* 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.
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.0833333 h; Stage #2: With tetra-(n-butyl)ammonium iodide In tetrahydrofuran; mineral oil at 20℃;
Example 137C 3-(benzyloxy)-2,2-dimethylpropan-1-ol A solution of 2,2-dimethylpropane-1,3-diol (2 g, 19.20 mmol) in THF (30 mL) was treated with 60percent sodium hydride (0.256 g, 6.40 mmol) at room temperature, and the mixture stirred at room temperature for 5 minutes. Benzyl bromide (0.761 mL, 6.40 mmol) and tetrabutylammonium iodide (0.709 g, 1.920 mmol) were then added, and the reaction stirred overnight at room temperature. After this time, the mixture was diluted with ethyl acetate (150 mL) and water (50 mL), and the phases were separated. The aqueous layer was extracted with ethyl acetate (2*50 mL). The combined organics were washed with water (2*50 mL) and brine (50 mL) sequentially, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified on silica gel chromatography (10 to 50percent ethyl acetate-heptanes, eluent) to afford the title compound (0.992 g, 80percent). 1H NMR (400 MHz, CDCl3) δ 7.41-7.32 (m, 5H), 4.51 (s, 2H), 3.46 (d, J=5.7 Hz, 2H), 3.33 (s, 2H), 2.55 (t, J=5.9 Hz, 1H), 0.93 (s, 6H). MS (DCI+) m/z 195.0 (M+H).
77%
With tetra-(n-butyl)ammonium iodide In toluene at 0 - 20℃; for 16 h;
Into a 10-L 4-neck round-bottom flask, was placed 2,2-dimethylpropane-1,3-diol (200 g, 1920 mmol), toluene (1 L), 50percent KOH (aq. solution, 1L), n-Bu4NI (36 g, 97 mmol). Then (bromomethyl)benzene (328 g, 1920 mmol, 1.00 equiv.) was added at 0 °C. The resulting solution was stirred at room temperature for 16 h. The reaction was then quenched by the addition of 1 L of ice-water. The resulting solution was extracted with 2x4 L of ethyl acetate. The combined organic layer was washed with 2x4 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to afford the title compound as light yellow oil (77percent). LCMS:mlz=195.0 [M+1]. ‘H-NMR (300 MHz, CDC13) ö: 7.37-7.25 (m, 5H), 4.47 (m, 3H), 3.18 (d, 1=6.4Hz, 4H), 0.82 (s, 6H).
64%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.75 h; Inert atmosphere Stage #2: at 0 - 20℃; Inert atmosphere
General procedure: The diol (48 mmol, 1 eq) wasdissolved into DMF (120 mL) under argon. At 0°C NaH (1.1 eq, 60percent in mineral oil) was added inone portion and the mixture was stirred at 0°C during 45 min. BnBr (0.97 eq) was added dropwise,the mixture was allowed to warm at room temperature and stirred overnight. The reaction wasquenched with saturated NH4Cl solution (20 mL) and then diluted with water. The crude mixturewas extracted with Et2O and the organic layer was washed with brine, dried over anhydrous MgSO4,filtered and concentrated in vacuo. Benzylated compound was then purified by flashchromatography on silica gel.
62%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 1 h; Stage #2: at 0 - 20℃;
Step A: 3-Phenylmethoxy-neopentylol (31a) Adapting a procedure or a variation thereof according to Effenberger, et al., Tetrahedron: Asymmetry 1995, 6, 271-282, a 1000 mL round-bottomed flask equipped with a magnetic stirring bar and a rubber septum was charged under a nitrogen atmosphere with 2.40 g of a 60 wt-percent suspension of sodium hydride (NaH) in mineral oil (1.44 g, 60.0 mmol). The hydride was suspended in 50 mL of hexane and the supernatant was decanted, and the residue was dried under reduced pressure. Six-hundred (600) mL of anhydrous tetrahydrofuran (THF) were added under a nitrogen atmosphere and the suspension was cooled to ca. 0° C. (ice bath). 6.24 g (60 mmol) of commercially available neopentyl glycol (2,2-dimethyl-1,3-propandiol) was added and the reaction mixture was stirred for one hour at this temperature until the hydrogen evolution subsided. 5.9 mL of benzyl bromide (8.5 g, 50.0 mmol) was added to the stirred reaction mixture. The reaction mixture was stirred overnight with gradual warming to room temperature and the solvent was then partially removed under reduced pressure using a rotary evaporator. The reaction was quenched by addition of a one normal (1 N) aqueous solution of hydrogen chloride (HCl) and the product was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate (MgSO4), filtered, and the solvents were removed under reduced pressure using a rotary evaporator. The residue was purified by silica gel chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:4) to provide 6.0 g (62percent yield) of the title compound (31a) as a colorless liquid. Rf=0.34 (EtOAc/Hxn=1:4). 1H NMR (400 MHz, CDCl3): δ=0.953 (s, 6H), 2.62 (br. t, J=5.6 Hz, 1H), 3.34 (s, 2H), 3.47 (d, J=5.6 Hz, 2H), 4.54 (s, 2H), 7.27-7.38 (m, 5H) ppm. MS (ESI) m/z 195.10 (M+H)+, 217.10 (M+Na)+. The analytical data was consistent with the data given in the literature.
