Reference：
[1] Chemistry - A European Journal, 2012, vol. 18, # 48, p. 15267 - 15271
2
[ 105-13-5 ]
[ 2746-25-0 ]
Yield
Reaction Conditions
Operation in experiment
94%
With phosphorus tribromide In dichloromethane at 0 - 20℃;
Example 10 Preparation of 4-methoxybenzylic Bromide (13) Phosphorus tribromide (6.2 g; 25.0 mmol; 1.15 eq.) is added to a 4-methoxybenzylic alcohol solution (3 g; 21.7 mmol; 1 eq.), cooled to 0° C., in dichloromethane (35 ml). After 5 h at room temperature, the reaction mixture is poured into ice water (100 ml) and then is extracted with ether (3*100 ml). The organic phase is washed, dried on MgSO4, filtered and evaporated to obtain 4.1 g of a colorless oil. Yield: 94percent Empirical formula: C8H9BrO
90%
With phosphorus pentoxide; potassium bromide In acetonitrile at 20℃; for 0.416667 h;
General procedure: To a mixture of alcohol (1 mmol) and KBr (1.5 mmol, 0.18 g) in acetonitrile (5 mL), P2O5 (1.5 mmol, 0.23 g) was added and the reaction was stirred at room temperature for the time specified in Table 3. After reaction completion (TLC or GC), the reaction mixture was filtered and the residue washed with ethyl acetate (3 × 8 mL). The combined organic layers were washed with water (10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure to afford the corresponding product. If necessary, further purification was performed by column chromatography.
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[109] Patent: CN105585467, 2016, A, . Location in patent: Paragraph 0024; 0025; 0026
3
[ 631-61-8 ]
[ 105-13-5 ]
[ 104-21-2 ]
[ 2746-25-0 ]
Yield
Reaction Conditions
Operation in experiment
86%
With N-Bromosuccinimide; triphenylphosphine In acetonitrile at 20℃; for 1.9 h; Cooling with ice
General procedure: To a solution of Ph3P(OAc)2, was added 3-phenylpropanol (1 mmol, 0.137 mL). The progress of the reaction was monitored by TLC (Table 3, entry 2). After completion of the reaction (0.3 h) the reaction mixture was filtered to remove the precipitated NH4Br followed by evaporation of the solvent. Column chromatography of the crude mixture on silica gel using n-hexane/EtOAc (3:1) as the eluent gave 3-phenylpropyl acetate in 90percent yield (0.159 g).
With 1-pyrrolidinecarboxaldehyde; benzoyl chloride; sodium bromide In acetone at 0 - 20℃; for 20.5 h;
General procedure: Using 10 molpercent of FPyr benzyl bromide 85 was prepared with BzCI (1.2 equiv) according to general procedure VIII (chapter 4.9.1, t = 20 h, T = rt) in 86percent yield (internal standard). Moreover, 4- methoxybenzyl chloride 25 was obtained in 14percent yield (ratio bromide 85/chloride 25 86:14) togetherwith 4-methoxybenzyl benzoate 35 in 2percent yield (ratio 85+25/35 97:3).
Reference：
[1] Journal of the American Chemical Society, 1916, vol. 38, p. 1215
10
[ 10035-10-6 ]
[ 105-13-5 ]
[ 2746-25-0 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1911, vol. <4> 9, p. 824
[2] Monatshefte fuer Chemie, 1913, vol. 34, p. 1998
11
[ 105-13-5 ]
[ 78-93-3 ]
[ 5440-80-2 ]
[ 123-11-5 ]
[ 104-27-8 ]
Reference：
[1] Catalysis Science and Technology, 2017, vol. 7, # 9, p. 1928 - 1936
12
[ 105-13-5 ]
[ 34841-06-0 ]
Yield
Reaction Conditions
Operation in experiment
55 %Chromat.
