* 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 sodium tetrahydroborate In ethanol at 20℃; for 2 h;
To a solution of 3,5-dichlorobenzaldehyde (340 mg, 1.94 mmol) in ethanol (4 mL)Sodium borohydride (74 mg, 1.94 mmol) was added.After stirring at room temperature for 2 hours, 1N hydrochloric acid was added to quench the reaction. The solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (10 mL), washed with 1N hydrochloric acid and then water (10 mL×2), and the organic phase was dried over anhydrous sodium sulfate. After concentration, the product 3-e (320 mg) was obtained. 94percent).
90%
Stage #1: With Triethoxysilane; [cis-Fe(H)(SPh)(PMe3)4] In tetrahydrofuran at 50℃; for 2 h; Stage #2: With methanol; sodium hydroxide In tetrahydrofuran; water at 60℃; for 24 h;
General procedure: To a 25 mL Schlenk tube containing a solution of 1 in 2 mL of THF was added an aldehyde (1.0 mmol) and (EtO)3 SiH (0.20 g, 1.2 mmol). The reaction mixture was stirred at 50–55 °C until there was no aldehyde left (monitored by TLC and GC–MS). The reaction was then quenched byMeOH (2mL) and a 10percent aqueous solution of NaOH (5 mL) with vigorous stirring at 60 °C for about 24 h.The organic product was extracted with diethyl ether (10 mL × 3), dried over anhydrous MgSO4, and concentrated under vacuum. The alcohol product was further purified using flash column chromatography (elute with 5–10percent ethyl acetate in petroleum ether). The 1H NMR and 13C NMR spectra of the alcohol products are providedin Supporting information.
90%
With Triethoxysilane; potassium phenyltrifluoborate In methanol at 20℃; for 0.166667 h;
Take a 25mL reaction bottle,Place a magnet in the bottle.Weigh 2,6-dichlorobenzaldehyde (0.131 g, 0.75 mmol),Potassium phenyl trifluoroborate (2.5percent eq. 3.5 mg),Add 3 mL of methanol to the reaction flask as a solvent.The pipette was then used to remove trimethoxysilane (2.2 eq. 202 μL).The reaction is carried out in an air atmosphere at room temperature.The progress of the reaction was detected by TLC.After 10 minutes, it was extracted with dichloromethane (3×40 mL).The dichloromethane phases were combined and washed with 40 mL of deionized water.Dry over anhydrous sodium sulfate,Rotary evaporation to remove the solvent,Column chromatography gave 120 mg of the product as a white solid.Yield 90percent;The NMR is as follows:
Reference：
[1] ChemMedChem, 2016, vol. 11, # 23, p. 2607 - 2620
[2] Patent: CN103304571, 2018, B, . Location in patent: Paragraph 0142; 0143; 0144
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[5] Patent: CN109020779, 2018, A, . Location in patent: Paragraph 0049; 0050
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[7] Tetrahedron Letters, 1983, vol. 24, # 40, p. 4287 - 4290
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[9] RSC Advances, 2018, vol. 8, # 25, p. 14092 - 14099
[10] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 19, p. 3131 - 3132
[11] Journal of Organic Chemistry, 1999, vol. 64, # 9, p. 3230 - 3236
[12] Journal of Organic Chemistry, 1956, vol. 21, p. 142
[13] Chemical and pharmaceutical bulletin, 1967, vol. 15, # 12, p. 1990 - 1995
[14] Organometallics, 2013, vol. 32, # 18, p. 5235 - 5238
[15] Organic and Biomolecular Chemistry, 2014, vol. 12, # 30, p. 5781 - 5788
[16] ACS Catalysis, 2015, vol. 5, # 9, p. 5540 - 5544
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[19] Catalysis Science and Technology, 2017, vol. 7, # 13, p. 2828 - 2837
[20] Patent: WO2017/212289, 2017, A1, . Location in patent: Page/Page column 19; 20
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2
[ 14920-87-7 ]
[ 15258-73-8 ]
Yield
Reaction Conditions
Operation in experiment
95%
With zinc(II) tetrahydroborate In ethanol at 78℃; for 3 h;
Add 100 ml of absolute ethanol to the four-necked flask and heat to reflux.15 g of the raw material methyl 2,6-dichlorobenzoate was added to the ethanol.10 g of zinc borohydride was slowly added thereto, and the reaction was stirred at 78 ° C for 3 h.After the GC reaction was completed, the solvent was evaporated to dryness to obtain 12 g.2,6-dichlorobenzyl alcohol.The product yield was 95percent and the purity was 98percent.
