* 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.
Reference：
[1] Journal of Medicinal Chemistry, 2004, vol. 47, # 25, p. 6349 - 6362
[2] Journal of the Chemical Society, 1915, vol. 107, p. 1637
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 10, p. 5022 - 5034
With hydrogen In water at 200℃; for 3 h; Autoclave
General procedure: General procedure for the amination of resorcinol with secondaryamine catalyzed by Raney Ni. Resorcinol (2.2 g, 20 mmol), secondaryamine (30 mmol) and Raney Ni (110 mg) were added to water(50 ml) in a 100 ml autoclave. The autoclave was purged with hydrogengas three times, then maintained 0.05 Mpa pressure. The mixturewas heated to 200 °C rapidly. Then stirring was maintained for 3 h.The reaction mixture was cooled to room temperature, and then extractedwith N-butyl acetate. The organic layer was dried (MgSO4), filteredand concentrated to give the crude product. The pure productwas got through flash column chromatography on silica gel (petroleumether/acetylacetic ester (3/1, v/v)).
Reference：
[1] Journal of Organic Chemistry, 1999, vol. 64, # 26, p. 9719 - 9721
6
[ 591-27-5 ]
[ 74-88-4 ]
[ 99-07-0 ]
Reference：
[1] Patent: KR2016/107998, 2016, A, . Location in patent: Paragraph 0069-0071
7
[ 50-00-0 ]
[ 591-27-5 ]
[ 99-07-0 ]
Reference：
[1] RSC Advances, 2014, vol. 4, # 81, p. 43195 - 43203
[2] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 2, p. 193 - 196
8
[ 626-02-8 ]
[ 124-40-3 ]
[ 99-07-0 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2015, vol. 357, # 4, p. 714 - 718
9
[ 591-20-8 ]
[ 124-40-3 ]
[ 99-07-0 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2015, vol. 357, # 4, p. 714 - 718
10
[ 121-69-7 ]
[ 99-07-0 ]
Reference：
[1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 2, p. 11
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 2, p. 11
11
[ 178752-79-9 ]
[ 99-07-0 ]
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 32, p. 10391 - 10398
12
[ 77-78-1 ]
[ 591-27-5 ]
[ 99-07-0 ]
Reference：
[1] Journal of the American Chemical Society, 1952, vol. 74, p. 573,577
13
[ 5857-93-2 ]
[ 74-88-4 ]
[ 99-07-0 ]
Reference：
[1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 4, p. 109
14
[ 506-59-2 ]
[ 124-40-3 ]
[ 108-46-3 ]
[ 99-07-0 ]
Reference：
[1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 2, p. 14
15
[ 121-69-7 ]
[ 619-60-3 ]
[ 3743-22-4 ]
[ 99-07-0 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1986, # 4, p. 625 - 629
[2] Tetrahedron Letters, 1984, vol. 25, # 14, p. 1479 - 1482
[3] Bulletin de la Societe Chimique de France, 1986, # 4, p. 625 - 629
16
[ 2836-04-6 ]
[ 99-07-0 ]
Reference：
[1] Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian Federation), 1941, vol. 14, p. 524,526[2] Chem.Abstr., 1942, p. 3159
[3] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 2, p. 70
17
[ 87-01-4 ]
[ 99-07-0 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1911, vol. 379, p. 105
18
[ 65-49-6 ]
[ 77-78-1 ]
[ 27559-59-7 ]
[ 99-07-0 ]
Reference：
[1] Archiv der Pharmazie (Weinheim, Germany), 1951, vol. 284, p. 341,346
Reference：
[1] Bulletin de la Societe Chimique de France, 1986, # 4, p. 625 - 629
[2] Tetrahedron Letters, 1984, vol. 25, # 14, p. 1479 - 1482
[3] Bulletin de la Societe Chimique de France, 1986, # 4, p. 625 - 629
29
[ 68-12-2 ]
[ 99-07-0 ]
[ 41602-56-6 ]
Yield
Reaction Conditions
Operation in experiment
90.9%
at 20 - 100℃; for 1 h;
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
[9] Dyes and Pigments, 2011, vol. 90, # 1, p. 56 - 64
[10] Journal of the American Chemical Society, 2013, vol. 135, # 33, p. 12360 - 12365
[11] Chemical Communications, 2011, vol. 47, # 8, p. 2435 - 2437
[12] Chemical Communications, 2014, vol. 50, # 66, p. 9329 - 9332
[13] Tetrahedron, 1982, vol. 38, # 9, p. 1203 - 1211
[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
