* 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.
Argon under the protection,A solution of 1,3-dibromobenzene (4.1 g, 17.5 mmol)And AlCl3 (5.6 g, 42 mmol) were placed in a 50 ml two-necked flask,At room temperature,Acetyl chloride (2.0 ml, 28 mmol) was slowly added dropwise,Dripping finished system slowly heated to 100 , a large number of HCl gas release,High temperature reaction for 1.5 hours.System down to room temperature,Slowly pour into crushed ice and concentrated hydrochloric acid.The organic phase was washed with water, washed with Na2CO3 solution and brine, dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The compound 16a (4.5 g, 93percent yield) was isolated by column chromatography.
Reference：
[1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 6, p. 926 - 939
[2] Patent: CN106316958, 2017, A, . Location in patent: Paragraph 0145; 0146; 0152; 0153
[3] Journal of the Chemical Society, 1949, p. 1133,1136
[4] Roczniki Chemii, 1973, vol. 47, p. 2333 - 2337
15
[ 75-15-0 ]
[ 7446-70-0 ]
[ 108-36-1 ]
[ 75-36-5 ]
[ 33243-33-3 ]
Reference：
[1] Journal of the Chemical Society, 1949, p. 1133,1136
16
[ 108-36-1 ]
[ 52927-23-8 ]
Reference：
[1] Journal of Organic Chemistry, 1991, vol. 56, # 23, p. 6704 - 6708
17
[ 108-36-1 ]
[ 108-95-2 ]
[ 6876-00-2 ]
Yield
Reaction Conditions
Operation in experiment
53%
With caesium carbonate In 1-methyl-pyrrolidin-2-one at 195℃; for 0.333333 h; Microwave
Example 6 1-Bromo-3-phenoxy-benzene (A) A mixture of dibromobenzene (3 g, 12.75 mmol), phenol (1 g, 10.6 mmol), copper(I) oxide (152 mgs, 1 mmol), and cesium carbonate (3.46 g, 10.6 mmol) in 8 mL of NMP is heated at 195° C. for 20 minutes in a microwave. The heterogeneous mixture is filtered through a bed of Celite and the residue is washed with EtOAc (1*20 mL). The filtrate is diluted with 1N NaOH (200 mL) and extracted with EtOAc (3*100 mL). The organics were combined, dried over Na2SO4, filtered and concentrated under reduced pressures to give crude product as a yellow oil which is purified by column chromatography (100percent hexanes) to give 1-bromo-3-phenoxy-benzene as a colorless oil (1.4 g, 53percent). LCMS m/z 250 (M+1).
Reference：
[1] Patent: US2005/234042, 2005, A1, . Location in patent: Page/Page column 25-26
[2] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 16, p. 5900 - 5905
[3] Patent: EP1489077, 2004, A1, . Location in patent: Page 31
18
[ 108-36-1 ]
[ 108-95-2 ]
[ 6876-00-2 ]
Reference：
[1] Patent: US4152455, 1979, A,
19
[ 108-36-1 ]
[ 139-02-6 ]
[ 6876-00-2 ]
Reference：
[1] Acta Chemica Scandinavica, 1996, vol. 50, p. 802 - 807
[2] Journal of Organic Chemistry, 1960, vol. 25, p. 1194 - 1198
[3] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 3, p. 527 - 530
20
[ 108-36-1 ]
[ 633-12-5 ]
Reference：
[1] European Journal of Organic Chemistry, 2003, # 23, p. 4625 - 4629
21
[ 626-39-1 ]
[ 141-78-6 ]
[ 108-36-1 ]
[ 14401-73-1 ]
Reference：
[1] Australian Journal of Chemistry, 1997, vol. 50, # 4, p. 425 - 434
[2] Australian Journal of Chemistry, 1997, vol. 50, # 4, p. 425 - 434
22
[ 626-39-1 ]
[ 75-36-5 ]
[ 108-36-1 ]
[ 14401-73-1 ]
Reference：
[1] Australian Journal of Chemistry, 1997, vol. 50, # 4, p. 425 - 434
[2] Australian Journal of Chemistry, 1997, vol. 50, # 4, p. 425 - 434
23
[ 108-22-5 ]
[ 108-36-1 ]
[ 21906-32-1 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1984, vol. 57, # 1, p. 241 - 246
24
[ 108-36-1 ]
[ 19821-80-8 ]
Yield
Reaction Conditions
Operation in experiment
91%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexanes at -75℃; for 2 h; Stage #2: With iodine In tetrahydrofuran; hexanes
Example 1: l,3-Dibromo-2-iodobenzene (II); Diisopropylamine (0.14 L, 0.10 kg, 1.0 mol) and 1,3-dibromobenzene (0.12 L, 0.24 kg,1.0 mol) were consecutively added to a solution of n-butyllithium (1.0 mol) in tetrahydrofuran (2.0 L) and hexanes (0.64 L) at -75 °C. After 2 h at -75 °C, a solution of iodine(0.26 kg, 1.0 mol) in tetrahydrofuran (0.5 L) was added. The solvents were evaporated andthe residue dissolved in diethyl ether (1.0 L). After washing with a 10percent aqueous solutionof sodium thiosulfate (2x0.1 L), the organic layer was dried over sodium sulfate beforebeing evaporated to dryness. Upon crystallization from ethanol (1.0 L), colorless platelets0.33 kg (91percent) were obtained;m.p. 99tolOO°C;'H-NMR (CHC13, 400 MHz): 8 = 7.55 (d, J= 8.1 Hz, 2 H), 7.07 (t, J - 8.1 Hz, 2 H);C6H3Br2I (361.80): calculated (percent) C 19.92, H 0.84; found C 19.97, H 0.80.
