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USD 0.00
Limited Quantity
USD 15-60
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USD 80+
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Structure of 61676-62-8 * 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.
Stage c) Preparation of iso-Propyl pinacol borate To a 20 L four-neck bottle tri-isopropyl borate (261.0 g, 1.388 mol) and pinacol (142.5 g, 1.207 mol) were added and heated to ˜90° C. for 12-16 h. The criteria for a reaction completion is pinacol<4.0percent by GC. After completion, the reaction was converted to distillation, and the product fractions (boiling at 174-178° C.) collected. Thus the title product was obtained as a colourless oil in a yield range of 80-90percent th across the six 20 L batches which were operated. GC records purity of 87-96percent, but 1H NMR shows the product to be very pure. [discrepancy due to product instability to GC conditions.]
87.5%
at 80 - 85℃; Inert atmosphere
2-Isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (16).; A 5 L 4-neck flask equipped with a reflux condenser, mechanical stirrer, N2 inlet, and thermowell was flushed well with N2 and charged with isopropyl borate (2.673 L, 11.5 mol, 1.15 equiv) and pinacol (1.179 kg, 10 mol). The resulting mixture was heated at reflux (80-85°) for overnight. The mixture was then cooled to room temperature, transferred to a 5 L 4-neck flask equipped with a 24 inch Vigreux column, magnetic stirrer, and thermowell. The mixture was distilled at atmospheric pressure under nitrogen. After the low boiling fraction (bp 90-180°) which contained predominately 2-propanol and isopropyl borate (GC analysis) was removed, the completed distillation afforded 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (10, 1.628 kg, 1.86 Kg theoretical, 87.5percent) as a colorless liquid (bp 180-185° C. with GC purity >97.5percent). This material was stored in Sure/Seal bottles to minimize hydrolysis.
Reference：
[1] Journal of the American Chemical Society, 2001, vol. 123, # 19, p. 4617 - 4618
[2] Organic Letters, 2012, vol. 14, # 22, p. 5644 - 5647
[3] Patent: US2013/40984, 2013, A1, . Location in patent: Paragraph 0482-0483
[4] Chemische Berichte, 1989, vol. 122, p. 1777 - 1782
[5] Organic Letters, 2013, vol. 15, # 18, p. 4666 - 4669
[6] Patent: US2010/190981, 2010, A1, . Location in patent: Page/Page column 104
[7] European Journal of Organic Chemistry, 2010, # 17, p. 3295 - 3301
[8] Chemistry - A European Journal, 2013, vol. 19, # 7, p. 2450 - 2456
[9] Bioorganic Chemistry, 2003, vol. 31, # 6, p. 464 - 474
[10] Patent: WO2011/134971, 2011, A1, . Location in patent: Page/Page column 16; 17; 72; 73
[11] Tetrahedron Letters, 2012, vol. 53, # 8, p. 910 - 913
2
[ 25015-63-8 ]
[ 75-56-9 ]
[ 61676-62-8 ]
[ 1130-16-1 ]
Reference：
[1] Patent: CN108569984, 2018, A, . Location in patent: Paragraph 0069; 0070
3
[ 5419-55-6 ]
[ 61676-62-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2015, vol. 2015, # 11, p. 2498 - 2502
Reference：
[1] Journal of the Chemical Society, 1962, p. 3819 - 3821
7
[ 129217-85-2 ]
[ 67-63-0 ]
[ 6224-91-5 ]
[ 61676-62-8 ]
[ 14657-22-8 ]
Reference：
[1] Organic Process Research and Development, 2012, vol. 16, # 5, p. 1131 - 1140
8
[ 109-72-8 ]
[ 61676-62-8 ]
[ 69190-62-1 ]
Reference：
[1] Organic Process Research and Development, 2012, vol. 16, # 5, p. 1131 - 1140
9
[ 75-11-6 ]
[ 61676-62-8 ]
[ 70557-99-2 ]
Reference：
[1] Bioorganic Chemistry, 2003, vol. 31, # 6, p. 464 - 474
[2] Journal of Molecular Catalysis A: Chemical, 2007, vol. 271, # 1-2, p. 86 - 88
10
[ 61676-62-8 ]
[ 31103-51-2 ]
[ 70557-99-2 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2007, vol. 5, # 6, p. 889 - 891
11
[ 61676-62-8 ]
[ 586-77-6 ]
[ 28611-39-4 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 11, p. 3629 - 3634
12
[ 61676-62-8 ]
[ 103-88-8 ]
[ 101251-09-6 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 11, p. 3629 - 3634
13
[ 593-71-5 ]
[ 61676-62-8 ]
[ 83622-42-8 ]
Yield
Reaction Conditions
Operation in experiment
46%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: With chloro-trimethyl-silane In tetrahydrofuran at 20℃; for 24.17 h;
To a stirred solution of 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (1 1 .0 mL, 53.75 mmol) and chloroiodomethane (4.3 mL, 59.12 mmol) in anhydrous THF (100 mL), cooled to -78 °C, was added cold n-butyllithium solution (23.94 mL, 59.12 mmol) dropwise. After stirring for 30 min at this temperature, chlorotrimethylsilane (8.2 mL, 64.50 mmol) was added dropwise. After stiring for 10 min, the reaction mixture was allowed to return to room temperature and stirred for 24 h. Water (80 mL) was added and the mixture extracted with Ε∑0 (2 x 80 mL). The organic extracts were combined, washed with water (2 x 80 mL), dried over MgS04 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (Heptane/EtOAc 99:1 to 95:5).to yield 2-(chloromethyl)-4, 4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (4.35 g, 24.65 mmol, 46percent yield) as a colourless oil. NMR (400 MHz, DMSO-cfe, δ): 2.99 (s, 2H), 1 .32 (s, 12H).
Reference：
[1] Journal of the American Chemical Society, 2012, vol. 134, # 42, p. 17470 - 17473
[2] Angewandte Chemie, International Edition, 2009, vol. 48, # 34, p. 6317 - 6319[3] Angewandte Chemie, 2009, vol. 121, # 34, p. 6435 - 6437
[4] Patent: WO2017/46604, 2017, A1, . Location in patent: Paragraph 00339; 00346
14
[ 74-97-5 ]
[ 61676-62-8 ]
[ 83622-42-8 ]
Reference：
[1] Organic Letters, 2010, vol. 12, # 21, p. 4876 - 4879
[2] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 8, p. 2622 - 2624
15
[ 61676-62-8 ]
[ 768-33-2 ]
[ 185990-03-8 ]
Reference：
[1] Chemistry - A European Journal, 2010, vol. 16, # 36, p. 10980 - 10983
[2] Angewandte Chemie - International Edition, 2013, vol. 52, # 6, p. 1785 - 1788[3] Angew. Chem., 2013, vol. 125, # 6, p. 1829 - 1832,4
[4] Advanced Synthesis and Catalysis, 2013, vol. 355, # 16, p. 3137 - 3140
[5] Chemistry - A European Journal, 2014, vol. 20, # 7, p. 1834 - 1838
[6] Angewandte Chemie - International Edition, 2016, vol. 55, # 39, p. 11810 - 11813[7] Angew. Chem., 2016, vol. 128, # 39, p. 11989 - 11992,4
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 17, p. 6618 - 6620
19
[ 61676-62-8 ]
[ 1122-91-4 ]
[ 128376-64-7 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 1, p. 263 - 271
20
[ 61676-62-8 ]
[ 104-95-0 ]
[ 190788-58-0 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 1, p. 263 - 271
21
[ 636-98-6 ]
[ 61676-62-8 ]
[ 171364-83-3 ]
Reference：
[1] Chemical Communications, 2012, vol. 48, # 91, p. 11211 - 11213
22
[ 61676-62-8 ]
[ 577-19-5 ]
[ 190788-59-1 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: at -78 - 20℃; for 25 h;
Synthesis of Intermediate B-1 4.77 g (23.6 mmol) of 1-bromo-2-nitrobenzene was dissolved in 100 mL of THF, and then, 10 mL of n-BuLi (25.0 mmol, 2.5M in Hexane) was slowly added dropwise thereto at a temperature of -78° C. After 1 hour of stirring the result at the same temperature, 9.3 mL (50 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was slowly added dropwise to the solution, and then, the obtained reaction solution was stirred at a temperature of -78° C. for 1 hour. The resulting solution was additionally stirred for 24 hours at room temperature, and once the reaction was completed, 50 mL of a 10percent HCl aqueous solution and 50 mL of H2O were added thereto, followed by three times of extraction using 80 mL of diethylether. An organic layer collected from the resulting solution was dried using magnesium sulfate, and a solvent was removed therefrom by evaporation. The residue obtained therefrom was separation-purified by silica gel column chromatography, thereby completing the preparation of 5.29 g (yield: 90percent) of Intermediate B-1. The prepared compound was identified by LC-MS. (C12H16BNO4: M+ 249.07)
Reference：
[1] Chemical Communications, 2012, vol. 48, # 91, p. 11211 - 11213
24
[ 61676-62-8 ]
[ 536-74-3 ]
[ 159087-45-3 ]
Yield
Reaction Conditions
Operation in experiment
92%
With C15H14N4; caesium carbonate; triphenylphosphine; silver(I) chloride In N,N-dimethyl-formamide at 50℃; for 24 h; Inert atmosphere; Schlenk technique
General procedure: A mixture of 1 (0.5 mmol), B(OiPr)pin (0.75 mmol), PPh3+L1+AgCl (1 mol percent), and Cs2CO3 (1.1 mmol) in DMF (5 mL) was stirred at 50°C under Ar atmosphere for 24 h. The reaction mixture was acidified by 1 M solution of hydrochloric acid in an ice water bath, and the aqueous phase was extracted with ethyl acetate (three times). The combined organic layer was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to give the corresponding products.
76%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; Stage #2: at -78℃; Inert atmosphere
To a stirred solution of Md' (10 ml_, 91 mmol) in dry THF (50 ml.) at -78 0C was added n-BuLi (2.5 M in n- hexane, 40 ml_, 100 mmol). Another flask was charged with 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane (18.7 ml_, 91 mmol) in dry THF (100 ml_) under argon atmosphere, and the reaction mixture was cooled to -78 0C. The lithium acetylide from the first flask, which was cooled to -78 0C, was slowly added to the second by a double-ended needle. The mixture was stirred at -78 0C for 2 hours, after which anhydrous HCI (105 mmol) was added. Then, reaction mixture was warmed to room temperature. After removal of the precipitated LiCI by filtration and removal of solvents under reduced pressure, the residue was purified by distillation (185-200 °C/15 mbar) to afford MId (16.05 g, 76 percent) as a colourless oil. 1H NMR (CDCI3): δ (ppm) = 1.32 (s, 12H), 7.26-7.36 (m, 3H), 7.52 (d, 2H).131C NMR (CDCI3): δ (ppm) = 24.6, 84.4, 121.8, 128.2, 129.3, 132.5.
Reference：
[1] Organic Letters, 2014, vol. 16, # 17, p. 4670 - 4673
[2] Journal of the American Chemical Society, 2007, vol. 129, # 42, p. 12634 - 12635
[3] Tetrahedron, 2014, vol. 70, # 35, p. 5815 - 5819
[4] Angewandte Chemie - International Edition, 2012, vol. 51, # 2, p. 521 - 524
[5] Patent: WO2010/146172, 2010, A2, . Location in patent: Page/Page column 37
[6] Angewandte Chemie - International Edition, 2012, vol. 51, # 4, p. 1014 - 1018
[7] Synlett, 2007, # 18, p. 2885 - 2887
[8] Chemistry - A European Journal, 2007, vol. 13, # 19, p. 5408 - 5425
[9] Tetrahedron Letters, 2010, vol. 51, # 2, p. 306 - 308
[10] Organometallics, 2002, vol. 21, # 21, p. 4533 - 4539
[11] Journal of Organic Chemistry, 2014, vol. 79, # 16, p. 7391 - 7398
[12] Chemical Communications, 2016, vol. 52, # 60, p. 9363 - 9366
[13] Journal of the American Chemical Society, 2017, vol. 139, # 14, p. 5027 - 5030
25
[ 61676-62-8 ]
[ 38614-36-7 ]
[ 126689-00-7 ]
Reference：
[1] Journal of the American Chemical Society, 2017, vol. 139, # 14, p. 5027 - 5030
26
[ 61676-62-8 ]
[ 17529-98-5 ]
[ 287944-10-9 ]
Reference：
[1] Journal of the American Chemical Society, 2008, vol. 130, # 26, p. 8481 - 8490
[2] Synthetic Communications, 2008, vol. 38, # 22, p. 3984 - 3995
27
[ 61676-62-8 ]
[ 86724-17-6 ]
[ 287944-05-2 ]
Reference：
[1] Journal of the American Chemical Society, 2008, vol. 130, # 26, p. 8481 - 8490
[2] Synthetic Communications, 2008, vol. 38, # 22, p. 3984 - 3995
28
[ 61676-62-8 ]
[ 302554-80-9 ]
[ 302554-81-0 ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Inert atmosphere Stage #2: at -78 - 20℃; for 25 h;
In an argon atmosphere,2-Bromo-9,9-dioctylfluorene (14. lg, 0.03 mol) was dissolved in 180 mL of purified THFin,A solution of 1.6 mol of L-1 of n-butyllithium was gradually added dropwise at -78 ° C,To maintain low temperature -78 ° C conditions,Reaction for 2 hours,Then, 25 mL of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborane was added,The reaction was continued at -78 ° C for 1 hour,Slowly rose to room temperature for 24 hours.The reaction mixture was poured into water,Extracted with ethyl acetate,After the organic layer was completely washed with brine,Add anhydrous magnesium sulfate dry.After the solution was concentrated,Get light yellow viscous thick,Purification by silica gel column chromatography (eluent selection petroleum ether / ethyl acetate = 20/1, ν / ν)The product is frozen in a refrigerator for a long time to give a white solid,Yield 70percent
70%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Inert atmosphere Stage #2: at -78 - 20℃; for 25 h;
2-bromo-9,9-dioctylfluorene (5 g, 10.65 mmol) was dissolved in 180 mL of purified THF under an argon atmosphere, A solution of 1.6 mol of L-1 of n-butyllithium was gradually added dropwise at -78 ° C for 2 hours, followed by the addition of 2-isopropoxy-4,4,5, 5-tetramethyl-1,3,2-dioxaborolane, the reaction was continued at -78 ° C for 1 hour, and the temperature was raised to room temperature for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed thoroughly with brine and dried over anhydrous magnesium sulfate. The solution was concentrated to give a crude product as a pale yellow viscous material which was purified by silica gel column chromatography (eluent selection of petroleum ether / ethyl acetate =20/1, v / v), the product was left in a refrigerator for a long time to give a white solid in 70percent yield. 1H NMR, 13CNMR, MS and elemental analysis The results show that the obtained compound is the target product. The chemical reaction equation is as follows:
70%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Inert atmosphere Stage #2: at -78℃; for 1 h;
Under an argon atmosphere,2-Bromo-9,9-dioctylfluorene (15 g, 31.95 mmol) was dissolved in 200 mL of purified tetrahydrofuran (THF)39.9 mL of n-butyllithium of 1.6 mol.L-1 was gradually added dropwise at -78 ° C.,After 2 hours of reaction, 7.73 g of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added and the reaction was continued at -78 ° C for 1 hour. Then The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed thoroughly with brine and dried over anhydrous magnesium sulfate. After the solution was concentrated, the crude product was obtained as pale yellow viscous crude material which was purified by silica gel Column chromatography purification (eluent petroleum ether / ethyl acetate = 15/1, v / v), the product was placed in the refrigerator for a long time to give a white solid, the yield was 70percent
Reference：
[1] Journal of Materials Chemistry C, 2016, vol. 4, # 17, p. 3765 - 3773
[2] Patent: CN106366067, 2017, A, . Location in patent: Paragraph 0066; 0067; 0068; 0069
[3] Patent: CN106831728, 2017, A, . Location in patent: Paragraph 0054; 0055; 0056; 0057
[4] Patent: CN107501232, 2017, A, . Location in patent: Paragraph 0046; 0047; 0048; 0049; 0050
[5] Journal of Physical Chemistry B, 2000, vol. 104, # 39, p. 9118 - 9125
[6] Chemistry - A European Journal, 2011, vol. 17, # 50, p. 14031 - 14046
[7] Dyes and Pigments, 2013, vol. 99, # 3, p. 895 - 902
[8] RSC Advances, 2014, vol. 4, # 91, p. 50027 - 50034
29
[ 61676-62-8 ]
[ 2586-62-1 ]
[ 312303-48-3 ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: With magnesium; ethylene dibromide In tetrahydrofuran at 20℃; for 3.5 h; Stage #2: at 20℃; for 0.25 h;
1 ,2-Dibromoethane (-0.3 ml) was added to 6.10 g (0.25 mol) of magnesium turnings in 1000 cm3 of THF. This mixture was stirred for 10 min, and then 55.3 g (0.25 mol) of l-bromo-2-methylnaphtalene was added by vigorous stirring for 3.5 h at room temperature. Further on, 46.5 g (250 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane was added in one portion. The resulting mixture was stirred for 15 min and then poured into 1000 cm3 of cold water. The product was extracted with 3 x 300 ml of ethyl acetate. The organic layer was separated, washed by water, brine, dried over MgS04, and, finally, evaporated to dryness. The formed white solid was washed by 2 x 75 ml of pentane and then dried in vacuum. Yield 47.3 g (70percent). Anal. calc. for C17H21B02: C, 76.14; H, 7.89. Found: C, 76.21 ; H, 7.96. NMR (CDC13): δ 8.12 (m, 1H, 8-H), 7.77 (m, 1H, 5-H), 7.75 (d, J = 8.4 Hz, 1H, 4-H), 7.44 (m, (0291) 7-H), 7.38 (m, 1H, 6-H), 7.28 (d, J = 8.4 Hz, 1H, 3-H), 2.63 (s, 3H, 2-Me), 1.48 (s, 12H, CMe2CMe2).
70%
Stage #1: With magnesium In tetrahydrofuran; ethylene dibromide at 20℃; for 3.5 h; Stage #2: for 0.25 h;
1,2-Dibromoethane (ca. 0.3 ml) was added to 6.10 g (250 mmol) of magnesium turnings in 1000 mL of THF. This mixture was stirred for 10 min, then 55.3 g (250 mmol) of l-bromo-2- methylnaphthalene was added by vigorous stirring, and the resulting mixture was stirred for 3.5 hours at room temperature. Further on, 46.5 g (250 mmol) of 2-isopropoxy-4,4,5,5- tetramethyl-l,3,2-dioxaborolane was added in one portion. The obtained mixture was stirred for 15 min and then poured into 1000 mL of cold water. The product was extracted with 3 x 300 mL of ethyl acetate. The combined organic extract was washed by water, brine, then dried over MgSC , and, finally, evaporated to dryness. The resulting white solid was washed by 2 x 75 mL of pentane and dried in vacuum. Yield 47.3 g (70percent). NMR (CDCb): δ 8.12 (m, 1H, 8-H), 7.77 (m, 1H, 5-H), 7.75 (d, J = 8.4 Hz, 1H, 4-H), 7.44 (m, 1H, 7-H), 7.38 (m, 1H, 6-H), 7.28 (d, J = 8.4 Hz, 1H, 3-H), 2.63 (s, 3H, 2-Me), 1.48 (s, 12H, CMe2CMe2).
Reference：
[1] Chemical Communications, 2012, vol. 48, # 91, p. 11211 - 11213
33
[ 584-12-3 ]
[ 61676-62-8 ]
[ 374790-93-9 ]
Yield
Reaction Conditions
Operation in experiment
78%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2 h; Stage #2: at -78 - 20℃; Stage #3: With methanol In tetrahydrofuran; hexane
General procedure: n-BuLi in hexane (1.6 M, 65 mL, 0.10 mol) was slowly added toa solution of 2-bromothiophene (11 g, 0.068 mol) in THF (200 mL) at 78 C. After stirring for 2 h at this temperature, the mixturewas added to a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13 g, 0.068 mol) in 150 mL of THF. The mixture was warmed to room temperature and stirred overnight. The reactionwas terminated by adding a small amount of methanol and the resultant solution was washed with water three times. The solution was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: hexane) to give 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)thiophene
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2 h; Inert atmosphere Stage #2: at 20℃; for 20 h; Inert atmosphere
Under argon protection,In a 500 mL long three-necked flask,Was added 2,7-dibromo-9,9-dioctylfluorene (21.9 g, 40 mmol)And 250 mL of anhydrous tetrahydrofuran,The reaction solution was cooled to -78 ° C with liquid nitrogen,A n-hexane solution of n-butyllithium (48 mL, 2.5 M, 120 mmol) was slowly added dropwise,After stirring at -78 ° C for 2 hours,2-isopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (26 g, 140 mmol) was injected in one portion,Let it naturally rise to room temperature,Continue to react for 20 h.The reaction mixture was poured into water and extracted with methylene chloride. The mixture was washed five times. The organic phase was separated, dried, filtered and the solvent was dried. The residue was purified by column chromatography. The crude product was purified by silica gel as a stationary phase and petroleum ether / dichloromethane as the mobile phase. After purification, 43.8 g of a white solid was obtained in 80percent yield.
