* 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.
Step 1. Synthesis of 3,6,6-trimethyl-6,7-dihydro-lH-indole-4(5H)-on [formula 6-2]Anti-pyruvic aldehyde- 1-oxime [formula 6-1] (0.50 g, 5.74 mmol) and 5,5-dimethyl- 1,3-cyclohexandion [formula 6-7] (0.80 g, 5.74 mmol) were dissolved in acetic acid (35 mL) and H20 (15 mL) . Thereto, zinc powder (0.75 g, 11.5 mmol) was added slowly maintaining room temperature. The reaction mixture was refluxed with stirring, concentrated under reduced pressure and extracted with CH2C12 and brine, of which pH was adjusted to 6 using saturated NaHC03. The reaction mixture was extracted with CH2C12; organic layer was dried over anhydrous MgS04 and filtered. Residue was concentrated under reduced pressure and purified by column chromatography (Si02; hexane/ethylacetate, 1/3) to yield the title compound as yellow solid (4.9 g, 52 percent).
45%
With zinc In water; acetic acid at 20℃; Heating / reflux
To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5, 5-dimethyl-l, 3-cyclohexanedione (16.1 g, 1 eq) in HOAc- H2O (7:3, 200 mL) was added zinc powder (14.95 g, 2 eq) slowly with cooling by a water bath at room temperature. The mixture then was refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL) . The pH was adjusted to ca. 6 with saturated aqueous NaHCO3, then the mixture was extracted with dichloromethane (3x200 mL) . The organic layers were combined, dried overNa2SO4, filtered, concentrated. The crude product was purified by flash chromatography eluting with 5percent ethyl acetate in dichloromethane. The combined organic fractions were concentrated, triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give the pure title compound (9 g, 45percent yield) as a solid. LCMS m/z: (M+H) = 178.1.
45%
Stage #1: With acetic acid; zinc In water at 20℃; Heating / reflux Stage #2: With sodium hydrogencarbonate In dichloromethane; water
To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5,5-dimethyl-1,3-cyclohexanedione (16.1 g, 1 eq) in HOAc-H2O (7:3, 200 mL), was added zinc powder (14.95 g, 2 eq) slowly cooling with a water bath at room temperature. The mixture was refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL). The pH was adjusted to ca. 6 with saturated aqueous NaHCO3, then extracted with dichloromethane (3.x.200 mL). The organic layers were combined, dried over Na2SO4, filtered, concentrated to give crude product. This was purified by flash chromatography, eluting with 5percent ethyl acetate in dichloromethane to give expected product, which was triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give pure title compound (9 g, 45percent yield) as a solid.
45%
With acetic acid; zinc In water at 20℃; Heating / reflux
Example 1; 3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one; To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5,5-dimethyl-1,3-cyclohexanedione (16.1 g, 1 eq) in HOAc-H2O (7:3, 200 mL), was added zinc powder (14.95 g, 2 eq) slowly cooling with a water bath at room temperature. The mixture was refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL). The pH was adjusted to ca. 6 with saturated aqueous NaHCO3, then extracted with dichloromethane (3.x.200 mL). The organic layers were combined, dried over Na2SO4, filtered, concentrated to give crude product. This was purified by flash chromatography, eluting with 5percent ethyl acetate in dichloromethane to give expected product, which was triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give pure title compound (9 g, 45percent yield) as a solid.
Anti-pyruvic aldehyde-1-oxime [formula 6-1] (0.50 g, 5.74 mmol) and 5,5-dimethyl-1,3-cyclohexandion [formula 6-7] (0.80 g, 5.74 mmol) were dissolved in acetic acid (35 mL) and H2O (15 mL). Thereto, zinc powder (0.75 g, 11.5 mmol) was added slowly maintaining room temperature. The reaction mixture was refluxed with stirring, concentrated under reduced pressure and extracted with CH2Cl2 and brine, of which pH was adjusted to 6 using saturated NaHCO3. The reaction mixture was extracted with CH2Cl2; organic layer was dried over anhydrous MgSO4 and filtered. Residue was concentrated under reduced pressure and purified by column chromatography (SiO2; hexane/ethylacetate, 1/3) to yield the title compound as yellow solid (4.9 g, 52percent).
