* 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] Zhurnal Obshchei Khimii, 1931, vol. 1, p. 193,195[2] Chem. Zentralbl., 1931, vol. 102, # II, p. 3200
[3] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 20, p. 1371
[4] Patent: US1924443, 1929, ,
[5] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 20, p. 1370,1376
3
[ 108-88-3 ]
[ 95-46-5 ]
[ 60956-23-2 ]
Reference：
[1] Journal of the American Chemical Society, 1916, vol. 38, p. 2548
4
[ 106-49-0 ]
[ 60956-23-2 ]
Reference：
[1] Journal of Organic Chemistry, 1977, vol. 42, p. 2426 - 2431
5
[ 583-68-6 ]
[ 60956-23-2 ]
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 2837,2842
[2] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 153[3] Justus Liebigs Annalen der Chemie, 1878, vol. 192, p. 202
6
[ 103-89-9 ]
[ 60956-23-2 ]
Reference：
[1] Journal of the Chemical Society, 1914, vol. 105, p. 514
[2] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 153[3] Justus Liebigs Annalen der Chemie, 1878, vol. 192, p. 202
7
[ 106-49-0 ]
[ 106-38-7 ]
[ 60956-23-2 ]
[ 73557-59-2 ]
Reference：
[1] Journal of Organic Chemistry, 1980, vol. 45, # 13, p. 2570 - 2575
8
[ 106-38-7 ]
[ 60956-23-2 ]
[ 31543-75-6 ]
Reference：
[1] Journal of the Chemical Society, 1892, vol. 61, p. 1029
[2] Justus Liebigs Annalen der Chemie, 1875, vol. 176, p. 286,288
9
[ 53078-85-6 ]
[ 60956-23-2 ]
Reference：
[1] Journal of the Chemical Society, 1914, vol. 105, p. 514
10
[ 7726-95-6 ]
[ 7697-37-2 ]
[ 108-88-3 ]
[ 95-46-5 ]
[ 60956-23-2 ]
Reference：
[1] Journal of the American Chemical Society, 1916, vol. 38, p. 2548
11
[ 10035-10-6 ]
[ 60956-23-2 ]
Reference：
[1] Chem. Zentralbl., 1899, vol. 70, # II, p. 1050
12
[ 698-64-6 ]
[ 7726-95-6 ]
[ 60956-23-2 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1880, vol. 201, p. 243
13
[ 106-38-7 ]
[ 7726-95-6 ]
[ 7553-56-2 ]
[ 60956-23-2 ]
[ 31543-75-6 ]
Reference：
[1] Journal of the Chemical Society, 1892, vol. 61, p. 1029
14
[ 106-38-7 ]
[ 60956-23-2 ]
[ 31543-75-6 ]
Reference：
[1] Journal of the Chemical Society, 1892, vol. 61, p. 1029
[2] Justus Liebigs Annalen der Chemie, 1875, vol. 176, p. 286,288
15
[ 106-38-7 ]
[ 7726-95-6 ]
[ 7553-56-2 ]
[ 60956-23-2 ]
[ 31543-75-6 ]
Reference：
[1] Journal of the Chemical Society, 1892, vol. 61, p. 1029
16
[ 60956-23-2 ]
[ 64382-93-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 13, p. 2843 - 2866
[2] Journal of the American Chemical Society, 1948, vol. 70, p. 2837,2842
[3] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1977, vol. 15, p. 386 - 387
[4] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 11, p. 2969 - 2973
17
[ 60956-23-2 ]
[ 101580-70-5 ]
Yield
Reaction Conditions
Operation in experiment
77%
With nitric acid In water
Step A: 1,2-Dibromo-4-methyl-5-nitrobenzene 3,4-dibromotoluene (108.11 mL, 800 mmol) was added dropwise over 4 hours to nitric acid (90percent, 280 mL, 6000 mmol) that was cooled to 0° C. under a nitrogen atmosphere with 10 mechanical stirring. The internal temperature of the mixture was maintained below 10° C. during the addition and was stirred for 1 hour at 0° C. after completion of addition. Water (840 mL) was added drop-wise to the mixture maintaining the internal temperature below 10° C. The crude product was collected by filtration and was washed with water (5*500 mL) to remove the excess nitric acid. The solids were dried under high vacuum and purified by recrystallization from ethanol (800 mL) to produce 180.9 g (77percent yield) of the desired product as a solid. 1H NMR (400 mHz, CDCl3) δ 8.24 (s, 1H), 7.64 (s, 1H), 2.55 (s, 3H)
77%
With nitric acid In water at 0 - 10℃; for 5 h;
Step A: 1,2-Dibromo-4-methyl-5-nitrobenzene