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In dichloromethane at 25℃; for 0.5 h;
General procedure: DBDMH (1 mmol) was added to a mixture of 1b (1 mmol) and dichloromethane (20ml). The reaction was kept at room temperature. After the mixture was stirred for0.5h, the mixture was washed with water (330 ml),dried with anhydrous MgSO4,filtered, and vacuum evaporated. The residue was purified by column chromatography (silica gel: petroleum ether/ethyl acetate, 30:1) to afford the product as light yellowsolid (93percent yield).
Reference：
[1] Tetrahedron, 1976, vol. 32, p. 109 - 113
15
[ 105-13-5 ]
[ 4903-09-7 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1965, vol. 38, p. 1032 - 1034
16
[ 105-13-5 ]
[ 2314-37-6 ]
[ 123-11-5 ]
Yield
Reaction Conditions
Operation in experiment
71%
With iodic acid In N,N-dimethyl-formamide at 60℃; for 2 h; Inert atmosphere
General procedure: To a solution of p-bromobenzyl alcohol I-1 (187 mg, 1.0 mmol) in DMF (2.0 mL) was added HIO3 (194 mg, 1.1 mmol). The mixture was stirred at 60 °C for 2 h under an Ar atmosphere. After the reaction, the reaction mixture was poured into aq Na2S2O3, and extracted with a mixture of Et2O: hexane=1:1 (3*10 mL). The organic layer was dried over Na2SO4. After being filtration and removal of the solvent under reduced pressure, the residue was purified by flash short column chromatography on silica gel (EtOAc-hexane, 1:4) to give p-bromobenzaldehyde II-1 in 95percent yield.
71%
With iodic acid In N,N-dimethyl-formamide at 20 - 60℃; for 2 h; Inert atmosphere
General procedure: 4-Bromobenzyl alcohol (187 mg, 1.0 mmol)Was dissolved in 2.0 mL of DMF solvent,This was mixed with iodic acid (194 mg, 1.1 mmol).The mixture was stirred for 2 hours at room temperature to 60 ° C. in an Ar atmosphere.To the reaction mixture was added aqueous sodium thiosulfate solution and extracted with diethyl ether: hexane = 1: 1 (3 × 10 mL).The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give 4-bromobenzaldehyde as a final product (yield 91percent). The same treatment was carried out except that the primary alcohol or secondary alcohol was used instead of 4-bromobenzyl alcohol used in Example 1 based on the following general formula (1) to obtain a carbonyl compound shown in Table 1 Were obtained in yields shown in Table 1, respectively.
Reference：
[1] Tetrahedron, 2016, vol. 72, # 44, p. 6948 - 6954
[2] Patent: JP2018/2680, 2018, A, . Location in patent: Paragraph 0032-0035
17
[ 121-98-2 ]
[ 67-63-0 ]
[ 18228-46-1 ]
[ 261930-06-7 ]
[ 105-13-5 ]
Reference：
[1] Journal of Organic Chemistry, 2001, vol. 66, # 3, p. 862 - 867
18
[ 107-21-1 ]
[ 105-13-5 ]
[ 13807-89-1 ]
Yield
Reaction Conditions
Operation in experiment
78%
With Amberlyst-15 In dichloromethane for 3.5 h; Reflux
General procedure for selective mono PMB protection of diols: (Z)-4-((4-Methoxybenzyl)oxy)but-2-en-1-ol (Table 5, entry 1): A mixture of cis-2-butene-1,4-diol (200 mg, 2.3 mmol), p-anisyl alcohol (345 mg, 2.5 mmol), and catalytic amount (10percent w/w, 20 mg) of Amberlyst-15 resin in anhydrous CH2Cl2 (10 mL) was refluxed. After 3 h, the crude reaction mixture was filtered through a Whatman filter paper and the residue washed with CH2Cl2, dried (over anhydrous Na2SO4), filtered and concentrated in vacuo and purified using flash chromatography (pet ether/ethyl acetate 70:30) to provide 401 mg (85percent) of pure product as a colorless dense liquid.