[17] Chemistry - An Asian Journal, 2017, vol. 12, # 8, p. 936 - 946
[18] Beilstein Journal of Organic Chemistry, 2015, vol. 11, p. 563 - 567
Reference：
[1] Patent: WO2012/142162, 2012, A2, . Location in patent: Page/Page column 24
[2] Journal of the American Chemical Society, 2011, vol. 133, # 30, p. 11482 - 11484
35
[ 99-07-0 ]
[ 114-80-7 ]
Reference：
[1] Patent: CH208883, 1938, ,
36
[ 75-03-6 ]
[ 99-07-0 ]
[ 116-38-1 ]
Reference：
[1] DRP/DRBP Org.Chem.,
37
[ 74-96-4 ]
[ 99-07-0 ]
[ 116-38-1 ]
Reference：
[1] DRP/DRBP Org.Chem.,
38
[ 77-78-1 ]
[ 99-07-0 ]
[ 79-44-7 ]
[ 51-60-5 ]
Reference：
[1] Chemistry - A European Journal, 2018, vol. 24, # 11, p. 2776 - 2784
39
[ 99-07-0 ]
[ 51-60-5 ]
Reference：
[1] Patent: CH208883, 1938, ,
40
[ 99-07-0 ]
[ 150188-64-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 9, p. 1310 - 1326
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.
Stage #1: 5-bromoveratralaldehyde; malononitrile With polyethyleneimine covalently bound on the surface of Fe3O4 magnetic nanoparticle by [3-(2,3-epoxypropoxy)propyl]trimethoxysilane as cross linker In water for 0.0166667h; Sonication; Green chemistry;
Stage #2: 3-Dimethylaminophenol In water for 1.66667h; Sonication; Green chemistry;
2.3 General procedure for catalytic synthesis of compounds 4, 6.9,11
General procedure: A stirring mixture of an active carbonyl compound (aldehyde 1 or isatin 7, 1mmol), malononitrile 2 (1.2mmol), magnetic catalytic system ([PEISi-MNPs], 5mg) and ethylene glycol/water (EG/H2O 20/80, 2mL) were sonicated for one minute. To this stirred mixture, an enolizable compounds (3-(dimethylamino)phenol 3, 4-hydroxycoumarin 5 or dimedone 10, 1mmol) was added. The reaction mixture was heated at appropriate temperature as mentioned in Table 1. The progress of the reaction was monitored by TLC. After completion of the reaction (as shown in Tables 2-4), the reaction mixture was allowed to cool at room temperature and diluted with ethyl acetate and the catalyst was easily separated from the reaction mixture with an external magnet and washed twice with ethyl acetate. The combined organic layers were concentrated in vacuum and the residue was purified by crystallization from ethanol. All compounds gave satisfactory spectral data and they were identical with those reported in the literature [29,31-37].
2-amino-3-cyano-4-(3-fluorophenyl)-7-(dimethylamino)-4H-benzopyran[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
Stage #1: malononitrile; 3-Fluorobenzaldehyde With polyethyleneimine covalently bound on the surface of Fe3O4 magnetic nanoparticle by [3-(2,3-epoxypropoxy)propyl]trimethoxysilane as cross linker In water for 0.0166667h; Sonication; Green chemistry;
Stage #2: 3-Dimethylaminophenol In water for 1.66667h; Sonication; Green chemistry;
2.3 General procedure for catalytic synthesis of compounds 4, 6.9,11
General procedure: A stirring mixture of an active carbonyl compound (aldehyde 1 or isatin 7, 1mmol), malononitrile 2 (1.2mmol), magnetic catalytic system ([PEISi-MNPs], 5mg) and ethylene glycol/water (EG/H2O 20/80, 2mL) were sonicated for one minute. To this stirred mixture, an enolizable compounds (3-(dimethylamino)phenol 3, 4-hydroxycoumarin 5 or dimedone 10, 1mmol) was added. The reaction mixture was heated at appropriate temperature as mentioned in Table 1. The progress of the reaction was monitored by TLC. After completion of the reaction (as shown in Tables 2-4), the reaction mixture was allowed to cool at room temperature and diluted with ethyl acetate and the catalyst was easily separated from the reaction mixture with an external magnet and washed twice with ethyl acetate. The combined organic layers were concentrated in vacuum and the residue was purified by crystallization from ethanol. All compounds gave satisfactory spectral data and they were identical with those reported in the literature [29,31-37].
