was monitored by TLC, reaction contents were decanted into crushed ice with constant stirring. The settled solid was sieved, washed with water, dried and purified by recrystallization using ethyl acetate to afford final pure product 2(a-e) in good yield. Thus, obtained 2(a-e) (0.0131 mol) were refluxed at 100°C in a mixture containing 1 g of KOH (0.00178 mol) in 50 mL dried methanol for 2.5-3 h and then cooled to room temperature and decanted on crushed ice. The precipitated solid was sieved, washed with water, dried and purified by recrystallization from petroleum ether at 450 C. | |
| 81 % | With potassium carbonate In N,N-dimethyl-formamide at 70℃; | General procedure for the synthesis of 2-methoxy-3-formylquinoline (5 a-c) General procedure: 2-chloro-3-formylquinoline (0.5 g, 2.6 mmol, 1 equiv.) wasdissolved in 10 mL DMF and methanol or ethanol (15 mL)for respective substitution. K2CO3 (1 g, 26.0 mmol, 1equiv.) was added, and the reaction mixture was refluxed at70 °C till the completion of the reaction. The solvent wasevaporated, and the reaction mixture was poured onto thecrushed ice. The precipitate was filtered out using vacuumfiltration, dried under vacuum, and recrystallized withethanol. The desired product 5a was obtained with a goodyield of 78%, and all other derivatives were synthesizedusing the same procedure to get 5b-c (50-77%). |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 81% | With copper(II) sulfate In 1,2-dichloro-ethane at 55℃; | 1.1 Step-1: (R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide To a mixture of 2,6-dichloroquinoline-3-carbaldehyde (15.0 g, 66.37 mmol) and (R)-2-methylpropane-2-sulfinamide (8.85 g, 73.14 mmol) in 1,2-dichloroethane (150 mL) was added CuSO4 (16.0 g, 100.25 mmol). The resulting mixture was heated to 55° C. and stirred at 55° C. overnight. After TLC and MS showed complete disappearance of starting materials, the mixture was cooled to room temperature and filtered through a pad of Celite. The pad of celite was then rinsed with CH2Cl2. The filtrate was evaporated to dryness in vacuo and purified by SiO2 column chromatography (0 to 25% hexanes/EtOAc) to afford the title compound, (R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide, as a yellow solid (17.7 g, 81% yield). |
| 81% | With copper(II) sulfate In 1,2-dichloro-ethane at 55℃; | 1.1 (R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide To a mixture of 2,6-dichloroquinoline-3-carbaldehyde (15.0 g, 66.37 mmol) and (i?)-2-methylpropane-2-sulfinamide (8.85 g, 73.14 mmol) in 1 ,2-dichloroethane (150 mL) was added CuS04 (16.0 g, 100.25 mmol). The resulting mixture was heated to 55 °C and stirred at 55 °C overnight. After TLC and MS showed complete disappearance of starting materials, the mixture was cooled to room temperature and filtered through a pad of Celite*. The pad of celite was then rinsed with CH2CI2. The filtrate was evaporated to dryness in vacuo and purified by S1O2 column chromatography (0 to 25% hexanes/EtOAc) to afford the title compound, (i?,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2- sulfinamide, as a yellow solid (17.7 g, 81% yield). |
| 81% | With copper(II) sulfate In 1,2-dichloro-ethane at 55℃; | 1.1 Step-1: (R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide. Step-1: (R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide. [0090] To a mixture of 2,6-dichloroquinoline-3-carbaldehyde (15.0 g, 66.37 mmol) and (R)-2-methylpropane -2-sulfinamide (8.85 g, 73.14 mmol) in 1,2-dichloroethane (150 mL) was added CuSO4 (16.0 g, 100.25 mmol). The resulting mixture was heated to 55 °C and stirred at 55 °C overnight. After TLC and MS showed complete disappearance of starting materials, the mixture was cooled to room temperature and filtered through a pad of Celite. The pad of celite was then rinsed with CH2Cl2. The filtrate was evaporated to dryness in vacuo and purified by SiO2 column chromatography (0 to 25% hexanes/EtOAc) to afford the title compound, (R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2- sulfinamide, as a yellow solid (17.7 g, 81% yield). |
