* 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：
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[3] Angewandte Chemie - International Edition, 2016, vol. 55, # 36, p. 10806 - 10810[4] Angew. Chem., 2016, vol. 128, p. 10964 - 10968,4
[5] Organometallics, 2017, vol. 36, # 21, p. 4095 - 4098
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[8] Journal of Chemical Research, Miniprint, 1988, # 1, p. 201 - 223
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2
[ 64-19-7 ]
[ 103-89-9 ]
[ 66047-05-0 ]
[ 122-85-0 ]
[ 556-08-1 ]
Reference：
[1] Russian Journal of Applied Chemistry, 2008, vol. 81, # 7, p. 1198 - 1201
Reference：
[1] New Journal of Chemistry, 2005, vol. 29, # 11, p. 1469 - 1474
6
[ 122-85-0 ]
[ 16375-88-5 ]
Yield
Reaction Conditions
Operation in experiment
85%
With sodium tetrahydroborate In methanol at 20℃;
To a solution of 4-acetamidobenzaldehyde (10 g, 61.3 mmol) in methanol (100 mL) was added sodium borohydride (800 mg) at room temperature in portions. The reaction mixture was stirred over night, and the progress of reaction checked by TLC using 4:1 hexanes: EtOAc as eluent. Absence of starting material indicated the completion of reduction and the reaction mixture was concentrated in a rotavap. The residue was partitioned between water (25 mL) and ethyl acetate (4*50 mL) and the organic layer was washed with brine (25 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and the removal of the solvent gave the alcohol as a pale yellow solid, which was dried under high vacuum. 8.6 g (85percent); 1H NMR (DMSO-d6): δ 2.0 (s, 3H), 4.5 (d, 2H), 5.2 (t, 1H), 7.25 (d, 2H), 7.55 (d, 2H), 9.95 (s, 1H).
85%
at 20℃;
Preparation of 4-acetamidobenzyl alcohol. To a solution of 4-acetamidobenzaldehyde (10 g, 61.3 mmol) in methanol (100 mE) was added sodium borohydride (800 mg) at room temperature in portions. The reaction mixture was stirred over night, and the progress of reaction checked by TLC using 4:1 hexanes:EtOAc as eluent. Absence of starting material indicated the completion of reduction and the reaction mixture was concentrated in a rotavap. The residue was partitioned between water (25 mE) and ethyl acetate (4x50 mE) and the organic layer was washed with brine (25 mE). The ethyl acetate layer was dried over anhydrous sodium sulfate and the removal of the solvent gave the alcohol as a pale yellow solid, which was dried under high vacuum. 8.6 g (85percent); ‘H NMR (DMSO-d5): ö 2.0 (s, 3H), 4.5 (d, 2H), 5.2 (t, 1H), 7.25 (d, 2H), 7.55 (d, 2H), 9.95 (s, 1H) ppm.
61%
With ReOBr2(2-(2-hydroxy-5-methylphenyl)benzotriazole-(H))(PPh3); phenylsilane In tetrahydrofuran for 1.33333 h; Reflux
General procedure: In a typical experiment, to a mixture of carbonyl compound (1.0mmol) and [ReOBr2(hmpbta)(PPh3)] (5molpercent) in THF (3mL) at reflux temperature was added PhSiH3 (2.0mmol). The reaction mixture was stirred under air atmosphere (the reaction times are indicated in the Table 4) and the progress of the reaction was monitored by TLC or 1H NMR. Upon completion, the reaction was quenched with 1equiv of tetrabutylammonium fluoride (TBAF) (1.0M THF) during 1h. Then, the reaction mixture was evaporated and purified by silica gel column chromatography with the appropriate mixture of n-hexane and ethyl acetate to afford the alcohols, which are all known compounds.
Reference：
[1] Advanced Synthesis and Catalysis, 2018, vol. 360, # 4, p. 676 - 681
[2] Chemical Communications, 2015, vol. 51, # 46, p. 9567 - 9570
[3] Organic Letters, 2017, vol. 19, # 13, p. 3656 - 3659
[4] Catalysis Science and Technology, 2013, vol. 3, # 1, p. 81 - 84
[5] Patent: US2007/149462, 2007, A1, . Location in patent: Page/Page column 22
[6] Patent: US9138442, 2015, B2, . Location in patent: Page/Page column 37
[7] ChemCatChem, 2017, vol. 9, # 1, p. 80 - 83
[8] Tetrahedron, 1981, vol. 37, p. 2165 - 2172
[9] Journal of the Chemical Society, Chemical Communications, 1981, # 3, p. 121 - 122
[10] Tetrahedron Letters, 2015, vol. 56, # 2, p. 414 - 418
[11] Tetrahedron, 2006, vol. 62, # 34, p. 8164 - 8168
[12] Chemistry - A European Journal, 2012, vol. 18, # 50, p. 15935 - 15939
[13] Angewandte Chemie - International Edition, 2013, vol. 52, # 19, p. 5120 - 5124[14] Angew. Chem., 2013, vol. 125, # 19, p. 5224 - 5228
Reference：
[1] Tetrahedron Letters, 2006, vol. 47, # 39, p. 7093 - 7096
[2] New Journal of Chemistry, 2005, vol. 29, # 11, p. 1469 - 1474
[3] Journal of the American Chemical Society, 2004, vol. 126, # 10, p. 3357 - 3367
[4] Journal of the Chemical Society, 1927, p. 25
11
[ 122-85-0 ]
[ 178265-65-1 ]
Reference：
[1] Molecular Crystals and Liquid Crystals Science and Technology Section A: Molecular Crystals and Liquid Crystals, 2000, vol. 343, p. 511/193 - 516/198
Catalytic tests
General procedure: Alcohol, phenol, and/or amine (1 mmol) were added to amixture of the ZnAl2O4SiO2 nanocomposite (100 mg) andacetic anhydride (1 mmol). The mixture was stirred at 75 °C(for alcohols and phenols) or at room temperature (for amines)for a time. The progress of the reaction was monitored by TLCand/or GC-MS. When the reaction was completed, ethyl acetate(10 mL) was added and the mixture was filtered to separate offthe catalyst. The catalyst was washed twice with 7.5 mL ethylacetate. The combined organic phases were washed with a10% solution of NaHCO3 and then dried over MgSO4. The solventwas removed to yield the product. If further purificationwas needed, the product was passed through a short column ofsilica gel. All products were characterized on the basis ofGC-MS, FT-IR, and 1H-NMR spectral data by comparing thesespectra with those of standard samples or literature data.
86%
With ZnAl2O4 nanoparticles at 20℃; for 0.133333h; Neat (no solvent);
With sodium acetate
With platinum nanoparticles supported on zirconia In methanol at 20℃; for 0.5h;
2.2.2. N-{4-[(1E)-3-oxo-3-phenylprop-1-en-1-yl]phenyl}acetamide (1b)
Acetophenone (0.72ml, 6mmol) and 4-acetoamidobenzaldehyde (1g, 6mmol) catalysed with 40% KOH under stirring and then neutralization followed by addition of dil.HCl gave 1b as solid product. m.p. 182-185oC. FT-IR (KBr)3345(C-HAr), 1510(Ar-NH), 1643(C=O), 1561(C=C),1625(C=O amide) cm-1.1H-NMR (300 MHz, DMSO-d6):δ=8.0(N-H amide), 7.90 (-C=C-H), 7.81 (d, 2H, J = 9 Hz),7.56 (-H-C=C-), 7.59 (d, 2H, J = 9 Hz), 7.54 (m, 1H), 7.45(m, 2H), 7.28 (d, 2H, J = 9 Hz), 5.0 (CHAr-OH), 2.02 (O=CCH3).13C-NMR(300 MHz, DMSO-d6): δ=168.2, 142.8,140.0, 136.7, 134.3, 129.7, 129.0, 126.4, 123.3, 120.3, 187.0,168.2, 17.6. MS m/z: 253 (M+).
78%
With iodine; triphenylphosphine In 1,4-dioxane for 12h; Reflux;
General procedure for the synthesis of compounds 3
General procedure: A mixture of PPh3 (524 mg, 2.0 mmol, 1.0 equiv), I2 (507 mg, 2.0 mmol, 1.0 equiv) and 1,4-dioxane (4 mL) was stirred at rt for 30 min. Then, compounds 1 (2.0 mmol) and 2 (2.4 mmol) were added to the mixture, and stirred for appropriate time (Tabel 2) under reflux temperuture. After completion of the reaction (TLC), DCM (20 mL) was added and the solution was washed with NaS2O3 (20 mL, 10%). Then, organic layer was washed with water (2 × 20 mL) and brine (2 × 20 mL) and was dried over anhyd. MgSO4. The organic layer was concentrated under reduced pressure and the crude product was purified by column chromatography to afford the corresponding product 3.
74%
With sodium hydroxide In ethanol for 16h; Heating;
With piperidine In ethanol for 0.5h; Heating / reflux;
22.1
1. Step: N-[4-(2,2-Dicyanovinyl)phenyl]acetamide 32.6 g (0.2 mol) of 4-acetaminobenzaldehyde and 13.74 g (0.208 mol) of malononitrile are initially charged in 140 ml of ethanol, and 24 drops of piperidine are added. The mixture is stirred at reflux for 30 min. After cooling, the crystals are filtered off with suction and dried. Yield: 38.6 g (90.6% of theory) of product Mass spectrum: molecular mass calculated: 211, found [M+H]+=212
63%
With piperidine In ethanol at 80℃; for 2h;
3 3.1.3. N-[4-(2,2-Dicyanovinyl)phenyl]acetamide
Malononitrile (17.3 mmol) and piperidine (two drops) were added to a solution of commercially available 4-acetamidobenzaldehyde 34 (17.3 mmol) in EtOH (20 mL). The mixture was heated at reflux for 2 h, then cooled to rt affording an orange solid which was filtered, washed with Et2O (5 mL) and petroleum ether (2 mL), and recrystallized. Yield 63%; mp 234-236 °C (EtOH); 1H NMR (DMSO-d6) 10.51 (s, 1H, NH), 8.37 (s, 1H, CH), 7.94 (d, 2H, Ar, J = 8.4 Hz), 7.80 (d, 2H, Ar, J = 8.8 Hz), 2.11 (s, 3H, CH3); IR 2224, 1693. Anal. Calcd for C12H9N3O.
With acetamide; ammonium acetate; acetic acid
With triethylamine
With piperidine In ethanol for 2h; Reflux;
4
4-Acetamide-benzaldehyde (1000 g) was dissolved in ethanol (16000 ml). To the mixture were added malononitrile (607 g) and piperidine (40 g), and the resulting mixture was stirred under reflux for 2 hours. The reaction mixture was cooled to room temperature and then stirred for 30 minutes. The precipitated crystal was collected on a filter, washed with ethanol (2000 ml) and dried to give 1049 g of N-[4-(2,2-dicyanovinyl)phenyl]acetamide as a yellow powder.
With potassium carbonate In water; glycerol at 80℃; for 0.0333333h; Green chemistry;
General procedure: A mixture of K2CO3 (0.140 g, 0.001 mol) and glycerol(0.360 g, 0.004 mol) was stirred at 80 oC for 2 h to form a homogenous colorless liquid as DES1. Under the same conditions, the distilled water (0.25 mL), malononitrile (1) (0.660 g, 0.001 mol) and benzaldehydes 2a-f (2a: 0.163 g,2b: 0.136 g, 2c: 0.151 g, 2d: 0.152 g, 2e: 0.175 g, 2f: 0.175 g; 0.001 mol) were respectively added to it. The intermediate benzylidene malononitriles 6a-f were produced in 2 min. 2,4-Dinitrophenylhydrazine (3) (0.198 g, 0.001 mol) was added to the mixture. The reaction continued for another 18-28 min. The reaction mixture was cooled to room temperature, and neutralized with glacial acetic acid (0.120 g,0.002 mol). After adding 1 mL of ethanol, the mixture was poured into ice-cold saturated aqueous NaCl (5 mL). The resulting precipitates were collected by filtration, washed respectively with distilled water (5 mL) and ethanol (5mL), and recrystallized from methanol to afford pure pyrazoles
With piperidine In ethanol Reflux;
With piperidine In ethanol for 2h; Reflux;
With triethylamine In ethanol at 20℃; for 2h;
General procedure for the synthesis of Knoevenagel products 4[1]
General procedure: Malononitrile (2.0 mmol) and the aldehyde (2.0 mmol) were dissolved in 2 mL of EtOH in a 10 mL flask tube and one drop of Et3N was addedto this mixture. After stirring at room temperature for 2 h, the solid was filtered to obtain the crude product. Further purification was done byflash chromatography on silica gel using EtOAc/hexanes (1:4) as the eluent.