62%
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 12 h;
[00319] Into a 250-mL round-bottom flask, was placed 2,2-dimethylpropane-1,3-diol (10.4 g, 99.86 mmol) and N,N-dimethylformamide (100 mL). This was followed by the addition of 60percent sodium hydride (4 g, 100.00 mmol), in portions at 0°C. To this was added (bromomethyl)benzene (13.68 g, 79.98 mmol) at 0°C. The resulting solution was stuffed for 12 h at room temperature and then diluted with 200 mL of NH4C1 (sat. aq). The resulting solution was extracted with 2x200 mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column with ethyl acetate/petroleum ether (1:10) to obtain 12 g (62percent) of 3-(benzyloxy)-2,2-dimethylpropan-1-ol as light yellow oil. ‘H NMR (300 MHz, DMSOd 6): 7.43-7.24 (m, 5H), 4.51-4.41 (m, 3H), 3.25-3.15 (m, 4H), 0.84 (s, 6H) ppm.
58%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5 h; Inert atmosphere Stage #2: at 20℃;
[00509] 2,2-Dimethylpropane-l,3-diol 159 (4.24 g, 40 mmol) was dissolved in 120 mL of THF. To this mixture, was added NaH (1.92 g, 48 mmol, 60percent in mineral oil) at 0 °C under nitrogen atmosphere. After stirring at 0 °C for 30 min, benzyl bromide (6.84 g, 40 mmol) was added to this mixture, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then transferred into iced water and extracted with ethyl acetate (50 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to obtain crude product, which was purified by silica gel chromatography (10percent ethyl acetate/petroleum ether) to give 4.5 g 3- (benzyloxy)-2,2-dimethylpropan-l-ol 160 (58percent yield). LCMS: m/z 195.1 [M+H]+, fR = 1.70 min.
51%
Stage #1: With potassium <i>tert</i>-butylate In 1,4-dioxane at 0 - 20℃; for 1 h; Inert atmosphere Stage #2: at 90℃; for 4 h; Inert atmosphere
A solution of 2,2-dimethyl-propane-l,3-diol (25.85 g, 248 mmol) in dioxane (400 mL) was cooled to 0°C. Potassium tert-butoxide (30 g, 267 mmol) was added portionwise to the cooled solution. The resulting mixture was stirred at room temperature for 1 h. (Bromomethyl)benzene (29.5 mL, 248 mmol) was added dropwise via addition funnel. The mixture was heated to 90°C and stirred for 4 h. The resulting mixture was concentrated in vacuo. The resulting residue was partitioned between water (200 mL) and ethyl acetate (200 mL) and extracted with ethyl acetate (3x200 mL). The organics were combined, washed with brine (100 mL), dried on sodium sulfate, and concentrated in vacuo. The crude material was purified by column chromatography (Si02, 5percent to 60percent ethyl acetate in heptane) to afford 3-benzyloxy-2,2-dimethyl-propan-1-ol as a yellow oil (24.84 g, 51percent). 1H NMR (CDCl3) : 7.28 - 7.42 (m, 5H), 4.52 (s, 2H), 3.47 (s, 2H), 3.34 (s, 2H), 0.94 (s, 6H). MS calcd. for C12H18O2 [(M+H)+] 195.3, obsd. 195.
