* 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] Justus Liebigs Annalen der Chemie, 1900, vol. 312, p. 332
3
[ 1761-61-1 ]
[ 2316-64-5 ]
Yield
Reaction Conditions
Operation in experiment
84%
With sodium tetrahydroborate In ethanol at 0 - 20℃; for 18 h; Schlenk technique; Inert atmosphere
The compound was prepared according to the literature using a modified synthetic procedure: 5-bromo-2-hydroxybenzaldehyde (10.1 g, 50 mmol) was dissolved in 250 mL of ethanol at 0 °C. NaBH4 (1.88 g, 50 mmol) was added in portions ( 0.3 g) to the stirred solution. The mixture was stirred at room temperature for 18 h. After removal of ethanol under reduced pressure (10 2 mbar) the resulting pale yellow solid was dissolved in 200 mL of a saturated, aqueous NH4Cl solution. The crude product was extracted with diethyl ether (three times 80 mL). The organic phase was washed with brine (three times 20 mL) and dried with MgSO4 for 2 h. After removal of MgSO4 by filtration and excess solvent under reduced pressure (10 2 mbar) the product was purified by flash chromatography with silica (eluent: n-hexane/ethyl acetate – volume ratio of 8/2) to give a colorless solid after evaporation of the solvent (8.52 g, 84percent);
150 g
at 0 - 20℃; for 5 h;
5L three bottles, Compound 1 -7 (154 g, 0.766 mol 1) was dissolved in ethanol (3 L) 0 ° C Under conditions, sodium borohydride (298, 0.762 mol) was slowly added, Stirred at room temperature for 5 hours. The reaction solution was added with hydrochloric acid to adjust the pH to 2 to 3, Control temperature below 10 ° C; Ethyl acetate (500 mL) The organic phase was washed with saturated brine (500 mL) Sodium sulfate, filter, Concentration gave 150 g of a gray solid.
Reference：
[1] Tetrahedron Asymmetry, 2011, vol. 22, # 13, p. 1395 - 1399
[2] Journal of Chemical Research - Part S, 2003, # 6, p. 335 - 339
[3] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2003, vol. 58, # 12, p. 1220 - 1226
[4] Bulletin of the Chemical Society of Japan, 2005, vol. 78, # 2, p. 307 - 315
[5] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2005, vol. 60, # 4, p. 453 - 457
[6] Bulletin of the Chemical Society of Japan, 2003, vol. 76, # 2, p. 317 - 326
[7] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2004, vol. 59, # 6, p. 704 - 710
[8] Nucleosides, Nucleotides and Nucleic Acids, 2007, vol. 26, # 6-7, p. 861 - 864
[9] Journal of Medicinal Chemistry, 2007, vol. 50, # 7, p. 1658 - 1667
[10] Inorganica Chimica Acta, 2014, vol. 409, # PART B, p. 472 - 478
[11] Journal of Materials Chemistry A, 2016, vol. 4, # 7, p. 2705 - 2719
[12] Asian Journal of Chemistry, 2010, vol. 22, # 9, p. 6761 - 6764
[13] European Journal of Organic Chemistry, 2018, vol. 2018, # 23, p. 2910 - 2917
[14] Acta Chemica Scandinavica (1947-1973), 1965, vol. 19, p. 255 - 256
[15] Journal of Physical Chemistry, 1984, vol. 88, # 9, p. 1913 - 1916
[16] Tetrahedron, 1999, vol. 55, # 2, p. 433 - 448
[17] Nucleosides, Nucleotides and Nucleic Acids, 2007, vol. 26, # 10-12, p. 1325 - 1328
[18] ChemMedChem, 2013, vol. 8, # 6, p. 956 - 966
[19] Organic and Biomolecular Chemistry, 2013, vol. 11, # 45, p. 7838 - 7842
[20] Chemical Communications, 2014, vol. 50, # 56, p. 7531 - 7534
[21] Patent: WO2014/130608, 2014, A1, . Location in patent: Page/Page column 102
[22] Organic Letters, 2015, vol. 17, # 19, p. 4790 - 4793
[23] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 9, p. 2308 - 2313
[24] European Journal of Organic Chemistry, 2016, vol. 2016, # 28, p. 4824 - 4833
[25] Patent: CN107188813, 2017, A, . Location in patent: Paragraph 0054; 0065-0066
[26] Advanced Synthesis and Catalysis, 2018, vol. 360, # 21, p. 4246 - 4251
4
[ 924-44-7 ]
[ 1761-61-1 ]
[ 30482-66-7 ]
Reference：
[1] Journal of the Chemical Society [Section] C: Organic, 1971, p. 146 - 149
5
[ 95-54-5 ]
[ 1761-61-1 ]
[ 62871-28-7 ]
Yield
Reaction Conditions
Operation in experiment
89%
With A-FGO catalyst In tetrahydrofuran for 2 h; Reflux; Ionic liquid; Green chemistry
General procedure: A mixture of 1,2-phenylenediamine (0.54 g, 5.0 mmol) and 4-nitrobenzaldehyde(1.133 g, 7.5 mmol) in tetrahydrofuran (10 mL) was taken and A-FGO as thecatalyst (0.1 g) was added at room temperature. The resulting mixture was stirredfor 2 h at reflux temperature. Upon completion of the reaction (monitored by TLC), dichloromethane (10 mL) was added while being stirred for 15 min at ambient temperatures. The catalyst was removed by filtration and washed with dichloromethane for reuse in the next cycles (up to five runs) (Fig. 5). The crude product was purified by recrystallisation from ethanol to produce 0.53 g of 2-(4-nitrophenyl)benzimidazole (3d) (Ra = 98 percent). A similar procedure was applied for all other compounds. All the benzimidazole derivatives were fully characterised using the usual spectroscopic techniques.
Reference：
[1] New Journal of Chemistry, 2018, vol. 42, # 22, p. 17931 - 17938
[2] Research on Chemical Intermediates, 2017, vol. 43, # 3, p. 1751 - 1766
[3] Applied Organometallic Chemistry, 2018, vol. 32, # 4,
[4] Journal of Organic Chemistry, 2013, vol. 78, # 22, p. 11184 - 11193
[5] Applied Organometallic Chemistry, 2018, vol. 32, # 10,
[6] Journal of Heterocyclic Chemistry, 2012, vol. 49, # 5, p. 1187 - 1195
[7] Magnetic Resonance in Chemistry, 2005, vol. 43, # 7, p. 551 - 556
[8] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 6, p. 1231 - 1240
6
[ 1761-61-1 ]
[ 62871-28-7 ]
Reference：
[1] Recueil: Journal of the Royal Netherlands Chemical Society, 1983, vol. 102, # 2, p. 73 - 77
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1982, vol. 21, # 9, p. 872 - 874
7
[ 95-54-5 ]
[ 1761-61-1 ]
[ 29979-27-9 ]
[ 62871-28-7 ]
Reference：
[1] Recueil: Journal of the Royal Netherlands Chemical Society, 1983, vol. 102, # 2, p. 73 - 77
8
[ 1761-61-1 ]
[ 121124-98-9 ]
[ 5896-17-3 ]
Reference：
[1] Organic Process Research and Development, 2011, vol. 15, # 6, p. 1348 - 1357
9
[ 105-36-2 ]
[ 1761-61-1 ]
[ 84102-69-2 ]
Yield
Reaction Conditions
Operation in experiment
83%
With potassium carbonate In N,N-dimethyl-formamide at 130℃; for 5 h;
Add to a 250 mL two-necked flask5-bromo-2-hydroxybenzaldehyde (15 g, 74.63 mmol)Ethyl bromoacetate (18.7g, 111.9mmol),Potassium carbonate (31 g, 223.9 mmol)And anhydrous DMF (80 mL),The reaction mixture was heated to 130 ° C for 5 hours to complete the reaction.Filtration, the filtrate is concentrated under reduced pressure,The residue was dissolved in ethyl acetate (100 mL)Washed with saturated brine (50 mL x 3)Dried over anhydrous sodium sulfate.Filtration, evaporation of the solvent under reduced pressure,The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1: 20, V / V)A pale yellow solid of 16.6 g,Yield 83percent.
