* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Chemische Berichte, 1919, vol. 52, p. 1083
2
[ 120-66-1 ]
[ 7597-18-4 ]
Reference：
[1] Chemische Berichte, 1884, vol. 17, p. 265
3
[ 120-66-1 ]
[ 3970-40-9 ]
Reference：
[1] Journal of the Chemical Society, 1901, vol. 79, p. 1128[2] Journal of the Chemical Society, 1902, vol. 81, p. 1327,1347
4
[ 120-66-1 ]
[ 635-21-2 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1937, vol. 7, p. 842,844[2] Chem. Zentralbl., 1939, vol. 110, # I, p. 1366
5
[ 120-66-1 ]
[ 2687-25-4 ]
Reference：
[1] Chemische Berichte, 1919, vol. 52, p. 1083
[2] Polyhedron, 2016, vol. 105, p. 137 - 149
6
[ 120-66-1 ]
[ 5428-54-6 ]
Reference：
[1] Chemische Berichte, 1884, vol. 17, p. 265
7
[ 120-66-1 ]
[ 615-59-8 ]
Reference：
[1] Journal of the Chemical Society, 1914, vol. 105, p. 514
8
[ 120-66-1 ]
[ 570-24-1 ]
Yield
Reaction Conditions
Operation in experiment
39.78 g
Stage #1: With nitric acid In acetic anhydride at 10 - 12℃; for 2.5 h; Stage #2: With sulfuric acid In water for 3 h; Reflux
A slightly modified procedure of Howard was applied [27]. Toluidine (1a or 1b; 53.5mL, 0.5mol) was introduced, in small portions and under constant stirring, to Ac2O (325mL). The obtained solution was cooled to 12–13°C in an ice-salt bath. After that, under stirring and at a rate which maintained the temperature within the limits of 10–12°C, 70percent HNO3 (63mL) was added dropwise to the reaction mixture. The addition was completed in 2.5h and the solution was poured, with stirring, into 1.5L of ice-water. The precipitate (cream-colored solid) of acetamide (3a, or mixture of 3b and 3c) was collected on a Büchner funnel, washed with four 250-mL portions of ice-water and partially dried by suction. The moist acetamide (3a, or mixture of 3b and 3c) was mixed with 70percent H2SO4 (100mL) and stirred at reflux for 3h. The hydrolysis product of acetamide 3b, 2-methyl-6-nitroaniline (4b), was isolated from the reaction mixture by steam distillation. The bright orange needles of 4b, which separated when the distillate was cooled, were collected on a Büchner funnel and dried in a vacuum desiccator. In the case of the hydrolysis of acetamide 3a, the warm reaction mixture was diluted with 350mL of water and made alkaline with 10percent aq. NaOH. After cooling to room temperature 4-methyl-2-nitroaniline (4a) precipitated as a brown powder that was separated by vacuum filtration, washed with three 200-mL portions of water, and dried in a vacuum desiccator. The yield was 53.6percent (40.73g) and 52.3percent (39.78g) for compounds 4a and 4b, respectively.
Reference：
[1] Bulletin des Societes Chimiques Belges, 1969, vol. 78, p. 571 - 582
[2] Chemistry Letters, 1989, p. 1849 - 1852
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 13, p. 6047 - 6060
[4] Polyhedron, 2016, vol. 105, p. 137 - 149
9
[ 120-66-1 ]
[ 570-24-1 ]
[ 99-52-5 ]
Reference：
[1] Tetrahedron Asymmetry, 2003, vol. 14, # 10, p. 1267 - 1273
[2] Chemische Berichte, 1900, vol. 33, p. 2505
[3] Journal of the Chemical Society, 1901, vol. 79, p. 1128[4] Journal of the Chemical Society, 1902, vol. 81, p. 1327,1347
[5] Journal of the Chemical Society, 1923, vol. 123, p. 3238
[6] Journal fuer Praktische Chemie (Leipzig), 1921, vol. <2>102, p. 184
[7] Chemische Berichte, 1900, vol. 33, p. 2505
[8] Journal of the Chemical Society, 1901, vol. 79, p. 1128[9] Journal of the Chemical Society, 1902, vol. 81, p. 1327,1347
10
[ 120-66-1 ]
[ 570-24-1 ]
[ 2719-15-5 ]
Reference：
[1] Chemische Berichte, 1919, vol. 52, p. 1083
[2] Chemische Berichte, 1919, vol. 52, p. 1174
11
[ 591-09-3 ]
[ 120-66-1 ]
[ 570-24-1 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1929, vol. 38, p. 372
12
[ 120-66-1 ]
[ 89-20-3 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1893, vol. 274, p. 291
13
[ 120-66-1 ]
[ 50712-68-0 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1893, vol. 274, p. 291
14
[ 120-66-1 ]
[ 116632-39-4 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 153[2] Justus Liebigs Annalen der Chemie, 1878, vol. 192, p. 202