3,4-dibromotoluene (108.11 mL, 800 mmol) was added dropwise with mechanical stirring over 4 hours to nitric acid (90percent, 280 mL, 6000 mmol) that was cooled to 0° C. under a nitrogen atmosphere. The internal temperature of the mixture was maintained below 10° C. during the addition and the reaction mixture was stirred for 1 hour at 0° C. after completion of addition. Water (840 mL) was added drop-wise to the mixture while maintaining the internal temperature below 10° C. The crude product was collected by filtration and washed with water (5*500 mL) to remove the excess nitric acid. The solids were dried under high vacuum and purified by recrystallization from ethanol (800 mL) to provide 180.9 g (77percent yield) of the desired product as a solid. 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.64 (s, 1H), 2.55 (s, 3H).
77%
With nitric acid In water at 0 - 10℃; for 5 h;
Example 16; Preparation of (-SV5-(2,4-difluorophenoxy')-l -isobutyl-N-(2-oxopyrrolidin-3-yr)-lH- indazole-6-carboxamide (Ia); [00251] Step A: l,2-Dibromo-4-methyl-5-nitrobenzene: 3,4-dibromotoluene (108.11 mL, 800 mmol) was added dropwise- with mechanical stirring over 4 hours to nitric acid (90percent, 280 mL, 6000 mmol) that was cooled to 0 0C under a nitrogen atmosphere. The internal temperature of the mixture was maintained below 10 0C during the addition and the reaction mixture was stirred for 1 hour at 0 0C after completion of addition. Water (840 mL) was added drop- wise to the mixture while maintaining the internal temperature below 10 0C. The crude product was collected by filtration and washed with water (5 x 500 mL) to remove the excess nitric acid. The solids were dried under high vacuum and purified by recrystallizaton from ethanol (800 mL) to provide 180.9 g (77percent yield) of the desired product as a solid. 1H NMR (400 MHz5 CDCl3) δ 8.24 (s, IH), 7.64 (s, IH), 2.55 (s, 3H).
Reference：
[1] Patent: US2004/192653, 2004, A1,
[2] Patent: US2006/264431, 2006, A1, . Location in patent: Page/Page column 23
[3] Patent: WO2007/126871, 2007, A1, . Location in patent: Page/Page column 65
[4] Chemische Berichte, 1881, vol. 14, p. 418
[5] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 153[6] Justus Liebigs Annalen der Chemie, 1878, vol. 192, p. 202
Step A: 1,2-Dibromo-4-methyl-5-nitrobenzene <strong>[60956-23-2]3,4-dibromotoluene</strong> (108.11 mL, 800 mmol) was added dropwise over 4 hours to nitric acid (90%, 280 mL, 6000 mmol) that was cooled to 0 C. under a nitrogen atmosphere with 10 mechanical stirring. The internal temperature of the mixture was maintained below 10 C. during the addition and was stirred for 1 hour at 0 C. after completion of addition. Water (840 mL) was added drop-wise to the mixture maintaining the internal temperature below 10 C. The crude product was collected by filtration and was washed with water (5*500 mL) to remove the excess nitric acid. The solids were dried under high vacuum and purified by recrystallization from ethanol (800 mL) to produce 180.9 g (77% yield) of the desired product as a solid. 1H NMR (400 mHz, CDCl3) delta 8.24 (s, 1H), 7.64 (s, 1H), 2.55 (s, 3H)
77%
With nitric acid; In water; at 0 - 10℃; for 5h;
Step A: 1,2-Dibromo-4-methyl-5-nitrobenzene <strong>[60956-23-2]3,4-dibromotoluene</strong> (108.11 mL, 800 mmol) was added dropwise with mechanical stirring over 4 hours to nitric acid (90%, 280 mL, 6000 mmol) that was cooled to 0 C. under a nitrogen atmosphere. The internal temperature of the mixture was maintained below 10 C. during the addition and the reaction mixture was stirred for 1 hour at 0 C. after completion of addition. Water (840 mL) was added drop-wise to the mixture while maintaining the internal temperature below 10 C. The crude product was collected by filtration and washed with water (5*500 mL) to remove the excess nitric acid. The solids were dried under high vacuum and purified by recrystallization from ethanol (800 mL) to provide 180.9 g (77% yield) of the desired product as a solid. 1H NMR (400 MHz, CDCl3) delta 8.24 (s, 1H), 7.64 (s, 1H), 2.55 (s, 3H).
