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Nitrothiazole-Thiazolidinone Hybrids: Synthesis and in Vitro Antimicrobial Evaluation
Dylan Hart ; Lesetja J. Legoabe ; Omobolanle J. Jesumoroti , et al. Chem. Biodivers.,2022,19(11):e202200729. DOI: 10.1002/cbdv.202200729 PubMed ID: 36102043
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Abstract: Herein we report the synthesis of novel compounds inspired by the antimicrobial activities of nitroazole and thiazolidin-4-one based compounds reported in the literature. Target compounds were investigated in vitro for antitubercular, antibacterial, antifungal, and overt cell toxicity properties. All compounds exhibited potent antitubercular activity. Most compounds exhibited low micromolar activity against S. aureus and C. albicans with no overt cell toxicity against HEK-293 cells nor haemolysis against human red blood cells. Notably, compound 3b exhibited low to sub-micromolar activities against Mtb, MRSA, and C. albicans. 3b showed superior activity (0.25 μg/ml) against MRSA compared to vancomycin (1 μg/ml).
Purchased from AmBeed: 613-45-6 ; 121-66-4 ; 587-04-2 ; 104-87-0 ; 552-89-6 ; 456-48-4 ; 830-79-5 ; 555-16-8 ; 104-88-1 ; 591-31-1 ; 3132-99-8 ; 446-52-6 ; 459-57-4 ; 529-20-4 ; 6287-38-3 ; 123-08-0 ; 100-52-7 ; 349121-09-1 ; 89-98-5 ...More
CAS No. : | 123-08-0 | MDL No. : | MFCD00006939 |
Formula : | C7H6O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RGHHSNMVTDWUBI-UHFFFAOYSA-N |
M.W : | 122.12 | Pubchem ID : | 126 |
Synonyms : |
4-Formylphenol;p-Formylphenol;4-Hydroxybenzaldehyde
|
Chemical Name : | 4-Hydroxybenzaldehyde |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
55% | With sulfuryl dichloride; In chloroform;Inert atmosphere; Reflux; | Compound R53 (4.9 g, 40 mmol) was dissolved in 80 ml of dry chloroform, followed by argon gasProtected, heated to reflux, slowly added dropwise a solution of 20 ml of sulfonyl chloride (6.4 ml, 80 mmol) in chloroform, and then refluxed overnight. The reaction solution was spin-dried and purified on a silica gel column. Yield 4.2g (55percent). |
Yield | Reaction Conditions | Operation in experiment |
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97.5% | In water; at 20 - 85℃; for 5.5h;Large scale; | At room temperature, water (400 L) and p-hydroxybenzaldehyde (100 kg)Heated to 85 C,Keep stirring for about 30 minutes to clarify,Then p-fluoroaniline was added slowly over 2 hours at 85 C,Continue to heat and stir for 1 hour.Slowly cool to room temperature and stir for 2 hours.Centrifugal, spin-dry for 30 minutes,Washed with water (500 L)Spin dry for 1 hour.Centrifuge the material at 50 C for 5 hours4 - [(4-Fluoro-phenylimino) -methyl] phenol,Called Schiff base.Yield: 97.5%. |
90% | In methanol; at 20 - 30℃;Large scale; | 12 Kg 4-hydroxybenzaldehyde and 60 L methanol were added to a 100 L reaction tank and were dissolved under stirring, 12 Kg 4-fluoroaniline was added drop by drop at room temperature, the mixture was reacted continuously for 23 hours after the addition. The reaction was monitored by TLC until the spots of the raw material (4-hydroxylbenzaldehyde) disappeared, the solid produced by the reaction was filtered, dried and weighted 19 Kg (yield: 90%). (0056) 1H NMR (400 MHz, DMSO-d6): delta 6.88 (d, 2H, J=8.4 Hz), 7.18-7.27 (m, 4H), 7.76 (d, 2H, J=8.4 Hz), 8.46 (s, 1H), 10.11 (s, 1H). |
88% | In isopropyl alcohol; at 50℃; for 1h; | Equip a three necked 1L flask with a mechanical stirrer, thermometer and an addition funnel. Add 480 mL of isopropanol, 144 g (1.18 moles) of p-hydroxybenzaldehyde (endothermic) and agitate the mixture while heating to a temperature of 50C. Agitate the mixture at 50C for 15 min (making sure all the material is in solution), then add 114 mL (1.2 moles) of p-fluoroaniline slowly via the addition funnel (exothermic reaction). After the addition is complete, agitate the thick slurry for 1 hr at 50C, cool to r.t. and agitate for 30 min. Filter the product, wash the cake with 150 mL of isopropanol, dry the wet cake in a draft oven at 50C for 24 h or until dry to yield 222 g of the imine (88%); mp: 180-182C |
84% | In ethanol; | Preparation of N-(4-hydroxybenzylidene)-4-fluorobenzenamine (Intermediate 1). N-(4-hydroxybenzylidene)-4-fluorobenzenamine (Intermediate 1) was synthesized following the procedure described in Layer Chem. Rev. 1963, 63, 489; Ojima et. al. Tetrahedron Lett. 1990, 31, 4289 and Poljak et. al. J. Mol. Struct. 2005, 751, 60. To an ethanol solution of 4- hydroxybenzaldehide (5 g, 40.94 mmol), 4-fluoroaniline (4.5 g, 40.94 mmol) was added and the mixture was stirred for 3h. Solvent was evaporated to dryness and the product recrystallized in ethyl acetate. Intermediate 1 was obtained as white crystals (7.6 g, 84%) (Scheme 1). 1H NMR (600 MHz, DMSO-d6): 6.88 (d, 2H, J = 8.6 Hz), 7.19-7.27 (m, 4H), 7.76 (d, 2H, J = 8.6 Hz), 8.46 (s, 1H), 10.12 (bs, 1H). |
80% | In isopropyl alcohol; at 50℃; for 1h; | The compound (1) (10 g, 81.90 mmol) and p-fluoroaniline (9 g, 81.00 mmol) were dissolved in isopropanol (75 ml)Heated to 50 C,Stir for 1h,Down to room temperature,Filter,Add isopropyl alcohol (10ml) leaching,To give a pale yellow solid,Compound (2) (14.2 g, 80% yield). |