Reference：
[1] Patent: CN108794297, 2018, A, . Location in patent: Paragraph 0007; 0008; 0009
With oxalyl dichloride; In dichloromethane; at 20℃;Reflux;
General procedure: To 16 (0.6 g, 0.6 mmol) was added dichloromethane (5 mL) in a round-bottom flask. After 10 min, oxalyl chlorideor oxalyl bromide was added (0.6 mmol). The reaction mixture was magnetically stirred at room temperature. Uponcessation of gas evolution, 4 was added (0.5 mmol), and the reaction mixture was heated to reflux. After thereaction was complete according to TLC analysis, the mixture was cooled to room temperature and filtered. Thesolid on the funnel was washed with dichloromethane (3 × 10 mL), and the filtrate was concentrated under reducedpressure to afford the desired product 5 in an essentially pure state based on 1H and 13C NMR spectroscopicanalyses.
With Oxalyl bromide; In dichloromethane; at 20℃;Reflux;
General procedure: To 16 (0.6 g, 0.6 mmol) was added dichloromethane (5 mL) in a round-bottom flask. After 10 min, oxalyl chlorideor oxalyl bromide was added (0.6 mmol). The reaction mixture was magnetically stirred at room temperature. Uponcessation of gas evolution, 4 was added (0.5 mmol), and the reaction mixture was heated to reflux. After thereaction was complete according to TLC analysis, the mixture was cooled to room temperature and filtered. Thesolid on the funnel was washed with dichloromethane (3 × 10 mL), and the filtrate was concentrated under reducedpressure to afford the desired product 5 in an essentially pure state based on 1H and 13C NMR spectroscopicanalyses.
With dmap; triethylamine; In dichloromethane; at 5 - 20℃;
Preparation 38; Acetic acid 2,6-dichloro-benzyl ester; Add 500 mL of dichloromethane to 100 g of <strong>[15258-73-8]2,6-dichlorobenzyl alcohol</strong> followed by 117 mL of triethylamine. Cool the solution to 5C and add 65 mL of acetic anhydride. After 2.5 hr at room temperature, add another 10 mL of acetic anhydride, 20 mL of triethylamine and 0.5 g of 4-dimethylaminopyridine. Wash the organic layer with IN HCl followed by saturated aqueous sodium bicarbonate and brine. Dry the organic layer (sodium sulfate) and evaporate to afford 131.5 g of the titled compound as an oil.
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; for 18h;
To a solution of I-5 (0.126 g, 0.43 mmol), 2,6-dichlorobenzylalcohol (0.075 g, 0.43 mmol) and PPh3 (0.113 g, 0.43 mmol) in dry THF (4 mL) at 0 C. under Ar is added DEAD (0.068 mL). The reaction mixture is permitted to warm to rt, and is stirred for 18 h. It is concentrated, and the residue is purified by silica flash chromatography (700:300:1 hexanes/EtOAc/iPrOH) to give 0.149 g of the title compound: TLC (7:3 hexanes/EtOAc) Rf 0.34; 1H NMR (CDCl3, 300 MHz) delta 8.31 (1H), 7.37 (2H), 7.25 (2H), 7.08 (1H), 5.81 (1H), 5.29 (2H), 4.65 (1H), 3.70 (3H), 3.24 (2H), 1.63 (1H), 1.43 (9H).
