* 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.
To 20-40 ° C, 13.8 g (0.1 mol) of N, N-dimethyl-m-hydroxyaniline, 16.0 g (0.22 mol) of N, N-(0.125 mol) of methylsulfonyl chloride was added dropwise to control the dropwise temperature of not more than 40 ° C, and the mixture was stirred for 1.0 hour and kept at a temperature of 50 to 100 ° C. After the reaction was completed, the temperature was lowered to 30 ° C , Add appropriate amount of water hydrolysis, filtration, a small amount of water, 4-N, N-dimethyl-2-hydroxybenzaldehyde 15.0g. Yield 90.9percent, content 95.5percent.
68%
Stage #1: at 0℃; for 0.5 h; Stage #2: at 0 - 90℃; for 4.5 h;
The compound was prepared following the literature procedure with some modifications [24]. The Vilsmeier Haack adduct wasprepared by addition of POCl3 (15.0 mL, 0.16 mol) dropwise to dryDMF (30 mL) at 0° C, and the mixturewas then stirred for 30 min atthe same temperature. To the adduct, a solution of 3-(N,N-dimethylamino)phenol (11.0 g, 80.3 mmol) in dry DMF (23 mL) wasadded dropwise at 0° C. The reaction mixture was slowly warmedto room temperature, stirred for 4 h, and then heated at 85-90° Cfor 30 min. The reaction mixture was allowed to cool to roomtemperature and kept at that temperature with stirring overnight.It was then poured into crushed ice and neutralized with saturatedaqueous solution of Na2CO3 (120 mL). The precipitate was filteredoff, washed with water and dried in a vacuum oven at 25° C for 4 h.Yield: 9.00 g (68percent), m.p. 78-79° C (lit. 80.5-81° C). The compoundwas used without further purification. 1H NMR (500 MHz, CDCl3)(Fig. S1-S3): δ=11.56 (1H, s, OH), 9.47 (1H, s, CHO), 7.24 (1H, d,J 9 Hz, H-6), 6.24 (1H, dd, J 9, 2.1 Hz, H-5), 6.03 (1H, d, J 2.1 Hz,H-3), 3.02 (6H, s, CH3); 13C NMR (125 MHz, CDCl3) (Fig. S4):δ= 192.4, 164.1, 156.2, 135.2, 111.7, 104.6, 97.2, 40.1. FT-IR:nCO 1628 cm-1.
65%
at 20 - 80℃; for 1.16667 h;
3-N, N-dimethylaminophenol(10.5 g, 0.075 mol) was dissolved in 20 mL of dry DMF,(0.1 mL, 0.22 mol) in fresh Vilsmeier Haack reagent, followed by stirring at room temperature for 20 min,Heating to 40 reaction 20min, and then heated to 80 reaction 30min. Cooled to room temperature,The reaction mixture was quickly poured into a large amount of ice water, and the solution was neutralized with NaHCO3,The precipitate was collected and filtered, washed with water and dried to give 8.8 g of the desired product in 65percent yield.
65%
Stage #1: at 20 - 40℃; for 0.666667 h; Stage #2: at 80℃; for 0.5 h;
3-N, N-dimethylaminophenol (10.5 g, 0.075 mol)Was dissolved in 20 mL of dry DMF,And added dropwise from phosphorus oxychloride (8.2 mL, 0.09 mol) and at room temperatureAnhydrous DMF (17 mL, 0.22 mol)In the new Vilsmeier Haack reagent,Followed by stirring at room temperature for 20 min,Heated to 40 reaction 20min,Then warmed to 80 reaction 30min.Cool to room temperature,The reaction mixture is quickly poured into a large amount of ice water,The above solution was neutralized with NaHCO3, the precipitate was collected and filtered, washed with water,After drying, 8.8 g of the target product was obtained in a yield of 65percent.