Reference：
[1] Journal of Organic Chemistry, 1981, vol. 46, p. 5373 - 5376
[2] Chemical and Pharmaceutical Bulletin, 1962, vol. 10, p. 1 - 8
[3] Journal of the American Chemical Society, 1981, vol. 103, # 3, p. 645 - 653
17
[ 120-66-1 ]
[ 1205-39-6 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1990, # 4, p. 619 - 624
[2] Journal of the American Chemical Society, 1928, vol. 50, p. 864
Reference：
[1] Journal of the Indian Chemical Society, 1956, vol. 33, p. 129
[2] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 22, p. 6366 - 6379
20
[ 120-66-1 ]
[ 2835-95-2 ]
Reference：
[1] Chemische Berichte, 1884, vol. 17, p. 265
21
[ 120-66-1 ]
[ 37074-40-1 ]
Reference：
[1] Patent: CN107629029, 2018, A,
22
[ 120-66-1 ]
[ 78881-21-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 7, p. 1860 - 1864
23
[ 120-66-1 ]
[ 76153-06-5 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1980, vol. 19, # 12, p. 1035 - 1037
With water; acetic acid; calcium chloride Erw.des ausgeschiedenen 5-Chlor-2-<acetyl-chlor-amino>-toluols mit Eisessig und einig.Tropfen konz.Schwefelsaeure und Verseifung des so gewonnenen 3.5-Dichlor-2-acetamino-toluols mit konz.Salzsaeure im geschloss.Rohr bei 150grad;
With ethanol; chlorine; acetic acid Erhitzen des entstandenen 3.5-Dichlor-2-acetamino-toluols mit alkoh.Kalilauge;
(i) (chlorination), (ii) (hydrolysis); Multistep reaction;
With hydrogen bromide; Selectfluor; In water; at 20℃; for 0.25h;
General procedure: 1a as example: To a stirred suspension of N-(p-tolyl)acetamide 1a (75 mg, 0.5 mmol) and Selectfluor (213 mg, 0.6 mmol) in water (3.0 mL) was added HBr (40% aqueous, 0.08 mL, 0.55 mmol), and the mixture was stirred for 5 min at room temperature. After 1a was consumed, as indicated by TLC, the reaction mixture was quenched with saturated aqueous Na2S2O3 (2.0 mL) and water (20.0 mL), and extracted with CH2Cl2 (10.0 mL) three times. The residue obtained after evaporation of the solvent was purified by column chromatography on silica gel (petroleum ether-ethyl acetate = 6:1, v/v) to afford N-(2-bromo-4-methylphenyl)acetamide 2a as a white solid (108 mg, 95% yield).
With bromine; acetic acid; at 50 - 55℃; for 1.5h;
To a stirred solution of step-a product (24 g, 0.16 mol) in acetic acid (88 ml, 3.7 times), bromine (25.6 g (8.3 ml), 0.16 mol) was added drop wise at rt. Heated the reaction mass to 50 - 550C and allowed stirred for 1.5 hrs at the same temperature. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, Rr0.6). On completion of the reaction, poured the reaction contents into ice cold water. The solid thrown out was filtered and dried to obtain the crude product as a pale pink solid (55g, crude). The crude obtained was directly used for the next step without any further purification.
A mixture of 2-methylaniline (5 g, 47 mmol, 1 eq.), acetic anhydride (5 g, 49 mmol, 1.1 eq.) and hexamethylphosphoramide (trace) was stirred at room temperature. The reaction was monitored by TLC or HPLC. After completion of amide formation, aqueous hydrobromic acid (40%, 9.53 g, 47 mmol, 1.0 eq.) was added to the resulting solution of /V-(2-methylphenyl)acetamide and the mixture was cooled to 0 0C. Aqueous hydrogen peroxide (30%, 5.48 g, 47 mmol, 1.0 eq.) was then added slowly within 30 min and stirring was continued overnight. A white precipitate formed and was collected by filtration. The filtrate was concentrated using a rotary evaporator and a second crop of white solid was collected by filtration. The combined white solid was washed with water and aqueous sodium carbonate and dried to give Lambda£(4-bromo- 2-methylphenyl)acetamide as a white solid. Yield: 8.50 g (80%).1H NMR (400 MHz, DMSO-fe): delta 9.32 (s, 1H), 7.41 (d, J= 2.0 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1 H), 7.32 (dd, J = 2.0 Hz, J= 8.8 Hz, 1 H), 2.19 (s, 3H), 2.05 (s, 3H). 13C NMR (100 MHz, DMSO-alphafe): delta 168.8, 136.4, 134.5, 133.1 , 129.1, 127.0, 117.4, 23.8, 18.0.