82%
With sodium chloride for 0.666667h;
30 Example 30
(A) Add 3 stainless steel balls with a diameter of 10 mm into a 50 mL stainless steel ball mill, and then add 0.5 mmol 3-fluorobenzaldehyde, 0.5 mmol malononitrile, 0.5 mmol N,N-dimethyl meta-hydroxyaniline, 80 mg bovine serum albumin and 300 mg sodium chloride, ball milled at 30 Hz for 40 minutes; (B) After ball milling, scrape the reaction mixture out, add 30 mL ethyl acetate to dissolve and filter, take the filtrate by rotary evaporation and concentrate, and finally purify by column chromatography. The eluent used is a mixed solution of petroleum ether and ethyl acetate. , The volume ratio of petroleum ether to ethyl acetate is 4:1; (C) Rotate the eluent containing the product to obtain an orange solid 2-Amino-3-cyano-4-(3-fluorophenyl)-7-(dimethylamino)-4H-benzopyran, the yield was 82.0%.
7-(Dimethylamino)-4-hydroxy-2H-chromen-2-one (3)
Solution of diphenyl malonate (2.36 g, 10 mmol) and 3-(N,N-dimethylamino)phenol (1.52 g, 16mmol) in toluene (30 mL) was refluxed for 10 h. The reaction mixture was cooled and crystalsformed were filtered off. The crude product was recrystallized from ethanol. Yield: 1.84 g, 9.0mmol, 89%. 1H NMR (DCl3): 7.56 (1, d, J 8.9, H5), 6.68 (1H, dd, J 9.0, 2.2, 6), 6.48 (1, d,J 2.1, 8), 5.28 (1, s, 3), 2.99 (6, s, N(CH3)2).
85%
In toluene for 7h; Heating;
70%
for 7h; Reflux;
65%
In toluene for 5h; Reflux; Inert atmosphere;
Synthesis of compound 3.
(2) To a solution of diphenyl malonate A (2.00 g, 7.81 mmol) in toluene (30 mL) was added 3-(dimethylamino) phenol (1.00 g, 7.30 mmol) at room temperature. The reaction mixture was allowed to reflux for 5 h until massive solid was emerged. The reaction mixture was cooled to room temperature and filtrated, the filtrate cake was washed with petroleum ether (50 mL × 3). The solid residue was dried at 45 °C for 6 h, gave 7-(dimthylamino)-4-hydroxy-2H-1-benzopyran-2-one B as a gray solid (972 mg, 65%).
In toluene for 4h; Reflux;
With trichlorophosphate In toluene for 4h; Reflux;
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%).
A solution of tetrafluorophthalic anhydride (2.32 g, 10.6 mmol) and 3-dimethylaminophenol (1.46 g, 10.6 mmol) in 20 mL of toluene was refluxed for 20 h. The solvent was removed in vacuo and the residue was resolved in CH2Cl2. The organic phase was washed with 1N HCl and extracted with NaHCO3 aq. The aqueous phase was acidified (pH 1.0) by adding 1 N HCl and then extracted with CH2Cl2. The organic phase was dried with Na2SO4, and then filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (CH2Cl2/AcOEt: liner gradient from1:0 to 1:1(v/v)) to give the product in 55 % yield (2.08 g, 5.83 mmol).1H NMR (CDCl3, 400MHz) :δ 6.98 (d, 1H, J = 9.00 Hz), 6.16 (dd, 1H, J = 9.00 Hz, 2.68 Hz), 6.13 (d, 1H, J = 2.68 Hz ), 3.07 (s, 6H).