45%
With acetic acid; zinc In waterReflux
Example 1 3,6,6-Trimethyl-1,5,6,7-tetrahydro-indo1-4-one (Intermediate 1) To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5,5-dimethyl-1,3-cyclohexanedione (16.1 g, 1 eq) in HOAc-H2O (7:3, 200 mL) is added zinc powder (14.95 g, 2 eq) slowly with cooling by a water bath at room temperature. The mixture is then refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL). The pH is adjusted to ca. 6 with saturated aqueous NaHCO3, then the mixture is extracted with dichloromethane (3*200 mL). The organic layers are combined, dried over Na2SO4, filtered, concentrated. The crude product is purified by flash chromatography eluting with 5percent ethyl acetate in dichloromethane. The combined organic fractions are concentrated, triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give the pure title compound (9 g, 45percent yield) as a solid. LCMS m/z: (M+H)=178.1.
Reference：
[1] Bulet. Soc. chim. Romania, vol. 10, p. 134[2] Chem. Zentralbl., 1929, vol. 100, # I, p. 2185
4
[ 31915-82-9 ]
[ 126-81-8 ]
[ 56008-20-9 ]
Reference：
[1] Journal and Proceedings of the Royal Society of New South Wales, 1932, vol. 66, p. 477,481
5
[ 555-16-8 ]
[ 126-81-8 ]
[ 105-45-3 ]
[ 3357-14-0 ]
[ 40588-46-3 ]
[ 21829-09-4 ]
Yield
Reaction Conditions
Operation in experiment
8%
With C22H25F6N5S; ammonium acetate In dichloromethane at 20℃; for 1 h;
To a mixture of 0.014 g (0.1 mol) of dimedone, 0.01 mL (0.1 mol) of methyl acetoacetate, 0.015 g (0.1 mol) of p-nitrobenzaldehyde, and 0.096 g (0.125 mmol) of ammonium acetate at room temperature was added 1 mL of methylene chloride and 5 mmol of catalyst 5–9, the mixture was stirred for 1 h, then the solution was evaporated on a rotary evaporator. From the residue the reaction products were isolated by column chromatography, eluent ethyl acetate–hexane,1 : 8. Compounds were eluted in the following order: 4, 2, 3, and 1. Yield of compound 1 64–72percent.
Reference：
[1] Russian Journal of Organic Chemistry, 2016, vol. 52, # 5, p. 701 - 705[2] Zh. Org. Khim., 2016, vol. 52, # 5, p. 713 - 717,5
6
[ 126-81-8 ]
[ 77571-23-4 ]
[ 354-38-1 ]
[ 57857-72-4 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1981, vol. 17, p. 777[2] Zhurnal Organicheskoi Khimii, 1981, vol. 17, # 4, p. 883 - 884
7
[ 4244-59-1 ]
[ 126-81-8 ]
[ 62462-05-9 ]
Yield
Reaction Conditions
Operation in experiment
47%
With pyridine In dichloromethane at 0 - 20℃;
To a solution of 3-methoxy propionyl chloride (51.7 g, 359 mmol) and pyridine (87 mL, 1077 mmol) in DCM (400 mL), dimedon (44 g, 359 mmol) was added dropwise at 0 °C to 10 °C. The reaction mixture was stirred overnight at room temperature, 1 N HC1 (400 mL) was added, extracted with DCM (500 mL x 3). The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated to dryness. The oily residue was dissolved in MeOH (400 mL) and refluxed for 2 hrs. The reaction mixture was concentrated to dryness. The residue was purified by silica gel column (PE : EA = 15 : 1) to give the title compound (27 g, 47.0 percent yield) as white oil. 1H NMR (400 MHz CDCl3): δ 3.72 (s, 3H), 3.65-3.62 (m, 2H), 3.49 (s, 2H), 3.31 (s, 3H), 2.78-2.75 (m, 2H).
