* 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.
With 2.9-dimethyl-1,10-phenanthroline; oxygen; copper (I) acetate; silver sulfate; sodium chloride In dimethyl sulfoxide at 160℃; for 24 h; Schlenk technique
Silak reaction tube equipped with a magnetic stirrer was charged with 6.2 mg of silver sulfate,36.3 mg of copper acetate, 12.5 mg of 2,9-dimethyl-1,10-o-phenanthroline,36.2 mg of 2-nitro-4-methylbenzoic acid and 17.5 mg of sodium chloride4 mL of dimethyl sulfoxide.The reaction was heated at 160 ° C for 24 hours in the presence of oxygen.After the reaction was completed, distilled water was added to quench the reaction,Extraction with ethyl acetate 3 times, each time 10mL,The combined organic phases are concentrated,17.5 mg of 2-nitro-4-methylchlorobenzene was obtained,The yield is 51percent.
Reference：
[1] Patent: CN107325002, 2017, A, . Location in patent: Paragraph 0091
[2] Organic and Biomolecular Chemistry, 2018, vol. 16, # 30, p. 5416 - 5421
[3] Journal of Organic Chemistry, 2016, vol. 81, # 7, p. 2794 - 2803
3
[ 27329-27-7 ]
[ 2305-36-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
With palladium 10% on activated carbon; hydrogen In ethanol at 20℃;
Toasolutionof2-nitro-4-methylbenzoicacid(500mg,2.76mmol)inEtOH(5.50mL) was added 10percent palladium on charcoal (8percent w/w). The reaction mixture wassequentiallyevacuatedandpurgedwithhydrogenthreetimesthenstirredunderhydrogenat approximately atmospheric pressure and room temperature. The reaction wasmonitored by TLC and upon completion the catalyst was filtered off through a pad ofCeliteTM.Thesolventwasremovedinvacuotogive2-amino-4-methylbenzamide(416mg,2.75mmol,quant.)asawhiteamorphoussolid;mp181–183°C,lit.177–179°C.
Reference：
[1] Synthesis (Germany), 2017, vol. 49, # 1, p. 135 - 144
[2] Organic Letters, 2012, vol. 14, # 6, p. 1444 - 1447
[3] Journal of Organic Chemistry, 2016, vol. 81, # 19, p. 9046 - 9074
[4] American Chemical Journal, 1888, vol. 10, p. 474,483
[5] Chemische Berichte, 1888, vol. 21, p. 1998
[6] Patent: CN105503646, 2016, A, . Location in patent: Paragraph 0004; 0006; 0007
4
[ 27329-27-7 ]
[ 5326-34-1 ]
Yield
Reaction Conditions
Operation in experiment
69%
With 2.9-dimethyl-1,10-phenanthroline; oxygen; copper (I) acetate; silver sulfate; sodium bromide In dimethyl sulfoxide at 160℃; for 24 h; Schlenk technique
Silak reaction tube equipped with a magnetic stirrer was charged with 6.2 mg of silver sulfate,36.3 mg of copper acetate, 12.5 mg of 2,9-dimethyl-1,10-o-phenanthroline,36.2 mg of 2-nitro-4-methylbenzoic acid and 30.9 mg of sodium bromide4 mL of dimethyl sulfoxide.The reaction was heated at 160 ° C for 24 hours in the presence of oxygen.After the reaction was completed, distilled water was added to quench the reaction,Extraction with ethyl acetate 3 times, each time 10mL,The combined organic phases are concentrated,29.8 mg of 2-nitro-4-methylbromobenzene was obtained in a yield of 69percent.