With ammonium hydroxide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen; In ethanol; at 50℃; for 24h;
General procedure: Under an air atmosphere, a Schlenk tube was charged with MCM-41-bpy-CuI (40 mg, 0.025 mmol), alcohol (0.5 mmol), TEMPO (4 mg, 0.025 mmol), aqueous ammonia (0.5 mmol, 25e28%, w/w) and EtOH (1.0 mL). The mixture was stirred at 50 C for 18-48 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and filtered. The MCM-41-bpy-CuI complex was washed with EtOH (2*5 mL), and Et2O (5 mL) and reused in the next run. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (petroleum/ethyl acetate=15:1 to 10:1) to provide the desired product.
86%Spectr.
With bismuth vanadate; oxygen; In acetonitrile; at 40℃; under 760.051 Torr; for 3h;Schlenk technique; Irradiation;
General procedure: Bismuth vanadate (32.3 mg, 100 mmol) was added to a Schlenkflask containing benzyl alcohol stock solution (1 mL, 0.1 mmol inacetonitrile) and acetonitrile (9 mL). The mixture was left to stirfor 30 min to disperse the catalyst under a dioxygen atmospherevia a balloon. The mixture was then irradiated with a 30W blueLED array at a distance of 2 cmwith an irradiance of 245mWcm2.The mixture reached ca. 40 C by the end of the reaction and afterirradiation, the catalyst was removed using centrifugation at4000 rpm for 30 min. For GC analysis, 1 mL of supernatant wastaken and 1 lL injected. For NMR analysis, the supernatant wasreduced in volume using a rotary evaporator at 65 mbar at 20 C,and the residue dissolved in d6-DMSO containing maleic acid asan internal standard.
566.566A Example 566; 3-(3-methoxy-4-nitrophenyl)-8-[(4-methylpiperazin-1-yl)methyl]-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one; Example 566A; N-(4-formyl-2-nitrophenyl)acetamide
To fuming HN03 (30mL) at 0 C was added N- (4-formylphenyl) acetamide (10.3g, 63. lmmoles) portionwise. After two hours, the reaction mixture was poured into 4 C water (1L). The resulting solid was filtered, washed with water (0. 5LX3), and dried in vacuo to give the desired product (10.57g, 80%). MS (APCI) + M/E 209 (M+H) + ; 1H NMR (300 MHz, DMSO-d6) 8 10.61 (s, 1H), 10.00 (s, 1H), 8.46 (d, J= 1.70 Hz, 1H), 8.17 (dd, J= 8.31, 1.86 Hz, 1H), 7.91 (d, J= 8.48 Hz, 1H), 2.13 (s, 3H).
71%
With nitronium tetrafluoborate In acetonitrile at 0 - 20℃; for 3h; Inert atmosphere;
Method A
10 mmol of the desired p-substituted benzaldehyde was dissolved in 10 mL of anhydrous acetonitrile and cooled to 0 °C, then 1.01 equiv. of nitronium tetrafluoroborate, NO2BF4, were added under vigorous stirring. The cold bath was then removed and the reaction was stirred for 3 h at room temperature. The solvent was partially evaporated then poured into 50 mL of ice-cold water. The product was obtained as a precipitate, which was filtered and washed with cold water. The product was purified using reverse phase column chromatography with gradient increase of methanol in water containing 0.1% of formic acid as eluent.
64%
With sulfuric acid; nitric acid at 0℃;
64%
With sulfuric acid; nitric acid at 0℃;
1.1
A mixed acid was prepared by adding fuming nitric acid (1 mL), which was added 3 times as divided portions, to concentrated sulfuric acid (6 mL) under ice cooling, and added portionwise with 4-acetamidobenzaldehyde (1.91 g, 11.7 mmol). After the addition, the reaction mixture was immediately poured onto ice, and the solids were collected by filtration. The solids were sufficiently washed with cold water, dried, purified by silica gel column chromatography (developing solvent: CH2Cl2), and then recrystallized from water to obtain the target compound as pale yellow needlelike solid (1.57 g, yield: 64%).1H-NMR (300 MHz, CDCl3) 2.36 (3H, s), 8.16 (1H, dd, J=8.79, 1.65Hz), 8.74 (1H, d, J=1.65Hz), 9.04 (1H, d, J=8.79Hz), 9.99 (1H, S), 10.63 (1H, S) MS (El): 208 (M+) m.p.: 156°C
63.9%
With sulfuric acid; nitric acid at 0℃; for 0.333333h;
52%
With water; nitric acid for 2h;
50.2%
With nitric acid at -40 - -20℃; for 0.666667h;
Multi-step reaction with 2 steps
1: acetic acid anhydride / <50
2: concentrated hydrochloric acid / 40 °C
With sodium tetrahydroborate; In methanol; at 20℃;
To a solution of 4-acetamidobenzaldehyde (10 g, 61.3 mmol) in methanol (100 mL) was added sodium borohydride (800 mg) at room temperature in portions. The reaction mixture was stirred over night, and the progress of reaction checked by TLC using 4:1 hexanes: EtOAc as eluent. Absence of starting material indicated the completion of reduction and the reaction mixture was concentrated in a rotavap. The residue was partitioned between water (25 mL) and ethyl acetate (4*50 mL) and the organic layer was washed with brine (25 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and the removal of the solvent gave the alcohol as a pale yellow solid, which was dried under high vacuum. 8.6 g (85%); 1H NMR (DMSO-d6): delta 2.0 (s, 3H), 4.5 (d, 2H), 5.2 (t, 1H), 7.25 (d, 2H), 7.55 (d, 2H), 9.95 (s, 1H).
85%
With methanol; sodium tetrahydroborate; at 20℃;
Preparation of 4-acetamidobenzyl alcohol. To a solution of 4-acetamidobenzaldehyde (10 g, 61.3 mmol) in methanol (100 mE) was added sodium borohydride (800 mg) at room temperature in portions. The reaction mixture was stirred over night, and the progress of reaction checked by TLC using 4:1 hexanes:EtOAc as eluent. Absence of starting material indicated the completion of reduction and the reaction mixture was concentrated in a rotavap. The residue was partitioned between water (25 mE) and ethyl acetate (4x50 mE) and the organic layer was washed with brine (25 mE). The ethyl acetate layer was dried over anhydrous sodium sulfate and the removal of the solvent gave the alcohol as a pale yellow solid, which was dried under high vacuum. 8.6 g (85%); ?H NMR (DMSO-d5): oe 2.0 (s, 3H), 4.5 (d, 2H), 5.2 (t, 1H), 7.25 (d, 2H), 7.55 (d, 2H), 9.95 (s, 1H) ppm.
61%
With ReOBr2(2-(2-hydroxy-5-methylphenyl)benzotriazole-(H))(PPh3); phenylsilane; In tetrahydrofuran; for 1.33333h;Reflux;
General procedure: In a typical experiment, to a mixture of carbonyl compound (1.0mmol) and [ReOBr2(hmpbta)(PPh3)] (5mol%) in THF (3mL) at reflux temperature was added PhSiH3 (2.0mmol). The reaction mixture was stirred under air atmosphere (the reaction times are indicated in the Table 4) and the progress of the reaction was monitored by TLC or 1H NMR. Upon completion, the reaction was quenched with 1equiv of tetrabutylammonium fluoride (TBAF) (1.0M THF) during 1h. Then, the reaction mixture was evaporated and purified by silica gel column chromatography with the appropriate mixture of n-hexane and ethyl acetate to afford the alcohols, which are all known compounds.
With 4,4'-dimethoxyphenyl disulfide; iridium(lll) bis[2-(2,4-difluorophenyl)-5-methylpyridine-N,C20]-4,40-di-tert-butyl-2,20-bipyridine hexafluorophosphate; triphenylphosphine In toluene for 24h; Irradiation;
91%
With palladium(II) acetylacetonate; hydrogen; 2,2-dimethylpropanoic anhydride; dicyclohexylphenylphosphine In tetrahydrofuran at 80℃; for 20h; Inert atmosphere;
69%
With potassium phosphate; sodium hypophosphite; 2,2-dimethylpropanoic anhydride In tetrahydrofuran at 60℃; for 16h;
With glycerol-3-Phosphate Dehydrogenase; D-glucose; NADP<SUP>+</SUP>; Nocardia PPTase; Segniliparus CAR; ATP; coenzyme A; magnesium chloride In dimethyl sulfoxide at 35℃; for 16h; Enzymatic reaction;
2.4. Standard reduction procedure
General procedure: The His-CAR (1.5 mg) was incubated with His-PPTase (295 g) in the presence of CoA (1 mM) as a cofactor for 1 h at 28°C in a final volume of 600 L of sodium phosphate buffer (100 mM, pH 7.5) containing 10 mM of MgCl2. The resulting enzyme mixture (holo-CAR, 50 g) was mixed with NADP+ (0.9 mM), GDH (1 U, one unitcorresponds to the amount of enzyme which could reduce 1 molNADP+ to NADPH per minute), glucose (60 mM), MgCl2 (10 mM), substrate (5 or 10 mM, from 1 M stock solution in DMSO), and ATP (15 mM) in Tris-HCl buffer (100 mM, pH 9) with a nal volume of 1 mL. The reaction mixture was incubated at 100 rpm in a rotaryshaker at 35C for 16 h, and extracted with 1 mL of ethyl acetateafter the pH was adjusted to 2-3 with 1 M HCl solution. The organicextracts were dried over anhydrous sodium sulfate and analyzedby gas chromatography (GC) and gas chromatography-mass spec-trometry (GC-MS) to determine the amount of substrate (a) andproducts (aldehyde b, alcohol c) in the mixture. All experimentswere conducted in triplicate.
bis-(1H-indol-3-yl)-(4-acetamidophenyl)-methane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With HMTAB In acetonitrile at 20℃; for 0.0833333h;
88%
With Graphene oxide (GO) In water at 40℃; for 1.5h; Green chemistry;
2.2 General experiment for the synthesis of bis(indolyl)methanes (3a as an example)
General procedure: A mixture of benzaldehyde 1a (0.5mmol), indole 2a (1.5mmol) and GO 150mg were added in 10ml water with a condenser and then stirred under air at 40°C for 3h. After the completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and the solvent was evaporated to dryness. The crude residue was purified by flash chromatography on silica to afford pure 3,3′-(phenylmethylene)bis(1H-indole) 3a as a pink solid (92% yield).
(2S,3R,4R,5S)-1-[[(4-acetylamino)phenyl]methyl]-2-hydroxymethyl-3,4,5-piperidinetriol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With (polystyrylmethyl)trimethylammonium cyanoborohydride; acetic acid In methanol at 20℃;
4 Example 4; 3,4, [5-PIPERIDINETRIOL, 1- [ [ (4-ACETYLAMINO) PHENYL] METHYL]-2- (HYDROXYMETHYL),] [(2S.] [3R,] [4R.] 5S)
To a mixture of 3, 4,5-piperidinetriol, 2- (hydroxymethyl)-, (2S, 3R, 4R, 5S) [(50MG,] 0. [31MMOL)] and (polystyrylmethyl) trimethylammonium cyanoborohydride (180mg, 0. [78MMOL)] in 10% acetic acid in methanol [(2ML)] was added 4-acetylaminobenzaldehyde (124mg, 0. [76MMOL)] and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified using a plug of acidic Dowex 50X4-200 resin (3g), which had been pre-washed with 10% aqueous hydrochloric acid. The resin was eluted with methanol [(25ML)] to remove all non-basic side products. The desired compound was then eluted using a solution of 2: 2: 1 methanol/water/ammonium hydroxide [(100MOL).] The resulting solution was concentrated to a small volume [(LRNL)] and freeze dried to afford the title compound as a white solid (65mg, [69%).'H] NMR (d4-methanol) 8 2.15 (3H, s), 2.61 [(1H,] m), 2.74 [(1H,] m), 3.10 [(1H,] m), 3.42 (1H, m), 3.55 [(1H,] m), 3.78 [(1H,] m), 3.81-3. 96 (4H, m), 7.34 (2H, d, [J = 9 HZ),] 7.52 (2H, d, [J = 9 HZ). MS M/Z] 311.2 (M+H) +.