(1-3) Preparation of 2,2-dimethyl-propionic acid 4-[(4-fluorophenyl imino)-methyl] -phenyl ester (Formula 6); 180 g of 4- [(4-fluorophenylimino)-methyl] -phenol, which had been prepared by the reaction of 4-hydroxybenzaldehyde with 4-fluoroaniline according to the method described in U.S. Pat. No. 6,207,822, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tert.-butylhydroperoxide; sulfuric acid; acetic acid; In water; ethyl acetate; | EXAMPLE 6 This example illustrates production of a benzothiazole derivative of the present invention using a benzothiazole reactant having a substituent corresponding to R1 and a benzaldehyde reactant having a substituent corresponding to R2 4.37 g of <strong>[13599-84-3]6-hydroxybenzothiazole</strong> and 11.0 g of 4-hydroxybenzaldehyde were dissolved in a mixed solvent of 22 ml of water and 66 ml of acetic acid containing 1.3 ml of concentrated sulfuric acid and the mixture was cooled at 0 C. 65 ml of an aqueous solution containing 25.7 g of FeSO4 7H2 O and 3 equivalents of t-butylhydroperoxide were separately added dropwise into the mixture with stirring. After the mixture was stirred for 1 hour, the crystals were collected by filtration, dissolved in ethyl acetate and washed with water. The organic layer was dried over mirabilite and concentrated. Then the residue was recrystallized from ethanol-water (1:1) to yield 5.50 g of the Compound 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; In dichloromethane; water; | (a) 0.6 g of N,N'-dicyclodicyclohexylcarbodiimide is added at room temperature while stirring to a solution of 1.0 g of 4-[6-acryloyloxyhexyloxy]benzoic acid, 0.3 g of 4-hydroxybenzaldehyde and 0.04 g of 4-dimethylaminopyridine in 20 ml of dichloromethane. The reaction mixture is stirred at room temperature overnight, poured into 100 ml of water and then extracted three times with 50 ml of dichloromethane each time. The combined organic phases are washed twice with 100 ml of water each time, dried over magnesium sulphate, filtered and the filtrate is subsequently concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 1:1) and two-fold recrystallization from ethanol of the fractions which are pure according to thin-layer chromatography gives 0.9 g of 4-(4-[6-acryloyloxyhexyloxy]phenylcarbonyloxy)benzaldehyde. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium acetate; acetic anhydride; In ethanol; | A. 4-(p-Acetoxybenzylidene)-2-(p-chlorophenyl)-5-oxazolone A mixture of 60 g of <strong>[13450-77-6]N-(p-chlorobenzoyl)glycine</strong>, 34.5 g of p-hydroxybenzaldehyde, 23 g of fused sodium acetate and 170 ml of acetic anhydride was heated under reflux for 1 hour. The reaction mixture was cooled slightly and 400 ml of ethanol was added. A solid precipitated on cooling and was filtered and washed with cold ethanol and cold water. An analytical sample was made by recrystallization from CCL4 /EtOH/AcOH, m.p. 185-186. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In dichloromethane; water; | (a) To a solution of sodium hydroxide (5 g) in water (30 ml), were added methylene chloride (100 ml), 5-ethyl-2-pyridineethanol (15 g) and benzyltributylammonium chloride (50% aqueous solution, 6 g), p-toluenesulfonyl chloride (23 g), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added p-hydroxybenzaldehyde (12 g), water (100 ml) and sodium hydroxide (8 g) and the mixture was stirred at 40-50 C. for 12 hours. The reaction mixture was separated into two phases and the methylene chloride layer was dried (MgSO4) and concentrated to give 28.6 g of crude 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde as oil. This oil was purified by silica gel chromatography to give 15.8 g (62%) of pure 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde as oil. NMR(CDCl3) delta: 1.15 (t, 3H), 2.6 (q, 2H), 3.2 (t, 2H), 4.4 (t, 2H), 6.89-8.35 (m, 7H), 9.88 (s, 1H). | |
With sodium hydroxide; In dichloromethane; water; | a) To a solution of sodium hydroxide (5 g) in water (30 ml), were added methylene chloride (100 ml), 5-ethyl-2-pyridineethanol (15 g) and benzyltributylammonium chloride (50% aqueous solution, 6 g), p-toluenesulfonyl chloride (23 g), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added p-hydroxybenzaldehyde (12 g), water (100 ml) and sodium hydroxide (8 g) and the mixture was stirred at 40-50C for 12 hours. The reaction mixture was separated into two phases and the methylene chloride layer was dried (MgSO4) and concentrated to give 28.6 g of crude 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde as oil. This oil was purified by silica gel chromatography to give 15.8 g (62%) of pure 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde as oil. NMR(CDCl3) delta: 1.15 (t, 3H), 2.6 (q, 2H), 3.2 (t, 2H), 4.4 (t, 2H), 6.89-8.35 (m, 7H), 9.88 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | 100 ml of DMF, p-hydroxybenzaldehyde (12.2 g, 0.1 mol), potassium carbonate (16.6 g, 0.12 mol) were successively added to a 250 ml three-necked flask, Benzyl bromide (20.4 g, 0.12 mol) was added dropwise, Room temperature reaction for 12 hours, The reaction solution was poured into ice water, Solid precipitation,filter, Washed cake, The filter cake is dry. To give benzyl-protected p-hydroxybenzaldehyde (26.2 g)Yield 91%. And then take another 250ml single neck round bottom flask, Followed by adding 100 ml of acetone, benzyl-protected p-hydroxybenzaldehyde (14.4 g, 0.05 mol), p-fluoroaniline (5.55 g, 0.05 mol) After the reaction was refluxed for 4 h, the reaction solution was cooled to 5 C to precipitate a solid, filter, The solid was washed with cold acetone, The solid was dried to give N-(4-fluorophenyl)-4-benzyloxybenzylideneamine (Compound IV) 14g, Yield 92%. | |