78%
With Amberlyst-15 resin In dichloromethane for 3.5 h; Reflux
A mixture of ethylene glycol (0.31 g, 5 mmol), 4-methoxybenzyl alcohol (0.75g, 5.43 mmol), and catalytic amount of Amberlyst-15 resin (31 mg, 10percent w/w) in anhydrous dichloromethane (20 mL) was refluxed for 3.5 h. The crude reaction mixture was filtered through a Whatman filter paper and the residue washed with dichloromethane (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel using 40-50percent EtOAc/hexane (v/v) as the eluent to afford a compound III (0.71 g, 3.9 mmol) in 78percent yield as a colourless liquid. TLC: Rf 0.2 (40percent EtOAc/hexane). IR (neat): 3422, 2934, 2863, 1611, 1513, 1461, 1248, 1106, 1033, 820 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.27 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 4.49 (s, 2H), 3.80 (s, 3H), 3.74 (t, J = 4.4 Hz, 2H), 3.57 (td, J = 4.4, 1.8 Hz, 2H), 2.15-2.07 (bs, 1H); 13C NMR (125 MHz, CDCl3): δ 158.7, 129.6, 128.9, 113.2, 72.2, 70.8, 60.9, 54.6; MS (ESI): m/z 205 [M+Na]+. HRMS (ESI): calcd for C10H14O3Na: 205.0841, found: 205.0840.
Reference：
[1] Chemistry Letters, 1987, p. 1113 - 1116
23
[ 105-13-5 ]
[ 21038-22-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 1964, vol. 7, p. 329 - 334
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 19, p. 3155 - 3159
[3] Tetrahedron, 1993, vol. 49, # 17, p. 3521 - 3532
[4] Journal of the Chemical Society, 1962, p. 3915 - 3926
[5] Organic Letters, 2012, vol. 14, # 2, p. 596 - 599
[6] Journal of Organic Chemistry, 2013, vol. 78, # 1, p. 9 - 34
[7] Molecules, 2013, vol. 18, # 4, p. 3872 - 3893
[8] European Journal of Medicinal Chemistry, 2016, vol. 108, p. 564 - 576
[9] Organic Letters, 2018, vol. 20, # 18, p. 5714 - 5717
24
[ 52-90-4 ]
[ 105-13-5 ]
[ 2544-31-2 ]
Yield
Reaction Conditions
Operation in experiment
64%
Stage #1: With hydrogenchloride In diethyl ether; water for 3 h; Stage #2: With sodium hydroxide In diethyl ether; ethanol; water at 20℃; for 2 h; Stage #3: With hydrogenchloride In diethyl ether; ethanol; water at 0℃;
4-Methoxybenzyl alcohol (280 g, 1780 mmol) dissolved in diethylether (400 mL) was added in drops to a mixture of diethylether (400 niL) and cone, hydrochloric acid (400 mL) over 2 h, and the mixture was stirred for 1 h. The organic layer was separated, and added to a solution prepared by dissolving L-cysteine (197 g, 1625 mmol) and 2N aqueous sodium hydroxide solution (980 mL) to ethanol (1890 mL).The mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction mixture was cooled to 0°C, and neutralized to pH 7 using 3N aqueous hydrochloric acid solution. The resulting solid was filtered and dried to give the title compound (250 g, Yield 64percent).
64%
Stage #1: With hydrogenchloride In diethyl ether Stage #2: With sodium hydroxide In diethyl ether; ethanol; water at 20℃; for 2 h; Stage #3: With hydrogenchloride In diethyl ether; ethanol; water at 0℃;
4-Methoxybenzyl alcohol (280 g, 1780 mmol) dissolved in diethylether (400 mL) was added in drops to a mixture of diethylether (400 mL) and conc. hydrochloric acid (400 mL) over 2 h, and the mixture was stirred for 1 h. The organic layer was separated, and added to a solution prepared by dissolving L-cysteine (197 g, 1625 mmol) and 2N aqueous sodium hydroxide solution (980 mL) to ethanol (1890 mL). The mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction mixture was cooled to 0°, and neutralized to pH 7 using 3N aqueous hydrochloric acid solution. The resulting solid was filtered and dried to give the title compound (250 g, Yield 64percent).