Reference：
[1] Journal of the Chemical Society, 1913, vol. 103, p. 2181
[2] Journal of the Chemical Society, 1913, vol. 103, p. 1301
[3] Proceedings of the Chemical Society, London, 1913, vol. 28, p. 333[4] Journal of the Chemical Society, 1913, vol. 103, p. 989
9
[ 7789-69-7 ]
[ 126-81-8 ]
[ 71942-14-8 ]
[ 203808-81-5 ]
[ 838841-06-8 ]
Reference：
[1] Journal of the Chemical Society, 1913, vol. 103, p. 2181
[2] Journal of the Chemical Society, 1913, vol. 103, p. 1301
[3] Proceedings of the Chemical Society, London, 1913, vol. 28, p. 333[4] Journal of the Chemical Society, 1913, vol. 103, p. 989
10
[ 126-81-8 ]
[ 150629-67-7 ]
Reference：
[1] Patent: US2014/134110, 2014, A1,
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 22, p. 9290 - 9298
Reference：
[1] RSC Advances, 2015, vol. 5, # 60, p. 48506 - 48515
[2] ACS Catalysis, 2013, vol. 3, # 7, p. 1420 - 1430
[3] Chemistry - A European Journal, 2013, vol. 19, # 13, p. 4156 - 4168
13
[ 126-81-8 ]
[ 100-83-4 ]
[ 17356-08-0 ]
[ 863774-58-7 ]
[ 1242471-67-5 ]
Reference：
[1] Letters in Organic Chemistry, 2010, vol. 7, # 4, p. 314 - 318
14
[ 141-97-9 ]
[ 126-81-8 ]
[ 3218-36-8 ]
[ 1099644-42-4 ]
Yield
Reaction Conditions
Operation in experiment
97%
With ammonium acetate In neat (no solvent) at 80℃; for 0.166667 h; Green chemistry
General procedure: A mixture of aromatic aldehyde (1 mmol), dimedone (0.14 g, 1 mmol), ethyl acetoacetate (0.13 g, 1 mmol), ammonium acetate (0.115 g, 1.5 mmol), and Fe2O3(at)HAP(at)Melamine (0.15 g) was heated at for 80 °C. Completion of the reactions was monitored by TLC (n-hexan/ethyl acetate 10:3). After satisfactory completion of the reaction and cooling, the reaction mixture was washed with hot ethel acetate and the catalyst was removed by a magnetic field. The solid residue was isolated and purified by recrystallization in hot EtOH.
96%
With ammonium acetate In neat (no solvent) at 20℃; for 0.166667 h; Green chemistry
General procedure: The nickel(II) Schiff base complex immobilized on MWCNTs as a heterogeneous catalyst (0.005 g) was added to a mixture of aromatic aldehyde (1 mmol), 1,3-dione (1 mmol), ethyl acetoacetate (1 mmol), and ammonium acetate (1.5 mmol) in a round bottom flask and the resulting mixture was stirred magnetically under solvent-free conditions at room temperature. After reaction, as observed by TLC (n-hexane/ethyl acetate: 5/2), ethyl acetate (5 mL) was added to the reaction mixture, stirred and refluxed for 10 min, washed with ethanol (5 mL) and decanted to separate catalyst from other materials (the reaction mixture was soluble in hot ethyl acetate and nanocatalyst was insoluble). The solvent of organic layer was evaporated and the crude product was purified by recrystallization from ethanol. In this study, nanoheterogeneous catalyst was recycled and reused for seven times without significant loss of its catalytic activity.
96%
With ammonium acetate; ascorbic acid In neat (no solvent) at 80℃; for 5 h; Green chemistry
General procedure: A mixture of aldehyde (1 mmol), cyclic 1,3-diketone (1 mmol), ethyl acetoacetate (1 mmol), ammonium acetate (1 mmol), and ascorbic acid (5percent mol) was stirred at 80 °C under solvent-free conditions for appropriate time (Table 3). After complete conversion as indicated by TLC, the reaction mixture was cooled to room temperature, poured onto ice-cold water (10 mL), and stirred for about 10 min. The formed solid was filtered off, washed with cold water, and purified by simple crystallization in ethanol.