59.7%
With caesium carbonate In N,N-dimethyl-formamide at 20 - 120℃; for 2.5 h;
5-bromosalicylaldehyde (0504-89) (5 g, 25 mmol, 1.0 eq.)And cesium carbonate (8.2 g, 25 mmol, 1.0 eq.)Mix in 80 ml DMF,Ethyl bromoacetate (8.3 g, 50 mmol, 2.0 eq.) was added dropwise.After the addition was completed, the reaction was performed at room temperature for half an hour.Warm up to 120°C for two hoursAfter the liquid detection reactionAll, cool to room temperature, pour it into ice water and stir for half an hour. Filter, filter cake washed with water,Drying gave a yellow powdered solid product, ethyl 5-bromobenzofuran-2-carboxylate (4 g, 59.7percent).
Reference：
[1] Patent: CN106478564, 2017, A, . Location in patent: Paragraph 0216; 0217; 0218
[2] Patent: CN107383024, 2017, A, . Location in patent: Paragraph 0473
[3] Patent: US2004/209865, 2004, A1,
[4] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 20, p. 5591 - 5593
10
[ 1761-61-1 ]
[ 84102-69-2 ]
Yield
Reaction Conditions
Operation in experiment
78%
With potassium carbonate In butanone for 72 h; Heating / reflux
A solution of 5-bromo-salicylaldehyde (5.0 g, 25 mmol) and bromo diethylmalonate (8.9 g, 37 mmol) in methyl ethyl ketone (50 ml) is treated with potassium carbonate (6.8 g, 50 mmol) and heated to reflux. The reaction is stirred over 3 days at reflux. The reaction is then concentrated to a crude solid that is purified by silica gel column chromatography (9:1 hexane / EtOAc) to afford 5.2 g (78 percent) of the desired product. 1H NMR (CDCl3) 7.81 (d, 1H), 7.26-7.55 (m, 3H), 4.44 (q, 2H), 1.42 (t, 3H)
Reference：
[1] Synlett, 2001, # 5, p. 670 - 672
[2] Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 2, p. 445 - 459
13
[ 685-87-0 ]
[ 1761-61-1 ]
[ 84102-69-2 ]
Reference：
[1] The Journal of pharmacy and pharmacology, 1999, vol. 51, # 4, p. 427 - 433
14
[ 105-56-6 ]
[ 1761-61-1 ]
[ 65673-63-4 ]
Yield
Reaction Conditions
Operation in experiment
94%
With N,N,N',N'-tetramethylguanidine In neat liquid at 20℃; for 0.583333 h;
General procedure: TMG (3.5 mmol) was added to a mixture of SA (1 mmol), MN (1 mmol) and DAP (1 mmol) in neat condition. The resulting mixture was stirred at room temperature. After completion of the reaction (monitored by TLC), distilled water (15 mL) was added to the reaction mixture and stirring continued till a free flowing solid was obtained. It was filtered and then washed successively with water, n-hexane. The crude product was purified by recrystallization from ethanol solution. For this, the crude product was saturated in boiling ethanol and then the solution mixture was filtered when it was hot to remove the undissolved solid. The hot filtrate cooled down to room temperature to afford elemental analytically pure crystalline product. The similar experimental procedures were adopted for the synthesis of all the 2-amino-4H-chrormens.
55%
at 20℃; Molecular sieve
Ethyl-2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA14-1) was purchased from Wako (Tokyo, Japan) or prepared by following an established procedure [12]. In short, 5-bromosalicylaldehyde was treated with ethyl cyanoacetate in the presence of MS3A in dry ethanol at room temperature to produce HA14-1 with a 55percent yield. Synthesized HA14-1 had inhibitory activity comparable with commercial HA14-1.
Reference：
[1] Tetrahedron Letters, 2005, vol. 46, # 20, p. 3497 - 3499
[2] RSC Advances, 2015, vol. 5, # 80, p. 65526 - 65531
[3] Tetrahedron, 2013, vol. 69, # 49, p. 10544 - 10551
[4] Tetrahedron Letters, 2006, vol. 47, # 43, p. 7629 - 7633
[5] Russian Chemical Bulletin, 2008, vol. 57, # 3, p. 595 - 600
[6] Tetrahedron Letters, 2000, vol. 41, # 36, p. 6993 - 6996
[7] Tetrahedron Letters, 2008, vol. 49, # 20, p. 3276 - 3278
[8] Biochemical and Biophysical Research Communications, 2013, vol. 433, # 2, p. 170 - 174
15
[ 90-02-8 ]
[ 90-59-5 ]
[ 1761-61-1 ]
Yield
Reaction Conditions
Operation in experiment
74%
With perchloric acid; C74H104N4O7V2; dihydrogen peroxide; potassium bromide In tetrahydrofuran; methanol; water at 25℃; for 12 h;
General procedure: In this method, a representative substrate, namely salicylaldehyde (20mmol), was dissolved in mixed solvent (H2O:MeOH:THF=4:3:2) [29] and the resulting solution was taken in a 50ml capacity round bottom flask. To the above solution was then added KBr (40mmol) followed by 2ml (67mmol) of 30percent H2O2. (0018) An appropriate catalyst (say, complex 1) (0.05g, 0.04mmol) and 70percent HClO4 (0.10ml) were added to it and the reaction was initiated with stirring. After 2h of stirring at ambient temperature 0.1ml of 70percent HClO4 was further added and stirring was continued for next 10h. The separated white product was filtered, washed with water followed by diethyl ether and dried in air. The crude mass was dissolved in CH2Cl2 and insoluble material was separated by filtration. After evaporation of the solvent to ca. 5ml it was loaded over column packed with silica gel. The fast moving band on elution with CH2Cl2 was collected and evaporated to dryness to give 5-bromo-salicylaldehyde. We have performed the several sets of such reaction for varying time (3h, 6h, 9h and 12h) and products were isolated and quantified in each case. Then the calculated yield (percent) are tabulated in Table 3.
Reference：
[1] Dalton Transactions, 2018, vol. 47, # 8, p. 2799 - 2809
[2] Inorganica Chimica Acta, 2018, vol. 480, p. 149 - 158
[3] Journal of Organometallic Chemistry, 2018, vol. 858, p. 37 - 46
[4] Canadian Journal of Chemistry, 2009, vol. 87, # 2, p. 440 - 447
[5] Dalton Transactions, 2005, # 3, p. 537 - 544
[6] Tetrahedron Letters, 2010, vol. 51, # 10, p. 1383 - 1385
[7] Tetrahedron Letters, 2012, vol. 53, # 2, p. 127 - 131
[8] Journal of Chemical Sciences, 2011, vol. 123, # 2, p. 215 - 228
[9] Applied Organometallic Chemistry, 2016, vol. 30, # 3, p. 116 - 124
[10] Inorganica Chimica Acta, 2018, vol. 469, p. 366 - 378
16
[ 90-02-8 ]
[ 90-59-5 ]
[ 1761-61-1 ]
[ 118-79-6 ]
Reference：
[1] European Journal of Inorganic Chemistry, 2009, # 35, p. 5377 - 5390
[2] European Journal of Inorganic Chemistry, 2012, # 15, p. 2560 - 2577
[3] Polyhedron, 2014, vol. 67, p. 1 - 10
[4] Polyhedron, 2014, vol. 67, p. 436 - 448
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5823 - 5828
[2] Applied Organometallic Chemistry, 2016, vol. 30, # 3, p. 116 - 124
[3] New Journal of Chemistry, 2017, vol. 41, # 22, p. 13625 - 13646
20
[ 1761-61-1 ]
[ 90-59-5 ]
Reference：
[1] Berzelius'Jahresber., vol. 25, p. 486
21
[ 7726-95-6 ]
[ 90-02-8 ]
[ 64-19-7 ]
[ 90-59-5 ]
[ 1761-61-1 ]
Reference：
[1] Journal of Organic Chemistry, 1941, vol. 6, p. 722,725, 729
22
[ 1761-61-1 ]
[ 17345-77-6 ]
Reference：
[1] RSC Advances, 2015, vol. 5, # 128, p. 105583 - 105586
[2] Journal of Materials Chemistry, 2007, vol. 17, # 14, p. 1399 - 1411
[3] Chemistry - A European Journal, 2009, vol. 15, # 37, p. 9530 - 9542
[4] Journal of Materials Chemistry C, 2018, vol. 6, # 16, p. 4471 - 4478
[5] Green Chemistry, 2015, vol. 17, # 9, p. 4533 - 4536
[6] European Journal of Organic Chemistry, 2016, vol. 2016, # 16, p. 2802 - 2814
[7] European Journal of Organic Chemistry, 2014, vol. 2014, # 5, p. 1037 - 1046
[8] European Journal of Organic Chemistry, 2014, vol. 2014, # 5, p. 1037 - 1046
[9] Tetrahedron Letters, 2005, vol. 46, # 19, p. 3357 - 3358
[10] Journal of Organic Chemistry, 2011, vol. 76, # 4, p. 1013 - 1030
23
[ 56-23-5 ]
[ 7722-84-1 ]
[ 1761-61-1 ]
[ 17345-77-6 ]
Reference：
[1] American Chemical Journal, 1909, vol. 42, p. 495
24
[ 1761-61-1 ]
[ 16740-73-1 ]
Reference：
[1] Drug Metabolism and Disposition, 2012, vol. 40, # 10, p. 2002 - 2008,7
25
[ 1761-61-1 ]
[ 16634-88-1 ]
Yield
Reaction Conditions
Operation in experiment
82%
at 32℃; for 1 h;
[000244] To a solution of Compound Dl (80 g, 266 mmol) in CH3C02H (400 ml) was added fuming HN03 (24 mL) at 10 °C and the mixture was stirred at 32 °C for 1 h. Water (200 mL) was added and the mixture filtered. The filtrate was washed with water to remove CH3CO2H and was dried to give Compound D2 (80 g, yield 82percent) as a yellow solid. LC-MS (m/z): 244 [M-l]~.