15 g
With bromine; acetic acid; at 50℃; for 1.5h;
Step2: Compound [90] ( l O.Og, 0.067 mol) was dissolved in 37 ml glacial acetic acid in two necked RBF. Bromine ( 1 1 ml, 0.067 mol, leq.) was added drop wise to the mixture and then heated at 50C for 1.5 hrs. On completion of reaction, the mixture was poured into ice cold water. The aqueous layer was extracted with ethyl acetate (3 X 100 ml). The organic layer was separated, dried over concentrated under vacuum to obtain compound [91] ( 15. Og, ESIMS: 229 (M+ + 1 )
With poly(4-vinylpyridine) perchlorate; In neat (no solvent); at 20℃; for 0.25h;
General procedure: The substrate (alcohol, phenol or amine; 1.0 mmol) was treated with Ac2O (2.0 mmol) in the presence of P(4-VPH)ClO4 (50 mg) at room temperature under solvent-free conditions and magnetic stirring. After completion of the reaction as indicated by TLC, the mixture was diluted with Et2O (25 ml) and the catalyst allowed to settle down. The supernatant ethereal solution was decanted off, the catalyst washed with Et2O (2 ml) and the combined ethereal solution concentrated under vacuum to afford the product, identical(mp, IR, 1H and 13C NMR, and GC-MS) to an authentic sample of acetylated product. The recovered catalyst was dried at 50 C under vacuum for 2 h. The recovered catalyst, after drying, was reused for four more consecutive acetylation reactions of benzyl alcohol (1.0 mmol) affording 96, 96, 94, and 94% yields, respectively, in 22, 23, 23, and 25 min (Scheme 2).
90%
at 110 - 115℃; for 2h;
Stepl: Compound [89] ( lO.Og, 0.093 mol) was dissolved in 20 ml glacial acetic acid in two necked RBF and mixture was heated at 1 10- 1 15C for 2 hrs. The mixture was cooled to RT and poured into ice water mixture. The mixture was extracted with DCM (3 X 200 ml). The organic layer was separated, dried over Na?S04, .concentrated under vacuum to obtain compound [90] ( 12.5g, 90%) as pale pink solid. , ESIMS: 150 (M+ + 1 )
87%
at 110 - 115℃; for 2h;
Acetic acid (74 ml, ~4 times) was added to o-toluidine (20 g, 0.18 mol) at r.t., heated the contents to 110 - 1150C and refluxed for 2 hrs at the same temperature. Progress of the reaction was monitored by TLC (30% ethyl acetate/hexane, Rr0.2). On completion of the reaction, reaction contents were poured into ice cold water and solid thrown out was filtered. The solid obtained was washed with water and dried. Then the solid was dissolved in DCM (25 ml), dried over sodium sulfate and the DCM was distilled off completely to yield the required product as a pale pink solid (22 g, 87% yield).
86%
With 1-methyl-3-(4-sulfonylbutyl)-1H-imidazol-3-ium trifluoromethanesulfonate; at 96 - 100℃; for 5h;
General procedure: A mixture of amine (0.02 mol), acetic acid (0.025 mol, 1.5 mL) and [BMIM(SO3H)][OTf] (50 mol %) was charged in an oven-dried round bottom flask and the reaction mixture was refluxed on an oil bath. Progress of the reaction was monitored by TLC and by GC-MS. After completion of reaction, the reaction mass was cooled at room temperature and poured into ice water. The crystals of N-acylated product so obtained were filtered, washed with of cold ethanol-water mixture (10-15 mL) and dried. The purity of all the products was checked by TLC and GC, and all the pure products were characterized by IR, GC-MS/LC-MS, 1HNMR and 13CNMR. The filtrate (water + ethanol + IL) was set aside for recovery and reuse of the IL.
With aluminum (III) chloride; In 1,2-dichloro-ethane; at 60℃; for 24h;
The compound 2 (2.98 g, 20 mmol) and 100 ml 1,2-dichloroethane (ClCH2CH2Cl) were placed to a flask, and stirred at room temperature, then acetyl chloride (3.12, 40 mmol), aluminium trichloride (AlCl3) (8.54 g, 64 mmol) were added. The mixture was heated to 60 C and kept for 24 h, monitored by TLC. After the reaction was completed, it was cooled to room temperature. Pour the mixture into the ice water, and extracted with CH2Cl2. The organic phase was combined and dried with Na2SO4. The solvent was evaporated and the residue was applied to a flash column chromatography by eluting with petroleum ether/ethyl acetate (2:1) to give the compound 5 as a yellow solid. Yield 78%, mp 47-48 C; 1H NMR (400 Hz, CDCl3) delta (ppm): 2.23 (s, 3H, Ar-CH3), 2.31 (s, 3H, CH3CONH), 2.57 (s, 3H, COCH3), 7.20 (s, 1H, Ar-NH), 7.28 (d, JH = 5.6 Hz, Ar-H), 7.69(d, 1H, JH = 8.0 Hz, Ar-H), .8.31 (s, 1H, Ar-H).
