* 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] Synlett, 1997, # 12, p. 1395 - 1396
[2] Synlett, 1997, # 12, p. 1395 - 1396
2
[ 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
3
[ 89-55-4 ]
[ 2316-64-5 ]
Yield
Reaction Conditions
Operation in experiment
60%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 16 h; Stage #2: With hydrogenchloride In tetrahydrofuran; water
Step 3 4-Bromo-2-(hydroxymethyl)phenol: A solution of 5-bromo-2-hydroxybenzoic acid (21.7 g; 100 mmol; 1.00 equiv) in tetrahydrofuran (200 mL) was added to a suspension of lithium aluminum hydride (5.7 g; 150 mmol; 1.50 equiv) in tetrahydrofuran (100 mL). The suspension was virgously stirred for about 16 hours at ambient temperature and then quenched by adding 3M hydrochloric acid (300 mL). Following standard extractive workup with ethyl acetate, the crude residue was re-crystallized from ethyl acetate/hexane (1/10) to give the title product as gray solid (12.4 g; 60percent yield). 1H NMR (400 MHz, CDCl3) 6: 9.68 (s, 1H), 7.39 (s, 1H), 7.19 (dd, J=2.0, 2.0 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 5.10 (s, 1H), 4.44 (s, 2H).
Reference：
[1] Patent: US5587392, 1996, A,
[2] Patent: US2010/9950, 2010, A1, . Location in patent: Page/Page column 20
[3] Chemische Berichte, 1906, vol. 39, p. 2938
[4] Journal of Organic Chemistry, 2006, vol. 71, # 9, p. 3646 - 3649
4
[ 90-01-7 ]
[ 2316-64-5 ]
Reference：
[1] Journal of the American Chemical Society, 1923, vol. 45, p. 2419
[2] Justus Liebigs Annalen der Chemie, 1988, vol. 302, p. 138
[3] Patent: US4217360, 1980, A,
5
[ 82944-17-0 ]
[ 2316-64-5 ]
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 9, p. 3646 - 3649
6
[ 50-00-0 ]
[ 106-41-2 ]
[ 2316-64-5 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 19, p. 3100 - 3107
7
[ 106-41-2 ]
[ 2316-64-5 ]
Reference：
[1] Patent: US4814343, 1989, A,
8
[ 5532-69-4 ]
[ 2316-64-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1898, vol. 302, p. 145
9
[ 886504-46-7 ]
[ 2316-64-5 ]
Reference：
[1] J. Soc. chem. Ind. Japan Spl., vol. 31, p. 253 B[2] Chem. Zentralbl., 1929, vol. 100, # I, p. 383
10
[ 90-01-7 ]
[ 7732-18-5 ]
[ 7726-95-6 ]
[ 2316-64-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1898, vol. 302, p. 145
11
[ 5532-69-4 ]
[ 7732-18-5 ]
[ 67-64-1 ]
[ 36138-76-8 ]
[ 2316-64-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1898, vol. 302, p. 145
12
[ 2316-64-5 ]
[ 95-54-5 ]
[ 62871-28-7 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2018, vol. 360, # 18, p. 3563 - 3571
13
[ 2316-64-5 ]
[ 2362-12-1 ]
Reference：
[1] Synthesis, 2005, # 15, p. 2479 - 2481
Example 11 Synthesis of 4-bromo-2-hydroxymethylphenol Under ice cooling, the solution of 5-bromosalicylic acid (21.7 g) in ether (200 ml) was slowly added dropwise to the suspension of LiAlH4 (5.7 g) in ether (200 ml). After stirring at room temperature for 30 minutes, the reaction solution was slowly poured into 3N HCl with floating ice for extraction with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The oily residue generated after the evaporation of the solvent under reduced pressure was crystallized from ether-hexane, and the crystal was filtered, to give the title compound (15.5 g; 76.5%).
60%
Step 3 4-Bromo-2-(hydroxymethyl)phenol: A solution of 5-bromo-2-hydroxybenzoic acid (21.7 g; 100 mmol; 1.00 equiv) in tetrahydrofuran (200 mL) was added to a suspension of lithium aluminum hydride (5.7 g; 150 mmol; 1.50 equiv) in tetrahydrofuran (100 mL). The suspension was virgously stirred for about 16 hours at ambient temperature and then quenched by adding 3M hydrochloric acid (300 mL). Following standard extractive workup with ethyl acetate, the crude residue was re-crystallized from ethyl acetate/hexane (1/10) to give the title product as gray solid (12.4 g; 60% yield). 1H NMR (400 MHz, CDCl3) 6: 9.68 (s, 1H), 7.39 (s, 1H), 7.19 (dd, J=2.0, 2.0 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 5.10 (s, 1H), 4.44 (s, 2H).