60%
With nitric acid In water; acetic acid at 60 - 65℃; for 1.16667 h;
The first step was the nitration of 5-bromo-2-hydroxybenzaldehyde (1*) yielding 5- bromo-2-hydroxy-3-nitrobenzaldehyde (2*) : 0 0 Br HN03 Br H H OH ACOH OH step 1 (1*) recryst. (2*) (step 1a) A solution of 1.0 mol of 5-bromo-2-hydroxybenzaldehyde (1*) in 3.75 litres acetic acid (98percent) was formed on heating the mixture to about 60°C. 1.5 mol of concentrated nitric acid (137 g = 97 ml) was added slowly in approximately 1 hour. After the completion of the addition stirring was continued at 65 °C for a further 10 minutes. The solution was then cooled to 45 °C, and the product was precipitated by the addition of 4 litres of water. After stirring for at least 3 hours the product was collected on a filter and washed with water until the pH of the mother liquor was approximately 6. The material is dried as much as possible by centrifugation. The crude product was dissolved in 800 ml acetone under refluxing and stirring. 400 mi acetone was removed by distillation. After cooling to 20°C, the mixture was stirred for 3 hours. The precipitate was collected on a filter an d washed with petroleum ether 40-65°C. The solid was dried overnight in an air stream at 40°C. Finally, the crude (2*) was recrystallized from acetone to yield an end product with a purity of 98percent as shown by NMR analysis. 5-bromo-2-hydroxybenzaidehyde (1*) was identified by its characteristic chemical shift 8 9.84 ppm; 5-bromo-2-hydroxy-3-nitrobenzaldehyde (2*) had a characteristic chemical shift of 8 10. 4 ppm. The overall yield of this step was approximately 60percent (crude on crude).
60%
With nitric acid In water; acetic acid at 60 - 65℃; for 1.16667 h;
The first step was the nitration of 5-bromo-2-hydroxybenzaldehyde (1*) yielding 5- bromo-2-hydroxy-3-nitrobenzaldehyde (2*) : 0 Br HN03 Br I H I w OH Ar OH OH step 1 "Nn sfep'"-'2 (1*) recryst. (2*) (step la) A solution of 1.0 mol of 5-bromo-2-hydroxybenzaldehyde (1*) in 3.75 litres acetic acid (98percent) was formed on heating the mixture to about 60°C. 1. 5 mol of concentrated nitric acid (137 g = 97 mi) was added slowly in approximately 1 hour. After the completion of the addition stirring was continued at 65 °C for a further 10 minutes. The solution was then cooled to 45 °C, and the product was precipitated by the addition of 4 litres of water. After stirring for at least 3 hours the product was collected on a filter and washed with water until the pH of the mother liquor was approximately 6. The material is dried as much as possible by centrifugation. The crude product was dissolved in 800 mi acetone under refluxing and stirring. 400 mi acetone was removed by distillation. After cooling to 20°C, the mixture was stirred for 3 hours. The precipitate was collected on a filter and washed with petroleum ether 40-65°C. The solid was dried overnight in an air stream at 40°C. Finally, the crude (2*) was recrystallized from acetone to yield an end product with a purity of 98percent as shown by NMR analysis. 5-bromo-2-hydroxybenzaldehyde (1*) was identified by its characteristic chemical shift 8 9.84 ppm; 5-bromo-2-hydroxy-3-nitrobenzaldehyde (2*) had a characteristic chemical shift of 8 10.4 ppm. The overall yield of this step was approximately 60percent (crude on crude).
60%
With nitric acid In acetic acid at 60 - 65℃; for 1.16667 h;
The first step was the nitration of 5-bromo-2-hydroxybenzaldehyde (1*) yielding 5- bromo-2-hydroxy-3-nitrobenzaldehyde (2*) : 0 0 Br HN03 Br H H OH AH OH step t No2 (1*) recryst. (2) (step 1a) A solution of 1.0 mol of 5-bromo-2-hydroxybenzaldehyde (1*) in 3. 75 litres acetic acid (98percent) was formed on heating the mixture to about 60C. 1.5 mol of concentrated nitric acid (137 g = 97 mi) was added slowly in approximately 1 hour. After the completion of the addition stirring was continued at 65C for a further 10 minutes. The solution was then cooled to 45C, and the product was precipitated by the addition of 4 litres of water. After stirring for at least 3 hours the product was collected on a filter and washed with water until the pH of the mother liquor was approximately 6. The material was dried as much as possible by centrifugation. The crude product was dissolved in 800 mi acetone under refluxing and stirring-400 m) acetone was removed by distillation. After cooling to 20C, the mixture was stirred for 3 hours. The precipitate was collected on a filter and washed with petroleum ether 40-65C. The solid was dried overnight In an air stream at 40C. Finally, the crude (2*) was recrystallized from acetone to yield an end product with a purity of 98percent as shown by NMR analysis. 5-bromo-2-hydroxybenzaldehyde (1*) was identified by its characteristic chemical shift 8 9.84 ppm; 5-bromo-2-hydroxy-3-nitrobenzaldehyde (2*) had a characteristic chemical shift of 8 10. 4 ppm. The overall yield of this step was approximately 60percent (crude on crude).
60%
at 60 - 65℃; for 1.16667 h;
A solution of 1.0 mol of 5-bromo-2-hydroxybenzaldehyde (1*) in 3.75 litres acetic acid (98percent) was formed on heating the mixture to about 60° C. 1.5 mol of concentrated nitric acid (137 g=97 ml) was added slowly in approximately 1 hour. After the completion of the addition stirring was continued at 65° C. for a further 10 minutes. The solution was then cooled to 45° C., and the product was precipitated by the addition of 4 litres of water. After stirring for at least 3 hours the product was collected on a filter and washed with water until the pH of the mother liquor was approximately 6. The material is dried as much as possible by centrifugation. The crude product was dissolved in 800 ml acetone under refluxing and stirring. 400 ml acetone was removed by distillation. After cooling to 20° C., the mixture was stirred for 3 hours. The precipitate was collected on a filter and washed with petroleum ether 40-65° C. The solid was dried overnight in an air stream at 40° C. Finally, the crude (2*) was recrystallized from acetone to yield an end product with a purity of 98percent as shown by NMR analysis. 5-bromo-2-hydroxybenzaldehyde (1*) was identified by its characteristic chemical shift δ 9.84 ppm; 5-bromo-2-hydroxy-3-nitrobenzaldehyde (2*) had a characteristic chemical shift of δ 10.4 ppm. The overall yield of this step was approximately 60percent (crude on crude)
42%
at 85℃; for 2 h;
0.1 mol of 5-bromosalicylaldehyde was dissolved in 20 ml of acetic acid and the solution was heated to 85° C. with stirring. Under this condition, 6.9 ml of a 65percent nitric acid solution was added dropwise to the solution, which was added dropwise. Reaction 2h. After completion of the reaction, 50 ml of ice water was added to the solution to precipitate a yellow precipitate which was filtered and dried. After recrystallization from ethanol, a yellow needle-like solid was obtained with a yield of 42percent.