With hydroxyapatite supported copper(I) oxide; In acetonitrile; at 50℃; for 0.0666667h;
General procedure: To a mixture of amine (1 mmol), acetyl chloride (1 mmol)in acetonitrile (5 mL) were added hydroxyapatite -Cu2O(0.1 g) under air atmosphere. The reaction mixture wasrefluxed at 50 C for an appropriate time. The progress ofthe reaction was monitored through TLC. Upon completionof the reaction, the reaction mixture was cooled toroom temperature and filtered. The residue was washedwith water followed by EtOAc (3 × 10 mL). The productwas obtained after the removal of solvent under reducedpressure followed by crystallization from pet ether orEtOAc:pet ether or passing through column of silica andelution with EtOAc:pet ether.
86%
With pyridine; In dichloromethane; at 0 - 20℃;
Acetyl chloride (3.32 mL, 46.7 mmol) was slowly added to a stirred solution of o-toluidine (5 g, 46.7 mmol) and pyridine (9.8 mL, 121.4 mmol) in DCM (50 mL) at 0C. The mixture was stirred for 1 hour at 0C and then allowed to warm to room temperature. The organics were washed with water and twice with brine, dried over MgS04 and filtered and the solvent removed under reduced pressure to give N- acetyl-o-toluidine (6 g, 86% yield). N-acetyl-o-toluidine (4.8 g, 0.032 mol), 1 ,4- dibromobenzene (9.1 1 g, 0.039 mol), 2C03 (4.42 g, 0.032 mol), Cu powder (2.03 g, 0.032 mol) and iodine (812 mg, 0.032 mol) combined in NMP (70 mL) were heated at 180C overnight under an argon atmosphere. The reaction was then allowed to cool to room temperature and diluted with ethyl acetate (300 mL). This mixture was filtered through celite and washed with additional ethyl acetate. The organics were washed with water and twice with brine, dried over MgS04 and filtered and the solvent removed under reduced pressure. The residue was purified over silica (100% heptane to 100 % ethyl acetate) to give N-(4-bromophenyl)-N-o-tolylacetamide (3.2 g, 33% yield). N-(4-bromophenyl)-N-o-toIylacetamide (1.13 g, 3.72 mmol) was dissolved in toluene. Sodium methoxide (4.5 mL, 26 mmol of a 30% solution in methanol) was added and the reaction heated at 100C. After 3 hours, TLC analysis indicated that all starting material had been consumed and the reaction was allowed to cool to room temperature. Water (1 mL) was added to quench the reaction before dilution with ethyl acetate (200 mL). The organics were washed with water and twice with brine, dried over MgS(¾ and filtered and the solvent removed under reduced pressure to give N-(4-bromophenyl)-2-methylaniline (76 mg, 100% yield). N-(4-bromophenyl)-2-methylaniline (l g, 3.82 mmol) and 2,3-dihydrobenzofuran-5- boronic acid (688.0 mg, 4.19 mmol) were combined in deoxygenated dioxane (30 mL). A potassium phosphate solution (2.43 g, 1 1.46 mmol, 6 mL deoxygenated water) was added to the reaction mixture. The reaction mixture was stirred rapidly under argon. PdCl2dppf (279.5 mg, 0.38 mmol) was added and the reaction mixture transferred to a pre-heated oil bath and stirred rapidly under argon at 90C. After 1 hour, TLC analysis indicated that all starting material had been consumed. The reaction was allowed to cool to room temperature and diluted with ethyl acetate (100 mL). This mixture was filtered through celite and washed with additional ethyl acetate. The organics were washed with water and twice with brine, dried over MgS04 and filtered and the solvent removed under reduced pressure. The residue was purified over silica (100% heptane to 9: 1 heptane/ethyl acetate) to give N-(4- (2,3-dihydrobenzofuran-5-yl)phenyl)-2-methylaniline (312 mg, 27% yield). N-(4- (2,3-dihydrobenzofuran-5-yl)phenyl)-2-methylaniline (100 mg, 0.033 mmol) was dissolved in a mixture of toluene (0.2 mL) and acetic acid (0.8 mL). Pd(OAc)2 (7.5 mg, 0.33 mmol) and Cs2C03 (1 1.7 mg, 0.036 mmol) were added and the reaction was heated at 100C for two hours. The reaction was allowed to cool to room temperature and diluted with ethyl acetate (50 mL). This mixture was filtered through celite and washed with additional ethyl acetate. The organics were washed with water and twice with brine, dried over MgS04 and filtered and the solvent removed under reduced pressure. The residue was purified over silica (100% heptane to 7:3 heptane/ethyl acetate) to give crude product. This residue was recrystalised from heptane (15 mL) which on cooling gave product 20.5 mg (19%) of E58
With triethylamine; at 0 - 28℃;
Description 8: N-acetyl-2-toluidine; Ortho toluidine (0.75 moles, 80 g.) was taken in a one liter round bottom flask equipped with a liquid addition funnel and a guard tube. Triethylamine (1.13 moles, 113.77 g.) was added to it in one lot. Above mixture was cooled to 0-5 C. and acetyl chloride was added drop-wise maintaining the temperature below 10 C. After addition of acetyl chloride the cooling was removed and reaction was stirred at 25-28 C. for 3 hours. After the completion of reaction (TLC), the reaction mixture was poured on 500 g. of ice-water, and aqueous layer was extracted with dichloromethane (2×300 mL). The combined dichloromethane extracts were then washed with water, brine and dried over anhydrous magnesium sulfate. The volatiles were removed under the reduced pressure to obtain 113.6 grams solid.