91%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -75℃; for 2 h; Stage #2: With iodine In tetrahydrofuran; hexane
Diisopropylamine (0.14 L, 0.10 kg, 1.0 mol) and 1,3-dibromobenzene (0.12 L, 0.24 kg, 1.0 mol) were consecutively added to a solution of n-butyllithium (1.0 mol) in tetrahydrofuran (2.0 L) and hexanes (0.64 L) at -75 °C. After 2 h at -75 °C, a solution of iodine (0.26 kg, 1.0 mol) in tetrahydrofuran (0.5 L) was added. The solvents were evaporated and the residue dissolved in diethyl ether (1.0 L). After washing with a 10percent aqueous solution of sodium thiosulfate (2.x.0.1 L), the organic layer was dried over sodium sulfate before being evaporated to dryness. Upon crystallization from ethanol (1.0 L), colorless platelets were obtained; m.p. 99 to 100 °C; 0.33 kg (91percent);1H-NMR (CHCl3, 400 MHz): δ = 7.55 (d, J= 8.1 Hz, 2 H), 7.07 (t, J = 8.1 Hz, 2 H); C6H3Br2I (361.80): calculated (percent) C 19.92, H 0.84; found C 19.97, H 0.80.
91%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexanes at -75℃; for 2 h; Stage #2: With iodine In tetrahydrofuran; hexanes at -75℃;
Example 1: l,3-Dibromo-2-iodobenzene (II); Diisopropylamine (0.14 L, 0.10 kg, 1.0 mol) and 1,3-dibromobenzene (0.12 L, 0.24 kg,1.0 mol) were consecutively added to a solution of n-butyllithium (1.0 mol) in tetrahydro- furan (2.0 L) and hexanes (0.64 L) at -75 °C. After 2 h at -75 °C, a solution of iodine(0.26 kg, 1.0 mol) in tetrahydrofuran (0.5 L) was added. The solvents were evaporated andthe residue dissolved in diethyl ether (1.0 L). After washing with a 10percent aqueous solutionof sodium thiosulfate (2x0.1 L), the organic layer was dried over sodium sulfate beforebeing evaporated to dryness. Upon crystallization from ethanol (1.0 L) 0.33 kg (91percent)colorless platelets were obtained;m.p. 99 to 100 °C;*H-NMR (CHC13, 400 MHz): 8 = 7.55 (d, J= 8.1 Hz, 2 H), 7.07 (t, J = 8.1 Hz, 2 H).C6H3Br2I (361.80): calculated (percent) C 19.92, H 0.84; found C 19.97, H 0.80.
91%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -70℃; Stage #2: With iodine In tetrahydrofuran; hexane at -70 - 20℃;
Synthesis Example 1 (Synthesis of 1,3-Dibromoiodobenzene) A 65 mL solution of n-butyllithium (1.6M hexane solution, 105 mmol), a hexane solution thereof (made by Tokyo Chemical Industry Co., Ltd.), was added to 100 mL of THF, and the mixture was cooled to -70°C.To the mixture was slowly added dropwise at -70°C 14.7 mL (105 mmol) of diisopropylamine (Aldrich), followed by stirring for 30 minutes at -70°C. To the reaction mixture was slowly added dropwise at -70°C 12.7 mL (105 mmol) of 1,3-dibromobenzene (Tokyo Chemical Industry Co., Ltd.), followed by stirring for 2 hours at -70°C. In 50 mL of THF was dissolved 26.7 g (105 mmol) of iodine (Wako Pure Chemical Industries, Ltd.). This liquid was added dropwise to the above reaction liquid of 1,3-dibromobenzene at -70°C, and the mixture was slowly warmed to room temperature. The solvent was removed under reduced pressure from the mixture, and the residue was dissolved in diethyl ether. To the solution was added a saturated aqueous solution of sodium thiosulfate, followed by separation and drying of the organic layer with magnesium sulfate. MgSO4 and the solvent were removed, and the residue was recrystallized from methanol, giving 34.6 g of white crystals of 1,3-dibromobenzene (91percent in yield). It was confirmed that the product was 1,3-dibromobenzene by 1H-NMR. 1H-NMR (400 MHz, CDCl3) 7.07 (t, J = 8.0 Hz, 1H, p-H), 7.56 (d, J = 8.0 Hz, 2H, m-H).