Reference：
[1] Patent: CN107325002, 2017, A, . Location in patent: Paragraph 0091
[2] Organic and Biomolecular Chemistry, 2018, vol. 16, # 30, p. 5416 - 5421
[3] Journal of Organic Chemistry, 2016, vol. 81, # 7, p. 2794 - 2803
5
[ 27329-27-7 ]
[ 35674-27-2 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 30, p. 5416 - 5421
6
[ 27329-27-7 ]
[ 5326-39-6 ]
Yield
Reaction Conditions
Operation in experiment
53%
With 2.9-dimethyl-1,10-phenanthroline; oxygen; copper (I) acetate; silver sulfate; sodium iodide In dimethyl sulfoxide at 160℃; for 24 h; Schlenk technique
Silak reaction tube equipped with a magnetic stirrer was charged with 6.2 mg of silver sulfate,21.8 mg of copper acetate, 12.5 mg of 2,9-dimethyl-1,10-o-phenanthroline,36.2 mg of 2-nitro-4-methylbenzoic acid and 45 mg of sodium iodide4 mL of dimethyl sulfoxide. Heat 160 ° C in the presence of oxygenReaction for 24 hours. After the reaction was completed, distilled water was added to quench the reaction,Extraction with ethyl acetate 3 times, each time 10mL,The combined organic phases were concentrated to give 27.9 mg of 2-nitro-4-methyliodobenzene,The yield is 53percent.
Reference：
[1] Journal of Organic Chemistry, 2016, vol. 81, # 7, p. 2794 - 2803
[2] Patent: CN107325002, 2017, A, . Location in patent: Paragraph 0091
[3] Organic and Biomolecular Chemistry, 2018, vol. 16, # 30, p. 5416 - 5421
7
[ 89-58-7 ]
[ 27329-27-7 ]
Yield
Reaction Conditions
Operation in experiment
75%
With oxygen; sodium hydroxide In ethanol; water at 65℃; for 24 h; Autoclave
1,4-dimethyl-2-nitrobenzene (907 mg, 6 mmol, 1.0 eq)Sodium hydroxide (1.8 g, 45.0 mmol, 7.5 eq)Was added to a 100 ml autoclave,10 ml of 80percent (v / v) ethanol (8 ml of ethanol, 2 ml of water)After charging oxygen three times,Passing oxygen gas (pressure 1.8MPa),In the oil bath temperature control 65 for 24 hoursAfter the reaction was diluted with methanol,Neutral and PH = 2-3,The solvent was removed under reduced pressure,After adding ethyl acetate, the mixture was dried and filtered.Separated by chromatography,1,4-dimethyl-2-nitrobenzene recovered 129mg (0.85mmol),The conversion of 1,4-dimethyl-2-nitrobenzene was 86percent4-methyl-2-nitrobenzoic acid was obtained811 mg (4.48 mmol) in 75percent yield
Reference：
[1] Patent: CN106995374, 2017, A, . Location in patent: Paragraph 0031; 0032; 0033; 0034; 0035; 0036; 0037-0042
[2] Journal of Organic Chemistry, 2018, vol. 83, # 15, p. 8092 - 8103
Reference：
[1] Chemische Berichte, 1888, vol. 21, p. 1993
[2] American Chemical Journal, 1888, vol. 10, p. 474,483
[3] Justus Liebigs Annalen der Chemie, 1891, vol. 266, p. 218
[4] Journal of the American Chemical Society, 1952, vol. 74, p. 4296,4301
14
[ 544-92-3 ]
[ 89-60-1 ]
[ 27329-27-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2002, vol. 10, # 12, p. 3807 - 3815
15
[ 33757-49-2 ]
[ 27329-27-7 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 32, p. 9902 - 9905
16
[ 874-60-2 ]
[ 27329-27-7 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 32, p. 9902 - 9905
17
[ 106-42-3 ]
[ 7697-37-2 ]
[ 100-21-0 ]
[ 27329-27-7 ]
[ 99-94-5 ]
Reference：
[1] Chlorine Alkali News, 1953, # 11, p. 44[2] Chem.Abstr., 1955, p. 7523
18
[ 27329-27-7 ]
[ 81335-87-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 19, p. 5810 - 5831
[2] Journal of Organic Chemistry, 2016, vol. 81, # 19, p. 9046 - 9074
[3] Synlett, 2017, vol. 28, # 14, p. 1724 - 1728
With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; under 760.051 Torr;
Toasolutionof2-nitro-4-methylbenzoicacid(500mg,2.76mmol)inEtOH(5.50mL) was added 10% palladium on charcoal (8% w/w). The reaction mixture wassequentiallyevacuatedandpurgedwithhydrogenthreetimesthenstirredunderhydrogenat approximately atmospheric pressure and room temperature. The reaction wasmonitored by TLC and upon completion the catalyst was filtered off through a pad ofCeliteTM.Thesolventwasremovedinvacuotogive2-amino-4-methylbenzamide(416mg,2.75mmol,quant.)asawhiteamorphoussolid;mp181-183C,lit.177-179C.