With triethylamine; at 0 - 28℃; for 3h;
Ortho toluidine (0.75 moles, 80 g.) was taken in a one liter round bottom flask equipped with a liquid addition funnel and a guard tube. Triethylamine (1.13 moles, 113.77 g.) was added to it in one lot. Above mixture was cooled to 0-5 0C and acetyl chloride was added drop-wise maintaining the temperature below 10 0C. After addition of acetyl chloride the cooling was removed and reaction was stirred at 25 - 28 0C for 3 hours. After the completion of reaction (TLC), the reaction mixture was poured on 500 g. of ice-water, and aqueous layer was extracted with dichloromethane (2 X 300 mL). The combined dichloromethane extracts were then washed with water, brine and dried over anhydrous magnesium sulfate. The volatiles were removed under the reduced pressure to obtain 113.6 grams solid.
With triethylamine; In dichloromethane; at -78 - 23℃;Inert atmosphere;
General procedure: In a dried RBF cooled to -78 C under argon, o-toluidine was added, an acetyl chloride (10-15 eq.) and triethylamine (10-15 eq.) in 10 mL of DCM. The reaction was allowed to warm to RT and was stirred overnight. The reaction was then quenched with water (10 mL) and extracted with water (3 x 25 mL), dried over anhydrous MgSO4 and concentrated under vacuum. The product was sufficiently pure to carry on to the next step without further purification (80-90%)
With triethylamine; In dichloromethane; at 0 - 20℃;
General procedure: To a solution of aniline (10 mmol) in anhydrous CH2Cl2 (20 mL) was added triethylamine (12 mmol) and benzenesulfonyl chloride / trifluoromathanesulfonyl chloride / benzoyl chloride / acetyl chloride (11 mmol) at 0 C. The reaction mixture was stirred at room temperature until the reaction was completed (monitored by TLC). Water (50 mL) was added to the mixture and extracted with CH2Cl2 (30 mL). The organic phase was dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel or recrystalization to afford the corresponding products in 85~96% yield.
With triethylamine; at 0 - 28℃; for 3h;
Ortho toluidine (0.75 mol, 80 grams) was taken in a 1 L round bottom flask equipped with a liquid addition funnel and a guard tube. Triethylamine (1.13 mmol, 113.77 grams) was added to it in one lot. Above mixture was cooled to 0 - 5 0C and acetyl chloride (1.13 mmol, 88.7 grams) was added drop wise by maintaining the temperature below 10 0C. After addition of acetyl chloride, cooling was removed and the reaction mass was stirred at 25 - 28 0C for a period of 3 hours. After completion of the reaction, the reaction mixture was poured onto 500 grams of ice- water and extracted with dichloromethane (2 x 300 mL). The combined dichloromethane extracts were then washed with water, brine and dried over anhydrous magnesium sulfate. The volatiles were removed under the reduced pressure to obtain 1 13.6 grams of solid product.