Stage #1: 3-Trifluoromethylbenzaldehyde; malononitrile With polyethyleneimine covalently bound on the surface of Fe3O4 magnetic nanoparticle by [3-(2,3-epoxypropoxy)propyl]trimethoxysilane as cross linker In water for 0.0166667h; Sonication; Green chemistry;
Stage #2: 3-Dimethylaminophenol In water for 1.33333h; Sonication; Green chemistry;
2.3 General procedure for catalytic synthesis of compounds 4, 6.9,11
General procedure: A stirring mixture of an active carbonyl compound (aldehyde 1 or isatin 7, 1mmol), malononitrile 2 (1.2mmol), magnetic catalytic system ([PEISi-MNPs], 5mg) and ethylene glycol/water (EG/H2O 20/80, 2mL) were sonicated for one minute. To this stirred mixture, an enolizable compounds (3-(dimethylamino)phenol 3, 4-hydroxycoumarin 5 or dimedone 10, 1mmol) was added. The reaction mixture was heated at appropriate temperature as mentioned in Table 1. The progress of the reaction was monitored by TLC. After completion of the reaction (as shown in Tables 2-4), the reaction mixture was allowed to cool at room temperature and diluted with ethyl acetate and the catalyst was easily separated from the reaction mixture with an external magnet and washed twice with ethyl acetate. The combined organic layers were concentrated in vacuum and the residue was purified by crystallization from ethanol. All compounds gave satisfactory spectral data and they were identical with those reported in the literature [29,31-37].
Stage #1: 3-nitro-benzaldehyde; malononitrile With polyethyleneimine covalently bound on the surface of Fe3O4 magnetic nanoparticle by [3-(2,3-epoxypropoxy)propyl]trimethoxysilane as cross linker In water for 0.0166667h; Sonication; Green chemistry;
Stage #2: 3-Dimethylaminophenol In water for 1.5h; Sonication; Green chemistry;
2.3 General procedure for catalytic synthesis of compounds 4, 6.9,11
General procedure: A stirring mixture of an active carbonyl compound (aldehyde 1 or isatin 7, 1mmol), malononitrile 2 (1.2mmol), magnetic catalytic system ([PEISi-MNPs], 5mg) and ethylene glycol/water (EG/H2O 20/80, 2mL) were sonicated for one minute. To this stirred mixture, an enolizable compounds (3-(dimethylamino)phenol 3, 4-hydroxycoumarin 5 or dimedone 10, 1mmol) was added. The reaction mixture was heated at appropriate temperature as mentioned in Table 1. The progress of the reaction was monitored by TLC. After completion of the reaction (as shown in Tables 2-4), the reaction mixture was allowed to cool at room temperature and diluted with ethyl acetate and the catalyst was easily separated from the reaction mixture with an external magnet and washed twice with ethyl acetate. The combined organic layers were concentrated in vacuum and the residue was purified by crystallization from ethanol. All compounds gave satisfactory spectral data and they were identical with those reported in the literature [29,31-37].
90%
With 1-(4-ferrocenylbutyl)-3-{3-[dihydroxy(methoxy)silyl]propyl}benzimidazol-3-ium chloride supported on Fe3O4(at)SiO2 core-shell/BiOCl nano-composite In ethanol; water at 20℃; for 0.366667h; Sonication;
89%
With mesoporous Al-MCM-41 functionalized by layered double hydroxide nanosheets and (3-aminopropyl)triethoxysilane In ethanol at 80℃; for 6h; Schlenk technique;
General procedure: The catalytic model reaction was carried out as follows:In a Schlenk flask equipped with a magnetic stirrer, septum and condenser, 4-chlorobenzaldehyde (1.0 mmol), (phenylsulfonyl)acetonitrile (1.0 mmol), 70% ALAM (5 mol%) and95% EtOH (5 mL) were added. The flask was immersed ina heating oil bath and the reaction mixture was stirred at80 °C. Upon complete consumption of starting materials asanalysed by TLC (hexane : ethyl acetate, 8 : 2), then the catalystwas separated by centrifuge, washed with water, ethanoland acetone. Resulting reaction mixture was extracted withdiethyl ether (3 × 10 mL). The combined organic layer wasdried over anhydrous Na2SO4and concentrated to affordcrude products, which were purified by column chromatography.It was observed that on MCM-41 surfaces there isalways some residual adsorbed water left behind, even afterheating under vacuum as it was done here. Nevertheless,that does not seem to affect the model reaction, which has infact been reported to take place even in aqueous media [72,73]. Moreover, our final product, 2-amino-4H-chromenes,requires a subsequent cascade type Knoevenagel-Michaeladdition, and that also appears to be promoted readily by ouroptimized catalytic protocol.
