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Structure of 1195-66-0 * Storage: {[proInfo.prStorage]}
* 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.
at 20℃; for 12 h; Inert atmosphere; Schlenk technique
A solution of (PhPSiP)Ni(η3-C8H13) (1.0 mg, 0.0014 mmol) and 1,3,5-trimethoxybenzene (11.5 mg, 0.068 mmol) was added to a J. Young NMR tube and the solution was frozen. A layer of HB(pin) (9.9 μL, 0.068 mmol) was added while cold. On a dual-manfold Schlenk line, the headspace was evacuated and charged with 1 atm of CO2 at room temperature. After 15 minutes, near complete depletion of HB(pin) along with the appearance of three major products was observed. Listed below are the characteristic resonances (in ppm) of the products in the reaction. The products have been assigned by comparison to those reported by Sabo-Etienne.[4] After 15 minutes, the products a, b, c were present in a 61:5:34 ratio along with unreacted starting material HB(pin). However c was consumed over time and after 12 hours, all the HB(pin) had been consumed, and only a trace amount of c was left in the reaction mixture. Integration of the products show there was 13percent (pin)BOMe, 85percent (pin)BOB(pin), and miscellaneous products that cannot be identified. However, a peak at 8.72 ppm that corresponds to formaldehyde was also present.
Reference：
[1] Polyhedron, 2014, vol. 84, p. 37 - 43
[2] Journal of the American Chemical Society, 2010, vol. 132, # 26, p. 8872 - 8873
[3] Angewandte Chemie - International Edition, 2012, vol. 51, # 45, p. 11343 - 11345[4] Angew. Chem., 2012, vol. 05, # 741, p. 11505 - 11507
[5] Journal of the American Chemical Society, 2015, vol. 137, # 16, p. 5332 - 5335
[6] Angewandte Chemie - International Edition, 2015, vol. 54, # 17, p. 5098 - 5102[7] Angew. Chem., 2015, vol. 127, # 17, p. 5187 - 5191,5
[8] Inorganic Chemistry, 2015, vol. 54, # 15, p. 7506 - 7515
[9] Chemical Communications, 2016, vol. 52, # 89, p. 13155 - 13158
[10] ACS Catalysis, 2017, vol. 7, # 3, p. 1853 - 1859
[11] Dalton Transactions, 2017, vol. 46, # 19, p. 6183 - 6186
[12] Dalton Transactions, 2018, vol. 47, # 25, p. 8199 - 8203
2
[ 929887-18-3 ]
[ 629-05-0 ]
[ 1006881-50-0 ]
[ 1195-66-0 ]
Reference：
[1] Journal of the American Chemical Society, 2008, vol. 130, # 5, p. 1526 - 1527
3
[ 76-09-5 ]
[ 121-43-7 ]
[ 1195-66-0 ]
Yield
Reaction Conditions
Operation in experiment
90%
for 6 h; Inert atmosphere; Reflux
Synthesis of 2-methoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane A flask equipped with a reflux condenser, stirrer, an inert gas inlet and a thermocouple set in heating mantle was charged with trimethyl borate and pinacol under positive pressure of nitrogen. The resulting mixture was heated at reflux for 6 hours. The mixture was cooled to ambient temperatures and transferred to a flask with a Vigreux column. The mixture was distilled at atmospheric pressure to afford 2-methoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (bp 159° C.) in high yield (90percent). 1H NMR (400 MHz, CDCl3): δ.box. 3.41 (m, 3H), 1.11 (m, 12H). 11B NMR (128.3 MHz, CDCl3): δ 22.2. 13C NMR (100.6 MHz, CDCl3): δ.box. 82.7, 52.6, 24.6.
Reference：
[1] Patent: US2012/289733, 2012, A1, . Location in patent: Page/Page column 4
[2] Angewandte Chemie - International Edition, 2005, vol. 44, # 20, p. 3133 - 3135
Stage #1: With TurboGrignard In 2-methyltetrahydrofuran at -15 - -10℃; Stage #2: at 20℃;
2nd step: under the protection of nitrogen, the 1M isopropyl magnesium chloride-lithium chloride (88 ml, 88mmol) into the reaction bottle, temperature control -15 ° C to -10 °C, dropwise N-Cbz-1, 2, 5, 6-tetrahydro-pyridine-4-bromo, 2-methyl tetrahydrofuran (90 ml) solution, stirring finishing joining 1-2 hours. After the end of the exchange, then drop by adding methoxy boronic acid pinacone ester (14.2g, 90mmol), subsequently maintain the reaction at room temperature overnight. Adding 10percent hydrochloric acid aqueous solution quenching reaction, adjusting PH= 4-5, adding 220 ml ethyl acetate, saturated salt water an organic layer, the organic layer after evaporation to dryness, add ethanol/heptane 10:1 obtained after pulping 19.2g a buff solid N-Cbz-1, 2, 5, 6-tetrahydro-pyridine-4-boronic acid frequency that alcohol ester, GC: 99.6percent, yield: 56percent.
Reference：
[1] Patent: CN105566367, 2016, A, . Location in patent: Paragraph 0020
43
[ 20469-65-2 ]
[ 1195-66-0 ]
[ 365564-07-4 ]
Reference：
[1] Chemical Communications, 2016, vol. 52, # 43, p. 7009 - 7012
44
[ 1195-66-0 ]
[ 87630-36-2 ]
[ 365564-11-0 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2009, vol. 7, # 5, p. 860 - 862
[2] Organic and Biomolecular Chemistry, 2009, vol. 7, # 5, p. 860 - 862
[3] Organic and Biomolecular Chemistry, 2009, vol. 7, # 5, p. 860 - 862
45
[ 624-28-2 ]
[ 1195-66-0 ]
[ 214360-62-0 ]
Reference：
[1] Chemical Science, 2014, vol. 5, # 11, p. 4317 - 4327
46
[ 2044-08-8 ]
[ 1195-66-0 ]
[ 89490-05-1 ]
Yield
Reaction Conditions
Operation in experiment
81%
With iodine; magnesium In tetrahydrofuran at 40 - 55℃; Inert atmosphere
Under the protection of nitrogen, adding magnesium metal in the reaction bottle 8.0g (0.33mol) and several grain of iodines, prior to dropping funnel in the uniformly mixed methoxy boronic acid frequency that alcohol ester 56.9g (0.36mol), cyclohexene-1-polybromide 48.3g (0.3mol) and anhydrous tetrahydrofuran 300 ml, the temperature rising to outside bath 40-45 degrees, to a first 25 ml mixed solution, after color treats the iodine triggered evanishment standard, the oven-keeping 40-55 degrees between the completion of the dropping of the remaining mixed solution, then subsequently gradually heated up to reflow to continue reaction 2-3 hours, disappearance of the raw material after detection GC, to the reaction liquid 0-10 degree, slowly adding saturated NH4Cl quenching, adjusting for PH 5-6, separating the organic layer, the water layer using MTBE 150 ml extraction a, combined with the organic layer, the saturated salt water washing, solvent evaporation to dryness of the organic layer is concentrated under reduced pressure, then replace the high vacuum pump, collecting 80-83 °C fraction, get colorless transparent liquid 50.5g, yield 81percent
Reference：
[1] Angewandte Chemie - International Edition, 2015, vol. 54, # 9, p. 2780 - 2783[2] Angew. Chem., 2015, vol. 127, # 9, p. 2820 - 2824,5
48
[ 1195-66-0 ]
[ 460-00-4 ]
[ 214360-58-4 ]
Reference：
[1] Chemical Communications, 2016, vol. 52, # 43, p. 7009 - 7012
49
[ 10075-52-2 ]
[ 1195-66-0 ]
[ 837392-62-8 ]
Reference：
[1] Chemical Communications, 2016, vol. 52, # 43, p. 7009 - 7012
50
[ 3469-69-0 ]
[ 1195-66-0 ]
[ 269410-08-4 ]
Reference：
[1] Patent: CN108276418, 2018, A, . Location in patent: Paragraph 0085; 0086; 0087
51
[ 1195-66-0 ]
[ 454482-11-2 ]
Yield
Reaction Conditions
Operation in experiment
63%
Stage #1: With TurboGrignard In tetrahydrofuran at -15 - -10℃; Inert atmosphere Stage #2: at 20℃;
2nd step: under the protection of nitrogen, the 1.3M isopropyl magnesium chloride-lithium chloride (72 ml, 94mmol) into the reaction bottle, temperature control -15 ° C to -10 °C, dropwise N-methyl -1, 2, 5, 6-tetrahydro-pyridine-4-polybromide tetrahydrofuran (80 ml) solution, stirring finishing joining 1-2 hours. After the end of the exchange, then drop by adding methoxy boronic acid pinacone ester (15.8g, 0 . 1mol), subsequently maintain the reaction at room temperature overnight. Adding 10percent hydrochloric acid aqueous solution quenching reaction, adjusting PH= 4-5, by adding 150 ml ethyl acetate, saturated salt water an organic layer, the organic layer after evaporation to dryness, add ethanol/heptane 40:1 obtained after pulping 14.1g kind of white solid N-methyl -1, 2, 5, 6-tetrahydro-pyridine-4-boronic acid frequency that alcohol ester, GC: 98.3percent, yield: 63percent.