With pyridine; In dichloromethane; at 20℃;
General procedure: 1.607g was added to a 100mL round bottom flask with a magnetic stir bar.15.0 mmol of toluidine, 50.0 mL of CH 2 Cl 2 and 4.170 mL, 30.0 mmol of Et 3 N,Finally, 1.273 mL, 18.0 mmol of acetyl chloride was added, and the reaction mixture was stirred at room temperature with a magnetic stirrer;TLC showed that after the consumption of p-toluidine was completed, the reaction was quenched with 100 mL of saturated NaHCO3 solution.It was then extracted 3 times with 100.0 mL of CH 2 Cl 2 and the combined organic phases were washed twice with 50 mL of brine.The solid obtained by distilling off the organic solvent was washed with a 5:1 mixture of petroleum ether/ethyl acetate to give a white solid p-methylacetanilide;
With dipotassium peroxodisulfate; In water; at 100℃; for 0.166667h;Microwave irradiation; Green chemistry;
General procedure: Amide (1.0 mmol), amine (1.0 mmol) and K2S2O8 (1.5 mmol) were charged in microwave vial added water (2.0 mL), the reaction mixture was treated at 100C and 100W for 10 min. After the complete conversion (by TLC) of the amine, distilled water (10 mL) was added and extracted with ethyl acetate (2 ×10 mL). The combined organic phase was dried over Na2SO4, and then concentrated using rotary vacuum evaporator. The crude product was purified by column chromatography (30% Ethyl acetate/hexane) to get pure compound.
65%
With graphene oxide; at 150℃; for 24h;
General procedure: In a typical procedure, a mixture of amine (1 mmol), amide (1 mmol) and 50 mg GO was taken in a round-bottom flask (50 mL) and stirred the mixture using a magnetic stirring bar under open air at 150 C for 24 h. After the reaction was completed, ethyl acetate (5 mL) was added to the reaction mixture and the catalyst was filtered off. The filtered catalyst was further washed with ethyl acetate and the combined organic layer was evaporated to afford nearly pure product. The residue was further purified by passing through a silica gel columnand eluting with ethyl acetate petroleum ether mixture. All products were characterized by spectral data as well as melting points (for solid compounds).
General procedure: Dimethylformamide (12 mmol, 3 equiv.) was cooled at 0C in a round flask equipped with a drying tube and phosphorus pentachloride (18 mmol, 4.5 equiv.) was added slowly and the mixture was stirred for 15 minutes keeping the temperature below 0C. To this solution was added in a portion the corresponding acetanilide (4 mmol, 1 equiv.) and the reaction mixture was heated under reflux and stirring for the appropiate time depending of the acetanilide. The resulted mixture was cooled to 0C and the solution was poured slowly into ice-water and stirring for ten minutes, obtaining a yellow solid which was filtered, washed several time with cold water and dried under vacuum. The 2-chloroquinoline-3-carbaldehydes were recrystallized according to the literature.
68%
INTERMEDIATE 322-Chloro-8-methylquinoline-3-carbaldehydeN,N-Dimethylformamide (51.8 mL, 668 mmol) was added portionwise over 15 minutes, with stirring, to phosphorus oxychloride (175 mL, 1.87 mol) at 0C. The reaction mixture was allowed to warm to room temperature and treated with Intermediate 31 (39.8 g, 267 mmol), then heated to 80C and stirred for 72 h. The reaction mixture was cooled to room temperature, then carefully poured portionwise into a vigorously stirred mixture of ice-water. The ice-water mixture was allowed to warm to room temperature over 30 minutes, then filtered. The precipitate was washed with water and dried under vacuum. The title compound (37.3 g, 68%>) was obtained as a cream-coloured solid. deltaEta (CDC13) 10.50 (s, 1H), 8.73 (s, 1H), 7.83 (d, J 8.1 Hz, 1H), 7.76-7.72 (m, 1H), 7.55 (dd, J 7.9, 7.3 Hz, 1H), 2.81 (s, 3H). LCMS (ES+) 206 (M+H)+, RT 1.54 minutes.
37%
A solution of phosphoryl trichloride (62.4 ml_, 700.0 mmol) in N,N- dimethylformamide (19.2 ml_, 250.0 mmol) was cooled to 0 0C and stirred for 30 min under nitrogen. To this solution N-O-tolylacetamide (14.9 g, 100.0 mmol) was added at 20 0C and the resulted mixture was stirred for 30 min under nitrogen. The temperature of the reaction mixture was slowly raised to 80 0C and stirred for 20 h under nitrogen. Yellow solid precipitated out upon slow addition of crushed ice (300 g) to the reaction mixture. The resulting solid was filtered, washed with water and dried under high vacuum at 60 0C to afford 2-chloro-8-methylquinoline-3-carbaldehyde (7.61 g, 37%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) delta 10.36 (s, 1 H), 8.92 (s, 1 H), 8.08 (d, J = 8.1 Hz, 1 H), 7.82 (d, J = 6.9 Hz, 1 H), 7.61 (t, J = 7.6 Hz, 1 H), 2.65 (s, 3H).