12.50 g
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5 h; Stage #2: at 20℃; for 16 h;
Sodium hydride (2.50 g, 105.62 mmol, 60percent in mineral oil) was suspended in dry DMF (150 ml) at 0° C. and a solution of 2,2-dimethylpropane-1,3-diol (10.0 g, 96.02 mmol) in DMF (50.0 ml) was added dropwise. The RM was stirred at 0° C. for 30 min. To the RM was added dropwise benzyl bromide (11.50 ml, 96.02 mmol) and the RM was allowed to warm to RT and stirred for 16 h. The RM was diluted with water (300 ml) and the organic product was extracted with EtOAc (3*200 ml). The organic layer was washed with brine (2*200 ml), dried over Na2SO4, filtered and the solvent evaporated in vacuo to give the crude product, which was purified by column chromatography (silica gel 60-120 mesh, 0-10percent EtOAc in PE) to get the title compound (12.50 g).
Reference：
[1] Tetrahedron Letters, 2009, vol. 50, # 13, p. 1466 - 1468
[2] Tetrahedron, 1986, vol. 42, # 21, p. 5941 - 5948
[3] Journal of the American Chemical Society, 2013, vol. 135, # 14, p. 5467 - 5474
[4] Patent: US2017/15675, 2017, A1, . Location in patent: Paragraph 1274
[5] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 8, p. 1986 - 1990
[6] Chemistry - A European Journal, 2012, vol. 18, # 52, p. 16823 - 16827
[7] Patent: WO2016/44626, 2016, A1, . Location in patent: Paragraph 00435
[8] Angewandte Chemie - International Edition, 2000, vol. 39, # 1, p. 209 - 213
[9] Tetrahedron, 2016, vol. 72, # 2, p. 318 - 327
[10] Patent: US2009/82464, 2009, A1, . Location in patent: Page/Page column 45
[11] Patent: WO2014/153226, 2014, A1, . Location in patent: Paragraph 00319
[12] Patent: WO2015/42414, 2015, A1, . Location in patent: Paragraph 00509
[13] Patent: WO2013/189904, 2013, A1, . Location in patent: Page/Page column 47
[14] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 9, p. 1019 - 1024
[15] Journal of Organic Chemistry, 1985, vol. 50, # 15, p. 2707 - 2711
[16] Tetrahedron: Asymmetry, 1995, vol. 6, # 1, p. 271 - 282
[17] Patent: US2017/101397, 2017, A1, . Location in patent: Paragraph 0468; 0469
[18] Patent: WO2018/108231, 2018, A1, . Location in patent: Page/Page column 50
2
[ 96556-40-0 ]
[ 66582-32-9 ]
Yield
Reaction Conditions
Operation in experiment
94%
With lithium aluminium tetrahydride In tetrahydrofuran at -78 - 0℃; for 0.75 h; Inert atmosphere
Methyl 3-(benzyloxy)-2,2-dimethylpropanoate (8a) (2.91 g, 13.1 mmol) was dissolved in THF and was cooled to -78 °C. LiAlH4 (14.4 mL, 14.4 mmol, 1 M) was added slowly via syringe to the solution. After stirring for 15 min at -78 °C, the cooling bath was removed and was replaced with an ice-water bath. The reaction mixture was stirred at 0 °C for 30 min. Excess LiAlH4 was quenched with ethyl acetate (3 mL). The mixture was warmed to r.t. and 0.55 mL water followed by 0.55 mL NaOH (15percent aq solution) followed by 1.65 mL water was added to the mixture and the resulting precipitate was removed by filtration through a pad of Celite with ethyl acetate rinsing. The filtrate was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (50 mL) and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography on silica gel (20percent → 25percent ethyl acetate in hexanes) to afford 3-(benzyloxy)-2,2-dimethylpropan-1-ol (8b) (2.40 g, 94percent yield) as a colorless oil: 1H NMR (400 MHz, CHLOROFORM-d) δ 7.39 - 7.25 (m, 5H), 4.50 (s, 2H), 3.45 (d, J=5.8 Hz, 2H), 3.31 (s, 2H), 0.92 (s, 6H); MS (ESI) m/e 195.2 [(M+H)+, calcd for C12H19O2 195.1].