77%
With nitric acid; In water; at 0 - 10℃; for 5h;
Example 16; Preparation of (-SV5-(2,4-difluorophenoxy')-l -isobutyl-N-(2-oxopyrrolidin-3-yr)-lH- indazole-6-carboxamide (Ia); [00251] Step A: l,2-Dibromo-4-methyl-5-nitrobenzene: <strong>[60956-23-2]3,4-dibromotoluene</strong> (108.11 mL, 800 mmol) was added dropwise- with mechanical stirring over 4 hours to nitric acid (90%, 280 mL, 6000 mmol) that was cooled to 0 0C under a nitrogen atmosphere. The internal temperature of the mixture was maintained below 10 0C during the addition and the reaction mixture was stirred for 1 hour at 0 0C after completion of addition. Water (840 mL) was added drop- wise to the mixture while maintaining the internal temperature below 10 0C. The crude product was collected by filtration and washed with water (5 x 500 mL) to remove the excess nitric acid. The solids were dried under high vacuum and purified by recrystallizaton from ethanol (800 mL) to provide 180.9 g (77% yield) of the desired product as a solid. 1H NMR (400 MHz5 CDCl3) delta 8.24 (s, IH), 7.64 (s, IH), 2.55 (s, 3H).
With sodium nitrite; In concentrated hydrobromic acid; water;
The above aminotoluene (24 g), was stirred in concentrated hydrobromic acid (230 ml) at 0 C. Sodium nitrite (9.8 g) (ex BDH) in water (35 ml) was added keeping the reaction temperature between 0 and 5. The mixture was poured onto cuprous bromide (37 g) (ex BDH) in water (230 ml) and hydrobromic acid at 50. After 2 hours at 50 and 18 hours at 25, water was added and the mixture worked up in the usual manner. Purification by distillation (100, 0.5 mmHg) gave 3,4-dibromotoluene (12.7 g). NMR 1 H 7.53(2H,m), 6.95(1H,dd), 2.30(3H,s).
With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃; for 20h;
General procedure: A 12 mL vial was charged with Pd(OAc)2 (2 mol%), BuPAd2 (6 mol%), and a stirring bar. Then, 2 ml dioxane and 1 mmol of bromobenzene were injected by syringe. The vial (or several vials) was placed in an alloy plate, which was transferred into a 300 mL autoclave of the 4560 series from Parr Instruments under argon atmosphere. After flushing the autoclave three times with NH3, a pressure of 2 bar NH3 and 2 bar CO was adjusted at ambient temperature. Then, the reaction was performed for 16 hours at 100 oC. After the reaction is finished, the autoclave was cooled down to room temperature and the pressure was released carefully. Then, CuI (5 mol%), DMEDA (10%), K2CO3 (3 mmol) and 1,2-dibromobenzene were added in under air, the vial was closed and heated to 110oC for 20 hours. The reaction mixture cooled down to room temperature. The solution was extracted 3-5 times with 2-3 ml of ethyl acetate from aqua solution. After evaporation of the organic solvent the residue was adsorbed on silica gel and the crude product was purified by column chromatography using n-heptane/AcOEt (20:1) as eluent.