88%
With bismuth(III) bromide; ammonium acetate In ethanol at 20℃; for 3 h;
General procedure: A homogeneous mixture of p-tolualdehyde (0.5000 g,4.16 mmol), dimedone (0.6417 g, 4.58 mmol, 1.1 equiv), ethyl acetoacetate(0.5968 g, 0.58 mL, 4.58 mmol, 1.1 equiv), and ammonium acetate (0.3528 g,4.58 mmol, 1.1 equiv) was stirred in anhydrous ethanol (10.0 mL) at roomtemperature as BiBr3 (0.0373 g, 2.0 mol percent) was added. The reaction progresswas monitored by TLC (2,4-DNP stain). After 1.5 h, the reaction mixture waspoured onto 20 g of ice and the resulting yellow precipitate was collected viasuction filtration. The crude product was recrystallized using anhydrousethanol (approximately 30 mL) to yield 1.2694 g (86percent yield) of a slightly offwhite,powdery compound. Mpt: 258–259 C (Lit: 258–259 C).
38%
With ammonium acetate; iodine In ethanol at 20℃;
General procedure: 1 eq. of a cyclic 1,3-dicarbonyl compound 2, 1 eq. of the desired aldehyde 5, 1 eq. of a 1,3-dicarbonyl compound 3, 1 eq. of dried NH4OAc and 0.3 eq. of iodine were stirred in EtOH (2.5 mL/mmol) overnight at room temperature. The solvent was evaporated and the residue was dissolved in EtOAc. The organic layer was washed twice with a saturated solution of NaS2O3 and brine, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by recrystallization or flash chromatography.
Reference：
[1] RSC Advances, 2014, vol. 4, # 101, p. 57662 - 57670
[2] Research on Chemical Intermediates, 2015, vol. 41, # 10, p. 7227 - 7244
[3] Applied Organometallic Chemistry, 2016, vol. 30, # 5, p. 311 - 317
[4] Journal of Coordination Chemistry, 2017, vol. 70, # 2, p. 340 - 360
[5] Synthetic Communications, 2017, vol. 47, # 12, p. 1185 - 1191
[6] RSC Advances, 2016, vol. 6, # 110, p. 108896 - 108907
[7] RSC Advances, 2015, vol. 5, # 68, p. 55303 - 55312
[8] Tetrahedron Letters, 2015, vol. 56, # 27, p. 4060 - 4062
[9] Chemical Communications, 2011, vol. 47, # 1, p. 529 - 531
[10] RSC Advances, 2017, vol. 7, # 89, p. 56764 - 56770
[11] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 249 - 266
15
[ 126-81-8 ]
[ 105-45-3 ]
[ 3218-36-8 ]
[ 1099644-42-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 9946 - 9957
In toluene; for 12.0h;Heating / reflux; dean stark apparatus;
A mixture of v-1 (0.0089 mol) and v-2 (0.0089 mol) in toluene (50 ml) was stirred and refluxed for 12 h in a Dean Starck apparatus, then cooled to room temperature. The precipitate was filtered, washed with diethyl ether and dried, yielding: 2 g of v-3 (100percent).A mixture of v-3 (0.0106 mol) and v-4 (0.0106 mol) in AcOH (2.6 ml) and EtOH (50 ml) was stirred at 750C for 24 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was taken up in CH2Cl2. The organic layer was washed with K2C O3 10percent, dried (over MgSO4), filtered and the solvent was evaporated. The residue (5.7 g) was purified by column chromatography over silica gel (eluent: CH2C12/CH3OH/NH4OH 100/0/0 to 99/1/0.1). Three fractions were collected and the EPO <DP n="118"/>solvent was evaporated, yielding: 0.27 g of v-5 (4.5percent) (melting point > 2600C), 0.4 g of v-6 (6.7percent) and 0.34 g of v~7 (5.7percent) (melting point > 2600C).A mixture of v-6 (0.0006 mol) and NH2-NH2/H2O (0.003 mol) in EtOH (20 ml) was stirred and refluxed for 6 hours, then concentrated under reduced pressure. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding: 0.12 g (50percent). Part of this fraction (0.04 g) was crystallized from CH3CN. The precipitate was filtered off and dried, yielding: 0.03 g of v-8 (melting point: 248°C).