Example 3: Preparation of Benzylated Schiff Base p-Hydroxy benzaldehyde (100 g) was taken along with demineralized water (1.0 L), sodium hydroxide (34.40 g) and stirred at ambient temperature for 5 minutes. Dichloromethane (750 ml) and tetrabutylammonium bromide (26.40 g) were added and stirred for 10 minutes. Benzyl bromide (107 ml) was added and then the reaction mass was stirred at 25-3O0C for 90 minutes. The two layers were separated. Aqueous layer was extracted with dichloromethane (200 ml) and the extraction was added to the main organic layer. The combined organic layer was washed with 10% aqueous sodium hydroxide solution (2x500 ml), demineralized water (500 ml) and finally with 10% brine (1.0 L). Solvent was distilled out completely at atmospheric pressure. Isopropyl alcohol (1.20 L) was added and the reaction mass was heated to 600C to get a clear solution. 4-Fluoroaniline (156 g) was added dropwise and then the reaction mass was maintained at 600C for 2 hours. After 2 hours the reaction mass was cooled to ambient temperature and stirred for 30 minutes. The solid was filtered and washed with isopropyl alcohol (100 ml) and then with hexane (100 ml). Finally the solid was dried under vacuum at 50-600C to get 230 g of benzylated Schiff base having purity of 95.97% by HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 65℃; for 18h; | Step 1: 4-[(3-Amino-2,6-difluoro-4-nitrophenyl)oxy]benzaldehyde Preparation 2,3,4-Trifluoro-6-nitroaniline (5 g, 26 mmol), 4-hydroxybenzaldehyde (3.5 g, 28.6 mmol) and Cs2CO3 (10.5 g, 32.6 mmol) were stirred in 150 mL of dimethylformamide at 65 degrees Centigrade for approximately 18 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate. The organic layers were combined, washed five times with brine, dried over Mg2SO4 and concentrated onto basic alumina. The residue was purified by silica gel column chromatography (hexane to ethyl acetate gradient) to give 4-[(3-amino-2,6-difluoro-4-nitrophenyl)oxy]benzaldehyde. 1H NMR (400 MHz, DMSO-d6) delta ppm 7.29 (d, J=8.8 Hz, 2H) 7.46 (s., 2H) 7.93 (d, J=8.8 Hz, 2H) 7.98 (dd, J=11.0, 1.7 Hz, 1H) 9.93 (s., 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.8% | With sodium acetate; acetic acid; for 3h;Reflux; | General procedure: [0268] Synthesis of Compounds 120 to 122, which are (Z)-5-(substituted benzylidene)-2-iminothiazolidin-4-one analogs, was performed as follows. In detail, in an acetic acid (4 mL/1 g sodium acetate) solvent, a mixture including a substituted benzaldhehyde (300 mg), <strong>[556-90-1]pseudothiohydantoin</strong> (1.1 eq.), and sodium acetate (3.0 eq.) was refluxed for 3 to 7 hours. Afier cooling, water was added thereto, and the produced precipitate was filtered, and in consideration of physical characteristics of the used starting materials, the resultant precipitate was washed with water and methylene chloride and/or ethyl acetate to obtain a solid target product. [0271] Orange solid; a reaction time of 3 hours; a yield of61.8%; a melting point of >300 C.; ?H NMR (500 MHz,DMSO-d5) oe 10.10 (s, 1H), 9.29 (brs, 1H), 9.04 (s, 1H), 7.49(s, 1H), 7.40 (d, 2H, J=9.0 Hz), 6.88 (d, 2H, J=8.5 Hz); ?3CNMR (100 MHz, DMSO-d5) oe 181.4, 176.1, 159.6, 132.1,130.2, 126.0, 125.5, 116.8; ERMS (ES) mlz 219 (M-H)-. |
61.8% | With sodium acetate; acetic acid; for 3h;Reflux; | General procedure: Synthesis of Compounds 120 to 122, which are (Z)-5-(substituted benzylidene)-2-iminothiazolidin-4-one analogs, was performed as follows. In detail, in an acetic acid (4 mL/1 g sodium acetate) solvent, a mixture including a substituted benzaldhehyde (300 mg), <strong>[556-90-1]pseudothiohydantoin</strong> (1.1 eq.), and sodium acetate (3.0 eq.) was refluxed for 3 to 7 hours. After cooling, water was added thereto, and the produced precipitate was filtered, and in consideration of physical characteristics of the used starting materials, the resultant precipitate was washed with water and methylene chloride and/or ethyl acetate to obtain a solid target product. |
61.8% | With sodium acetate; acetic acid; for 3h;Reflux; | General procedure: The desired compounds, (Z)-5-(substituted benzylidene)-2-iminothiazolidin-4-one analogues (1a- 1l) (Figure 1), were prepared by Knoevenagel condensation.With one exception, refluxing a solution of appropriate benzaldehydes and <strong>[556-90-1]pseudothiohydantoin</strong>in acetic acid in the presence of NaOAc produced (Z)-5-benzylidene-2-iminothiazolidin-4-ones as a single stereoisomer in yields of 41.4-94.1%. A Knoevenagel condensation between 2,4-dimethoxybenzaldehyde and <strong>[556-90-1]pseudothiohydantoin</strong> under the same conditions gave amixture of (E)- and (Z)-5-(2,4-dimethoxybenzylidene)-2-iminothiazolidin-4-ones. These compounds could not be easily separated by conventional silica gel column chromatography. Milder reaction conditions