Reference：
[1] Patent: CN105566367, 2016, A, . Location in patent: Paragraph 0017
52
[ 877399-73-0 ]
[ 1195-66-0 ]
[ 877399-74-1 ]
Reference：
[1] Organic Process Research and Development, 2011, vol. 15, # 5, p. 1018 - 1026
[2] Tetrahedron Letters, 2014, vol. 55, # 9, p. 1528 - 1531
[3] Patent: CN107417603, 2017, A, . Location in patent: Paragraph 0021
Stage #1: With isopropyl magnesium chloride - lithium chloride complex In tetrahydrofuran at 20 - 25℃; for 16 h; Stage #2: at -20 - 25℃; for 2 h;
Step 3[00251j To an oven-dried vial was charged a solution of isopropyl magnesium /lithium chloride solution (1.0 M in THF) (6.32 ml, 8.22 mmol) at room temperature, andto this solution was added 4-bromo-1-(1-ethoxyethyl)-1H-pyrazole (1.00 g, 4.56 mmol)dropwise and the resulting mixture was stirred at room temperature for 16 h. Theresulting solution was then cooled to -20 °C and 2-methoxy-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (1.73 1 g, 10.95 mmol) was added via syringe and the resulting mixture was allowed to warm to rt. After 2h at room temperature, the reaction was quenched by addition of aq. sat. ammonium chloride (15 mL) causing a white precipitate to form.After diluting with additional water (20 mL), the mixture was extracted with hexanes (140 mL x 2) and the combined extracts were washed with aq. sat. sodium bicarbonate, brine, then dried over sodium sulfate, filtered and concentrated to afford 1.20 g (99percent) of the product as a colorless oil
99%
Stage #1: With TurboGrignard In tetrahydrofuran at 20℃; Stage #2: at -20 - 20℃; for 2 h;
Step 3 To an oven dried vial was charged a solution of isopropylmagnesium chloride - lithium chloride complex (1.0 M in THF) (6.32 ml, 8.22 mmol) at rt, and 4-bromo-l-(l- ethoxyethyl)-lH-pyrazole from Step 2 (1.00 g, 4.56 mmol) was added dropwise and the resulting mixture was stirred at rt overnight. The solution obtained was then cooled to -20 °C and 2-methoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.731 g, 10.95 mmol) was added dropwise via syringe. After the addition was complete, the reaction was allowed to slowly warm to rt and stir at rt for 2 h. The reaction was quenched at this time by the addition of aq. sat. NH4C1 (15 mL) which caused a white precipitate to form. Water was added (20 mL) and the mixture was extracted with hexanes (140 mL x 2). The combined extracts were washed with aq. sat. sodium bicarbonate, brine, then dried over anhyd sodium sulfate, filtered and concentrated to afford 1.20 g (99percent) of the desired product as a colorless oil. 1H NMR (400MHz, chloroform-d) δ 7.91 (s, 1H), 7.79 (s, 1H), 5.55 (q, J=5.9 Hz, 1H), 3.51 - 3.39 (m, 1H), 3.37 - 3.25 (m, 1H), 1.67 (d, J=5.9 Hz, 3H), 1.37 - 1.30 (m, 12H), 1.15 (t, J=7.0 Hz, 3H).
99%
Stage #1: With TurboGrignard In tetrahydrofuran at 20℃; Stage #2: at -20 - 20℃; for 2 h;
A solution of isopropylmagnesium chloride-lithium chloride complex (1.0 M in THF) (6.32 ml, 8.22 mmol) was charged to the dried flask under rt,And 4-bromo-1- (1-ethoxyethyl) -1H-pyrazole (1.00 g, 4.56 mmol) from step 2 was added dropwise and the resulting mixture was stirred overnight at rt. The resulting solution was then cooled to -20 ° C and 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added dropwise via syringe (1.731 g, 10.95 mmol). After the addition was complete, the reaction was slowly warmed to rt and stirred at rt for 2 h. The reaction was quenched by the addition of saturated aqueous NH4Cl (15 mL) to form a white precipitate. Water (20 mL) was added and the mixture was extracted with hexane (140 mL x 2). The combined extracts were washed with saturated aqueous sodium bicarbonate, brine, then dried over anhydrous sodium sulfate, filtered and concentrated to afford 1.20 g (99percent) of the desired product as a colorless oil.
56.4%
Stage #1: at 20℃; for 12 h; Stage #2: at -20 - 10℃;
1-(Ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (19).; To a 100 ml solution of iPrMgCl.LiCl (50 mmol, 1.8 equiv) was added 4-bromo-1-(ethoxyethyl)-1H-pyrazole (22, 6.15 g, 28 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 12 hrs and then cooled to -20° C. Methoxy pinacolborate (23, 10.6 g, 67 mmol, 2.4 equiv) was then added to the reaction mixture. The resulting mixture was stirred at 0-10° C. for 1 h. Aqueous NH4Cl was added to quench the reaction. The mixture was then extracted with petroleum ether (PE). The combined PE extracts were washed with saturated NaHCO3, dried over Na2SO4 and concentrated under reduced pressure. The crude product was crystallized in PE to afford 1-(ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (19, 4.2 g, 7.45 g theoretical, 56.4percent yield) as a white to off-white solid (GC purity: 99percent). For 19: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.09 (s, 1H), 8.58 (s,1H), 7.62 (s,1H), 5.55 (q, 1H, J=6.1 Hz), 3.37 (dq, 1H, J=7.1, 9.6 Hz), 3.12 (dq, 1H, J=7.0, 9.7 Hz), 1.56 (d, 3H, J=6.0 Hz), 1.24 (s, 12H), 1.00 (t, 3H, J=7.0 Hz); C13H23BN2O3 (MW, 266.14), LCMS (EI) m/e 267 (M++H).