Reference：
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 35, p. 6460 - 6469
[2] Tetrahedron, 2003, vol. 59, # 46, p. 9239 - 9247
[3] Patent: WO2015/42397, 2015, A1, . Location in patent: Paragraph 000244
[4] Patent: WO2005/92340, 2005, A1, . Location in patent: Page/Page column 17-18
[5] Patent: WO2005/92339, 2005, A1, . Location in patent: Page/Page column 16-17
[6] Patent: WO2005/92338, 2005, A1, . Location in patent: Page/Page column 12-13
[7] Patent: US2006/13874, 2006, A1, . Location in patent: Page/Page column 2
[8] Patent: CN108069929, 2018, A, . Location in patent: Paragraph 0060-0061
[9] Chemische Berichte, 1904, vol. 37, p. 3934
[10] J. Prakt. Chem./Chem.-Ztg., 1998, vol. 340, # 6, p. 562 - 566
[11] Journal of Coordination Chemistry, 2015, vol. 68, # 13, p. 2296 - 2306
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5823 - 5828
[2] Applied Organometallic Chemistry, 2016, vol. 30, # 3, p. 116 - 124
[3] New Journal of Chemistry, 2017, vol. 41, # 22, p. 13625 - 13646
28
[ 1761-61-1 ]
[ 40530-18-5 ]
Yield
Reaction Conditions
Operation in experiment
95%
at 100℃; for 7 h;
<Referential Example 1> 5-Bromo-2-hydroxybenzonitrile; To a solution of 5-bromosalicylaldehyde (80.0 g, 0.40 mol) in formic acid were added hydroxylamine hydrochloride (36.0 g, 0.52 mol) and sodium format (37.0 g, 0.52 mol) followed by stirring at 100°C for 7 hours. Ethyl acetate was added to the residue prepared by evaporation of the solvent, the mixture was washed with water and then an organic layer was dried. Petroleum ether was added to the residue prepared by evaporation of the solvent and the crystals separated out therefrom were filtered to give the title compound (75.2 g, 95percent). 1H-NMR (DMSO-d6) δ: 6.98 (d, J=8.9 Hz, 1H), 7.65 (dd, J=8.9, 2.4 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 11.41 (s, 1H).
Reference：
[1] Patent: EP2128136, 2009, A1, . Location in patent: Page/Page column 7
[2] Heterocyclic Communications, 2009, vol. 15, # 5, p. 335 - 341
[3] Indian Journal of Heterocyclic Chemistry, 2010, vol. 20, # 2, p. 129 - 132
[4] Synthetic Communications, 1992, vol. 22, # 14, p. 2125 - 2128
[5] New Journal of Chemistry, 2000, vol. 24, # 7, p. 541 - 546
[6] European Journal of Organic Chemistry, 2014, vol. 2014, # 27, p. 6077 - 6083
[7] Patent: CN106854174, 2017, A,
[8] Patent: CN106810513, 2017, A,
29
[ 1761-61-1 ]
[ 40530-18-5 ]
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 17, p. 8657 - 8667
30
[ 68-12-2 ]
[ 1761-61-1 ]
[ 40530-18-5 ]
Reference：
[1] Indian Journal of Heterocyclic Chemistry, 2011, vol. 21, # 2, p. 167 - 172
31
[ 1761-61-1 ]
[ 74901-29-4 ]
Yield
Reaction Conditions
Operation in experiment
21%
at 150℃; for 5 h; Inert atmosphere
5-Bromosalicylaldehyde (20 g, 0.099 mol) was dissolved in dry DMF (80 mL) and CuCN (18.6 g, 0.21 mol) was added. The reaction mixture was heated to 150 °C under N2 for 5 h. The reaction mixture was allowed to cool to rt. The reaction mixture was diluted with EtOAc and filtered through Celite®. The filtrate was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2S04, filtered, and concentrated. The resultant residue was purified by column chromatography (20 - 25percent EtOAc/petroleum ether) to afford the title compound (3.0 g, 21percent) as yellow solid. TLC: 20percent EtOAc/petroleum ether, Rf= 0.2. lU NMR (300 MHz, CDC13) δ ppm 1 1.47 (s, 1H), 9.93 (s, 1H), 7.94 (s, 1H), 7.78 (dd, J = 8.7, 1.2 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H)
Reference：
[1] Liebigs Annalen der Chemie, 1982, # 10, p. 1836 - 1869
[2] Chemical and Pharmaceutical Bulletin, 1997, vol. 45, # 12, p. 1994 - 2004
33
[ 79-08-3 ]
[ 1761-61-1 ]
[ 24589-89-7 ]
Yield
Reaction Conditions
Operation in experiment
55%
With sodium hydroxide In tetrahydrofuran; water
Step A: (4-Bromo-2-formyl)phenoxyacetic acid. Monohydrate To a solution of 5-bromosalicylaldehyde (5.0 kg, 24.87 mol) in tetrahydrofuran (12.1 L) at 40° C. under a nitrogen atmosphere is added a solution of bromoacetic acid (3.8 kg, 27.42 mol) in water (50 L). The mixture is stirred at 40° C. and a solution of sodium hydroxide (2.09 kg, 52.29 mmol) in water (8.1 L) added over 20 min. The deep red solution is warmed to gentle reflux for 18 hours. Tetrahydrofuran (~7 L) is distilled from the reaction mixture at atmospheric pressure and the resultant yellow solution cooled to room temperature (25° C.). The pH is adjusted to 8+-0.2 by addition of saturated sodium bicarbonate solution. The resultant mixture is extracted with isopropylacetate (2*15 L) and the aqueous layer acidified to pH 3+-0.2 with concentrated hydrochloric acid (2.4 L). The resultant slurry is aged at 20° C. for 1 hour, filtered, and the cake washed with water (7 L). The product is air dried for 3 hours, and in vacuo overnight to give the product as a pale yellow solid (3.77 Kg, 55percent yield).
Reference：
[1] Patent: US5149838, 1992, A,
34
[ 1761-61-1 ]
[ 24589-89-7 ]
Reference：
[1] Patent: US5378718, 1995, A,
[2] Journal of Medicinal Chemistry, 1969, vol. 12, # 3, p. 420 - 424
[3] Organic Letters, 2015, vol. 17, # 23, p. 5824 - 5827
35
[ 79-11-8 ]
[ 1761-61-1 ]
[ 24589-89-7 ]
Reference：
[1] Journal of the Indian Chemical Society, 2008, vol. 85, # 7, p. 754 - 758
[2] Archiv der Pharmazie, 2015, vol. 348, # 6, p. 421 - 432
36
[ 1761-61-1 ]
[ 6329-74-4 ]
Reference：
[1] European Journal of Organic Chemistry, 2014, vol. 2014, # 34, p. 7590 - 7593
[2] Applied Organometallic Chemistry, 2018, vol. 32, # 6,
37
[ 75-30-9 ]
[ 1761-61-1 ]
[ 138505-25-6 ]
Yield
Reaction Conditions
Operation in experiment
99%
With potassium carbonate; caesium carbonate In <i>N</i>-methyl-acetamide
Step A: Synthesis of 5-bromo-2-isopropoxybenzaldehyde AX. To a suspension of potassium carbonate (34.4 g, 249 mmol) and cesium carbonate (16.2 g, 50 mmol) in dimethylformamide were added 5-bromosalicaldehyde (25.0 g, 124 mmol) and 2-iodopropane (25.0 mL, 249 mmol). The suspension was stirred at room temperature overnight, then at 70° C. for 4 hrs. The volatiles were removed, and the residue was partitioned between methyl t-butylether and water. The aqueous layer was extracted with methyl t-butylether and the combined organic phases were washed with water, sodium hydroxide, and brine, and then dried over magnesium sulfate. Concentration to dryness afforded compound AX (30.0 g) as a pale yellow oil in 99percent yield. 1H NMR (CDCl3, 400 MHz): δ 1.40 (d, J=6.3 Hz, 6H), 4.65 (sept., J=6.0 Hz, 1H), 6.89 (d, J=9.0 Hz, 1H), 7.59 (dd, J=9.0 and 2.7 Hz, 1H), 7.91 (d, J=2.7 Hz, 1H), 10.39 (s, 1H).