64%
Stage #1: With hydrogenchloride In diethyl ether; water for 3 h; Stage #2: With sodium hydroxide In diethyl ether; ethanol; water at 20℃; for 2 h; Stage #3: With hydrogenchloride In diethyl ether; ethanol; water
To a solvent mixture of diethylether (400 ml) and conc. hydrochloric acid (400 ml) was added in drops 4-methoxybenzylalcohol (280 g, 1780 mmol) dissolved in diethylether (400 ml) for 2 h, and the mixture was stirred for 1 h. The organic layer was separated, and added to a solution prepared by dissolving L-cysteine (197 g, 1625 mmol) and 2N aqueous sodium hydroxide solution (980 ml) in ethanol (1890 ml). The mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction solution was cooled to 0° C., and neutralized to pH 7 using 3N aqueous hydrochloric acid solution. The resulting solid was filtered, and dried to give (R)-2-amino-3-(4-methoxy-benzylsulfanyl)-propionic acid (250 g, 1035 mmol, Yield: 64percent).
Reference：
[1] Bulletin de la Societe Chimique de France, 1911, vol. <4> 9, p. 824
[2] Bulletin de la Societe Chimique de France, 1911, vol. <4> 9, p. 824
30
[ 79-08-3 ]
[ 105-13-5 ]
[ 88920-24-5 ]
Yield
Reaction Conditions
Operation in experiment
71%
With sodium hydride In tetrahydrofuran; mineral oil at 0 - 23℃; for 4 h;
To a solution of (4-methoxyphenyl)methanol (1 equiv.) and 2-bromoacetic acid (1.2 equiv.) in anhydrous THF at 0 °C was added sodium hydride (60percent w/w in mineral oil, 3 equiv.) in 3 portions. The mixture was stirred at 70 °C for 4 h. After cooling to ambient temperature, water was added the resultant mixture was washed with hexanes. The aqueous phase was acidified to pH 2 with iN HC1 and extracted with ethyl acetate. The organic layer was dried, filtered and the solvent was removed in vacuo. Purification via silica gel chromatography with 50percent ethyl acetate in hexanes delivered 2-((4-methoxybenzyl)oxy)acetic acid (0.51 g, 71percent yield) as a clear solid.1H NMR (500 MHz, CDC13) ö ppm 7.29 (m, 2 H), 6.90 (m, 2 H), 4.59 (s, 2 H), 4.10 (s, 2 H),3.81 (s, 3 H).
Reference：
[1] Bioorganic and medicinal chemistry letters, 2001, vol. 11, # 21, p. 2837 - 2841
[2] Synlett, 2012, vol. 23, # 19, p. 2845 - 2849
[3] Tetrahedron Letters, 2002, vol. 43, # 41, p. 7427 - 7429
[4] Patent: WO2014/144100, 2014, A2, . Location in patent: Paragraph 00274
[5] Patent: WO2006/109729, 2006, A1, . Location in patent: Page/Page column 138-139
[6] Journal of Medicinal Chemistry, 1984, vol. 27, # 8, p. 967 - 978
[7] Journal of Organic Chemistry, 1996, vol. 61, # 13, p. 4369 - 4373
[8] Patent: US5811550, 1998, A,
[9] Journal of Organic Chemistry, 2008, vol. 73, # 11, p. 4338 - 4341
[10] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3576 - 3581
[11] Journal of Medicinal Chemistry, 2017, vol. 60, # 12, p. 5162 - 5192
31
[ 79-11-8 ]
[ 105-13-5 ]
[ 88920-24-5 ]
Reference：
[1] Chemical Communications, 1997, # 19, p. 1919 - 1920
[2] Tetrahedron Letters, 2008, vol. 49, # 23, p. 3762 - 3765