56.4%
Stage #1: With TurboGrignard In tetrahydrofuran at 20℃; for 12 h; Stage #2: at -20 - 10℃; for 1 h; Stage #3: With water; ammonium chloride In tetrahydrofuran
1-(Ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (24) [0165] To a 100 ml solution of iPrMgCl.LiCl (50 mmol, 1.8 equiv) in THF was added 4-bromo-1-(ethoxyethyl)-1H-pyrazole (6.15 g, 28 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 12 h and then cooled to −20° C. Methoxy pinacolborate (10.6 g, 67 mmol, 2.4 equiv) was then added to the reaction mixture at −20° C. The resulting mixture was stirred at 0-10° C. for 1 h. Aqueous NH4Cl was added to quench the reaction. The mixture was then extracted with petroleum ether (PE). The combined PE extracts were washed with saturated NaHCO3, dried over Na2SO4 and concentrated under reduced pressure. The crude product was crystallized in PE to afford 1-(ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (24, 4.2 g, 7.45 g theoretical, 56.4percent yield) as a white to off-white solid (GC purity: 99percent). For 24: 1H NMR (DMSO-d6, 400 MHz) δ 8.09 (s, 1H), 8.58 (s, 1H), 7.62 (s, 1H), 5.55 (q, 1H, J=6.1 Hz), 3.37 (dq, 1H, J=7.1, 9.6 Hz), 3.12 (dq, 1H, J=7.0, 9.7 Hz), 1.56 (d, 3H, J=6.0 Hz), 1.24 (s, 12H), 1.00 (t, 3H, J=7.0 Hz) ppm; C13H23BN2O3 (MW, 266.14), LCMS (EI) m/e 267 (M++H).
Stage #1: 1,3-Diiodobenzene With TurboGrignard In tetrahydrofuran at -20℃; for 1h;
Stage #2: 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In tetrahydrofuran at -20 - 20℃;
Step 2 To a solution of 4-iodo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazole (1.0 g, 3.1 mmol) in anhydrous THF (8 mL) was added iPrMgCl (2M in THF, 3.10 mL, 6.21 mmol) at 0 C. drop by drop under nitrogen. The reaction was stirred for 1 hour at 0 C. under nitrogen. To the solution was added 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.736 g, 4.66 mmoL) at 0 C. and the resulting yellow solution was allowed to stir for 1 hour at ambient temperature under nitrogen. The reaction was quenched with sat. aqueous solution of NH4Cl (10 mL). EtOAc (50 mL) and sat aqueous NH4Cl solution (10 mL) were added. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3*50 mL), dried over Na2SO4, and concentrated to give the crude product as yellow oil. The oil was purified a silica gel column eluding with EtOAc and hexanes to provide 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole as clear oil (800 mgs, 80% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.91 (s, 1H) 4.48-4.54 (m, 1H) 4.26-4.33 (m, 2H) 3.86-3.90 (m, 1H) 3.66-3.76 (m, 1H) 3.45-3.57 (m, 1H) 3.33-3.39 (m, 1H) 1.33-1.70 (m, 6H) 1.24 (s, 12H). on a high vacuum for 1 hour. The solid was re-crystallized from EtOH (50 mL) to provide 2-[4-(3-Quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-pyrazol-1-yl]-ethanol (400, 63% yield) as a white crystalline solid with a melting point of 222 C. 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H) 8.89 (dd, J=4.14, 1.70 Hz, 1H) 8.63 (s, 1H) 8.37 (dd, J=8.38, 1.04 Hz, 1H) 8.32 (s, 1H) 7.98-8.04 (m, 2H) 7.82 (dd, J=8.67, 2.07 Hz, 1H) 7.53 (dd, J=8.29, 4.14 Hz, 1H) 6.15 (s, 2H) 4.96 (t, J=5.27 Hz, 1H) 4.24 (t, J=5.46 Hz, 2H) 3.78 (q, J=5.46 Hz, 2H).
Stage #1: 1,3-dibromo-5-fluorobenzene With n-butyllithium In diethyl ether; hexane at -80℃; for 0.5h; Inert atmosphere;
Stage #2: 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In tetrahydrofuran; diethyl ether; hexane at -70℃; for 0.5h; Inert atmosphere;
Stage #3: carbon dioxide Further stages;
Step 3[00251j To an oven-dried vial was charged a solution of isopropyl magnesium /lithium chloride solution (1.0 M in THF) (6.32 ml, 8.22 mmol) at room temperature, andto this solution was added 4-bromo-1-(1-ethoxyethyl)-1H-pyrazole (1.00 g, 4.56 mmol)dropwise and the resulting mixture was stirred at room temperature for 16 h. Theresulting solution was then cooled to -20 C and 2-methoxy-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (1.73 1 g, 10.95 mmol) was added via syringe and the resulting mixture was allowed to warm to rt. After 2h at room temperature, the reaction was quenched by addition of aq. sat. ammonium chloride (15 mL) causing a white precipitate to form.After diluting with additional water (20 mL), the mixture was extracted with hexanes (140 mL x 2) and the combined extracts were washed with aq. sat. sodium bicarbonate, brine, then dried over sodium sulfate, filtered and concentrated to afford 1.20 g (99%) of the product as a colorless oil
99%
Step 3 To an oven dried vial was charged a solution of isopropylmagnesium chloride - lithium chloride complex (1.0 M in THF) (6.32 ml, 8.22 mmol) at rt, and 4-bromo-l-(l- ethoxyethyl)-lH-pyrazole from Step 2 (1.00 g, 4.56 mmol) was added dropwise and the resulting mixture was stirred at rt overnight. The solution obtained was then cooled to -20 C and 2-methoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.731 g, 10.95 mmol) was added dropwise via syringe. After the addition was complete, the reaction was allowed to slowly warm to rt and stir at rt for 2 h. The reaction was quenched at this time by the addition of aq. sat. NH4C1 (15 mL) which caused a white precipitate to form. Water was added (20 mL) and the mixture was extracted with hexanes (140 mL x 2). The combined extracts were washed with aq. sat. sodium bicarbonate, brine, then dried over anhyd sodium sulfate, filtered and concentrated to afford 1.20 g (99%) of the desired product as a colorless oil. 1H NMR (400MHz, chloroform-d) delta 7.91 (s, 1H), 7.79 (s, 1H), 5.55 (q, J=5.9 Hz, 1H), 3.51 - 3.39 (m, 1H), 3.37 - 3.25 (m, 1H), 1.67 (d, J=5.9 Hz, 3H), 1.37 - 1.30 (m, 12H), 1.15 (t, J=7.0 Hz, 3H).
99%
A solution of isopropylmagnesium chloride-lithium chloride complex (1.0 M in THF) (6.32 ml, 8.22 mmol) was charged to the dried flask under rt,And 4-bromo-1- (1-ethoxyethyl) -1H-pyrazole (1.00 g, 4.56 mmol) from step 2 was added dropwise and the resulting mixture was stirred overnight at rt. The resulting solution was then cooled to -20 C and 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added dropwise via syringe (1.731 g, 10.95 mmol). After the addition was complete, the reaction was slowly warmed to rt and stirred at rt for 2 h. The reaction was quenched by the addition of saturated aqueous NH4Cl (15 mL) to form a white precipitate. Water (20 mL) was added and the mixture was extracted with hexane (140 mL x 2). The combined extracts were washed with saturated aqueous sodium bicarbonate, brine, then dried over anhydrous sodium sulfate, filtered and concentrated to afford 1.20 g (99%) of the desired product as a colorless oil.
56.4%
1-(Ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (19).; To a 100 ml solution of iPrMgCl.LiCl (50 mmol, 1.8 equiv) was added 4-bromo-1-(ethoxyethyl)-1H-pyrazole (22, 6.15 g, 28 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 12 hrs and then cooled to -20 C. Methoxy pinacolborate (23, 10.6 g, 67 mmol, 2.4 equiv) was then added to the reaction mixture. The resulting mixture was stirred at 0-10 C. for 1 h. Aqueous NH4Cl was added to quench the reaction. The mixture was then extracted with petroleum ether (PE). The combined PE extracts were washed with saturated NaHCO3, dried over Na2SO4 and concentrated under reduced pressure. The crude product was crystallized in PE to afford 1-(ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (19, 4.2 g, 7.45 g theoretical, 56.4% yield) as a white to off-white solid (GC purity: 99%). For 19: 1H NMR (DMSO-d6, 400 MHz) delta ppm 8.09 (s, 1H), 8.58 (s,1H), 7.62 (s,1H), 5.55 (q, 1H, J=6.1 Hz), 3.37 (dq, 1H, J=7.1, 9.6 Hz), 3.12 (dq, 1H, J=7.0, 9.7 Hz), 1.56 (d, 3H, J=6.0 Hz), 1.24 (s, 12H), 1.00 (t, 3H, J=7.0 Hz); C13H23BN2O3 (MW, 266.14), LCMS (EI) m/e 267 (M++H).