99%
With potassium carbonate; caesium carbonate In N,N-dimethyl-formamide at 20 - 70℃; for 4 h;
To a suspension of potassium carbonate (34.4 g, 249 mmol) and cesium carbonate (16.2 g, 50 mmol) in dimethylformamide were added 5-bromosalicaldehyde (25.0 g, 124 mmol) and 2-iodopropane (25.0 mL, 249 mmol). The suspension was stirred at room temperature overnight, then at 70° C. for 4 hrs. The volatiles were removed, and the residue was partitioned between methyl t-butylether and water. The aqueous layer was extracted with methyl t-butylether and the combined organic phases were washed with water, sodium hydroxide, and brine, and then dried over magnesium sulfate. Concentration to dryness afforded compound AX (30.0 g) as a pale yellow oil in 99percent yield. 1H NMR (CDCl3, 400 MHz): δ (ppm) 1.40 (d, J=6.3 Hz, 6H), 4.65 (sept., J=6.0 Hz, 1H), 6.89 (d, J=9.0 Hz, 1H), 7.59 (dd, J=9.0 and 2.7 Hz, 1H), 7.91 (d, J=2.7 Hz, 1H), 10.39 (s, 1H).
98%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 0.5 h; Inert atmosphere
To a solution of 5-bromo-2-hydroxybenzaldehyde 3 (600 mg, 3.0mmol) and 2-iodopropane (1.4 ml, 15 mmol) in dry-DMF wasadded K2CO3 (3.2 g, 24 mmol). The mixture was heated at 60 Cunder N2 in oil bath. The mixture was stirred for 30 min. The excessK2CO3 was quenched with 1 M aq. HCl. After the addition 1 M aq.HCl, extracted with ethyl acetate and washed with brine. Theorganic layer was dried over Na2SO4, filtered and concentrated. The residue waspurified by column chromatography on silica gel (hexane / AcOEt = 20 : 1 ) to give5-bromo-2-isopropoxybenzaldehyde (712.6 mg, 98percent) as a colorless oil. 1H NMR (270MHz, CDCl3) δ 1.40 (d. J = 5.94 Hz, 6H), 4.58-4.71 (m, 1H), 6.89 (d, J = 9.2 Hz, 1H),7.59 (d, J = 8.6 Hz, 1H), 7.91 (s, 1H), 10.40 (s, 1H).
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1991, p. 2783 - 2787
[2] European Journal of Organic Chemistry, 2018, vol. 2018, # 33, p. 4614 - 4627
39
[ 1761-61-1 ]
[ 452339-73-0 ]
Reference：
[1] Patent: CN107188813, 2017, A,
40
[ 1761-61-1 ]
[ 57260-71-6 ]
[ 343306-50-3 ]
Yield
Reaction Conditions
Operation in experiment
56%
Stage #1: With sodium t-butanolate In toluene at 42℃; for 22 h; Inert atmosphere Stage #2: With acetic acid In water; toluene for 0.166667 h;
5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-hydroxybenzaldehyde Toluene (9.7 L) was introduced into a reactor and degassed using vacuum /nitrogen. Under nitrogen at 23°C was palladium acetate (11.0 g, 0.049 mol, 0.01 equiv.) was loaded and the mixture was stirred until complete dissolution of palladium. A solution of tri-tert-butyl-phosphine (10.0 g, 0.049 mol, 0.01 equiv.) in toluene (0.3 L) was then added, followed by the addition of 5-bromo-2-hydroxybenzaldehyde (1000 g, 4.97 mol, 1 equiv.), tert-butyl-1-piperazinecarboxylate (1065.4 g, 5.72 mol, 1.1 equiv.) and sodium-tert-butoxide (1052.4 g, 10.9 mol, 2.2 equiv.). The resulting yellow-orange solution was stirred for 22 h at 42°C. The red-brownish slurry was mixed with a mixture (pH around 5-6) of distilled water (8 L) and glacial acetic acid (800 mL), and stirred for 10 min. The organic phase was separated from the aqueous phase and washed twice with distilled water (2 x 8 L). The organic phase was then dried by addition of sodium sulphate (2.5 kg), stirred for 30 min. and filtered. The resulting dark-orange organic phase was weighed (9.65 kg) and an aliquot (100 g) was taken. The aliquot was concentrated in vacuo to yield a dark-orange oil which was purified by column chromatography (SiO2, h: 30 cm, d: 4 cm, eluant: MTBE/heptane 1:1). The named compound was obtained as yellow crystals (8.9 g). Calculation of the total yield from the aliquot gave 56percent. MS (ES+): 307 (M+H).
Reference：
[1] Patent: EP2110374, 2009, A1, . Location in patent: Page/Page column 30
[2] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 18, p. 4843 - 4852
41
[ 13716-12-6 ]
[ 1761-61-1 ]
[ 57260-71-6 ]
[ 343306-50-3 ]
Yield
Reaction Conditions
Operation in experiment
51%
With sodium t-butanolate In n-heptane; water; toluene
1) Synthesis of 5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-hydroxybenzaldehyde 0.58 g of bis(dibenzylideneacetone)palladium and 0.16 g of tri-tert-butylphosphine are added under nitrogen to 200 ml of toluene, and the resultant solution, which becomes dark red, is stirred at 20° for 30 minutes. 10 g of 5-bromo-2-hydroxybenzaldehyde, 10.2 g of tert-butyl 1-piperazinecarboxylate and 7.2 g of sodium tert-butoxide are then added. The mixture is stirred at 60° for 24 hours and cooled, 800 ml of water are added, and the mixture is extracted with 2*500 ml of ethyl acetate. The organic phases are combined and washed with 300 ml of water, and the solvent is removed at 30° under reduced pressure. The dark-orange oil which remains (11 g) is purified by chromatography (300 g of silica gel; MTB ether/heptane 5:1; 1.5 litres) leaving 7.8 g of pale-yellow crystals (51percent), m.p. 84-86°; MS 306 (M+), 250 (100percent), 233, 176, 164.
[000244] To a solution of Compound Dl (80 g, 266 mmol) in CH3C02H (400 ml) was added fuming HN03 (24 mL) at 10 C and the mixture was stirred at 32 C for 1 h. Water (200 mL) was added and the mixture filtered. The filtrate was washed with water to remove CH3CO2H and was dried to give Compound D2 (80 g, yield 82%) as a yellow solid. LC-MS (m/z): 244 [M-l]~.
~ 60%
With nitric acid; In water; acetic acid; at 60 - 65℃; for 1.16667h;
The first step was the nitration of 5-bromo-2-hydroxybenzaldehyde (1*) yielding 5- bromo-2-hydroxy-3-nitrobenzaldehyde (2*) : 0 0 Br HN03 Br H H OH ACOH OH step 1 (1*) recryst. (2*) (step 1a) A solution of 1.0 mol of 5-bromo-2-hydroxybenzaldehyde (1*) in 3.75 litres acetic acid (98%) was formed on heating the mixture to about 60C. 1.5 mol of concentrated nitric acid (137 g = 97 ml) was added slowly in approximately 1 hour. After the completion of the addition stirring was continued at 65 C for a further 10 minutes. The solution was then cooled to 45 C, and the product was precipitated by the addition of 4 litres of water. After stirring for at least 3 hours the product was collected on a filter and washed with water until the pH of the mother liquor was approximately 6. The material is dried as much as possible by centrifugation. The crude product was dissolved in 800 ml acetone under refluxing and stirring. 400 mi acetone was removed by distillation. After cooling to 20C, the mixture was stirred for 3 hours. The precipitate was collected on a filter an d washed with petroleum ether 40-65C. The solid was dried overnight in an air stream at 40C. Finally, the crude (2*) was recrystallized from acetone to yield an end product with a purity of 98% as shown by NMR analysis. 5-bromo-2-hydroxybenzaidehyde (1*) was identified by its characteristic chemical shift 8 9.84 ppm; 5-bromo-2-hydroxy-3-nitrobenzaldehyde (2*) had a characteristic chemical shift of 8 10. 4 ppm. The overall yield of this step was approximately 60% (crude on crude).
~ 60%
With nitric acid; In water; acetic acid; at 60 - 65℃; for 1.16667h;
The first step was the nitration of 5-bromo-2-hydroxybenzaldehyde (1*) yielding 5- bromo-2-hydroxy-3-nitrobenzaldehyde (2*) : 0 Br HN03 Br I H I w OH Ar OH OH step 1 "Nn sfep'"-'2 (1*) recryst. (2*) (step la) A solution of 1.0 mol of 5-bromo-2-hydroxybenzaldehyde (1*) in 3.75 litres acetic acid (98%) was formed on heating the mixture to about 60C. 1. 5 mol of concentrated nitric acid (137 g = 97 mi) was added slowly in approximately 1 hour. After the completion of the addition stirring was continued at 65 C for a further 10 minutes. The solution was then cooled to 45 C, and the product was precipitated by the addition of 4 litres of water. After stirring for at least 3 hours the product was collected on a filter and washed with water until the pH of the mother liquor was approximately 6. The material is dried as much as possible by centrifugation. The crude product was dissolved in 800 mi acetone under refluxing and stirring. 400 mi acetone was removed by distillation. After cooling to 20C, the mixture was stirred for 3 hours. The precipitate was collected on a filter and washed with petroleum ether 40-65C. The solid was dried overnight in an air stream at 40C. Finally, the crude (2*) was recrystallized from acetone to yield an end product with a purity of 98% as shown by NMR analysis. 5-bromo-2-hydroxybenzaldehyde (1*) was identified by its characteristic chemical shift 8 9.84 ppm; 5-bromo-2-hydroxy-3-nitrobenzaldehyde (2*) had a characteristic chemical shift of 8 10.4 ppm. The overall yield of this step was approximately 60% (crude on crude).