2-ethylhexyl 3-(4-acetylaminophenyl)-2-cyanoacrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
In isopropyl alcohol;
a) Preparation of 2-ethylhexyl 3-(4-acetylaminophenyl)-2-cyanoacrylate A mixture of 35 g (0.18 mol) of 2-ethylhexyl cyanoacetate and 30 g (0.18 mol) of 4-acetamidobenzaldehyde in 300 ml of isopropanol is refluxed for 3 hours. The reaction mixture is then allowed to cool and is crystallized. The crystals formed are separated out by filtration and are recrystallized from a minimum amount of isopropanol. After filtration and drying, 33.3 g (54% yield) of 2-ethylhexyl 3-(4-acetylaminophenyl)-2-cyanoacrylate are obtained in the form of a pale yellow powder. Melting point: 119 C. UW absorption (as a solution in ethanol): λmax=351 nm, εmax=30 960, EI %=904 Elemental analysis for C20H26N2O3 calculated: C 70.15; H 7.65; N 8.18; O 14.02 found: C 70.08; H 7.65; N 8.16; O 14.03
With pyridinium p-toluenesulfonate In methanol; acetic acid; toluene; acetonitrile
94 Preparation of 2-(4-Acetylaminobenzyl)amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide
EXAMPLE 94 Preparation of 2-(4-Acetylaminobenzyl)amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide To a small sample of 2-amino-5-chloro-N-(5-chloropyridin-2-yl)benzamide (0.01 g, 0.035 mmol) weighed out in a sealable vial toluene was added (200 μL), followed by 4-acetamidobenzaldehyde (0.006 g, 0.035 mmol) and pyridinium p-toluenesulfonate (catalytic amount). A few molecular sieves were added; then the vial was sealed and placed in a shaker at 75° C. After 18 h, the reaction mixture was treated with borane-trimethylamine complex (100 μL of a 1 M solution in acetic acid) and the vial was placed in the shaker at room temperature for an additional 5 h. The reaction mixture was then diluted with methanol and applied to a 0.5 g SCX column, washed with methanol and gravity-eluted with 1 N ammonia in methanol. The product fractions were combined and concentrated in vacuo to a residue which was triturated in acetonitrile to provide the title compound as a yellowish powder (0.015 g, 100%) in 98% purity by LC-MS (method A). LC-MS: 98% pure, Rt=6.647 min, m/e 429.2 (m).
With hydrogenchloride; sodium hydroxide; sodium borohydrid; In methanol;
(1) In 1.3 liters of methanol was suspended 326 g of p-acetamidobenzaldehyde, and 204 g of <strong>[1001-53-2]N-acetylethylenediamine</strong> was added dropwise thereto over a period of one hour. Subsequently, the resulting mixture was refluxed for one hour, after which 75.7 g of sodium borohydride was added to the mixture with ice-cooling over a period of one hour. After the completion of the addition, the mixture thus obtained was allowed to stand overnight at room temperature, after which the solvent was removed by distillation under reduced pressure. One liter of concentrated hydrochloric acid was added dropwise to the resulting oily residue with ice-cooling over a period of one hour. After the completion of the addition, the resulting mixture is refluxed for 2 hours. To the mixture was gradually added 700 g of sodium hydroxide with ice-cooling to make the mixture strongly basic, after which the mixture was extracted with one liter of dioxane. The dioxane layer obtained was dried over sodium hydroxide, and the dioxane was thereafter removed by distillation under reduced pressure. The oily residue thus obtained was distilled under reduced pressure to obtain 218 g (66.1% yield) of N-(4-aminobenzyl)ethylenediamine (b.p. 150 to 156 C./3 mmHg).
With 18-crown-6 ether; potassium carbonate In dichloromethane Reflux;
4.2.5. General procedure D (GP-D)
General procedure: To a solution of nitrobenzaldehyde in dehydrated CH2Cl2 were added benzyltriphenylphosphonium salt (1.0 equiv), potassium carbonate (1.1 equiv) and 18-crown-6 (0.18 equiv), and the mixture was refluxed, then filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the target compound as an EZ mixture.
Stage #1: 5-chloro-2-(2-((tetrahydropyran-4-yl)amino)anilin-5-yl)benzoxazole; para-acetamidobenzaldehyde With Oxone In N,N-dimethyl-formamide at 20℃; for 2h;
Stage #2: With potassium carbonate In water; N,N-dimethyl-formamide
100.100.3
Working Example 100-3 Synthesis of 2-(4-acetylaminophenyl)-5-(5-chlorobenzoxazol-2-yl)-1-(tetrahydropyran-4-yl)benzimidazole To a solution of 5-chloro-2-(2-(tetrahydropyran-4-yl)aminoanilin-5-yl)benzoxazole (see Working Example 100-2) (250 mg, 0.727 mmol) in dimethylformamide (3 mL) was added 4-formylacetanilide (142 mg, 0.872 mmol) and oxone (313 mg, 0.509 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (261 mg, 74% yield) as white crystals. 1H-NMR (CDCl3) δ: 1.86-1.93 (2H, m), 2.25 (3H, s), 2.66-2.80 (2H, m), 3.47 (2H, t, J = 11.4 Hz), 4.11-4.20 (2H, m), 4.60-4.69 (1H, m), 7.32 (1H, dd, J = 8.7,2.1 Hz), 7.52-7.83 (7H, m), 8.22 (1H, dd, J = 8.7, 1.5 Hz), 8.65 (1H, d, J = 1.5 Hz).
With ytterbium(III) triflate In dichloromethane at 20℃; for 2.5h;
Typical procedure for one-pot synthesis of N-silylated α-aminophosphonates
General procedure: A solution of benzaldehyde (53 mg, 0.5 mmol), 1,1,1,3,3,3-hexamethyldisilazane (121 mg, 0.75 mmol), and diethylphosphite (103 mg, 0.75 mmol) in the presence of Yb(OTf)3 (31 mg, 0.05 mmol) in CH2Cl2 (4 mL) was stirred at room temperature for 2.5 h. The reaction mixture was washed with a saturated aqueous NaHCO3 solution, and the product was extracted into ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous MgSO4 and were evaporated under reduced pressure to afford a residue which was purified by silica gel column chromatography (ethyl acetate/hexane, 3:7) to afford the product (151 mg, 96%): 1H NMR (CDCl3): δ 7.45-7.27 (5H, m), 4.96 (1H, d, JPH = 15.0 Hz), 4.08-3.93 (4H, m), 1.33-1.15 (6H, m), 0.09 (9H, s); 31P NMR (CDCl3): δ 20.4.
With iron(II) chloride; In decane; acetonitrile; at 85℃; for 1h;Inert atmosphere;
General procedure: To a mixture of alkene 1 (0.5 mmol), aldehyde 2 (2.5 mmol), and FeCl2 (1.6 mg, 0.0125 mmol), acetonitrile (3.0 mL) was added under nitrogen at room temperature. Then tert-butyl hydroperoxide 3 (TBHP, 2.0 mmol, 5-6 M in decane) was dropped into the mixture under nitrogen at room temperature. The resulting mixture was stirred under 85 oC for 1 h. The temperature of reaction was cooled to room temperature. The resulting reaction solution was directly filtered through a pad of silica by ethyl acetate. The solvent was evaporated in vacuo to give the crude products. NMR yields are determined by 1H NMR using dibromomethane as an internal standard. Solvent was evaporated and the residue was purified by flash column chromatography on silica gel with ethyl acetate/petroleum ether as eluent to afford the pure product 4.
With copper(II) choride dihydrate In dimethyl sulfoxide at 100℃; for 6h;
4.2 General procedure for the synthesis of pyrrolo[2,1-f][1,2,4]triazin-4(3H)-ones
General procedure: A mixture of 1-amino-1H-pyrrole-2-amides (0.3 mmol), CuCl2·2H2O 0.3 mmol) and aldehydes or acetals (0.3 mmol) in 5 mL of DMSO was heated at indicated temperature in air until completion. After cooling, the reaction solution was poured into 20 mL of water. The solid was precipitated, filtered to give the crude product, which was purified by column chromatography on silica gel, with CH2Cl2/MeOH as eluent to give the pure product.
With tert.-butylhydroperoxide; zinc dibromide In water at 80℃; for 16h;
Typical procedure for preparation of N-phenethylbenzamide 3a
General procedure: In a glass pressure tube (25 mL), ZnBr2 (22.2 mg, 0.1 mmol), benzaldehyde 1a (106 mg, 1 mmol), 2-phenylethanamine 2a (133.1 mg, 1.1 mmol), and tert-butyl hydroperoxide 3a (270 mg, 3 mmol; 70% solution in water) were added successively. Next, the pressure tube was closed and the resulting mixture was stirred at 80 oC in an oil bath for 16 h. After cooling down to room temperature, the solvent was removed under vacuum. The residue was directly purified by flash chromatography on silica gel eluting with heptane : ethanol (15 : 1) to give N-phenethylbenzamide 3a as a white solid (176mg, 78%).
With poly(4-vinylpyridine) In neat (no solvent) at 80℃; for 0.333333h; Green chemistry;
General procedure for the synthesis of chromene derivatives
General procedure: A mixture of β-naphthol (1 mmol), malononitrile (1 mmol), aldehyde (1 mmol) and PVPy (0.1 g) was heated in an oil bath (80 °C) for the appropriate times as shown on Table 1 . After completion of the reaction (monitored by TLC), the resulting mixture was cooled, ethylacetate (10 mL) was added and the catalyst was recovered by filtration to be reused subsequently. Evaporation of the solvent from the filtrate and recrystallization of the solid residue from hot ethanol affords the pure products in high yields.
With ammonium acetate In neat (no solvent) at 100℃; for 0.666667h;
2 General experimental procedure for the synthesis of quinazolin-4(3H)-one derivatives in the presence of (α-Fe2O3)-MCM-41-l-prolinium nitrate
General procedure: A mixture of isatoic anhydride (1 mmol), aldehyde or benzyl halide (1 mmol), ammonium acetate (2 mmol) or aniline derivatives (1 mmol) and the catalyst (0.03 gr) was ground thoroughly and then transferred into a reaction vessel where this mixture was stirred under 100 °C for the appropriate time. The reactions were monitored by TLC (EtOAc:Petroleum ether, 1:2). After completion of the reaction, the mixture was allowed to be cooled down to room temperature. Then chloroform (10 mL) was added and the mixture was stirred for an extra 30 min. After collecting the magnetic catalyst with an external magnet, MeOH (1 mL) was added to the chloroform solution and this solution was then concentrated in vacuo until the precipitates were formed. The products were vacuum filtered by Buchi funnel dried and recrystallized from ethanol to furnish the desired quinazolin-4(3H)-one derivative.
Synthesis of (E)-2-(2-(4-aminostyryl)-4H-chromen-4-ylidene)malononitrile (5, DCM- NH2): DCM (252 mg, 1.20 mmol) and 4-acetamido benzaldehyde (147 mg, 1.2 mmol) were dissolved in toluene (40 mL). Piperidine (0.6 mL) and acetic acid (0.6 mL) were added and the mixture was refluxed for 3 hours. The orange solid that formed was filtered off and concentrated HCl/ethanol (45 mL, 2: 1) was added. The mixture was refluxed for 2 hours. The mixture was then neutralized with saturated aqueous Na2C03 to pH 8 and then extracted with ethyl acetate. The ethyl acetate layers were combined, washed with brine, and dried over Na2S04. The organic solvent was removed in vacuo and the residue was purified by silica chromatography with hexane/ethyl acetate as the eluent. Compound 5 was obtained as a deep red solid (146 mg, 39 %).