In neat (no solvent) at 20℃; for 0.05h; Microwave irradiation;
General procedure
General procedure: In a small-scale experiment 4-hydroxypyridinium chlorochromate functionalized silica gel (3.95 g, contain 10 mmol of 4-hydroxypyridinium chlorochromate) an alcohol (10 mmol) was rapidly added at room temperature and the resulting mixture stirred vigorously for the appropriate time. The mixture was irradiated for the time indicated in the table by microwave radiation (Table 2). The progresses of the reactions were monitored by TLC. After cooling to room temperature the product was extracted with diethyl ether (2 × 10 mL) and filtered. Evaporation of solvent gave a crude product which was passed through a short silica gel column by ethyl acetate: pet.ether (1:7) as eluent to afford the pure product. The structures of the products were confirmed by their melting point, IR and /or NMR spectral data and comparison with commercially available authentic samples.36-38
With potassium dichromate; sulfuric acid
With oxygen In aq. buffer at 45℃; Green chemistry;
With sodium tetrahydridoborate; Dowex1-x8 In tetrahydrofuran at 20℃; for 0.01h;
98%
With sodium tetrahydridoborate; ethanol at 0 - 5℃; for 2h;
1.1; 2.1; 3.1; 4.1 Example 1
1) Dissolve 5-bromosalicylaldehyde (40.2g, 200mmol) in absolute ethanol (400mL) in a 1L three-necked flask, cool the system to 0-5°C, add sodium borohydride (9.1g, 240mmol), and complete the addition. After stirring for 2 hours, the reaction was stopped and concentrated under reduced pressure. The residue was added with 1N hydrochloric acid (400mL) and ethyl acetate (200mL) for liquid separation. The organic phase obtained by extraction was washed with water (400mL), dried with anhydrous sodium sulfate, and pumped. After filtration, the filtrate was concentrated under reduced pressure and dried to obtain 39.8 g of intermediate I, with a yield of 98%, as a white solid.
96%
With sodium tetrahydridoborate In acetonitrile at 20℃; for 0.05h;
96%
With sodium tetrahydridoborate In tetrahydrofuran; water monomer at 20℃; for 0.0333333h;
95%
With sodium tetrahydridoborate; sodium hydrogen sulphate In acetonitrile at 20℃; for 0.0333333h;
94%
With Zn(BH4)2(bpy) In acetonitrile at 20℃; for 0.0166667h;
94%
With sodium tetrahydridoborate In tetrahydrofuran at 20℃; for 0.1h; ultrasound irradiation;
91%
With lithium aluminium hydride In tetrahydrofuran for 3h; Heating;
89%
With lithium aluminium hydride In tetrahydrofuran for 3h;
84%
With sodium tetrahydridoborate In ethanol at 0 - 20℃; for 18h; Schlenk technique; Inert atmosphere;
2.1. Synthesis of 5-bromo-2-hydroxybenzyl alcohol [7]
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, 84%);
84%
With sodium tetrahydridoborate In ethanol at 0 - 20℃; for 18h; Inert atmosphere;
79%
With methanol at 20℃; Neat (no solvent);
79%
With sodium tetrahydridoborate In methanol at 0℃; for 2.08333h;
76%
Stage #1: 5-bromosalicyclaldehyde With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; C6H13ClO2Si; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;
Stage #2: With N,N,N-tributylbutan-1-aminium fluoride In tetrahydrofuran; dichloromethane Inert atmosphere;
With sodium hydroxide; sodium tetrahydridoborate
With hydrogen In ethanol; water monomer
With sodium tetrahydridoborate In tetrahydrofuran; water monomer at 0℃;
With lithium aluminium hydride
With sodium tetrahydridoborate In ethanol at 0 - 20℃; for 1h;
With sodium tetrahydridoborate In tetrahydrofuran; water monomer at 20℃; for 0.0833333h;
With sodium tetrahydridoborate In tetrahydrofuran at 0℃;
With sodium tetrahydridoborate; ethanol at 0℃; for 2h;
B Step B: 4-bromo-2-(hvdroxymethyl)phenol.
To a cooled (0° C) ethanol (50 mL) solution of 4-bromosalicaldehyde (5.00 g, 24.9 mmol) was added NaBH4 (941 mg, 24.9 mmol) in a single portion. After 2 h, the mixture was quenched with 1 N HC1 (50 mL) and poured into a separatory funnel. The mixture was partitioned between brine (100 mL) and EtOAc (2 x 100 mL). The combined orgainc layers were dried (MgS04), concentrated, and purified by HPLC (ISCO, 0 to 50% EA/Hex) to give the product. 1H NMR (500 MHz, MeOD) δ 7.41 (s, 1H), 7.19 (d, 1H), 6.68 (d, 1H), 4.60 (s, 2H).