~ 60%
With nitric acid; In acetic acid; at 60 - 65℃; for 1.16667h;
The first step was the nitration of 5-bromo-2-hydroxybenzaldehyde (1*) yielding 5- bromo-2-hydroxy-3-nitrobenzaldehyde (2*) : 0 0 Br HN03 Br H H OH AH OH step t No2 (1*) recryst. (2) (step 1a) A solution of 1.0 mol of 5-bromo-2-hydroxybenzaldehyde (1*) in 3. 75 litres acetic acid (98%) was formed on heating the mixture to about 60C. 1.5 mol of concentrated nitric acid (137 g = 97 mi) was added slowly in approximately 1 hour. After the completion of the addition stirring was continued at 65C for a further 10 minutes. The solution was then cooled to 45C, and the product was precipitated by the addition of 4 litres of water. After stirring for at least 3 hours the product was collected on a filter and washed with water until the pH of the mother liquor was approximately 6. The material was dried as much as possible by centrifugation. The crude product was dissolved in 800 mi acetone under refluxing and stirring-400 m) acetone was removed by distillation. After cooling to 20C, the mixture was stirred for 3 hours. The precipitate was collected on a filter and washed with petroleum ether 40-65C. The solid was dried overnight In an air stream at 40C. Finally, the crude (2*) was recrystallized from acetone to yield an end product with a purity of 98% as shown by NMR analysis. 5-bromo-2-hydroxybenzaldehyde (1*) was identified by its characteristic chemical shift 8 9.84 ppm; 5-bromo-2-hydroxy-3-nitrobenzaldehyde (2*) had a characteristic chemical shift of 8 10. 4 ppm. The overall yield of this step was approximately 60% (crude on crude).
60%
With nitric acid; acetic acid; at 60 - 65℃; for 1.16667h;
A solution of 1.0 mol of 5-bromo-2-hydroxybenzaldehyde (1*) in 3.75 litres acetic acid (98%) was formed on heating the mixture to about 60 C. 1.5 mol of concentrated nitric acid (137 g=97 ml) was added slowly in approximately 1 hour. After the completion of the addition stirring was continued at 65 C. for a further 10 minutes. The solution was then cooled to 45 C., and the product was precipitated by the addition of 4 litres of water. After stirring for at least 3 hours the product was collected on a filter and washed with water until the pH of the mother liquor was approximately 6. The material is dried as much as possible by centrifugation. The crude product was dissolved in 800 ml acetone under refluxing and stirring. 400 ml acetone was removed by distillation. After cooling to 20 C., the mixture was stirred for 3 hours. The precipitate was collected on a filter and washed with petroleum ether 40-65 C. The solid was dried overnight in an air stream at 40 C. Finally, the crude (2*) was recrystallized from acetone to yield an end product with a purity of 98% as shown by NMR analysis. 5-bromo-2-hydroxybenzaldehyde (1*) was identified by its characteristic chemical shift delta 9.84 ppm; 5-bromo-2-hydroxy-3-nitrobenzaldehyde (2*) had a characteristic chemical shift of delta 10.4 ppm. The overall yield of this step was approximately 60% (crude on crude)
42%
With nitric acid; acetic acid; at 85℃; for 2.0h;
0.1 mol of 5-bromosalicylaldehyde was dissolved in 20 ml of acetic acid and the solution was heated to 85 C. with stirring. Under this condition, 6.9 ml of a 65% nitric acid solution was added dropwise to the solution, which was added dropwise. Reaction 2h. After completion of the reaction, 50 ml of ice water was added to the solution to precipitate a yellow precipitate which was filtered and dried. After recrystallization from ethanol, a yellow needle-like solid was obtained with a yield of 42%.
With N,N,N',N'-tetramethylguanidine; In neat liquid; at 20℃; for 0.583333h;
General procedure: TMG (3.5 mmol) was added to a mixture of SA (1 mmol), MN (1 mmol) and DAP (1 mmol) in neat condition. The resulting mixture was stirred at room temperature. After completion of the reaction (monitored by TLC), distilled water (15 mL) was added to the reaction mixture and stirring continued till a free flowing solid was obtained. It was filtered and then washed successively with water, n-hexane. The crude product was purified by recrystallization from ethanol solution. For this, the crude product was saturated in boiling ethanol and then the solution mixture was filtered when it was hot to remove the undissolved solid. The hot filtrate cooled down to room temperature to afford elemental analytically pure crystalline product. The similar experimental procedures were adopted for the synthesis of all the 2-amino-4H-chrormens.
55%
In ethanol; at 20℃;Molecular sieve;
Ethyl-2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA14-1) was purchased from Wako (Tokyo, Japan) or prepared by following an established procedure [12]. In short, 5-bromosalicylaldehyde was treated with ethyl cyanoacetate in the presence of MS3A in dry ethanol at room temperature to produce HA14-1 with a 55percent yield. Synthesized HA14-1 had inhibitory activity comparable with commercial HA14-1.
General procedure: The synthetic route of Schiff bases L1, L2 and L3 were described in Scheme 1. 3,5-Dimethyl-4-amino-isoxazole (1.0 mmol) was dissolved in hot methanol to which methanolic solution of 2-hydroxy naphthalene-1-carbaldehyde/2-hydroxy-5-methoxy benzaldehyde/2-hydroxy-5-bromo benzaldehyde (1.0 mmol) was added and the resulting mixture was refluxed with stirring at 60-80 C for 3 h. Microwave assisted synthesis was also carried out using few drops of methanol in a domestic oven (LG, 1300W, 28L capacity). The reaction mixture was subjected to microwave irradiation at 320 W for the period of 60-90 s. The dark yellow product formed was washed with petroleum ether and recrystallized from methanol. Purity of the compounds was checked by TLC. Microwave assisted synthesis brought down the reaction time from 3 h to 90 s and improved the yield from 70-75% to 90-95% in comparison with the conventional method. The suitable crystals for single crystal X-ray study were grown in (1:1) methanol and dichloromethane mixture.
With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 12h;
3-Fluoroisonicotinaldehyde (9.7 g, 78 mmol), 5- bromosalicylaldehyde (13 g, 65 mmol) and K2C03 (9.8 g, 71 mmol) were diluted with DMSO (125 mL). The reaction was heated to 70C and stirred for 12 hours. The reaction was allowed to cool, diluted with ethyl acetate and water. The layers were separated, and the organics were dried over MgS04, filtered and concentrated. The material was purified on silica gel eluting with 5-50% ethyl acetate/hexanes to yield 3-(4-bromo-2- formylphenoxy)isonicotinaldehyde (7 g, 23 mmol, 35% yield).
General procedure: A mixture of substituted O-benzylhydroxylamine hydrochloride (1 equiv), TEA (1 equiv) and substituted salicylaldehyde (1 equiv) was dissolved in absolute ethanol and stirred for 0.5 h. The reaction was monitored by TLC. The precipitate was filtered and recrystallized from ethanol to gain salicylaldoxime (compounds 1g-20g).
rac-(6bR,14S,14aR)-5-bromo-14-phenyl-14,14a-dihydro-6bH-benzo[5',6'][1,2]oxathiino [4',3':4,5]pyrano[3,2-c]quinolin-7(8H)-one 1,1-dioxide[ No CAS ]
rac-(6aR,7S,14bR)-2-bromo-7-phenyl-9,14b-dihydro-6aH-benzo[5',6'][1,2]oxathiino[4',3':4,5]pyrano[2,3-b]quinolin-14(7H)-one 6,6-dioxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%; 20%
General procedure: To a stirring solution of 2-hydroxybenzaldehyde derivative 1 (1.0 mmol), styrenesulfonyl chloride (0.20 g, 1.0 mmol), and K2CO3 (0.14 g, 1.0 mmol) in H2O (15 mL) for 2 h was added 4-hydroxycoumarin derivative 2 (1.2 mmol) or 4-hydroxyquinolinone (0.19 g, 1.2 mmol) and EDDA (20 mmol%) and the mixture was heated at reflux for 12 h. After completion of the reaction as indicated by TLC, the mixture was cooled to room temperature and the organics were extracted using CH2Cl2 (30 mL). Evaporation of the solvent under reduced pressure followed by column chromatography on silica gel using hexane-ethyl acetate (3:1), afforded products 3 and 4.