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 6, p. 1360 - 1363
[2] Patent: US2012/322837, 2012, A1, . Location in patent: Page/Page column 98
3
[ 776-88-5 ]
[ 66582-32-9 ]
Reference：
[1] Chemistry Letters, 1995, # 3, p. 179 - 180
[2] Journal of Organic Chemistry, 1989, vol. 54, # 12, p. 2817 - 2825
[3] Tetrahedron Asymmetry, 2007, vol. 18, # 17, p. 2021 - 2029
[4] Journal of the Chinese Chemical Society, 2009, vol. 56, # 3, p. 510 - 523
[5] Synlett, 2004, # 4, p. 647 - 650
[6] Chemistry Letters, 1983, p. 1593 - 1596
[7] Organic Letters, 2011, vol. 13, # 5, p. 995 - 997
[8] Journal of the American Chemical Society, 2000, vol. 122, # 43, p. 10521 - 10532
4
[ 100-44-7 ]
[ 126-30-7 ]
[ 66582-32-9 ]
Reference：
[1] Tetrahedron Letters, 1997, vol. 38, # 8, p. 1359 - 1362
[2] European Journal of Organic Chemistry, 1999, # 11, p. 2817 - 2823
[3] Synlett, 2011, # 10, p. 1413 - 1418
[4] Tetrahedron Letters, 1977, p. 4257 - 4260
[5] Tetrahedron, 1988, vol. 44, # 13, p. 3899 - 3918
[6] Journal of pharmaceutical sciences, 1988, vol. 77, # 2, p. 149 - 152
5
[ 116945-47-2 ]
[ 66582-32-9 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2013, vol. 355, # 11-12, p. 2151 - 2157
General procedure: To a solution of oxalyl chloride (40 mmol,2 eq), in dichloromethane (20 mL) at -78C, was added DMSO (80 mmol, 4 eq) in dichloromethane(20 mL) dropwise. After stirring during 30 min, a solution of monobenzylated diol (20 mmol, 1 eq)in dichloromethane (20 mL) was added dropwise. The mixture was stirred 2 h, and triethylamine (6eq) in CH2Cl2 (15 mL) was added dropwise. The mixture was allowed to reach room temperature,and quenched with 50 mL of water. The organic layers were washed with a solution of saturated NaCl, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The yellow oil was purified by flash chromatography.
66%
With Dess-Martin periodane; In tetrahydrofuran; dimethyl sulfoxide; at 0 - 23℃; for 16h;
Dess-Martin periodinane (10.90 g, 25.77 mmol) was slowly added to a solution of <strong>[66582-32-9]3-(benzyloxy)-2,2-dimethylpropan-1-ol</strong> (5.0 g, 25.77 mmol) in THF-DMSO (1:1 v/v, 200 ml) at 0 C., and the mixture was slowly warmed to RT and stirred for 16 h. The RM was filtered through a celite bed and washed with DCM. The organic layer was washed with sat. sodium bicarbonate solution (2*100 ml) and brine (2*100 ml), dried over anhydrous Na2SO4, filtered and the solvent evaporated in vacuo to give the crude product, which was purified by column chromatography (60-120 mesh silica gel, 0-10% EtOAc in PE) to give the title compound (3.3 g, 66%).
60%
With sulfur trioxide pyridine complex; dimethyl sulfoxide; triethylamine; In dichloromethane; at 0℃; for 1.16667h;
Example 137D 3-(benzyloxy)-2,2-dimethylpropanal A solution of the product from Example 137C in CH2Cl2 (20 ml) and DMSO (3.6 mL, 50.7 mmol) was cooled to 0 C., then triethylamine (1.43 mL, 10.26 mmol) was added. Pyridine-sulfur trioxide complex (1.625 g, 10.21 mmol) was added in 5 portions over about 40 minutes. After the final addition, the reaction mixture was continued to stir at 0 C. for 30 minutes. The mixture was then poured into a separatory funnel and washed with water (3*5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude oil was purified by silica gel chromatography, eluting with 0 to 15% ethyl acetate-heptanes to afford the title compound (0.584 g, 60%). 1H NMR (400 MHz, CDCl3) delta 9.57 (s, 1H), 7.47-7.15 (m, 5H), 4.51 (s, 2H), 3.45 (s, 2H), 1.09 (s, 6H). MS (DCI+) m/z 210.0 (M+NH4).