| 81% | With copper(II) sulfate In 1,2-dichloro-ethane at 55℃; | 1.1 Step-i: (R,E)-N-((2,6-dichloroquinolin-3-yl)methyl- ene)-2-methylpropane-2-sulfinamide10442] To a mixture of 2,6-dichloroquinoline-3-carbalde- hyde (15.0 g, 66.37 mmol) and (R)-2-methylpropane-2- sulfinamide (8.85 g, 73.14 mmol) in 1,2-dichloroethane (150 mE) was added Cu504 (16.0 g, 100.25 mmol). The resulting mixture was heated to 55° C. and stirred at 55° C. overnight. After TEC and MS showed complete disappearance of starting materials, the mixture was cooled to room temperature and filtered through a pad of Celite. The pad of celite was then rinsed with CH2C12. The filtrate was evaporated to dryness in vacuo and purified by 5i02 column chromatography (0 to 25% hexanes/EtOAc) to afford the title compound, (R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2- methylpropane-2-sulfinamide, as a yellow solid (17.7 g, 81% yield) |
| 81% | With copper(II) sulfate In 1,2-dichloro-ethane at 55℃; | |
| 81% | With copper(II) sulfate In dichloromethane at 55℃; | 1.1.1 Step-1: (R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide To a mixture of 2,6-dichloroquinoline-3-carbaldehyde (15.0 g, 66.37 mmol) and (R)-2-methylpropane-2-sulfinamide (8.85 g, 73.14 mmol) in 1,2-dichloroethane (150 mL) was added CuSO4 (16.0 g, 100.25 mmol). The resulting mixture was heated to 55° C. and stirred at 55° C. overnight. After TLC and MS showed complete disappearance of starting materials, the mixture was cooled to room temperature and filtered through a pad of Celite. The pad of Celite was then rinsed with CH2Cl2. The filtrate was evaporated to dryness in vacuo and purified by SiO2 column chromatography (0 to 25% hexanes/EtOAc) to afford the title compound, (R,E)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide, as a yellow solid (17.7 g, 81% yield). |
| 81% | With copper(II) sulfate In 1,2-dichloro-ethane at 55℃; | |
| 81 % | With copper(II) sulfate In 1,2-dichloro-ethane at 55℃; | 1.1 Step 1: (R,E)-N-((2,6-Dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfamide 2,6-Dichloroquinoline-3-carbaldehyde (15.0 g, 66.37 mmol) and (R)-2-methylpropane-2-sulfinamide (8.85 g, 73.14 mmol) were added to 1,2-dichloro In ethane (150mL), add CuSO4(16.0 g, 100.25 mmol).The resulting mixture was heated to 55°C and stirred overnight at 55°C.After TLC showed that the raw material disappeared completely, the reaction solution was cooled to room temperature and filtered with a pad of celite.CH2Cl2Rinse.The filtrate was evaporated to dryness under reduced pressure and purified by silica gel column chromatography (0 to 25% hexane/EtOAc) to give the title compound (R,E)-N-((2,6-dichloroquinolin-3-yl)ylidene Methyl)-2-methylpropane-2-sulfamide as a yellow solid (17.7 g, 81% yield). |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 88% | With <i>L</i>-proline In ethanol for 24h; Reflux; | Typical Procedure for the preparation of compounds: General procedure: A dry 25 mL flask was charged with aldehyde (1.5 mmol), methylene active compound (1.5 mmol), 6-aminouracil (1 mmol), L-proline (0.1 mmol) and ethanol (5 mL). The mixturewas stirred at reux for 24 h. After reaction completion (TLC), the reactionmixture was cooled to room temperature. The mixture was ltered and theprecipitate washed with EtOH to afford the product. Physical data and spectraldata as well as copies of NMR for all compounds are provided in the ESI. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 70% | With copper(II) sulfate In 1,2-dichloro-ethane at 55℃; for 18h; | 2.1 Step-1: (R)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide. Step-1: (R)-N-((2,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide. [0093] To a mixture of 2,6-dichloroquinoline-3-carbaldehyde (500 mg, 2.21 mmol) and (R)-2-methylpropane-2-sulfinamide (295 g, 2.43 mmol) in 1,2-dichloroethane (15 mL) was added CuSO4 (530 mg, 3.31 mmol). The resulting mixture was heated to 55 °C and stirred at 55 °C for 18 hours. Once TLC and MS showed complete disappearance of starting materials, the reaction mixture was cooled to room temperature and filtered through a pad of Celite. The pad of celite was then rinsed with CH2Cl2. The filtrate was evaporated to dryness in vacuo and purified by column chromatography on an ISCO chromatography system (SiO2; hexanes to 60% EtOAc/hexanes) to afford the title compound, (R)-N-((2,6-dichloroquinolin- 3-yl)methylene)-2-methylpropane-2-sulfinamide, as a yellow solid (510 mg,70% yield). |