Multi-step reaction with 4 steps
1: glacial acetic acid; calcium chloride / 0 °C / Verseifung des entstandenen Acetylderivats mit alkoholischer Kalilauge
2: hydrochloric acid / Diazotization.Eintragen von Kaliumcuprocyanidloesung in Diazoniumsalzloesung
3: KOH-solution
4: HCl
Multi-step reaction with 4 steps
1: glacial acetic acid; calcium chloride / 0 °C / Verseifung des entstandenen Acetylderivats mit alkoholischer Kalilauge
2: hydrochloric acid / Diazotization.Eintragen von Kaliumcuprocyanidloesung in Diazoniumsalzloesung
3: KOH-solution
4: 140 °C / im Druckrohr
With palladium diacetate; Selectfluor; trifluoroacetic acid; In 1,2-dichloro-ethane; at 20℃; for 8h;
General procedure: A solution of anilides, alkene, Selectfluor, Pd(OAc)2, TFA or methanesulfonic acid in DCE was stirred at room temperature. After the reaction was completed, the mixture was extracted with EtOAc (10 mL * 3). The organics were dried over Na2SO4. Then the solvent was removed under reduced pressure to provide the crude product. The purification was performed by flash column chromatography on silica gel.
With boron trifluoride diethyl etherate; bis-[(trifluoroacetoxy)iodo]benzene; In acetonitrile; at 20℃; for 0.5h;
General procedure: To a stirred solution of anilide 1a (1a-1m, 0.2 mmol) and BF3·OEt2 (0.038 mL, 0.3 mmol) in acetonitrile (1.0 mL) at room temperature, was added PIFA (0.129g, 0.3 mmol) and arylsulfonic acid (0.6 mmol). The resulting mixture was stirred at room temperature for 0.5 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography using petroleum ether/EtOAc as the eluent to afford pure product 2a (2b-2o)
97%
With boron trifluoride diethyl etherate; N-(4-bis(trifluoroacetoxy)iodophenyl)pyridine p-toluenesulfonate; In acetonitrile; at 20℃; for 1h;
Will be 353mg (2.37mmol)2-methylacetanilide (IIIb structure in Table 1) dissolved in 15mLIn water-free acetonitrile,Add 505mg (3.56mmol) BF3·Et2OLewis acid catalyst,2.42 g (3.56 mmol) was added with stirring at room temperature.Oxidant Formula II and 1.35 g (7.11 mmol) of TsOH·H2O,Continue stirring at room temperature,The TLC method tracks the progress of the reaction.After the reaction,The acetonitrile was removed by rotary evaporation.The residual solid was washed with diethyl ether.Filter and recycle the filter cake,The resulting filter cake was washed three more times with diethyl ether.Combine the filtrate,The residual solid after concentration of the filtrate is washed with water.Remove excess p-toluenesulfonic acid,The solid was separated by silica gel column chromatography.Eluent: petroleum ether / ethyl acetate = 5:1,Got a white solid,Has the IVb structure as shown in Table 1,The yield was 97%.
With tris(2,4-pentanedionato)ruthenium(III); methanesulfonic acid; hydrogen; [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine] In tetrahydrofuran at 200℃; for 16h; Autoclave; Inert atmosphere;
With 2,2'-azobis(isobutyronitrile); oxygen; In acetonitrile; at 80℃; for 24h;Sealed tube;
General procedure: A sealed tube was equipped with a magnetic stir bar was charged with 1,3-di-ketone 1a (0.075 g, 0.75 mmol), aniline 2a (0.0232 g, 0.25 mmol), AIBN (0.0164 g, 0.0001 mmol), and acetonitrile (1.0 mL). The above reaction mixture was stirred at 80C under O2 atmosphere for 24 h. After completion of the reaction, the reaction was then cooled to room temperature, mixture was diluted with ethyl acetate. After removal of the solvent under reduced pressure the left out residue was purified by column chromatography using silica gel with hexane and ethyl acetate as eluent to get 3a in 82% yield (0.0278 g). The spectral data was well matched with reported values. The above procedure is followed for the synthesis of all products reported in this manuscript.
With O-trifluorobenzenesulfonyl-acetohydroxamic acid ethyl ester; toluene-4-sulfonic acid; In water; acetonitrile; at 20℃;Inert atmosphere;
General procedure: Table 2 shows the results of examining various catalysts in the reaction of synthesizing N- (2-naphthyl) acetamide from 2-acetonaphthone. Examples of the acid catalyst include hydrochloric acid, sulfuric acid, methanesulfonic acid, tosylic acid monohydrate, trifluoromethanesulfonic acid, bistrifluoromethanesulfonimide, boron trifluoride diethyl ether complex, scandium (III) trifluoromethanesulfonate, trifluoromethanesulfone Iron (III) oxide, trifluoromethanesulfoCopper (II) trifluoromethanesulfonate, bismuth trifluoromethanesulfonate (III), titanium tetrachloride and iron trichloride have excellent effects (Entries 2 to 14).