87%
With 2-amino-2-hydroxymethyl-1,3-propanediol In ethanol; water at 20℃; for 2h; Green chemistry;
86%
With sodium chloride for 0.666667h;
27 Example 27
(A) Add 3 stainless steel balls with a diameter of 10 mm into a 50 mL stainless steel ball mill, and then add 0.5 mmol 3-nitrobenzaldehyde, 0.5 mmol malononitrile, 0.5 mmol N,N-dimethyl meta-hydroxyaniline, 80 mg bovine serum albumin and 300 mg sodium chloride, ball milled at 30 Hz for 40 minutes; (B) After ball milling, scrape the reaction mixture out, add 30 mL ethyl acetate to dissolve and filter, take the filtrate by rotary evaporation and concentrate, and finally purify by column chromatography. The eluent used is a mixed solution of petroleum ether and ethyl acetate. , The volume ratio of petroleum ether to ethyl acetate is 2:1; (C) Rotate the eluent containing the product to obtain an orange solid 2-Amino-3-cyano-4-(3-nitrophenyl)-7-(dimethylamino)-4H-benzopyran, the yield was 86.0%.
General procedure: A stirring mixture of an active carbonyl compound (aldehyde 1 or isatin 7, 1mmol), malononitrile 2 (1.2mmol), magnetic catalytic system ([PEISi-MNPs], 5mg) and ethylene glycol/water (EG/H2O 20/80, 2mL) were sonicated for one minute. To this stirred mixture, an enolizable compounds (3-(dimethylamino)phenol 3, 4-hydroxycoumarin 5 or dimedone 10, 1mmol) was added. The reaction mixture was heated at appropriate temperature as mentioned in Table 1. The progress of the reaction was monitored by TLC. After completion of the reaction (as shown in Tables 2-4), the reaction mixture was allowed to cool at room temperature and diluted with ethyl acetate and the catalyst was easily separated from the reaction mixture with an external magnet and washed twice with ethyl acetate. The combined organic layers were concentrated in vacuum and the residue was purified by crystallization from ethanol. All compounds gave satisfactory spectral data and they were identical with those reported in the literature [29,31-37].
With triethylamine; at 150℃; under 15514.9 Torr; for 0.0833333h;Microwave irradiation;
General procedure: An equimolar mixture of an 3-dimethylaminophenol (1), substituted naphthaldehydes (2) and malononitrile (3) with 2-4 drops of triethyamine was thoroughly mixed and irradiated at 150 oC using 300 psi pressure and 300 Watts power nearly 5 minutes in CEM Discover. The reaction mixture was cooled and dissolved in dichloromethane. The mixture was subjected to flash chromatography to obtain the pure chromenes using ethyl acetate and hexane solvent mixture (3:7).
Stage #1: 3-Dimethylaminophenol With Mesitol; sodium hydride In mineral oil at 100℃; for 0.0833333h; Glovebox;
Stage #2: carbon dioxide In mineral oil at 185℃; for 2h;
6,6"-oxybis(3',6'-bis(dimethylamino)-3H-spiro[isobenzofuran-1,9'-xanthen]-3-one)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With ammonium chloride; In neat (no solvent); at 180 - 190℃; for 1.5h;
General procedure: General Procedure:In a 250 ml round bottom flask a well mixed mixture of 0.308 gm(0.001mol) of 4,4?-oxydiphthalic anhydride (1) and substituted phenols (2a-eScheme 1) 0.004 mol were taken and fused in oil bath at 180 oC. The fused melt was added 0.2 g of NH4Cl, and stirred the reaction mixture mechanicallyat 180-190oC until the solid mass obtained. The solid mass was dissolvedin 10 ml of 5 % sodium hydroxide solution. The solution was filtered toremove any insoluble impurities and filtrate was treated with 3 ml of 30%hydrochloric acid and precipitated the dyes (3a-e). Similarly the derivativesof 1,4,5,8-Naphthalenetetracarboxylic dianhydride (6a-e) with substitutedphenols (2a-e, Scheme 2) were synthesized by following the same procedure.