78%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Stage #2: at -78 - 20℃; for 50 h;
2,7-dibromo-9,9-dioctyl-9H-fluorene (Compound e-2) after a round bottom flask containing a 1g and a tetrahydrofuran (Tetrahydrofuran) 200mL. at -78 was added a n-BuLi (2.0M in Hexane), and the mixture was stirred for 2 hours. Again at -78 2--4,4,5,5,--1,3,2-(2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) And then slowly added, after stirring for 2 hours and was stirred at room temperature for 48 hours, to complete the reaction. After completion of the reaction (quenching) with methanol and extracted with MC and the organic layer and aqueous NaCl (brine), remove the remaining water over anhydrous magnesium sulfate (MgSO4) and the solvent was evaporated, recrystallized from methanol and the MC 2,2 (9,9-dioctyl-9Hfluorene-2,7-diyl) a bis (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (compound E) was obtained. (Yield: 78percent)
77%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2 h; Inert atmosphere Stage #2: at 20℃; for 20 h;
argon protection, in the 500mL long three bottles,Was added 2,7-dibromo-9,9-dioctylfluorene (21.9 g, 40 mmol) and anhydrous tetrahydrofuran (250 mL)The reaction solution was cooled to -78 ° C with liquid nitrogen,A n-hexane solution of n-butyllithium (48 mL, 2.5 M, 120 mmo 1) was slowly added dropwise,After stirring at -78 ° C for 2 hours,2-isopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (26 g, 140 mmol) was injected in one portion,Let it naturally rise to room temperature,Continue to react for 20 h.Adding ammonium chloride aqueous solution quenching reaction,Rotate to evaporate most of the solvent,The reaction mixture was poured into water,And extracted with dichloromethane,Washed 5 times,Separation of organic phase,dry,After filtering the dry solvent,The crude product was purified by column chromatography (eluent: petroleum ether)Purification gave 19.8 g of a white solid,Yield about 77percent.
74%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: at 20℃;
n-BuLi (2.5 M in hexane;2.4 mL, 6.0 mmol) was added slowly over 30 min to astirred solution of 2,7-dibromo-9,9-dioctylfluorene (1.5 g,2.7 mmol) in dry tetrahydrofuran (70 mL) at −78 C. Themixture was stirred for 1 h at the same temperature andthen 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.7 mL, 8.2 mmol) was added slowly. The mixturewas allowed to warm up slowly to room temperatureand stirred vigorously for overnight. The reaction wasquenched with water and the residue was extracted withdichloromethane. The combined organic phase was driedover MgSO4 and evaporated under reduced pressure. Thecrude product was purified by flash chromatography onsilica gel and recrystallized from acetone to give the titlecompound as colourless crystals (1.3 g, 74percent). 1H NMR(CDCl3, 300 MHz) [ppm]: 7.83 (d, 2 H), 7.74–7.72(m, 4 H), 1.96 (m, 4 H), 1.42 (s, 24 H), 1.26–1.05(m, 20 H), 0.81 (t, 6 H), 0.62 (m, 4 H); 13C NMR (CDCl3,75 MHz) [ppm]: 150.5, 143.5, 133.3, 128.6, 119.4,119.3, 83.7, 55.5, 40.1, 31.8, 29.8, 29.1, 29.0, 24.9, 23.7,22.7, 14.1.
70%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Inert atmosphere Stage #2: at -78 - 20℃; for 25 h;
(2) Under an argon atmosphere,2,7-dibromo-9,9-dioctylfluorene (5 g, 10.65 mmol) was dissolvedIn 180 mL of purified THF, 28 mL of 1.6 mol of L-1 n-butyllithium was gradually added dropwise at -78 ° C,The reaction was carried out for 2 hours,Then, 25 mL of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added, and the reaction was continued at -78 ° C for 1 hour. The reaction was allowed to proceed to room temperature for 24 hours . The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed thoroughly with brine and dried over anhydrous magnesium sulfate. After concentrating, the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20/1, v / v)The product was left in the freezer for a long time to give a white solid in 70percent yield.
70%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Inert atmosphere Stage #2: at -78 - 20℃; for 25 h; Inert atmosphere
2,7-dibromo-9,9-dioctylfluorene (5 g, 10.65 mmol) was dissolved in 180 mL of purified THF under argon atmosphere and 1.6 mol of L-1 was gradually added dropwise at -78 ° C N-butyllithium 28 mL, Reaction for 2 hours, Then, 25 mL of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborane was added and the reaction was continued at -78 ° C for 1 hour. The temperature was raised to room temperature for 24 hours The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed thoroughly with brine and dried over anhydrous magnesium sulfate. After the solution was concentrated, a crude product was obtained as a pale yellow viscous solid which was purified by silica gel column chromatography The product was placed in a refrigerator to give a white solid in 70percent yield. & Lt; / RTI & gt; 1H NMR, 13CNMR, MS and elemental analysis showed that the resulting compound was the target product, The reaction equation is as follows
70%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Inert atmosphere Stage #2: at -78 - 20℃; for 25 h;
2,7-dibromo-9,9-dioctylfluorene (5 g, 9.12 mmol) was dissolved in 180 mL of purified THF under an argon atmosphere,A dropwise addition of 1.6 mol at -78 & lt; 0 & gt; C.L-1Of n-butyllithium (28 mL) was reacted for 2 hours and then 25 mL of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborane was added at -78 ° C The reaction was continued for 1 hour,And then heated to room temperature for 24 hours; the reaction mixture was poured into water,Extracted with ethyl acetate, and the organic layer was completely washed with brine,Add anhydrous magnesium sulfate dry; solution concentrated,Get light yellow viscous thick,Purification by silica gel column chromatography (eluent selection of petroleum ether / ethyl acetate Ester = 15/1, v / v), the product was left in a refrigerator for a long time to give a white solid in 70percent yield.
70%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Inert atmosphere Stage #2: at -78 - 20℃; for 25 h;
Under argon atmosphere, 2,7-dibromo-9,9-dioctylfluorene (5 g, 9.12 mmol)Was dissolved in 180 mL of purified THF,A solution of 1.6 mol of L-1 of n-butyllithium (28 mL) was gradually added dropwise at -78 ° C,The reaction was carried out for 2 hours and then added2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, the reaction was continued at -78 ° C for 1 hour,And then heated to room temperature for 24 hours; the reaction mixture was poured into water,Extracted with ethyl acetate, and the organic layer was completely washed with brine,Add anhydrous magnesium sulfate dry; solution concentrated, get light yellow viscous thick,Purification by silica gel column chromatography (eluent selection of petroleum ether / ethyl acetate = 15/1, v / v) gave the product a long time in a refrigerator to give a white solid in 70percent yield.1H NMR, 13CNMR, MS and elementsThe results show that the obtained compound is the target product.
70%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Inert atmosphere Stage #2: at -78 - 20℃; for 25 h; Inert atmosphere
Under an argon atmosphere, 2,7-dibromo-9,9-dioctylfluorene (5 g, 9.12 mmol) was dissolved in 180 mL of purified tetrahydrofuran (THF), A solution of 1.6 mol of L-1 of n-butyllithium (28 mL) was gradually added dropwise at -78 °C, reaction for 2 hours, then, 25 mL of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborane was added, the reaction was continued at -78 ° C for 1 hour and then allowed to warm to room temperature for 24 hours; The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed thoroughly with brine and dried over anhydrous magnesium sulfate. After the solution was concentrated, a crude product was obtained as a pale yellow viscous and purified by silica gel column chromatography The product was allowed to stand for a long time in a refrigerator to give a white solid in 70percent yield.
70%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Inert atmosphere Stage #2: at -78 - 20℃; for 36.6667 h; Inert atmosphere
2,7-Dibromo-9,9-di-n-octylfluorene (5.6 g, 10.22 mmol) was dissolved in 130 mL of dry tetrahydrofuran. Under argon atmosphere, a 1.6 M n-butyllithium solution (20 mL, 32 mmol) was added dropwise at -78 ° C, and the mixture was reacted at -78 ° C for 2 hours. Then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-ethanedioxyborate (25 mL, 123 mmol) was quickly added and the reaction was continued for an additional 40 minutes. The reaction was gradually warmed to room temperature for 36 hours. After the reaction was completed, the reaction mixture was poured into water, extracted with dichloromethane, washed with brine, driedDry over magnesium sulfate. The solvent was evaporated and the residue was recrystallized from tetrahydrofuran / methanol. Further purification by silica gel column chromatography (petroleum ether: ethyl acetate = 9: 1) gave a white solid powder (4.59 g, 70percent).
70%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Inert atmosphere Stage #2: at -78 - 20℃; for 25 h;
(2) 2,7-dibromo-9,9-dioctylfluorene (5 g, 10.65 mmol) was dissolved in 180 mL of purified tetrahydrofuran (THF) under an argon atmosphere. 1.0 mL of n-butyllithium 28 mL was gradually added dropwise at -78 °C. Reaction for 2 hours,Then add 25 mL of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The reaction was continued at -78 °C for 1 hour and warmed to room temperature for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was completely washed with brine and dried over anhydrous magnesium sulfate; the solution was concentrated. Obtained as a pale yellow viscous crude product, which was purified by silica gel column chromatography (eluent selected petroleum ether/ethyl acetate=20/1, v/v) and the product was placed in a refrigerator to obtain a white solid with a yield of 70percent.
70%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Inert atmosphere Stage #2: at -78℃; for 1 h; Inert atmosphere
Under an argon atmosphere, 2,7-dibromo-9,9-dioctylfluorene (5 g, 9.12 mmol) was dissolved in 180 mL of purified tetrahydrofuran (THF).A 28 mL portion of n-butyllithium 1.6 mol.L-1 was gradually added dropwise at -78°C and reacted for 2 hours.Then 25 mL of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added, the reaction was continued at -78°C for 1 hour, and then the temperature was raised to room temperature. hour;The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was completely washed with brine and dried over anhydrous magnesium sulfate. After the solution was concentrated, a pale yellow viscous crude product was obtained and purified by silica gel column chromatography (eluting The agent was selected from petroleum ether/ethyl acetate = 15/1, v/v) and the product was left in the refrigerator for a long time to obtain a white solid with a yield of 70percent.
65%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Inert atmosphere Stage #2: at -78 - 20℃; for 14 h; Inert atmosphere
Example 1, this Example discloses the organic semiconductor material polymer P1, P2 with the following formula: [0048] The preparation method of P1, P2 is described as follows: [0049] Step one, preparation of 2,7 - bis (4,4,5,5 - tetramethyl-1 ,3,2 - dioxaborolan -yl) -9,9 - dioctylfluorene: [0050] Anhydrous anaerobic reactor was assembled, under a continuing stirring and N2 protection, white 9.0mmol of 2,7 - dibromo-9 ,9 - dioctylfluorene were added into a three-necked flask, 150mL of refined tetrahydrofuran solvent was added by a syringe, 27.0 mmol of n-BuLi was added by a syringe under a temperature of -78°C, the mixture was stirred for 2 hours. Then, 30.6mmol of 2 - isopropoxy-4, 4, 5, 5 - tetramethyl-1, 3, 2 - two hetero oxygen pentaborane was added by a syringe under a temperature of -78°C, the temperature was raised to 20°C, and the reaction was carried out for 14 hours. [0051] After the reaction was finished, a saturated aqueous NaCl solution was added, extracted with chloroform, dried by anhydrous sodium sulfate, suction filtered, and the filtrate was collected and solvent was rotary evaporated. The raw product was finally refined by a silica gel column chromatography using petroleum ether: ethyl acetate (v/v=15:1) as eluent to obtain powdered solid 2, 7 - bis (4,4,5,5 - tetramethyl-1 ,3,2-dioxaborolan -yl) -9,9 - dioctylfluorene in a yield of 65percent. GC-MS (EI-m/z): 642 (M+).
65%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Inert atmosphere Stage #2: at -78 - 20℃; for 14 h; Inert atmosphere
Anhydrous anaerobic reactor was assembled, under a continuing stirring and N2 protection, white 9.0mmol of2, 7- dibromo-9 , 9- dioctylfluorene were added into a three-necked flask, 150mL of refined tetrahydrofuran solvent wasadded by a syringe, 27.0 mmol of n-BuLi was added by a syringe under a temperature of -78°C, the mixture was stirredfor 2 hours. Then, 30.6mmol of 2- isopropoxy-4, 4, 5, 5-tetramethyl-1, 3, 2- dioxaborolane was added by a syringe undera temperature of -78°C, the temperature was raised to 20°C, and the reaction was carried out for 14 hours.[0051] After the reaction was finished, a saturated aqueous NaCl solution was added, extracted with chloroform, driedby anhydrous sodium sulfate, suction filtered, and the filtrate was collected and solvent was rotary evaporated. The rawproduct was finally refined by a silica gel column chromatography using petroleum ether: ethyl acetate (v/v=15:1) aseluent to obtain powdered solid 2, 7- bis (4, 4, 5, 5-tetramethyl-1,3,2- the dioxaborolan- yl) -9, 9- dioctylfluorene in ayield of 65percent. GC-MS (EI-m/z) : 642 (M+).
Reference：
[1] Journal of Materials Chemistry, 2003, vol. 13, # 4, p. 807 - 813
[2] Patent: CN106588869, 2017, A, . Location in patent: Paragraph 0053; 0054; 0055; 0056
[3] Patent: KR101495152, 2015, B1, . Location in patent: Paragraph 0152; 0159-0160
[4] Patent: CN106366067, 2017, A, . Location in patent: Paragraph 0053; 0054; 0055; 0056
[5] Macromolecules, 2004, vol. 37, # 4, p. 1211 - 1218
[6] Soft Matter, 2011, vol. 7, # 21, p. 10025 - 10031
[7] Journal of Nanoscience and Nanotechnology, 2014, vol. 14, # 8, p. 6331 - 6336
[8] Patent: CN106187908, 2016, A, . Location in patent: Paragraph 0084; 0085
[9] Patent: CN106946878, 2017, A, . Location in patent: Paragraph 0080; 0084-0085
[10] Patent: CN106866679, 2017, A, . Location in patent: Paragraph 0048; 0049; 0050; 0051
[11] Patent: CN106866542, 2017, A, . Location in patent: Paragraph 0055; 0056; 0057; 0058; 0059
[12] Patent: CN107162984, 2017, A, . Location in patent: Paragraph 0055-0059
[13] Patent: CN105001233, 2017, B, . Location in patent: Paragraph 0082; 0084; 0087
[14] Patent: CN107011269, 2017, A, . Location in patent: Paragraph 0060; 0061
[15] Patent: CN107573299, 2018, A, . Location in patent: Paragraph 0052-0056
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[17] Macromolecules, 2004, vol. 37, # 3, p. 709 - 715
[18] Chemical Communications, 1997, # 17, p. 1597 - 1598
[19] Patent: EP2657226, 2013, A1, . Location in patent: Paragraph 0047; 0048; 0049; 0050; 0051
[20] Patent: EP2657239, 2013, A1, . Location in patent: Paragraph 0049; 0050
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Reference：
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[4] Organic Letters, 2011, vol. 13, # 13, p. 3312 - 3315
[5] Dalton Transactions, 2013, vol. 42, # 24, p. 8939 - 8950
44
[ 61676-62-8 ]
[ 1066-54-2 ]
[ 159087-46-4 ]
Yield
Reaction Conditions
Operation in experiment
88%
With C15H14N4; caesium carbonate; triphenylphosphine; silver(I) chloride In N,N-dimethyl-formamide at 50℃; for 24 h; Inert atmosphere; Schlenk technique
General procedure: A mixture of 1 (0.5 mmol), B(OiPr)pin (0.75 mmol), PPh3+L1+AgCl (1 mol percent), and Cs2CO3 (1.1 mmol) in DMF (5 mL) was stirred at 50°C under Ar atmosphere for 24 h. The reaction mixture was acidified by 1 M solution of hydrochloric acid in an ice water bath, and the aqueous phase was extracted with ethyl acetate (three times). The combined organic layer was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to give the corresponding products.
65%
Stage #1: With n-butyllithium In diethyl ether; hexane at -30 - 0℃; for 1.5 h; Inert atmosphere Stage #2: at -50℃; Inert atmosphere Stage #3: With hydrogenchloride In diethyl ether at -50 - -10℃; for 1.5 h; Inert atmosphere
To a solution of trimethylsilyl acetylene (200 g, 2.04 mol, 1 equiv) in diethylether (4 L) at −30 °C under argon in a 10 L jacketed vessel was added nBuLi (1.8 mol in hexanes, 1.14 L, 2.04 mol, 1 equiv) by cautious dropwise addition (internal reaction temperature rose to ≤−21 °C) and the reaction mixture was allowed to stir at this temperature for 1 h prior to warming to 0 °C. After 30 min the reaction mixture was cooled to −50 °C and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (380 g, 2.04 mol, 1 equiv) was added dropwise and the reaction mixture was stirred overnight. To the white precipitate was added ethereal 2 N HCl (1.33 L, 2.65 mol, 1.3 equiv) and the reaction was warmed to −10 °C and stirred for 1.5 h, filtered through Celite, concentrated in vacuo and allowed to recrystallise in the refrigerator, yielding trimethyl((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethynyl)silane 1a as a white crystalline solid (299 g, 65percent, obtained by four successive recrystallisations from the mother liquor). Mp 91–93 °C; 1H NMR (250 MHz, CDCl3) δ: 0.00 (9H, s), 1.09 (12H, s); 13C NMR (62 MHz, CDCl3) δ: −0.5, 24.6, 84.4, 111.3. All data in accordance with literature.21
51%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 1 h; Inert atmosphere Stage #2: at -78℃; for 2 h; Inert atmosphere
To a solution of compound 19 (3 g, 30.5 mmol, 1.0 eq) in ethyl ether (30 mL) was added a solution of n-BuLi (2.5 M in hexane, 12.8 mL, 1.05 eq) dropwise at -78 °C over a period of 5 min under a nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 1 h, then a solution of 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (5.7 g, 30.5 mmol, 1.0 eq) in TH F (8 mL) was added dropwise. After stirring for 2 h at -78 °C, the mixture was poured into cooled sat. aq. NH4CI (100 mL) and extracted with EtOAc (3 x 30 mL). The combined organic fractions were washed with saturated brine (3 x 30 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was dissolved in petroleum ether (30 mL) and cooled to -60 °C. The resulting precipitate was collected by filtration and dried under vacuum to afford compound 20 (3.5 g, .15.6 mmol, 51percent yield) as white solid: H N R (300 MHz, CDCI3) 60.21 (s, 9H) 1.30 (s, 12H).
Reference：
[1] Dalton Transactions, 2013, vol. 42, # 24, p. 8939 - 8950
[2] Angewandte Chemie - International Edition, 2016, vol. 55, # 44, p. 13724 - 13728[3] Angew. Chem., 2016, vol. 128, p. 13928 - 13932,5
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[5] Macromolecules, 2010, vol. 43, # 17, p. 6968 - 6979
[6] Journal of the American Chemical Society, 2003, vol. 125, # 26, p. 7796 - 7797
[7] Chemistry Letters, 2007, vol. 36, # 6, p. 802 - 803
[8] Chemical Communications, 2015, vol. 51, # 56, p. 11276 - 11279
46
[ 61676-62-8 ]
[ 144981-85-1 ]
[ 569343-09-5 ]
Reference：
[1] Journal of Organometallic Chemistry, 2009, vol. 694, # 19, p. 3172 - 3178
[2] Journal of Organometallic Chemistry, 2009, vol. 694, # 19, p. 3172 - 3178
47
[ 61676-62-8 ]
[ 28320-31-2 ]
[ 333432-28-3 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 11, p. 3629 - 3634
48
[ 930-36-9 ]
[ 61676-62-8 ]
[ 847818-74-0 ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: With n-butyllithium In tetrahydrofuran at 0 - 20℃; for 1 h; Stage #2: at -78 - 0℃; for 1.25 h; Stage #3: With ammonium chloride In tetrahydrofuran
To a solution of 1-methyl pyrazole (4.1 g, 50 mmole) in THF (100 mL) at 00C was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to -78°C [J. Heterocyclic Chem. 41 , 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (12.3 mL, 60 mmole). After 15 min at -78°C, the reaction was allowed to warm to 00C over 1 hour. The reaction <n="32"/>was diluted with saturated NH4CI solution and extracted with DCM. The organic fractions were washed with H2O (2 x 100 ml_), dried over Na2SO4 and concentrated under vacuum to afford a tan solid (8.0 g, 77percent) which was used without further purification. LCMS (ES) m/z 127 (M+H)+ for [RB(OH)2]; 1H NMR (CDCI3, 400 MHz) δ 7.57 (s, 1 H), 6.75 (s, 1 H), 4.16 (s, 3H), and 1.41 (s, 12H).
77%
Stage #1: With n-butyllithium In tetrahydrofuran at 0 - 20℃; Stage #2: at -78℃;
Preparation 2 Preparation of 1-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazoleTo a solution of 1-methyl pyrazole (4.1 g, 50 mmole) in THF (100 mL) at 00C was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to -78°C [J. Heterocyclic Chem. 41 , 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (12.3 mL, 60 mmole). After 15 min at -78°C, the reaction was allowed to warm to 00C over 1 hour. The reaction was diluted with saturated NH4CI solution and extracted with DCM. The organic fractions were washed with H2O (2 x 100 mL), dried over Na2SO4 and concentrated under vacuum to afford a tan solid (8.0 g, 77percent) which was used without further purification. LCMS (ES) m/z 127 (M+H)+ for [RB(OH)2]; 1H NMR (CDCI3, 400 MHz) δ 7.57 (s, 1 H), 6.75 (s, 1 H), 4.16 (s, 3H), and 1.41 (s, 12H).
76%
Stage #1: With n-butyllithium In tetrahydrofuran at -78 - 20℃; for 1 h; Stage #2: at -78 - 0℃; for 1.25 h;
To a solution of 1 -methyl pyrazole (4.1 g, 50 mmole) in THF (100 mL) at 00C was added n-BuLi (2.2M in THF, 55 mmole). The reaction solution was stirred for 1 hour at RT and then cooled to -78°C [J. Heterocyclic Chem. 41 , 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (12.3 mL, 60 mmole). After 15 min at -78°C, the reaction was allowed to warm to 00C over 1 hour. The reaction was diluted with saturated NH4CI solution and extracted with DCM. The organics were dried over Na2SO4 and concentrated under vacuum to afford a tan solid (8.0 g, 76percent) which was used without further purification. LCMS (ES) m/z 127 (M+H)+ for [RB(OH)2]; 1H NMR (CDCI3, 400 MHz) δ 7.57 (s, 1 H), 6.75 (s, 1 H), 4.16 (s, 3H), and 1.41 (s, 12H).