| 70% | With copper(II) sulfate In 1,2-dichloro-ethane at 55℃; for 18h; | 2.1 Step-i: (R)-N-((2,6-dichloroquinolin-3-ymethyl- ene)-2-methylpropane-2-sulfinamide To a mixture of 2,6-dichloroquinoline-3-carbalde- hyde (500 mg, 2.21 mmol) and (R)-2-methylpropane-2- sulfinamide (295 g, 2.43 mmol) in i,2-dichloroethane (15 mE) was added Cu504 (530 mg, 3.31 mmol). The resulting mixture was heated to 55° C. and stirred at 55° C. for 18 hours. Once TEC and MS showed complete disappearance of starting materials, the reaction mixture was cooled to room temperature and filtered through a pad of Celite. The pad of celite was then rinsed with CH2C12. The filtrate was evaporated to dryness in vacuo and purified by column chromatography on an ISCO chromatography system (5i02 hexanes to 60% EtOAc/hexanes) to afford the title compound, (R)-N-((2,6-dichloroquinolin-3-ymethyl- ene)-2-methylpropane-2-sulfinamide, as a yellow solid (510 mg, 70% yield) |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 88% | With <i>L</i>-proline In ethanol for 4h; Reflux; | General procedure for the synthesis of compounds 3 and 5 General procedure: A dry 25 mL flask was charged with aldehyde (1 mmol) and pyrazolone derivatives (2 mmol), L-proline (0.017 g, 0.15 mmol) and ethanol (5 mL). The mixture was stirred at reflux for the appropriate time. After reaction completion (TLC), the reaction mixturewas cooled to room temperature. The mixture was filtered and the precipitate washed several times with EtOH to afford the product. Copies of NMR spectra for all compounds are provided in the ESI. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 62% | With <i>L</i>-proline In ethanol at 100℃; for 0.5h; Microwave irradiation; Sealed tube; | 4 The 2 - chloroquinolin -3 - formaldehyde (0.2mmol), malononitrile (0.2mmol) and 4 - hydroxy -6 - methyl -2 - pyrone (0.2mmol) added to 5 ml in a microwave reaction tube, then adding L - proline (0.1mmol) and ethanol 2 ml, the reaction tube seal, pre-stirring 10 seconds, the microwave radiation under the mixture 100 °C reaction 30 minutes, after the reaction, the reaction system is cooled to room temperature, to precipitate solid after filtration, then the DMF for a mixture of water and a solvent for recrystallization to obtain 2-(3-methyl-1-oxo-1,12-dihydro[3',4':5,6]pyrano[2,3-b]quinolin-12-yl)malononitrile(Ia)According to example 1 of the method, the 2 - chloroquinolin -3 - formaldehyde into 2, 6 - dichloro quinolinic -3 - formaldehyde, to L - proline as the catalyst, the reaction under microwave radiation 30 minutes, after the reaction, the reaction system is cooled to room temperature, to precipitate solid after filtration, DMF and water for re-crystallizing mixed solvent to obtain the target product 2 - (9 - chloro -3 - methyl -1 - oxo - 1, 12 - two hydrogenated pyrano [3 ', 4': 5, 6] pyrano [2, 3 - b] quinoline -12 - yl) malononitrile (Id): |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 69% | With toluene-4-sulfonic acid In ethanol at 100℃; for 0.5h; Microwave irradiation; | 11 Example 11 2-chloroquinoline-3-carbaldehyde (0.2 mmol), malononitrile (0.2 mmol) and 5,5-dimethyl-1,3-cyclohexanedione(0.2 mmol) were added to a 5 mL microwave reaction tube, L-proline (0.1 mmol) and 2 mL of ethanol were added. The reaction tube was sealed andstirred for 10 seconds. The mixture was reacted at 100 ° C for 30 minutes under microwave irradiation. After completion of the reaction, the reaction system was cooled toroom temperature Solid, followed by suction filtration, followed by recrystallization of DMF and water to give 2- (3,3-dimethyl-1-oxo-2,3,4,12-tetrahydro-1H-chromene [2,3-b] quinoline-12-yl) malononitrile (Ia):% yield 71% |