56.4%
1-(Ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (24) [0165] To a 100 ml solution of iPrMgCl.LiCl (50 mmol, 1.8 equiv) in THF was added 4-bromo-1-(ethoxyethyl)-1H-pyrazole (6.15 g, 28 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 12 h and then cooled to -20 C. Methoxy pinacolborate (10.6 g, 67 mmol, 2.4 equiv) was then added to the reaction mixture at -20 C. The resulting mixture was stirred at 0-10 C. for 1 h. Aqueous NH4Cl was added to quench the reaction. The mixture was then extracted with petroleum ether (PE). The combined PE extracts were washed with saturated NaHCO3, dried over Na2SO4 and concentrated under reduced pressure. The crude product was crystallized in PE to afford 1-(ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (24, 4.2 g, 7.45 g theoretical, 56.4% yield) as a white to off-white solid (GC purity: 99%). For 24: 1H NMR (DMSO-d6, 400 MHz) delta 8.09 (s, 1H), 8.58 (s, 1H), 7.62 (s, 1H), 5.55 (q, 1H, J=6.1 Hz), 3.37 (dq, 1H, J=7.1, 9.6 Hz), 3.12 (dq, 1H, J=7.0, 9.7 Hz), 1.56 (d, 3H, J=6.0 Hz), 1.24 (s, 12H), 1.00 (t, 3H, J=7.0 Hz) ppm; C13H23BN2O3 (MW, 266.14), LCMS (EI) m/e 267 (M++H).
4.2 g
1-(Ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (24) To a 100 ml solution of iPrMgCl.LiCl (50 mmol, 1.8 equiv) in THF was added 4-bromo-1-(ethoxyethyl)-1H-pyrazole (6.15 g, 28 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 12 h and then cooled to -20 C. Methoxy pinacolborate (10.6 g, 67 mmol, 2.4 equiv) was then added to the reaction mixture at -20 C. The resulting mixture was stirred at 0-10 C. for 1 h. Aqueous NH4Cl was added to quench the reaction. The mixture was then extracted with petroleum ether (PE). The combined PE extracts were washed with saturated NaHCO3, dried over Na2SO4 and concentrated under reduced pressure. The crude product was crystallized in PE to afford 1-(ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (24, 4.2 g, 7.45 g theoretical, 56.4% yield) as a white to off-white solid (GC purity: 99%). For 24: 1H NMR (DMSO-d6, 400 MHz) delta 8.09 (s, 1H), 8.58 (s, 1H), 7.62 (s, 1H), 5.55 (q, 1H, J=6.1 Hz), 3.37 (dq, 1H, J=7.1, 9.6 Hz), 3.12 (dq, 1H, J=7.0, 9.7 Hz), 1.56 (d, 3H, J=6.0 Hz), 1.24 (s, 12H), 1.00 (t, 3H, J=7.0 Hz) ppm; C13H23BN2O3(MW, 266.14), LCMS (EI) m/e 267 (M++H).
Stage #1: 1-ethynyl-3-fluoro-benzene With 1,3-bis[(diphenylphosphino)propane]dichloronickel(II); diisobutylaluminium hydride In tetrahydrofuran at 0 - 22℃; Inert atmosphere;
Stage #2: 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In tetrahydrofuran at 0 - 80℃;
Stage #3: With water In tetrahydrofuran at 0 - 22℃;
To a solution of 4-iodo-1-(2-(tetrahydropyran-2-yloxy)-ethyl]-1H-pyrazole (Stage 106.1.3, 8.50 g, 26.4 mmol) in THF at 0 C under argon was added dropwise iPrMgCI 2 M in THF (26.4 ml, 52.8 mmol) The RM was stirred at 0 C for 1h Then 2-methoxy-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (Aldrich, Buchs, Switzerland, 6 25 g, 52 8 mmol) was added at 0 C and the solution was stirred again and allowed to warm to rt for 1 h After that, the RM was quenched with saturated aqueous NH4CI (140 ml) and extracted with EtOAc (3x) The combined organic layers were washed with saturated aqueous NH4CI, dried over Na2SO4, filtered and evaporated The residue was puriffed by flash chromatography (hexane/EtOAc 5 % to 45 %). The fractions containing product were combined and evaporated to dryness to give the title compound as a colorless oil. (HPLC tR 3.23 mm (Method A); M+H = 323 MS- ES).
A solution of iPrMgCl (2M in THF, 68.3mL, 136.6 mmol) was added drop wise to a solution of 4-iodo-l-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-lH-pyrazole(22 g, 68.3 mmol) in anhydrous THF (200 mL) 0 C. The reaction was stirred for 1 hour at 0 C under nitrogen. 2- Methoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (16.1 g, 0.101 mol) was added and the resulting yellow solution was allowed to stir for 1 hour at ambient temperature under nitrogen. The reaction was quenched with sat. aqueous solution of NH4CI and was diluted with EtOAc. The organic layer was washed with brine, and dried over Na2SC>4, concentrated under reduced pressure, and purified by silica gel chromatography to give l-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole as a oil. H-NMR (400 MHz, CDCI3): δ 7.75 (m, 2 H), 4.48 (s, 1 H), 4.30 (m, 2 H), 4.10 (m, 1 H), 3.78-3.71 (m, 1 H), 3.63-3.59 (m, 1 H), 3.42-3.38 (m, 1 H), 1.60-1.46 (m, 6 H), 1.29 (s, 12 H).
Tert-butyl-4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylate 2(25.0 g, 0.036 mol) was dissolved in tetrahydrofuran (50 ml) at -10 Cand a solution of isopropyl magnesium chloride in tetrahydrofuran(60% w/w, 60 ml) was added under an atmosphere of nitrogen while keeping the temperature below 0 C. After the addition was completed,the mixture was heated up to 20 C and stirred for 2 h. Subsequently, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.8 g, 0.087 mol)was dissolved in tetrahydrofuran (10 ml), and slowly added dropwise tothe above reaction system. Then the reaction was stirred at roomtemperature for 12 h. After completion of reaction indicated by TLC, themixture was pooled into saturated ammonium chloride solution(200 ml) and stirred for 20 min, and then extracted with ethyl acetate(200 ml×2), The organic layer was washed with water and brine,dried with anhydrous sodium sulfate, and concentrated under reducedpressure. The resulting residue was purified by column chromatography(eluent=dichloromethane:methanol=97:3) to afford 3 as a whitesolid (15.38 g, 61.5%). MS (ESI) m/z: 378.2 [M+H]+.