3.30 g
at 0 - 80℃;
4-(Dimethylamino)salicylaldehydewas synthesized according to the literature [15,16] with littlemodification. POCl3 (4.0 mL, 43.2 mmol) was added dropwiseto dry DMF (21.0 mL, 271.8 mmol) containing 3-(dimethylamino)phenol (3.10 g, 22.6 mmol) at 0 °C, and the mixture wasstirred for 10 min, slowly warmed to room temperature andstirred for another 30 min. The reaction mixture was heated at80 °C overnight. After cooling to room temperature, the mixturewas poured into ice cold water. The solution was neutralizedwith saturated Na2CO3. The precipitate was washedseveral times with distilled water, and dried under vacuum to yield 3.30 g of 1. 1H NMR (400 MHz, CDCl3) δ 3.09 (s, 6H,CH3), 6.10–7.29 (m, 3H, Ar-H), 9.53 (s, 1H, OH), 11.61 (s, 1H,CHO). This was consistent with the literature.
Reference：
[1] Chemistry - An Asian Journal, 2010, vol. 5, # 9, p. 2053 - 2061
[2] Patent: CN104262253, 2017, B, . Location in patent: Paragraph 0049; 0050; 0051; 0052
[3] Molecules, 2009, vol. 14, # 12, p. 4838 - 4848
[4] Journal of Molecular Structure, 2018, vol. 1154, p. 373 - 381
[5] Chemical Papers, 2010, vol. 64, # 6, p. 806 - 811
[6] Journal of Chemical Sciences, 2011, vol. 123, # 4, p. 459 - 466
[7] Patent: CN106543126, 2017, A, . Location in patent: Paragraph 0026; 0027
[8] Patent: CN106543125, 2017, A, . Location in patent: Paragraph 0020; 0026; 0027
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[10] Journal of the American Chemical Society, 2013, vol. 135, # 33, p. 12360 - 12365
[11] Chemical Communications, 2011, vol. 47, # 8, p. 2435 - 2437
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[14] Chemical & Pharmaceutical Bulletin, 1989, vol. 37, # 2, p. 373 - 376
[15] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 22, p. 7107 - 7117
[16] Journal of Photochemistry and Photobiology B: Biology, 2014, vol. 138, p. 75 - 79
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[18] Beilstein Journal of Organic Chemistry, 2015, vol. 11, p. 563 - 567
With methanesulfonyl chloride; at 20 - 100℃; for 1h;
To 20-40 C, 13.8 g (0.1 mol) of N, N-dimethyl-m-hydroxyaniline, 16.0 g (0.22 mol) of N, N-(0.125 mol) of methylsulfonyl chloride was added dropwise to control the dropwise temperature of not more than 40 C, and the mixture was stirred for 1.0 hour and kept at a temperature of 50 to 100 C. After the reaction was completed, the temperature was lowered to 30 C , Add appropriate amount of water hydrolysis, filtration, a small amount of water, 4-N, N-dimethyl-2-hydroxybenzaldehyde 15.0g. Yield 90.9%, content 95.5%.
68%
The compound was prepared following the literature procedure with some modifications [24]. The Vilsmeier Haack adduct wasprepared by addition of POCl3 (15.0 mL, 0.16 mol) dropwise to dryDMF (30 mL) at 0 C, and the mixturewas then stirred for 30 min atthe same temperature. To the adduct, a solution of 3-(N,N-dimethylamino)phenol (11.0 g, 80.3 mmol) in dry DMF (23 mL) wasadded dropwise at 0 C. The reaction mixture was slowly warmedto room temperature, stirred for 4 h, and then heated at 85-90 Cfor 30 min. The reaction mixture was allowed to cool to roomtemperature and kept at that temperature with stirring overnight.It was then poured into crushed ice and neutralized with saturatedaqueous solution of Na2CO3 (120 mL). The precipitate was filteredoff, washed with water and dried in a vacuum oven at 25 C for 4 h.Yield: 9.00 g (68%), m.p. 78-79 C (lit. 80.5-81 C). The compoundwas used without further purification. 1H NMR (500 MHz, CDCl3)(Fig. S1-S3): delta=11.56 (1H, s, OH), 9.47 (1H, s, CHO), 7.24 (1H, d,J 9 Hz, H-6), 6.24 (1H, dd, J 9, 2.1 Hz, H-5), 6.03 (1H, d, J 2.1 Hz,H-3), 3.02 (6H, s, CH3); 13C NMR (125 MHz, CDCl3) (Fig. S4):delta= 192.4, 164.1, 156.2, 135.2, 111.7, 104.6, 97.2, 40.1. FT-IR:nCO 1628 cm-1.