91%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -75℃; for 2 h; Stage #2: With iodine In tetrahydrofuran; hexane
At -75 °C, butyllithium (42.4 mmol) in hexanes (50 mL) and diisopropylamine (42.4 mmol) were added successively to tetrahydrofuran (20 mL). After 15 mm i ,3-dibromobenzene (5.12 mL, 10 g, 42.4 mmol) was added. The mixture was kept for 2 h at -75 °C before a solution of iodine(10.76 g, 42.4 mmol) in tetrahydrofuran (50 mL) was added. After addition of a 10percent aqueous solution (0.10 L) of sodium thiosulfate, the mixture was extracted with diethyl ether(3X 10 mL). The combined organic layers were dried over sodium sulfate before being evaporated to dryness. Upon crystallization from ethanol (100 mL), colorless platelets were obtained. Colorless platelets (yield = 91percent)
85%
Stage #1: With n-butyllithium; lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 2 h; Inert atmosphere Stage #2: With iodine In tetrahydrofuran at 20℃;
500mL three-necked flask baked,After exchanging argon three times,Under argon, 150 mL of THF was added and driedIce-acetone bath to -78 ° C,I-Pr2NH (10 mL, 71 mmol) was added sequentially,NBuLi (2.5M in hexane, 27 mL, 67 mmol),Stir for 30 min.Then slowly add 107(8.0 mL, 67 mmol),Stir for 2 h.A solution of I2 in THF (17 g, 67 mmol, THF, 30 mL) was slowly added,After adding the natural rise to room temperature.Steaming most of the solvent,Add 150 mL of ether,Followed by Na2S2O3 solution (50 mL),Saturated NaCl solution (3 x 100 mL) and dried over Na2SO4.The solvent was removed under reduced pressure,The resulting solid was recrystallized from ethanol (50 mL)A white flaky solid 108 (1,3-dibromo-2-iodobenzene) (20.3 g, yield 85percent) was obtained,The melting point is 99-100 ° C.
84%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 2 h; Stage #2: With iodine In tetrahydrofuran at -78 - 25℃;
Example 1 1,3-Dibromo-2-iodobenzene 1,3-Dibromobenzene (47.2 g, 24.2 mL, 200 mmol, 1 eq) was added dropwise to a solution of lithium diisopropylamide (LDA, 200 mmol, 1 eq) in tetrahydrofuran (400 mL) at -78 °C. After 2 h, a solution of iodine (50.8 g, 200 mmol, 1 eq) in tetrahydrofuran (200 mL) was added and the reaction mixture was then allowed to reach 25 °C. The solvent was evaporated and the residue was taken up in diethyl ether. The organic layer was washed with a saturated solution of sodium sulfite (3*100 mL), dried and evaporated. Crystallization from ethanol afforded 1,3-dibromo-2-iodobenzene (60.6 g, 167 mmol, 84percent) as white platelets; m.p. 99 - 100 °C. - 1H NMR (300 MHz, CDCl3): δ = 7.47 (2 H, d, J = 8 Hz), 6.99 (1 H, t, J = 7.9 Hz). - 13C NMR (75 MHz, CDCl3): δ = 131.3, 131.0, 130.3, 109.4.- C6H3Br2I (361.8): calculated C 19.92percent, H 0.84percent; found C 19.97percent, H 0.80percent.
84%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 2 h; Stage #2: With iodine In tetrahydrofuran at -78 - 25℃;
Example 1: l,3-Dibromo-2-iodobenzene; 1,3-Dibromobenzene (47.2 g, 24.2 mL, 200 mmol, 1 eq) was added dropwise to a solution of lithium diisopropylamide (LDA, 200 mmol, 1 eq) in tetrahydrofuran (400 mL) at -78 °C. After 2 h, a solution of iodine (50.8 g, 200 mmol, 1 eq) in tetrahydrofuran (200 mL) was added and the reaction mixture was then allowed to reach 25 0C. The solvent was evaporated and the residue was taken up in diethyl ether. The organic layer was washed with a saturated solution of sodium sulfite (3x100 mL), dried and evaporated. Crystallization from ethanol afforded 1 ,3-dibromo-2-iodobenzene (60.6 g, 167 mmol, 84percent) as white platelets; m.p. 99 - 100 0C. - 1H NMR (300 MHz, CDCl3) : δ = 7.47 (2 H, d, J= 8 Hz), 6.99 (1 H, t, J= 7.9 Hz). - 13C NMR (75 MHz, CDCl3): δ = 131.3, 131.0, 130.3, 109.4.- C6H3Br2I (361.8): calculated C 19.92percent, H 0.84percent; found C 19.97percent, H 0.80percent.
84%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; Stage #2: With iodine In tetrahydrofuran at -78 - 25℃;
1,3-Dibromobenzene (47.2 g, 24.2 mL, 200 mmol, 1 eq) was added dropwise to a solution of lithium diisopropylamide (LDA, 200 mmol, 1 eq) in tetrahydrofuran (400 mL) at -78° C. After 2 h, a solution of iodine (50.8 g, 200 mmol, 1 eq) in tetrahydrofuran (200 mL) was added and the reaction mixture was then allowed to reach 25° C. The solvent was evaporated and the residue was taken up in diethyl ether. The organic layer was washed with a saturated solution of sodium sulfite (3.x.100 mL), dried and evaporated. Crystallization from ethanol afforded 1,3-dibromo-2-iodobenzene (60.6 g, 167 mmol, 84percent) as white platelets; m.p. 99-100° C. -1H NMR (300 MHz, CDCl3): δ=7.47 (2 H, d, J=8 Hz), 6.99 (1 H, t, J=7.9 Hz). -13C NMR (75 MHz, CDCl3): δ=131.3, 131.0, 130.3, 109.4.- C6H3Br2I (361.8): calculated C 19.92percent, H 0.84percent; found C 19.97percent, H 0.80percent.