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1983, # 10, p. 2479 - 2483
32
[ 105-36-2 ]
[ 105-13-5 ]
[ 88920-24-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 1998, vol. 6, # 11, p. 2061 - 2073
33
[ 616-45-5 ]
[ 105-13-5 ]
[ 72432-10-1 ]
Reference：
[1] Chemical Science, 2018, vol. 9, # 21, p. 4756 - 4768
34
[ 105-13-5 ]
[ 104146-10-3 ]
Reference：
[1] Patent: CN107033162, 2017, A,
35
[ 105-13-5 ]
[ 150308-80-8 ]
Reference：
[1] Journal of Peptide Science, 2013, vol. 19, # 2, p. 65 - 73
36
[ 68797-61-5 ]
[ 105-13-5 ]
[ 1325694-78-7 ]
Yield
Reaction Conditions
Operation in experiment
33%
With potassium <i>tert</i>-butylate In tetrahydrofuran at 50℃; for 16 h; Inert atmosphere
General procedure: To a mixture of dichloride 21 (0.625 g, 2.7 mmol) and potassium tert-butoxide (0.395 g, 4.1 mmol) was added a solution of para-methoxybenzyl alcohol (0.568 g, 4.1 mmol) in THF (8 mL). Reaction mixture was heated to 50 °C overnight. Reaction mixture was filtered and concentrated under reduced pressure. Product was purified via automated chromatography (EtOAc: Hexanes, 20:80) to provide 22 as a clear oil in 33percent yield. 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.30 (d, J = 8.6 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 5.38 (s, 2H), 3.73 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 166.68, 160.23, 159.85, 155.22, 130.28, 130.16, 130.00, 127.24, 114.02, 106.27, 70.10, 55.32.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 15, p. 4592 - 4596
37
[ 105-13-5 ]
[ 1384122-86-4 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 1, p. 9 - 34
2-chloro-4-[(4-methoxybenzyl)oxy]-3-methylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate; In toluene; at 110℃; for 4.0h;
The mixture of 234 mg of 2-chloro-4-iodo picoline, 17.6 mg of copper iodide, 33.3 mg of 1,10-phenanthroline, 601 mg of cesium carbonate, 230 muL of 4-methoxybenzyl alcohol, and 0.5 mL of toluene, was stirred at 110C for 4 hours. After adding water and a saturated aqueous solution of sodium hydrogen carbonate, the mixture was extracted with chloroform, and the organic layer was washed with saturated brine. The thus-obtained organic layer was dried over anhydrous sodium sulfate, insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative thin-layer chromatography, and 207 mg of 2-chloro-4-[(4-methoxybenzyl)oxy]-3-methylpyridine [64-1] as a white solid.
With sodium hydride; In tetrahydrofuran; at 0℃; for 1.5h;
Step b: 4-Chloro-6-(4-methoxybenzyloxy)-2-phenylpyrimidine (6b); NaH (60percent) (469 mg, 11.73 mmol) was added in portions to a stirred solution of <strong>[3740-92-9]4,6-dichloro-2-phenyl-pyrimidine</strong> (2.2 g, 9.78 mmol) and 4-methoxy benzyl alcohol (1.62 mg, 11.73 mmol) in dry THF (55 ml) at 00C. After 1.5 h, NaHCO3 (aq) was added. Some solvent was evaporated and the residue was extracted with DCM, dried (MgSO4), filtered and evaporated to give the title compound, (3.19g, 100percent), MS (M+H)+327.