With hydroxylamine hydrochloride; trifluoroacetic acid; at 70℃; for 16h;Inert atmosphere;
General procedure: In a typical experiment a glass reactor equipped with magneticbar was charge with 1.5 mmol of the selected ketone or aldehyde,4.4 mmol of hydroxylamine hydrochloride and 22 mmol oftrifluoroacetic acid under inert atmosphere of nitrogen. The reactiontime was computed after the heating fluid starts to circulate in the reactor jacket. The reaction mixture was heated at 70 C for 16 h, andthen cooled down.Products were isolated after distillation of the TFA (at 40 C and250 Pa of pressure) and in a rotary evaporator, washed with coldwater and recrystallized from hexane or light petroleum ether.
With carbon monoxide; palladium diacetate In acetonitrile at 60℃;
4.5 General procedure for the synthesis of acetanilides from guanidines
General procedure: To a screw-cap reaction tube was added symmetrical N,N′-disubstituted guanidines 1a (0.2 mmol), Pd(OAc)2 (5 mol%, 2.2 mg), Cu(OAc)2 (0.2 mmol, 36.3 mg). The reaction tube was evacuated and back-filled with CO (three times, balloon). MeCN (2mL) was added using a syringe and the mixture was heated to the desired temperature with use of an oil bath. When the reaction was completed (detected by TLC), the mixture was cooled to room temperature and vented to discharge the excess CO. The solvent was concentrated by evaporation in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desired product amides 2a with petroleum ether/ethyl acetate as the eluent.
With tris(2,4-pentanedionato)ruthenium(III); ytterbium(III) trifluoromethanesulfonate nonohydrate; hydrogen; [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine] In 1,4-dioxane at 150℃; for 45h; Autoclave;
N-{2-methyl-6-[(E)-2-(2-oxo-1,3-dioxolan-4-yl)ethenyl]phenyl}acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
General procedure: To a 30 mL test tube was added anilide 4 (0.300 mmol), AgSbF6 (10.3mg, 0.0300 mmol), Rh(III) complex 1 (6.4 mg, 0.00750 mmol), Cu(OAc)2?H2O (12.0 mg, 0.0600mmol), and acetone (1.5 mL) under air. After stirring at room temperature for 30 minutes, alkene 6(0.300 mmol) was added to the mixture. The mixture was sealed and stirred at room temperaturefor 72 hours. The resulting mixture was filtered through a silica gel pad and washed withCHCl3/MeOH (4:1). The filtrate was concentrated under reduced pressure and the residue waspurified by a silica gel preparative thin layer chromatography (CHCl3/MeOH) to give olefinatedproduct 7.
Stage #1: N-(2-methylphenyl)acetamide With iodine; triethylamine; triphenylphosphine In dichloromethane at 0℃; for 0.5h;
Stage #2: 2-carbomethoxyaniline In dichloromethane at 0 - 20℃;
N-(2-methyl-4-(N-(phenylsulfonyl)phenylsulfonamido)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With [bis(acetoxy)iodo]benzene; In tetrahydrofuran; at 25℃; for 8h;Sealed tube; Neutral conditions;
A vial containing a stirring bar and sealed with a Teflon-linedcap was charged with a mixture of 2-methylacetanilide (1a, 0.2mmol), PhI(OAc)2 (0.4 mmol), and HN(SO2Ph)2 (2a, 0.3mmol).THF (2 mL) was added, and the mixture was stirred at 25 C for8 h. The mixture was then added to H2O (15 mL), and the resultingmixture was extracted with EtOAc (3 × 10 mL). The organiclayers were combined, dried (MgSO4), filtered, and concentratedin vacuo. The residue was purified by column chromatography[silica gel, EtOAc-PE (2:1)] to give a white solid; yield: 64.0 mg(72%); mp 184-186 C.1H NMR (400 MHz, CDCl3): delta = 2.14 (s, 3 H), 2.18 (s, 3 H), 6.79-6.84 (m, 2 H), 7.21 (s, 1 H), 7.54 (t, J = 7.54 Hz, 4 H), 7.67 (t, J =7.36 Hz, 2 H), 7.92 (d, J = 7.92 Hz, 4 H), 7.98 (d, J = 8.48 Hz, 1 H).13C NMR (100 MHz, CDCl3): delta = 7.63, 24.57, 122.40, 128.52,129.06, 129.81, 130.09, 133.23, 133.53, 134.03, 137.86, 139.30,168.52. HRMS-ESI: m/z [M + H]+ calcd for C21H21N2O5S2:445.0886; found: 445.0884.
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