capable of accomplishing the Knoevenagel condensation were needed to synthesize only (Z)-stereoisomer. Interestingly,heating a solution of 2,4-dimethoxy benzaldehyde and <strong>[556-90-1]pseudothiohydantoin</strong> in ethanol:H2O (1:1) in the presence of 1.0 equiv. of piperidine as a base catalyst at 80 C afforded the corresponding (Z)-stereoisomer(1l) as a sole product. A suspension of an appropriate benzaldehyde (300 mg, 1.53-2.46 mmol), <strong>[556-90-1]pseudothiohydantoin</strong>(1.1 eq.), and sodium acetate (3.0 eq.) in acetic acid (1 mL/1 mmol of benzaldehyde) was refluxed for 3-7 h. The reaction mixture was cooled and water was added. The resulting precipitates were filtered, and washed with water and, if necessary, a small amount of methylene chloride or ethyl acetate, to produce (Z)-5-(substituted benzylidene)-2-iminothiazolidin-4-oneproducts (1a - 1k) in 41.4-94.1% yields. The resulting precipitates were filtered, and washed with water,ethyl acetate and methylene chloride to give (Z)-5-(2,4-dimethoxybenzylidene)-2-iminothiazolidin-4-one (1l) all final products were confirmed by 1H and 13C NMR spectroscopy and mass spectroscopy. (Z)-5-(4-Hydroxybenzylidene)-2-iminothiazolidin-4-one (1a, MHY762) Orange colored solid; reaction time, 3 h; yield, 61.8%; melting point, >300 C; 1H-NMR (500 MHz, DMSO-d6)delta 10.10 (s, 1H, OH), 9.29 (br s, 1H, NH), 9.04 (s, 1H,NH), 7.49 (s, 1H, vinylic H), 7.40 (d, 2H, J = 9.0 Hz,2?-H, 6?-H), 6.88 (d, 2H, J = 8.5 Hz, 3?-H, 5?-H); 13CNMR(100 MHz, DMSO-d6) delta 181.4 (C-4), 176.1 (C-2),159.6 (C-4?), 132.1 (C-2?, C-6?), 130.2 (benzylic C), 126.0(C-5), 125.5 (C-1?), 116.8 (C-3?, C-5?); LRMS (ESI-) m/z 219 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
perchloric acid; In methanol; water; for 18h; | A.3: Chemical Synthesis for N,O-dialkylatbetad derivatives (R31 ? H and R2 = substituted aryl or heterocydyl) Starting material: 4- [ 3- (3-Chloro-phenylamino) -8-methyl- imidazo [1, 2-a] pyrazin-2-yl] -phenolcat To a stirred solution of 3-methyl-2-pyrazineamine (10.9 g, 100 mmol; see Example 1.1), 4-hydroxy-benzaldehyde(18.3 g, 150 ??nol) and 3-chlorophenylisonitrile (15.1 g, 110 mmol) in MeOH (200 mL) a few drops of 70% aq. HC1O4 diluted with MeOH (1 mL) were syringed. The reaction mixture was allowed to stir overnight (approx. 18 h) fol- lowed by concentration of the reaction mixture to 1/3 of initial volume and cooling down to -100C for crystallization. After few hours in a freezer an off-white precipitate deposited. It was collected by filtration, washed with several portions of pre-cooled to -100C abs . MeOH and dried under high vacuum for 24 h. MS: m/z = 351.5 (N++l; MW = 350.81); HPLC: Rt = 1.61 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium tert-butylate; In N,N-dimethyl-formamide; at 120℃; for 20h;Inert atmosphere; | Example 3A; rac-trans-4-[4-Hydroxytetrahydrofuran-3-yl]oxy}benzaldehyde 6.00 g (49.1 mmol) of 4-hydroxybenzaldehyde were initially charged in 16 ml of DMF, 6.34 g (73.7 mmol) of <strong>[285-69-8]3,4-epoxytetrahydrofuran</strong> and 551 mg (4.91 mmol) of potassium tert-butoxide were added and the mixture was stirred under argon at 120° C. for 20 h. The reaction mixture was then stirred into 200 ml of water, and the resulting suspension was extracted with 300 ml of ethyl acetate. The organic phase was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue obtained was chromatographed on silica gel using the mobile phase dichloromethane/methanol (100:1).Yield: 4.10 g (40percent of theory)LC-MS (Method 9): Rt=1.32 min; MS (ESIpos): m/z=209 [M+H]+ 1H-NMR (400 MHz, DMSO-d6): delta=9.89 (s, 1H); 7.89 (d, 2H); 7.18 (d, 2H); 5.57 (d, 1H); 4.81 (d, 1H); 4.24 (br. t, 1H); 4.09 (dd, 1H); 3.93 (dd, 1H); 3.80 (d, 1H); 3.61 (dd, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With ethylammonium nitrate; at 20℃; for 3h; | General procedure: To a mixture of aldehyde (1 mmol), amine (1 mmol), diethylphosphite (1 mmol) and ethyl ammonium nitrate (2 ml) was added in 50 ml round bottom flask and stirred at room temperature for the appropriate time (Tables 1 and 2). The progress of reaction was monitored by thin layer chromatography. After completion of the reaction 50 ml ice cold water was added to the reaction mixture. The separated solid was filtered off, dried and purified, unreacted aromatic amines separated by column chromatography using petroleum ether/ethyl acetate (7:3 ml) as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In N,N-dimethyl-formamide; for 24h;Reflux; | Example 2A4-(2-Hydroxy-2-methylpropoxy)benzaldehyde5.00 g (40.94 mmol) of 4-hydroxybenzaldehyde, 4.44 g (40.94 mmol) of 1-chloro-2-methyl-2-propanol and 6.08 g (57.32 mmol) of sodium carbonate are initially charged in 50 ml of dry DMF and stirred under reflux for 24 h.After cooling to RT, 20 ml of ethyl acetate and 20 ml of sat. aqueous sodium bicarbonate solution are added.The phases are separated, and the organic phase is dried over magnesium sulfate.After removal of the solvent, the residue is purified by column chromatography on silica gel 60 (mobile phase gradient: cyclohexane/ethyl acetate 5:1?1:1).This gives a reddish solid which is used without further purification for the subsequent step.Yield: 4.40 g (50percent of theory, 90percent purity)LC-MS (method 2): Rt=1.37 min; MS (ESIpos): m/z=195 [M+H]+. | |