64%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃; for 2 h; Inert atmosphere Stage #2: With iodine In tetrahydrofuran at 20℃; for 1.5 h; Inert atmosphere
Diisopropylamine (7.0 mL, 50 mmol) was added to a solution of n-butyllithium (18.6 mL of2.69 M hexane solution, 50 mmol) in THF (10 mL) at 78 °C, and the mixture was stirredat 0 °C for 15 min, then cooled to 78 °C, 1,3-dibromo-benzene (6.0 mL, 50 mmol) was added dropwiseand stirred at 78 °C for another 2 h. A solution of iodine (12.7 g, 50 mmol) in anhydrous THF (15 mL)was added, and the mixture was stirred at room temperature for 90 min. The reaction was quenched by theaddition of saturated aqueous Na2S2O3, and the mixture was extracted with EtOAc. The combined extractswere washed with brine and separated. The organic layer was dried over Na2SO4 and concentrated underreduced pressure. The resulting crude solid was recrystallized from MeOH to give pure product (11.5 g,64percent). 1H NMR (500 MHz, CDCl3): 7.55 (d, J = 8.0 Hz, 2H), 7.07 (t, J = 8.0 Hz, 1H); 13C NMR (125MHz, CDCl3): 131.3, 131.1, 130.3, 109.3.
Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 14, p. 4726 - 4729
[2] Angewandte Chemie - International Edition, 2002, vol. 41, # 22, p. 4272 - 4274
[3] Patent: WO2006/2731, 2006, A1, . Location in patent: Page/Page column 14-15
[4] Advanced Synthesis and Catalysis, 2007, vol. 349, # 17-18, p. 2705 - 2713
[5] Patent: EP1609795, 2005, A1, . Location in patent: Page/Page column 11
[6] Patent: WO2006/2730, 2006, A1, . Location in patent: Page/Page column 16
[7] Patent: EP2133357, 2009, A1, . Location in patent: Page/Page column 14
[8] Chemistry - A European Journal, 2012, vol. 18, # 45, p. 14232 - 14236
[9] Patent: WO2015/121785, 2015, A1, . Location in patent: Page/Page column 39; 42
[10] Patent: CN106631726, 2017, A, . Location in patent: Paragraph 0045; 0046
[11] Patent: EP1905755, 2008, A1, . Location in patent: Page/Page column 3
[12] Patent: WO2008/37440, 2008, A1, . Location in patent: Page/Page column 4
[13] Tetrahedron Asymmetry, 2009, vol. 20, # 9, p. 1004 - 1007
[14] Patent: US2010/137659, 2010, A1, . Location in patent: Page/Page column 2
[15] Synlett, 2010, # 19, p. 2953 - 2955
[16] Angewandte Chemie - International Edition, 2018, vol. 57, # 35, p. 11233 - 11237[17] Angew. Chem., 2018, vol. 130, # 35, p. 11403 - 11407,5
[18] Synlett, 2013, vol. 24, # 19, p. 2550 - 2554
[19] Chemical Communications, 2010, vol. 46, # 23, p. 4100 - 4102
[20] Tetrahedron Letters, 2009, vol. 50, # 17, p. 1920 - 1923
[21] Journal of Organic Chemistry, 2012, vol. 77, # 5, p. 2107 - 2120
25
[ 401631-86-5 ]
[ 108-36-1 ]
[ 19821-80-8 ]
Reference：
[1] Synthesis, 2001, # 14, p. 2180 - 2190
26
[ 124-38-9 ]
[ 108-36-1 ]
[ 601-84-3 ]
Yield
Reaction Conditions
Operation in experiment
66%
With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 1.83333 h; Inert atmosphere
2,6-dibromobenzoic acid was synthesized according to literature procedure. See, e.g., Varcoe, J.R. et al., Chem. Mater. 2007, 19, 2686–2693, incorporated herein in its entirety. More specifically, dry tetrahydrofuran (THF, 400 mL) in a 2-neck round- bottom flask under argon was cooled to 0 °C in an ice-water bath. n-Butyllithium (2.5 M in hexanes, 117 mL) was added followed by a slow addition of diisopropylamine (45 mL) at 0 °C to form lithium diisopropylamide (LDA). The mixture was stirred for 45 min and then cooled to -78 °C in a dry ice/acetone bath. While at this temperature, 1,3-dibromobenzene (50.0 g, 0.212 mol) was added drop-wise over 5 min and stirred for 1 h. Dry ice was then closed in a glass container and connected by syringe into the reaction mixture. After bubbling the mixture with the evolved gaseous CO2 for 45 min, pieces of dry ice were added into the mixture. The mixture was allowed to slowly warm up to room temperature. Aqueous sodium hydroxide (0.5 M) and ethyl acetate (400 mL) were added until all of the solid was dissolved. The aqueous layer was washed with ethyl acetate and then acidified with concentrated hydrochloric acid until approximately pH=1. The precipitate was dissolved in fresh ethyl acetate, washed with brine, dried over MgSO4, filtered, and the solvent was evaporated at 40 °C under vacuum. The oil was cooled to room temperature, resulting in crystallization. The solid was boiled in hexanes (2 L) for 1 h and then cooled to room temperature. The solid was collected, washed with hexanes, and dried under vacuum at 80 °C, resulting in 1 (39.3 g, 66percent) as an off-white powder. 1H NMR (500 MHz, DMSO-d6, δ 7.70 (d, J = 8.1 Hz, 2H), 7.29 (t, J = 8.1 Hz, 1H).13C NMR (125 MHz, DMSO-d6, δ 166.87, 138.67, 131.87, 131.65.
