| 89% |
With trimethylsilyl bromide; triethylamine; In diethyl ether; |
4-Benzyloxybenzylalcohol (19) was converted to the bromide (20) using trimethylsilyl bromide (TMSBR) and triethylamine. Reaction with 13C-labelled potassium cyanide, in the presence of 18-crown-6 then gives the nitrile (21) in good yield. The Hoesch reaction was achieved by treatment of a solution of resorcinol, nitrile (21) and catalytic zinc chloride in diethyl ether with hydrogen chloride to give the deoxybenzoin (22) in good yield (Scheme 4). Finally formylation and cyclisation gave the 13C-daidzein (18) which was successfully purified by flash chromatography. This material was analysed and found to be pure by both GC-MS and microanalysis. The presence of a 13C atom at the 4- position was established by 13C NMR spectroscopy and mass spectrometry. |
| 85% |
With phosphorus tribromide; In diethyl ether; |
Synthesis of Compound 173 Preparation of (4-benzyloxy)benzyl bromide: To a solution of (4-benzyloxy)benzyl alcohol (1.00 g, 4.67 mmol) in anhydrous diethyl ether (20 mL) was added PBr3 (0.22 mL, 2.34 mmol) in one portion, and the resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with diethyl ether (30 mL) and washed with H2O (2*20 mL), saturated NaHCO3 (2*20 mL); and brine (2*20 mL). The ether layer was dried over anhydrous MgSO4, and the solvent was removed under reduced pressure to afford (4-benzyloxy)benzyl bromide (1.10 g, 85%) as a white solid. |
| 85% |
With phosphorus tribromide; In diethyl ether; |
Synthesis of Compound 173 Preparation of (4-benzyloxy)benzyl bromide: To a solution of (4-benzyloxy)benzyl alcohol (1.00 g, 4.67 mmol) in anhydrous diethyl ether (20 mL) was added PBr3 (0.22 mL, 2.34 mmol) in one portion, and the resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with diethyl ether (30 mL) and washed with H2O (2*20 mL), saturated NaHCO3 (2*20 mL), and brine (2*20 mL). The ether layer was dried over anhydrous MgSO4, and the solvent was removed under reduced pressure to afford (4-benzyloxy)benzyl bromide (1.10 g, 85%) as a white solid. |
| 85% |
With phosphorus tribromide; In diethyl ether; |
Synthesis of Compound 173 Preparation of (4-benzyloxy)benzyl bromide: To a solution of (4-benzyloxy)benzyl alcohol (1.00 g, 4.67 mmol) in anhydrous diethyl ether (20 mL) was added PBr3 (0.22 mL, 2.34 mmol) in one portion, and the resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with diethyl ether (30 mL) and washed with H2O (2*20 mL), saturated NaHCO3 (2*20 mL); and brine (2*20 mL). The ether layer was dried over anhydrous MgSO4, and the solvent was removed under reduced pressure to afford (4-benzyloxy)benzyl bromide (1.10 g, 85%) as a white solid. |
| 80% |
With N-Bromosuccinimide; dimethylsulfide; In dichloromethane; at -20 - 20℃; for 22h; |
To a solution of N-bromosuccinimide (NBS) (42mg, 2.38mmol) in CH2Cl2 (75mL) at 0C, dimethylsulfide (0.2mL, 2.7mmol) was added over 10min. The mixture was kept at 0C for 10min after addition was complete. The mixture was further cooled to-20C and 4-(benzyloxy)phenyl)methanol (417mg, 1.94mmol) dissolved in CH2Cl2 (10mL) was added, then the mixture was allowed to warm to ambient temperature and stirring continuously for 22h. The mixture was poured onto brine (6mL), and extracted with hexane:diethyl ether (4:1) (3×10mL). The combined organic phases were washed with brine (3×15mL), and dried over Na2SO4. Evaporation of the solvent gave 436mg (1.57mmol, 80%) as a white solid; mp. 84-86C (lit [27]. 85-86C); 1H NMR (CDCl3, 400MHz) delta: 4.50 (s, 2H), 5.07 (s, 2H), 6.94 (m, 2H), 7.31-7.42 (m, 7H). 1H NMR confirmed with that reported previously [27]. |
| 9.7 g (92%) |
With N-Bromosuccinimide; triphenylphosphine; In dichloromethane; |
4-Benzyloxybenzyl bromide (1) To 4-benzyloxybenzyl alcohol (8.1 g, 37.8 mmol) in dichloromethane (160 mL) was added N-bromosuccinimide (7.4 g, 41.6 mmol) followed by portionwise addition of triphenylphosphine (10.9 g, 41.6 mmol). The reaction mixture was stirred at room temperature for 5 minutes, and was then concentrated in vacuo. Purification by flash chromatography, eluding with 80:20 hexanes/ethyl acetate, provided 9.7 g (92%) of 1 as a white solid. |
|
With phosphorus tribromide; |
Step A Preparation of 4-benzyloxybenzyl bromide (9-2) STR33 To a cold suspension of 4-benzyloxybenzyl alcohol 9-1 (21.4 g, 0.10 mol) in ether (250 ml) was added phosphorus tribromide (10.8 g, 40 mmol) as in Example 7. Recovered 27.2 g of white solid which was recrystallized from hexane (200 ml). Obtained pure bromide 9-2. 1 H NMR (CDCl3) delta 4.5 (2H, s), 5.05 (2H, s), 6.94 (2H, d), 7.26-7.45 (7H, m). |