39%
With piperidine; acetic acid; In dichloromethane; toluene; for 3h;Reflux;
To a solution of DCM (252 mg, 1.20 mmol) and 4-acetamidobenzaldehyde (147 mg, 1.2 mmol) in toluene (40 mL) was addedpiperidine (0.6 mL) and acetic acid (0.6 mL), the reaction mixturewas refluxed for 3 h. The orange solid was filtered off, and con.HCl/ethanol (45 mL, 2:1) was added to the filtrate, followed by furtherreflux for another 2 h. The mixture was neutralized with Sat.Na2CO3 to pH 8, then extracted with ethyl acetate. The ethyl acetatelayers were combined and washed with brine, dried over Na2-SO4. The organic solvent was removed in vacuo, the residue waspurified by silica chromatography with hexane/ethyl acetate aselute to afford a deep red solid 5 (146 mg, 39%). 1H NMR (DMSO,400 MHz): d 8.72 (dd, 1H, J = 1.2, 1.2 Hz), 7.89 (m, 1H), 7.77 (m,1H), 7.64 (d, 1H, J = 15.6 Hz), 7.58 (m, 1H), 7.49 (d, 2H, J = 8.4Hz), 7.08 (d, 1H, J = 16 Hz), 6.87 (s, 1H), 6.61 (d, 2H, J = 8.8 Hz),6.00 (s, 2H).
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 4h;
A mixture of 4-acetamidobenzaldehyde (200mg), piperidine (0.121 mL), NaBH(OAc)3 (636mg) and DIPEA (0.617ml) in DCM (4ml) was stirred at RT for 4h. DCM and sat. NaHCO3 were added. The phases were separated, the org. layer was dried (Na2SO4), filtered off and evaporated to dryness to afford 267 mg of white solid. LC-MS (B): tR = 0.45 min; [M+H]+: 233.24.
With potassium carbonate; In methanol; water; at 130℃; for 0.5h;Microwave irradiation;
General procedure: In a microwave reaction vial with a magnetic stirring bar was placed the azaindoleor indole (0.38 mmol), aldehyde (0.19 mmol), and K2CO3 (176 mg, 1.27 mmol), followedby addition of 2.5 mL of 1:1 mixture of MeOH:H2O. The resulting mixture was placed ina microwave reactor and irradiated at 130 oC for 30 minutes. After cooling to roomtemperature, the volatiles were removed under reduced pressure. The crude residue wasdiluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combinedorganic layers were dried over sodium sulfate, filtered, and the resulting filtrate evaporated in vacuo to give a crude solid that was purified using reversed-phase HPLC,eluting with MeCN/H2O with a trace of TFA to give the desired compound.
N-benzyl-N-[(tert-butoxycarbonyl)methyl]-N',N''-ethylene-N',N''-dimethylguanidinium bromide[ No CAS ]
C22H26N2O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With sodium hydride In N,N-dimethyl-formamide at -20℃; for 2h; Inert atmosphere;
Aziridination under Optimized Conditions (Table 4); ReactionConditions A
General procedure: A solution of arylaldehyde 3 (1 mmol) in DMF (1-4 mL) was added to a stirred mixture of a guanidinium bromide 7·Br (1.1-1.3 equiv) and 60% NaH (1.2-1.4 equiv) in DMF (1-2 mL) at -20 °C, and the mixture was stirred at this temperature and worked up. In workup A, the reaction mixture was poured into ice-water and extracted with EtOAc. The combined organic solution extracts were washed with H2O and brine, and evaporated to give a crude product. In workup B, after evaporation of the reaction mixture, the residue was dissolved in either CHCl3 or MeCN (ca 30 mL) and then stirred with silica gel (ca 20 g) at r.t. for an appropriate time. The silica gel was filtered off and repeatedly washed with either CHCl3 or MeCN. The filtrate and washings were combined and evaporated to give a crude product. Purification of the latter by column chromatography (silica gel, hexane-EtOAc) afforded an aziridine product 5.
[(4-acetamidophenyl)(benzylamino)methyl]phosphonic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With chloro-trimethyl-silane In acetonitrile at 20℃; for 2h; Sonication;
1cg
General procedure: Me3SiCl (0.432 g, 4 mmol) was added dropwise to a solution ofamine 2 (1 mmol) and carbonyl compound 3 (1 mmol) in anhydrousMeCN (1.5-2 mL), and the resulting mixture was sonicated for 2 hat r.t. P(OSiMe3)3 (0.328 g, 1.1 mmol) was added dropwise and themixture was sonicated for another 2 h at r.t. The mixture was dilutedwith MeOH (5 mL) and H2O (0.1 mL, 5 mmol). Dilution normallycaused precipitation of the product. The precipitated product wasfiltered and washed with MeOH (1 mL). In cases where no precipitationoccurred, the mixture was further sonicated for 2 h and thenleft to stand for 24 h at 0 °C. Alternatively, the solvents were removedunder reduced pressure and the residue was triturated withcold MeOH (2 mL) and filtered.
With tert.-butylhydroperoxide; tetra-(n-butyl)ammonium iodide In decane at 100℃; for 16h; Schlenk technique; Inert atmosphere;
4 4.2.1 Reaction of 4-bromobenzaldehydel with 1,4-dioxane (Table 1, entry 14)
General procedure: A Schlenk tube was charged with Bu4NI (37 mg, 0.1 mmol), 4-bromobenzaldehydel (92 mg, 0.5 mmol), TBHP (0.73 mL, 5.5 M in decane, 4.01 mmol), and 1,4-dioxane (2 mL) under N2. The mixture was stirred at 100 °C for 16 h. Volatiles were removed by rotary evaporation. The residue was purified by column chromatography on silica gel (eluted using a 20:1 mixture of petroleum ether and EtOAc) to afford 1,4-dioxan-2-yl 4-bromobenzoate (112 mg, 78%).
With 10-camphorsufonic acid In acetonitrile for 0.75h; Microwave irradiation;
Typical procedure for the solvent-free condensation of 2-naphthol (1) with benzaldehyde (2a)to the dibenzoxanthene 4a under microwave irradiation
General procedure: A mixture of 2-naphthol (1.44 g, 10.0 mmol), benzaldehyde (0.584 g, 5.50 mmol) and(±)-CSA (0.026 g, 2.0 mol. %) was placed in a microwave vessel and irradiated (400 W, 63--64 °C). After 15 min, TLC showed complete consumption of both the starting materials andthe formation of 4a as the only product. The thus formed solid was quenched with water,filtered, washed with water and air-dried. The crude solid was recrystallized with hexane--ethyl acetate, 9:1, to afford pure 4a (1.59 g, 88 %)
80%
With MCM-41-SO3H In ethanol; water at 30℃; for 0.0833333h; Sonication; Irradiation;
2.4. Preparation of Aryl-14H-dibenzo [a,j]xanthenes
General procedure: Procedure: aldehyde (1 mmol), 2-naphthol (2 mmol) and MCM-41-SO3H (0.1g) and water: EtOH (50:50) (10 ml) were mixed. The temperature rose to 30°C while the mixturewas kept under ultrasonic irradiation for a proper duration oftime (Table 1). After the reaction was completed (controlledby TLC, 2/1 petroleum ether/ethyl acetate), the evaporationand dilution of the water with CHCl3/CH3OH occurred, andsubsequently the catalyst was filtrated off. Under vacuum,the solvent evaporation was taken into account. Finally,recrystallization of the resultant solid materials from ethanolwas observed.The spectral data of some representative products;Compound 3a: IR (KBr): 3281, 3121, 3044, 1668, 1586,1534, 1509, 1401, 1242. 1H NMR (300 MHz DMSO) δ= 1.8(s, J=1.88 HZ, 3 H), 6.63 (s, J=6.63 HZ, 1H), 7.29 (d,J=6.30 HZ, 2H), 7.45 (d, J=8.08 Hz, 2H), 7.52 (t, J=6.57HZ, 4H), 7.59 (d,J=6.43 HZ, 2H), 7.91 (d, J=6.57, 4H), 8.63(d, J=7.46HZ , 2H), 9.7 (s, J=9.72 Hz,1H). 13C NMR (75MHz, DMSO) δ=168, 147.85, 140.17, 137.38, 130.84,130.62,128.91, 128.57, 128.15, 123.4, 119, 117.66, 117.36,35.94, 23.75. MS (EI): m/e (%)=415 (44.8), 416 (30.4), 417(3.4).Compound
N-(4-((5-chloro-2-oxoindolin-3-ylidene)methyl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With pyridine; In methanol; at 100℃; for 0.5h;Microwave irradiation;
General procedure: A suspension of indolinone (0.3mmol), aldehyde (0.3mmol) and pyridine (30muL) in methanol (1mL) were heated under microwave irradiation at 100 C for 30 minutes. The reaction mixture was cooled to room temperature and the resulting precipitate was removed by filtration, carefully washed with methanol and dried in vacuo. When no precipitate was observed methanol was removed under vacuum and the residue was purified by silica gel chromatography to give the desired product.
N4-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)-N1-(4-methoxybenzyl)-1,2,4-triamine[ No CAS ]
[ 122-85-0 ]
N-(4-(5-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-1-(4-methoxybenzyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With oxone In water; N,N-dimethyl-formamide at 0℃; for 0.5h;
55 N-(4-(5-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-1-(4-methoxybenzyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamide
N-(4-(5-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-1-(4-methoxybenzyl)-1H-benzo[d]imidazol-2-yl)phenyl)acetamideA cooled (0°C) solution of N4-(5-chloro-4-(l-(phenylsulfonyl)-lH-indol-3-yl)pyrimidin-2-yl)- Nl-(4-methoxybenzyl)benzene-l,2,4-triamine (301 mg , 0.49 mmol), 4-acetamidobenzaldehyde (84 mg, 0.52 mmol) in DMF (6 mL) and de-ionized water (0.2 mL) was treated with Oxone (1967 mg, 1.10 mmol). The resulting mixture was stirred 30 min at 0°C and diluted with EtOAc (30mL), washed with sat. NaHC03, dried (MgS04), filtered and concentrated under reduced pressure. The residue was purified by Si02 chromatography (DCM/ MeOH 0 to 10% gradient) and afforded the title compound (340 mg, 0.451 mmol, 92%) as an orange solid.
tert-butyl 1-(4-acetamidobenzyl)piperidin-4-ylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 1h;
7 tert-butyl 1-(4-acetamidobenzyl)piperidin-4-ylcarbamate
tert-butyl 1-(4-acetamidobenzyl)piperidin-4-ylcarbamateTo a suspension of 4-Boc-aminopiperidine (500mg, 2.5mmol) in DCE (lOmL) was added AcOH (43uL, 0.75mmol) affording pale yellow solution which was treated with N-(4- formylphenyl)acetamide (407mg, 2.5mmol) followed by NaBH(OAc)3 (794mg, 3.74mmol). The resulting solution was stirred lh at rt, diluted with DCM (50ml), washed with sat. NaHC03, (60mL), brine (3x30mL), dried (MgS04), filtered, concentrated under reduced pressure and afforded the title compound (783mg, 2.26mmol, 90%) as a white solid which was used in the next step without further purification.
N-(4-(3-hydroxy-4-oxo-4H-chromen-2-yl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
Stage #1: o-hydroxyacetophenone; para-acetamidobenzaldehyde With sodium hydroxide In ethanol; water at 20℃;
Stage #2: With dihydrogen peroxide In ethanol; water at 20℃;
59%
Stage #1: o-hydroxyacetophenone; para-acetamidobenzaldehyde With sodium hydroxide In ethanol; water at 20℃;
Stage #2: With dihydrogen peroxide In ethanol; water at 20℃; Cooling with ice;
N-(4-(3-hydroxy-4-oxo-4H-chromen-2-yl)phenyl)acetamide (Dye 5)
N-(4-(3-hydroxy-4-oxo-4H-chromen-2-yl)phenyl)acetamide (Dye 5) 10 mmol of N-(4-formylphenyl)acetamide was added to a solution of 1-(2-hydroxyphenyl)ethanone (10 mmol) in ethanol (20 mL) and aqueous NaOH (3 g in 10 ml water). The mixture was stirred at room temperature for overnight. The reaction mixture was neutralized with 1M HCl, and the solid precipitate was collected by filtration. The solid was dissolved in 20 mL ethanol and aqueous NaOH (3 g in 10 mL water). Then reaction mixture was placed in an ice-water bath and 5 mL of 30% H2O2 solution was slowly added. The resulting mixture was stirred at room temperature overnight. The precipitate was observed and collected by filtration, washed with water. The crude product was recrystallized from ethanol/CH2Cl2. Yield=59%. 1H NMR (d6-DMSO, 300 MHz): δ=10.2(s, 1H, OH), 8.22(d, 2H, J=8.7), 8.10 (d, 1H, J=7.8), 7.77(m, 4H), 7.46(m, 1H), 2.08(s, 3H). 13C NMR (d6-DMSO, 75 MHz): 173.2, 169.2, 154.9, 145.7, 141.2, 139.0, 134.0, 128.8, 126.1, 125.2, 124.9, 121.8, 118.9, 118.8, 24.6.