Stage #1: 2-bromo-4,4'-di-tert-butylbiphenyl With n-butyllithium In tetrahydrofuran; hexane at -80℃; for 0.25h;
Stage #2: 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In tetrahydrofuran; hexane at 20℃;
Multi-step reaction with 2 steps
1.1: TurboGrignard / tetrahydrofuran / 0.33 h / 0 - 20 °C
1.2: 16 h / 20 °C
2.1: toluene-4-sulfonic acid / ethanol / 16 h / 20 °C
2.2: 0.5 h / 20 °C
[0133] Example 7 Synthesis of Compound 53/B-0[0134] Synthesis of 2-(Cyclopent-l-en-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane. A mixture of 1-chlorocyclopent-l-ene (10 g, 98 mmol), ethyl ether (40 mL) and lithium (0.82 g, 118 mmol) and some broken glass (a microscope slide) were stirred in a 250 mL 3-neck at room temperature overnight. The above reaction mixture was then cooled in a dry ice/acetone bath and 2-methoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (23.11 g, 146 mmol) was added dropwise over about 20 minutes. The bath was removed and the reaction was stirred at room temperature overnight. The reaction mass was then poured into a solution of 12 g of NH4C1 in 200 mL water and stirred to break up the formed emulsion, then transferred into a separator funnel. The ether layer was separated and washed ether with H20 (2 x) (the rag layer was discarded) and dried with Na2S04 to give 7.3 g of 2-(cyclopent-l-en-l-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (64% crude yield). This was taken as is to the next step.
With iodine; magnesium; In tetrahydrofuran; at 40 - 55℃;Inert atmosphere;
Under the protection of nitrogen, adding magnesium metal in the reaction bottle 8.0g (0.33mol) and several grain of iodines, prior to dropping funnel in the uniformly mixed methoxy boronic acid frequency that alcohol ester 56.9g (0.36mol), cyclohexene-1-polybromide 48.3g (0.3mol) and anhydrous tetrahydrofuran 300 ml, the temperature rising to outside bath 40-45 degrees, to a first 25 ml mixed solution, after color treats the iodine triggered evanishment standard, the oven-keeping 40-55 degrees between the completion of the dropping of the remaining mixed solution, then subsequently gradually heated up to reflow to continue reaction 2-3 hours, disappearance of the raw material after detection GC, to the reaction liquid 0-10 degree, slowly adding saturated NH4Cl quenching, adjusting for PH 5-6, separating the organic layer, the water layer using MTBE 150 ml extraction a, combined with the organic layer, the saturated salt water washing, solvent evaporation to dryness of the organic layer is concentrated under reduced pressure, then replace the high vacuum pump, collecting 80-83 °C fraction, get colorless transparent liquid 50.5g, yield 81percent
benzyl 4-iodo-3,6-dihydropyridine-1(2H)-carboxylate[ No CAS ]
[ 286961-15-7 ]
Yield
Reaction Conditions
Operation in experiment
56%
2nd step: under the protection of nitrogen, the 1M isopropyl magnesium chloride-lithium chloride (88 ml, 88mmol) into the reaction bottle, temperature control -15 C to -10 C, dropwise N-Cbz-1, 2, 5, 6-tetrahydro-pyridine-4-bromo, 2-methyl tetrahydrofuran (90 ml) solution, stirring finishing joining 1-2 hours. After the end of the exchange, then drop by adding methoxy boronic acid pinacone ester (14.2g, 90mmol), subsequently maintain the reaction at room temperature overnight. Adding 10% hydrochloric acid aqueous solution quenching reaction, adjusting PH= 4-5, adding 220 ml ethyl acetate, saturated salt water an organic layer, the organic layer after evaporation to dryness, add ethanol/heptane 10:1 obtained after pulping 19.2g a buff solid N-Cbz-1, 2, 5, 6-tetrahydro-pyridine-4-boronic acid frequency that alcohol ester, GC: 99.6%, yield: 56%.
N-methyl-4-bromo-1,2,5,6-tetrahydropyridine[ No CAS ]
[ 454482-11-2 ]
Yield
Reaction Conditions
Operation in experiment
63%
2nd step: under the protection of nitrogen, the 1.3M isopropyl magnesium chloride-lithium chloride (72 ml, 94mmol) into the reaction bottle, temperature control -15 ° C to -10 °C, dropwise N-methyl -1, 2, 5, 6-tetrahydro-pyridine-4-polybromide tetrahydrofuran (80 ml) solution, stirring finishing joining 1-2 hours. After the end of the exchange, then drop by adding methoxy boronic acid pinacone ester (15.8g, 0 . 1mol), subsequently maintain the reaction at room temperature overnight. Adding 10percent hydrochloric acid aqueous solution quenching reaction, adjusting PH= 4-5, by adding 150 ml ethyl acetate, saturated salt water an organic layer, the organic layer after evaporation to dryness, add ethanol/heptane 40:1 obtained after pulping 14.1g kind of white solid N-methyl -1, 2, 5, 6-tetrahydro-pyridine-4-boronic acid frequency that alcohol ester, GC: 98.3percent, yield: 63percent.
Under nitrogen protection, in the reaction flask was added 29.2 mL of the previously prepared n-BuMgBr solution (1M tetrahydrofuran solution) cooled to -20C. Maintaining the internal temperature at -20 to -10C, added 23.4 mL of n-BuLi (2.5 M in hexane). After completion of the dropwise addition and stirring for 30 minutes, 14.1 g (73 mmol) of 2-chloro-5-bromopyrimidine obtained in the first step and 40 mL of anhydrous tetrahydrofuran were added. Addition was complete and insulation for 1 hour. TLC detection exchange completely. Subsequently, a solution of 13.3 g (84 mmol) of methoxyboronic acid pinacol ester in anhydrous tetrahydrofuran was added dropwise maintaining the temperature. Insulation for 1 hour. The solution was naturally warmed to room temperature. Stirring overnight. Add saturated ammonium chloride quenching adjustment PH is 4-5. Ethyl acetate 70mL extraction. The combined organic layers were evaporated to dryness to give 12.1 g of crude 2-chloropyrimidine-5-boronic acid pinacol ester. GC content greater than 95%, yield 69%. Can be directly used into the next reaction.
4 L of freshly distilled tetrahydrofuran was added to a 50 L autoclave,1. 9 Kg of 4-bromopyrazole compound (12) was added, followed by the dropwise addition of 10 L of isopropylmagnesium chloride solution (3. 0 M). And the mixture was stirred at room temperature for 12 hours.After completion of the reaction by TLC, 3L of a tetrahydrofuran solution of 1.2 Kg of boronic acid pinacol ester (22) was added dropwise.After completion of the dropwise addition, stirring was continued for 12 hours.The reaction was complete by TLC and quenched with saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous sodium hydrogencarbonate, washed with water and concentrated to give a solid1. 8 Kg.
General procedure: According to Scheme A-2, the intermediate (1 eq.) Obtained in the above general preparation procedure 3 was dissolved in THF under anhydrous and nitrogen substitution. Isopropyl magnesium chloride (iPrMgCl, 1.5 eq.) Was added at 0 o C and stirred for 10 min.After further stirring at room temperature for 1 hour, a 2-methoxyboronic ester (1.55 equivalent) was added at 0 C, and the mixture was stirred at room temperature for 14 hours.After completion of the reaction, a saturated aqueous sodium chloride solution was added under ice-cooling, and the organic matter was extracted three times with ethyl acetate in this solution.The combined organic solvent layers were dried over sodium sulfate and concentrated.This is passed through a silica filter to obtain the desired substituted heteroaryl-introduced boronic ester compound,Concentrated and used directly in the next reaction without further purification.