Preparation of 2-chloro-5-ethyl-4-(4-methoxybenzyloxy)pyrimidineIn a round bottom flask, (4-methoxyphenyl)methanol (859 mg) and lithium f-butoxide (453 mg) are stirred in THF (5.65 ml_) at 70 C for 15 minutes and then cooled to room temperature. In a separate flask, 2,4- dichloro-5-ethylpyrimidine (1.00 g) is dissolved in DMF (10 ml_) and this solution is than transferred dropwise (over 30 minutes) to the previous mixture at 0 C and then let warmed to room temperature. After 3 hours, the reaction proved to be completed by GC-MS with an isomers ratio of ~ 18 / 1. Reaction mixture diluted with ethyl acetate and washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated to afford the crude. The residue was purified by flash column chromatography (S1O2, 5%-30% ethyl acetate / heptane) to provide 2-chloro-5-ethyl-4-(4- methoxybenzyloxy)pyrimidine (787 mg, 50%) as a colorless oil (Isomers ratio after purification ~ 32 / 1 ). MS (M+1 ): 279.0. 1H NMR (400 MHz, CDCI3) delta ppm 1.16 (m, J=7.43, 7.43 Hz, 3 H), 2.52 (q, J=7.62 Hz, 2 H), 3.81 (s, 3 H), 5.37 (s, 2 H), 6.85 - 6.95 (m, 2 H), 7.34 - 7.43 (m, 2 H), 8.10 (s, 1 H).
3,5-Bis(4-methoxybenzyloxy)pyridine-2-carbonitrile (12). Sodium hydride (60percent, 3.66 g, 91.5 mmol) was added to 4-methoxybenzyl alcohol (11.5 mL, 92.6 mmol) in DMF (89 mL). The reaction mixture was stirred for 50 min and was cooled in an ice water bath, followed by addition of 11 (5.13 g, 36.6 mmol). After stirring at room temperature for 30 min and heating at 95-100 °C for 18 h, the reaction was quenched at 0 °C with EtOH and was concentrated by rotary evaporation under high vacuum. The residue was treated with H2O (250 mL) and extracted with warm EtOAc (400 mL, 2 × 100 mL). The organic extracts were washed with saturated NaCl (150 mL). Purification by flash column chromatography using 2percent acetone/CH2Cl2 gave 10.11 g of 12 (73percent) as a white solid, mp 122-122.5 °C: 1H NMR 3.81 (s, 3 H), 3.82 (s, 3 H), 5.04 (s, 2 H), 5.11 (s, 2 H), 6.85 (d, 1 H, J = 2.0), 6.92 (dd, 4 H, J = 8.6, 6.6), 7.31 (d, 4 H, J = 8.6), 8.01 (d, 1 H, J = 2.0). 13C NMR 55.44, 55.47, 70.98, 71.00, 106.86, 114.41, 115.63, 116.26, 126.83, 126.94, 129.04, 129.56, 131.98, 158.41, 159.10, 160.00, 160.14. HRMS m/z calculated for C22H21N2O4, 377.1496 (M + H); found: 377.1500. Anal. (C22H20N2O4) C, H, N.
Step 1. N-methoxy-2-((4-methoxybenzyl)oxy)-N-methylacetamide To a suspension of sodium hydride (1.86 g, 46.5 mmol) in THF (80 ml) at 0° C. was added (4-methoxyphenyl)methyl alcohol (5.80 mL, 46.7 mmol) over 5 min. The reaction mixture was warmed to RT for 1 h, then cooled to 0° C. and a solution of <strong>[67442-07-3]2-chloro-N-methoxy-N-methylacetamide</strong> (6.50 g, 47.3 mmol) in THF (20 mL) was added. The reaction mixture was warmed to room temperature and stirred for 72 hr then quenched with NH4Cl and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (2*) and the combined organic extracts were washed with brine (1*), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (120 g, 30percent to 80percent EtOAc in hexanes) gave N-methoxy-2-((4-methoxybenzyl)oxy)-N-methylacetamide (1.10 g, 4.60 mmol, 9.85percent yield) as a yellow oil. ESI (M+Na) 262.1.