Reference：
[1] Patent: WO2009/158372, 2009, A1, . Location in patent: Page/Page column 30; 31
[2] Patent: WO2009/158374, 2009, A2, . Location in patent: Page/Page column 30
[3] Patent: WO2008/98105, 2008, A1, . Location in patent: Page/Page column 36
[4] Patent: US2010/216843, 2010, A1, . Location in patent: Page/Page column 20-21
[5] Patent: WO2008/121786, 2008, A1, . Location in patent: Page/Page column 42-43
[6] Drugs of the Future, 2014, vol. 39, # 8, p. 541 - 546
49
[ 39806-90-1 ]
[ 61676-62-8 ]
[ 761446-44-0 ]
Yield
Reaction Conditions
Operation in experiment
1 g
Stage #1: With isopropylmagnesium chloride; lithium chloride In tetrahydrofuran at 0℃; for 1 h; Inert atmosphere Stage #2: at 0 - 20℃; for 1.5 h;
To 1-methyl-4-iodopyrazole (1.0 g) and 10 mL of THF,Under the protection of nitrogen, slowly add isopropylmagnesium chloride/lithium chloride solution (3.97mL), the temperature during the dropwise addition does not exceed 0 °C,After the addition, stir for 1 h, then at 0 ° C,Slowly add isopropyl pinacol borate (1.11g) to control the temperature not to exceed 0 ° C, and then stir at room temperature for 1.5 h after the addition.After the reaction was completed, 10 mL of a saturated ammonium chloride solution was added dropwise.Quenched.Then add 50 mL of ethyl acetate and 10 mL of saturated ammonium chloride solution.The organic layer was separated, and the aqueous layer was extracted twice with 50 mL of ethyl acetate. The organic layer was combined and dried over anhydrous Na2SO?Dry under reduced pressure,The title product (1 g) was obtained.
Reference：
[1] Patent: CN108484609, 2018, A, . Location in patent: Paragraph 0155; 0156; 0157; 0159
50
[ 61676-62-8 ]
[ 1407429-97-3 ]
[ 847818-71-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 17, p. 4774 - 4786
51
[ 61676-62-8 ]
[ 844891-04-9 ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78 - 40℃; for 0.333333 h; Stage #2: at -78 - 40℃;
Example 21; 1,3,5-Trimethyl-4-{4-[3-(2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-1H-pyrazole; Example 21A; 1,3,5-Trimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole; A solution of 4-bromo-1,3,5-trimethyl-1H-pyrazole (1 g, 5.3 mmol) in anhydrous THF (20 mL) cooled to -78° C. under a nitrogen atmosphere was treated dropwise with n-butyl lithium (4.2 mL, 1.6 M in hexane) and stirred at room temperature for 20 minutes. Then, 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.7 mL, 8.3 mmol) was added dropwise at -78° C. and allowed to warm to ambient temperature overnight. Ethyl acetate was added and the mixture was filtered through diatomaceous earth. The filtrate was concentrated and chromatographed on silica gel eluting with 40percent ethyl acetate in hexanes to provide the title compound as white crystals (996 mg, 77percent). 1H NMR (300 MHz, CDCl3) δ 1.29 (s, 12H), 2.33 (s, 3H), 2.37 (s, 3H), 3.69 (s, 3H); (DCl/NH3) m/z 237 (M+H)+.
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: at 20℃; for 2 h;
9,9-dimethyl-9H-2,7-dipinacolborylfluorene: the solution of 9,9-dimethyl-9H-2,7-dibromofluorene (17.6g, 50mmol) in anhydrous THF(100mL) was stirred and cooled to 78 °C, to which the n-Butyllithium(2.5M,44mL)was added over a period of 30 min.T wo hour slater isopropoxyboronicacid pinacol ester (25.5 mL)was add edand the mixture was still stirred at room temperature for two hours. After the addition of NH4Cl (20percent,20 mL), tesolvents were removed and the residue was extracted by dichloromethane.The solvent was removed ina vacuum and the crude product was pure enough .Yield:90percent. 1H NMR(CDCl3) δ 1.38(s,24H),1.52(s,6H),7.76(d,2H),7.82(q,2H), 7.89(s,2H)(Fig. S2).
Reference：
[1] Journal of Solid State Chemistry, 2015, vol. 231, p. 47 - 52
[2] Advanced Functional Materials, 2013, vol. 23, # 10, p. 1323 - 1330
[3] Journal of Materials Chemistry, 2004, vol. 14, # 17, p. 2622 - 2626
[4] Patent: US8779204, 2014, B2, . Location in patent: Page/Page column 13
53
[ 61676-62-8 ]
[ 57103-20-5 ]
[ 618442-57-2 ]
Reference：
[1] Journal of Materials Chemistry, 2011, vol. 21, # 25, p. 9139 - 9148
[2] Organic Letters, 2006, vol. 8, # 22, p. 5033 - 5036
[3] Tetrahedron Letters, 2005, vol. 46, # 5, p. 855 - 858
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; Inert atmosphere Stage #2: at 20℃; Inert atmosphere
Under nitrogen, 9- (4-bromophenyl) carbazole (3g, 9.32mmol) was dissolved in dry tetrahydrofuran (120mL) And cooled to about -78 ° C, was slowly added dropwise a solution of n-butyllithium (1.6mL, 2.5M, 4.84mmol) via syringe, and the Temperature for 15 to 20 minutes, and then added isopropoxy pinacol boronate (2.6mL, 13.04mmol); slow reaction system Slow return to room temperature and under N 2 atmosphere overnight. After completion of the reaction was added 1 ~ 2mL of ethanol to terminate the reaction, and evaporate After the solvent was distilled off, and distilled water was added methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure After the solvent was separated by a silica gel column, eluted with dichloromethane and petroleum ether to give a white solid, a yield of 80percent (2.75g).
71%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Inert atmosphere Stage #2: at -78 - 20℃; for 25 h; Inert atmosphere
In an argon atmosphere,9-(4-bromophenyl)-9H-carbazole (12.4 g, 38.4 mmol)Dissolved in 180 mL refined THF2.4 mL of n-butyllithium (2.4 mL) was gradually added dropwise at -78°C.After reacting for 2 hours, 12.5 g of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added.The reaction was continued at -78 °C for 1 hour.Then warmed to room temperature for 24 hours;The reaction mixture was poured into water, extracted with ethyl acetate, the organic layer was completely washed with brine, and dried over anhydrous magnesium sulfate;After the solution was concentrated, a pale yellow viscous crude product was obtained, which was purified by silica gel column chromatography. The mixture of petroleum ether and dichloromethane (6/1, v/v) was used as eluent to obtain a white solid with a yield of 71percent.
66.7%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -70 - -40℃; for 1 h; Inert atmosphere Stage #2: at -70 - 20℃;
37.8 g (117 mmol) of the intermediate product (F) was dissolved in 378 ml of tetrahydrofuran, 100.5 ml (lδlmmol) of 1.6M n-butyl lithium hexane solution was added at -70 ° C under argon atmoshhere, and then the resulting solution was agitated at -70 ° C to -40 C for 1 hour. The reaction fluid was cooled to -70 ° C and 47.9 ml (235 mmol) of isopropyl tetramethyl dioxaboloane was added in a dropwise fashion. After the resulting solution was agitated at -70 °C for 1 hour, the temperature increased to a room temperature and agiting was performed for 6 hours. 200 ml of water was added to the resulting solution and then agitated for 20 minutes.<159> After separating the reaction fluid into two layers, an organic layer was washed with a saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate.<i60> The organic solvent was distillated and removed under reduced pressure, and then the residue was recrystallized with toluene. The obtained crystal was separated by filtration and washed with toluene to obtain 28.9 g (yield- 66.7 percent) of intermediate product (G).
66.7%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -70 - 40℃; for 1 h; Inert atmosphere Stage #2: at -70 - 20℃; for 7 h;
Step 2: Synthesis of Intermediate (B)37.8 g (117 mmol) of the intermediate (A) was dissolved in 378 ml of tetrahydrofuran, then 100.5 ml (161 mmol) of n-butyl lithium hexane solution (1.6M) was added thereto under an argon atmosphere at -70° C. The obtained solution was agitated at -70° C. to 40° C. for 1 hour. The reaction fluid was frozen to -70° C., and 47.9 ml (235 mmol) of isopropyl tetramethyl dioxaborolane was slowly added thereto in a dropwise fashion. The obtained solution was agitated at -70° C. for 1 hour and heated to room temperature, and then agitated for 6 hours. To the obtained reaction solution, 200 ml of water was added and agitated for 20 minutes.The reaction solution was separated into two liquid layers, and an organic layer thereof was dried with anhydrous sodium sulfate. After the organic solvent was removed under a reduced pressure, the obtained residue was purified with silica gel column chromatography to provide 28.9 g of the intermediate (B) (yield 66.7percent).
54%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h; Inert atmosphere Stage #2: at 20℃; for 12 h; Inert atmosphere
n-Butyllithium (26 ml, 41.59 mmol) was added to a solution of 9-(4-bromophenyl)-9H-carbazole (6.7 g, 20.79 mmol) in anhydrous tetrahydrofuran (70 ml) at −78°C under nitrogen atmosphere. The mixture was stirred for 30 min at the same temperature. And then, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (21.2 ml, 103.97 mmol) was added dropwise to the reaction mixture and stirred for 12h at room temperature. The reaction mixture was poured into water and extracted with chloroform. The organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using toluene eluent to afford ( 2) a white powder, yield 54percent. 1H NMR (CDCl3, 400MHz) 8.17–7.15 (d, J=8Hz, 2H), 8.10–8.08 (d, J=8Hz, 2H), 7.64–7.62 (d, J=8.4Hz, 2H), 7.49–7.47 (d, J=8Hz, 2H), 7.45–7.41 (t, J=6.8Hz, 2H), 7.33–7.29 (t, J=6.8Hz, 2H), 1.43 (s, 12H) ppm.
Reference：
[1] Chinese Journal of Chemistry, 2015, vol. 33, # 8, p. 873 - 880
[2] Journal of Organic Chemistry, 2006, vol. 71, # 16, p. 6281 - 6284
[3] Chemistry Letters, 2008, vol. 37, # 9, p. 986 - 987
[4] Patent: CN105461717, 2016, A, . Location in patent: Paragraph 0087-0089
[5] Patent: CN107954921, 2018, A, . Location in patent: Paragraph 0085; 0086
[6] Patent: WO2010/24572, 2010, A2, . Location in patent: Page/Page column 27-28
[7] Patent: US2012/280221, 2012, A1, . Location in patent: Page/Page column 22
[8] Dyes and Pigments, 2014, vol. 111, p. 116 - 123
[9] Journal of Materials Chemistry C, 2013, vol. 1, # 24, p. 3871 - 3878
[10] Chemistry Letters, 2007, vol. 36, # 9, p. 1156 - 1157
[11] Chemistry Letters, 2007, vol. 36, # 9, p. 1156 - 1157
[12] European Journal of Organic Chemistry, 2012, # 27, p. 5263 - 5274
[13] Dyes and Pigments, 2013, vol. 99, # 1, p. 41 - 51
59
[ 61676-62-8 ]
[ 594-19-4 ]
[ 785051-54-9 ]
Reference：
[1] Patent: US2011/245429, 2011, A1,
60
[ 61676-62-8 ]
[ 57102-42-8 ]
[ 419536-33-7 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 11, p. 3629 - 3634
61
[ 2039-82-9 ]
[ 61676-62-8 ]
[ 870004-04-9 ]
Reference：
[1] ChemPlusChem, 2017, vol. 82, # 10, p. 1274 - 1281
[2] Chemistry - A European Journal, 2014, vol. 20, # 1, p. 263 - 271
62
[ 61676-62-8 ]
[ 269410-08-4 ]
Yield
Reaction Conditions
Operation in experiment
54.8%
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at -6 - 0℃; Inert atmosphere Stage #2: at 0 - 20℃; Inert atmosphere
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (17).; A flask equipped with a mechanical stirrer, nitrogen inlet, addition funnel and thermowell was charged with 1-trimethylsilyl-4-iodopyrazole (15, 225.1 g, 0.85 mol) and THF (2200 mL). This mixture was cooled to -6° C. in an ice/salt/brine bath and isopropyl magnesium chloride (2 M in THF, 510 ml, 1.02 mol, 1.2 equiv) was added at a rate such that the temperature did not exceed 0° C. The extent of metal/halogen exchange was monitored by GC and was found complete after about 10 min. To the orange brown solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (isopropylpinacolborate, 16, 347 mL, 1.7 mol, 2.0 equiv) slowly at first keeping the temperature below 0° C. and then fairly rapidly after about 1/2 of the compound was added allowing the temperature to reach 5° C. (the reaction becomes quite thick and then thins out slowly). The reaction is then stirred at 0° C. for 10 min before being warmed to room temperature over 1 hr and stirred at room temperature for an additional 1 hr. The reaction was cooled to 6° C. and saturated aqueous ammonium chloride solution (2.2 L) was added with a temperature increase to 25° C. The mixture was stirred for 5 minutes before being diluted with toluene (10 L). The layers were separated (a large amount of solid is present in the aqueous layer) and the organic layer was sequentially washed with water (6.x.2.2 L), brine (2.x.2.2 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Residual toluene was co-evaporated with heptane to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (17, 90.3 g, 164.9 g theoretical, 54.8percent) as a white solid. For 17: 1H NMR (DMSO-d6, 400 MHz) δ ppm 13.08 (bs, 1H), 7.94 (s,1H), 7.62 (s,1H), 1.23 (s, 12H); C9H15BN2O2 (MW, 194.04), LCMS (EI) m/e 195 (M++H).
54.8%
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at -6 - 0℃; for 0.166667 h; Inert atmosphere Stage #2: at 0 - 20℃; for 2 h; Inert atmosphere Stage #3: With water; ammonium chloride In tetrahydrofuran at -6 - 0℃;
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1) [0161] A flask equipped with a mechanical stirrer, a nitrogen inlet, an addition funnel and a thermowell was charged with 1-trimethylsilyl-4-iodopyrazole (225.1 g, 0.85 mol) and THF (2200 mL) at ambient temperature. This mixture was cooled to approximately −6° C. in an ice/salt/brine bath before a solution of isopropyl magnesium chloride in THF (2 M solution in THF, 510 mL, 1.02 mol, 1.2 equiv) was added at a rate such that the internal temperature did not exceed 0° C. The extent of metal/halogen exchange was monitored by GC and was found complete after about 10 min. To the orange brown solution was then added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (isopropylpinacolborate, 347 mL, 1.7 mol, 2.0 equiv) slowly at first keeping the temperature below 0° C. and then fairly rapidly after about half of the compound was added allowing the temperature to reach 5° C. (the reaction becomes quite thick and then thins out slowly). The reaction is then stirred at 0° C. for 10 min before being warmed to ambient temperature over 1 h and stirred at ambient temperature for an additional 1 h. The reaction mixture was cooled to approximately 6° C. and the saturated aqueous ammonium chloride solution (NH4Cl, 2.2 L) was added with a temperature increase to 25° C. The mixture was stirred for 5 minutes before being diluted with toluene (10 L). The layers were separated (a large amount of solid is present in the aqueous layer) and the organic layer was sequentially washed with water (6×2.2 L) and brine (2×2.2 L) before being dried over sodium sulfate (Na2SO4). The drying reagent, sodium sulfate (Na2SO4), was removed by filtration and the solution was concentrated under reduced pressure. Residual toluene was co-evaporated with n-heptane to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1, 90.3 g, 164.9 g theoretical, 54.8percent) as a white solid. For 1: 1H NMR (400 MHz, DMSO-d6) δ 13.08 (bs, 1H), 7.94 (s, 1H), 7.62 (s, 1H), 1.23 (s, 12H) ppm; C9H15BN2O2 (MW, 194.04), LCMS (EI) m/e 195 (M++H).
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 16, p. 6276 - 6279
[2] Journal of the American Chemical Society, 2016, vol. 138, # 30, p. 9521 - 9532
64
[ 766-96-1 ]
[ 61676-62-8 ]
[ 1034287-04-1 ]
Reference：
[1] Journal of Polymer Science, Part A: Polymer Chemistry, 2011, vol. 49, # 15, p. 3355 - 3365
65
[ 2105-94-4 ]
[ 61676-62-8 ]
[ 760990-08-7 ]
Reference：
[1] Chemical Communications, 2006, # 24, p. 2589 - 2591
66
[ 61676-62-8 ]
[ 445264-61-9 ]
Yield
Reaction Conditions
Operation in experiment
67.5%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #2: at 20℃; for 1 h;
To a solution of 5-bromo-2-methoxy-pyridine (1.453 g, 7.73 mmol) in THF (50 mL) at -78° C. under N2 was added n-BuLi (3.4 mL, 2.5 M in hexanes, 8.5 mmol) dropwise. The mixture was stirred at -78° C. for 30 minutes, then 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.4 mL, 11.60 mmol) was added. The reaction mixture was warmed to room temperature for 1 hour, then poured into water and extracted with EtOAc. The combined extracts were washed with water and brine, dried (MgSO4), filtered and concentrated to give 2A (1.221 g, 67.5percent) as a colorless oil.
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: at -78 - 20℃;
2-(2-Difluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane To a solution of 1-bromo-2-difluoromethyl-benzene (19.8 g, 95.7 mmol) in dry THF (200 ml) at -78° C. under a nitrogen atmosphere was added 2.5 M n-BuLi in hexanes (42 ml, 105 mmol) slowly. After completion of the addition, the resulting dark solution was stirred for an additional hour at -78° C. Subsequently, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25 ml, 123 mmol) was added, and the solution was slowly warmed to room temperature. After stirring overnight at room temperature under a nitrogen atmosphere the solution was poured into 400 ml water. Ethyl acetate (300 ml) was added and the layers were separated. The aqueous layer was extracted twice with ethyl acetate (150 ml and 50 ml respectively), and the combined organic layers were washed with water, dried over Na2SO4, filtered, and evaporated to dryness under reduced pressure. The resulting brown oil (21 g) was purified by bulb-to-bulb-distillation at 3*10-3 mbar at 90-95° C. to yield 2-(2-difluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (14.4 g, 59percent) as a slightly yellow oil.
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 1, p. 263 - 271
72
[ 101-55-3 ]
[ 61676-62-8 ]
[ 269410-26-6 ]
Yield
Reaction Conditions
Operation in experiment
72%
With n-butyllithium In tetrahydrofuran at -78 - -40℃; for 18 h; Inert atmosphere
4-bromodiphenyl ether(6.2g, 25.0mmol) Isopropanol pinacol borate (10.3 mL, 50 mmol)Soluble in dry tetrahydrofuran,Cooled to -78°C under nitrogen protection.n-Butyllithium (2.5M, 18 mL, 45 mmol) was added dropwise,After completion of the addition, the mixture was stirred for 6 hours and slowly warmed to -40°C for 12 hours.The reaction was added to saturated ammonium chloride solution and extracted three times with ethyl acetate.The organic phases were combined and dried over anhydrous sodium sulfate.It was evaporated to dryness by rotary evaporation and purified by column to give 5.4 g of the target compound in a yield of 72percent.
Reference：
[1] Patent: CN107759602, 2018, A, . Location in patent: Paragraph 0180-0182
73
[ 61676-62-8 ]
[ 656257-43-1 ]
[ 656257-45-3 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: at -78 - 20℃;
1- (4-bromophenyl) -4-ethylpiperazine (300 mg, 1.11 mmol)In tetrahydrofuran (10 mL)An n-butyllithium hexane solution (1.60 M, 1.05 mL, 1.67 mmol) was added dropwise at -78 ° C.After stirring for 1 hour,A solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (270 μL, 1.34 mmol) in tetrahydrofuran (5 mL) was added dropwise.The mixture was warmed to room temperature and stirred overnight.After completion of the reaction,A saturated aqueous ammonium chloride solution was added dropwise,And extracted with chloroform.The organic layer was dried over anhydrous sodium sulfate,Filtration,And concentrated under reduced pressure.The residue was purified by silica gel column chromatography (chloroform / methanol)Made,To give the title compound (283 mg, 80percent)
With n-butyllithium In tetrahydrofuran; hexane at -70 - 20℃; for 3 h;
To a stirred solution of tert-butyl 4-(4-bromo-lH-pyrazol-1-yl)piperidine-1-carboxylate (25.0g, 0.076 mole) in THF ( 500 ml) at- 70°C was added BuLi 1.6 Min Hexane solution (10 56.75 ml, 0.091 mole) dropwise followed by addition of 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18.52 ml , 0.091 mole) at same temperature. Reaction mixture wasstirred at -70°C for lh then warmed to room temperature and continued stirring for 2h atroom temperature. Reaction mixture was quenched with ammonium chloride solution (25 ml)water (500 ml), and ethyl acetate (750 ml) was added to reaction mixture, followed by15 extraction with ethylacetate (100 ml x 2). The combined organic layer was washed withbrine, concentrated under vacuum to get crude product which was crystallized from nHeptaneto give pure title compound.Yield: 51 percent (14.7g)HPLC Purity: 96.7percent20 MS (m/z): 378 (M + 1) 1HNMR (400 MHz, CDCh) 8: 7.81 (s, lH), 7.75 (s, lH), 4.27 (m, 3H), 2.9 (m, 2H), 2.14 (m,2H), 1.91 (m, 2H), 1.49 (s, 9H), 1.33 (s, 12 H).