With iron(III) chloride; hydrazine hydrate; sodium hydroxide; In water; at 70℃; for 1h;
15 g of 3-nitro-4-methylbenzoic acid and 9 g of sodium hydroxide were weighed into a 500 mL three-necked flask and 100 mLDistilled water, and then add 2g of ferric chloride and 5g of activated carbon, water bath heated to 70 , and then dropping 12g hydrazine hydrateReaction 1h, filtered to obtain light yellow powder;Into a 500 mL three-necked flask, 15 g of the above-prepared light was addedYellow powder and 1 g of pyridine and 100 mL of acetonitrile were added and the temperature was raised to 50 C while stirring.Dropping speed was controlled so that the dropping was completed in 1 hour, and the reaction was kept for 4 hours and cooled to room temperature.To the aboveStep in the three-neck flask by adding 1g mass concentration of 80% acetic acid solution, start the mixer,Stirring at 300r / min for 20min. After stirring, the mixture is poured into a refluxing device and heated to60 C, and 10 mL of a 40% aqueous solution of methylamine was dropwise added thereto to control the dropping speed,30min within the drop is completed, insulation reaction 1h;To the mixed solution after the completion of the above reaction, 50 mL of distilled water was addedWater, stirring 10min and then into the separatory funnel, put it aside 1h layered, separated from the organic phase, spare;The organic phase was transferred to a 500 mL three-necked flask, heated in a water bath to 40 C,20g of sulfonyl chloride and 10mL of acetonitrile were added under stirring. The dropping rate was controlled so as to be added dropwise within 1 hour, and the reaction was kept for 3 hours.To room temperature, filtered to filter residue, into the oven, at 105 drying in the 3-amino-6-chloro-N,Methylbenzamide.
With pyridine; In tetrahydrofuran; dichloromethane; N,N-dimethyl-formamide;
26b N-(2-Cyanophenyl)-4-methyl-2-nitrobenzamide To a stirred suspension of <strong>[27329-27-7]4-methyl-2-nitrobenzoic acid</strong> (5 g) in THF (30 ml) was added dropwise a solution of oxalyl chloride (2.7 ml) in DMF (0.1 ml) and the mixture was stirred at room temperature for 17 hours and concentrated to dryness. To an ice-cooled, stirred solution of 2-aminobenzonitrile (3.26 g) and pyridine (2.5 ml) in methylene chloride (30 ml) was added dropwise a solution of the resulting acid chloride in methylene chloride (30 ml) and the mixture was stirred at room temperature for 4 hours and concentrated to dryness. The residue was extracted with a mixture of ethyl acetate-THF. The extract was washed with dilute hydrchloric acid and water, dried and evaporated. Recrystallization from ethyl acetate-ether afforded colorless needles (7.4 g, 95%), m.p. 230-232 C. 1 H-NMR(200 MHz,DMSO-d6) delta: 2.49(3H,s), 7.39-7.48(1H,m), 7.65-7.90(2H,m), 8.02(1H,s), 10.91(1H,s)
26a 4-Methyl-2-nitrobenzoic acid A mixed solution of <strong>[26830-95-5]2-nitro-4-methylbenzonitrile</strong> (15.8 g) in a mixture of 65% sulfuric acid and acetic acid (150 ml) was heated under reflux for 17 hours. After concentration, the residue was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. Recrystallization of crystals from ether-hexane afforded colorless crystals (16.5 g, 94%), m.p. 156-157 C. 1 H-NMR(200 MHz,DMSO-d6) delta: 2.44(3H,s), 7.56-7.61(1H,m), 7.75-7.79(2H,m)
CuCN; In aq H2 SO4; benzonitrile; N,N-dimethyl-formamide;