5-(4-acetamidophenyl)-9,10-dihydropyrido[2,3-d:6,5-d′]dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With SBA-15 supported sulfonic acid nanocatalyst In neat (no solvent) at 120℃; for 1h;
General procedure for the synthesisof pyrido[2,3-d:6,5-d′]dipyrimidine derivatives in thepresence of SBA-15-SO3H under solvent-free conditions
General procedure: In a reaction vessel, a mixture of 6-aminouracil (2 mmol),aldehyde (1 mmol), and SBA-15-SO3H (0.05 g) was heatedat 120 °C under solvent-free conditions for a specified time(completion of the reaction was monitored by TLC). Aftercompletion of the reaction, hot DMF (5 mL) was added andthe catalyst was separated by simple filtration. Then water(15 mL) was added to the filtrate to give the solid product.
2-(3-(4-aminostyryl)-5,5-dimethylcyclohex-2-en-1-ylidene)malononitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
Stage #1: 2-(3,5,5-trimethyl-2-cyclohexen-1-ylidene)-propanedinitrile; N-(4-formylphenyl)acetamide With piperidine In ethanol for 8h; Reflux;
Stage #2: With hydrogenchloride In ethanol; lithium hydroxide monohydrate for 10h; Reflux;
Synthesis of compound TMN-NH2
To a stirred solution of 2-(3,5,5-trimethylcyclohex-2-enylidene)malononitrile (0.93 g, 5 mmol), and 4-acetamidobenzaldehyde (0.82 g, 5 mmol) in absolute ethanol (30 ml) was added piperidine (200 μL). The mixture was stirred at refluxed for 8 hour. After cooling to room temperature, the mixtures were added into concentrated hydrochloric acid (30 mL), and then the system was refluxed until the mixture solution becomes clear (about 10 hours). Then, the reaction mixture was neutralized by adding 10% aqueous sodium hydroxide until to neutral. The aqueous solution was extracted with ethyl acetate and then the organic layers were dried over Na2SO4, filtered, and concentrated to obtain the crude product which was purified by silica column chromatography to obtain TMN-NH2 as a dark red solid (1.19 g, 83%). The chemical structure of TMN-NH2 was determined using 1H-NMR: 1H NMR (400 MHz, Chloroform-d) δ 7.35 - 7.33 (d, J = 8.6 Hz, 2H),7.01- 6.97 (d, J = 15.9 Hz, 1H), 6.82-6.78 (dd, J = 16.0, 2.4 Hz, 1H), 6.75 (s, 1H), 6.68-6.66 (d, J = 8.6 Hz, 2H), 4.01 (s, 2H), 2.56 (s, 2H), 2.43 (s, 2H), 1.06 (s, 6H). Note: compound TMN-NH2 is a known compound[2].
75%
Stage #1: 2-(3,5,5-trimethyl-2-cyclohexen-1-ylidene)-propanedinitrile; N-(4-formylphenyl)acetamide With piperidine; glacial acetic acid In toluene at 120℃; for 12h; Inert atmosphere;
Stage #2: With hydrogenchloride In ethanol; lithium hydroxide monohydrate for 6h; Reflux;
1.S2 Step S2, Synthesis of Compound V
Compound III (0.93 g, 5 mmol) and compound IV p-acetamidobenzaldehyde (0.99 g, 6 mmol) were added to a reaction flask containing 20 ml of toluene,Then, 0.5 ml of piperidine and 0.5 ml of acetic acid were added successively, and under nitrogen protection, the reaction was refluxed at 120°C for 12 h, After the reaction was cooled to normal temperature, the solvent in the reaction product was removed by suction filtration, the obtained solid was dissolved in the mixed solution of 60ml of ethanol and hydrochloric acid (the volume ratio of ethanol and hydrochloric acid was 1 to 1), and the reaction was heated under reflux for 6h, After the reaction was completed and cooled to room temperature, the reaction product was neutralized to weakly alkaline (with a pH in the range of 7 to 8) with sodium hydroxide, and the reaction product was extracted three times with ethyl acetate, the organic phases were combined, and anhydrous After drying over sodium sulfate to remove water, the organic substance was separated and purified by column chromatography to obtain compound V with a yield of 75%.Wherein, in the column chromatography separation and purification, the eluents are dichloromethane and ethyl acetate, and the volume ratio of dichloromethane and ethyl acetate is 100:1.
64%
Stage #1: 2-(3,5,5-trimethyl-2-cyclohexen-1-ylidene)-propanedinitrile; N-(4-formylphenyl)acetamide With piperidine; glacial acetic acid In toluene for 8h; Inert atmosphere; Reflux;
Stage #2: With hydrogenchloride In ethanol; lithium hydroxide monohydrate; toluene for 16h; Reflux; Inert atmosphere;
44%
Stage #1: 2-(3,5,5-trimethyl-2-cyclohexen-1-ylidene)-propanedinitrile; N-(4-formylphenyl)acetamide With piperidine; glacial acetic acid In toluene for 5h;
Stage #2: With hydrogenchloride In ethanol
Stage #1: 2-(3,5,5-trimethyl-2-cyclohexen-1-ylidene)-propanedinitrile; N-(4-formylphenyl)acetamide With piperidine In ethanol
Stage #2: With hydrogenchloride In lithium hydroxide monohydrate
N-(4-((3-methyl-5-oxoisoxazol-4(5H)-ylidene)methyl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With hydroxylamine hydrochloride; 5-sulfosalicylic Acid In water at 20℃; for 1.25h;
Typical procedure for the synthesis of 3,4-disubstituted isoxazol-5(4H)-ones(7a-s)
General procedure: A mixture of hydroxylamine hydrochloride 5 (0.0695 g, 1 mmol), b-oxoeser 6(1 mmol), and 2-HSBA (15 mol%) in 4 mL of distilled water was stirred at room temperature for 15 min, then aromatic aldehyde 2 (1 mmol) was added to the mixture. The reaction mixture was stirred at RT until the reaction was completed. The reaction was monitored by TLC analysis up to the starting materials wereconsumed completely and the final product spot was not changed. After completionof the reaction, the precipitate was separated by simple filtration, and washed withcold distilled water and dried in the air. Crude products were recrystallized from ethanol (95 %) to afford the title pure compounds. The HSBA is soluble in waterand ethanol. After removal of the solvent from the filtrate by evaporation, thecatalyst is recovered and reused for the subsequent reactions. The identity of theknown products was confirmed by comparison of their spectroscopic data andphysical properties with those available in recent papers [68-85].
(3-(bis(trimethylsilyl)amino)phenyl)magnesium bromide[ No CAS ]
N-(4-((3-aminophenyl)(hydroxy)methyl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
Stage #1: para-acetamidobenzaldehyde; (3-(bis(trimethylsilyl)amino)phenyl)magnesium bromide In tetrahydrofuran at 0℃; for 12h;
Stage #2: With hydrogenchloride In tetrahydrofuran; water at 20℃; for 6h;
1 Step-I: Preparation of N-(4-((3-aminophenyl)(hydroxy)methyl)phenyl)acetarnide (1 38b)
To a stirred solution of N-(4-forrnylphenyl)acetamide (138a) (I g, 6.13 mmol) in tetrahydrofuran (7 mL) was added (3-(bis(trimethylsilyl)arnino)phenyl)rnagnesiurn chloride (49c) (7.40 mL, 7.40 mrnol) at 0 °C. The reaction was stirred for 12 h quenched with 2 N HCI (15 mL) and stirred for additional 6 Ii at room temperature. The reaction mixture wasbasified with 2 N NaOH (15 mL) and extracted with ethyl acetate (2 x 50 rnL). The organic layers were combined washed with saturated NH4CI (50 mL), dried over anhydrous MgSO4, filtered, evaporated to dryness. The crude residue was purified by flash column chromatography [silica gel 40 g, eluting with chloroform/methanol (1:0 to 9: 1)110 give N(4-((3-aminophenyl)(hydroxy)methyl)phenyl)acetarnide (l38b) (1 .455 g, 93%) as a yellowsolid; ‘H NMR (300 MHz, DMSO-d6) ö 9.86 (s, I H), 7.50- 7.41 (rn, 2H), 7.29- 7.18 (rn,21-1), 6.90 (t,J= 7.7 Hz, 1H), 6.54 (t,J 2.0 Hz, IH), 6.51 -6.46(m, 1H), 6.37 (ddd,J7.9, 2.3, 1.1 Hz, IH), 5.61 (d, J= 3.8 Hz, IH), 5.44 (d,J= 3.8 Hz, IH), 4.97 (s, 2H), 2.00(s, 3H); MS (ES+): 279.2 (M + Na).
N-(4-(hydroxy(p-tolyl)methyl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
Stage #1: para-acetamidobenzaldehyde; para-methylphenylmagnesium bromide In tetrahydrofuran at 0 - 20℃;
Stage #2: With hydrogenchloride In tetrahydrofuran; water
General Procedure for the preparation of Benzhydryl Alcohols
General procedure: A solution of the indicated para- substituted benzaldehyde (1.0 equiv) in dry THF was treated with the indicated phenylmagnesium bromide solution (1.3-4.0 equiv) at 0°C). After addition was complete, the mixture was allowed to stir at room temperature for 60-180 min. The reaction was quenched with 1 M HCl solution and extracted with 50 mL of EtOAc. The organic layer was washed with water (3×30mL) followed by brine (1×25 mL). The organic layer was dried with MgSO4 and concentrated. The product was either purified by flash chromatography with hexanes/ ethyl acetate or precipitated using hexanes.
C-4-acetamidophenylcalix[4]-2-methylresorcinarene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
Stage #1: para-acetamidobenzaldehyde With hydrogenchloride In ethanol; water for 0.5h;
Stage #2: 2-methylbenzene-1,3-diol In ethanol; water at 80℃; for 24h;
Synthesis of C-4-acetamidophenylcalix[4]-2-methyl resorcinarene.
Concentrated hydrochloric acid (7 mL) was added into a round-bottom flask containing a solution of 4-acetamidobenzaldehyde (0.01 mol, 1.63 g) in absolute ethanol (40 mL). The mixture was stirred for 30 min and a solution of 2-methylresorcinol (0.01 mol, 1.24 g) in absolute ethanol (20mL) was added. The mixture was refluxed for 24 h at 80 °C. The yellow precipitate formed was collected by filtration, washed with distilled water and acetone several times and dried under vacuum. IR (KBr pellets) υ/cm-1: 3449 (NH), 3392 (OH), 1670 (C=O), 1476 (C=C), and 1321 (C-N), δH (600 MHz; crystallized, DMSO-d6), 1.93 (6H, s, Ar-CH3), 2.03 (12H, s, CH3), 2.12 (6H, s, Ar-CH3), 5.49 (2H,s, Ar-CH), 5.55 (4H, s, Ar-H), 6.16 (2H, s, Ar-CH), 6.57 (8H, d, J 8.4, Ar-H), 7.12 (8H, d, J 8.4, Ar-H), 7.14 (4H, s, OH), 7.55 (4H, s, OH), 9.43 (4H, s, NH), δC (150 MHz; DMSO-d6), 10.1 (2 × CH3), 10.4 (2 × CH3), 24.4 (4 ×CH3), 43.7 (4 × CH), 111.1 (2 × ArC-CH3), 111.4 (2 ×ArC-CH3), 118.9 (8 × ArCH), 122.3 (4 × ArC-CH), 123.6 (4 × ArC-CH), 125.8 (2 × ArCH), 128.4 (2 × ArCH), 129.7 (8 × ArCH), 136.6 (2 × ArC-NH), 138.4 (2 × ArC-NH), 151.0 (4 ×ArC-OH), 151.1 (4 ×ArC-OH), 168.2 (C=O). Calculated for (C64H60N4O12): C, 71.36; H, 5.61; N, 5.20%. Found: C, 70.90; H, 5.46; N, 5.16%. Suitable yellowish crystals for X-ray investigation were obtained by recrystallization from DMSO but changed to a powder after a few hours exposure to air. Coating the fresh crystals with Princeton-H oil allowed the X-ray experiment to be conducted for at least 10 h.