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.75 h; Stage #2: at -78℃; for 3 h;
Example 2A 2,6-Dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine A solution of 3-bromo-2,6-dimethylpyridine (5.10 g, 27.4 mmol) in anhydrous ether (160 ml) cooled to -78° C. under a nitrogen atmosphere was treated dropwise with n-butyl lithium (4.1 ml, 10 M in hexane) and stirred at -78° C. for 45 minutes. 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.2 g, 54.8 mmol) in 20 ml of ether was added dropwise at -78° C. and stirred at -78° C. for 3 hours. The mixture was quenched with 10 ml of isopropanol, and allowed to warm to room temperature. 150 ml of saturated aqueous NaCl solution was added. The aqueous phase was separated and extracted with dichloromethane (100 ml*6). The combined organic phases were dried and concentrated to provide the title compound as light brown oil (6.29 g, 98.4percent). 1H NMR (300 MHz, CDCl3) δ ppm 7.92 (d, J=7.46 Hz, 1H) 6.96 (d, J=7.80 Hz, 1H) 2.73 (s, 3H) 2.53 (s, 3H) 1.34 (s, 12H). MS: (M+H)+=234.
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h;
To a solution of 2-(4'-bromophenyl)pyridine (0.468 g, 2 mmol). in anhydrous THF (10 ml) was added dropwse n-BuL (3 ml, 3.6 mmol) at -78"C The reaction was stirred 1 h, then 2-isopropoxy-4,4,5>5-tetramethyl-l,3,2-dioxaborolane (0.52 ml, 2.5 mmol) was added. The mixture was stirred overnight. Then Hie reaction was quenched with water and extracted with dchloromethane (30 ml) 3 times. The organic layer was -washed with brine and dried over MgSO4 and concentrated in vacuo. After column chromatography (silica gel, ethyl acetate: hexane = 1: 20) to give product 0.22 g (39percent).
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -60℃; for 1 h; Inert atmosphere Stage #2: for 1 h;
Under a nitrogen atmosphere, 129 g (0.4 mol) of the compound (E) was dissolved in 600 mL of THF and cooled to -60 ° C. 263 mL of normal butyllithium (1.6 M hexane solution) was added dropwise and the mixture was stirred for 1 hour. 81.87 g (0.44 mol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added dropwise and the mixture was further stirred for 1 hour. The temperature of the mixture was raised to room temperature, neutralized with dilute hydrochloric acid, extracted with ethyl acetate / water, and the organic layer was washed with water and saturated brine and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, purification with silica gel column chromatography (hexane / ethyl acetate) gave 105.5 g (yield 72percent) of compound (F).
With n-butyllithium In tetrahydrofuran at -65 - -50℃; for 2 h; Inert atmosphere; Large scale
The compound 3-iodo-1-methyl-1H-pyrazole (2000 g, 9.6 mol, 1.0 eq)Was dissolved in 8 L of dry tetrahydrofuran,Then, Isopropoxyboronic acid pinacol ester (2146.1 g, 11.5 mol, 1.2 eq) was added to the solution,The solution was cooled to -65 to -50 ° C,Under argon protection,Was added dropwise n-butyllithium (6.25L, 12.5mol, 1.3eq),After completion of the dropwise addition, the reaction was stirred for 2 h at this low temperature,An aqueous solution of hydrochloric acid (1 mol / L) was added to the reaction solution to quench the reaction,The reaction solution was extracted three times with ethyl acetate,The combined organic layers were dried over saturated brine and the organic phase was concentrated. 1-methyl-1H-pyrazol-3-boronic acid pinacol ester(1080.9 g, 0.24 mol),Yield 54.0percentPurity 97percent +.
Reference：
[1] Patent: CN105669733, 2016, A, . Location in patent: Paragraph 0037; 0038; 0039; 0040
81
[ 61676-62-8 ]
[ 32779-36-5 ]
[ 1003845-08-6 ]
Yield
Reaction Conditions
Operation in experiment
65%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: at -78 - 20℃; for 5 h;
Synthesis of Intermediate 1-1 (0337) 1.93 g (10 mmol) of 5-bromo-2-chloropyrimidine was dissolved in 200 mL of THF, and then, at a temperature of −78° C., 4 mL (2.5M in hexane) of normal butyllithium was added thereto. At the same temperature about one hour thereafter, 2.0 mL (10 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added thereto. At room temperature, the result was stirred for about 5 hours, and then, water was added thereto and a washing process was performed three times thereon using diethylether (100 mL). A washed diethylether layer was dried by using MgSO4, and then, dried under reduced pressure, thereby obtaining a product. The product was separation-purified by silica gel column chromatography, thus preparing 1.56 g (Yield 65percent) of Intermediate 1-1.
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -80℃; for 0.5 h; Stage #2: at -80 - 20℃; for 4 h;
0124-2 A 1.6 mol/L n-butyllithium-hexane solution (1.2 mL) was added to a solution of 4-bromo-1-methyl-3-phenyl-1H-pyrazole (300 mg) in tetrahydrofuran (6 mL) at -80° C., followed by stirring at the same temperature for 30 minutes, and 2-isopropyloxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (470 mg) was added thereto at the same temperature, followed by stirring while heating to room temperature over a period of 4 hours. A saturated ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (184 mg). MS m/z (M+H): 285.
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2 h; Stage #2: at 20℃; for 44 h;
Compound f-5 (5.0 g, 9.0 mmol) into a round bottom flask in a vacuum caught after 4 Holding time Vacuum THF (150mL) into the dissolve. at -78 °C n-butyllithium (2.0M in Hexanes, 11.26mL) was slowly added after the mixture was stirred for two hours. 2 hours later, 2-isopropoxy -4,4,5,5- tetramethyl 1-1,3,2- Sabo dioxane was added to lane (5.52mL) slowly and stirred for 4 hours and allowed to react for 40 hours at room temperature. After completion of the reaction it was cooled with methanol and methylene chloride to remove the remaining moisture in the salt water over anhydrous magnesium sulfate (MgSO4), extract the organic layer and then rotary evaporated to end with ethyl acetate-hexane 1: 9 to 9 column with a solid-state to yield (heptadecane-9-yl)-2,7-bis (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) -9Hcarbazole (compound F) (yield: 70percent ).
Reference：
[1] Macromolecules, 2012, vol. 45, # 21, p. 8658 - 8664
[2] Patent: KR101495152, 2015, B1, . Location in patent: Paragraph 0164; 0180-0181
[3] Journal of Polymer Science, Part A: Polymer Chemistry, 2012, vol. 50, # 24, p. 5011 - 5022
[4] Journal of the American Chemical Society, 2012, vol. 134, # 46, p. 19035 - 19042
[5] New Journal of Chemistry, 2011, vol. 35, # 6, p. 1327 - 1334
[6] Polymer, 2010, vol. 51, # 14, p. 3196 - 3202
84
[ 61676-62-8 ]
[ 575452-22-1 ]
[ 1029716-44-6 ]
Yield
Reaction Conditions
Operation in experiment
85.1%
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at -15 - -5℃; for 1.25 h; Inert atmosphere Stage #2: at -5 - 16℃; for 0.75 h; Inert atmosphere
1-(Ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (19). A 22 L 4-neck flask equipped with a mechanical stirrer, thermowell, addition funnel, and N2 inlet was charged with 1-(ethoxyethyl)-4-iodo-1H-pyrazole (20, 700.0 g, 2.63 mol) and THF (5.5 L). The resulting solution was cooled to between -12° C.--15° C. A solution of 2 M i-PrMgCl in THF (1513 mL, 3.03 mol, 1.15 equiv) was added via an addition funnel over 30 min while maintaining the reaction temperature at <-5° C. and the tan suspension was stirred at <-5° C. for 0.75 hr. The resulting reaction mixture was further cooled to -15° C. and 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (16, 734 g, 805 mL, 3.95 mol, 1.5 equiv) was added rapidly via an addition funnel with the reaction temperature increasing to -5°. [Note: previous work with the analogous TMS-protected pyrazole has shown that slow addition of 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane results in a lower yield.] A nearly clear light brown solution was developed followed by reformation of grayish light suspension. The cooling bath was then removed and the reaction mixture was allowed to warm to 16° C. over 0.75 hr. The mixture was poured into 50 L reparatory funnel containing a stirred saturated aqueous NH4Cl solution (4 L). The mixture was diluted with toluene (8 L), heptane (8 L) and H2O (2 L). The aqueous phase was removed and the organic phase was washed with warm (30° C.) H2O (4.x.3 L) and saturated brine (2.x.3 L). The organic phase was dried over Na2SO4, and the solvents weree removed under reduced pressure. The residual toluene was further removed by co-evaporation with heptane (2 L). The residual oil was transferred to a 4 L beaker using a minimum amount of heptane (100 mL) and scratched to induce crystallization. The solid was filtered, washed with heptane (200 mL) and dried overnight in a vacuum oven at 30-40° C. The filtrate was concentrated under reduced pressure and the residue was allowed to stand overnight. The resulting solid was filtered, washed with heptane (100 mL) and dried overnight in a vacuum oven at 30-40° C. The two crops were combined to afford 1-(ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (19, 596 g, 700 g theoretical, 85.1percent) as a white to off-white solid. 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).
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 43, p. 13580 - 13584[2] Angew. Chem., 2016, vol. 128, p. 13778 - 13782,5
87
[ 1072-68-0 ]
[ 61676-62-8 ]
[ 1047644-76-7 ]
Yield
Reaction Conditions
Operation in experiment
142 mg
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at 0 - 20℃; for 1 h; Stage #2: at -78 - 0℃; for 1 h;
1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole A solution of 1,4-dimethyl-1H-pyrazole (480.0 mg, 4.993 mol) in tetrahydrofuran (20 mL, 300 mmol) at 0° C. was added 1.6 M n-butyllithium in hexane (4.7 mL, 7.5 mmol). The solution was stirred at room temperature for 1 h and then cooled to -78° C. To the solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.63 mL, 7.99 mmol). The reaction mixture was stirred at -78° C. for 0.5 h, then warmed up to 0° C. (taking 0.5 h). The reaction was quenched with brine and extracted with EtOAc (3*). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by combi-flash chromatography and eluted with EtOAc/hexane (0-60percent). The purification gave 142 mg of product as white solid.
Reference：
[1] Journal of the American Chemical Society, 2008, vol. 130, # 24, p. 7670 - 7685
[2] Journal of Materials Chemistry, 2011, vol. 21, # 32, p. 11800 - 11814
[3] Journal of the American Chemical Society, 2008, vol. 130, # 24, p. 7670 - 7685
89
[ 654676-12-7 ]
[ 61676-62-8 ]
[ 871696-12-7 ]
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 23, p. 9207 - 9213
90
[ 61676-62-8 ]
[ 1239363-40-6 ]
[ 1151802-22-0 ]
Yield
Reaction Conditions
Operation in experiment
83%
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at 0℃; for 0.75 h; Stage #2: at 0 - 20℃; for 1 h;
Step 2 In a flask 1-cyclopropyl-4-iodo-1H-pyrazole (405 mg, 1.73 mmol) was dissolved in THF (8.0 mL) and the solution cooled to 0° C. Isopropylmagnesium chloride (2.0 M in THF, 1.04 mL, 2.08 mmol) was added dropwise and the mixture stirred at 0° C. for 45 min, after which 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.53 mL, 2.60 mmol) was added and the mixture allowed to warm to room temperature over 1 h. The mixture was quenched with 50percent sat aqueous NH4Cl and extracted with EtOAc. The organic extract was washed with sat. NaCl, dried over MgSO4 and the solution was concentrated. The residue was purified by SiO2 chromatography (20-50percent EtOAc/heptane) to afford 405 mg (83percent) of 1-cyclopropyl-1H-pyrazole-4-boronic acid pinacol ester as a colorless viscous oil.
Reference：
[1] Australian Journal of Chemistry, 2014, vol. 67, # 4, p. 675 - 678
93
[ 61676-62-8 ]
[ 1161009-88-6 ]
[ 1161009-89-7 ]
Yield
Reaction Conditions
Operation in experiment
73%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: at -78 - 20℃; for 12 h;
4-Bromo-9,9'-spirobifluorene (2.5 g, 6.4 mmol) was dissolved in 90 mL of anhydrous THF solution and cooled to -78 °C. Then, 2 M n-BuLi (7 mL,14 mmol) was dropped slowly. After stirring at -78 °C for 30 min, 2-isopropoxy-4,4',5,5'-tetramethyl-[1-3]dioxaborolane (2.75 mL, 14 mmol) was added in one portion. The resulting mixture was stirred for another 12 h and gradually warmed to room temperature. The reaction was quenched with water and extracted with ethyl acetate and water. The organic layer was dried with anhydrous MgSO4 and filtered. The solution was evaporated. Then, the residue was purified by recrystallized from chloroform/ethanolto give a white powder. (2.08 g, Yield 73percent) 1H NMR (300 MHz,DMSO): δ (ppm) 8.72-8.74 (d, 1H), 7.68-7.73 (t, 3H), 7.17-7.25 (q,3H), 6.92-6.97 (t, 4H), 6.56-6.66 (m, 4H), 1.32-1.39 (d, 12H).
Reference：
[1] Dyes and Pigments, 2017, vol. 136, p. 255 - 261
[2] Organic Letters, 2009, vol. 11, # 12, p. 2607 - 2610
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.16667 h; Inert atmosphere Stage #2: at -78 - 20℃; for 24 h; Inert atmosphere
To a 100-mL flame-dried two necked flask was added M1 (3.0g, 11.6mmol) and freshly distilled THF (80mL). The resulting solution was cooled at−78°C and 8.7mL n-butyllithium (13.9mmol, 1.6M in hexane) was added over 10min under a nitrogen atmosphere. The mixture was stirred at−78°C for 1h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.6g, 13.9mmol) was added rapidly to the solution, and the resulting mixture was slowly warmed to room temperature for 24h. The mixture was poured into 50mL water and extracted with CHCl3 (300mL). The combined organic layers were washed with brine and dried over anhydrous MgSO4. The solvent was removed by rotary evaporation, and the residue purified by column chromatography on silica gel (ethylacetate:dichloromethane as eluent) to obtain the product as a light-yellow oil (1.6g, yield: 45.0percent). 1H NMR (400MHz; CDCl3; Me4Si): δ=7.77 (d, 2H, J=8.8Hz), 6.90 (d, 2H, J=8.8Hz), 3.94 (t, 2H, J=6.4Hz), 2.46 (t, 2H, J=6.8Hz), 2.26 (s, 6H), 1.88 (m, 2H, J=6.8Hz) 1.25 (s, 12H). 13C NMR (100MHz; CDCl3; Me4Si): 161.57; 136.73; 113.41; 83.13; 74.40; 66.02; 54.09; 45.42; 27.43; 25.00. Anal. Calcd for: C17H28BNO3: C, 66.90; H, 9.25; N, 4.59. Found: C, 66.73; H, 9.23; N, 4.63. IR (KBr, cm−1): 2981, 2936, 2816, 2716, 1566, 1463, 1281, 1245.
45%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Inert atmosphere Stage #2: at -78 - 20℃; for 26 h; Inert atmosphere
Dissolved in dry 30 Compound A 3g in a nitrogen atmosphere, THF, -78° C after the temperature was reduced to 2.2equivalent of n-butyllithium(nBuLi,Aldrich Co.) was slowly added. The reaction mixture was stirred at -78° C for 2 hours andthen, 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,Aldrich) was added, and the mixture was stirred while the temperature gradually to room temperature after stirring at -78° Cfor 2 hours, the height for 24 hours. After the reaction was completed to extract the organic material with chloroform, to giveafter washing the column with water to obtain the compound B, 1.6 g (yield 45.0percent).
Reference：
[1] Dyes and Pigments, 2015, vol. 113, p. 210 - 218
[2] Patent: KR2015/122308, 2015, A, . Location in patent: Paragraph 0094; 0095; 0098; 0099
Stage #1: With n-butyllithium In tetrahydrofuran; hexanes at -78℃; for 1.16667 h; Inert atmosphere; Cooling with ice Stage #3: With ammonium chloride In tetrahydrofuran; hexanes; water
To a solution of thieno[3,2-b]thiophene (1 .5 g, 10.70 mmol) in THF (25.5 mL) at -78 °C under N 2 is added dropwise a solution of BuLi in hexanes (8.988 mL of 2.5 M, 22.47 mmol), stirred for 20 min, cooling bath is replaced with ice bath and stirred for 50 min. The resultant thick suspension is quenched with 2- isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (4.181 g, 4.584 mL, 22.47 mmol). The reaction mixture is kept for overnight and then quenched with saturated aq. NH4Cl solution. After extraction with CH2Cl2 (2 x 100 mL), the combined extracts are washed with brine and dried (Na2S04). Organic solution is diluted with -20 mL of ethyl acetate, concentrated slowly on rotary evaporator until CH2Cl2 is removed. The resultant white fine crystals are collected by filtration. The solid is washed with heptanes and dried under high vacuum to afford 4,4,5,5-tetramethyl-2-[5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)thieno[3,2-b]thiophen-2-yl]-1 ,3,2-dioxaborolane (2.57 g, 6.554 mmol, 61.25percent) as half-white solid. 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 2H), 1.343 (s, 12H).
Reference：
[1] Journal of Materials Chemistry, 2011, vol. 21, # 25, p. 9224 - 9231
102
[ 1153-85-1 ]
[ 61676-62-8 ]
[ 1126522-69-7 ]
Yield
Reaction Conditions
Operation in experiment
83%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: at 20℃; for 8 h;
Synthesis of 9-phenyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-9H- carbazole. To a solution of 3-bromo-9-phenyl-9H-carbazole (20.3 g, 63 mmol) in THF (150 mL) at -78 °C was added 47.25 mL (75.8 mmol) of n-butyllithium (1.6 M in hexane). The mixture was stirred at -78 °C for 1 h. 21 mL (100 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl- [l,3,2]-dioxaborolane was added to the solution, and the resulting mixture was warmed to room temperature and stirred for 8 h. The mixture was poured into water and extracted with dichloromethane. The organic extracts were washed with brine and dried over magnesium sulfate. The solvent was removed by rotary evaporation, and recrystallization was made in hexane to afford 19.3 g (83 percent) of product as a white solid.
68%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: at -78 - 20℃;
3-bromo-9-phenyl-9H-carbazole (5 g, 15 mmol) was dissolved in 75 mL of anhydrous THFsolution and cooled to −78 °C. Next, 10 mL of 2M n-butyllithium(16.5 mmol) was slowly added dropwise. After the mixture was stirredat −78 °C for 30 min, 2.2 mL of 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (19 mmol) was slowly added. The resulting mixturewas stirred for 3 h and gradually allowed warm to room temperature.After the reaction was completed, the crude product was extractedusing ethyl acetate and D.I water. Water remaining in theorganic layer is removed using anhydrous magnesium sulfate. Thesolvent was vaporized and recrystallized using hexane. (3.65 g, Yield68percent) 1H NMR (300 MHz, CDCl3): δ(ppm) 8.64 (s, 1H), 8.19–8.16 (d,1H), 7.87–7.84 (d, 1H), 7.63–7.54 (m, 4H), 7.54–7.49 (t, 1H),7.40–7.35 (m, 3H), 7.31–7.28 (d, 1H), 1.40 (s, 12H).
65%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Stage #2: at 20℃;
After a mixed solution of 10 g (31.0 mmol) of 3-bromo-9-phenyl-9H-carbazole with anhydrous tetrahydrofuran (THF) was cooled down to −78° C., about 3 equivalents of n-butyllithium (n-BuLi) was slowly dropwise added thereto and stirred at −78° C. for about 2 hours. Then, about 3 equivalents of 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane was dropwise added to the solution and stirred at room temperature overnight. A resulting product was extracted with an organic solvent, followed by removing water with magnesium sulfate (MgSO4) and filtration through a filter under a reduced pressure to obtain a filtrate, which was then concentrated under a reduced pressure, and recrystallized (using methanol and THF) to obtain 7.5 g of Intermediate (2) (Yield: 65percent).
Reference：
[1] Patent: WO2012/23947, 2012, A1, . Location in patent: Page/Page column 141-142
[2] Journal of Materials Chemistry, 2011, vol. 21, # 25, p. 9139 - 9148
[3] Dyes and Pigments, 2018, vol. 156, p. 369 - 378
[4] Patent: KR2015/133089, 2015, A, . Location in patent: Paragraph 0367-0369; 0373; 0374
103
[ 61676-62-8 ]
[ 502161-03-7 ]
[ 1126522-69-7 ]
Reference：
[1] Journal of Materials Chemistry, 2012, vol. 22, # 1, p. 123 - 129
104
[ 70951-85-8 ]
[ 61676-62-8 ]
[ 1256359-15-5 ]
Yield
Reaction Conditions
Operation in experiment
63.5%
Stage #1: With n-butyllithium In tetrahydrofuran at -85 - -75℃; for 1 h; Industry scale Stage #2: for 3 h;
To a 20L four-neck bottle, 4-bromo-(tert-butyl)pyrazole (1.15kg, 5.66mol) and THF (9.2L) were added, then the mixture was cooled to between -78°C and -85°C and treated with nBuLi (6.23mol) dropwise at that temperature. After addition the solution was stirred at the same temperature for 1 h and /sopropyl pinacol borate (1.47kg, 7.92mol) was added dropwise. The reaction was complete after stirring for ~3h (starting material <1.0percenta/a by GC) then water (2.3L) was added to quench the reaction; and the pH adjusted to 8-9 by addition of 3.45kg 1 M HCI. The aqueous phase was extracted with TBME (3.45L x 2), and the combined organic phase washed with 5percent NaCI (3.45L x 2) and water (3.45L) in sequence. The organic phase was evaporated to give the crude product. After subsequent recrystallization from heptanes the pure product was obtained as a white solid (GC purity 99.7percenta/a) in a 63.5percentth overall yield. (Two 20L reactions were run, then combined in the heptane recrystallization).