In dichloromethane;
b. 2,2-Dimethyl-3-(phenylmethoxy)-propionaldehyde In a dry three-neck flask equipped with a mechanical stirrer and an addition funnel was placed 78.8 g (0.21 moles) of pyridinium dichromate, Aldrich Chemical, see Tetrahedron Lett., 399 (1979), ibid., 731, (1980) and 200 ml of dry CH2 Cl2. The mixture was vigorously stirred and a solution of 26.8 g (0.138 mole) of 2,2-dimethyl-3-(phenylmethoxy)propanol, the product of Example 1a, in 50 ml of CH2 Cl2 was added in one portion. The reaction was followed by gas liquid chromatography (GC) and required four days stirring at room temperature. The black brown reaction mixture was poured into 200 ml ethyl ether and the mixture was filtered through a dry silica gel column to obtain a colorless solution. Removal of solvent gave a residue which was distilled through a vigreux column to obtain the title compound, a colorless liquid, bp 72-75/0.02 mmHg.
Example 137C 3-(benzyloxy)-2,2-dimethylpropan-1-ol A solution of 2,2-dimethylpropane-1,3-diol (2 g, 19.20 mmol) in THF (30 mL) was treated with 60% sodium hydride (0.256 g, 6.40 mmol) at room temperature, and the mixture stirred at room temperature for 5 minutes. Benzyl bromide (0.761 mL, 6.40 mmol) and tetrabutylammonium iodide (0.709 g, 1.920 mmol) were then added, and the reaction stirred overnight at room temperature. After this time, the mixture was diluted with ethyl acetate (150 mL) and water (50 mL), and the phases were separated. The aqueous layer was extracted with ethyl acetate (2*50 mL). The combined organics were washed with water (2*50 mL) and brine (50 mL) sequentially, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified on silica gel chromatography (10 to 50% ethyl acetate-heptanes, eluent) to afford the title compound (0.992 g, 80%). 1H NMR (400 MHz, CDCl3) delta 7.41-7.32 (m, 5H), 4.51 (s, 2H), 3.46 (d, J=5.7 Hz, 2H), 3.33 (s, 2H), 2.55 (t, J=5.9 Hz, 1H), 0.93 (s, 6H). MS (DCI+) m/z 195.0 (M+H).
77%
With tetra-(n-butyl)ammonium iodide; In toluene; at 0 - 20℃; for 16h;
Into a 10-L 4-neck round-bottom flask, was placed 2,2-dimethylpropane-1,3-diol (200 g, 1920 mmol), toluene (1 L), 50% KOH (aq. solution, 1L), n-Bu4NI (36 g, 97 mmol). Then (bromomethyl)benzene (328 g, 1920 mmol, 1.00 equiv.) was added at 0 C. The resulting solution was stirred at room temperature for 16 h. The reaction was then quenched by the addition of 1 L of ice-water. The resulting solution was extracted with 2x4 L of ethyl acetate. The combined organic layer was washed with 2x4 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography to afford the title compound as light yellow oil (77%). LCMS:mlz=195.0 [M+1]. ?H-NMR (300 MHz, CDC13) oe: 7.37-7.25 (m, 5H), 4.47 (m, 3H), 3.18 (d, 1=6.4Hz, 4H), 0.82 (s, 6H).
64%
General procedure: The diol (48 mmol, 1 eq) wasdissolved into DMF (120 mL) under argon. At 0C NaH (1.1 eq, 60% in mineral oil) was added inone portion and the mixture was stirred at 0C during 45 min. BnBr (0.97 eq) was added dropwise,the mixture was allowed to warm at room temperature and stirred overnight. The reaction wasquenched with saturated NH4Cl solution (20 mL) and then diluted with water. The crude mixturewas extracted with Et2O and the organic layer was washed with brine, dried over anhydrous MgSO4,filtered and concentrated in vacuo. Benzylated compound was then purified by flashchromatography on silica gel.