36.5 g (0.1 mol) of 5-benzyloxy-2-bromobenzaldehyde diethyl acetal (compound of formula III), 300 ml of THF was added to the reaction vessel, and the temperature was lowered to -20 C under the protection of nitrogen. 2.0M isopropylmagnesium chloride solution (75ml, 0.15mol) was added dropwise, the temperature did not exceed 0 C, about 2h drop was added, stirred at 20 C for 1h, the solution was used;300 ml of THF, 23.7 g (0.15 mol) of 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added to the reaction flask, and the mixture was cooled to 0-10 C.The above-mentioned standby solution was added dropwise, about 1.5 h, and the reaction was carried out at 25 C for 9 h.Hydrochloric acid was added to the ice bath to a pH of 3 or less, and the reaction was continued at 80 C for 2 hours to recover an organic solvent and crystallize.Filtration and drying to obtain 20 g of compound, the yield was 78%;
[5-(4-nitrylphenoxy)-2-bromophenyl-1-methoxy]trimethylsilane[ No CAS ]
[ 906673-24-3 ]
Yield
Reaction Conditions
Operation in experiment
72%
[5-(4-nitrilephenoxy)-2-bromophenyl-1-methoxy]trimethylsilane 37.6 g (0.1 mol), THF 300 ml was added to the reaction kettle, Under nitrogen protection, reduce the temperature to -20 C, add 2.0 mol / L Isopropylmagnesium chloride tetrahydrofuran solution (75ml, 0.15mol), the temperature does not exceed -10 C, after about 2 hours of dropwise addition, stirring at 20 C for 1 h, and the solution was reserved (stand by); Add 300 ml of THF to the reaction flask. 23.7 g (0.15 mol) of 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolan, Cool to 0-10 C, add the above backup solution, About 2h was added dropwise, and the reaction was completed at 25 C for 6 h. Add salt acid to the ice bath to a pH of 3 or less. The reaction was stirred at room temperature for 5 hours, and the organic solvent was recovered. Crystallization at 0-10 C, Filtration and drying gave 18 g of compound. Yield 72%;
Compound 64 (260 mg), THF (10 mL) was added to the dried two-necked flask, and the mixture was cooled to -70 ° C, and then butyllithium was added dropwise.(2 mL, 3 eq), the reaction was red.After stirring at this temperature for 0.5 h, the tablets were added dropwise.Methyl alcohol borate(1.26g, 5eq),The temperature was raised to room temperature and stirred for 1 h. Add water to quench the reaction,Extracted with ethyl acetate, dried and concentrated.The crude product is directly subjected to the next step reaction
Stage #1: N'-(1-ethylpiperidin-4-ylidene)-4-methylbenzenesulfonohydrazide With N,N,N,N,-tetramethylethylenediamine; isopropylmagnesium chloride for 3h; Reflux;
Stage #2: 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for 3h; Reflux;
2
The sulfonyl hydrazide compound (49 g, 0.18 mol), isopropylmagnesium chloride solution (370 mL, 1.0 M), tetramethylethylenediamine (23 g, 0.2 mol) were mixed and reacted at 40 ° C for 3 h. Methylboronic acid pinacol ester (26.5 g, 0.19 mol) was added, and the reaction was carried out for 2 h, and then the temperature was raised to reflux for 1 h. After completion of the reaction, the solvent was distilled off, and the product cyclohexene-1-boronic acid pinacol ester was further distilled off at about 100 ° C to obtain 27.5 g of a yield of 89%
With [{Ph2P(BH3)N}2C6H4Ti(CH2SiMe3)2] In hexadeuterobenzene at 20℃; for 2h; Schlenk technique;
96%
With trimethylsilylmethyllithium In neat (no solvent) at 20℃; for 6h; Schlenk technique; Glovebox; Inert atmosphere; chemoselective reaction;
5.2 General procedure for the synthesis of compounds 4a-4o
General procedure: Catalyst 1 (3mol%), esters (0.5mmol, 1 equiv.), and corresponding HBpin (1.0mmol, 2 equiv.) were placed in a 25mL Schlenk flask equipped with a magnetic stir bar inside the glove box. Then the reaction mixture was stirred at room temperature for six hours. The progress of the reaction was monitored by 1H NMR, based on the internal standard, HMB (10mol%). In all cases, yields were calculated based on isolated yields.
With tris[N,N-bis(trimethylsilyl)amide]lanthanum In hexadeuterobenzene at 25℃; for 1.5h; Glovebox; Overall yield = 93 percent;
With La(CH<SUB>2</SUB>C<SUB>6</SUB>H<SUB>4</SUB>NMe<SUB>2</SUB>-o)<SUB>3</SUB> In hexadeuterobenzene at 25℃; for 1h; Inert atmosphere; Schlenk technique; Glovebox; Overall yield = > 99 percentSpectr.;
With [(Me3Si)2N]2Th[κ2-(N,C)-CH2Si(CH3)2N(SiMe3)] In hexadeuterobenzene at 70℃; for 24h; Sealed tube; Inert atmosphere; Schlenk technique; Overall yield = 85 percentSpectr.;
With [(η6-p-cymene){(IMes)P}RuCl] In neat (no solvent) at 70℃; for 8h; Schlenk technique; Glovebox; Inert atmosphere; Overall yield = 93 percentSpectr.;
99 %Spectr.
With HC(CMeN(2,6-Et<SUB>2</SUB>C<SUB>6</SUB>H<SUB>3</SUB>))<SUB>2</SUB>AlH<SUB>2</SUB> In neat (no solvent) at 60℃; for 12h; Glovebox; Schlenk technique;
The beta-diimine monovalent magnesium compound catalyzes the reaction of <strong>[623-53-0]ethyl methyl carbonate</strong> with pinacol borane as follows:In the glove box, 1 mol% of beta-diimine monovalent magnesium compound, 0.4 mmol of <strong>[623-53-0]methyl ethyl carbonate</strong>, and 1.6 mmol of pinacol borane were sequentially added to the reaction flask.It was then removed from the glove box and stirred for 6 h. The yield was 98% by NMR
Stage #1: C7H12BrN With isopropylmagnesium bromide In tetrahydrofuran
Stage #2: 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In tetrahydrofuran at 0℃; for 6h; Inert atmosphere; Reflux;
3.3
In the third step, 19.1 g (0.1 mol) of N-Et piperidin-4-enyl bromide and 12.9 g (0.105 mol) of isopropyl bromide are subjected to a Grignard exchange reaction in tetrahydrofuran. Then, under the protection of nitrogen, At 0 ° C, 19.03 g (0.11 mol) of pinacol methoxyboronic acid was added dropwise to the reaction solution, the reaction was held for 4 h, and then heated to reflux for 2 h. After the reaction was completed, 20 ml of 10% dilute hydrochloric acid was added to quench the reaction. After the solvent was distilled off, the temperature was further raised to 120 ° C. under reduced pressure to obtain 18.73 g of a target product as a pale yellow liquid with a yield of 79%.
In the third step, a Grignard exchange reaction of 26.21 g (0.1 mol) of N-Boc piperidin-4-enyl bromide with 12.9 g (0.105 mol) of isopropyl bromide in tetrahydrofuran, and then, under the protection of nitrogen, At 0 C, 19.03 g (0.11 mol) of pinacol methoxyboronic acid was added dropwise to the Grignard reaction solution, the reaction was held for 4 h, and then the temperature was raised to reflux for 1 h. After the reaction was completed, 10 ml of 10% dilute hydrochloric acid was added to quench the reaction. After the solvent was distilled off, 120 ml of ethanol was added for beating. The white solid was filtered to obtain 26.9 g, and the yield was 87%.
With trimethylsilylmethyllithium In neat (no solvent) at 20℃; for 6h; Schlenk technique; Glovebox; Inert atmosphere; chemoselective reaction;
5.2 General procedure for the synthesis of compounds 4a-4o
General procedure: Catalyst 1 (3mol%), esters (0.5mmol, 1 equiv.), and corresponding HBpin (1.0mmol, 2 equiv.) were placed in a 25mL Schlenk flask equipped with a magnetic stir bar inside the glove box. Then the reaction mixture was stirred at room temperature for six hours. The progress of the reaction was monitored by 1H NMR, based on the internal standard, HMB (10mol%). In all cases, yields were calculated based on isolated yields.
99 %Spectr.