63.5%
Stage #1: With n-butyllithium In tetrahydrofuran at -85 - -78℃; Large scale Stage #2: for 0.3 h; Large scale
Stage d) Preparation of 1-(1,1-Dimethylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Intermediate 11) To a 20 L four-neck bottle, 4-bromo-(tert-butyl)pyrazole (1.15 kg, 5.66 mol) and THF (9.2 L) were added, then the mixture was cooled to between -78° C. and -85° C. and treated with nBuLi (6.23 mol) dropwise at that temperature. After addition the solution was stirred at the same temperature for 1 h and isopropyl pinacol borate (1.47 kg, 7.92 mol) was added dropwise. The reaction was complete after stirring for ˜3 h (starting material<1.0percent a/a by GC) then water (2.3 L) was added to quench the reaction; and the pH adjusted to 8-9 by addition of 3.45 kg 1M HCl. The aqueous phase was extracted with TBME (3.45 L*2), and the combined organic phase washed with 5percent NaCl (3.45 L*2) and water (3.45 L) in sequence. The organic phase was evaporated to give the crude product. After subsequent recrystallization from heptanes the pure product was obtained as a white solid (GC purity 99.7percent a/a) in a 63.5percent th overall yield. (Two 20 L reactions were run, then combined in the heptane recrystallization).
44.26 g
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -60℃; for 0.0833333 h; Inert atmosphere Stage #2: at -60 - 20℃;
Synthesis of 1 -tert-Butyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazole 4.19 To a stirred mixture of 50 g of 4-bromo-1 -tert-butyl-pyrazole 3J. in 230 mL THF was added dropwise 100 mL 2.5M N-butyllithium solution in hexane under argon atmosphere below - 60 °C, then the mixture was stirred at this temperature for 5 min, before 52 mL 2-isopropoxy- 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane were added dropwise below -60 °C. The reaction mixture was allowed to reach ambient temperature. The mixture was cooled with an ice bath and diluted with aqueous phosphate buffer solution and water and neutralized with 2M aqueous hydrochloric acid. The organic solvent was removed by destination and the residue was extracted with DCM. The combined organic extracts were washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield 44.26 g of 1 -tert-butyl-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazole as solid.Analysis: HPLC-MS: Rt = 0.904 min (method F), M+H = 251
Reference：
[1] Chemistry of Materials, 2011, vol. 23, # 20, p. 4435 - 4444
[2] Electrochimica Acta, 2014, vol. 128, p. 430 - 438
106
[ 61676-62-8 ]
[ 94994-62-4 ]
[ 1246669-45-3 ]
Yield
Reaction Conditions
Operation in experiment
78%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 2 h; Inert atmosphere Stage #2: at -78℃; for 2 h;
Synthesis of Intermediate 16-a 10 g of 2-bromo-9-phenyl-9H-carbazole was put in a reaction vessel, which was then supplied with N2 in a vacuum, followed by an addition of 69 ml of anhydrous THF to obtain a mixture. While the temperature of the mixture was maintained at about −78° C., 13.04 ml (1.05 eq) of n-BuLi was slowly dropwise added thereto. The resulting mixture was stirred for about 2 hours while being kept at the same temperature, followed by an addition of 7.6 ml (1.2 eq) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and stirring for about 2 hours. The solvent was removed from the mixture using a rotary evaporator. The reaction product was extracted twice with 200 ml of dichloromethane (CH2Cl2) and then 150 ml of water 200 ml. The organic layer was collected and was dried using magnesium sulfate to evaporate the solvent. The residue was separated and purified by silica gel column chromatography to obtain 9 g of Intermediate 16-2 (Yield: 78percent). This compound was identified using LC-MS. C24H24BNO2: M+ 369.19
70%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: at -78 - 20℃;
2-bromo-9-phenyl-9H-carbazole (2.27 g, 7 mmol) was dissolved in 100 mL of anhydrousTHF solution and cooled to −78 °C. Then, 7.07 mL of 2.0M n-butyllithium(14 mmol) was slowly added dropwise. After the mixture wasstirred at −78 °C for 30 min, 4 mL of 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (21 mmol) was slowly added. The resulting mixturewas stirred for 3 h and gradually allowed to warm to room temperature.After the reaction was finished, the reaction mixture wasextracted with ethyl acetate and water. The organic layer was driedwith anhydrous MgSO4 and filtered. The solvent was vaporized andrecrystallized using hexane. (1.9 g, Yield 70percent) 1H NMR (300 MHz,THF): δ(ppm) 8.17–7.81 (t, 2H), 7.79 (s, 1H), 7.69–7.62 (t, 2H),7.60–7.56 (t, 3H), 7.52–7.46 (t, 1H), 7.40–7.33 (m, 2H), 7.25–7.20 (t,1H), 1.31 (s, 12H).
Reference：
[1] Patent: US9455409, 2016, B2, . Location in patent: Page/Page column 59-61; 73; 74
[2] Dyes and Pigments, 2018, vol. 156, p. 369 - 378
[3] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 11, p. 3629 - 3634
[4] Journal of Physical Chemistry B, 2012, vol. 116, # 15, p. 4603 - 4614
107
[ 57268-16-3 ]
[ 61676-62-8 ]
[ 1218791-01-5 ]
Yield
Reaction Conditions
Operation in experiment
64%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h; Inert atmosphere Stage #2: at -78℃; for 1.5 h;
5-bromo-2-methylthiazole 10a (2 g, 11.23 mmol) was dissolved in 70 mL of tetrahydrofuran, and 5.6 mL of a solution of 2.4 M n-butyllithium was added at -78°C. After the mixture was stirred for 30 minutes, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.5 g, 13.44 mmol) was added. The reaction was stirred for 1.5 hours, then stopped. The reaction solution was warmed up to room temperature, then 10 mL of a mixture of saturated ammonium chloride solution and water (V/V = 1: 1) were added to quench the reaction. Then, 50 mL of ethyl acetate was added, and two phases were separated. The aqueous phase was extracted with 30 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole 10b (1.6 g, yield 64percent) as a light yellow oil. MS m/z (ESI): 226.1 [M+1].
Stage #1: With TurboGrignard In tetrahydrofuran at 0 - 20℃; for 2 h; Stage #2: for 1.16667 h;
Example 47 Preparation of 2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 5-Bromo-2-(difluoromethoxy)pyridine (1.0 g, 4.5 mmol) was dissolved in dry THF (10 mL), cooled to 0° C., and treated in portions with isopropylmagnesium lithium chloride complex (1.3 M; 3.3 mL, 4.3 mmol). The mixture was allowed to warm to 20° C., stirred for 2 h, treated with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (910 μl, 4.3 mmol) and stirred for 70 min more. The mixture was quenched with saturated ammonium chloride (NH4Cl; 5 mL) and partitioned between ethyl acetate and water. The organic phase was washed with saturated NaCl, dried (Na2SO4), and evaporated to provide the title compound as a brown oil that was used without further purification (1.1 g, 86percent): 1H NMR (400 MHz, CDCl3) 8.54 (dd, J=1.9, 0.6 Hz, 1H), 8.07 (dd, J=8.2, 1.9 Hz, 1H), 7.54 (t, J=73.0 Hz, 2H), 6.87 (dd, J=8.2, 0.8 Hz, 1H), 1.34 (s, 13H); 19F NMR (376 MHz, CDCl3) δ -89.22.
A THF solution containing 2.51 g (10.7 mmol) of <strong>[4373-60-8]2-(3-bromophenyl)pyridine</strong> was cooled to -78 °C. To this solution was added 1 ml. portions of n-BuLi (1.6M in hexanes, 5.1 imL, 13 mmol) resulting in a dark green solution. After 45 min of stirring at -78 °C, 3.0 g (16 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane was added and stirred at -78 °C for 30 min. The dry ice bath was then removed, and the reaction was left to warm to room temperature overnight. The reaction was then quenched with MeOH (5 ml_), preabsorbed on silica, and the solvent was removed in vacuo. The sample was purified using chromatography [Si02: (DCM/EtOAc 9:1 ): Rf = 0.57] to afford 2.2 g (73percent) of a colorless oil. 1H NMR (400 MHz, CDCI3): delta=8.67 (ddd, 3J=5 Hz, J=2 Hz, 5J=1 Hz, 1 H, Ha), 8.37 (s, 1 H, He), 8.11 (ddd, 3J=8 Hz, J=2 Hz, 5J=1 Hz, 1 H, Hf), 7.84 (dt, 3J=8 Hz, 4J=1 Hz, 1H, Hh), 7.77 (dt, 3J=8 Hz, 4J=1 Hz, 1 H, Hd), 7.71 (dt, 3J=7 Hz, 4J=2 Hz, 1 H, Hc), 7.47 (t, 3J=8 Hz, H, Hg), 7.19 (ddd, 3J=7 Hz, 4J=5 Hz, 5J=1 Hz, 1 H,Hb), 1.34 (s, 12H, HMethyi); 3C NMR (100 MHz, CDCI3): delta = 157.7, 149.8, 139.0, 136.8, 135.5, 133.4, 130.0, 128.4, 122.2, 120.9, 84.1 ,25.1 ;HRMS (El): m/z = 281.1598 [(M)+] (calcd for Ci7H2oBN02+: m/z = 281.1587).
Example 21 Preparation of a Poly(carbazole-co-phenylene) Block-Copolymer Part A Synthesis of 9-Phenyl-3,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole A 2L flask was charged with 600 mL dry THF and 3,6-dibromo-9-phenylcarbazole (60 g, 0.15 mole). This was cooled to -78° C. with an acetone-dry ice bath. n-Butyllithium (138 mL of a 2.5M solution in hexanes, 0.34 mole) was added drop-wise via syringe. The reaction was stirred for 20 minutes and then warmed to -50° C. The temperature was reduced to -78° C. and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (64 g, 0.34 mole) added via syringe at such a rate as to maintain the temperature below -60° C. The temperature was maintained at -78° C. for two hours and then poured into an aqueous solution of ammonium acetate (90 g in 2100 mL water). The layers were phase separated and the aqueous phase extracted with methy tert-butyl ketone (2*200 mL). The combined organic phase and extracts were washed with brine (2*200 mL) and dried over magnesium sulfate. Concentration and re-crystallization of the resulting solid from acetone gave pure 9-phenyl-3,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole (PBTDC).
Example 21; 1,3,5-Trimethyl-4-{4-[3-(2-methyl-pyrrolidin-1-yl)-trans-cyclobutyl]-phenyl}-1H-pyrazole; Example 21A; 1,3,5-Trimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole; A solution of 4-bromo-1,3,5-trimethyl-1H-pyrazole (1 g, 5.3 mmol) in anhydrous THF (20 mL) cooled to -78 C. under a nitrogen atmosphere was treated dropwise with n-butyl lithium (4.2 mL, 1.6 M in hexane) and stirred at room temperature for 20 minutes. Then, 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.7 mL, 8.3 mmol) was added dropwise at -78 C. and allowed to warm to ambient temperature overnight. Ethyl acetate was added and the mixture was filtered through diatomaceous earth. The filtrate was concentrated and chromatographed on silica gel eluting with 40% ethyl acetate in hexanes to provide the title compound as white crystals (996 mg, 77%). 1H NMR (300 MHz, CDCl3) delta 1.29 (s, 12H), 2.33 (s, 3H), 2.37 (s, 3H), 3.69 (s, 3H); (DCl/NH3) m/z 237 (M+H)+.
A solution of 1-(5-bromo-pyridin-2-yl)-4-methyl-piperazine (0.52 g, 2.3 mmol) in 15 ml THF is cooled to - 78 0C and n-butyllithium (1.7 ml, 1.6 M solution in hexane) is added dropwise. Stirring is continued for 30 minutes after which time 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2- dioxoborolan (511 mg, 2.7 mmol) is added. After 2 hours the mixture is allowed to warm to room temperature and quenched by addition of aq. NaHCO3. Extraction with ethylactetate, drying with Na2SO4 and removal of the solvent gives the desired boronate which was used as crude material in subsequent reactions.MS (ESI+) m/z: 304 [MH]+
With ammonium acetate; In tetrahydrofuran; water; acetone;
Part B: Synthesis of 9-Phenyl-3,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole A 2 L flask was charged with 600 mL dry THF and 3,6-dibromo-9-phenylcarbazole (60 g, 0.15 mole). This was cooled to -78° C. with an acetone-dry ice bath. n-Butyllithium (138 mL of a 2.5M solution in hexanes, 0.34 mole) was added drop-wise via syringe. The reaction was stirred for 20 minutes and then warmed to -50° C. The temperature was reduced to -78° C. and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (64 g, 0.34 mole) added via syringe at such a rate as to maintain the temperature below -60° C. The temperature was maintained at -78° C. for two hours and then poured into an aqueous solution of ammonium acetate (90 g in 2100 mL water). The layers were phase separated and the aqueous phase extracted with methyl-t-butyl ether (2*200 mL). The combined organic phase and extracts were washed with brine (2*200 mL) and dried over magnesium sulfate. Concentration and re-crystallization of the solid obtained from acetone gave pure 9-phenyl-3,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole. This compound can be used to modify the hole transport properties of for example the compound of Example 17. To do this 9-Phenyl-3,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole is used in place of 2-[9,9-dioctyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in Example 17.
EXAMPLE 467A 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole A solution of <strong>[1075-34-9]5-bromo-2-methyl-1H-indole</strong> (5.04 g, 24 mmol) in THF (25 mL) was added dropwise to a suspension of potassium hydride (3.2 g, 24 mmol) in THF at 0° C. After fifteen minutes at 0° C., the solution was cooled to -78° C. and a t-butyl lithium solution (1.7 M in pentane, 28.2 mL, 48 mmol) was added dropwise via syringe while maintaining the temperature below -55° C. After an additional 15 minutes, the solution was cooled to -78° C. and treated with a 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (9.8 mL, 48 mmol) dropwise via syringe. The solution was stirred at -78° C. for 1.5 hours, allowed to warm to room temperature and quenched with saturated aqueous ammonium chloride. The solution was diluted with ethyl acetate and filtered to remove inorganic material. The filtrate was extracted with ethyl acetate. The combined organics were washed with brine, dried (MgSO4) and concentrated. The concentrate was purified by flash chromatography on silica gel using 10percent ethyl acetate/hexanes to give 3.9 g (63percent yield) of the desired product. MS (ESI(+)) m/e 258 (M+H)+.
To a suspension of NaH (60% in mineral oil, 3.5 g, 146 mmol, washed with 200 mL of hexane) in THF (200 mL) was added 4-methyl-1 H-pyrazole (10 g, 122 mmol) at 0 0C dropwise. After stirring at RT for 1 h, to above suspension was added MeI (7.3 mL, 117 mmol) dropwise at 0 0C. The reaction mixture was stirred overnight. The NaI by-product was removed by filtration and the filtrate solution was used directly in the next step.At 00C, to above THF solution of 1 ,4-dimethyl pyrazole was added n-BuLi (2.5M in hexane, 58.5 mL, 146 mmole). The reaction solution was stirred for 2 hour at RT and then cooled to -78C [J. Heterocyclic Chem. 41 , 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (27.2 g, 146 mmole). After 15 min at -78C, the reaction was allowed to warm to 00C and stir for 3h. The reaction was diluted with saturated NH4CI solution and extracted with DCM. The organics were dried over Na2SO4 and concentrated under vacuum to afford the title compound as a brown solid (21 g, 78%) which was used directly without further purification: LC-MS: 141 (M-C6H12)"1", 223 (M+H)+. 1H NMR (CDCI3): delta 7.28 (s, 1 H), 4.03 (s, 3H), 2.22 (s, 3H), and 1.32 (s, 12H).
142 mg
1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole A solution of <strong>[1072-68-0]1,4-dimethyl-1H-pyrazole</strong> (480.0 mg, 4.993 mol) in tetrahydrofuran (20 mL, 300 mmol) at 0 C. was added 1.6 M n-butyllithium in hexane (4.7 mL, 7.5 mmol). The solution was stirred at room temperature for 1 h and then cooled to -78 C. To the solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.63 mL, 7.99 mmol). The reaction mixture was stirred at -78 C. for 0.5 h, then warmed up to 0 C. (taking 0.5 h). The reaction was quenched with brine and extracted with EtOAc (3*). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by combi-flash chromatography and eluted with EtOAc/hexane (0-60%). The purification gave 142 mg of product as white solid.
Step 1. 1, 4-Dimethyl-5-( 4, 4, 5, 5-tetrame orolan-2-yl)-lH-pyrazole l,4-Dimethyl-7H-pyrazole (50 mg, 0.5 mmol) was stirred in THF (2 mL) and cooled to 0 C. A solution of 1.6 M w-butyllithium in hexanes (390 mL) was added dropwise by syringe and the mixture was allowed to warm to room temperature for 2 h. The mixture was cooled to -78 C and 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane(110 mL, 0.52 mmol) was added dropwise by syringe. The mixture was stirred at -78 C for 15 min. and at 0 C for 3 h. The mixture was diluted with EtOAc and washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography on silica gel using EtOAc in hexanes gave the sub-title compound. LCMS calc. for CnH2oB 202 (M+H)+: m/z = 223.2; found: 223.0.
With n-butyllithium;
Step 1 To a solution of <strong>[1072-68-0]1,4-dimethyl-1H-pyrazole</strong> (2.5 g, 26.0 mmol, 1 equiv) in tetrahydrofuran (50 mL) was added n-butyllithium in hexane solution (2.5 M in hexane, 78.0 mmol, 31 mL, 3 equiv) dropwise at 0 C. under nitrogen atmosphere. The resulting solution was stirred at room temperature for 1 h and then cooled to -78 C. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (14.52 g, 78.017 mmol, 3 equiv) was added and the reaction mixture was stirred at -78 C. for 0.5 hour, then slowly warmed up to 0 C. The reaction was quenched with brine and extracted with EtOAc (250 mL*3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1:5). This resulted in 2.6 g (45%) of 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a white solid.
A 2.5 M solution of n-butyllithium (3.4 mL, 8.5 mmol) was added to a stirred solution of diisopropylamine (1.2 mL, 8.5 mmol) in THF (25 mL) at -20 C. The resulting solution was stirred at -20 C. for 10 minutes, then cooled to -78 C. A solution of <strong>[3828-49-7]1,2-difluoro-3-methylbenzene</strong> (1.0 g, 7.8 mmol) in THF was added dropwise and stirred at -78 C. for 2 h. 2-Isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (1.6 g, 8.6 mmol) in THF was then added and the brown solution was slowly warmed to 23 C. over 16 hours. The reaction mixture was then added to ether and extracted with water and with 0.1N sodium hydroxide. The combined aqueous extracts were acidified with concentrated HCl then extracted with dichloromethane. The organic phase was dried and concentrated to give the title compound (1.0 g, 50% yield): 1H NMR (CDCl3): delta 7.32 (m, 1H), 6.92 (m, 1H), 2.31 (s, 3H), 1.32 (s, 12H).
<strong>[172921-33-4]1-Bromo-4-chloro-2,5-difluorobenzene</strong> (1.11 g, 4.9 mmol) was dissolved in tetrahydrofuran (THF; 15 mL) and cooled to -10° C. A 2.0M solution of isopropyl-magnesium chloride (2.7 mL, 5.4 mmol) in THF was added dropwise via syringe. The reaction mixture was stirred at -10° C. for 1 h, allowed to warm toward 0° C. for 1 h, then cooled again to -10° C. A solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 5.4 mmol) in THF (1.0 mL) was then added dropwise and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was then added to diethyl ether and extracted with 1N sodium hydroxide twice. The aqueous phases were combined, acidified to pH 3 with concentrated HCl, and extracted with dichloromethane twice. The organic phases were combined, dried, filtered and concentrated to give the title compound (0.97 g, 72.3percent yield) that was used without further purification: 1H NMR (CDCl3) delta 7.45 (dd, 1H), 7.09 dd, 1H), 1.36 (s, 12H).
62%
To a solution of l-bromo-4-chloro-2,5-difluorobenzene (200 mg, 0.879 mmol) in THF (10 mL) cooled to -10 0 C was added isopropylmagnesium bromide (1M in THF, 1.055 mL, 1.055 mmol) dropwise and the reaction mixture was stirred at this temperature for 1 h. The reaction mixture was then warmed to 0 °C and stirred for another 1 h. The resultant mixture was again cooled to -10 °C and treated dropwise with a solution of 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (196 mg, 1.055 mmol). The reaction mixture was allowed to warm up to room temperature and treated with a saturated solution of ammonium chloride (3 mL). The layers were separated and aqueous layer was extracted with dichloromethane (2 x 2 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude compound which was purified by column chromatography on a silica (7:3 - Ethyl acetate :hexane) to afford 2-(4- chloro-2,5-difluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (150 mg, 0.546 mmol, 62percent yield) as an oil. 1H NMR (400 MHz, DMSO-d6) delta ppm 7.46 - 7.49 (m, 1H), 7.09 - 7.13 (m, 1 H), 1.35 (s, 12H).
62%
To a solution of <strong>[172921-33-4]1-bromo-4-chloro-2,5-difluorobenzene</strong> (200 mg, 0.879 mmol) in THF (10 mL) cooled to -10°C was added isopropylmagnesium bromide (1M in THF, 1.055 mL, 1.055 mmol) dropwise and the reaction mixture was stirred at this temperature for 1 h. The reaction mixture was then warmed to 0 °C and stirred for another 1 h. The resultant mixture was again cooled to -10 °C and treated dropwise with a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (196 mg, 1.055 mmol). The reaction mixture was allowed to warm up to room temperature and treated with a saturated solution of ammonium chloride (3 mL). The layers were separated and aqueous layer was extracted with dichloromethane (2x2 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude compound which was purified by column chromatography on a silica (7:3 - Ethyl acetate:hexane) to afford 2-(4-chloro-2,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (150 mg, 0.546 mmol, 62percent yield) as an oil.