5-methyl-2-(3-(2-oxoazepan-1-yl)propyl)isoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; carbon monoxide; 1,3-bis-(diphenylphosphino)propane; water; In water; toluene; at 140℃; under 7500.75 Torr; for 16h;Inert atmosphere; Autoclave;
General procedure: A 12 mL vial was charged with [Pd(cinnamyl)Cl]2(1,5 mol%), dppp (3 mol%). and a stirring bar. Then, 1,2-dibromo-benzene(0.5 mmol), DBU (4.0 eq) and toluene (3 mL) were injected by syringe underargon. The vial (or several vials) was placed in an alloy plate, which wastransferred into a 300 mL autoclave of the 4560 series from Parr Instrumentsunder argon atmosphere. After flushing the autoclave three times with CO, apressure of 10 bar of CO was adjusted at ambient temperature. Then, thereaction was performed for 16-24 h at 140 oC. After the reactioncompleted, the autoclave was cooled down with ice water to room temperature andthe pressure was released carefully. After evaporation of the organic solventthe residue was adsorbed on silica gel and the crude product was purified bycolumn chromatography using EA/pentane(1:1) for phthalimides and MeOH/EA (1:40) for the amides as eluent.
General procedure: Into a dried two-necked flask (50 mL) equipped with a condenser were placed a stirrer bar, Mg powder (99.9%, 24 mmol), LiCl (24mmol), DMI (20 mL), and chlorodimethylsilane (48 mmol). After stirring the mixture at rt for 15 min, 1,2-dibromoarene (3 mmol) was added and the mixture was stirred for 4 h. The mixture was quenched with sat. NaHCO3 and the resulting precipitates were filtered off. The filtrate was extracted with hexane (3 ×) and the combined organic extract was washed with brine, dried (anhyd Na2SO4), and concentrated by a rotary evaporator. The crude product was purified by column chromatography (silica gel, hexane or hexane/CH2Cl2).
General procedure: Into a dried two-necked flask (50 mL) equipped with a condenser were placed a stirrer bar, Mg powder (99.9%, 8 mmol), LiCl (8 mmol),DMI (10 mL), and chlorotrimethylsilane (16 mmol). After stirring the mixture at rt for 15 min, 1,2-dibromoarene (1 mmol) was added and the mixture was stirred for 4 h. The mixture was quenched with sat.NaHCO3 and the resulting precipitates were filtered off. The filtrate was extracted with hexane (3 ×) and the combined organic extracts were washed with brine, dried (anhyd Na2SO4), and concentrated by a rotary evaporator. The crude product was purified by column chromatography (silica gel, hexane or hexane/CH2Cl2).
With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; XPhos; In tert-Amyl alcohol; at 90℃; for 16h;
General procedure: Fuel additive d was prepared according to the following scheme: The fuel additive was prepared using the following procedure: to a set of reaction tubes (dimensions 110 mm x 17 mm) was weighed the catalysts and bases by use of a Mettler Toledo FlexiWeigh automated solid dispenser. Separate tubes were used for the catalyst and for the base and internal standard. To the catalyst tube containing Pd2(dba)3 (14 mg, 0.016 mmol) and XPhos (30 mg, 0.062 mmol) was added tert- amyl alcohol (1 mL) and heated with stirring to 60 C for 0.5 hours before cooling to ambient temperature. To each reaction tube of pre-weighed potassium carbonate as base (94 mg, 0.68 mmol) and di-/er/-butyl biphenyl (12 mg) as internal standard was added tert- amyl alcohol (2 mL) with stirring and the liquid reagents dichlorotoluene (80 pL; 0.62 mmol) and ethanolamine (75 pL, 1.24 mmol) added. Subsequently, the 1 mL of pre-formed?Pd-XPhos? catalyst solution was charged to the main reaction tube and the resulting reaction mixture heated to 90 C with a chilled- condenser head block to avoid solvent loss. Sampling of the reaction was conducted manually extracting an aliquot by syringe or Eppendorf pipette at 0, 2 and 16 hours. The reaction was repeated using the same procedure, but modified in line with conditions in the following table:
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