|
With phosphorus tribromide; In diethyl ether; at -18℃; |
1 -(Benzyloxy)-4-(bromomethyl)benzene.; PBr3 (0.66 ml_, 7.00 mmol) was added to a -18 C cooled solution of [4-(benzyloxy)phenyl]methanol (1.0 g, 4.667 mmol) in Et2O (20 ml_). The reaction was stirred at low temperature for 5 min and poured into H2O (100 ml_). It was extracted with Et2O (100 ml_), and washed with NaHCO3 (200 ml_, saturated aqueous solution). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified slurred with Et2O (10 ml_), to give 734 mg of 1 -(benzyloxy)-4-(bromomethyl)benzene (white solid, yield: 57%). 1H NMR (CDCI3, 250 MHz) delta ppm: 7.37 (m, 7H), 6.93 (d, J = 8.5 Hz, 2H), 5.07 (s, 2H), 4.43 (s, 2H). |
|
With hydrogen bromide; In acetic acid; at 0℃; for 1h; |
Step a: A solution of HBr in acetic acid (33%, 25.12 mL, 140.1 mmol) was added to a slightly heterogeneous solution of 4-benzyloxy-benzyl alcohol in acetic acid (50 mL) at 0 C. After stirring at 0 C for 1 h the thick slurry was poured into a mixture of ice and water. The precipitate that formed was collected by filtration, rinsed with water and dried to give crude benzyl bromide as a white solid (11.10 g). |
|
With phosphorus tribromide; In diethyl ether; at 0 - 20℃; for 3.5h; |
[0513] Step A: To a solution of (4-(benzyloxy)phenyl)methanol (21.4 g, 100 mmol) in diethyl ether (250 mL) at 0 C was added phosphorous tribromide (10.8 g, 40 mmol) and stirred at 0 C for 30 minutes and at room temperature for 3 hours. The reaction was quenched with water and the layers were separated. The organic layer was washed with water (2 x 400 mL), saturated sodium bicarbonate (2 x 400 mL), and brine. The ether layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford 1- (benzyloxy)-4-(bromomethyl)benzene (746). |
|
With phosphorus tribromide; In dichloromethane; at 0 - 5℃; for 0.75h; |
General procedure: crude product 2a which was then dissolved in anhydrous methylene chloride (50 mL) and cooled to 0-5 ºC by ice bath. To this solution was added dropwise phosphorus tribromide (0.5 mL, 5 mmol) over a period of 15 min and stirred for 0.5 h at the same temperature, and then washed with saturated brine (3 Chi 15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound 3a. |
|
With phosphorus tribromide; In diethyl ether; at 8 - 20℃; for 2h;Inert atmosphere; |
Synthesis of compound 34C14Hi3BrO M = 277.16 g.mol" Mass: (CI+): 107; 197, 277 (M + H)To an ice-cold suspension of crude alcohol 33 (6g, 28.0mmol, 2.4eq.) in diethyl ether (50mL), was added PBr3 (1.1 mL, 1 1.67mmol, leq) at a rate such that the temperature did not exceed 8C. The resultant mixture was stirred 2 hours under inert atmosphere at room temperature. The reaction mixture was then cooled in an ice-bath, quenched with iced water and diluted with diethyl ether and ethyl acetate. The organic layer was washed with an aqueous saturated solution of NaHC03, dried over MgSC>4, filtered and concentrated to give crude compound 34 (99% yield) as a white amorphous solid. |
|
With phosphorus tribromide; lithium bromide; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h; |
Example 4A 1-(benzyloxy)-4-(bromomethyl)benzene A mixture of (4-(benzyloxy)phenyl)methanol (2.14 g) and lithium bromide (1.0 g) in N,N-dimethylformamide (20 mL) was cooled to 0 C. To this solution was added PBr3 (1.0 mL). The solution was stirred at room temperature for 2 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate, twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5% ethyl acetate in hexanes to provide the title compound. |
|
With phosphorus tribromide; In diethyl ether; at 0 - 20℃; for 3.5h; |
[0505] Step A: To a solution of (4-(benzyloxy)phenyl)methanol (21.4 g, 100 mmol) in diethyl ether (250 mL) at 0 0C was added phosphorous tribromide (10.8 g, 40 mmol) and stirred at 0 0C for 30 minutes and at room temperature for 3 hours. The reaction was quenched with water and the layers were separated. The organic layer was washed with water (2 x 400 mL), saturated sodium bicarbonate (2 x 400 mL), and brine. The ether layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford l-(benzyloxy)-4- (bromomethyl)benzene (746). |
|
With trimethylsilyl bromide; at 0 - 20℃; |
The synthesis of a BP-linker-deacetyl-linezolid (BP-L-dLD, L: -OC(O)N-) conjugate is exemplified in the synthesis scheme depicted in FIG. 8. This chemistry is also applicable to other deacetyl- oxazolidinones, such as eperezolid, radezolid, ranbezolid, sutezolid, et al. |
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