2-(6-(diethylamino)-3-(dimethyliminio)-3H-xanthen-9-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With sulfuric acid; In water; at 100 - 110℃; for 7h;
Solution of 300 mg (1 mmol) of2-(4-diethylamino-2-hydroxybenzoyl)benzoic acid and 140 mg (1 mmol) of 3-dimethylaminophenol in3 ml of 75% sulfuric acid was heated for 7 hours at 100-110C. Aftercooling reaction mixture was poured in 50 ml of water, neutralized with20% sodium hydroxide solution to pH = 6-7. The obtained red-violet precipitatewas collected by filtration and washed with small amount of water. Yield:380 mg (92%). Raw product was purified by column chromatography on Silicagel 60 with acetone/methanol (12:1, v/v). Mp 116 C. UV-Vis(ethanol): lmax(abs) 545 nm (e = 82,000 M-1×cm-1), lmax(fluor) 568 nm.1H-NMR(200 MHz, DMSO-d6), d, ppm: 1.11 (6H, t, 7.2 Hz, N(CH2CH3)2), 2.94 (6H, s, N(CH3)2), 3.25-3.5(4H, q, N(CH2CH3)2), 6.40-6.57 (6H, m,xanth.), 7.22 (1H, d, 7.1 Hz, 9-phenyl), 7.54-7.83 (2H, m, 9-phenyl), 7.96 (1H,d, 7.0 Hz, 9-phenyl).
3-(6-(4-chlorophenyl)pyrimidin-4-yloxy)-N,N-dimethylbenzenamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 3-Dimethylaminophenol With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.166667h;
Stage #2: 4-chloro-6-(4-chlorophenyl)pyrimidine In N,N-dimethyl-formamide at 20℃; for 2h;
4-(4-Chlorophenyl)-6-phenoxypyrimidine (3a)
General procedure: Phenol (1 equivalent) was added to NaH (1.2 equivalent) in dry dimethylformamide (7 ml) and stirred at rt for 10 min. Then, compound 2 (1 equivalent) was added portion wise and allowed to stir for further 2 h at rt. Reaction mixture was quenched with ice water and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Crude product was purified by silica gel (100-200 mesh) column chromatography using 0-15% ethyl acetate in pet-ether as an eluent. The other derivatives were also prepared by same procedure.
With toluene-4-sulfonic acid; In propionic acid; at 60℃;Inert atmosphere;
Compound R33 (0.8 g, 4 mmol), m-dimethylaminophenol (1.15 g, 8 mmol) andThe p-toluenesulfonic acid monohydrate (80 mg) was dissolved in 5 ml of propionic acid, protected by argon at 60°C overnight, then poured into 50 ml of ice water, neutralized with sodium bicarbonate, and extracted with dichloromethane, and the organic phase was spin-dried. Through the pillars. Starting with pure DCM, increasing to DCM:MeOH=100:1 yielded 0.6 g (34percent) product.
With potassium carbonate; In dimethyl sulfoxide; at 0 - 60℃;Inert atmosphere;
3-nitrophthalicnitrile (20 mmol) and N,N-dimethyl-m-hydroxyaniline (20-30 mmol, preferably 25 mmol) as reactants, dimethyl sulfoxide (60-80 mL, preferably 70 mL) The solvent is stirred in the presence of potassium carbonate (30-60 mmol, preferably 50 mmol) and nitrogen, and the reaction is stirred at room temperature to 60C (preferably 60C) for 24-72 hours and monitored by thin layer chromatography. After the completion of the reaction, after the reaction was completed, water was allowed to stand for 4 to 12 hours and precipitated. The double-layer filter paper was suction filtered at room temperature and freeze-dried to obtain a brown-yellow powdery solid with a yield of 61%.