Reference：
[1] European Journal of Organic Chemistry, 2003, # 23, p. 4625 - 4629
[2] Organic Letters, 2009, vol. 11, # 5, p. 1051 - 1054
[3] Angewandte Chemie - International Edition, 2016, vol. 55, # 15, p. 4818 - 4821[4] Angew. Chem., 2016, vol. 128, # 15, p. 4898 - 4902,5
[5] Patent: WO2017/117678, 2017, A1, . Location in patent: Page/Page column 29; 34; 35
27
[ 108-36-1 ]
[ 75-03-6 ]
[ 2725-82-8 ]
Reference：
[1] Journal of Organic Chemistry, 2000, vol. 65, # 10, p. 3200 - 3206
28
[ 108-36-1 ]
[ 5188-07-8 ]
[ 33733-73-2 ]
Reference：
[1] Organic Process Research and Development, 2003, vol. 7, # 3, p. 385 - 392
29
[ 108-36-1 ]
[ 62456-32-0 ]
Reference：
[1] Journal of Organic Chemistry, 1991, vol. 56, # 23, p. 6704 - 6708
Reference：
[1] Gazzetta Chimica Italiana, 1874, vol. 4, p. 341[2] Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften, 1875, p. 317
[3] Recueil des Travaux Chimiques des Pays-Bas, 1906, vol. 25, p. 202[4] Recueil des Travaux Chimiques des Pays-Bas, 1908, vol. 27, p. 151,159
[5] Gazzetta Chimica Italiana, 1874, vol. 4, p. 341[6] Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften, 1875, p. 317
[7] Justus Liebigs Annalen der Chemie, 1873, vol. 165, p. 169
[8] Recueil des Travaux Chimiques des Pays-Bas, 1906, vol. 25, p. 202[9] Recueil des Travaux Chimiques des Pays-Bas, 1908, vol. 27, p. 151,159
[10] Journal of Organic Chemistry, 2011, vol. 76, # 19, p. 8088 - 8094
32
[ 108-36-1 ]
[ 7697-37-2 ]
[ 13402-32-9 ]
[ 51686-78-3 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1906, vol. 25, p. 202[2] Recueil des Travaux Chimiques des Pays-Bas, 1908, vol. 27, p. 151,159
33
[ 108-36-1 ]
[ 24239-82-5 ]
[ 13402-32-9 ]
[ 51686-78-3 ]
[ 861601-98-1 ]
Reference：
[1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1913, vol. <5> 22 II, p. 630
34
[ 401631-86-5 ]
[ 108-36-1 ]
[ 19230-27-4 ]
Reference：
[1] Synthesis, 2001, # 14, p. 2180 - 2190
35
[ 108-36-1 ]
[ 51686-78-3 ]
Yield
Reaction Conditions
Operation in experiment
97%
at 0 - 20℃; for 1.5 h;
To 20 mL of ice-cooled and vigorously stirred concentrated sulphuric acid 20 mL of concentrated nitric acid is added drop wise. After cooling to 0 °C 11.8 g 1,3-dibromobenzene (50 mmol) is added slowly drop wise, keeping the temperature below 20 °C (30min). The cooling is removed and the mixture is stirred at room temperature for one hour. After cooling to 0 °C 40 g of ice is added slowly in portions. The precipitate is sucked off, washed several times with ice water and dried to give 13.96 g (48.3 mmol) of the desired product as light yellow crystals (97 percent). Melting point: 54-57 °C. 1H-NMR (200 MHz, DMSO-d6): 8.23 (d, 4J = 1.8 Hz, 1H), 7.99 (d, 3J = 8.8 Hz, 1H), 7.86 (dd, 4J = 1.8 Hz, 3J = 8.8 Hz, 1H).
90%
at 20℃; for 5 h;
Add 1,3 dibromobenzene (25g) over sulfuric fumante acid (20 mL). Stir for 5 hours at room temperature and then pour into ice-water, extract with ethyl acetate, wash with saturated aqueous sodium chloride, dry over magnesium sulfate and concentrate under reduced pressure. Crystallize the residue with methanol to provide (26.8 g, 90percent) of the desired product a light yellow solid. MS [(ES+)] : [MAZ] = 281. 90 [(M+H) +]
73%
at 0℃; for 0.5 h;
Sulfuric acid (744 mE) and nitric acid (144 mE) were mixed. In the temperature of 00 C., 1 ,3-dibromoben- zene (300 g, 1,270 mmol) were slowly dropped and stirred for 30 minutes. Afier completion of the reaction, ice water was slowly dropped into the mixture, and the solid was filtered and extracted using ethylacetate in several times. The organic solvent was removed, and the silica-gel column process was performed to obtain 2,4-dibromo-1 -nitrobenzene (261 g, yield: 73percent).
67.2%
With ammonium nitrate; sulfuric acid In water at 0℃; for 0.166667 h;
To an iced cold solution of 1,3-dibromobenzene (10g, 42.3mmol) in sulfuric acid (200ml) was added portionwise ammonium nitrate (3.39g, 42.3mmol) and the mixture was stirred at 0°C for 10 minutes and then poured into water. After extraction withvpercentCH2CI2, the organic phase was washed with a saturated solution of NaHCO3, dried over Na2SO4 and concentrated under reduced pressure. After trituration with pentane, the title compound was obtained as a pale yellow solid (8g, 67.2percent); NMR H1 (300MHz, CDCI3, ppm) 5: 7.95 (s, 1H), 7.75 (d, 1H), 7.6 (d, 1H).