With copper(I) iodide; In water; at 20℃; for 3.5h;Green chemistry;
A mixture of aromatic aldehydes 1 (1 mmol), dimedone (2, 1 mmol), 5-aminouracil (3, 1 mmol), and CuI NPs (2.9 mg, 15 mol%) was stirred at room temperature in water (10 mL) for the appropriate times. After completion of the reaction (TLC), the reaction mixture filtered and the solid mass was then diluted with DMF (5 mL), and the mixture was centrifuged at 2000-3000 rpm for 5 min to recover the catalyst and then the catalyst was dried in a vacuum oven at 100 C for several hours. The organic solution was the npoured into cold water (15 mL) and filtered. The resulting solid was recrystallized from EtOH to afford the pure product 4.
With copper(I) iodide; In water; at 20℃; for 4h;Green chemistry;
A mixture of aromatic aldehydes 1 (1 mmol), dimedone (2, 1 mmol), 5-aminouracil (3, 1 mmol), and CuI NPs (2.9 mg, 15 mol%) was stirred at room temperature in water (10 mL) for the appropriate times. After completion of the reaction (TLC), the reaction mixture filtered and the solid mass was then diluted with DMF (5 mL), and the mixture was centrifuged at 2000-3000 rpm for 5 min to recover the catalyst and then the catalyst was dried in a vacuum oven at 100 C for several hours. The organic solution was the npoured into cold water (15 mL) and filtered. The resulting solid was recrystallized from EtOH to afford the pure product 4.
With copper(I) iodide; In water; at 20℃; for 4.5h;Green chemistry;
A mixture of aromatic aldehydes 1 (1 mmol), dimedone (2, 1 mmol), 5-aminouracil (3, 1 mmol), and CuI NPs (2.9 mg, 15 mol%) was stirred at room temperature in water (10 mL) for the appropriate times. After completion of the reaction (TLC), the reaction mixture filtered and the solid mass was then diluted with DMF (5 mL), and the mixture was centrifuged at 2000-3000 rpm for 5 min to recover the catalyst and then the catalyst was dried in a vacuum oven at 100 C for several hours. The organic solution was the npoured into cold water (15 mL) and filtered. The resulting solid was recrystallized from EtOH to afford the pure product 4.
With copper(I) iodide; In water; at 20℃; for 4h;Green chemistry;
A mixture of aromatic aldehydes 1 (1 mmol), dimedone (2, 1 mmol), 5-aminouracil (3, 1 mmol), and CuI NPs (2.9 mg, 15 mol%) was stirred at room temperature in water (10 mL) for the appropriate times. After completion of the reaction (TLC), the reaction mixture filtered and the solid mass was then diluted with DMF (5 mL), and the mixture was centrifuged at 2000-3000 rpm for 5 min to recover the catalyst and then the catalyst was dried in a vacuum oven at 100 C for several hours. The organic solution was the npoured into cold water (15 mL) and filtered. The resulting solid was recrystallized from EtOH to afford the pure product 4.
With copper(I) iodide; In water; at 20℃; for 5h;Green chemistry;
A mixture of aromatic aldehydes 1 (1 mmol), dimedone (2, 1 mmol), 5-aminouracil (3, 1 mmol), and CuI NPs (2.9 mg, 15 mol%) was stirred at room temperature in water (10 mL) for the appropriate times. After completion of the reaction (TLC), the reaction mixture filtered and the solid mass was then diluted with DMF (5 mL), and the mixture was centrifuged at 2000-3000 rpm for 5 min to recover the catalyst and then the catalyst was dried in a vacuum oven at 100 C for several hours. The organic solution was the npoured into cold water (15 mL) and filtered. The resulting solid was recrystallized from EtOH to afford the pure product 4.