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; for 18h;
To a solution of M-5 (0.126 g, 0.43 mmol), 2,6-dichlorobenzylalcohol (0.075 g, 0.43 mmol) and PPh3 (0.113 g, 0.43 mmol) in dry THF (4 mL) at 0 C under Ar is added DEAD (0.068 mL). The reaction mixture is permitted to warm to room temperature, and is stirred for 18 h. It is concentrated, and the residue is purified by silica chromatography: TLC (7:3 hexanes/EtOAc) Rf = 0.34; 1H NMR (CDCl3, 300 MHz) delta 8.31 (m, 1H), 7.37 (m, 2H), 7.25 (m, 2H), 7.08 (m, 1H), 5.81 (m, 1H), 5.29 (s, 2H), 4.65 (m, 1H), 3.70 (s, 3H), 3.24 (m, 2H), 1.63 (m, 1 H), 1.43 (s, 9H); 13C NMR (CDCl3, 75 MHz) delta 172.47, 155.50, 153.82, 149.71, 137.33, 137.00, 131.51, 130.72, 128.56, 123.99, 122.78, 79.74, 65.64, 53.25, 52.27, 38.43, 28.33 (3C); MS (+ESI) m/z 454.9 [M + H]+
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; for 3h;
To a solution of H-2 (5.11 g, 20.0 mmol), PPh3 (5.30 g, 20.0 mmol), and 2,6-dichlorobenzylalcohol (3.54 g, 20.0 mmol) in dry THF (100 mL) at 0 C. under Ar is added DEAD (3.15 mL, 20.0 mmol). The reaction mixture is kept at 0 C. for 1.5 h and at rt for 1.5 h. It is concentrated to a residue, that is purified by silica flash chromatography (17:3 hexanes/EtOAc) to give 7.61 g of the title compound: TLC (1 7:3 hexanes/EtOAc) Rf 0.57; 1H NMR (CD3SOCD3, 300 MHz) delta 7.85 (1H), 7.62 (1H), 7.58-7.45 (3H), 5.34 (2H).
piperazine-1-carboxylic acid 2,6-dichloro-benzyl ester hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 16 Piperazine-1-carboxylic acid 2,6-dichloro-benzyl ester hydrochloride was prepared from <strong>[15258-73-8]2,6-dichlorobenzyl alcohol</strong>; MS (ISP): 289.1 MH+.
1-(2-Butenyl)-7-(2,6-dichlorobenzyloxy)-2,3-dimethylpyrrolo[2,3-d]pyridazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83.5%
EXAMPLE 49 1-(2-Butenyl)-7-(2,6-dichlorobenzyloxy)-2,3-dimethylpyrrolo[2,3-d]pyridazine The title compound (cis/trans=21:79) was prepared as a pale yellow powder in 83.5% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=24/76) and <strong>[15258-73-8]2,6-dichlorobenzyl alcohol</strong>. m.p.: 133-140 C. Mass spectrum (CI, m/z): 376 (M+ +1), 378 (M+ +3), 380 (M+ +5). NMR spectrum (CDCl3, deltappm): 1.34-1.60 (m, 3H), 2.24 (s, 3H), 2.30 (s, 3H), 4.71 (d;J=6 Hz, 1.58H), 4.89 (d;J=6 Hz, 0.42 Hz), 5.02-5.50 (m, 2H), 5.94 (s, 2H), 7.19-7.47 (m, 3H), 8.99 (s, 1H). Elementary analysis (%): Calc'd for C19 H19 Cl2 N3 O: C, 60.65; H, 5.09; N, 11.17, Found: C, 60.53; H, 5.03; N, 11.17.
With HBF4; In diethyl ether; dichloromethane; water;
b) In a reaction vessel equipped with stirrer and thermometer, 14.1 g (40 mmol) of bis(2,6-dichlorobenzyl) sulfide and 9.5 g (53.6 mmol) of <strong>[15258-73-8]2,6-dichlorobenzyl alcohol</strong> are dissolved under a N2 atmosphere in 72 ml of methylene chloride. 18.53 g (114 mmol) of hydrogen tetrafluoroborate (54% in diethyl ether) are added dropwise at an inside temperature of 20-30 C. over a period of 20 minutes with stirring, and the reaction mixture is stirred for 4 hours. Afterwards, another 2.26 g (13.9 mmol) of HBF4 are added to the reaction mixture at RT, and stirring is continued for 1 hour. The reaction mixture is filtered, and the solvent is removed on a rotary evaporator. The residue is stirred in 100 ml of water at RT, the mixture is filtered, and the residue is dried at RT overnight in a high vacuum. This gives 17.49 g (74.25% of theory) of tris(2,6-dichlorobenzyl)sulfonium tetrafluoroborate in the form of white crystals of decomposition point 185-195 C.