EXAMPLE C Preparation of 2-Nitro-p-Toluic Acid A slurry of 100 g of <strong>[89-60-1]4-chloro-3-nitrotoluene</strong> and 80 g of copper (I) cyanide in 500 ml of DMF was refluxed for 12 hours. An additional 20 g of CuCN was added and the reaction refluxed another 4 hours. Ether was added and the ether phase decanted from the dark oil. The ether phase was dried with molecular sieves, filtered and the solvent removed under reduced pressure to yield an orange-brown semi-solid. The semi-solid product was triturated with hexane. The hexane was evaporated off under reduced pressure to yield 30.5 g of the desired product which was used without further purification. The benzonitrile (10 g) was refluxed for 90 min. in 50% aq H2 SO4. TLC indicated complete hydrolysis of the nitrile. The reaction was pured onto ice and extracted with ether. The ether phase was washed with saturated brine, dried over molecular sieves, filtered and the solvent removed under reduced pressure to yield 4.2 g of the desired product, IR (Nujol) 1695 (C=O--acid), NMR (CDCl3 /DMSO/TMS) 2.52 ppm, (S, 3H), 7.80 ppm, (M, 3H). This material was used without further purification in the preparation of the corresponding benzoyl chloride. IR (neat) 1775 cm-1 (C=O) acid halide.
General procedure: To a solution of the substituted 2-nitrobenzoic acid (1 eq.) in dried THF (0.13 M), at room temperatureand under argon, was added dropwise borane dimethylsulfide complex (3.0 eq.). The resulting solutionwas then refluxed over 12 h. After allowed to reach room temperature, an aqueous solution ofhydrochloric acid (3M) was added dropwise into this reaction system until effervescence was nolonger observed. The resulting mixture was then extracted with 3 × 30 mL of ethyl acetate. Thecombined organic phases were washed with a saturated aqueous solution of Na2CO3 followed by brine.The resulting organic phase was dried over MgSO4 and filtered. The filtrate was concentrated in vacuoto afford the product 12.
98%
With borane-THF; In tetrahydrofuran; for 3h;Heating / reflux;
To a stirred solution of <strong>[27329-27-7]4-methyl-2-nitrobenzoic acid</strong> (5 g, 27.6 mmol) in tetrahydrofuran (THF) (27 ml.) was added borane tetrahydrofuran complex (35.9 ml_, 35.9 mmol) and the mixture stirred at reflux for 3 hours. After cooling, the reaction mixture was extracted with water and DCM. The combined organic layers were dried over MgSO4 and then evaporated to dryness to give the alcohol (D139) as a pale yellow solid (4.52 g, 98%) which was used without further purification.1H-NMR (CDCI3) delta: 2.45 (s, 3H), 4.89-4.91 (d, 2H), 7.44-7.48 (dd, 1 H), 7.55-7.59 (d, 1 H), 7.90-7.91 (s,1 H).LC/MS Retention time = 2.67 min. (100%) (no ionisation)
89%
With dimethylsulfide borane complex; In tetrahydrofuran; at 80℃;
Borane dimethyl sulfide complex (9.9 mL; 19.87 mmol) was added dropwise to asolution of <strong>[27329-27-7]4-methyl-2-nitrobenzoic acid</strong> (3 g; 16.56 mmol) in THF (18 mL) and the mixture was stirred at 80C overnight. The mixture was cooled down to rt and a 3Maqueous solution of HC1 was added dropwise into the reaction system until effervescence was no longer observed.The mixture was extracted with EtOAc. The organic layer was washed with a saturated aqueous solution of Na2CO3 and brine, dried over MgSO4, filtered and removed under reduced pressure to give 2.46 g (89%) ofintermediate 24.