2-(thiazol-2-yl)-4-(2-chloro-4-fluorophenyl)-7,7-dimethyl-7,8-dihydroquinazolin-5(1 H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
<strong>[247037-82-7]2-thiazolecarboxamidine hydrochloride</strong> (Schaefer F.C., Peters G. A., et al.) 2.164mmol, 2-chloro-4-fluorobenzaldehyde 2.164mmol, 5,5-dimethyl-1,3-cyclohexanedione 2.164mmoland sodium acetate 3.2mmol were reacted in 8ml of anhydrous ethanol under refluxing for 18hr, condensed, to which ethyl acetate and water and 1N HCl were added, and separated. The water layer was adjusted with concentrated NaOH solution until pH value to be basic, then ethyl acetate was added and extracted twice. The organic layers were combined, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain a yellow crystal 0.23g (yield 28%); 1H-NMR (400MHz, CDCl3-d1) delta 7.95-7.85(m, 1H, ArH); 7.64-7.47 (m, 1H, ArH); 7, 34-7.24(m, 1H, ArH); 7.13-7.11(m, 1H, ArH); 6.11 (s, 1H, CH); 2.70-2.52(m, 2H, CH2); 2.43-2.26(m, 2H, CH2); 1.15(s, 6H, CH3). HREI: 389.0765(M+).
General procedure: A dry 50 mL flask was charged with 2-aminobenzamides 1 (2.1 mmol), 5,5-dimethyl-1,3-cyclohexanedione 2 (1.0 mmol), iodine (0.026 g, 0.01 mmol) and toluene (10.0 mL). The mixture was stirred at reflux until the reactant 1 was consumed. After the completion of the reaction monitored by TLC, toluene was recovered by distillation under reduced pressure, and the residue was purified by silica column chromatography using ethyl acetate and petroleum ether (1:3) as the eluent to give products 3.#10;
With glucose sulfonic acid; In water; at 90℃; for 3h;
General procedure: A mixture of aromatic aldehydes (1, 2.0 mmol), dimedone (2, 2.0 mmol), 2-naphthol or beta-naphthylamine (3 or 4, 2.0 mmol) and 5 molpercent GSA was stirred in water (2 mL) at 90 °C until completely (monitored by TLC). After the completion, water (20?25 mL) was added to quench the reaction and then the reaction mixture was filtered, concentrated, the precipitate was collected, and purified by 95percent EtOH/DMF (8:1).
With glucose sulfonic acid; In water; at 90℃; for 7h;
General procedure: A mixture of aromatic aldehydes (1, 2.0 mmol), dimedone (2, 2.0 mmol), 2-naphthol or beta-naphthylamine (3 or 4, 2.0 mmol) and 5 molpercent GSA was stirred in water (2 mL) at 90 °C until completely (monitored by TLC). After the completion, water (20?25 mL) was added to quench the reaction and then the reaction mixture was filtered, concentrated, the precipitate was collected, and purified by 95percent EtOH/DMF (8:1).
With perchloric acid * acetic acid; In ethanol; water; at 80℃; for 3h;pH 4.4;Green chemistry;
General procedure: A mixture of 5-amimotetrazole (1 mmol, 0.085 g), appropriateisatin (1 mmol), dimedone (1 mmol, 0.14 g) and [MeC(OH)2]+ClO4?(10 molpercent) was stirred in EtOH/H2O (1:1, 4 mL) at 80 °C. After theindicated time, the reaction was quenched into water (50 mL) andcooled. The precipitated product was separated by centrifugation andpurified by silica gel chromatography to afford the desired product. Allthe products were characterised by melting point, 1H NMR, 13C NMRand LC-MS.
2-amino-4-[4-(di-p-tolyl-amino)-phenyl]-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; In ethanol; for 5h;Reflux;
General procedure: Compounds 1?3 were synthesized according to a reported procedure [11]. A mixture of 1,1-dimethyl-3,5-cyclohexanedione (3,5-cyclohexanedione, 4-hydroxycoumarin) (10 mmol), 4-(di-p-tolyl-amino)-benzaldehyde (10 mmol), malononitrile (10 mmol) and 4-(dimethylamino)pyridine (DMAP) (1 mmol) in ethanol (100 mL) was refluxed for 5 h and then cooled to room temperature. The precipitates were filtered and sequentially washed with ice-cooled water and ethanol and then dried under a vacuum.