With tris[N,N-bis(trimethylsilyl)amide]lanthanum In neat (no solvent) at 25℃; for 0.333333h; chemoselective reaction;
2-(1-(3,5-difluorophenyl)vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: 1-ethynyl-3,5-difluorobenzene With 1,3-bis[(diphenylphosphino)propane]dichloronickel(II); diisobutylaluminium hydride In tetrahydrofuran at 0 - 20℃; for 2h;
Stage #2: 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In tetrahydrofuran at 80℃; for 24h;
Stage #1: 7-bromobenzo(b)furan With n-butyllithium In tetrahydrofuran at -70℃; for 0.666667h; Inert atmosphere;
Stage #2: 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In tetrahydrofuran at -70℃; for 1h;
50.50a Step 50a: Preparation of 7-pinacol borate benzofuran (compound 0903-107)
Under the protection of nitrogen, at -70°C, to 7-bromo-benzofuran (Compound 0901-107) (300 mg, 1.53 mmol, 1.0 equivalent) in tetrahydrofuran (10 mL) was added dropwise n-butyl Lithium (1.6 mol, 1.24 ml, 1.99 mmol, 1.3 equivalents), the mixture was stirred at -70C for 40 minutes. Then methanol pinacol borate (387 mg, 2.45 mmol, 1.6 equivalents) in tetrahydrofuran (1.5 mL) was added dropwise at -70C, and the mixture was stirred for 1 hour. The reaction solution was quenched by adding ammonium chloride aqueous solution dropwise, the mixture was extracted with water and ethyl acetate, the organic phase was dried and concentrated under reduced pressure. The residue (0.4 g, crude product) was used directly in the next step without further purification.
Stage #1: Benzo[b]thiophene With 2,2,6,6-tetramethyl-piperidine; sodium; chlorobenzene In hexane at 30℃; for 0.5h;
Stage #2: 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In tetrahydrofuran; hexane at 0℃; for 10h;
2.7 Experiment No. 7
1.64 mmol of SD was added to 0.7 ml of hexane, 0.73 mmol of chlorobenzene was dripped, and a reaction was carried out at 30° C. for 30 minutes to prepare phenylsodium. 0.76 mmol of 2,2,6,6-tetramethylpiperidine was added to the reaction system and a reaction was carried out at 30° C. for 30 minutes to obtain Na-TMP. Benzothiophene (0.60 mmol) was added to the reaction system and a reaction was carried out at 30° C. for 30 minutes to perform deprotonation and obtain 2-benzothiophenylsodium. Subsequently, the reaction system was cooled to 0° C., and then 1.2 molar equivalents of pinacol methoxyboronate (MeOBpin) and 0.6 ml of THF were added to the produced 2-benzothiophenylsodium in this order and a reaction was carried out for 10 minutes to obtain pinacol 2-benzothiophenylboronate. Subsequently, 0.3 ml of water was added, and then 1.0 molar equivalent of 4-chlorobenzaldehyde (0.5 mmol) was added and a reaction was βcarried out at 70° C. for 5 hours in the presence of 2 mol % of palladium catalyst Pd-PEPPSI (registered trademark)-IPr to obtain 4-(2-benzothiophenyl)benzaldehyde as a coupling product. The isolation yield of the synthesized 4-(2-benzothiophenyl)benzaldehyde was 90%. It can be understood from the above that pinacol 2-benzothiophenylboronate can be synthesized with a high yield from 2-chloro-benzothiophene through the synthesis of 2-benzothiophenylsodium, and Suzuki-Miyaura coupling in which pinacol 2-benzothiophenylboronate is used efficiently progresses, and consequently 4-(2-benzothiophenyl)benzaldehyde can be obtained with a high yield as a coupling product.
Stage #1: 1-benzofurane With 2,2,6,6-tetramethyl-piperidine; sodium; chlorobenzene In hexane at 30℃; for 0.5h;
Stage #2: 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In tetrahydrofuran; hexane at 0℃; for 10h;
2.8 Experiment No. 8
1.60 mmol of SD was added to 0.7 ml of hexane, 0.69 mmol of chlorobenzene was dripped, and a reaction was carried out at 30° C. for 30 minutes to prepare phenylsodium. 0.75 mmol of 2,2,6,6-tetramethylpiperidine was added to the reaction system and a reaction was carried out at 30° C. for 30 minutes to obtain Na-TMP. Benzofuran (0.60 mmol) was added to the reaction system and a reaction was carried out at 30° C. for 30 minutes to perform deprotonation and obtain 2-benzofuranylsodium. Subsequently, the reaction system was cooled to 0° C., and then 1.2 molar equivalents of pinacol methoxyboronate (MeOBpin) and 0.6 ml of THF were added to the produced 2-benzofuranylsodium in this order and a reaction was carried out for 10 minutes to obtain pinacol 2-benzofuranylboronate. Subsequently, 0.3 ml of water was added, and then 1.0 molar equivalent of 4-chlorobenzonitrile (0.5 mmol) was added and a reaction was carried out at 70° C. for 3 hours in the presence of 2 mol % of palladium catalyst Pd-PEPPSI (registered trademark)-IPr to obtain 4-(2-benzofuranyl)benzonitrile as a coupling product. The isolation yield of the synthesized 4-(2-benzofuranyl)benzonitrile was 94%. It can be understood from the above that pinacol 2-benzofuranylboronate can be synthesized with a high yield from 2-chloro-benzofuran through the synthesis of 2-benzofuranylsodium, and Suzuki-Miyaura coupling in which pinacol 2-benzofuranylboronate is used efficiently progresses, and consequently 4-(2-benzofuranyl)benzonitrile can be obtained with a high yield as a coupling product.
Stage #1: PERYLENE; 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane With sodium In 1,2-dimethoxyethane; mineral oil at -40℃; for 12h; Schlenk technique;
Stage #2: With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In 1,2-dimethoxyethane; mineral oil at -40℃; for 0.5h; Schlenk technique; regioselective reaction;
4,4,5,5-tetramethyl-2-((4-(trifluoromethyl)benzyl)oxy)-1,3,2-dioxaborolane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With [{Ph2P(BH3)N}2C6H4Ti(CH2SiMe3)2] In hexadeuterobenzene at 20℃; for 2h; Schlenk technique;
95%
With trimethylsilylmethyllithium In neat (no solvent) at 20℃; for 6h; Schlenk technique; Glovebox; Inert atmosphere; chemoselective reaction;
5.2 General procedure for the synthesis of compounds 4a-4o
General procedure: Catalyst 1 (3mol%), esters (0.5mmol, 1 equiv.), and corresponding HBpin (1.0mmol, 2 equiv.) were placed in a 25mL Schlenk flask equipped with a magnetic stir bar inside the glove box. Then the reaction mixture was stirred at room temperature for six hours. The progress of the reaction was monitored by 1H NMR, based on the internal standard, HMB (10mol%). In all cases, yields were calculated based on isolated yields.
1: 99 %Spectr.
2: 94 %Spectr.
With N,N,N',N'-tetramethylethylenediamine adduct of 1,1'-dilithio-ferrocene In tetrahydrofuran at 45℃; for 8h; Inert atmosphere; Glovebox; Green chemistry;
General catalytic procedure for the hydroboration ofesters.
General procedure: Ester(0.25 mmol), pinacolborane (0.50 mmol), catalyst (6.0 mol% for 1a or,3.0 mol% for 1b) were mixed together in a Schlenk tube or in a screw capNMR tube inside the glove box. The reaction mixture was allowed to heat at 80°C for 10 h (for 1a) in neat condition or at 45 °C for 8 h (for 1b)in THF (0.5 mL). Upon completion of the reaction, mesitylene (0.25 mmol) as aninternal standard, was added while making the NMR inappropriate deuteratedsolvent. The progress of the reaction was monitored by 1H NMR, whichindicated the completion of the reaction by the appearance of a new Bpin-OCH2Rresonance.