3. Preparation of 2-(4-Chloro-2,5-difluorophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane <strong>[172921-33-4]1-Bromo-4-chloro-2,5-difluorobenzene</strong> (1.11 g, 4.9 mmol) was dissolved in tetrahydrofuran (THF; 15 mL) and cooled to -10° C. A 2.0M solution of isopropyl-magnesium chloride (2.7 mL, 5.4 mmol) in THF was added dropwise via a syringe. The reaction mixture was stirred at -10° C. for 1 hour, allowed to warm toward 0° C. for 1 hour, then cooled to -10° C. again. A solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 5.4 mmol) in THF (1.0 mL) was then added dropwise and the reaction was allowed to warm to ambient temperature. The reaction mixture was then added to diethyl ether and extracted with 1N sodium hydroxide twice. The aqueous phases were combined, acidified to pH 3 with concentrated HCl, and extracted with dichloromethane twice. The organic phases were combined, dried, filtered and concentrated to give the title compound (0.97 g, 72.3percent yield) that was used without further purification: 1H NMR (CDCl3): delta 7.45 (dd, 1H), 7.09 dd, 1H), 1.36 (s, 12H).
1-(Ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (19). A 22 L 4-neck flask equipped with a mechanical stirrer, thermowell, addition funnel, and N2 inlet was charged with 1-(ethoxyethyl)-4-iodo-1H-pyrazole (20, 700.0 g, 2.63 mol) and THF (5.5 L). The resulting solution was cooled to between -12 C.--15 C. A solution of 2 M i-PrMgCl in THF (1513 mL, 3.03 mol, 1.15 equiv) was added via an addition funnel over 30 min while maintaining the reaction temperature at <-5 C. and the tan suspension was stirred at <-5 C. for 0.75 hr. The resulting reaction mixture was further cooled to -15 C. and 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (16, 734 g, 805 mL, 3.95 mol, 1.5 equiv) was added rapidly via an addition funnel with the reaction temperature increasing to -5. [Note: previous work with the analogous TMS-protected pyrazole has shown that slow addition of 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane results in a lower yield.] A nearly clear light brown solution was developed followed by reformation of grayish light suspension. The cooling bath was then removed and the reaction mixture was allowed to warm to 16 C. over 0.75 hr. The mixture was poured into 50 L reparatory funnel containing a stirred saturated aqueous NH4Cl solution (4 L). The mixture was diluted with toluene (8 L), heptane (8 L) and H2O (2 L). The aqueous phase was removed and the organic phase was washed with warm (30 C.) H2O (4×3 L) and saturated brine (2×3 L). The organic phase was dried over Na2SO4, and the solvents weree removed under reduced pressure. The residual toluene was further removed by co-evaporation with heptane (2 L). The residual oil was transferred to a 4 L beaker using a minimum amount of heptane (100 mL) and scratched to induce crystallization. The solid was filtered, washed with heptane (200 mL) and dried overnight in a vacuum oven at 30-40 C. The filtrate was concentrated under reduced pressure and the residue was allowed to stand overnight. The resulting solid was filtered, washed with heptane (100 mL) and dried overnight in a vacuum oven at 30-40 C. The two crops were combined to afford 1-(ethoxyethyl)-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (19, 596 g, 700 g theoretical, 85.1%) as a white to off-white solid. 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).
To a stirred solution of 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (1 1 .0 mL, 53.75 mmol) and chloroiodomethane (4.3 mL, 59.12 mmol) in anhydrous THF (100 mL), cooled to -78 C, was added cold n-butyllithium solution (23.94 mL, 59.12 mmol) dropwise. After stirring for 30 min at this temperature, chlorotrimethylsilane (8.2 mL, 64.50 mmol) was added dropwise. After stiring for 10 min, the reaction mixture was allowed to return to room temperature and stirred for 24 h. Water (80 mL) was added and the mixture extracted with Epsilon?0 (2 x 80 mL). The organic extracts were combined, washed with water (2 x 80 mL), dried over MgS04 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (Heptane/EtOAc 99:1 to 95:5).to yield 2-(chloromethyl)-4, 4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (4.35 g, 24.65 mmol, 46% yield) as a colourless oil. NMR (400 MHz, DMSO-cfe, delta): 2.99 (s, 2H), 1 .32 (s, 12H).
With n-butyllithium; In tetrahydrofuran; at -78 - 20℃;
Part B begins with commercially available bromo-pyrazolopyrimidine 47 (755 mg, 3.83 mmol) and 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-l,3)2-dioxaborolane (2.3 mL, 11.50 mmol) in THF (1.5 mL) at -78 0C. To this solution was added n-butyllithium (4.8 mL, 7.66 mmol) dropwise over 10 minutes. The reaction was slowly warmed to room temperature and was poured into water (10 mL) and partitioned with dichloromethane (10 mL). The organic was dried over sodium sulfate and concentrated before purification by column chromatography (0- 20% ethyl acetate in hexanes) to yield the boronic ester 48 (18% yield, 170 mg). 1H NMR (500 MHz, cdcl3) delta 8.54 - 8.44 (m, OH), 8.03 (s, 1 H), 7.65 (s, 1 H), 7.62 (d, J - 8.8, 1 H), 6.89 (d, J - 7.2, 1 H), 6.72 (x, J ' 54.4, 1 H), 6.20 (d, J = 9.3, 1 H), 4.37 - 4.06 (m, 1 H), 2.80 (t, J = 9.7, 1 H), 2.31 - 2.20 (m, IH), 2.10 (d, J = 13.7, IH), 1.92 - 1.73 (m, J = 26.0, 13.5, 2H), 1.44 - 1.16 (m, 2H).; Scheme 10.Stop A.Molecules of type 50 were prepared according to scheme 10 with the synthesis of compounds 46 and 48. Compound 46 (step A) was synthesized from commercially available dibromide 44. Regioselective metal-exchange followed by DMF quench provided aldehyde 46. Aldehyde 46 was reacted with excess deoxofluor to furnish compound 46. Preparation of boronic ester 48 (step B) was accomplished from commercial starting material (compound 47) via lithium-halogen exchange in the presence of 4,4,5>5-tetramethyl-2-(propan-2-yloxy)-l,3»2- dioxaborolane. Palladium-mediated coupling of 46 and 48 was followed by saponifcation to yield carboxylic acid 49. Amide formation with intermediate Il and subsequent deprotection provided compound 50.
{2-(2-Bromo-9,9-spirobifluoren-7-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan}3.5 g of 2,7-dibromo-9,9-spirobifluorene (7.38 mmol) was dissolved in 80 ml of tetrahydrofuran in a flask filled with nitrogen gas, and the temperature of the flask was reduced to -78°C. 5.1 ml of normal-butyllithium (1.6M hexane solution) was added dropwise to the resultant mixture via a syringe.The resultant mixture was stirred at -78°C for 30 minutes, and 1.7 ml of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaboralne (8.33 mmol) was slowly added to the resultant mixture.The reaction temperature was raised to room temperature, and the resultant mixture was then stirred for 8 hours.Water was added to the resulting mixture to complete the reaction.The reaction mixture was extracted with dichloromethane, and the remaining moisture existing in the layer was removed with MgSO4.Then, column chromatography (stationary phase: silica gel, mobile phase:ethylacetate:hexane= 1:10 volume ratio) was performed on the resultant layer to obtain 3.26 g of a desired Compound 3 at a yield of 85percent.Mp: 305 °C1HNMR (300 MHz, CDCl3): delta 7.85 (d, 4H J=7.2Hz),7.73(d,1HJ=7.2Hz),7.48(d,1HJ=7.2Hz),7.38(dd,2HJ=7.2Hz),7.16(s,1H),7.11 (dd,2 HJ=7.2Hz),6.79(s,1H),6.71(d,2HJ=7.2Hz), 1.25(s,12H).13CNMR(300MHz,CDCl3):delta 151.8, 147.8, 147.61, 143.8, 142, 140.4, 135.08, 134.93, 131.01, 130.41, 128.08, 128.04, 127.34, 124.29, 122.11, 121.84, 120.29, 119.51, 83.9, 65.9, 48.2, 24.9.
Compound f-5 (5.0 g, 9.0 mmol) into a round bottom flask in a vacuum caught after 4 Holding time Vacuum THF (150mL) into the dissolve. at -78 °C n-butyllithium (2.0M in Hexanes, 11.26mL) was slowly added after the mixture was stirred for two hours. 2 hours later, 2-isopropoxy -4,4,5,5- tetramethyl 1-1,3,2- Sabo dioxane was added to lane (5.52mL) slowly and stirred for 4 hours and allowed to react for 40 hours at room temperature. After completion of the reaction it was cooled with methanol and methylene chloride to remove the remaining moisture in the salt water over anhydrous magnesium sulfate (MgSO4), extract the organic layer and then rotary evaporated to end with ethyl acetate-hexane 1: 9 to 9 column with a solid-state to yield (heptadecane-9-yl)-2,7-bis (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) -9Hcarbazole (compound F) (yield: 70percent ).
Step 2In a flask 1-cyclopropyl-4-iodo-1H-pyrazole (405 mg, 1.73 mmol) was dissolved in THF (8.0 mL) and the solution cooled to 0° C.Isopropylmagnesium chloride (2.0 M in THF, 1.04 mL, 2.08 mmol) was added dropwise and the mixture stirred at 0° C. for 45 min, after which 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.53 mL, 2.60 mmol) was added and the mixture allowed to warm to room temperature over 1 h.The mixture was quenched with 50percent sat aqueous NH4Cl and extracted with EtOAc.The organic extract was washed with sat.NaCl, dried over MgSO4 and the solution was concentrated.The residue was purified by SiO2 chromatography (20-50percent EtOAc/heptane) to afford 405 mg (83percent) of 1-cyclopropyl-1H-pyrazole-4-boronic acid pinacol ester as a colorless viscous oil.
To a solution of thieno[3,2-b]thiophene (1 .5 g, 10.70 mmol) in THF (25.5 mL) at -78 C under N 2 is added dropwise a solution of BuLi in hexanes (8.988 mL of 2.5 M, 22.47 mmol), stirred for 20 min, cooling bath is replaced with ice bath and stirred for 50 min. The resultant thick suspension is quenched with 2- isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (4.181 g, 4.584 mL, 22.47 mmol). The reaction mixture is kept for overnight and then quenched with saturated aq. NH4Cl solution. After extraction with CH2Cl2 (2 x 100 mL), the combined extracts are washed with brine and dried (Na2S04). Organic solution is diluted with -20 mL of ethyl acetate, concentrated slowly on rotary evaporator until CH2Cl2 is removed. The resultant white fine crystals are collected by filtration. The solid is washed with heptanes and dried under high vacuum to afford 4,4,5,5-tetramethyl-2-[5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)thieno[3,2-b]thiophen-2-yl]-1 ,3,2-dioxaborolane (2.57 g, 6.554 mmol, 61.25%) as half-white solid. 1H NMR (400 MHz, CDCl3) delta 7.75 (s, 2H), 1.343 (s, 12H).
Example 1 , 2, 5-Bis(4,4, 5, 5-tetramethyl- 1 , 3, 2-dioxaborolan-2-yl)thieno[ 3, 2- 6]thiophene (Compound 52)To a solution of thieno[3,2-b]thiophene (3.0 g, 21.39 mmol) in tetrahydrofuran (50 mL) at -78C under N2 was added n-butyl lithium (17.97 mL of 2.5 M in hexanes, 44.92 mmol). Let stir for 30 minutes at -78 C, then warmed to 0C for 1 hour. Cooled reaction to -78 C and added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (8.358 g, 9.164 mL, 44.92 mmol). Let warm to room temperature overnight. Added saturated ammonium chloride and extracted with ethyl acetate (2x). Combined organic extracts and washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was then triturated with hexanes and filtered. 5.996 g 1H NMR (300 MHz, DMSO) delta 7.84 (s, 2H), 1.31 (s, 24H)
To a 20L four-neck bottle, 4-bromo-(tert-butyl)pyrazole (1.15kg, 5.66mol) and THF (9.2L) were added, then the mixture was cooled to between -78°C and -85°C and treated with nBuLi (6.23mol) dropwise at that temperature. After addition the solution was stirred at the same temperature for 1 h and /sopropyl pinacol borate (1.47kg, 7.92mol) was added dropwise. The reaction was complete after stirring for ~3h (starting material <1.0percenta/a by GC) then water (2.3L) was added to quench the reaction; and the pH adjusted to 8-9 by addition of 3.45kg 1 M HCI. The aqueous phase was extracted with TBME (3.45L x 2), and the combined organic phase washed with 5percent NaCI (3.45L x 2) and water (3.45L) in sequence. The organic phase was evaporated to give the crude product. After subsequent recrystallization from heptanes the pure product was obtained as a white solid (GC purity 99.7percenta/a) in a 63.5percentth overall yield. (Two 20L reactions were run, then combined in the heptane recrystallization).
63.5%
Stage d) Preparation of 1-(1,1-Dimethylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Intermediate 11) To a 20 L four-neck bottle, 4-bromo-(tert-butyl)pyrazole (1.15 kg, 5.66 mol) and THF (9.2 L) were added, then the mixture was cooled to between -78° C. and -85° C. and treated with nBuLi (6.23 mol) dropwise at that temperature. After addition the solution was stirred at the same temperature for 1 h and isopropyl pinacol borate (1.47 kg, 7.92 mol) was added dropwise. The reaction was complete after stirring for ?3 h (starting material<1.0percent a/a by GC) then water (2.3 L) was added to quench the reaction; and the pH adjusted to 8-9 by addition of 3.45 kg 1M HCl. The aqueous phase was extracted with TBME (3.45 L*2), and the combined organic phase washed with 5percent NaCl (3.45 L*2) and water (3.45 L) in sequence. The organic phase was evaporated to give the crude product. After subsequent recrystallization from heptanes the pure product was obtained as a white solid (GC purity 99.7percent a/a) in a 63.5percent th overall yield. (Two 20 L reactions were run, then combined in the heptane recrystallization).
44.26 g
Synthesis of 1 -tert-Butyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazole 4.19To a stirred mixture of 50 g of 4-bromo-1 -tert-butyl-pyrazole 3J. in 230 mL THF was added dropwise 100 mL 2.5M N-butyllithium solution in hexane under argon atmosphere below - 60 °C, then the mixture was stirred at this temperature for 5 min, before 52 mL 2-isopropoxy- 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane were added dropwise below -60 °C. The reaction mixture was allowed to reach ambient temperature. The mixture was cooled with an ice bath and diluted with aqueous phosphate buffer solution and water and neutralized with 2M aqueous hydrochloric acid. The organic solvent was removed by destination and the residue was extracted with DCM. The combined organic extracts were washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield 44.26 g of 1 -tert-butyl-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazole as solid.Analysis: HPLC-MS: Rt = 0.904 min (method F), M+H = 251
To a stirred mixture of 4-bromo-1-tert-butyl-pyrazole 3.1 (50 g) in 230 mL THF was added dropwise 2.5M N-butyllithium (100 mL, hexane) under argon atmosphere below -60 00, then the mixture was stirred at this temperature for 5 mm, before 2-lsopropoxy-4,4,5,5- tetramethyl-1 ,3,2-dioxaborolane (52 mL) were added dropwise below -60 00 The reaction mixture was allowed to reach ambient temperature. The mixture was cooled with an ice bath and diluted with aqueous phosphate buffer and water and neutralized with 2M aqueous hydrochloric acid. The organic solvent was removed by destillation and the residue was extracted with DCM. The combined organic extracts were washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield 1-tert-butyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazole (44.26 g) as solid.Analysis: HPLC-MS: R1 = 0.904 mm (method F), M+H = 251
Synthesis of 2-(2,6-difluoro-4-methylphenyl)-4,4,5,5-tetramethyl-l ,3,2-dioxaboroane[00181] To a solution of 1 ,3-difluoro-5-methylbenzene (1.Oeq) in dry THF(0.2M) under an atmosphere of N2 at -78C was added n-butyllithium (leq, 1.6M in hexanes) slowly keeping the internal temperature below -65C. The reaction was stirred for 2 hrs at -78C, followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (1.15eq). The reaction was allowed to warm to room temperature. Upon completion, the reaction was quenched with NaHC03 (sat.) and extracted with EtOAc. The organics were washed with brine, dried over Na2S04, filtered and concentrated to yield 2-(2,6-difluoro-4-methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaboroane as a white solid in 92%. 1H NMR (400 MHz, <cdcl3>) delta ppm 6.67 (dd, J=9.39, 0.78 Hz, 2 H), 2.34 (s, 3 H), 1.38 (s, 12 H).
92%
To a solution of <strong>[117358-51-7]1,3-difluoro-5-methylbenzene</strong> (1.0 eq) in dry THF (0.2M) under an atmosphere of N2 at -78 C. was added n-butyllithium (1 eq, 1.6M in hexanes) slowly keeping the internal temperature below -65 C. The reaction was stirred for 2 hrs at -78 C., followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.15 eq). The reaction was allowed to warm to room temperature. Upon completion, the reaction was quenched with NaHCO3(sat.) and extracted with EtOAc. The organics were washed with brine, dried over Na2SO4, filtered and concentrated to yield 2-(2,6-difluoro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaboroane as a white solid in 92%. 1H NMR (400 MHz, <cdcl3>) delta ppm 6.67 (dd, J=9.39, 0.78 Hz, 2H), 2.34 (s, 3H), 1.38 (s, 12H).
92%
To a solution of <strong>[117358-51-7]1,3-difluoro-5-methylbenzene</strong> (1.0 eq) in dry THF (0.2M) under an atmosphere of N2 at -78 C. was added n-butyllithium (1 eq, 1.6M in hexanes) slowly keeping the internal temperature below -65 C. The reaction was stirred for 2 hrs at -78 C., followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.15 eq). The reaction was allowed to warm to room temperature. Upon completion, the reaction was quenched with NaHCO3 (sat.) and extracted with EtOAc. The organics were washed with brine, dried over Na2SO4, filtered and concentrated to yield a 2-(2,6-difluoro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaboroane as a white solid in 92%. 1H NMR (400 MHz, <cdcl3>) delta ppm 6.67 (dd, J=9.39, 0.78 Hz, 2H), 2.34 (s, 3H), 1.38 (s, 12H).
92%
Method 3 Synthesis of 2-(2,6-difluoro-4-methylphenyl)-4,4,5,5-tetramethyl-l ,3,2- dioxaboroane To a solution of l,3-difluoro-5-methylbenzene (l .Oeq) in dry THF (0.2M) under an atmosphere of N2 at -78C was added n-butyllithium (leq, 1.6M in hexanes) slowly keeping the internal temperature below -65C. The reaction was stirred for 2 hrs at - 78C, followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.15eq). The reaction was allowed to warm to room temperature. Upon completion, the reaction was quenched with NaHC03 (sat.) and extracted with EtOAc. The organics were washed with brine, dried over Na2S04, filtered and concentrated to yield 2-(2,6-difluoro- 4-methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaboroane as a white solid in 92%. 1H NMR (400 MHz, <cdcl3>) delta ppm 6.67 (dd, J=9.39, 0.78 Hz, 2 H), 2.34 (s, 3 H), 1.38 (s, 12 H).
92%
Method 3 Synthesis of 2-(2,6-difluoro-4-methylphenyl)-4,4,5,5-tetramethyl-l ,3,2- dioxaboroane To a solution of l,3-difluoro-5-methylbenzene (l .Oeq) in dry THF (0.2M) under an atmosphere of N2 at -78C was added n-butyllithium (leq, 1.6M_ in hexanes) slowly keeping the internal temperature below -65C. The reaction was stirred for 2 hrs at - 78C, followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.15eq). The reaction was allowed to warm to room temperature. Upon completion, the reaction was quenched with NaHC03 (sat.) and extracted with EtOAc. The organics were washed with brine, dried over Na2S04, filtered and concentrated to yield 2-(2,6-difluoro- 4-methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaboroane as a white solid in 92%. 1H NMR (400 MHz, <cdcl3>) delta ppm 6.67 (dd, J=9.39, 0.78 Hz, 2 H), 2.34 (s, 3 H), 1.38 (s, 12 H).
92%
To a solution of l,3-difluoro-5-methylbenzene (1.0 eq) in dry THF (0.2M) under an atmosphere of N2 at -78C was added n-butyllithium (leq, 1.6M in hexanes) slowly keeping the internal temperature below -65C. The reaction was stirred for 2 hrs at - 78C, followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.15eq). The reaction was allowed to warm to room temperature. Upon completion, the reaction was quenched with NaHC03 (sat.) and extracted with EtOAc. The organics were washed with brine, dried over Na2S04, filtered and concentrated to yield a 2-(2,6- difluoro-4-methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaboroane as a white solid in 92%. 1H NMR (400 MHz, <cdcl3>) delta ppm 6.67 (dd, J=9.39, 0.78 Hz, 2 H), 2.34 (s, 3 H), 1.38 (s, 12 H).
92%
Method 2 Synthesis of 2-(2,6-difluoro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of l,3-difluoro-5-methylbenzene (l .Oeq) in dry THF (0.2M) under an atmosphere of N2 at -78C was added n-butyllithium (leq, 1.6M in hexanes) slowly keeping the internal temperature below -65C. The reaction was stirred for 2 hrs at - 78C, followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.15eq). The reaction was allowed to warm to room temperature. Upon completion, the reaction was quenched with NaHC03 (sat.) and extracted with EtOAc. The organics were washed with brine, dried over Na2S04, filtered and concentrated to yield 2-(2,6-difluoro- 4-methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaboroane as a white solid in 92%. 1H NMR (400 MHz, <cdcl3>) delta ppm 6.67 (dd, J=9.39, 0.78 Hz, 2 H), 2.34 (s, 3 H), 1.38 (s, 12 H).