7,7-dimethyl-10-(4-methylphenyl)-1,5,6,7,8,10-hexahydropyrimido[5,4-b]quinoline-2,4,9(3H)-trione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With copper(I) iodide; In water; at 20℃; for 5h;Green chemistry;
A mixture of aromatic aldehydes 1 (1 mmol), dimedone (2, 1 mmol), 5-aminouracil (3, 1 mmol), and CuI NPs (2.9 mg, 15 mol%) was stirred at room temperature in water (10 mL) for the appropriate times. After completion of the reaction (TLC), the reaction mixture filtered and the solid mass was then diluted with DMF (5 mL), and the mixture was centrifuged at 2000-3000 rpm for 5 min to recover the catalyst and then the catalyst was dried in a vacuum oven at 100 C for several hours. The organic solution was the npoured into cold water (15 mL) and filtered. The resulting solid was recrystallized from EtOH to afford the pure product 4.
7,7-dimethyl-10-(3-nitrophenyl)-1,5,6,7,8,10-hexahydropyrimido[5,4-b]quinoline-2,4,9(3H)-trione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With copper(I) iodide; In water; at 20℃; for 4h;Green chemistry;
A mixture of aromatic aldehydes 1 (1 mmol), dimedone (2, 1 mmol), 5-aminouracil (3, 1 mmol), and CuI NPs (2.9 mg, 15 mol%) was stirred at room temperature in water (10 mL) for the appropriate times. After completion of the reaction (TLC), the reaction mixture filtered and the solid mass was then diluted with DMF (5 mL), and the mixture was centrifuged at 2000-3000 rpm for 5 min to recover the catalyst and then the catalyst was dried in a vacuum oven at 100 C for several hours. The organic solution was the npoured into cold water (15 mL) and filtered. The resulting solid was recrystallized from EtOH to afford the pure product 4.
7,7-dimethyl-10-(4-nitrophenyl)-1,5,6,7,8,10-hexahydropyrimido[5,4-b]quinoline-2,4,9(3H)-trione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With copper(I) iodide; In water; at 20℃; for 5h;Green chemistry;
A mixture of aromatic aldehydes 1 (1 mmol), dimedone (2, 1 mmol), 5-aminouracil (3, 1 mmol), and CuI NPs (2.9 mg, 15 mol%) was stirred at room temperature in water (10 mL) for the appropriate times. After completion of the reaction (TLC), the reaction mixture filtered and the solid mass was then diluted with DMF (5 mL), and the mixture was centrifuged at 2000-3000 rpm for 5 min to recover the catalyst and then the catalyst was dried in a vacuum oven at 100 C for several hours. The organic solution was the npoured into cold water (15 mL) and filtered. The resulting solid was recrystallized from EtOH to afford the pure product 4.
11,11-dimethyl-11,12-dihydroimidazo[4,5,1-ij]quinolino[4,3,2-de]thieno[3,2-b]quinolin-13(10H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 16h;Reflux;
General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature.
2-methoxy-7,7,9-trimethyl-6H-pyrido[2,1-b]quinazolin-11(7H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With toluene-4-sulfonic acid; In m-xylene; at 150℃; for 8h;Sealed tube;
General procedure: In a sealed tube equipped with a magnetic bar was charged with 2-amino benzamide derivatives (1, 3.67 mmol), cyclic 1,3-diones (2, 3.67 mmol) and TsOH.H2O (1.83mmol) in m-Xylene (5 mL). The reaction mixture was stirred at 150 °C for 8 h. After completion of the reaction, the reaction mass was cooled to room temperature, diluted with EtOAc, gave a water wash and the organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (eluent: ethyl acetate/ n-hexane = 10?90) on silica gel to afford the desired product (4a-k).
3-chloro-7,7,9-trimethyl-6H-pyrido[2,1-b]quinazolin-11(7H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With toluene-4-sulfonic acid; In m-xylene; at 150℃; for 8h;Sealed tube;
General procedure: In a sealed tube equipped with a magnetic bar was charged with 2-amino benzamide derivatives (1, 3.67 mmol), cyclic 1,3-diones (2, 3.67 mmol) and TsOH.H2O (1.83mmol) in m-Xylene (5 mL). The reaction mixture was stirred at 150 °C for 8 h. After completion of the reaction, the reaction mass was cooled to room temperature, diluted with EtOAc, gave a water wash and the organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (eluent: ethyl acetate/ n-hexane = 10?90) on silica gel to afford the desired product (4a-k).