67.2%
With ammonium nitrate; sulfuric acid In water at 0℃; for 0.166667 h;
To an iced cold solution of 1,3-dibromobenzene (10g, 42.3mmol) in sulfuric acid (200ml) was added portionwise ammonium nitrate (3.39g, 42.3mmol) and the mixture was stirred at 0°C for 10 minutes and then poured into water. After extraction with CH2CI2, the organic phase was washed with a saturated solution of NaHCO3, dried over Na2SO4 and concentrated under reduced pressure. After trituration with pentane, the title compound was obtained as a pale yellow solid (8g, 67.2percent); NMR H1 (300MHz, CDCI3, ppm) 5: 7.95-(s, 1H), 7.75 (d, 1H), 7.6 (d, 1H).
64%
at 0℃; for 0.25 h;
Intermediate 7: 6-Bromo-l-methyl-lH-benzoimidazole; Step 1: 2,4-Dibromo-l-nitro-benzene; [0309] To an ice-cold solution of 1,3-dibromobenzene (10 g, 42.4 mmol) in concentrated sulfuric acid (200 mL) was added ammonium nitrate (3.39 g, 42.4 mmol) portionwise. The reaction mixture was stirred at O0C for 15 min, then it was poured onto an ice-water mixture. The aqueous mixture was extracted with dichloromethane (2x). The combined organic layers were washed with water then a saturated aqueous solution of sodium bicarbonate (2x), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated with hexane, filtered, and dried in vacuo to give 7.63 g of 2,4-dibromo-l- nitro-benzene as a yellow solid (64percent yield): 1H NMR (CDCl3) δ 7.62 (dd, IH), 7.78 (d, IH), 7.95 (d, IH).
63%
at 0℃; for 1 h;
After putting HNO3 (95 mL, 1.5 mol) and H2SO4 (167 mL, 1.7 M) in a 1000 mL round bottom flask, the mixture was cooled to 0°C. After adding 1,3-dibromobenzene (50 g, 0.18 mol) slowly, the mixture was stirred for 1 hour. After completing the reaction, the mixture was slowly added to iced water of 0°C. Then, the mixture was filtered, and then separated through a column to obtain a yellow solid: compound 3-1 (75 g, 63 percent).
60%
at 0 - 20℃; for 5 h;
Example 13; Part A:To concentrated sulfuric acid (75 ml_) at O0C was added concentrated nitric acid (5.5 mLI) carefully. 1 ,3-Dibromobenzene 223 (25.0 g, 106 mmol) was added to the acid solution at O0C. The resulting solution was slowly warmed to room temperature and continued to stir at room temperature for 5 hours. The reaction mixture was poured into water, neutralized with solid sodium carbonate and extracted with diethyl ether (x2). The ether solution was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification by column chromatography (Siψ2, 10percent EtOAc/hexanes) afforded compound 224 as a yellow solid 17.7 g (60percent). 1H NMR (400 MHz, DMSO-de) δ 8.22 (d, 1 H), 7.97 (d, 1 H), 7.85 (dd, 1 H).
59%
at 0 - 10℃; for 0.5 h;
After making a bath of -4°C putting ice in aqueous solution of saturated NaCl, nitric acid (1.5 equivalents) was putted into sulfuric acid solvent, and was waited until the temperature of the reaction solvent became 0°C. 1,3-dibromobenzene (10 g, 42.4 mmol) was putted into a dropping funnel, and was dropwised to not exceed 10°C. After 30 minutes, the reaction mixture was quenched with water. The obtained solid was filtered, was washed with purified water several times, and was filtered through column to obtain compound 7-1 (7 g, 59 percent).
58.23%
With sulfuric acid; nitric acid In water at 0℃;
Add 1,3-dibromobenzene (45 g, 0.191 mol) to a 500 mL three-necked flask and add a mixed solution of sulfuric acid (133.59 g, 0.51 mol) and water (13.73 g, 0.763 mol).The solution was cooled to 0 ° C and nitric acid (32.21 g, 0.51 mol) was slowly added dropwise. When the addition was complete, the reaction system was transferred to room temperature for stirring and TLC followed.After the reaction is over, the reaction system is poured into ice water.Add 100mL ethyl acetate extraction.The aqueous phase is extracted once more with 100 mL of methylene chloride.Combine the organic phases.Drying over anhydrous sodium sulfate.Filtration and distillation of the solvent under reduced pressure, beating with petroleum ether gave 31.2 g of light yellow crystals.Yield: 58.23percent.
34%
at 0℃; for 0.5 h;
Sulfuric acid (124 mL) and 60percent nitric acid (28 mL) were mixed, and then cooled to 0°C. Then, 1,3-dibromobenzene (50 g, 0.21 mol) was slowly added dropwise thereto, followed by stirring for 30 minutes. After the stirring was completed, ice water was added thereto, followed by extraction with EA (300 mL). The organic layer was dried over anhydrous magnesium sulfate, followed by distillation under reduced pressure and then silica column purification, thereby obtaining Compound 11-1 (20 g, 34percent).