Multi-step reaction with 2 steps
1: dichloro(p-cymene)ruthenium(II) dimer / benzene / 4.5 h / 20 °C / Inert atmosphere; Glovebox
2: hydrogenchloride; water monomer / methanol / 1 h / Reflux
With sodium tetrahydridoborate In ethanol at 0 - 20℃; for 2h;
With sodium tetrahydridoborate In tetrahydrofuran; water monomer at 20℃; for 0.0833333h;
150 g
With sodium tetrahydridoborate; ethanol at 0 - 20℃; for 5h;
1.6 Step 6: Synthesis of Compounds 1-8
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.
With sodium tetrahydridoborate In ethanol at 0 - 20℃; for 1h;
With sodium tris(acetoxy)borohydride In acetonitrile at 20 - 25℃; for 0.5h; Inert atmosphere;
With sodium tetrahydridoborate In ethanol at 0 - 20℃; for 2h; Inert atmosphere;
With potassium acetate In 1,4-dioxane for 2h; Heating / reflux;
1
To a 0.18 M solution of 5-bromo-2-hydroxybenzyl alcohol (1 equiv) in dioxane was added bis(pinacolato)diboron (1.2 equiv) and potassium acetate (3.5 equiv) followed by 1,1'- bis(diphenylphosphino)ferrocene (0.05 equiv). The mixture was degassed with nitrogen for 20 minutes. PdCl2(dppf) (0.05 equiv) was added and the misxture degassed for a further 5 minutes. The reaction was then heated to reflux under an inert atmosphere for 2 hours. Upon completion, the reaction was cooled, filtered and concentrated in vacuo to give a crude residue which was purified by flash chromatography (SiO2) using EtOAc/Hexanes - 1:1 as eluent to give the desired product.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
[164.2] 3-Bromo-2-hydroxybenzyl alcohol (100 g) was dissolved in 1 L of N,N-dimethylformamide, and 84 g of benzyl bromide and 80 g of potassium carbonate were added successively to the solution. The mixture was stirred overnight at room temperature, the reaction mixture was filtered through Celite, and the filtrate was diluted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated, to give 140.3 g of the title compound.1H-NMR(CDCl3) delta: 2.21(br, 1H) 4.69 (s, 2H) 5.09 (s, 2H) 6.81 (d, J=8.8Hz, 1H) 7.33-7.40 (m, 6H) 7.45 (d, J=2.4Hz, 1H)
1-(5-bromo-2-hydroxybenzyl)-3-methylnaphthalen-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With potassium carbonate; In acetonitrile; at 150℃;Microwave irradiation;
General procedure: 2-(hydroxymethyl)phenols (1.5 mmol) in acetonitrile solution (2 mL) was combined with <strong>[17324-04-8]3-methyl-2-naphthol</strong>(1 mmol) and stoichiometric amount of K2CO3 (1 equiv.). The obtained mixture was hearted at 150 C for 1.5 ~2h under irradiation of microwave using Anton Paar Monowave 300. After microwave irradiation, the reactionmixture was extracted with ethyl acetate (10 mL x 2) and combined organic layers were dried over anhydrousNa2SO4 and concentrated in vacuo. The residue was subjected to chromatography on silica gel with hexanesand ethyl acetate (20:1 to 10:1) to obtain the desired product.
2,7-dibromo-3-nitro-9H-benzo[e]pyrazolo[5,1-b][1,3]oxazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
In N,N-dimethyl-formamide;Reflux;
General procedure: 3,4,5-Tribromopyrazole (9a; 762 mg, 2.5 mmol) or <strong>[104599-36-2]3,5-dibromo-4-nitropyrazole</strong>(9b; 677 mg, 2.5 mmol), o-quinone methide precursor 2(2.5 mmol) and K2CO3 (only for 9a, 1.035 g, 7.5 mmol) were refluxedfor 4 h in DMF (10 mL). Product was isolated analogously to compound4a.
With toluene-4-sulfonic acid; In chloroform; for 18h;Reflux;
To a solution of 5-bromo-2-hydroxybenzyl alcohol (102 g, 0.5mol) and N-Boc-4- piperidone (140 g, 0.7mmol) in chloroform (700 mL) was added p-toluenesulphonic acid (10 g). The mixture was heated at reflux for 18 h, during which time condensate (5x 50 mL) was removed and replaced with equal volume of fresh dry chloroform. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (500 mL) and washed with a 2M sodium hydroxide solution (100 mL) and brine (300 mL). The organic layer was dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by column chromatography (silica gel, 20% EtOAc (Ethyl Acetate) in petrol ether to 30% EtOAc in petrol ether) to give the title compound A3 (115 g, 60% yield).
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