With sodium carbonate; In N,N-dimethyl-formamide; at 130℃; | 5 g (40.94 mmol) of 4-hydroxybenzaldehyde were initially charged in 50 ml of DMF. 4.45 g (40.94 mmol) of 1-chloro-2-methylpropan-2-ol and 6.08 g (57.32 mmol) of sodium carbonate were added, and the mixture was then stirred at 130° C. overnight. Saturated aqueous sodium bicarbonate solution/ethyl acetate were added to the reaction mixture. The precipitate was filtered off and discarded. The two phases were separated from one another, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated using a rotary evaporator. The residue was purified by column chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 5/1?1/2). Yield: 8.6 g (82percent of theory, 76percent pure) LC-MS (Method 4): Rt=1.17 min; MS (ESIpos): m/z=195 [M+H]+. 1H NMR (400 MHz, DMSO-d6): delta=9.87 (s, 1H), 7.86 (d, 2H), 7.12 (d, 2H), 4.70 (s, 1H), 3.84 (s, 2H), 1.21 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 1,2-diphenyl-1,1,2,2-tetrahydroperoxyethane; hydrogen bromide; In water; acetonitrile; at 20℃; for 2.5h; | General procedure: To a solution of aniline/phenol (1 mmol) in CH3CN (4 mL), HBr and THPDPE (depending on the substrate as shown in Table 7) were added and the solution was stirred at room temperature. After the reaction was completed, Na2SO3 (3M, 1mL) was added to the stirring mixture followed by the addition of H2O (10 mL). The solution was stirred until the desired precipitates appeared. The products were filtered and more purification was carried out using silica- packed column chromatography (Hexane?EtOAc). All of the products were characterized on the basis of their melting points, IR, 1H NMR, and 13C NMR spectral analysis and compared with those reported |
With bromine; acetic acid; at 100℃; for 0.25h; | First, take into 100g of phenol in the reaction vessel, to which was added the CH 25 3I solution until completely dissolved phenol solution, then added thereto 10g of sodium hydroxide, stir, using a mixed gas of the container was sealed and pressurized to 0.8MPa, reaction at 40 1.5h, after the standing was right methylphenol; then on each apparatus with a stirrer, a condenser, a dropping funnel and a thermometer four flask at room temperature, poured into the above obtained methyl phenol, to which was added to the resulting methyl phenol mass 0.5 times CaO2And 0.4 times the magnesium oxide to elevate the temperature to 35 , stir quickly sealed container, in the 10s the pressure vessel as to the standard atmospheric pressure, the reaction after 45min, to obtain p-hydroxybenzaldehyde; subsequently obtained in the above hydroxybenzaldehyde and immediately added 150mL mass concentration of 37percent HAC solution and 120mL of bromine liquid, stir and stand for 15min, then placed in a blender, set the speed to 400r / min, the temperature is set to 100 , until the liquid container is less than 1/3 of its original volume, speed and stopping heating, cooled to room temperature, to give 2-bromo-hydroxybenzaldehyde; thereafter the resultant 2-bromo-hydroxybenzaldehyde was cooled to -3 after the negative pressure 1.5MPa added dropwise with stirring 120mL of nitroethane, dropping to 3 drops per second, after the completion of the dropwise addition the reaction was stirred at 2 2h, then increase normal temperature, and filtered to give 2- nitro-1- (2-bromo-4-hydroxy) propylene benzene; Next after filtration to give 2-nitro-1- (2-bromo-4-hydroxy) propylene benzene placed again after disinfection, means with a stirrer, a condenser, a dropping funnel and a thermometer, 4-neck flask, while adding 0.5g of Fe, heated to 105 deg.] C, then again in the form of added dropwise 60mL mass concentration of 40percent HCl solution, 3min the completion of the dropwise addition, stirring evenly, sealed reaction 2h, then cooled to room temperature, to obtain 2-bromo-4-hydroxyphenyl acetone; Finally, the 2-bromo-4-hydroxyphenyl acetone at a pressure of 0.6MPa, a temperature condition is 110 , was added 35mL of CH3OH solution and 50mL of PCl3Solution, and the pH was adjusted to 6.5, after mixing evenly, increasing the temperature to 115 deg.] C, reaction was continued for 2h, cooled, filtered and dried to give 2-methoxy-4-hydroxyphenyl acetone.This unique and novel method, during the operation without the environmental pollution, the reaction process easy, moderate, so that the finally obtained 2-methoxy-4-hydroxyphenyl acetone 7.4g, yield of 90percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With sodium hydrogencarbonate; In ethanol; at 100℃; for 0.166667h;Microwave irradiation; | General procedure: A mixture of the corresponding hydroxy benzaldehyde (1 equiv), N-tert-buthyl hydroxylamine hydrochloride (1.1 equiv), and sodium bicarbonate (1.1 equiv) in absolute ethanol (5 mL/mmol) as solvent was heated under microwave irradiation until the carbonyl compound was not present or there was no progress in the reaction (checked by TLC). The solvent was removed in vacuo and the reaction mixture diluted with H2O and extracted with EtOAc. After the workup of the combined organic layers, the residue was purified by column chromatography (SiO2, mixtures of petroleum ether/EtOAc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | General procedure: To a solution of the corresponding aromatic aldehyde (0.27 mmol) in EtOH (0.5 mL) was added urea (0.54 mmol) and CuSO4·5H2O (0.054 mmol). The mixture was stirred at 80 °C for 15 minutes before tetrahydrocurcumin or tetrahydrodemethoxycurcumin (0.27 mmol) was added. The reaction mixture was continued stirring for 24 hours and quenched with water (2 mL). The solution was washed with water (10 mL) and extracted with EtOAc (415 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated under reduced pressure to afford crude product as a yellow brown oil. Purification was accomplished by column chromatography eluting with 60percent-75percent EtOAc/hexane to furnish compounds 8-17. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium carbonate; In 2-methyl-propan-1-ol; N,N-dimethyl-formamide; at 130℃; for 20.0h; | Under argon, 785 mg (6.43 mmol) of 4-hydroxybenzaldehyde and 759 mg (8.04 mmol) of <strong>[19210-21-0](S)-(+)-2-chloro-1-propanol</strong> were initially charged in 15.7 ml of DMF. 2.04 g (19.3 mmol) of sodium carbonate were added, and the mixture was then stirred at 130 C. for 20 h. The reaction mixture was purified by preparative HPLC (Chromasil, water/acetonitrile). Yield: 755 mg (65% of theory) LC-MS (Method 2): Rt=1.58 min; MS (ESIpos): m/z=181 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 100℃; for 8h; | General procedure: Hydroxyl aldehyde dissolved in acetonitrile (ACN; 5.0 mL) was addedto a solution of intermediate 2 (1.0mmol) and potassium carbonate(1.2mmol) in ACN (25.0 mL) by dripping funnel (1.0mmol), refluxed for8 h, filtered, and concentrated under vacuum. The crude compound waspurified by flash chromatography on silica gel with n-hexane/EtOAc(3:1, v/v) to obtain the desired intermediate 3 as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.56% | With ammonium cerium (IV) nitrate; ammonium acetate; In ethanol;Reflux; | General procedure: A mixture of benzil (0.01 mol), aldehydes (0.01 mol), <strong>[3641-13-2]3-amino-1,2,4-triazole-5-carboxylic acid</strong> (0.01 mol), ammonium acetate (0.01 mol) and ceric ammonium nitrate (15 mol%) as a catalyst were refluxed in ethanol (15 mL) for about 3-4 h. The progress of the reaction was monitored by TLC. After completion of reaction, the mixture was cooled to room temperature. The solid formed was filtered and dried. The crude products were recrystallized by ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 6h; | P-hydroxybenzaldehyde (1.82 g, 14.9 mmol),Potassium carbonate (4.12 g, 29.8 mmol) and compound 3 (4.00 g, 14.9 mmol) were suspended in dry DMF (20 mL) and heated at 65 C. for 6 h.After allowing to cool to room temperature, ethyl acetate (200 mL) was added, followed by washing with water and saturated brine in this order.The organic phase was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure.The crude product was purified by silica gel column chromatography to obtain 3.97 g of Compound 4 as a colorless oil. Yield 86%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium acetate; acetic anhydride; at 100℃;Inert atmosphere; | General procedure: Aromatic aldehyde (1 equiv.) was added to the solution of hippuric acid (1 equiv.) and potassium acetate (1 equiv.) in acetic anhydride under stirring. The mixture was refluxed under argon for 2?4 h at 100 °C and then cooled for the product precipitation. The precipitate was filtered, washed by distilled water and ether and dried on air. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene; for 2h;Inert atmosphere; Dean-Stark; Reflux; | (1) 4-hydroxybenzaldehyde 7.32g (60mmol) in 30 ml toluene was added to three-necked flask. <strong>[16750-67-7]4-amino-o-bromophenol</strong> 11.3 g (60mmol) was added after raising an internal temperature to 40degrees C under a nitrogen atmosphere. Then, refluxed for 2 hours, water and toluene were made to distill off completely in Dean Stark equipment, and the yellow solid was obtained. This solid was dissolved completely in THF 50ml (it is considered as the solution A). (2) Separately, MsCl 10.2ml (132mmol) and THF 20ml were added in the three-necked flask,and it dipped in ice and a methanol, and made the internal temperature into -5 degree C. In this solution, an internal temperature was maintained at 5 degrees C or less, 4-acryloyloxy benzoicacid 31.7g (120mmol)/diisopropylethylamine. (Hereinafter, it is referred to as DIPEA) and 26.1 ml (150mmol) / 2,6-di-tert-butyl-4-methylphenol0.30 g/THF 70ml was added. After keeping this solution at 5 degrees C or less and stirred for 2 hours, the prepared solution A, DIPEA 26.1ml (150mmol), DMAP 0.15g, and (1) was added in this order (an internal temperature is maintained at 5 degrees C or less). Reaction temperature was increased to 25 degrees C, and stirred for 2-hour, 10 ml of methanol was added and quenched. After having added ethyl acetate/pure water, separating liquids and drying anorganic layer with sodium sulfate, it condensed and obtained the crude crystal. This crude crystal was recrystallized with ethyl acetate/methanol, and the compound (I-2) which is a whitesolid was obtained at 29.7 g (63% of yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.8% | With hydrogenchloride; In ethanol; water; at 20℃; for 120h; | At room temperature,(0.4425 g, 2 mmol) of intermediate M4 and (0.2928 g, 2.4 mmol) of p-hydroxybenzaldehyde was dissolved in 15 ml of ethanol with stirring,To this was added dropwise 10 drops of concentrated hydrochloric acid,Stirring at room temperature 120h,The solvent was removed by concentration in vacuo,90 ml of methylene chloride and 90 ml of water were added,The organic phase was collected,Dried over anhydrous magnesium sulfate,Filtration, concentration, drying in a yellow solid, theColumn chromatography (petroleum ether: ethyl acetate = 6: 1 to 4: 1) afforded 100 mg of the product as a pale yellow solid in 12.8percent yield. |