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 590 - 603
[2] Patent: WO2004/14900, 2004, A1, . Location in patent: Page 24; 57-58
[3] Journal of Organic Chemistry, 2011, vol. 76, # 19, p. 8088 - 8094
[4] Heteroatom Chemistry, 2009, vol. 20, # 2, p. 101 - 108
[5] Physical Chemistry Chemical Physics, 2018, vol. 20, # 25, p. 17504 - 17516
[6] Patent: US2018/130953, 2018, A1, . Location in patent: Paragraph 0135; 0136
[7] Patent: WO2004/111036, 2004, A1, . Location in patent: Page 20
[8] Patent: WO2004/111046, 2004, A2, . Location in patent: Page/Page column 17
[9] Patent: WO2008/51808, 2008, A2, . Location in patent: Page/Page column 82
[10] Patent: WO2013/81416, 2013, A1, . Location in patent: Paragraph 146-147
[11] Patent: WO2008/82487, 2008, A2, . Location in patent: Page/Page column 109
[12] Patent: WO2013/12296, 2013, A1, . Location in patent: Paragraph 154-156
[13] Patent: CN107266421, 2017, A, . Location in patent: Paragraph 0176; 0178; 0179
[14] Patent: WO2012/67425, 2012, A1, . Location in patent: Page/Page column 38
[15] Patent: WO2005/80388, 2005, A1, . Location in patent: Page/Page column 93
[16] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 1, p. 179 - 183
[17] Patent: US2010/160340, 2010, A1, . Location in patent: Page/Page column 9
36
[ 108-36-1 ]
[ 13402-32-9 ]
[ 51686-78-3 ]
Reference：
[1] Gazzetta Chimica Italiana, 1874, vol. 4, p. 341[2] Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften, 1875, p. 317
[3] Recueil des Travaux Chimiques des Pays-Bas, 1906, vol. 25, p. 202[4] Recueil des Travaux Chimiques des Pays-Bas, 1908, vol. 27, p. 151,159
[5] Gazzetta Chimica Italiana, 1874, vol. 4, p. 341[6] Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften, 1875, p. 317
[7] Justus Liebigs Annalen der Chemie, 1873, vol. 165, p. 169
[8] Recueil des Travaux Chimiques des Pays-Bas, 1906, vol. 25, p. 202[9] Recueil des Travaux Chimiques des Pays-Bas, 1908, vol. 27, p. 151,159
[10] Journal of Organic Chemistry, 2011, vol. 76, # 19, p. 8088 - 8094
37
[ 108-36-1 ]
[ 7697-37-2 ]
[ 13402-32-9 ]
[ 51686-78-3 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1906, vol. 25, p. 202[2] Recueil des Travaux Chimiques des Pays-Bas, 1908, vol. 27, p. 151,159
38
[ 108-36-1 ]
[ 24239-82-5 ]
[ 13402-32-9 ]
[ 51686-78-3 ]
[ 861601-98-1 ]
Reference：
[1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1913, vol. <5> 22 II, p. 630
39
[ 108-36-1 ]
[ 626-41-5 ]
Reference：
[1] Journal of the American Chemical Society, 2003, vol. 125, # 26, p. 7792 - 7793
40
[ 108-36-1 ]
[ 19393-94-3 ]
Reference：
[1] Journal of the American Chemical Society, 2004, vol. 126, # 48, p. 15770 - 15776
41
[ 108-36-1 ]
[ 19393-94-3 ]
[ 96843-23-1 ]
Reference：
[1] Journal of the American Chemical Society, 2018, vol. 140, # 24, p. 7526 - 7532
42
[ 108-36-1 ]
[ 5228-61-5 ]
Reference：
[1] Gazzetta Chimica Italiana, 1874, vol. 4, p. 341[2] Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften, 1875, p. 317
[3] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 590 - 603
43
[ 50339-64-5 ]
[ 108-36-1 ]
[ 4885-18-1 ]
Reference：
[1] Journal of Organic Chemistry, 1961, vol. 26, p. 2310 - 2316
Stage #1: With n-butyllithium In diethyl ether; acetone at -75 - 20℃; for 0.666667 h; Inert atmosphere Stage #2: at -75℃; for 12 h;
1,3-dibromobenzene 25g(106 mnol) was added to purified ether (150 ml) and sufficiently stirred.The reaction is carried out at -75 ° C or below using a bath of liquid nitrogen / acetone. When the temperature of the reactor dropped to -75 or less, 50.8 ml (127 mmol) of 2.5M n-BuLi was added slowly, and the temperature was raised to room temperature. After 40 minutes of reaction, The temperature of the reaction was dropped below -75 , and then 46.4 g(318 mmol) was added and reacted for 12 hours to obtain a product. Add 300 ml of 2M HCl to distilled water and ice-filled beaker, stir the product several times, stirring well until all the ice is dissolved. The product is extracted with EA and water. In this case, use distilled water and wash thoroughly until it becomes neutral. The product is recrystallized using n-hexane to obtain the final purified product. 85percent yield.
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h; Inert atmosphere Stage #2: at 20℃; for 3 h;
(105.9 mmol) of 1,3-dibromobenzene in 500 ml of nitrogen at -78 ° C under N2 atmosphereTHF for 10 minutes,then,To this was slowly added dropwise 44 ml of 2.5 M n-BuLi through a dropping funnel,The resulting solution was stirred for 30 minutes.After that,10.4 g (110 mmol) of trimethyl borate was slowly added dropwise thereto through a dropping funnel,then,The resulting solution was stirred at room temperature for 3 hours;Then, 300 ml of 1M hydrochloric acid solution was added thereto, and the extraction process was performed once. Then by usingThe organic layer separated from it was subjected to three extraction procedures with water and diethyl ether. And dried by using magnesium sulfateTo the organic layer, the residue obtained by evaporation of the solvent was isolated by silica gel column chromatography, To obtain 15.3 g (76.2 mmol, yield 71.9percent) of intermediate A-1.