61.15%
With potassium carbonate; In dimethyl sulfoxide; at 60℃;Inert atmosphere;
Using <strong>[51762-67-5]3-nitrophthalonitrile</strong> and N,N-dimethyl-m-hydroxyaniline as reactants,The feed ratio of the two is 1:1 to 1.5 with dimethyl sulfoxide as the solvent.The amount of solvent required is 3 to 4 mL per mmol of <strong>[51762-67-5]3-nitrophthalonitrile</strong>.In the presence of potassium carbonate and nitrogen protection,The reaction is stirred at room temperature ~60C for 48-72 hours.The amount of potassium carbonate used is 1.5 to 3 mmol per mmol of 3-nitro-phthalonitrile.Monitored by thin layer chromatographyThe reaction was terminated when the 3-nitro-phthalonitrile was almost consumed, and water was allowed to stand for 4 to 8 hours.Precipitate, double filter paper atmospheric pressure filtration,Freeze-drying gave a brown-yellow powdery solid, yield 61.15%.
61%
With potassium carbonate; In dimethyl sulfoxide; at 20 - 60℃;Inert atmosphere;
3-nitrophthalicnitrile (20 mmol) and N,N-dimethyl-m-hydroxyaniline (20-30 mmol, preferably 25 mmol) as reactants, dimethyl sulfoxide (60-80 mL, preferably 70 mL) The solvent is stirred in the presence of potassium carbonate (30-60 mmol, preferably 50 mmol) and nitrogen, and the reaction is stirred at room temperature to 60C (preferably 60C) for 24-72 hours and monitored by thin layer chromatography. After the completion of the reaction, after the reaction was completed, water was allowed to stand for 4 to 12 hours and precipitated. The double-layer filter paper was suction filtered at room temperature and freeze-dried to obtain a brown-yellow powdery solid with a yield of 61%.
With sulfuric acid; In water; at 0 - 160℃; for 16h;
Water (27 mL) was cooled to 0C, and 41 mL of cone. H2SO4 was slowly added. The solution was heated to l60C. Thoroughly premixed 2-formylbenzenesulfonic acid (5.03 g, 24.2 mmol) and 3-(dimethylamino)phenol (6.63 g, 48.3 mmol) was added portionwise over 1 minute to the sulfuric acid solution. The solution was stirred at l60C for 8 hr under air, then cooled to RT and stirred for another 8 h. Cold water (300 mL, ca. 0C) was mixed with 100 mL of 10 M NaOH. The crude reaction mixture was added dropwise to the NaOH solution, keeping the temperature below 25C. Once the reaction mixture was added, more 10 M NaOH was added until pH was about 8.5. The mixture was stirred at RT overnight. The solids were collected by vacuum filtration and dried under high vacuum over KOH to yield 10.6 g of crude material that contained approximately 50% inorganic salts. A 3.57 g portion of the crude material was chromatographed on a silica gel column (2" x 7") using a MeOH/DCM solvent gradient (4% to 10% MeOH). A mixture of isomers was produced, with the desired isomer eluting first. 780 mg (22%) of Compound 10 was obtained. LCMS: m/z 423.4 [M+H]
With mesoporous Al-MCM-41 functionalized by layered double hydroxide nanosheets and (3-aminopropyl)triethoxysilane In ethanol at 80℃; for 6h; Schlenk technique;
General procedure: The catalytic model reaction was carried out as follows:In a Schlenk flask equipped with a magnetic stirrer, septum and condenser, 4-chlorobenzaldehyde (1.0 mmol), (phenylsulfonyl)acetonitrile (1.0 mmol), 70% ALAM (5 mol%) and95% EtOH (5 mL) were added. The flask was immersed ina heating oil bath and the reaction mixture was stirred at80 °C. Upon complete consumption of starting materials asanalysed by TLC (hexane : ethyl acetate, 8 : 2), then the catalystwas separated by centrifuge, washed with water, ethanoland acetone. Resulting reaction mixture was extracted withdiethyl ether (3 × 10 mL). The combined organic layer wasdried over anhydrous Na2SO4and concentrated to affordcrude products, which were purified by column chromatography.It was observed that on MCM-41 surfaces there isalways some residual adsorbed water left behind, even afterheating under vacuum as it was done here. Nevertheless,that does not seem to affect the model reaction, which has infact been reported to take place even in aqueous media [72,73]. Moreover, our final product, 2-amino-4H-chromenes,requires a subsequent cascade type Knoevenagel-Michaeladdition, and that also appears to be promoted readily by ouroptimized catalytic protocol.