12.8% | With hydrogenchloride; In ethanol; water; at 20℃; | General procedure: M1-M8 (2 mmol) and p-hydroxybenzaldehyde (2.4 mmol) was dissolved in 10 mL ethanol, 10 drops concentrated hydrochloric acid was added dropwise at room temperature. The reaction was stirred at room temperature. The reaction was monitored by TLC. After the completion of the reaction, excess solvent was evaporated in vacuo. Then the solution was partitioned between 90 mL water and 90 mL methylene chloride. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to provide a crude product which was purified by flash column chromatography on silica gel (eluent: Ethyl acetate/petroleum) to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With bismuth (III) nitrate pentahydrate; ammonium acetate; silica gel; In neat (no solvent); at 110℃; for 24h; | General procedure: A mixture of N-(4-aminophenyl) azoles 2a-d (1 mmol), benzil (1 mmol, 0.21 g), aromatic aldehyde (1 mmol), and ammonium acetate (1 mmol, 0.077 g) was stirred vigorously. Bi(NO3)3*5H2O (0.15 mmol, 0.073 g, 15 mol%) and SiO2 (0.5 g) were mixed effectively and added to the mixed reactants. The resulting mixture was heated at 110 C for 24 h. Acetone (50 mL) was then added and the mixture was stirred at 50 C for 10 min. Filtering the hot mixture and then concentration of the filtrate produced the crude product. Recrystallization of the crude products in 96% EtOH gave the desired product 3-5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 70 - 80℃; for 3h; | General procedure: The mixture of <strong>[78364-55-3]6-fluoro-2-hydrazinylbenzo[d]thiazole</strong> (2) (0.01 mol) and benzalde-hyde/substituted benzaldehyde (0.01 mol) was reuxed in ethanol (15 ml) at 70?80 °C for 3 h. The separated product obtained was ltered off, washed withdistilled water and recrystallized from methanol to give the correspondinghydrazone. The product obtained was further dissolved in acetic acid (20 ml) atroom temperature followed by the addition of sodium acetate (0.5 g). Bromine(2 mmol) in acetic acid (10 ml) was added dropwise to the reuxing reactionmixture. After 1 h, the mixture was poured onto crushed ice (100 g). The precipitateobtained was ltered off and crystallized from ethanol-dimethylformamide (1:1) togive crystals of (3a?3t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57 g | With dmap; diisopropyl-carbodiimide; In dichloromethane;Inert atmosphere; | Under a nitrogen atmosphere, 50.0 g of the compound represented by the formula (I-1-1), 20.9 g of the compound represented by the formula (I-1-2), N, N-dimethylaminopyridine And 300 mL of dichloromethane were added. 25.9 g of diisopropylcarbodiimide was added dropwise and stirredIt was. After usual work-up, purification was carried out by column chromatography and recrystallization to obtain 57.0 g of a compound represented by the formula (I-1-3). |
4.3 g | With dmap; diisopropyl-carbodiimide; In dichloromethane; at 20℃;Cooling with ice; Inert atmosphere; | In a nitrogen atmosphere, 4.0 g of a compound represented by the formula (I-114-1), 1.7 g of a compound represented by the formula (I-114-2), 0.3 g of N,N-dimethylaminopyridine, and 30 mL of dichloromethane were put in a reactor. With cooling with ice, 2.1 g of diisopropylcarbodiimide was dropwise added thereto and stirred at room temperature. The precipitate was taken out through filtration, and the filtrate was washed with hydrochloric acid, water and salt solution. This was purified through column chromatography (silica gel) and recrystallization (dichloromethane/methanol) to give 4.3 g of a compound represented by the formula (I-114-3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium metabisulfite; In ethanol; water; for 24h;Reflux; | General procedure: To a solution of the appropriate 3,4-diaminobenzene derivative (1ad)(2 mmol) in ethanol (15 mL) 2.85 N aqueous solution of sodium metabisulphite (1.6 mL) and the appropriate substituted arylaldehyde(2 mmol) were added. The reaction mixture was heated at reflux for 24 h. The solvent was then evaporated under reduced pressure. The residue was added with HCl 1 N (10 mL), the formed precipitate was filtered off, washed with water (3×10 mL) and purified by crystallization from the adequate solvent to give the title compounds.Following the general procedure benzimidazoles 3 [19], 4 [20], 5 [21],7 [24], 6, 32 and 33 [15] were prepared and their analytical and spectral data are in agreement with those reported in literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With chitosan; In neat (no solvent); at 75℃; for 0.0666667h;Microwave irradiation; Green chemistry; | General procedure: An equimolar mixture of <strong>[54396-44-0]2-methyl-3-(trifluoromethyl)aniline</strong> (0.351 g, 0.002 mol), corresponding aldehyde (0.002 mol), dimethyl phosphite (0.18 ml, 0.002 mol) and chitosan catalyst (10 molpercent) were taken in a reaction glass tube, degassed for 10 min and microwave irradiated at 180 W for 2 min at 60 °C. The progress of the reaction was monitored by TLC using petroleum ether and ethyl acetate (3:7) as solvent. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with water (2 x 15 ml) followed by brine (1 x 10 ml), dried over Na2SO4 and evaporated to dryness. The crude mass was purified by column chromatography on silicagel (100-200 mesh) by using a 7:3 mixture of ethyl acetate in hexane to afford the pure alpha-aminophosphonates. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With ammonium acetate; In ethanol; for 6.0h;Reflux; Sealed tube; | General procedure: Solution of tanshinones (0.1 mmol), aryl aldehyde (0.2 mmol, 2 eq) and aminoacetate (0.4 mmol, 4 eq) in EtOH (0.1 M) was heated to reflux for 6 hours. After TLC monitoring showed the completion of the reaction, the solvent was evaporated and the residue was subjected to PTLC isolation (Pet/EtOAc=2/1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | General procedure: General Procedure for the Synthesis of IMCR Products 1a-f. A mixture of aromatic amine (1 mmol) andaromatic aldehyde (1 mmol) stirred at room temperature in methanol (3 mL) for 5 to 10 min afforded Schiffbase which further undergoes the reaction with chloroacetic acid (1 mmol) and isocyanide (1 mmol) at roomtemperature to gives 1a-f in affordable yields. After stirring at room temperature for 24 h, the solid wasfiltered out to obtain crude products then wash with 1-2 mL chilled methanol for purification which is ready touse for the next step.A post Ugi cyclisation of 1a-f were carried out by use of efficient reaction conditions by utilizing dry K2CO3 (2mmol), as a base and DMF (2 mL) solvent respectively under room temperature with portion wise addition of1a-f for 10 min which further heated at 100 oC for 2-4 hrs. The reacNon is monitored by TLC, aOer compleNonof reaction the resulting mixture was cooled to room temperature and poured on crushed ice. Collect solidand the residue was purified by flash column chromatography on silica gel by using hexane: EtOAc (95:5) as aeluent to afford the corresponding products 2a-f in 71-80% yields. |
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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.51 g | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; | p-Hydroxybenzaldehyde 0.5g (4mmol), cesium carbonate 0.5g (6mmol), <strong>[39267-79-3]3-bromo oxetane</strong> 0.5g (3.6 mmol), 5 ml of N,N-dimethylformamide was added to the reaction flask, and the reaction was carried out at 80 C overnight. Add water, extract, wash, dry and concentrate Column chromatography gave 0.51 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With potassium carbonate; potassium iodide; In N,N-dimethyl acetamide; at 130℃; for 7h; | Step (1), 4,4'-difluorodiphenyl sulfone (0.20 mol, 50.85 g), P-hydroxybenzaldehyde (0.6 mol, 73.27 g), Potassium carbonate (0.60 mol, 82.93 g) And potassium iodide (0.02 mol, 3.32 g) was sequentially added to the reactor; Heated to 130 C in a solution of N,N'-dimethylacetamide (500 ml), Continue to react for 7 h. After the reaction is over, it will be cooled to room temperature. Water and a mixed solution of water and ethanol are separately precipitated, dry, The product of pale yellow solid, Compound 1, was obtained in a yield of 59%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With silica-gel-supported sulfuric acid; ammonium acetate; In neat (no solvent); at 130℃; for 3h; | General procedure: To a mixture of aldehyde (1 mmol), <strong>[551-16-6]6-aminopenicillinic acid</strong> (1 mmol), and ammonium acetate (3 mmol), SiO2*H2SO4 (0.025 g) was added and heated in an oil bath up to 130 C in appropriate times. After the completion of the reaction (TLC monitoring, EtOAc: hexane 10/90 v/v), the mixture was diluted in hot ethanol, solid was filtered, and products were purified by recrystallization in watery ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | In ethanol; at 100℃; for 0.5h;Sealed tube; Microwave irradiation; | General procedure: All microwave irradiation experiments were carried out in CEM-Discover monomode microwavedevice, operating at a frequency of 2.45 GHz. Substituted aminobenzothiazole, equimolar amount ofsubstituted benzaldehyde (1.5 mmol) and mercaptoacetic acid in absolut ethanol (3 mL) were placed ina 10 mL reaction vial containing a stirring bar. The vial was sealed with a Teflon septum and placedinto the microwave cavity. It was irradiated at 100 C using 100 W as maximum power for 30 min.at the end of the reaction the mixture was rapidly cooled with gas jet cooling to room temperature.The clean product was obtained after filter under reduced pressure. |
A1267820[ 201595-48-4 ]
4-Hydroxy-benzaldehyde-1,2,3,4,5,6-13C6
Reason: Stable Isotope
A1354500[ 152404-52-9 ]
4-Hydroxy-Benzaldehyde-formyl-13C
Reason: Stable Isotope
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