84%
With borane-THF; In tetrahydrofuran; at 0 - 30℃; for 1.66667h;Inert atmosphere;
General procedure: To a solution of 6-chloroanthranilic acid (1.5 g, 8.74 mmol) in THF (5 mL) was added dropwise 1.08 M borane-tetrahydrofuran complex in THF (24.3 mL, 26.2 mmol) at 0 C under an Ar atmosphere for 10 min. After 1.5 h with stirring at 30 C, the solution was cooled at 0 C, added aqueous THF (THF/H2O = 1:1, 60 mL) and potassium carbonate, and extracted with diethyl ether three times. The combined organic extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was crystallized from AcOEt to give 1a (1.2 g, 88%) as a white needle crystal.
N-(4-fluorobenzyl)-4-methyl-2-nitrobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
General procedure: Dicyclohexylcarbodiimide (5.00 mmol) and a nitrobenzoic acid(5.55 mmol) were dissolved in DCM (20 mL) and allowed to stir for 5 min before the addition of a primary amine (5.55 mmol) and dimethylaminopyridine (0.055 mmol). The coupling reaction was allowed to proceed for 16 h, after which the DCM was removed in vacuo. The solid residue was resuspended in ethylacetate and filtered through a silica gel plug to remove the dicyclohexylurea byproduct. The filtrate was then concentrated and the desired nitrobenzamide isolated by silica gel flash chromatography using a hexanes/ethyl acetate solvent gradient.
With 2.9-dimethyl-1,10-phenanthroline; oxygen; copper diacetate; silver sulfate; In dimethyl sulfoxide; at 140℃; under 760.051 Torr; for 20h;Schlenk technique; Green chemistry;
General procedure: An oven-dried Schlenk tube equipped with a stir bar was charged with aryl carboxylic acid (0.2 mmol), Ag2SO4 (6.2 mg, 0.02 mmol, 0.1 equiv.), Cu(OAc)2 (36.3 mg, 0.2 mmol, 1 equiv.), K4Fe(CN)6 (13.2 mg, 0.036 mmol, 0.18 equiv.) and 2,9-dimethyl-1,10-phenanthrolinium (12.5 mg, 0.06 mmol, 0.3 equiv.). The tube was fitted with a rubber septum, and then it was evacuated and refilled with dioxygen three times. Under dioxygen, DMSO (4 mL) was added via syringe. The rubber septum was replaced with a Teflon screwcap under dioxygen flow, and the Schlenk tube was pressurized to 1 atm. With stirring, the reaction mixtures were heated at 140 C for the indicated amount of time (unless otherwise specified). After cooling to room temperature, the reaction mixtures were diluted with ether (10 mL) and filtered through a pad of silica gel that was then washed with ether (10 mL *3). The combined organic phase was washed with brine (20 mL *2), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified using flash column chromatography over silica gel to provide the corresponding product with ethyl acetate/hexane as eluent.
With 2.9-dimethyl-1,10-phenanthroline; oxygen; copper (I) acetate; silver sulfate; sodium chloride; In dimethyl sulfoxide; at 160℃; for 24h;Schlenk technique;
Silak reaction tube equipped with a magnetic stirrer was charged with 6.2 mg of silver sulfate,36.3 mg of copper acetate, 12.5 mg of 2,9-dimethyl-1,10-o-phenanthroline,36.2 mg of 2-nitro-4-methylbenzoic acid and 17.5 mg of sodium chloride4 mL of dimethyl sulfoxide.The reaction was heated at 160 C for 24 hours in the presence of oxygen.After the reaction was completed, distilled water was added to quench the reaction,Extraction with ethyl acetate 3 times, each time 10mL,The combined organic phases are concentrated,17.5 mg of 2-nitro-4-methylchlorobenzene was obtained,The yield is 51%.
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