62%
Step A: 3-Phenylmethoxy-neopentylol (31a) Adapting a procedure or a variation thereof according to Effenberger, et al., Tetrahedron: Asymmetry 1995, 6, 271-282, a 1000 mL round-bottomed flask equipped with a magnetic stirring bar and a rubber septum was charged under a nitrogen atmosphere with 2.40 g of a 60 wt-% suspension of sodium hydride (NaH) in mineral oil (1.44 g, 60.0 mmol). The hydride was suspended in 50 mL of hexane and the supernatant was decanted, and the residue was dried under reduced pressure. Six-hundred (600) mL of anhydrous tetrahydrofuran (THF) were added under a nitrogen atmosphere and the suspension was cooled to ca. 0 C. (ice bath). 6.24 g (60 mmol) of commercially available neopentyl glycol (2,2-dimethyl-1,3-propandiol) was added and the reaction mixture was stirred for one hour at this temperature until the hydrogen evolution subsided. 5.9 mL of benzyl bromide (8.5 g, 50.0 mmol) was added to the stirred reaction mixture. The reaction mixture was stirred overnight with gradual warming to room temperature and the solvent was then partially removed under reduced pressure using a rotary evaporator. The reaction was quenched by addition of a one normal (1 N) aqueous solution of hydrogen chloride (HCl) and the product was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate (MgSO4), filtered, and the solvents were removed under reduced pressure using a rotary evaporator. The residue was purified by silica gel chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:4) to provide 6.0 g (62% yield) of the title compound (31a) as a colorless liquid. Rf=0.34 (EtOAc/Hxn=1:4). 1H NMR (400 MHz, CDCl3): delta=0.953 (s, 6H), 2.62 (br. t, J=5.6 Hz, 1H), 3.34 (s, 2H), 3.47 (d, J=5.6 Hz, 2H), 4.54 (s, 2H), 7.27-7.38 (m, 5H) ppm. MS (ESI) m/z 195.10 (M+H)+, 217.10 (M+Na)+. The analytical data was consistent with the data given in the literature.
62%
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 12h;
[00319] Into a 250-mL round-bottom flask, was placed 2,2-dimethylpropane-1,3-diol (10.4 g, 99.86 mmol) and N,N-dimethylformamide (100 mL). This was followed by the addition of 60% sodium hydride (4 g, 100.00 mmol), in portions at 0C. To this was added (bromomethyl)benzene (13.68 g, 79.98 mmol) at 0C. The resulting solution was stuffed for 12 h at room temperature and then diluted with 200 mL of NH4C1 (sat. aq). The resulting solution was extracted with 2x200 mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column with ethyl acetate/petroleum ether (1:10) to obtain 12 g (62%) of 3-(benzyloxy)-2,2-dimethylpropan-1-ol as light yellow oil. ?H NMR (300 MHz, DMSOd 6): 7.43-7.24 (m, 5H), 4.51-4.41 (m, 3H), 3.25-3.15 (m, 4H), 0.84 (s, 6H) ppm.
58%
[00509] 2,2-Dimethylpropane-l,3-diol 159 (4.24 g, 40 mmol) was dissolved in 120 mL of THF. To this mixture, was added NaH (1.92 g, 48 mmol, 60% in mineral oil) at 0 C under nitrogen atmosphere. After stirring at 0 C for 30 min, benzyl bromide (6.84 g, 40 mmol) was added to this mixture, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then transferred into iced water and extracted with ethyl acetate (50 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to obtain crude product, which was purified by silica gel chromatography (10% ethyl acetate/petroleum ether) to give 4.5 g 3- (benzyloxy)-2,2-dimethylpropan-l-ol 160 (58% yield). LCMS: m/z 195.1 [M+H]+, fR = 1.70 min.
51%
A solution of 2,2-dimethyl-propane-l,3-diol (25.85 g, 248 mmol) in dioxane (400 mL) was cooled to 0C. Potassium tert-butoxide (30 g, 267 mmol) was added portionwise to the cooled solution. The resulting mixture was stirred at room temperature for 1 h. (Bromomethyl)benzene (29.5 mL, 248 mmol) was added dropwise via addition funnel. The mixture was heated to 90C and stirred for 4 h. The resulting mixture was concentrated in vacuo. The resulting residue was partitioned between water (200 mL) and ethyl acetate (200 mL) and extracted with ethyl acetate (3x200 mL). The organics were combined, washed with brine (100 mL), dried on sodium sulfate, and concentrated in vacuo. The crude material was purified by column chromatography (Si02, 5% to 60% ethyl acetate in heptane) to afford 3-benzyloxy-2,2-dimethyl-propan-1-ol as a yellow oil (24.84 g, 51%). 1H NMR (CDCl3) : 7.28 - 7.42 (m, 5H), 4.52 (s, 2H), 3.47 (s, 2H), 3.34 (s, 2H), 0.94 (s, 6H). MS calcd. for C12H18O2 [(M+H)+] 195.3, obsd. 195.