(3'aS)-4,4,5,5-tetramethyl-3',3'-diphenylhexahydrospiro[[1,3,2]dioxaborolane-2,1'-pyrrolo[1,2-c][1,3,2]oxazaborol]-7'-ium-1'-uide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
In toluene;Inert atmosphere; Reflux;
General procedure: To a solution of the corresponding diol (5.05 mmol) in 15 mL of dry toluene under a nitrogen flow was added via syringe triisopropyl borate (1.17 mL, 5.1 mmol). The reaction mixture was gently heated to reflux until an homogeneous colorless solution was observed. A solution of (S)-(-)-alpha,alpha-diphenyl-2-pyrrolidinemethanol (1.267 g, 5.0 mmol) in dry toluene (10 mL) was added to the warm stirring solution. The reaction mixture was then gently heated to reflux until a homogeneous colorless solution was formed. After cooling, the resulting solution with a white solid was concentrated in the rotovaporator by heating at 80 C/20 mm Hg for about 1 h. The white crystalline solid was then dried overnight using high vacuum (0.5 mm Hg). Generally, the desired compounds were obtained pure in quantitative yield. The impure spiroborates were further recrystallized in toluene.
In tetrahydrofuran; at 20℃; for 2h;Inert atmosphere;
General procedure: Preparation of 4,4,6-trimethyl-2-phenyl-[1,3,2]dioxaborinane (26): To a solution of 2-isopropoxy-4,4,6-trimethyl-[1,3,2] dioxaborinane (10) (5.58 g, 30 mmol, 1.5 equiv) in dry THF (15 ml) under an argon atmosphere a solution of phenylmagnesium bromide (1 M in THF, 20 mmol) was added dropwise via addition funnel at room temperature. The reaction mixture was allowed to stir at ambient temperature for 2 h. The reaction flask was then cooled to 0 C and an aqueous solution of hydrochloric acid (1 N, 30 ml) was added dropwise. After the addition was completed the reaction mixture was allowed to warm to ambient temperature for 1 h. The organic layer was then separated from water layer. The latter aqueous phase was extracted with ethyl acetate (3 × 30 ml). The combined organic layers were dried using magnesium sulfate. The volatiles were removed under reduced pressure and the residue was purified using flash chromatography on silica gel (5% ethyl acetate:hexanes) to obtain the title compound in 98% yield.
Methyl-6-(tetramethyl-l ,3,2-dioxaborolan-2-yl)-7H-indoleTo a solution of 6-bromo-2-methyl-7H-indole (2.0 g, 9.52 mmol) in dry tetrahydrofuran (100 mL) was added sodium hydride (381 mg, 9.53 mmol ) with ice-cooling. After stirring for about 30 min , a solution of n-BuLi (15 mL, 2.5 M solution in hexane) was added dropwise with stirring at -78°C under nitrogen. It was warmed slowly to -40°C during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below -78°C followed by dropwise addition of 4,4,5, 5-tetramethyl-2-(propan-2-yloxy)- 1 ,3,2- dioxaborolane (3.54 g, 19.03 mmol). After warming to room temperature, the mixture was quenched with NH4CI (aq) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the residue, which was purified by silica gel columnchromatography (2percent ethyl acetate in petroleum ether) to afford 2-methyl-6-(tetramethyl- l,3,2-dioxaborolan-2-yl)-7H-indole (1.2 g, 49percent).'H-NMR (300 MHz, CDCI3): delta 8.06 (s, 1Eta), 7.91(s, 1Eta), 7.58 - 7.60 (t, 7 = 7.5 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 6.24 (s, 1H), 2.46 (s, 3H), 1.39 (s, 12H)
38%
Step 2. 2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole To a solution of <strong>[1075-34-9]5-bromo-2-methyl-1H-indole</strong> (3.0 g, 14.35 mmol) in dry tetrahydrofuran (20 ml) was added sodium hydride (900 mg, 22.5 mmol) with ice-cooling. After stifling for about 30 min, a solution of t-BuLi (27.5 ml, 1.3 M solution in hexane) was added dropwise with stifling at -78° C. under an inert atmosphere of nitrogen. The reaction mixture was warmed slowly to -40° C. over 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below -78° C., followed by the addition of 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (5.3 g, 28.49 mmol) dropwise. After warming to room temperature, the mixture was quenched with NH4Cl solution (100 ml) and extracted with ethyl acetate (3.x.100 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the residue, which was purified by a silica gel column (2percent ethyl acetate in petroleum ether) to afford 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (1.4 g, 38percent). 1H NMR (300 MHz, CDCl3): delta 8.06 (s, 1H), 7.91 (s, 1H), 7.58-7.60 (t, J=7.5 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 6.24 (s, 1H), 2.46 (s, 3H), 1.39 (s, 12H).
With C15H14N4; caesium carbonate; triphenylphosphine; silver(I) chloride; In N,N-dimethyl-formamide; at 50℃; for 24h;Inert atmosphere; Schlenk technique;
General procedure: A mixture of 1 (0.5 mmol), B(OiPr)pin (0.75 mmol), PPh3+L1+AgCl (1 mol %), and Cs2CO3 (1.1 mmol) in DMF (5 mL) was stirred at 50C under Ar atmosphere for 24 h. The reaction mixture was acidified by 1 M solution of hydrochloric acid in an ice water bath, and the aqueous phase was extracted with ethyl acetate (three times). The combined organic layer was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to give the corresponding products.
65%
To a solution of trimethylsilyl acetylene (200 g, 2.04 mol, 1 equiv) in diethylether (4 L) at -30 C under argon in a 10 L jacketed vessel was added nBuLi (1.8 mol in hexanes, 1.14 L, 2.04 mol, 1 equiv) by cautious dropwise addition (internal reaction temperature rose to ?-21 C) and the reaction mixture was allowed to stir at this temperature for 1 h prior to warming to 0 C. After 30 min the reaction mixture was cooled to -50 C and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (380 g, 2.04 mol, 1 equiv) was added dropwise and the reaction mixture was stirred overnight. To the white precipitate was added ethereal 2 N HCl (1.33 L, 2.65 mol, 1.3 equiv) and the reaction was warmed to -10 C and stirred for 1.5 h, filtered through Celite, concentrated in vacuo and allowed to recrystallise in the refrigerator, yielding trimethyl((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethynyl)silane 1a as a white crystalline solid (299 g, 65%, obtained by four successive recrystallisations from the mother liquor). Mp 91-93 C; 1H NMR (250 MHz, CDCl3) delta: 0.00 (9H, s), 1.09 (12H, s); 13C NMR (62 MHz, CDCl3) delta: -0.5, 24.6, 84.4, 111.3. All data in accordance with literature.21
51%
To a solution of compound 19 (3 g, 30.5 mmol, 1.0 eq) in ethyl ether (30 mL) was added a solution of n-BuLi (2.5 M in hexane, 12.8 mL, 1.05 eq) dropwise at -78 C over a period of 5 min under a nitrogen atmosphere. The reaction mixture was stirred at -78 C for 1 h, then a solution of 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (5.7 g, 30.5 mmol, 1.0 eq) in TH F (8 mL) was added dropwise. After stirring for 2 h at -78 C, the mixture was poured into cooled sat. aq. NH4CI (100 mL) and extracted with EtOAc (3 x 30 mL). The combined organic fractions were washed with saturated brine (3 x 30 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was dissolved in petroleum ether (30 mL) and cooled to -60 C. The resulting precipitate was collected by filtration and dried under vacuum to afford compound 20 (3.5 g, .15.6 mmol, 51% yield) as white solid: H N R (300 MHz, CDCI3) 60.21 (s, 9H) 1.30 (s, 12H).
To a solution of trimethylsilylacetylene (125 mL, 881 mmol) in THF(1240 mL) at -78C was slowly added «-butyllithium (1.6 M in hexanes, 580 mL, 930 mmol). After 15 minutes, 2-isopropoxy-4,4,5,5-tetramethyl-[l , 3, 2]-dioxaborane (164 g, 881 mmol) was slowly added and the reaction mixture was maintained at -78C. After 2 hours, the reaction mixture was allowed to warm to ambient temperature and stirred for an additional 30 minutes. The reaction mixture was cooled to -30C, and the pH was adjusted to ~3 using anhydrous hydrochloric acid. The reaction mixture was filtered, and the filtrate was distilled (100-1 10C) to give trimethyl[(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)ethynyl]silane. ? NMR (400 MHz, CDC 13) 5 1.28 (s, 12H), 0.19 (s, 9H).
To a stirred solution of trimethylsilylacetylene (5.27 g, 53.76 mmol) in THF (100 mL) at-78C, 2.5 M of n-BuLi in n-hexane (35.3 mL, 53.76 mmol) was added drop wise under nitrogen atmosphere. After 15 mi 2-isopropoxy-4,4,5 , 5-tetramethyl- 1,3 ,2-dioxaborolane (10.0 g, 53.76 mmol) was slowly added and the reaction mixture was stirred at -78C. After 2 h, the reaction mixture was allowed to warm to -30C, and the p11 was adjusted to 3 using anhydrous HC1. Thereaction mixture was filtered, and the filtrate was distilled to give the title product (10.00 g, crude). 1H NMR (400 MHz, DMSO-d6): oe 1.17 (s, 12H), 0.14 (s, 9H).
Step-a Synthesis of trimethyl((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethynyl)silane To a stirred solution of trimethylsilylacetylene (5.27 g, 53.76 mmol) in THF (100 mL) at -78 C., 2.5 M of n-BuLi in n-hexane (35.3 mL, 53.76 mmol) was added drop wise under nitrogen atmosphere. After 15 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.0 g, 53.76 mmol) was slowly added and the reaction mixture was stirred at -78 C. After 2 h, the reaction mixture was allowed to warm to -30 C., and the pH was adjusted to 3 using anhydrous HCl. The reaction mixture was filtered, and the filtrate was distilled to give the title product (10.00 g, crude). 1H NMR (400 MHz, DMSO-d6): delta 1.17 (s, 12H), 0.14 (s, 9H).
4-methoxy-N-(4-methoxyphenyl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzenamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72.6%
2.00 g of solid 3 was dissolved in 50 mL of tetrahydrofuran under the protection of nitrogen, cooled to -78C, and 2.72 mL of 2.4 M n-butyllithium was slowly added to the solution via a syringe and reacted for 1 hour.Then 1.21 g of isopropyl pinacol borate was added dropwise to the reaction solution. After 1 hour of the low-temperature reaction, the temperature was gradually raised to room temperature. After the reaction was completed for 12 hours, 5 mL of water was added to the reaction solution, and the solvent was then evaporated to dryness under reduced pressure. Mixture solution in 80 mL of dichloromethane,Wash the organic layer three times with 50 mL of water. Then, the organic layer was dried over anhydrous magnesium sulfate, filtered to obtain a filtrate, and the filtrate was evaporated to dryness under reduced pressure.The resulting crude product was subjected to column chromatography using a 2:1 volume ratio of petroleum ether and dichloromethane as eluent to give 1.63 g of a white solid4.It is 4,4 -disubstituted triphenylamine borate with a yield of 72.6%.
33%
General procedure: 4-Bromo substituted triphenylamine was dissolved in dry THF under nitrogen atmosphere and it was cooled to -78 C . n-BuLi was added with syringe and kept at -78 C for one hour. 2-Isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane was added dropwise. After addition, the solution was allowed to warm up to room temperature for overnight reaction. After quenching of the reaction with ammonium chloride solution, the water layer was extracted with chloroform and the combined organic layer was dried over MgSO4. After the remove of the solvent under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/dichloromethane 1:1) to afford the product as white solids.
2-(4-Fluoro-3-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
<strong>[393-37-3]4-bromo-1-fluoro-2-(trifluoromethyl)benzene</strong> (2.00 g, 8.2 mmol) was placed in a 250 ml reaction flask, followed by injecting and evacuating nitrogen gas three times. Next, dehydrated THF (50 ml) was added into the reaction flask, followed by slowly adding 3.62 ml n-butyllithium in hexane solution (9.1 mmol) (2.5M, 9.1 mmol) at -78 C. and stirring at the same temperature for 30 minutes. Thereafter, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.85 ml, 9.1 mmol) was added into the reaction flask to obtain a mixture, and the temperature of the mixture was raised to room temperature, followed by stirring at room temperature for 12 hours. Next, water was added to terminate the reaction followed by removing THF using a rotary evaporator. Then, dichloromethane and water were added into the mixture for extraction. The dichloromethane layer was collected and added with magnesium sulfate to remove water therein. After water was removed, the dichloromethane layer was filtrated and the filtrate was collected. Next, the dichloromethane layer was concentrated by means of reduced pressure distillation to obtain a colorless oily liquid (1.95 g, 6.7 mmol, 82% yield).The spectrum analysis for the colorless oily liquid is: 1H NMR (400 MHz, CDCl3, 298K), delta(ppm): 8.03 (d, JHF=7.6 Hz, 1H), 7.98?7.90 (m, 1H), 7.16 (t, JHH=9.2 Hz, 1H), 1.35 (s, 12H).
With n-butyllithium; In tetrahydrofuran; hexane; at -70 - 20℃; for 3h;
To a stirred solution of tert-butyl 4-(4-bromo-lH-pyrazol-1-yl)piperidine-1-carboxylate (25.0g, 0.076 mole) in THF ( 500 ml) at- 70°C was added BuLi 1.6 Min Hexane solution (10 56.75 ml, 0.091 mole) dropwise followed by addition of 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18.52 ml , 0.091 mole) at same temperature. Reaction mixture wasstirred at -70°C for lh then warmed to room temperature and continued stirring for 2h atroom temperature. Reaction mixture was quenched with ammonium chloride solution (25 ml)water (500 ml), and ethyl acetate (750 ml) was added to reaction mixture, followed by15 extraction with ethylacetate (100 ml x 2). The combined organic layer was washed withbrine, concentrated under vacuum to get crude product which was crystallized from nHeptaneto give pure title compound.Yield: 51 percent (14.7g)HPLC Purity: 96.7percent20 MS (m/z): 378 (M + 1) 1HNMR (400 MHz, CDCh) 8: 7.81 (s, lH), 7.75 (s, lH), 4.27 (m, 3H), 2.9 (m, 2H), 2.14 (m,2H), 1.91 (m, 2H), 1.49 (s, 9H), 1.33 (s, 12 H).
Step 1 : l-Cyclopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyridaziiie To a 100 n L flask is added 4-bromo-l-cyclopropylpyrazol (6.57 g, 35.1 mmol) and anhydrous THF (30 niL). The solution is cooled to -78 °C under nitrogen; then n-butyl lithium (15.5 n L, 2.5 M in hexanes, 38.6 mmol) is added dropwise. The reaction mixture is stirred at the temperature for 1 hr, followed by addition of isopropyl boronate (9.17 g, 94.1 mmol) and stirred below -70 °C for 3 hours. The reaction is quenched with water (20 n L) and the resulted mixture is adjusted to pH 8-9 with aqueous hydrochloride solution (1 N). The combined organic phases are concentrated and used in next step without further purification (6.64 g, 81percent yield). (MS: [M+l] 235)
6-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 31 Preparation of 6-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine A 2.5M solution of n-butyllithium (3.6 mL, 9.1 mmol, 1.2 equiv) was added to a stirred solution of diisopropylamine (1.4 mL, 9.9 mmol, 1.3 equiv) in tetrahydrofuran (11 mL) at -78 C. The resulting pale yellow solution was stirred at -78 C. for 15 min, warmed to 0 C. and stirred for 15 min, and then cooled back to -78 C. and stirred for 15 min. A solution of <strong>[20885-12-5]2-chloro-6-fluoropyridine</strong> (1.0 g, 7.6 mmol, 1.0 equiv) in tetrahydrofuran (9 mL) was added via cannula at -78 C. The resulting pale yellow mixture was stirred at -78 C. for 2 h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.3 mL, 11 mmol, 1.5 equiv) was added and the reaction mixture was allowed to slowly warm to 23 C., by allowing the dry ice/acetone bath to melt, and stirred for 20 h. The reaction mixture was diluted with 2M sodium hydroxide (150 mL) and washed with Et2O (3*50 mL). The aqueous layer was adjusted to pH 2, using concentrated HCl, and extracted with dichloromethane (4*50 mL). The combined organic layers were dried (MgSO4), gravity filtered, and concentrated by rotary evaporation to afford the title compound as a colorless oil (1.9 g, 95% crude yield): 1H NMR (300 MHz, CDCl3) delta 8.11 (t, J=8 Hz, 1H), 7.23 (dd, J=8, 2 Hz, 1H), 1.36 (s, 12H).
Example 47 Preparation of 2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 5-Bromo-2-(difluoromethoxy)pyridine (1.0 g, 4.5 mmol) was dissolved in dry THF (10 mL), cooled to 0 C., and treated in portions with isopropylmagnesium lithium chloride complex (1.3 M; 3.3 mL, 4.3 mmol). The mixture was allowed to warm to 20 C., stirred for 2 h, treated with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (910 mul, 4.3 mmol) and stirred for 70 min more. The mixture was quenched with saturated ammonium chloride (NH4Cl; 5 mL) and partitioned between ethyl acetate and water. The organic phase was washed with saturated NaCl, dried (Na2SO4), and evaporated to provide the title compound as a brown oil that was used without further purification (1.1 g, 86%): 1H NMR (400 MHz, CDCl3) 8.54 (dd, J=1.9, 0.6 Hz, 1H), 8.07 (dd, J=8.2, 1.9 Hz, 1H), 7.54 (t, J=73.0 Hz, 2H), 6.87 (dd, J=8.2, 0.8 Hz, 1H), 1.34 (s, 13H); 19F NMR (376 MHz, CDCl3) delta -89.22.
To a 100-mL flame-dried two necked flask was added M1 (3.0g, 11.6mmol) and freshly distilled THF (80mL). The resulting solution was cooled at-78C and 8.7mL n-butyllithium (13.9mmol, 1.6M in hexane) was added over 10min under a nitrogen atmosphere. The mixture was stirred at-78C for 1h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.6g, 13.9mmol) was added rapidly to the solution, and the resulting mixture was slowly warmed to room temperature for 24h. The mixture was poured into 50mL water and extracted with CHCl3 (300mL). The combined organic layers were washed with brine and dried over anhydrous MgSO4. The solvent was removed by rotary evaporation, and the residue purified by column chromatography on silica gel (ethylacetate:dichloromethane as eluent) to obtain the product as a light-yellow oil (1.6g, yield: 45.0%). 1H NMR (400MHz; CDCl3; Me4Si): delta=7.77 (d, 2H, J=8.8Hz), 6.90 (d, 2H, J=8.8Hz), 3.94 (t, 2H, J=6.4Hz), 2.46 (t, 2H, J=6.8Hz), 2.26 (s, 6H), 1.88 (m, 2H, J=6.8Hz) 1.25 (s, 12H). 13C NMR (100MHz; CDCl3; Me4Si): 161.57; 136.73; 113.41; 83.13; 74.40; 66.02; 54.09; 45.42; 27.43; 25.00. Anal. Calcd for: C17H28BNO3: C, 66.90; H, 9.25; N, 4.59. Found: C, 66.73; H, 9.23; N, 4.63. IR (KBr, cm-1): 2981, 2936, 2816, 2716, 1566, 1463, 1281, 1245.
45%
Dissolved in dry 30 Compound A 3g in a nitrogen atmosphere, THF, -78 C after the temperature was reduced to 2.2equivalent of n-butyllithium(nBuLi,Aldrich Co.) was slowly added. The reaction mixture was stirred at -78 C for 2 hours andthen, 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,Aldrich) was added, and the mixture was stirred while the temperature gradually to room temperature after stirring at -78 Cfor 2 hours, the height for 24 hours. After the reaction was completed to extract the organic material with chloroform, to giveafter washing the column with water to obtain the compound B, 1.6 g (yield 45.0%).
(4-cyano-2,5-difluorophenyl)boronic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: To a solution of the appropriate bromophenyl substrate (1.0 eq) in dry THF (10 vol) at -40 C. was added isopropyl magnesium chloride lithium chloride complex solution (1.3 M solution in THF, 1.05 eq) dropwise. After addition was complete, the reaction mixture was stirred at -40 C. for 45 min then slowly warmed to 0 C. Isopropoxyboronic acid pinacol ester (1.07 eq) was added dropwise and stirring was continued at 0 C. for 2 h. The reaction mixture was warmed to room temperature, quenched with aqueous saturated ammonium chloride solution, and extracted with ethyl acetate. The organic extract was washed with saturated brine solution, dried (Na2SO4), filtered, and evaporated under reduced pressure. The boronic acids thus obtained were used in the next step without purification.1H NMR (300 MHz, CDCl3): delta 5.15 (br s, 2H), 7.29-7.36 (m, 1H), 7.69 (dd, J 4.80, 8.28 Hz, 1H)
0124-2 A 1.6 mol/L n-butyllithium-hexane solution (1.2 mL) was added to a solution of 4-bromo-1-methyl-3-phenyl-1H-pyrazole (300 mg) in tetrahydrofuran (6 mL) at -80 C., followed by stirring at the same temperature for 30 minutes, and 2-isopropyloxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (470 mg) was added thereto at the same temperature, followed by stirring while heating to room temperature over a period of 4 hours. A saturated ammonium chloride aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 1-methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (184 mg). MS m/z (M+H): 285.