General procedure: A mixture of succinic dihydrazide (0.146 g, 1 mmol) and 2-hydroxy-3-methoxybenzaldehyde (0.380 g, 2.5 mmol) was refluxed in ethanol (30 mL) for 4 h. After this time the white product was filtered and washed with ethanol. Yield: 0.40 g (91%);
87%
In methanol; for 0.5h;Reflux;
General procedure: Succinoyldihydrazine was prepared by reacting diethyl succinate (10.0 g, 49.50 mmol) with hydrazine hydrate (5.50 g, 110.00 mmol) under reflux for 4 hrs and recrystallized from methanol. Dihydrazones were prepared by reacting a solution of succinoyldihydrazine (10.37 mmol) in methanol with aldehydes and ketones (25.93 mmol) in hot methanol and refluxing the reaction mixture for 30 min. The precipitate obtained on cooling the solution was thoroughly washed with methanol and air dried to give H4L1, H4L2 and H4L3 respectively. Yellow needle shape crystals of ligand (H4L2) suitable for X-ray crystallography was obtained by slow evaporation of DMSO solution.
General procedure: Preparation of N?-(2-hydroxybenzylidene)naphthalene-2-sulfonohydrazide (SA78). A methanol (20ml) solution of salicylaldehyde (122mg; 1mmol) and naphthalene-2-sulfonohydrazide (222mg; 1mmol) was refluxed for 2h. Solvent was evaporated at reduced pressure to an oily residue. This residue was mixed with ether (?10ml) and sonicated at 5C for 5min. Ether solution was decanted and mixed with hexane (?50ml). The resulting slightly milky mixture was left at room temperature for 1h. The formed white powdery product was separated by filtration, washed with hexane (3×5ml) and dried on air to give pure product (250mg; 77%).
(E)-5-((5-bromo-2-hydroxybenzylidene)amino)-1H-benzo[d]imidazol-2(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.8%
With acetic acid; In isopropyl alcohol;Inert atmosphere; Reflux;
5-Bromo-2-hydroxybenzaldehyde (0.1 g, 0.50 mmol), 5-Amino-2-benzimidazolinone (0.05 g, 0.33 mmol), and isopropyl alcohol (2 mL) were stirred at room temperature under N2. Acetic acid (0.7 mL) was added drop-wise, and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH2Cl2, MeOH, and dried to give 1 (0.09 g, 0.28 mmol, 84.8%) as a dark yellow powder.1H NMR (DMSO, 300 MHz) delta 13.84 (s, 1H), 11.27 (s, 1H), 11.21 (s, 1H), 9.36 (s, 1H), 8.27 (s, 1H), 7.93 (d, 1H, J=8.7Hz), 7.39 (d, 1H, J=8.7 Hz), 7.51-7.32 (m, 3H); 13C NMR (DMSO, 500 MHz) delta 159.95, 156.27, 141.50, 135.56, 134.57, 131.30, 130.21, 122.02, 119.62, 116.17, 110.44, 109.51, 101.55, 31.39. Rf=0.39 (CH2Cl2/MeOH 9:1)
84.8%
With acetic acid; In isopropyl alcohol;Inert atmosphere; Reflux;
5-Bromo-2-hydroxybenzaldehyde (0.1 g, 0.50 mmol), 5-amino-2-benzimidazolidinone (0.05 g, 0.33 mmol) and isopropyl alcohol (2 mL) were stirred at room temperature under N2 . Acetic acid (0.7 mL) was then added dropwise and the mixture was refluxed overnight. The mixture was filtered, washed with CH2Cl2, MeOH and dried to give compound 1 (0.09 g, 0.28 mmol, 84.8%) as a thick yellow powder.
5-bromo-3-(trifluoromethyl)-2,3-dihydrobenzofuran-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22%
A mixture of <strong>[373-88-6]2,2,2-trifluoroethanamine hydrochloride</strong> (65 g, 0.48 mol) and sodium nitrite (40 g, 0.58 mol) were dissolved in dichloromethane (2.1 L) and water (70 mL) and stirred for 1 hour in an ice bath under nitrogen. The yellow mixture was then cooled to -78 C and stirred at this temperature for 10 minutes. 5-bromo-2-hydroxybenzaldehyde (32 g, 0.16 mol) and BF3 Et20 (35 mL, 0.32 mol) were added. The mixture was stirred at -78 C for 3 hours. On completion, the mixture was allowed to warm to room temperature before being quenched with methanol (40 mL). Aqueous saturated sodium bicarbonate was added, and the resulting solution was extracted with dichloromethane (3 x 500 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 5: 1] to give compound B-209 (10 g, 22% yield) as a white solid.
General procedure: Following the same procedure described for the synthesis of derivatives 1-4, the nitro-3-benzoylcoumarin derivatives were prepared and were used without further purification. To a solution of the corresponding nitro-3-benzoylcoumarin (1 mmol) in pure ethanol (5 mL) was treated with SnCl2*2H2O and the resulting mixture was left under reflux for 3-7 h. After completion of reaction monitored by TLC, water was poured over the reaction mixture (15 mL), and the solution was further neutralized with a 5% NaHCO3 solution. Extraction was carried out with EtOAc (3 x 20 mL), the combined organic layers were dried over anhydrous Na2SO4 and solvent was completely removed. The crude was purified by flash chromatography (7:3 hexane/EtOAc) to afford the desired amino derivatives (5-12).
2-(2-(5-bromo-2-hydroxybenzylidene)hydrazino)-6-fluorobenzothiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With acetic acid; In ethanol; at 80℃; for 0.166667h;Microwave irradiation;
General procedure: A mixture of compound 2 (0.0549 g, 0.0003 mol), the appropriate aromatic aldehyde (0.00033 mol) and glacial acetic acid (0.1 mL) in ethanol (5 mL) was heated under microwave (20 W) at 80 °C for 10 min. On cooling, the precipitated solid was collected by filtration, washed with water, dried and crystallized to give compounds 3-29.
To a stirred solution of <strong>[367-34-0]2,4,5-trifluoroaniline</strong> (448mg, 3.05mmol) in absolute ethanol (10mL), 5-bromo-2-hydroxybenzaldehyde (604mg, 3.00mmol) was added. The resulting mixture was refluxed 6h. After cooling to room temperature, the orange product precipitated was washed with cold ethanol and petroleum ether. Yield: 0.798g (80.9%). 1HMMR (CDCl3 400MHZ) delta 12.69 (s, 1H, OH), 8.59 (s, 1H, HC=N), 7.54-7.44 (m, 2H, Ar-H), 7.17-7.04 (m, 2H, Ar-H), 6.95 (d, J=8.7Hz, 1H, Ar-H). IR: 3417, 3066, 1627, 1517, 1477, 1429, 1330, 1278, 1155, 869, 767, 719, 626. C13H7BrF3NO (330.1000): calcd. C 47.30, H 2.14, N 4.24; found C 47.36, H 2.07, N 4.29.
1-(3-((5-bromo-2-hydroxybenzylidene)amino)-2-hydroxyphenyl)ethan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
In ethanol; at 49.84℃; for 2h;
2.010 g of analytically pure 5-bromosalicylaldehyde and1.512 g of analytically pure 3-amino-2-hydroxyacetophenone,Dissolved in 30mL of analytical ethanol solution,Two hours after heating to reflux, Schiff base ligand H2brah was obtained.Yield 3.208g,Yield 96%.
In ethanol; for 2h;Reflux;
(1) will be 2.012g analyze pure 5 - bromosalicylaldehyde, 1.512g analyze pure 3 - amino -2 - hydroxy acetophenone, dissolved in 30 ml analytical pure ethanol solution, heating to reflux for two hours to obtain the ligand H2Brah.