trans-6-(2,6-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
trichlorophosphate; In diethyl ether;
(a) Cis- and trans-6-(2,6-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran To a solution of 1.34 g of 2-tosyloxymethyl-3,4-dihydro-2H-pyran and 1.06 g of <strong>[15258-73-8]2,6-dichlorobenzyl alcohol</strong> in 25 ml of diethyl ether was added a catalytic amount (2 drops) of phosphorus oxytrichloride, and then the mixture was stirred at room temperature for 4 days. The colourless crystals which had precipitated were filtered off, giving 1.582 g of trans-6-(2,6-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran, melting at 123-124 C.
2,6-Dichlorobenzyl alcohol (1.1 mmol) was dissolved in dry DMF (5 ml) and treated with sodium hydride (60% dispersion in mineral oil, 1.21 mmol). The mixture was stirred at room temperature for 30 mins, then treated with lithium-5-chloro-pyrazine-2- carboxylate (1 mmol) and stirred at reflux overnight. The reaction mixture was partitioned between ethyl acetate and water, then the organic layer was separated, dried [(MGSO4),] filtered, evaporated and the residue purified by column chromatography on silica. Elution with mixtures of petroleum ether and diethyl ether afforded the title product. MS (ES): m/e 300 (M+H).
[Example 10] Synthesis of sodium 2,6-dichlorobenzyloxymethyl trifluoroborate To the mixture of sodium hydride (61 %, 180 mg, 4.5 mmol) and tetrahydrofuran (6 ml), <strong>[15258-73-8]2,6-dichlorobenzyl alcohol</strong> (740 mg, 4.2 mmol) was added at 0C (an outer temperature), and the obtained reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture, 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (92%, 500 mg, 2.1 mmol) synthesised in Production Example 2 and dissolved in tetrahydrofuran (4 ml) was added at 0C (an outer temperature), and the obtained mixture was stirred at 30C (an outer temperature) overnight. After cooling the reaction mixture to 0C (an outer temperature), sodium hydrogen fluoride (590 mg, 4.5 mmol) was added to the reaction mixture at the same temperature, followed by the dropwise addition of water (8 ml) at the same temperature. After stirring the reaction mixture for 30 minutes at room temperature, the solvents were evaporated under reduced pressure. Acetone (40 ml) was added to the obtained residue, followed by filtration. The solvents were evaporated under reduced pressure from the filtrate, and then the obtained residue was washed with diethyl ether, thereby obtaining the entitled compound (460 mg, 78%). 1H-NMR Spectrum (DMSO-d6) delta(ppm): 2.61(2H, q, J=5.4Hz), 4.46(2H, s), 7.30-7.35(1H, m), 7.44(2H, d, J=8.0Hz)
To an ice cooled solution of (2, 6-dichloro-phenyl)-methanol (5 G, 28. 2 MMOL) in anhydrous tetrahydrofuran (200 mL) was added sodium hydride (1. 13 G, 28. 2 mmol, 60% disp.) slowly under nitrogen atmosphere. After stirring for 30 minutes, 3, 5-dibromo-pyrazin-2-ylamine (7. 08 g, 28. 2 MMOL) in anhydrous tetrahydrofuran (50 mL) was added via an addition funnel. Once the addition was complete the ice bath was removed and the reaction was REFLUXED under nitrogen and monitored by reversed phase HPLC. After 18 hr HPLC showed that the majority of the starting 3, 5-dibromo-pyrazin-2- ylamine had been consumed and the reaction was allowed to cool to room temperature. The reaction mixture was concentrated in vacuum until 50 mL remained. The mixture was diluted with ethyl acetate (200 mL) and extracted with 50% brine (2 X 200 ML). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuum. The crude product was purified using a silica gel column ELUTING with 1 : 1 ETHYL ACETATE/DICHLOROMETHANE TO YIELD 5-BROMO-3- (2, 6-DICHLORO-BENZYLOXY)- PYRAZIN-2-YLAMINE as a white solid (8. 17 G, 83% yield).