With polyphosphoric acid; In N,N-dimethyl-formamide; at 120℃; for 12h;
A suspension of <strong>[5466-84-2]4-nitrophthalic anhydride</strong> (1.03 g, 5.33 mmol) and 3-(dimethylamino)phenol (1.65 g, 12.0 mmol) and polyphosphoric acid (105 mg) in DMF (30 ml) was stirred at 120 C for 12 h. After cooling to room temperature, the solution was evaporated under reduced pressure. The residue was dissolved in methanol (5 ml) and the methanol solution was poured onto H2O (100 ml) on ice. The precipitate was collected by filtration and washed three times with ice-cold water. The residue was purified by silica gel column chromatography (CHCl3/MeOH=8/1 to 1/1) to give 5(6)-NO2TMR as a red solid (131 mg, 0.304 mmol, yield 6%).
(E)-2-((4-(dimethylamino)-2-hydroxyphenyl)diazenyl)pyridine 1-oxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 2-aminopyridine N-oxide With tetrafluoroboric acid; sodium nitrite In water at -10 - -5℃; for 1h;
Stage #2: 3-Dimethylaminophenol In methanol at 15 - 20℃; Inert atmosphere;
1.2; 1.3
2-aminopyridine 1-oxide (0.8g, 6.55 mmol) was taken in 4 mL HBF4 and cooled to -5 °C to -10 °C. To this solution, a solution of NaNCh (0.56 g, 8.11 mmol) in water (1.0 mL) was added slowly with stirring at such rate that the temperature was kept below -5 °C. After the addition was complete, stirring was continued for lh at -5 °C, during which time yellow precipitation formed. The hygroscopic yellow solid was collected carefully by decanting the clear solution under nitrogen atmosphere. It was washed thoroughly with minimal THF and followed by ether, and dried in vacuum at room temperature for 2 h to afford the desired compound.
Stage #1: 2-aminopyridine N-oxide With tetrafluoroboric acid; sodium nitrite In water at -10 - -5℃; for 1h;
Stage #2: 3-Dimethylaminophenol In methanol at 15 - 20℃; Inert atmosphere;
1.2; 1.3
2-aminopyridine 1-oxide (0.8g, 6.55 mmol) was taken in 4 mL HBF4 and cooled to -5 °C to -10 °C. To this solution, a solution of NaNCh (0.56 g, 8.11 mmol) in water (1.0 mL) was added slowly with stirring at such rate that the temperature was kept below -5 °C. After the addition was complete, stirring was continued for lh at -5 °C, during which time yellow precipitation formed. The hygroscopic yellow solid was collected carefully by decanting the clear solution under nitrogen atmosphere. It was washed thoroughly with minimal THF and followed by ether, and dried in vacuum at room temperature for 2 h to afford the desired compound.
Stage #1: 2-aminopyridine N-oxide With tetrafluoroboric acid; sodium nitrite In water at -10 - -5℃; for 1h;
Stage #2: 3-Dimethylaminophenol In methanol at 15 - 20℃; Inert atmosphere;
1.2; 1.3
2-aminopyridine 1-oxide (0.8g, 6.55 mmol) was taken in 4 mL HBF4 and cooled to -5 °C to -10 °C. To this solution, a solution of NaNCh (0.56 g, 8.11 mmol) in water (1.0 mL) was added slowly with stirring at such rate that the temperature was kept below -5 °C. After the addition was complete, stirring was continued for lh at -5 °C, during which time yellow precipitation formed. The hygroscopic yellow solid was collected carefully by decanting the clear solution under nitrogen atmosphere. It was washed thoroughly with minimal THF and followed by ether, and dried in vacuum at room temperature for 2 h to afford the desired compound.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
120K+ Compounds
Competitive Price
1-2 Day Shipping