Stage #1: o-hydroxyacetophenone With sodium hydroxide In ethanol; water at 0 - 5℃;
Stage #2: para-acetamidobenzaldehyde In ethanol; water
2.1.1. General Procedure for the Synthesis of 3,4-dihydropyrimidine-2(1H)-thiones (1-13) [20]
General procedure: 2-Hydroxychalcones, the precursor of 3,4-DHPTMs, were prepared by the slow addition of 10% aq. sodium hy-droxide solution (2.0 mL) in the ethanolic solution of 2-hydroxyacetophenone (3.0 mmol, 0.40 ml) at 0-5oC. Then, (3.0 mmol, 320 mg) of benzaldehyde was slowly added to the reaction mixture on stirring. Upon the completion of re-action (monitored by TLC), the mixture was neutralized, and the precipitates formed were filtered, washed and recrystallized from ethanol. To proceed further, the chalcone (1.0 mmol) and thiourea (2.0 mmol) prepared in 10 mL of absolute ethanol were stirred for 10-15 minutes, and then alcoholic solution of KOH (0.002 mol, 10.0 ml) was added in portions. The obtained reaction mixture was refluxed further for 5-6 hours. After the completion of reaction (checked by TLC), the reaction mixture was allowed to cool at room temperature. The solvent was evaporated under reduced pressure and the crude product was purified by recrystalliza-tion in ethanol.
With sodium hydroxide In ethanol; water at 20℃;
Synthesis of 2'-hydroxychalcones 3a-m (General method)
General procedure: 50% NaOH aqueous solution (1.0 ml) was added to a well stirred solution of aldehyde 2a-m (10 mmol) and 2'-hydroxyacetophenone (1) (10 mmol) in EtOH (30 ml). The reaction mixture was stirred at room temperature until TLC monitoring indicated the completion of the reaction (2-4 h). Then the reaction mixture was poured into icewater. The precipitated chalcone was filtered, dried, and recrystallized from methanol. Melting points of the synthesized chalcones were compared with the reported melting points. These are consistent with the literature ones.2,4,7,24-27
Stage #1: o-hydroxyacetophenone With sodium hydroxide In methanol for 0.5h;
Stage #2: para-acetamidobenzaldehyde In methanol for 24h;
General procedure: Methanolic solution of 2-hydroxyacetophenone (1.2 mL, 10mmol)was mixed with 10 mL sodium hydroxide (30%) and stirred for 30 min.Benzaldehyde (1.0 mL, 10mmol) was then added drop wise and thereaction mixture was further stirred for 24 h. Progression of reaction wasmonitored by comparative TLC. Chalcone so formed was further cyclizedby adding 1.5 mL H2O2 (35%) followed by stirring for 1 h. After completion,HCl (10%) was added to the reaction mixture and precipitates offlavonol were formed. The precipitate were filtered followed by thoroughlywashing with water, the residue obtained was then dried andcrystallized from ethanol. Flavonol (238.23 mg, 1.0mmol) was dissolvedin 5.0 mL chloroform containing anhydrous potassium carbonate(414.6 mg, 3.0mmol), and tetrabutyl ammonium bromide (TBAB967.0 mg, 3.0mmol). Then H2O (5.0 mL) was added drop by drop to theabove mixture and stirred for 30 min. Subsequently, peracetylglycosylbromide (592.0 mg, 1.5mmol) of was added by further stirring at roomtemperature for 36 h. The reaction progress was monitored with TLC.The reaction mixture was quenched with the addition of water andneutralized by HCl (10%). The aqueous layer was then extracted withdichloromethane (3×5 mL). The combined organic layer was washedwith brine followed by drying over anhydrous sodium sulfate, it wasthen filtered and concentrated under reduced pressure. The residue waspurified by column chromatography through silica gel (pet-ether/ethylacetate(10:1 to 3:1) and furnished the product.
Stage #1: o-hydroxyacetophenone With sodium hydroxide In methanol; water at 20℃; for 0.5h;
Stage #2: para-acetamidobenzaldehyde In methanol; water at 20℃; for 4h;
2.1. Procedure for the synthesis of chalcones ( 1a-1 m ) [9d] , flavones ( 2a-2 m ) [9d] and flavone hydrazones ( 3a-3 m ) [9a]
General procedure: A solution of 2 -hydroxyacetophenone (0.12 mL, 1.0 mmol), aq. sodium hydroxide solution (10 mL) (30%) was dissolved in MeOH (25.0 mL) and stirred for 30 min at room temperature with the subsequent addition of various aryl aldehyde (1.0 mmol) dropwise at the same temperature, the reaction mixture was stirred for fur- ther 4 h. ‘The reaction mixture progress was observed by TLC us- ing a mixture of ethyl acetate: n -hexane (1:3) as a mobile phase. After the completion of the reaction, the reaction mixture was acidified with dilute HCl (10%). The precipitated solid was filtered, washed with distilled H 2 O and ultimately recrystallized from EtOH to get the purified product. Subsequently, the substituted chalcone (1.0 mmol), was dissolved in DMSO (10 mL) and oxidatively cy- clized in the presence of a small amount of iodine I 2 (254 mg, 1.0 mmol). The reaction mixture was refluxed at 130-140 °C on an oil bath for 4-5 hours. Afterwards, the reaction mixture was poured onto the crushed ice, the resulting solid was treated with a solution of 10% Na 2 S 2 O 3 to get rid of unreacted I 2 , finally with dis- tilled H 2 O and recrystallized from EtOH to get a purified product. The obtained substituted flavone and 2,4-dinitrophenylhydrazine (DNPH) were dissolved in EtOH (15 mL). To this mixture, 3-4 drops of concentrated sulfuric acid (H 2 SO 4 ) were added and allowed the mixture to reflux for 4 h. Upon cooling and diluting with ice-cold water, an intense colored solid mass separated out, which was fur- ther recrystallized from ethanol to give the desired product.
With sodium hydroxide In methanol; water at 20℃; for 4h;
2.1. Procedure for the synthesis of chalcones ( 1a-1q ) [44c] ,flavones ( 2a-2q ) [44c] and flavone hydrazones ( 3a-3q ) [ 29 , 44p ]
General procedure: A mixture of 2 -hydroxyacetophenone (0.12 mL, 1.0 mmol) and aq. sodium hydroxide solution (10 mL) (30%) was dissolved in methanol (25 mL) and stirred for 30 min at room tempera- ture with subsequent dropwise addition of various aryl aldehydes (1.0 mmol). The stirring was continued for further 4 h at the same temperature. The progress of reaction was observed through TLC using a mixture of ethyl acetate: n -hexane (1:3) as solvent system. After the completion of reaction, the reaction mixture was acidified with dilute HCl (10%). The precipitated solid was filtered, washed with distilled H 2 O, and ultimately recrystallized from EtOH to get the purified product in yields of 80-85%.
4-(4-acetamidophenyl)-6-phenylpyrimidin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With piperazine immobilized inside the mesochannels of magnetic MCM-41 as an organic base (a-Fe2O3-MCM-41-piperazine); In neat (no solvent); at 80℃; for 1h;Green chemistry;
General procedure: A mixture of benzaldehyde derivatives (1 mmol), acetophenone or 4-methylacetophenone(1 mmol), and benzamidine hydrochloride (1 mmol) or guanidiniumcarbonate (0.75 mmol) along with the catalyst (0.05 g) was thoroughly ground and then transferred into a reaction vessel where this mixture was stirred at 80 C for appropriate times. The reactions were monitored by thin-layer chromatography[TLC; ethyl acetate (EtOAc):petroleum ether, 1:4]. After completion of the reaction,the mixture was allowed to cool to room temperature, then chloroform (3 mL) wasadded and the mixture was stirred for an extra 30 min. After collecting the magneticcatalyst with an external magnet, the solvent was removed in vacuo and theprecipitates were recrystallized from ethanol to furnish the desired trisubstitutedpyrimidine derivatives.
4-(4-acetamidophenyl)-6-(4-methylphenyl)pyrimidin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With piperazine immobilized inside the mesochannels of magnetic MCM-41 as an organic base (a-Fe2O3-MCM-41-piperazine); In neat (no solvent); at 80℃; for 1h;Green chemistry;
General procedure: A mixture of benzaldehyde derivatives (1 mmol), acetophenone or 4-methylacetophenone(1 mmol), and benzamidine hydrochloride (1 mmol) or guanidiniumcarbonate (0.75 mmol) along with the catalyst (0.05 g) was thoroughly ground and then transferred into a reaction vessel where this mixture was stirred at 80 C for appropriate times. The reactions were monitored by thin-layer chromatography[TLC; ethyl acetate (EtOAc):petroleum ether, 1:4]. After completion of the reaction,the mixture was allowed to cool to room temperature, then chloroform (3 mL) wasadded and the mixture was stirred for an extra 30 min. After collecting the magneticcatalyst with an external magnet, the solvent was removed in vacuo and theprecipitates were recrystallized from ethanol to furnish the desired trisubstitutedpyrimidine derivatives.
With piperazine immobilized inside the mesochannels of magnetic MCM-41 as an organic base (a-Fe2O3-MCM-41-piperazine) In neat (no solvent) at 80℃; for 1h; Green chemistry;
Procedure for the solvent-free synthesis of trisubstituted pyrimidinesin the presence of a-Fe2O3-MCM-41-P
General procedure: A mixture of benzaldehyde derivatives (1 mmol), acetophenone or 4-methylacetophenone(1 mmol), and benzamidine hydrochloride (1 mmol) or guanidiniumcarbonate (0.75 mmol) along with the catalyst (0.05 g) was thoroughly ground and then transferred into a reaction vessel where this mixture was stirred at 80 C for appropriate times. The reactions were monitored by thin-layer chromatography[TLC; ethyl acetate (EtOAc):petroleum ether, 1:4]. After completion of the reaction,the mixture was allowed to cool to room temperature, then chloroform (3 mL) wasadded and the mixture was stirred for an extra 30 min. After collecting the magneticcatalyst with an external magnet, the solvent was removed in vacuo and theprecipitates were recrystallized from ethanol to furnish the desired trisubstitutedpyrimidine derivatives.
4-(4-acetamidophenyl)-6-(4-methylphenyl)-2-phenylpyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With piperazine immobilized inside the mesochannels of magnetic MCM-41 as an organic base (a-Fe2O3-MCM-41-piperazine) In neat (no solvent) at 80℃; for 1h; Green chemistry;
Procedure for the solvent-free synthesis of trisubstituted pyrimidinesin the presence of a-Fe2O3-MCM-41-P
General procedure: A mixture of benzaldehyde derivatives (1 mmol), acetophenone or 4-methylacetophenone(1 mmol), and benzamidine hydrochloride (1 mmol) or guanidiniumcarbonate (0.75 mmol) along with the catalyst (0.05 g) was thoroughly ground and then transferred into a reaction vessel where this mixture was stirred at 80 C for appropriate times. The reactions were monitored by thin-layer chromatography[TLC; ethyl acetate (EtOAc):petroleum ether, 1:4]. After completion of the reaction,the mixture was allowed to cool to room temperature, then chloroform (3 mL) wasadded and the mixture was stirred for an extra 30 min. After collecting the magneticcatalyst with an external magnet, the solvent was removed in vacuo and theprecipitates were recrystallized from ethanol to furnish the desired trisubstitutedpyrimidine derivatives.