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 4h;
Step A: Preparation of 4-(2,6-Dichlorobenzyloxy)acetophenone:; A solution of 2,6-Dichlorolbenzyl alcohol (15 g, 84.7 mmol) and diisopropyl azodicarboxylate (DIAD, 18.66 g, 92.2 mmol) in THF (50 ml) was added drop wise to a solution of 3 -Hydroxy acetophenone (11.53 g, 84.7 mmol) and triphenylphosphine (24.22 g, 92.3 mmol) in THF (200 ml) at O0C. The reaction mixture was stirred at room temperature for 4 hours, diluted with ether and washed with water, IN NaOH and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 4: 1) to give the title compound.1H NMR (270 MHz, CDCl3): 2.5 (s, 3H); 5.3 (s, 2H); 7.2-7.3 (m, 2H); 7.4 (m, 3H); 7.6 (m, 2H).
With di-isopropyl azodicarboxylate; triphenylphosphine; In dichloromethane; at 20℃; for 0.5h;
Tert-butyl 3-{6-[(2,6-dichlorophenyl)methoxy]-2H-spiro[l-benzofuran- 3,4'-piperidine]-l'-yl}propanoate. To a solution of (2,6- dichlorophenyl) methanol (0.79 g; 4.45 mmol) and tert-butyl 3-{6-hydroxy-2H- spiro[l-benzofuran-3,4'-piperidine]- l'-yl}propanoate (1 g, 2.97 mmol) in dichloromethane (60 mL) was added triphenyl-phosphine (1.95 g; 7.42 mmol), followed, after 30 minutes by DIAD (1.46 mL; 7.42 mmol). Subsequently, the resulting mixture was stirred at RT overnight, and concentrated in vacuo. The residue was purified by column chromatography (S1O2,dichloromethane/acetone 95:5) to afford the crude product (2 g). This product was dissolved in Et20 (60 mL) and 4 mL 1 M HCl/Ethanol was added. The formed white solid was isolated by filtration and washed with Et20 and EtOAc, after which it was partitioned between 5% aqueous NaHC03 and dichloromethane .The organic layer was dried (Na2S04), filtered, and concentrated in vacuo, to afford the product (1.10 g, 75%) . NMR (400 MHz, CHLOROFORM-d) delta ppm 7.36 (d, J =8 Hz, 2H,) 7.23 (d, J= 8 Hz, 1H), 7.03 (d, J =8 Hz, 1H), 6.56 (dd, J =8 and 2 Hz, 1H), 6.51 (d, J =2 Hz, 1H), 5.22 (s, 2H), 4.37 (s, 2H), 2.85-2.92 (m, 2H), 2.70 (t, J =8 Hz, 2H), 2.45 (dt, J =8 and 2 Hz, 2H), 2.03-2.11 (m, 2H), 1.89-1.98 (m, 2H), 1.69-1.77 (m, 2H), 1.46 (s, 9H). Rt 1.45 min (System B), [M+H]+ 492.1.
2-((2,6-dichlorobenzyl)oxy)-7,8-dihydroquinolin-5(6H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
A solution of(2,6-dichlorophenyl)methanol (1.07 g, 6.06 mmol) in DMF (15 mL) was treated with NaH (60% in mineral oil; 661 mg, 16.5 mmol) and stirred at rt for 15 mm. The mixture was treated with 2-chloro-7,8-dihydroquinolin-5(6B)-one (1.00 g, 5.51mmol) and stirred at rt for 1.5 h. Chipped ice (5 g) was added and the mixture was extracted twice with EtOAc. The combine organic phases were washed with brine, dried and concentrated. The residue was subjected to column chromatography on silica gel, eluting with EtOAc-hexanes (0-40%), to provide 2-((2,6-dichlorobenzyl)oxy)-7,8- dihydroquinolin-5(6B)-one (1.35 g, 76% yield). LCMS m/z 321.8, 323.8, 325.8 (M+H), HPLC tR 3.71 mm (method B). 1H NMR (400 MHz, CDCl3) delta 8.21 (d, J=8.58 Hz, 1H), 7.37-7.44 (m, 2H), 7.20-7.33 (m, 1H), 6.71 (d, J=8.58 Hz, 1H), 5.69 (s, 2H), 3.09 (t, J=6.16 Hz, 2H), 2.62-2.70 (m, 2H), 2.14-2.28 (m, 2H).
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