8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
The synthesis was performed in a dry nitrogen atmosphereusing Schlenk techniques. In a 250 mL roundbottomflask fitted with magnetic stirbar, <strong>[1006-47-9]8-iodoquinoline</strong> (5.0 g,20 mmol) was dissolved in 50 mL THF and cooled to -78 C.A solution of n-butyllithium (1.6 m in hexanes, 13 mL, 21mmol) was added, and the mixture was kept at -78 Cfor 1 h. A solution of pinacolisopropoxyborate (3.65 g,19.6 mmol) in 20 mL THF was added with a cannula, andthe flask was allowed to slowly reach room temperaturein the bath over the course of ~16 h. The mixture was thenrecooled to -78 C, and BF3·OEt2 (2.5 mL, 20 mmol) wasadded via cannula. The mixture was stirred and allowedto warm to room temperature, and then passed through afilter frit. A dull yellow ochre powder was collected. Thepowder was washed with CH2Cl2 and a light yellow powderremained. Yield 4.41 g (88%). - 1H NMR (200.1 MHz,CD3CN): deltaH = 1.42 (12H, s, pinacol CH3), 7.60 (1H, dd, J = 8.4and 4.4 Hz), 7.71 (1H, dd, J = 8.2 and 7.2 Hz), 8.15 (1H, dd,J = 8.2 and 1.6 Hz), 8.35, (1H, dd, J = 7.0 and 1.6 Hz), 8.48(1H, dd, J = 8.1 and 1.9 Hz), 8.90 (1H, dd, J = 4.4 and 1.8 Hz).- 13C NMR (50.3 MHz, CD3CN): deltaC = 24.8 (CH3), 86.5 (OC),122.5, 127.7, 129.2, 133.7, 140.3, 141.2, 151.5.
n-BuLi (2.5 M, 40 mL, 0.016 mol) was added to a solution of 1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole (2.0 g, 0.013 mol) in anhydrous THF (10 mL) at -78 under nitrogen atmosphere. The resulting mixture was stirred at -78 for 30 min before 2-isopropoxy-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (2.7 g, 0.014 mol) was added dropwise. After addition, the reaction was held at -78 for 3 h. Excess base was quenched with aqueous HCl solution (1 M, 10 mL) and the mixture was warmed to 25 , then extracted with EtOAc (15 mL ×3) . The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (PE:EtOAc 5:1) to afford the title compound. MS: m/z 279.1 (M + 1) .1H NMR (400 MHz, DMSO-d6) delta 7.51 (s, 1H) , 6.64 (s, 1H) , 5.70 (d, J 8.5 Hz, 1H) , 3.89 (d, J 11.3 Hz, 1H) , 3.48 -3.61 (m, 1H) , 2.20 -2.33 (m, 1H) , 1.83-2.03 (m, 2H) , 1.43-1.69 (m, 3H) , 1.28 (d, J 4.8 Hz, 12H) .
A solution of <strong>[106418-67-1]1-bromo-4-decylbenzene</strong> (11.9 g, 40 mmol) in dehydrated tetrahydrofuran (200 mL) was cooled to -70 C. and a 1.6 M hexane solution of n-BuLi (32.5 mL, 52 mmol) was added dropwise. After stirring for 1 hour, pinacol isopropoxyboronic acid (9.7 g, 52 mmol) was added and the mixture was gradually warmed to room temperature with stirring. Water and toluene were added, the organic layer was separated, sodium sulfate was added and dried, and the solvent was distilled off with an evaporator. The resulting oil was purified on a silica gel column using hexane / ethyl acetate (10/1) as a developing solvent,4-decylphenylboronic acid pinacol ester was obtained as a colorless oil (yield: 9.8 g, yield 71.1%).
It was added in dry nitrogen and continued through reactor 4-n-decyl dibromobenzene 4.41g (14.84mmol)And dried tetrahydrofuran 100ml, the solution was cooled to -78 , was added n-butyllithium in n-hexane21.32ml (35.2mmol), allowed to warm to room temperature and stirred for 2 hours. Mixture was recooled to -78 , was addedIsopropyl pinacolato boronate 5ml (37.2mmol), was slowly warmed to room temperature and stirred for 12 hours. With BThe reaction mixture was extracted with ether, the organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, and the solvent by rotary evaporation,To give a pale yellow oil by column chromatography (petroleum ether) to give the crude product as a colorless oily liquid 10 (4.24g),Yield 83%.
With n-butyllithium; In tetrahydrofuran; hexane; at -78 - 20℃; for 26h;
N-BuLi 10 mLs (25.0 mmol, 2.5M in Hexane) the slowly are dipped in -78 after 2- bromo -5-chloroanisol 5.2 g (23.6 mmol) is melted in the THF 100ml. In the same temperature, 2- isopropoxy -4,4,5,5- tetramethyl -1,3,2- dioxaborolane(2-isoproxy-4,4,5,5, -tetramethyl-1,3,2-dioxaborolane)9.3 mL (50.0 mmol) was dipped as the slowly for 1 hour after doing the mixingand after the reacting solution was stirred in -78 for 1 hour the additionallywas stirred in the room temperature for 24 hours. After reaction was concluded 10%HCl aqueous solution 50 mL and H2O 50 mL were added and H2O50 mL extracted in the diethylether 80 mL. The residue which was dry to themagnesium sulfate and disappeared the solvent and was the obtained organiclayer obtained was refined to the silicagel column chromatography afterdividing and the intermediate 2-1 5.83 g (yield 92 %) was obtained.
92%
With n-butyllithium; In tetrahydrofuran; hexane; at -78 - 20℃; for 24h;
<strong>[174913-09-8]2-bromo-5-chloro-anisole</strong>, 5.2 g (23.6 mmol) was dissolved in 100ml of THF and then at -78 n-BuLi 10 mL (25.0 mmol, 2.5M in Hexane) is added dropwise slowly. After stirring for 1 hour at the same temperature, then, 2-iso-proxy -4,4,5,5- tetramethyl-dioxa -1,3,2- beam is a (2-isoproxy-4,4,5,5- tetramethyl-1,3,2-dioxaborolane) was added dropwise 9.3 mL (50.0 mmol) slowly, stirring the reaction solution for 1 hour at -78 , then stirred at room temperature for 24 hours. After the reaction was completed, a 10% HCl solution 50 mL and 50 mL H2O was added and extracted three times with 80 mL diethyl ether. The combined organic layers were dried over magnesium sulfate and purified by separating the residue obtained by evaporation of the solvent by silica chromatography to give the intermediate 9-1 jelgwan 5.83 g (92% yield). The resulting compound was confirmed by LC-MS.
92%
<strong>[174913-09-8]2-bromo-5-chloro-anisole</strong>, 5.2 g (23.6 mmol) was dissolved in 100ml of THF and then at -78 n-BuLi 10 mL (25.0 mmol, 2.5M in Hexane) was added dropwise slowly. After stirring for 1 hour at the same temperature, then 2-isopropoxy -4,4,5,5- tetramethyl-dioxa -1,3,2- beam is a (2-isoproxy-4,4,5,5 , -tetramethyl-1,3,2-dioxaborolane) was added dropwise 9.3 mL (50.0 mmol) slowly, stirring the reaction solution for 1 hour at -78 , then stirred at room temperature for 24 hours. After the reaction was completed, a 10% HCl solution 50 mL and 50 mL H2O was added and extracted three times with 80 mL diethyl ether. Dry the organic layer obtained therefrom by magnesium sulfate, and evaporation of the solvents the obtained residue by silicaBy separation and purification by chromatography to give the intermediate 5-1 5.83 gelgwan g chromatography (92% yield).
90%
6.4 g (30 mmol) of <strong>[174913-09-8]2-bromo-5-chloroanisol</strong> was dissolved in 150 ml of THF, and then, at a temperature of -78 C., 12 ml of n-BuLi (30.0 mmol, 2.5 M in Hexane) was slowly dropped thereto. At the same temperature, the resultant solution was stirred for 1 hour, and then, 6.7 ml (36.0 mmol) of 2-isoproxy-4,4,5,5,-tetramethyl-1,3,2-dioxaborolane was slowly added thereto. The reaction solution was stirred at a temperature of -78 C. for 1 hour, and then, additionally stirred at room temperature for 24 hours. After the reaction was stopped, 50 ml of 10% HCl aqueous solution and 50 ml of H2O were added thereto, and an extraction process was performed thereon three times by using 80 ml of diethylether. An organic layer collected therefrom was dried by using magnesium sulfate and the residual obtained by evaporating a solvent therefrom was separation-purified by silica gel chromatography to obtain 7.25 g (yield: 90%) of Intermediate A-1.
55%
22.1 g (100 mmol) of <strong>[174913-09-8]<strong>[174913-09-8]2-bromo-5-chloroanisol</strong>e</strong> was dissolved in 500 mL of anhydrous tetrahydrofuran (THF) in a nitrogen atmosphere, and then cooled down to -78 C. After 1 hour, 100 mL of a 2.5M n-butyllithium solution was slowly dropwise added thereto. After 1 hour, 20.52 g (120 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was dropwise added to the resultant solution, followed by increasing the temperature of the solution to room temperature, and stirring for about 24 hours. The resulting product was extracted three times with 100 mL of water and 10 mL of ethyl ether. An organic layer was collected and dried using (utilizing) magnesium sulfate and evaporating the solvent. The resulting residue was separated and purified using (utilizing) silica gel column chromatography to obtain 14.76 g (55 mmol) of Intermediate A-1 (Yield: 55%).
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 -5 C, dropwise N-Boc-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 isopropoxy boric acid pinacone ester (16.4g, 88mmol), subsequently maintain the reaction at room temperature overnight. Adding 10% hydrochloric acid aqueous solution quenching reaction, adjusting PH= 4-5, by adding 160 ml ethyl acetate, saturated salt water an organic layer, the organic layer after evaporation to dryness, add ethanol/heptane 5:1 obtained after pulping 18.9g N-Boc-1 needle-like white crystals, 2, 5, 6-tetrahydro-pyridine-4-boronic acid frequency that alcohol ester, GC: 99.6%, yield: 61%.
Synthesis of 4,4,5,5-tetramethyl-2-(3-octylthiophen-2-yl)-1 ,3,2-dioxaborolane having formula (2) (0144) In a 250 ml three-neck flask equipped with a dropping funnel, an inert atmosphere was created through nitrogen (N2) insufflation. Subsequently, 5.0 g (18.16 mmol) of 2-bromo- 3-octylthiophene having formula (1) and 90 ml of tetrahydrofuran (THF) anhydrous were added. The solution obtained was cooled to -78C and 8.0 ml of n-butyl-lithium (LiBu) (2.5 M in hexane) were added slowly, over 15 minutes. The reaction mixture obtained was kept, under stirring, at -78C, for a further 2 hours, at the end of which 6.76 g (36.32 mmol) of 2-i'so-propoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane were added, and subsequently heated, under stirring, slowly, over 1 hour, to ambient temperature (25C). After 16 hours, under stirring, at ambient temperature (25C), the reaction was stopped by adding 1 10 ml of a saturated aqueous solution of sodium bicarbonate (NaHC03) and the residual solvent was removed through distillation at reduced pressure. The residue obtained having pH ~ 1 1 , was brought to pH 8 through the addition of 13 ml of a 10% hydrochloric acid (HCI) solution, and then extracted with ethyl acetate (3 x 150 ml). The global organic phase (obtained by joining the three organic phases obtained from the extraction) was washed with a saturated aqueous solution of sodium chloride (NaCI) (3 x 100 ml) and subsequently anhydrified on sodium sulfate anhydrous for 3 hours. The residual solvent was then removed through distillation at reduced pressure, obtaining a dark yellow oil, which was dissolved in 100 ml of ethyl acetate and filtered on Celite 545: the residual solvent was removed again at reduced pressure obtaining a light yellow oil. Said light yellow oil was purified through chromatography on a silica gel column using a hexane/ethyl ether mixture (39/1 v/v) as eluent obtaining 3.68 g (yield 64%) of 4,4,5,5- tetramethyl-2-(3-octylthiophen-2-yl)-1 ,3,2-dioxaborolane having formula (2), as a colorless oil, which was characterized through 1 H-NMR (400 MHz, CDCI3) obtaining the following spectrum: delta 7.48 (d, J? 5 Hz, 1 H), 7.01 (d, J? 5 Hz, 1 H), 2.88 (t, J= 7.5 Hz, 2H), 1.65-1.10 (m, 24H), 0,88 (t, J= 7.5 Hz, 3H) ppm; and through 13C-NMR (100 MHz, CDCI3) obtaining the following spectrum: delta 154.7, 131.2, 130.3, 83.5, 31.9, 31.8, 30.1 , 29.4, 29.3 (double signal), 24.8, 22.7, 14.1 ppm.
14.83 g
The compound (1-f)14. 2g dissolved in tetrahydrofuran (wako pure chemical industries (strain) made) 200 ml in, -80 C in cooling. N -1. 6M (wako pure chemical industries (strain) made) Phenylbicyclohexane soln. 35 ml is added, -heated to 50 C, cooled to -80 C again. 2-isopropoxydiphenyl -4, 4, 5, 5-tetramethyl -1, 3, 2-dioxaborolane (wako pure chemical industries (strain) made) 13. 6 ml is added, and heated to room temperature, the stirring 4 hours in a nitrogen atmosphere. A solution obtained by adding 200 ml and ethyl acetate 200 ml 1N aqueous ammonium chloride, fractionating the organic layer, after washing with 200 ml water, dried with magnesium sulfate. The resultant solution to column chromatography (filler: silica gel, eluent: Phenylbicyclohexane/dichlomethane) is purified by compd. (1-g)14. 83g is obtained.
3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.26 g
To a solution of <strong>[59337-89-2]3-chlorothiophene-2-carboxylic acid</strong> (1 .5 g) in tetrahydrofuran (63 mL) cooled to - 75°C, was added a solution of Lithium diisopropylamide in THF/HEXANES (1M, 28 mL) and the solution was stirred at -75°C for 30 minutes. The reaction temperature was allowed to raise to -30°Cand the solution was stirred at this temperature for 20 minutes. The 2-lsopropoxy-4,4,5,5-tetramethyl-,3,2-dioxaborolane (4.1 mL) was added dropwise and the reaction was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 16 hours, then it was poured into a solution of HCI (0.1 M). the mixture was extracted twice between Ethyl acetate and water. The combined organic layers were dried with MgSO4, filtered and evaporated to give a crude residue thatwas absorbed on isolute and purified by chromatography with 0-40percent EtOAc I Methanol (using a combiflash Rf machine) to give 2.26 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) oe ppm 1.29 (s, 12 H) 7.49 (s, 1 H) 13.62 (br. s., 1 H)
Synthesis of Intermediate B-1 4.77 g (23.6 mmol) of 1-bromo-2-nitrobenzene was dissolved in 100 mL of THF, and then, 10 mL of n-BuLi (25.0 mmol, 2.5M in Hexane) was slowly added dropwise thereto at a temperature of -78 C. After 1 hour of stirring the result at the same temperature, 9.3 mL (50 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was slowly added dropwise to the solution, and then, the obtained reaction solution was stirred at a temperature of -78 C. for 1 hour. The resulting solution was additionally stirred for 24 hours at room temperature, and once the reaction was completed, 50 mL of a 10% HCl aqueous solution and 50 mL of H2O were added thereto, followed by three times of extraction using 80 mL of diethylether. An organic layer collected from the resulting solution was dried using magnesium sulfate, and a solvent was removed therefrom by evaporation. The residue obtained therefrom was separation-purified by silica gel column chromatography, thereby completing the preparation of 5.29 g (yield: 90%) of Intermediate B-1. The prepared compound was identified by LC-MS. (C12H16BNO4: M+ 249.07)
10324] 2.59 g (10 mmol) of <strong>[40000-20-2]<strong>[40000-20-2]5-bromo-1,10-phenanthrolin</strong>e</strong> was dissolved in 40 mE of tetrahydrofuran (THF), and 4 mE (2.5 M in hexane) of normal butyllithium was added thereto at a temperature of ?78° C. After one hour, 2.0 mE (10 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxa- borolane was added thereto at the same temperature. The resultant mixture was stirred for 10 hours at room temperature. Then, water was added thereto and the resultant mixture was washed three times by using 30 mE of diethyl ether. The washed diethyl ether layer was dried by using Mg504 and dried under reduced pressure. The product obtained therefrom was separation-purified by silica gel colunm chromatography to obtain 1.84 g (yield of 60percent) of Intermediate I-i. The obtained compound was identified by EC-MS. C18H19BN202: M+1 307.2.
5,6-difluorobenzo[c][1,2,5]thiadiazole-4,7-diboronic acid bis(pinacol) ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36.1%
Compound 2 (9.47 g, 55.00 mmol) and tetrahydrofuran (400 mL) were added using a four-necked flask and argon bubbling was carried out at room temperature for 30 minutes. After cooling to -78 C., lithium diisopropylamide (hexane suspension 10 w%, 225 mL, 137.5 mmol) was added and stirred for 20 minutes to give 2-isopropoxy-4,4,5,5-tetramethyl- 2-dioxaborolane (30.70 g, 165.0 mmol) was added and stirred for 1 hour. Pinacol (26.00 g, 220.0 mmol) was then added and while sulfuric acid was brought to room temperature, sulfuric acid was added dropwise until the pH reached 1 to 2, and the mixture was stirred for 3 hours. After filtering through celite and concentration, methanol / water was placed in the system, the precipitated solid was collected by filtration and recrystallized from hexane to obtain 8.42 g of white solid compound 3. (Yield 36.1%)
Was dissolved in 1-methyl-2-phenyl-1 H-benzo [d] imidazole (4.16 g) and tetrahydrofuran (30 ml) to make it -78 ° C. Thereto was added n-butyllithium (1.6 M, n-hexane solution, 15 ml, Kanto Kagaku) and the mixture was stirred for 30 minutes.The temperature was brought to 0 degree, and the mixture was further stirred for 1 hour.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.85 ml, Tokyo Chemical Industry) was added dropwise thereto,The reaction was allowed to proceed overnight at room temperature.After the reaction,Quench with water,Extracted with chloroform (Wako Pure Chemical Industries, Ltd.)Twice washed with water,The organic layer was collected,The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.) and concentrated.The residue was purified by silica gel column chromatography,4 g of 1-methyl-2- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -1H-benzo [d] imidazole was obtained.
To a solution of i-PrMgCl (2 M in THF, 10 mL, 20 mmol) at 0 °C was added slowly a solution of S9 (2.51 g, 10 mmol) in THF (100mL). The resulting solution was stirred at this temperature under Ar for 1 h. 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane(2.8 g, 15 mmol) was then added slowly to maintain the temperature below 0 °C. After the addition, the reaction was stirred at room temperature for 1.5 h and then quenched slowly by the addition of aqueous ammonium chloride solution (80 mL). To the mixture was added H2O (80 mL), and extraction was done twice with EtOAc(100 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was concentrated to provide S10 as a pale yellow oil. MS (ESI) m/z: 253.2 [M+H]+
methyl 3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
To a solution of methyl 3-hydroxythiophene-2-carboxylate (815 mg, 5.15 mmol) in THF (36 mL) cooled at -78C, lithium diisopropylamide (2.0 M in THF/hexanes, 7.75 mL, 15.5 mmol) is added dropwise. The RM is stirred 10 mm at -78C then a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (2.36 mL, 11.3 mmol) in THF (12 mL) is added dropwise and the RM is kept stirring 15 mm at -78C then is allowed to warm to RT over 2h. HCI 1M (42 mL, 41.2 mmol) is added to the RM and it is extracted with EtOAc (3*4Q mL). The combinedorganic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo yielding the title compound as a brown oil which crytallizes upon standing (1.7 g, quant.). LC-MS B: tR = 0.86 mm; no ionization.
3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
To a solution of lithium diisopropylamide (2.0 M in THF/heptane/ethylbenzene, 9.84 mL, 39.4 mmol) in THF (74 mL) at -78C is added dropwise a solution of <strong>[32431-84-8]3-fluoro-2-thiophenecarboxylic acid</strong> (2.00 g, 13.1 mmol) in THF (37 mL). The RM is stirred for 10 min at -78C then a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.1 mL, 19.7 mmol) in THF (37 mL) is added dropwise, the RM is stirred for 20 min at -78C then it is allowed to warm to RT and stirred for 1 h. HCI 1 N (105 mL, 105 mmol) is added to the RM at 0C, and it is stirred for 5 min. The mixture is extracted with EtOAc (3 times). The combined organic layers are washed with brine, dried over MgS04 and concentrated to dryness. The crude is purified by FC (DCM/MeOH 1 :0 to 9:1) to afford the title compound as a green-yellow solid (2.64 g, 74%). LC-MS A: tR = 0.46 min; no ionization.
In a 1L reaction bottle,Add anhydrous THF,Compound D (50 g, 0.218 mol), under nitrogen,Cool down to -80 C,Add n-butyl lithium (100 mL, 2.5 M) dropwise and stir for 30 min.Then, isopropanol pinacol borate (41.8 g, 0.225 mol) was added dropwise at -80 C, and the temperature was maintained for 30 min.TLC detects raw materials.The reaction was quenched with 500 mL of a saturated aqueous solution of ammonium chloride.Spin dry THF,Add methyl tert-butyl ether MTBE, padded diatomaceous earth,Divide the organic phase,Wash once with saturated aqueous sodium chloride solution,Dry over anhydrous sodium sulfate,concentrate,Then beat with petroleum ether (PE),Filtration of a white solid 46 g. GC 99%,
Intermediate B '(0.8 g, 2.67 mmol) was added to the reaction flask and dissolved in anhydrous THF.Cooled to -78 C with acetone and dry ice.In another reaction flask,2,2,6,6-Tetramethylpiperidine (1.19 mL, 7 mmol) and anhydrous THF were added and stirred,Cooled to -78 C with acetone and dry ice.Next, n-BuLi (1.6M in hexane, 4.53 mL, 7.25 mmol) was added dropwise to a 2,2,6,6-Tetramethylpiperidine solution,The solution was kept at -78 C for 15 minutes.Lithium 2,2,6,6-tetramethylpiperidide (LTMP) was added dropwise to the solution of intermediate B ',Acetonitrile and dry ice were used for 1 hour at -40 C.Again lower the temperature to -78 ,2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.41 mL, 6.92 mmol) was slowly added using a syringe.The reaction temperature was raised to room temperature and stirred for 20 minutes.After the reaction, the reaction mixture was extracted with ether and brine.Dry the organic layer with anhydrous MgSO 4 and evaporate the solvent.Purification with acetonitrile gave a red solid.(0.57 g, 41% yield).
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