4-bromo-2-((2-(6-chloropyridin-2-yl)hydrazono)methyl)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
In ethanol; for 5h;Reflux;
HL2 was synthesized by a similar way to HL1(Scheme 1), except that 5-chloro-2-hydroxybenzaldehyde wasreplaced by 5-bromo-2-hydroxybenzaldehyde (Hbhbd). Yellowpowder had been obtained by filtration, washed with ethanol (5mL 3) and dried in air (yield: 3.168 g, ca. 97%, based on Hbhbd).Anal. calc. for HL2 (%): C12H9BrClN3O (Mr = 326.58), calc.: C, 44.13;H, 2.78; N, 12.87; Found: C, 44.02; H, 2.86; N, 12.93. IR data forHL2 (KBr, cm1, Fig. S3): 3451, 3291, 1585, 1529, 1482, 1430,1380, 1315, 1259, 1191, 1123, 979, 931, 887, 835, 777, 702, 517.1H NMR (CDCl3, Fig. S4): d 11.36 (s, 1H), 10.44 (s, 1H), 8.25 (s,1H), 7.70 (d, J = 2.6 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.21 (dd, J =8.7, 2.7 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 7.5 Hz, 1H),6.91 (d, J = 8.7 Hz, 1H).
In ethanol; for 2h;Reflux;
1) 2.010 g of analytically pure 5-bromosalicylaldehyde and 1.436 g of analytically pure 2-chloro-6-hydrazinopyridine were dissolved in 30 mL of analytically pure ethanol and heated under reflux for two hours to give the ligand Hbchp.
In ethanol; for 2h;Reflux;
(1) 2.010g of analytically pure 5-bromosalicylaldehyde and 1.436g of analytically pure 2-chloro-6-hydrazinopyridine were dissolved in 30mL of analytically pure ethanol and heated under reflux for two hours to obtain the ligand Hbchp .
In ethanol; for 2h;Reflux;
(1) 2.010 g of analytically pure 5-bromosalicylaldehyde, 1.436 g of analytically pure 2-chloro-6-mercapto-pyridine dissolved in 30 mLAnalyze pure ethanol solution and heat reflux for two hours to obtain ligand Hbchp.
In ethanol; for 2h;Reflux;
(1) 2.010 g of analytically pure 5-bromosalicylaldehyde,1.436g of analytically pure 2-chloro-6-hydrazinopyridine,Soluble in 30 mL of analytically pure ethanol solution,The ligand Hbchp was obtained after heating under reflux for two hours.
In ethanol; for 2h;Reflux;
(1) 2.010 g of analytically pure 5-bromosalicylaldehyde and 1.436 g of analytically pure 2-chloro-6-mercapto-pyridine are dissolved in 30 mL of analytically pure ethanol and heated to reflux for two hours to obtain a ligand. Hbchp.
9-bromo-5-methyl-2-phenyl-11,12-dihydro-5,11-methano[1,2,4]triazolo[1,5-c][1,3,5]benzoxadiazocine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With hydrogenchloride; In 1,4-dioxane; ethanol; at 150℃; for 0.5h;Microwave irradiation; Sealed tube;
General procedure: 3-Amino-1,2,4-triazole 8a?f (1.0 mmol), o-hydroxybenzaldehyde9a?e (1.0 mmol), acetone (10) (0.22 ml,3.0 mmol), and abs. EtOH (2 ml) were mixed in amicrowave process vial, and then 4 N solution of HCl indioxane (0.07 ml, 0.3 mmol) was added. The mixture wasirradiated at 150°C for 30 min. The reaction mixture wascooled by an air flow and stirred for 24 h at roomtemperature for complete precipitation of the product. Theprecipitate was filtered off, washed with EtOH (1 ml) andEt2O (3×1 ml), and dried. Compounds 1a?w were obtainedin a form of white solids.
2-((E)-(4-bromo-2-chlorophenylimino)methyl)-4-bromophenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80.83%
In benzene; at 55 - 60℃; for 2h;
General procedure: Schiff base was prepared by standard literature procedure[24,25]. The ligands 2-((E)-(4-bromo-2-chlorophenylimino)methyl)-4-bromophenol (HL1) and1-((E)-(4-bromo-2-chlorophenylimino)methyl)naphthalene-2-ol (HL2) were preparedby the following general procedure. To a stirred solution of <strong>[38762-41-3]4-bromo-2chlorobenzenamine</strong> (0.206 g, 1.0 mM)in 5 ml dry benzenewas added dropwise in 5 mL benzene solution of 5-bromo-2-hydroxybenzaldehyde (0.201 g, 1.0 mM) for HL1, added dropwise in5 mL benzene solution of 2-hydroxynapthalene-1-carbaldehyde(0.172 g, 1.0 mM) for HL2 and refluxed at 55-60 C for 2 h, themixture was filtered off, precipitatewas collected on a suction filterto afford HL1and HL2 as yellow powder. The obtained solids weredried in air and stored in a CaCl2 desiccator at RT. Yellow crystals ofSchiff base(HL1) suitable for X-ray analysis were obtained by crystallizationof the product in CHCl3 after seven days. The crystalswere filtered off and washed with cold ethanol and dried in air andstored in a CaCl2 desiccator at RT.For HL1(Yield: 329 mg, 80.83%), m.p.:148e149 C. Anal. Calc. forC13H8Br2ClNO (389.47): C, 40.09; H, 2.07; N, 3.60%. Found: C,40.01; H, 2.05; N, 3.54%.
3-(5'-sulfonylamine-2'-benzoxazole)-6-bromo-2H-1-benzopyran-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
In butan-1-ol; for 7h;Reflux;
General procedure: Salicylaldehyde (2 mmol), ethyl cyanoacetate (2 mmol), and o-aminophenol(2 mmol) were mixed in n-BuOH (20 mL), and the solution was refluxed for 7 h.The solvent was removed, and the residue was suspended in EtOH (10 mL) and stirred with 1 percent NaOH (10 mL) for 30 min. After filtration and washing with water,the product was obtained as yellow solid.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3h;
General procedure: To a DMF (25 mL) solution of 5- bromo -2-hydroxybenzaldehyde (500 mg, 2.5 mmol) were added potassium carbonate powder (518 mg, 3.75 mmol) and (R)-oxiran-2-ylmethyl 4-methylbenzenesulfonate (741 mg, 3.25 mmol). The resulting suspension was heated to 80C for 3 h. The reaction mixture was cooled to ambient temperature and added AcOEt and water. The extracts are combined, and washed by brine, then dried over anhydrous Na2SO4. The mixture was concentrated in vacuo and purified by column chromatography (ethyl acetate: petroleum ether =1:10) to give compound (R)-10 (475 mg, 74%) as a white solid.
With dihydrogen peroxide; acetic acid; In ethanol; for 12h;Reflux;
BIPP was prepared by a modified procedure [44,45]. The mixture of 21 5-bromosalicylaldehyde (1.00mmol, 1equiv), dap (1.00mmol, 1equiv), five drops of 22 hydrogen peroxide H2O2 (30percent aqueous) and three drops of 23 HOAc (2.00mol·L?1) was refluxed in 24 ethanol (20mL) for 12h. After completion of the reaction, the mixture was cooled to room temperature and the solvent was concentrated in vacuo. After filtration, the yellow desired precipitate was washed by cold ethanol and dried in vacuo. Yield: 73percent. 1H NMR (400MHz, DMSO-d6, delta, ppm): 13.997 (s, 1H, NH), 12.852 (s, 1H, OH), 9.064 (br, 2H), 8.879 (d, J=7.6Hz, 2H), 8.370 (d, J=2.4Hz, 1H), 7.849 (s, 2H), 7.533 (dd, J=8.8Hz, J?=2.0Hz, 1H), 7.061 (d, J=8.4Hz, 1H)
2-(5-bromo-2-hydroxyphenyl)-1H-benzo[d]imidazole-5-sulfonic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With sodium metabisulfite; In ethanol; water; for 24h;Reflux;
General procedure: To a solution of the appropriate 3,4-diaminobenzene derivative (1ad)(2 mmol) in ethanol (15 mL) 2.85 N aqueous solution of sodium metabisulphite (1.6 mL) and the appropriate substituted arylaldehyde(2 mmol) were added. The reaction mixture was heated at reflux for 24 h. The solvent was then evaporated under reduced pressure. The residue was added with HCl 1 N (10 mL), the formed precipitate was filtered off, washed with water (3×10 mL) and purified by crystallization from the adequate solvent to give the title compounds.Following the general procedure benzimidazoles 3 [19], 4 [20], 5 [21],7 [24], 6, 32 and 33 [15] were prepared and their analytical and spectral data are in agreement with those reported in literature.
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