(Z)-2-azido-3-(4-acetamidophenyl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With sodium methylate In methanol at 20℃; for 1.5h;
1 (Z)-2-Azido-3-(4-acetamidophenyl) acrylate(2a)
4-acetylamino-benzaldehyde(2g, 0.0122 mol) was dissolved in methanol (30 ml), sodium methoxide (0.85 g, 0.0159mol) was added, and a solution of methyl azidoacetate in methanol (1.658g, 0.0128mol), drop finished, reaction at room temperature 1.5h. After completion of the reaction, the reaction solution was added to a saturated ammonium chloride solution, extracted with ethyl acetate (3 X 50 ml), and the organic layers were combined. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate overnight. The filtrate was evaporated under reduced pressure and the residue was passed through a column to give a pale yellow solid (2.7 g, 85%). Since the compound was unstable, it was not characterized by NMR
A mixture of malonitrile (60 mg, 0.91 mmol) and N-(4-formylphenyl)acetamide (147 mg, 0.91 mmol) in anhydrous ethanol ( 4.0 mL) was charged with N-methylmorpholine (0.1 mL, 0.91 mmol) for 2 minutes. To the mixture was added 1,3-dimethyl-1H-pyrazol-5(4H)- one (100 mg, 0.91 mmol) in one portion at room temperature. The reaction mixture was stirred at room temperature for 48 hrs. The suspension was concentrated to dryness and the resulting crude product was purified by Teledyne-Isco flash system by using CH2Cl2/MeOH, 0 to 5% of methanol in dichloromethane to provide compound 35 as white solid (100 mg, 35%).1H NMR (400 MHz, DMSO-d6) delta (ppm): 9.90 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.09- 7.02 (m, 4H), 4.51 (s, 1H), 3.59 (s, 3H), 2.01 (s, 3H), 1.66 (s, 3H). MS (ESI): Calcd for C17H17N5O2: 323, found: 324 (M+H)+.
With N-Bromosuccinimide In water at 20℃; for 18h; Darkness;
14.14.1 Example 14 - Preparation of (E)-2-acetamido-5-styrylbenzoic acid - DC16
14.1 Preparation of N-(2-bromo-4-formylphenyl)acetamide (23) /y.(4-formylphenyl)acetamide (2.0 g, 12.26 mmol) in water (20 mL) was transferred to an aluminum foil wrapped flask. N-Bromosuccinimide (1.1 eq., 2.40 g, 13.48 mmol) was then slowly added to the reaction mixture that was stirred at 20°C for 18 h. The progress of the reaction was monitored by using TLC using hexane:ethyl acetate=8:2 as eluent. The solvent was removed under reduced pressure. The crude was diluted with DCM (100 mL) and a saturated solution of Na2S2O3 in water (100 mL). The aqueous phase was extracted further with DCM (2 x 100 mL). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain target compound 23 (2.76 g, 11.40 mmol) as a yellow oil and in a yield of 93%. 1H NMR (500 MHz, CDCl3) δ 9.88 (s, 1H), 8.63 (d, J= 8.5 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.82 (dd, J= 1.8, 8.5 Hz, 1H), 2.77 (s, 1H), 2.30 (s, 3H). Data consistent with literature.
N-(3,5-dichloro-4-formylphenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57.8%
With N-chloro-succinimide; palladium diacetate; silver trifluoroacetate; anthranilic acid In 1,2-dichloro-ethane; trifluoroacetic acid at 60℃; for 24h; Sealed tube;
A sealed tube with magnetic stir bar was charged withN-(4-formylphenyl)acetamide (500 mg, 3.06 mmol), NCS (1.02 g, 7.65 mmol),Pd(OAc)2 (67 mg, 0.3 mmol), 2-aminobenzoic acid (123 mg, 0.9 mmol), and AgTFA(66 mg, 0.3 mmol) in air. Then, premixed solution of DCE:TFA = 4:1 (20 mL) wasadded. The reaction mixture was stirred at 60 for 24 hours. Upon completion, thereaction mixture was quenched by sat. NaHCO3 (aq) (30 mL), and extracted withDCM (50 mL × 3). The combined organic layer was washed with water (50 mL),dried over anhydrous Na2SO4, and concentrated in vacuo. The crude residue waspurified by column chromatography on silica gel (P/E = 3:1) to afford the desiredproduct 11 (411 mg, 57.8%) as a white solid,
51%
With N-chloro-succinimide; palladium diacetate; silver trifluoroacetate; anthranilic acid; trifluoroacetic acid In 1,2-dichloro-ethane at 60℃; for 24h; Sealed tube;
(Z)-2-(((3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ylidene)amino)oxy)acetohydrazide[ No CAS ]
[ 122-85-0 ]
N-(4-((E)-(2-(2-((Z)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ylideneaminooxy)acetyl)hydrazono)methyl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With acetic acid In ethanol at 80℃; for 0.166667h; Microwave irradiation;
General procedure for preparation of title compounds acylhydrazones (4a-4s)
General procedure: A mixture of aromatic aldehyde (2.0mmol) and acylhydrazine 2 (2.1mmol) reacted in ethanol (10ml) under microwave irradiation (600W, 80 °C) within 5-15 min (TLCmonitoring). The reaction was catalyzed by two or three drops of acetic acid. After cooling, the precipitate was collected by filtration, washed with cold water and diethyl ether and then recrystallized from ethanol to yield the desired compounds.
Stage #1: 4-bromoacetanilide With isopropylmagnesium chloride In tetrahydrofuran at 0℃; for 0.166667h;
Stage #2: With n-butyllithium In tetrahydrofuran; hexane at -20℃; for 0.5h;
Stage #3: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -20℃; for 0.5h;
N-(4-Formyl-phenyl)-acetamide (3i)
To a solution of 4-Bromo-phen N-(4-Formyl -phenyl)-acetamide(1.5 g, 7.0 mmol, 1.0 equiv.) in dry THF (25 mL) at 0 C was added a 2 M solution of iPrMgCl in THF(3.5 mL, 7.0 mmol, 1.0 equiv.) during 5 min. The clear solution was stirred at that temperature for anadditional 5 min, and a 2.5 M solution of n-BuLi in hexanes (5.6 mL, 14.0 mmol, 2.0 equiv.) was addeddropwise during 5 min, while maintaining the temperature below 20 C. The resulting mixture wasstirred at that temperature for 0.5 h, dry DMF (0.5 g, 1.0 equiv.) in dry THF (5 mL) was added dropwiseduring 10 min. The resulting mixture was warmed to 20 C in 0.5 h and quenched with water (6 mL).After stirring the mixture below 20 C for 10 min, the phases were separated and the water phasewas extracted one additional time with ethyl acetate. The resulting suspension was allowed to reachroom temperature and fitered through a 0.5 1 cm pad of silica gel eluted with 10 mL of ethyl acetate.The filtrate was concentrated and the residue was purified by flash chromatography on silica gel(eluent: petroleum ether/ethyl acetate = 10:1) to afford product 3i as white solid, 1.0 g (yield: 94%) ,m.p.: 157-158 C. 1H-NMR (600 MHz, DMSO) 10.35 (s, 1H), 9.86 (s, 1H), 7.81 (dd, J = 32.9, 8.6 Hz,4H), 2.10 (s, 3H). 13C-NMR (151 MHz, DMSO) 191.92, 169.55, 145.29, 131.56, 131.27, 119.01, 24.68.
N-(4-((((1S*,2R*)-2-phenylcyclopropyl)amino)methyl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22%
General procedure: Trans-2-phenylcyclopropylamine hydrochloride (1.0 eq.), acetic acid (1.0eq.) and the appropriate aldehyde (0.9 eq.) were dissolved in around bottom flask in 10 mL dry DCE. The reaction mixture was stirred gently at room temperature for 2 h before sodium triacetoxyborohydride (3.0 eq.) was added in small portions to the reaction vessel. The reaction was monitored by TLC and quenched using 10 mL of an aqueous (5%) NaHCO3 solution. The organic layer was separated and the aqueous layer extracted three times with10 mL of DCE. All organic layers were combined, dried over anhydrous Na2SO4, concentrated in vacuo and purified using flash chromatography (silica gel; cyclohexane/ethyl acetate) to give the desired compound.
With hydroxylamine hydrochloride; In methanol; water; at 20℃; for 20h;Irradiation;
General procedure: A round bottom flask was charged with a mixture of benzaldehyde 1(1.0 mmol), NH2OH.HCl 2 (1.5 mmol), Cog-C3N4 (20 mg) in H2O/MeOH (1:1, 5 mL) and stirred under the visible light condition at roomtemperature for 14-20 h. After completion of the reaction (monitored by TLC), the catalyst was filtered and added EtOAc (10 mL). Remaining organic layer was washed with brine (2×5 mL) and distilled water(1×10 mL) and dried over anhydrous sodium sulfate. Solvent was evaporated under reduced pressure to afford the crude residue, which was further purified by flash chromatography, EtOAc/n-hexane: 10:90 to obtain the analytically pure product 3
(Z)-3-(4-acetylaminophenyl)-2-(4-nitrophenyl)acrylonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With piperidine In dichloromethane at 25℃; for 3h;
1.1; 2.1; 3.1 Example 1
1,To a three-necked flask containing 150 mL of dichloromethane, 1g (6.1 mmol) of p-acetamidobenzaldehyde and 1g (6.1 mmol) of p-nitrophenylacetonitrile were added.After stirring uniformly, 0.6 mL (6.5 mmol) of piperidine was added.The reaction was carried out at room temperature for 3 hours, the solvent was distilled off, methanol was added to precipitate, and the compound 1 was obtained by filtration.The yield was 75%.
Stage #1: 2-methylquinoline; para-acetamidobenzaldehyde With toluene-4-sulfonamide In toluene for 72h; Reflux;
Stage #2: With sodium hydroxide In water at 85℃; for 3h;
2
Route 2: 1.57g 2-methylquinoline with 1.63gN-(4-formylphenyl)acetamide was added to a 250 ml round bottom flask.The spherical condensation tube is placed on the Ika magnetic stirrer and heated in an oil bath.1.88 g of p-toluenesulfonamide was added as a catalyst, and 8 ml of toluene was used as a solvent.The reaction was heated to reflux for 72 h.Add 5 ml of 40% aqueous NaOH solution, heat to 85 ° C, and react for 3 h.Filtration gave a yellow solid in 88% yield.
(E)-3-(4-acetamidophenyl)-2-cyano-N-(4-phenylthiazol-2-yl)acrylamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With triethylamine In ethanol at 50℃; for 3h; Inert atmosphere;
82 General procedure Dl: Condensation with triethylamine as a base
General procedure: To a mixture of the appropriate aldehyde (0.95 eq) and cyanoacetamide (1 eq) in absolute EtOH (17 inL per 1 mmol of aldehyde, unless stated otherwise) was added triethylamine (1 eq) and the mixture was stirred at 50 °C for 2 h (unless stated otherwise). (0095) Work-up 1: (0096) When a precipitate appeared, the solvent was removed by filtration. The solid residue was dissolved in EtOAc (ca. 5 inL per 0.05 mmol of aldehyde) and a saturated aqueous solution of NH4CI (5 inL per 0.05 mmol of aldehyde) was added. The mixture was extracted with EtOAc (3 x 5 inL per 0.05 mmol of aldehyde). The combined organic extracts were washed with water (ca. 4 mL per 0.05 mmol of aldehyde), brine (ca. 4 mL per 0.05 mmol of aldehyde), dried over MgSC>4, filtered, and the solvent was evaporated in vacuo. The resulting product - the desired acrylamide - was usually sufficiently pure and was used directly in the next step without further purification (unless stated otherwise). (0097) Work-up 2: (0098) When no precipitate appeared, a saturated aqueous solution of NH4CI (5 mL per 0.05 mmol of aldehyde) was added to the reaction mixture, which was then extracted with EtOAc (3 x 5 mL per 0.05 mmol of aldehyde). The organic extracts were washed with water (4 mL per 0.05 mmol of aldehyde), brine (4 mL per 0.05 mmol of aldehyde), dried over MgSCb, filtered, and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel and/or by reverse phase column chromatography on Ci8 silica gel to provide the desired acrylamide.