65%
With trichlorophosphate; at 20 - 80℃; for 1.16667h;
3-N, N-dimethylaminophenol(10.5 g, 0.075 mol) was dissolved in 20 mL of dry DMF,(0.1 mL, 0.22 mol) in fresh Vilsmeier Haack reagent, followed by stirring at room temperature for 20 min,Heating to 40 reaction 20min, and then heated to 80 reaction 30min. Cooled to room temperature,The reaction mixture was quickly poured into a large amount of ice water, and the solution was neutralized with NaHCO3,The precipitate was collected and filtered, washed with water and dried to give 8.8 g of the desired product in 65% yield.
65%
3-N, N-dimethylaminophenol (10.5 g, 0.075 mol)Was dissolved in 20 mL of dry DMF,And added dropwise from phosphorus oxychloride (8.2 mL, 0.09 mol) and at room temperatureAnhydrous DMF (17 mL, 0.22 mol)In the new Vilsmeier Haack reagent,Followed by stirring at room temperature for 20 min,Heated to 40 reaction 20min,Then warmed to 80 reaction 30min.Cool to room temperature,The reaction mixture is quickly poured into a large amount of ice water,The above solution was neutralized with NaHCO3, the precipitate was collected and filtered, washed with water,After drying, 8.8 g of the target product was obtained in a yield of 65%.
With trichlorophosphate; at 0 - 90℃; for 1.25h;Inert atmosphere;
General procedure: We performed the Vilsmeier-Haack reaction to add the aldehyde function to the 2-aminophenol derivative. The phosphoryl oxychloride POCl3 (1.2 equiv in 3.0 equiv of anhydrous DMF) was carefully added dropwise to the previous synthesis product (also in anhydrous DMF: 200 mul for 1 mmol) under argon at 0 C. The reaction mixture was stirred 15 min at 0 C, then 15 min at room temperature,15 min at 37 C and finally 30 min at 80-90 C. After cooling, addition of ice and Na2CO3 in the reaction mixture and stirring, we obtain a precipitate (not pure but the cyclisation selects the desired coumarinic end product). This reaction step was used for the compounds 18-22. The previously synthesized salicylaldehyde (1.0 equiv) was dissolved in EtOH (10 ml for 1 mmol). Meldrum acid (1.2 equiv) was added to the stirred solution. Piperidineand acetic acid were added dropwise to catalyse the reaction (six drops for 1 mmol). The solution was stirred and heated 3 h under reflux. After cooling, the yellow to orange precipitate was filtered and obtained pure. This final reaction step was used for all the compounds (the only synthesis step of 17 and 23).
With trichlorophosphate; at 0 - 80℃;
4-(Dimethylamino)salicylaldehyde was prepared by the reported procedure [18] with little modification. To a dry DMF solution (21.0 ml) containing 3-(dimethylamino)phenol (3.10 g, 22.6 mmol) was added POCl3 (4.0 ml, 43.2mmol) at 0 C. The mixture was stirred for 10min, and further stirred for 30 min at room temperature. Then the resulting mixture was stirred overnight at 80 C. After cooling, the reaction mixture poured into ice-cold water. The solution was neutralized using saturated Na2CO3, and the formed precipitate was filtered off, washed several times with water and dried under vacuum. m.p. 80.1-81.2 C [19]; 1H NMR (400 MHz, CDCl3): delta 3.09 (s, 6H, CH3), 6.10-7.29 (m, 3H, Ar-H), 9.53 (s, 1H, OH), 11.61 (s, 1H, CHO).