With La(CH<SUB>2</SUB>C<SUB>6</SUB>H<SUB>4</SUB>NMe<SUB>2</SUB>-o)<SUB>3</SUB> In hexadeuterobenzene at 25℃; for 0.25h; Inert atmosphere; Schlenk technique; Glovebox; Overall yield = > 99 percentSpectr.;
With [(Me3Si)2N]2Th[κ2-(N,C)-CH2Si(CH3)2N(SiMe3)] In hexadeuterobenzene at 70℃; for 1h; Sealed tube; Inert atmosphere; Schlenk technique; Overall yield = > 99 percentSpectr.;
With [(η6-p-cymene){(IMes)P}RuCl] In neat (no solvent) at 70℃; for 8h; Schlenk technique; Glovebox; Inert atmosphere; Overall yield = 95 percentSpectr.;
With [{η1:(μ2-η1:η1):η1-(2-(2,6-iPr2C6H3N(C=O))C8H5N)YN(SiMe3)2}3(μ3-Cl)]Li(THF)4 In neat (no solvent) at 25℃; Glovebox; Schlenk technique;
With 1,1'-dilithioferrocene N,N,N'N'-tetramethylethylenediamine In tetrahydrofuran at 45℃; for 8h; Inert atmosphere; Glovebox; Green chemistry;
General catalytic procedure for the hydroboration ofesters.
General procedure: Ester(0.25 mmol), pinacolborane (0.50 mmol), catalyst (6.0 mol% for 1a or,3.0 mol% for 1b) were mixed together in a Schlenk tube or in a screw capNMR tube inside the glove box. The reaction mixture was allowed to heat at 80°C for 10 h (for 1a) in neat condition or at 45 °C for 8 h (for 1b)in THF (0.5 mL). Upon completion of the reaction, mesitylene (0.25 mmol) as aninternal standard, was added while making the NMR inappropriate deuteratedsolvent. The progress of the reaction was monitored by 1H NMR, whichindicated the completion of the reaction by the appearance of a new Bpin-OCH2Rresonance.
4,4,5,5-tetramethyl-2-(thiophen-2-ylmethoxy)-1,3,2-dioxaborolane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With trimethylsilylmethyllithium In neat (no solvent) at 20℃; for 6h; Schlenk technique; Glovebox; Inert atmosphere; chemoselective reaction;
5.2 General procedure for the synthesis of compounds 4a-4o
General procedure: Catalyst 1 (3mol%), esters (0.5mmol, 1 equiv.), and corresponding HBpin (1.0mmol, 2 equiv.) were placed in a 25mL Schlenk flask equipped with a magnetic stir bar inside the glove box. Then the reaction mixture was stirred at room temperature for six hours. The progress of the reaction was monitored by 1H NMR, based on the internal standard, HMB (10mol%). In all cases, yields were calculated based on isolated yields.
96%
With [{Ph2P(BH3)N}2C6H4Ti(CH2SiMe3)2] In hexadeuterobenzene at 20℃; for 2h; Schlenk technique;
With La(CH<SUB>2</SUB>C<SUB>6</SUB>H<SUB>4</SUB>NMe<SUB>2</SUB>-o)<SUB>3</SUB> In hexadeuterobenzene at 25℃; for 0.5h; Inert atmosphere; Schlenk technique; Glovebox; Overall yield = 96 percentSpectr.;
With [(η6-p-cymene){(IMes)P}RuCl] In neat (no solvent) at 70℃; for 8h; Schlenk technique; Glovebox; Inert atmosphere; Overall yield = 94 percentSpectr.;
With [{η1:(μ2-η1:η1):η1-(2-(2,6-iPr2C6H3N(C=O))C8H5N)YN(SiMe3)2}3(μ3-Cl)]Li(THF)4 In neat (no solvent) at 25℃; Glovebox; Schlenk technique;
With trimethylsilylmethyllithium In neat (no solvent) at 20℃; for 6h; Schlenk technique; Glovebox; Inert atmosphere; chemoselective reaction;
5.2 General procedure for the synthesis of compounds 4a-4o
General procedure: Catalyst 1 (3mol%), esters (0.5mmol, 1 equiv.), and corresponding HBpin (1.0mmol, 2 equiv.) were placed in a 25mL Schlenk flask equipped with a magnetic stir bar inside the glove box. Then the reaction mixture was stirred at room temperature for six hours. The progress of the reaction was monitored by 1H NMR, based on the internal standard, HMB (10mol%). In all cases, yields were calculated based on isolated yields.
97%
With [{Ph2P(BH3)N}2C6H4Ti(CH2SiMe3)2] In hexadeuterobenzene at 20℃; for 2h; Schlenk technique;
With [(Me3Si)2N]2Th[κ2-(N,C)-CH2Si(CH3)2N(SiMe3)] In hexadeuterobenzene at 70℃; for 24h; Sealed tube; Inert atmosphere; Schlenk technique; Overall yield = 78 percentSpectr.;
With [(η6-p-cymene){(IMes)P}RuCl] In neat (no solvent) at 70℃; for 8h; Schlenk technique; Glovebox; Inert atmosphere; Overall yield = 87 percentSpectr.;
With [{η1:(μ2-η1:η1):η1-(2-(2,6-iPr2C6H3N(C=O))C8H5N)YN(SiMe3)2}3(μ3-Cl)]Li(THF)4 In neat (no solvent) at 25℃; Glovebox; Schlenk technique;
With trimethylsilylmethyllithium In neat (no solvent) at 20℃; for 6h; Schlenk technique; Glovebox; Inert atmosphere; chemoselective reaction;
5.2 General procedure for the synthesis of compounds 4a-4o
General procedure: Catalyst 1 (3mol%), esters (0.5mmol, 1 equiv.), and corresponding HBpin (1.0mmol, 2 equiv.) were placed in a 25mL Schlenk flask equipped with a magnetic stir bar inside the glove box. Then the reaction mixture was stirred at room temperature for six hours. The progress of the reaction was monitored by 1H NMR, based on the internal standard, HMB (10mol%). In all cases, yields were calculated based on isolated yields.
94%
With [{Ph2P(BH3)N}2C6H4Ti(CH2SiMe3)2] In hexadeuterobenzene at 20℃; for 4h; Schlenk technique;
With [(η6-p-cymene){(IMes)P}RuCl] In neat (no solvent) at 70℃; for 12h; Schlenk technique; Glovebox; Inert atmosphere; Overall yield = 83 percentSpectr.;
2-(((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxy)methyl)pyridine[ No CAS ]
[ 1195-66-0 ]
Yield
Reaction Conditions
Operation in experiment
95%
With [{Ph2P(BH3)N}2C6H4Ti(CH2SiMe3)2] In hexadeuterobenzene at 20℃; for 2h; Schlenk technique;
93%
With trimethylsilylmethyllithium In neat (no solvent) at 20℃; for 6h; Schlenk technique; Glovebox; Inert atmosphere; chemoselective reaction;
5.2 General procedure for the synthesis of compounds 4a-4o
General procedure: Catalyst 1 (3mol%), esters (0.5mmol, 1 equiv.), and corresponding HBpin (1.0mmol, 2 equiv.) were placed in a 25mL Schlenk flask equipped with a magnetic stir bar inside the glove box. Then the reaction mixture was stirred at room temperature for six hours. The progress of the reaction was monitored by 1H NMR, based on the internal standard, HMB (10mol%). In all cases, yields were calculated based on isolated yields.
With [{η1:(μ2-η1:η1):η1-(2-(2,6-iPr2C6H3N(C=O))C8H5N)YN(SiMe3)2}3(μ3-Cl)]Li(THF)4 In neat (no solvent) at 25℃; Glovebox; Schlenk technique;
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