2-(2-nitro-4-trifluoromethylbenzoyl)-5,5-dimethylcyclohexane-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
2-Nitro-(4-trifluoromethyl)-benzoic acid (200 mg, 0.85 mmol) was dissolved in thionyl chloride (4 mL) and refluxed under nitrogen for 2 h. After coevaporation with toluene (2 x 5 mL) and dichlorometane (2 x 5 mL) under reduced pressure, a yellow oil was obtained and directly dissolved in 6 mL of dry dichlorometane. 5,5-Dimethyl-l,3-cyclohexanedione (dimedone, 239 mg, 1.7 mmol) and triethylamine (TEA, 383 mu, 3.25 mmol) were added under nitrogen. The reaction mixture was stirred at room temperature monitoring it by thin-layer chromatography (petroleum ether and ethyl acetate 1 :1). After 2 h, the reaction was washed with 1 M hydrochloric acid (2 x 5 mL). The organic phases was dried over dry sodium sulphate and the solvent evaporated under reduced pressure after filtration. The crude was purified by column chromatography using dichlorometane and methanol (9: 1). A pale yellow solid was obtained in 10% yield. 1H NMR: (400 MHz, CDC13) oe 16.20 (s, 1H), 8.44 (s, 1H), 7.92 (d, J 7.9 Hz, 1H), 7.36 (d, J7.9 Hz, 1H), 2.64 (s, 2H), 2.21 (s, 2H), 1.08 (s, 6H) ppm. 13C NMR: (101 MHz, CDC13) oe195.84, 194.55, 194.02, 139.56, 130.82, 130.78, 127.82, 121.18, 121.14, 111.84, 51.18, 45.26,31.29, 31.27, 29.68, 28.13 ppm. ESI MS: 380 [M+Na].
5-(4-hydroxyphenyl)-8,8-dimethyl-2-(methylsulfanyl)-5,8,9,10-tetrahydropyrimido[4,5-b]quinoline-4,6(1H,7H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
In water; at 80 - 90℃;
General procedure: A mixture of 1 mmol of the corresponding 6-aminopyrimidine,1 mmol of aldehyde, 1 mmol of 5,5-dimethylcyclohexane-1,3-dione 3 and 0.075 g (0.33 mmol)of triethylbenzylammonium chloride in 10 mL of water was stirred at 80-90 C for 12-20 h. After cooling to room temperature, the precipitate was filtered off, washed with alcohol and, if necessary,recrystallized from DMF or DMF-alcohol mixture.Compounds 4c, 4d, and 4i were obtained withoutthe use of a catalyst, the reaction time was 22-24 h.
General procedure: A mixture of o-phenylenediamine (1mmol), dimedone or1,3-cyclohexanedione (1mmol) and Fe(III)-NicTC(at)nSiO2(3.0molpercent, 30mg) was stirred at room temperature for 20min. Then, aldehyde (1mmol) and water (5mL) wereadded to the reaction mixture and stirred for the stipulated period time. Up to the end of the reaction, the catalyst was separated by centrifuge and the filtrate was concentrated under reduced pressure. After that, the oily mixture was dissolved in ethanol and the pure product was obtained by recrystallization from ethanol (Table2). The synthesis of mono and bis-benzodiazepine derivatives was also performed under the same conditions (Scheme2).
9-propyl-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydroacridine-1,8-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With ammonium acetate; In ethanol; for 14h;Reflux;
General procedure: A typical reaction was carried out in a 10mL flask. Dimedone (2mmol), aldehyde (1mmol), ammonium acetate (3mmol), Fe3+/4A (0.1g) and ethanol (3mL) were stirred at reflux temperature for 14h. The progression of the reaction was monitored by TLC. After completion, the solid was filtered, and washed with ethanol, then the filtrate was evaporated. The residue was extracted with dichloromethane and 0.25M NaOH solution. The organic phase was dried over anhydrous sodium sulphate, filtered and the solvent was evaporated. The product was subjected to 1H and 13C NMR spectroscopy.
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