3.30 g
With trichlorophosphate; at 0 - 80℃;
4-(Dimethylamino)salicylaldehydewas synthesized according to the literature [15,16] with littlemodification. POCl3 (4.0 mL, 43.2 mmol) was added dropwiseto dry DMF (21.0 mL, 271.8 mmol) containing 3-(dimethylamino)phenol (3.10 g, 22.6 mmol) at 0 C, and the mixture wasstirred for 10 min, slowly warmed to room temperature andstirred for another 30 min. The reaction mixture was heated at80 C overnight. After cooling to room temperature, the mixturewas poured into ice cold water. The solution was neutralizedwith saturated Na2CO3. The precipitate was washedseveral times with distilled water, and dried under vacuum to yield 3.30 g of 1. 1H NMR (400 MHz, CDCl3) delta 3.09 (s, 6H,CH3), 6.10-7.29 (m, 3H, Ar-H), 9.53 (s, 1H, OH), 11.61 (s, 1H,CHO). This was consistent with the literature.
4-N, N-dimethylamino-2-hydroxy-benzaldehyde (5 g, 30 mmol) and triphenylphosphinyloxyacetate (12 g,35 mmol) was heated to 180 C under argon for 1 h, cooled to room temperature,The crude product was purified by silica gel column chromatography to give 5.5 g of the desired product in 62% yield.
62%
at 180℃; for 1h;Inert atmosphere;
4-N, N-dimethylamino-2-hydroxy-benzaldehyde (5 g, 30 mmol)And triphenylphosphinylethyl acetate (12 g, 35 mmol)Heated to 180 C under argon for 1 h,Cool to room temperature,The crude product was purified by silica gel column chromatography to give the target product 5.5g, yield 62%.
EXAMPLE 23 N'-[2,6-Dichloro-4-[(4-dimethylaminosalicylidene)-amino]phenyl]-N,N-dimethylformamidine A 13.7 g. amount of 3-dimethylaminophenol is formylated with Vilsmeier reagent (N,N-dimethylformamide-phosphorus oxychloride) to give 6.6 g. of 4-dimethylaminosalicylaldehyde as brown plates, m.p. 81-83 C. A mixture of 6.0 g. of the preceding compound, 6.4 g. of recrystallized 2,6-dichloro-p-phenylenediamine and 100 ml. of absolute ethanol is refluxed for 4 hours. The reaction mixture is cooled at 5 C. for 16 hours to precipitate a product. The product is collected, washed with ethanol/n-hexane then n-hexane to yield 9.0 g. of 2[N-(4-amino-3,5-dichlorophenyl)formimidoyl]-5-dimethylaminophenol as golden-yellow, granular crystals, m.p. 166-167 C.
55
[ 41602-56-6 ]
[ 93392-00-8 ]
[ 83591-33-7 ]
Yield
Reaction Conditions
Operation in experiment
In acetic acid; acetone;
EXAMPLE I This example demonstrates the preparation of 7-dimethylamino-3-methyl-2,2'-spirobi[2H-1-benzopyran]. To a solution of 2-hydroxystyryl ethyl ketone (1.76 g, 0.01 mol) and <strong>[41602-56-6]4-dimethylamino-2-hydroxybenzaldehyde</strong> (1.65 g, 0.01 mol) in 25 ml of glacial acetic acid was added a cold solution of anhydrous hydrogen chloride (about 4 g) in 50 ml of glacial acetic acid. The steel blue solution rapidly turned deep magenta in color and was set aside. After 16 hours at room temperature the dark colored mixture was cooled and filtered. The filter-cake was washed with ether, air-dried and gave about 2.0 gms of an iridescent green solid. This solid, believed to be the pyrylium salt, was suspended in acetone (75 ml), and the dark blue mixture carefully neutralized with dilute ammonium hydroxide (diluted concentrated ammonium hydroxide with water 1 to 1). The pale yellow neutral reaction mixture containing a white solid (probably ammonium chloride) was filtered. The filtrate was concentrated to dryness under vacuum and left a deep blue residue. This residue was extracted with ether, and the combined ether extracts were dried over magnesium sulfate. The dried and filtered ethereal solution was concentrated to dryness and left a viscous dark blue oil. Repeated recrystallization of this colored residual oil from hot absolute alcohol gave pale green crystals (about 0.7 g), mp 148-149. The resulting crystals were subjected to elemental analysis by Galbraith Laboratories Inc., Knoxville, TN and analysis was calculated for C20 H19 NO2: C, 78.66; H, 6.27; N, 4.59. Found: C, 78.61; H, 6.49, N, 4.49.