With tert.-butylhydroperoxide; copper(II) acetate monohydrate; calcium carbonate; In acetonitrile; at 80℃; for 24h;
General procedure: An oven-dried 15 mL glass vial with a magnetic stirrer bar was charged with Cu(OAc)2·H2O (12 mg, 6 mol%), N,O-dimethylhydroxylamine hydrochloride (2; 117 mg, 1.2 mmol), the respective benzyl alcohol 1 (1 mmol), aq 70% TBHP (0.17 mL, 1.2 mmol), CaCO3 (120 mg, 1.2 mmol) in MeCN (1 mL). The glass vial was flushed with N2 three times and the contents were stirred at r.t. for 1 h. Then the reaction mixture was stirred for 24 h at 80 C. After completion of the reaction, the mixture was cooled to r.t. All volatiles were removed under vacuum. The product was extracted with EtOAc (20 mL) and the organic layer was washed with sat. aq NaHCO3 (20 mL), dried (Na2SO4), and the solvent removed under vacuum. The Weinreb amide product 3 was purified by column chromatography (silica gel, 100-200 mesh) using a gradient of petroleum ether (bp 60-80 C) and EtOAc. All the amides were identified by GC-MS, 1H, and 13C NMR spectroscopic analysis.
2-chloro-4-[(4-methoxybenzyl)oxy]-5,6,7,8-tetrahydroquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3.31 g
[Step 1] Production of 2-chloro-4-[(4-methoxybenzyl)oxy]-5,6,7,8-tetrahydr oquinoline To 4-methoxybenzylalcohol (2.05 g) were added DMF (50 mL) and NaH (60% dispersion in oil, 891 mg) under ice water cooling, and the mixture was stirred for 30 minutes. After the reaction mixture was allowed to return to room temperature, <strong>[858279-01-3]2,4-dichloro-5,6,7,8-tetrahydroquinoline</strong> (see, for example, ) (3 g) was added to the mixture, and the mixture was stirred at 60C for 4 hours. After the reaction mixture was allowed to return to room temperature, the reaction mixture was added with water and ethyl acetate, and subjected to extraction. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (3.31 g) as colorless oil.
4-methoxybenzyl (1-(4-chlorophenyl)cyclopropyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
To a stirred solution of 1-(4-chlorophenyl)cyclopropane-1-carboxylic acid (step 2, 20.0 g, 102.04 mmol, 1.0 eq) in 1,2-dichloroethane (200 ml) under nitrogen atmosphere wasadded TEA (16.4 g, 163.26 mmol, 1.6 eq) followed by DPPA (44.7 g, 163.26 mmol, 1.6 eq). After 15 minutes stirring at room temperature, the solution was heated to reflux for about 1.5 hours. After which it was converted completely to the isocyanate by TLC, 4-methoxybenzyl alcohol (22.5 g, 163.26 mmol, 1.6 eq) was added and refluxing was continued for about 4 hours. TLC indicated starting material was consumed and the desired product was observed.The reaction mixture was evaporated under reduced pressure and the residue was purified by silicagel column chromatography by using 10percent EtOAc: hexane as an eluent to obtain the desired product (25.0 g, 74percent yield) as a white solid. ?H NMR (300 MHz, CDC13): ppm 7.31-7.15 (m, 6H), 6.88 (d, J= 8.1 Hz, 2H), 5.41 (s, 1H), 5.01 (s, 2H), 3.81 (s, 3H), 1.30-1.13 (m, 4H); ESI-MS: mlz 354.12 (M+Na).
4-methoxy-6-((4-methoxybenzyl)oxy)pyrimidin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79.6%
With sodium hydride; In N,N-dimethyl-formamide; at 100℃; for 4h;Inert atmosphere;
In 500mL eggplant-shaped flask,2-Amino-4-chloro-6-methoxypyrimidine (40.0 g, 250.7 mmol)Was dissolved in N, N-dimethylformamide (200 mL),Under N2 was added sodium hydride protective batches (12.0g, 501.3mmol)And p-methoxybenzyl alcohol (43.3 g, 313.3 mmol),100 reaction 4h.After the reaction was completed, petroleum ether (60 mL × 2) was added to the mixture, the aqueous phase was collected and extracted with ethyl acetate (200 mL × 2). The organic phase was collected and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure to give 52.2 g of 4-methoxy-6 - ((4-methoxybenzyl) oxy) pyrimidin-2-amine in a yield of 79.6%.
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