N-(4-((3-methyl-5-oxoisoxazol-4(5H)-ylidene)methyl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With sulfuric acid immobilized on nano-SiO2 In water at 20℃; for 1h; Green chemistry;
General procedure forthesynthesis ofα,β-unsaturatedisoxazol-5(4H)-ones (4a-4aq)
General procedure: A mixture of hydroxylamine hydrochloride 2 (0.0695 g, 1 mmol), β-ketoester 3 (1 mmol), and catalyst (0.05 g) in 5 mL of distilled water was stirred at room temperature (rt) for 10min; then, aryl/heteroaryl aldehyde 1 (1mmol) was added to the vessel reaction. The reaction mixture was stirred at rt until the reaction was completed (monitored by TLC analysis). After the completion of the reaction, the precipitate was separated by simple filtration, washed with cold distilled water, and dried in the air. Crude products were dissolved in hot ethanol and filtered off for the separation of catalyst. The products were crystallized from ethanol (95%) to afford the title pure compounds. Spectral data for some compounds are as follows:
N-(4-((3-(chloromethyl)-5-oxoisoxazol-4(5H)-ylidene)methyl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With sulfuric acid immobilized on nano-SiO2 In water at 20℃; for 1h; Green chemistry;
General procedure forthesynthesis ofα,β-unsaturatedisoxazol-5(4H)-ones (4a-4aq)
General procedure: A mixture of hydroxylamine hydrochloride 2 (0.0695 g, 1 mmol), β-ketoester 3 (1 mmol), and catalyst (0.05 g) in 5 mL of distilled water was stirred at room temperature (rt) for 10min; then, aryl/heteroaryl aldehyde 1 (1mmol) was added to the vessel reaction. The reaction mixture was stirred at rt until the reaction was completed (monitored by TLC analysis). After the completion of the reaction, the precipitate was separated by simple filtration, washed with cold distilled water, and dried in the air. Crude products were dissolved in hot ethanol and filtered off for the separation of catalyst. The products were crystallized from ethanol (95%) to afford the title pure compounds. Spectral data for some compounds are as follows:
With Ferric Sulfasalazine Sulfa Drug Complex Supported on Cobalt Ferrite Cellulose In ethanol at 60℃; for 0.25h;
2.3 General Procedure for the 4H- Pyrans Derivatives Synthesis
General procedure: A suspension of malonitrile (1mmol), ethyl acetoacetate(methyl acetoacetate, acetoacetate) (1mmol), aldehyde(1mmol) and the catalyst (0.01g, 0.0016mmol) in ethanol(10ml) was stirred at 60°C. After completion of the reactionwhich was monitored by TLC, the catalyst was separatedby using an external magnet. The mixture was poured into cold water and the precipitate was filtered. The solid wasrecrystallized with ethanol and dried in an oven at 60°C.
With tetrakis(tetrabutylammonium)decatungstate(VI); 2,4,6-Triisopropylthiophenol; water-d2 In acetonitrile for 4h; Irradiation;
85%
With sodium benzoate; (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; water-d2; triisopropylsilanethiol In ethyl acetate at 20℃; for 36h; Inert atmosphere; Irradiation;
61%
With potassium <i>tert</i>-butylate; deuterium In tetrahydrofuran at 55℃; for 16h; regioselective reaction;
With rhodium(III) chloride trihydrate; hydrogen; triethylamine; triphenylphosphine In N,N-dimethyl acetamide at 90℃; for 12h; Autoclave;
General procedure for reductive carbonylation of aryl iodides with CO and H2
General procedure: All reactions were carried out in an 80 mL Teflon-lined stainless steel reactor equipped with a magnetic stirring bar. Typically, in a glovebox, the aryl iodides (1.0 mmol), RhI3(0.025 mmol), PPh3 (0.1 mmol), Et3N (1.2 mmol), and DMA (2 mL) were loaded into the reactor. Then, the autoclave was screwed up, charged with CO and H2 to a total pressure of 10 bar (1:1) and transferred to an oil bath preheated at 90 °C, which was controlled by a Haake-D3 temperature controller. After completion of the reaction, the reactor was cooled in iced water and the gas carefully vented. The conversion and yield of the aryl iodides and arylaldehydes were determined by GC analysis using dodecane as an internal standard. For yield determination of the other products, the reaction mixture was first analyzed by GC-MS to determine the structures of the aromatic aldehyde products. Then, CH2Cl2 (5 mL) was added to the reaction mixture, after which deionized water (10 mL) was added to extract the solvent DMA for 5 times. The organic layer was dried over anhydrous Na2SO4, concentrated by rotary evaporation and finally purified by column chromatography on silica gel using n-hexane/ethyl acetate as eluent to obtain the pure products and isolated yields.
4-(4-acetamide-styryl)-1-methylpyridinium iodide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With piperidine In ethanol for 0.25h; Sonication;
2.1. General procedure for synthesis of dyes under ultrasonic irradiation
General procedure: Ultrasonic irradiation (Ti horn from Sonics and Materials VCX 600,20 kHz, 600 W at 30% Amplitude) was performed on a mixture of 1.1 eq. of aldehyde and 1 eq. of 4-methyl pyridinium ion and a catalytic amount of piperidine in ethanol (10 mL) for 15 min. The volatile ethanol was removed by rotavapor and the crude residue is washed with diethylether to furnish the desired compounds in a good to excellent yield.
With piperidine In tetrahydrofuran at 65℃; for 5h;
68%
With piperidine In tetrahydrofuran at 65℃; for 5h;
2.1 Synthesis of compound 2
Compound 1 (0.5 g, 3.1 mmol), 4-nitrophenylacetonitrile (0.5 g, 3.1 mmol) and piperidine (0.3 mL) was added to a stirred THF solution (30 mL). The reaction mixture was stirred at 65 oC for 5 h and the reaction process was monitored by TLC analysis. Then, CH3OH (100 mL) was added in the reaction mixture and the precipitate was formed and filtered. After filtration, compound 2 was obtained as yellow solid in yield of 86%. 1H NMR (400 MHz, DMSO-d6): δppm: 10.35 (s, 1H, NH), 8.35 (d, J = 12.0 Hz, 2H, ArH), 8.22 (s, 1H, CH), 8.02 (d, J = 12.0 Hz, 2H, ArH), 7.99 (d, J = 12.0 Hz, 2H, ArH), 7.78 (d, J = 12.0 Hz, 2H, ArH), 2.10 (s, 3H, CH3). MALDI-TOF-MS (C17H13N3O3) Calcd. for m/z = 307.0957, found: m/z = 307.9966 (MH+), 330.9820 (MNa+), 346.9723 (MK+).
With bis-triphenylphosphine-palladium(II) chloride; 2,2'-azobis(isobutyronitrile); oxygen; triethylamine In N,N-dimethyl-formamide at 110℃; for 6h; Schlenk technique; Sealed tube;
1.2. General Procedure for PdCl2(PPh3)2 catalyzed hydroformylation of alkynes
General procedure: Standard reaction condition: PdCl2(PPh3)2(0.021g, 0.03mmol), glyoxylic acidmonohydrate (0.552g, 6.0mmol) and AIBN (0.082g, 0.05mmol) were transferred intoa 50ml Schlenk tube that was filled with oxygen. DMF (2.0 mL) and aryl halide (1.0mmol) were added to the reaction tube. After Et3N (0.606g, 6.0 mmol) were added,the tube was sealed, and the mixture was stirred at 110 °C for 4-8 h. Upon completionof the reaction, the mixture was poured into saturated aqueous NaCl solution (25ml)and extracted with CH2Cl2 (4x15ml), The combined organic layers were washedwith brine (4x20ml), dried over MgSO4, filtered, and concentrated. The residue waspurified by flash chromatography on silica gel to obtain the desired product by usinglight petroleum ether/ethyl acetate as the eluent.
(2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-11-(4-acetamidobenzylidene)-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82.3%
With potassium hydroxide In ethanol at 20℃; for 3h;
4.1.1 General procedure for the synthesis of GA derivatives (13~34)
General procedure: GA derivatives 13-34 were obtained according to Scheme 1. GA was dissolved in acetone at 0 °C; Jones reagent was added to the reaction mixture drop-wisely until the solution colour was stable in light brown, which implied that the Jones reagent was in slight excess to oxidize the C-3 hydroxyl group into ketone to produce the intermediate 10. Purification of compound 10 by flash column chromatography was carried out using eluent (petroleum ether/ethyl acetate, 3 : 1, containing 0.5% formic acid). Derivatives 13-34 could be prepared by Claisen Schmidt condensation of intermediate 10 with corresponding aldehydes in the presence of ethanolic potassium hydroxide in good yield at room temperature. All the results were detailed below.
N-(4-(5,7-di-tert-butylbenzo[d]oxazol-2-yl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With sodium periodate; ammonium acetate In ethyl acetate at 50℃; for 3h; Schlenk technique; Inert atmosphere;
85%
With sodium periodate; ammonium acetate In ethyl acetate at 50℃; for 3h; Inert atmosphere;
6 Synthesis of N-(4-(5,7-di-tert-butylbenzo[d]oxazol-2-yl)phenyl)acetamide
Add 0.2mmol 3,5-di-tert-butylcatechol, 0.4mmol p-acetaminobenzaldehyde, 0.4mmol ammonium acetate, 0.4mmol NaIO4, 2.0mL EA into the reactor. Under a nitrogen atmosphere, continue stirring at 50°C for 3 hours, stop the reaction, cool to room temperature, wash with saturated NaCl, then extract with ethyl acetate, concentrate under reduced pressure to remove the solvent, and dry. The crude product is separated by column chromatography. The target product has a yield of 85%
With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 2h;
General procedure: To a solution of the diphenyl ether aniline (1.5 eq.) and aldehyde (1 eq.) in DCE(2 mL/1 mmol), acetic acid (3 eq.) and sodium tri-acetoxyborohydride (2.5 eq.) wereadded. The resulting reaction mixture was stirred at r.t. for 2-18 h. NaHCO3 was thenadded and repeatedly extracted with DCM. The organic layers were combined and dried(MgSO4), filtered and evaporated in vacuo. The crude mixture was purified using flashchromatography to afford the desired compound.
Stage #1: 2-(2,4-dichloro-phenoxy)-phenylamine hydrochloride With potassium carbonate In dichloromethane at 20℃; for 0.5h;
Stage #2: para-acetamidobenzaldehyde With sodium tris(acetoxy)borohydride In acetic acid; 1,2-dichloro-ethane at 20℃; for 2h;
N-(4-([2-(2,4-Dichloro-phenoxy)-phenylamino]-methyl)-phenyl)-acetamide (19)
To a solution of 2-(2,4-dichloro-phenoxy)-phenylamine hydrochloride (0.15 g,0.52 mmol) in DCM (10 mL), K2CO3 (0.22 g, 1.04 mmol) was added,;the resulting solution was stirred at r.t for 30 min. Water was added and the mixture was extracted with DCM.The organic layers were combined and dried (MgSO4), filtered and evaporated in vacuo.The resulting amine was dissolved in DCE (3 mL) and 4-acetamidobenzaldehyde (0.126 g,0.0.75 mmol), acetic acid (0.11 mL) and sodium tri-acetoxy borohydride (0.27 g, 1.3 mmol)were added. The resulting reaction mixture was stirred at r.t. for 2 h. NaHCO3 was added,and the mixture was repeatedly extracted with DCM. The organic layers were combinedand dried (MgSO4), filtered and evaporated in vacuo. The crude mixture was purifiedusing flash chromatography (0-100% EtOAc in hexane) to afford the title compound as awhite wax, 142 mg, 69% yield. R.f. 5.8 (EtOAc), LCMS: tr = 1.2 min (95% MeOH in H2O),m/z M-H 399.03, 401.04, HPLC: tr = 2.42 min (90% acetonitrile in H2O), 98%, 1H NMR(CDCl3, 270 MHz): 2.15 (3H, s, CH3), 4.31 (2H, s, CH2), 4.59 (1H, br.s, NH), 6.59-6.68(2H, m, ArH), 6.75 (1H, dd, J = 1.5, 7.9 Hz, ArH), 6.80 (1H, d, J = 8.7 Hz, ArH), 6.96-7.02(1H, m, ArH), 7.12 (1H, dd, J = 2.5, 8.9 Hz, ArH), 7.22-7.31 (1H, m, ArH), 7.41-7.45 (2H, m,ArH). 13C NMR (CDCl3, 68 MHz): 24.7 (CH3), 47.3 (CH2), 112.2, 117.1, 118.5, 119.4, 120.2(ArCH), 125.3 (ArC), 125.5, 127.9, 128.0 (ArCH), 128.2 (ArC), 130.4 (ArCH), 135.1, 136.9,139.7, 142.7, 151.8 (ArC), 168.4 (CO). HRMS: Calcd. for C21H18Cl2N2O2 (M + H)+ 399.0673,found (M + H)+ 399.0674. Anal. Calcd. for C21H18Cl2N2O2 C 62.85, H 4.52 N 6.98%. Found:C 62.7, H 4.52, N 6.92%.
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