EXAMPLE 16a The reaction product (XV) obtained in accordance with Example 16 is suspended in warm ethanol. A clear solution is formed, following the addition of 5 ml of 5% aqueous hydrochloric acid. 10 ml of water are added and the aqueous solution is extracted by repeated shaking with 10 ml batches of chloroform. After the chloroform has been distilled off in vacuo from the combined chloroform extracts, 2-hydroxy-4-dimethylaminobenzaldehyde (XVI) is obtained in the form of pale yellow needles, melting at 77 to 78 C.
57
[ 41602-56-6 ]
[ 141-97-9 ]
[ 74696-95-0 ]
Yield
Reaction Conditions
Operation in experiment
81%
With piperidine; In ethanol; for 6h;Heating / reflux;
4 mmol of <strong>[41602-56-6]4-dimethylamino-2-hydroxybenzaldehyde</strong> and 5 mmol of the appropriate 1,3-dicarbonyl compound were dissolved in 8 ml of absolute ethanol. 16 drops of piperidine were added, and each mixture was heated under reflux for 2-6 hours. The mixtures were cooled in the freezer, and the precipitate was filtered off and washed with ethanol to provide the products set forth in Table 1.; 3-Acetyl-7-(dimethylamino)-2H-1-benzopyran-2-one(1) 1H NMR (360 MHz, CDCl3) delta: 2.70(3H, s, Ac); 3.14 (6H, s, NMe2); 6.48 (1H, d, aromatic H); 6.66 (1H, dd, aromatic H); 7.43 (1H, d, aromatic H); 8.47 (1H, s, 4-H).
Example 1(g) Preparation of 7-(Dimethylamino)-2H-1-benzopyran-2-ones Vielsmeier reagent was prepared by addition of 4.66 mL (~50 mmol) of POCl3 (dropwise) to 7.76 mL of DMF at 0 C. in small aliquots, and the mixture was stirred for 5 min at the same temperature and then for 30 min at room temperature. 3.43 g (25 mmol) of 3-(dimethylamino)phenol in 2 mL of DMF was added to the Vielsmeier reagent dropwise. The mixture was heated at 60-70 C. for 1 hour, and the excess of reagent was destroyed by pouring the mixture on 50 g of crushed ice. The mixture was extracted with ethyl acetate, and the organic portion dried with anhydrous magnesium sulfate and evaporated. 4-dimethylamino-2-hydroxybenzaldehyde was isolated from the oily residue by column chromatography (silica gel, chloroform). Yield: 2.32 g (14 mmol, 56%).
methyl 3-[7-(dimethylamino)-2-oxo-2H-1-benzopyran-3-yl]-3-oxo-propanoate[ No CAS ]
[ 41602-56-6 ]
Bis(7-(dimethylamino)-2-oxo-2H-1-benzopyran-3-yl)ketone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With piperidine; In ethanol; for 8h;Heating / reflux;
Example 1(h) Preparation of Bis(7-(dimethylamino)-2-oxo-2H-1-benzopyran-3-yl)ketone 300 mg (1 mmol) of methyl 3-[7-(dimethylamino)-2-oxo-2H-1-benzopyran-3-yl]-3-oxo-propanoate [Compound 4 from Example 1(g)] was mixed with 250 mg of <strong>[41602-56-6]4-dimethylamino-2-hydroxybenzaldehyde</strong> and dissolved in 2 mL of absolute ethanol. 4 drops of piperidine were added and the mixture refluxed for 8 hours. The mixture was brought to room temperature and the precipitated solid filtered off. 179 mg (44%) of an orange solid. 1H NMR (360 MHz, CDCl3) delta: 3.11 (6H, s, NMe2); 6.50 (1H, d, aromatic H); 6.63 (1H, dd, aromatic H); 7.41 (1H, d, aromatic H); 8.19 (1H, s, 4-H).
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