12.50 g
Sodium hydride (2.50 g, 105.62 mmol, 60% in mineral oil) was suspended in dry DMF (150 ml) at 0 C. and a solution of 2,2-dimethylpropane-1,3-diol (10.0 g, 96.02 mmol) in DMF (50.0 ml) was added dropwise. The RM was stirred at 0 C. for 30 min. To the RM was added dropwise benzyl bromide (11.50 ml, 96.02 mmol) and the RM was allowed to warm to RT and stirred for 16 h. The RM was diluted with water (300 ml) and the organic product was extracted with EtOAc (3*200 ml). The organic layer was washed with brine (2*200 ml), dried over Na2SO4, filtered and the solvent evaporated in vacuo to give the crude product, which was purified by column chromatography (silica gel 60-120 mesh, 0-10% EtOAc in PE) to get the title compound (12.50 g).
With potassium hydroxide; In toluene; at 0 - 20℃; for 12h;
To a stirred solution of 2,2-dimethyl propane-1,3-diol (100 g, 961.153 mmol) in toluene (1000 mL), potassium hydroxide (53.84 g, 961.5 mmol) and benzyl bromide (34 mL , 288.4 mmol) were added at 0 C. The resulting reaction mixture was stirred for 12h at RT. On completion, the reaction mixture was diluted with H20 (1000 mL) and extracted twice with EtOAc (2 x 1000 mL). The combined organic layers were washed with H20 (500 mL) and brine (500 mL), dried over anhydrous sodium sulfate and evaporated under vacuum. The resulting residue was purified by silica gel column chromatography (0-7% EtOAc in Pet ether as elute) to afford the title compound as colorless liquid.1H NMR (400MHz, CDCI3) delta = 7.40 - 7.23 (m, 5H), 4.51 (s, 2H), 3.46 (s, 2H), 3.32 (s, 2H), 2.60 (br s, 1H), 0.93 (s, 6H). LCMS: 86% (M + H) 234.
With triethylamine; In dichloromethane; at 0℃; for 2h;
[00510] 3-(Benzyloxy)-2,2-dimethylpropan-l-ol 160 (2.5 g, 12.9 mmol) was dissolved in dichloromethane (50 mL). Triethylamine (2.61 g, 25.8 mmol) and methane sulfonyl chloride (1.79 g, 15.5 mmol) were added at 0 C and the reaction mixture was stirred at 0 C for 2 h. The reaction mixture was transferred into iced water and extracted with dichloromethane (40 mL X 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to give crude 3 -(benzyl oxy)-2,2- dimethylpropyl methanesulfonate 161, which was purified by silica gel chromatography (17% ethyl acetate/petroleum ether) to give 3.2 g of 3-(benzyloxy)-2,2-dimethylpropyl methanesulfonate 3 (91% yield). LCMS: m/z 294.9 [M+Na]+, tK = 1.78 min.
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;
To a stirred solution of 3-benzyloxy-2,2-dimethyl-propan-l-ol (55 g, 283.5 mmol) in DCM (1000 mL), TEA (119 mL, 850 mmol) and mesyl chloride (32.7 mL, 425.0) were added at 0 C. The mixture was stirred for 3h at RT. On completion, the reaction mixture was diluted with H20 (500 mL) and extracted twice with EtOAc (2 x 1000 mL). The combined organic layers were washed with H20 (500 mL) and brine (500 mL), dried over anhydrous sodium sulfate and evaporated under vacuum to afford the title compound as pale yellow liquid (crude), which was used in the next step without further purification. 1H NMR (400MHz, CDCl3) delta = 7.44 - 7.26 (m, 5H), 4.50 (s, 2H), 4.05 (s, 2H), 3.25 (s, 2H), 2.94 (s, 3H), 0.99 (s, 6H) .LCMS: 89% (M + Na) 295.
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