Reference：
[1] Patent: CN105541778, 2016, A, . Location in patent: Paragraph 0376; 0377; 0378; 0379
52
[ 7647-01-0 ]
[ 121-43-7 ]
[ 108-36-1 ]
[ 89598-96-9 ]
Yield
Reaction Conditions
Operation in experiment
65%
Stage #1: With n-butyllithium In tetrahydrofuran at -78 - 20℃;
The experimental apparatus was thoroughly dried, and 35.4 g of 1,3-dibromobenzene was added to a 2L three-necked flask.Add 700ml of dried tetrahydrofuran,After dissolution, the temperature was lowered to -78C, and 66 ml of 2.5M n-BuLi was added dropwise.After stirring for one hour at the temperature,20.0 g of trimethyl borate was added dropwise at this temperature.After the addition was completed, the mixture was stirred at room temperature overnight.After the reaction is over,Add 4N hydrochloric acid solution,Extract with dichloromethane,The organic phase is washed to neutral with saturated saline solution.Dry, spin off the solvent,The crude product is boiled with ethyl acetate and filtered. The cake is the boric acid product.25g of intermediate G,The yield is 65percent.
Reference：
[1] Patent: CN107663214, 2018, A, . Location in patent: Paragraph 0083-0087
53
[ 5419-55-6 ]
[ 108-36-1 ]
[ 89598-96-9 ]
Reference：
[1] Organic Process Research and Development, 2018, vol. 22, # 6, p. 741 - 746
54
[ 108-36-1 ]
[ 74-88-4 ]
[ 69321-60-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 23, p. 9441 - 9456
55
[ 108-36-1 ]
[ 68-12-2 ]
[ 67713-23-9 ]
Yield
Reaction Conditions
Operation in experiment
89%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 0.833333 h; Stage #2: for 1 h;
To a solution of iPr2NH (21.2 mL, 150 mmol) in THF (180 mL) at 0° C. was slowly added n-BuLi (1.6 M, 94 mL, 150 mmol). The reaction mixture was stirred at 0° C. for 30 min and then cooled to −78° C. 1,3-Dibromobenzene (17.6 g, 74.6 mmol) in THF (80 mL) was slowly added over 20 min. The mixture was stirred at −78° C. for 30 min and N,N-dimethylformamide (11.6 mL, 150 mmol) was added. The mixture was stirred for 1 h, then treated with H2SO4 (2.5 M, 350 mL), and extracted with ethyl acetate/Et2O (50/50, 3×300 mL). The combined extract were dried over MgSO4 and filtered. The filtrate was concentrated to give 2,6-dibromobenzaldehyde (17.6 g, 89percent). 1H NMR (250 MHz, CDCl3) δ 10.3 (s, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.23 (t, J=8.1 Hz, 1H).
88%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: for 0.5 h;
In a 1-L reactor, tetrahydrofuran (500 mL) and 1,3-dibromobenzene (50 g, 212 mmol) were placed and cooled to −78° C. under a nitrogen atmosphere. Drops of 1.5M LDA (170 mL, 254 mmol) were slowly added and then stirred for 30 min. At the same temperature, DMF (18.5 g, 254 mmol) was slowly added in a dropwise manner, followed by stirring for 30 min. The reaction was terminated with an aqueous sulfuric acid solution. The organic layer was extracted and concentrated at a reduced pressure. Purification by column chromatography afforded Intermediate 1-b (49 g): yield 88percent
Reference：
[1] Chemical Communications, 2015, vol. 51, # 35, p. 7486 - 7488
[2] Patent: US2016/95858, 2016, A1, . Location in patent: Paragraph 2877; 2878
[3] Patent: US2018/72753, 2018, A1, . Location in patent: Paragraph 0106-0107
[4] Organic Process Research and Development, 2014, vol. 18, # 1, p. 228 - 238
[5] Journal of Organic Chemistry, 2003, vol. 68, # 13, p. 5384 - 5387
[6] Angewandte Chemie, International Edition, 2012, vol. 51, # 40, p. 10082 - 10085,4[7] Angewandte Chemie, 2012, vol. 124, # 40, p. 10229 - 10232,4
[8] Chemistry - A European Journal, 2007, vol. 13, # 9, p. 2701 - 2716
[9] Patent: WO2009/37220, 2009, A1, . Location in patent: Page/Page column 103
[10] Tetrahedron Letters, 2011, vol. 52, # 32, p. 4182 - 4185
[11] Chemistry - A European Journal, 2016, vol. 22, # 46, p. 16478 - 16488
56
[ 615-58-7 ]
[ 108-36-1 ]
[ 5436-43-1 ]
Yield
Reaction Conditions
Operation in experiment
85%
for 0.333333 h; Microwave irradiation
1,3-dibromobenzene (2.34g, 0.01mol) and 2,4-dibromo-phenol (2.50g, 0.01mol) was stirred in a beaker and mix, 24g of montmorillonite was added, stirred mix again into dedicated microwave reaction flask, 150w microwave heating reaction 20min, cooled. After 100mL of n-hexane was collected by washing the reaction solution was washed, evaporated under reduced pressure to give a red oil by column chromatography, to give a white solid 4.09 g, yield 85percent.
Reference：
[1] Molecular Crystals and Liquid Crystals, 2006, vol. 444, p. 95 - 101
63
[ 110-91-8 ]
[ 108-36-1 ]
[ 197846-82-5 ]
Yield
Reaction Conditions
Operation in experiment
71%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 60℃; Inert atmosphere
Intermediate 5: 3-Morpholin-4- lphenyl boronic acid1,3-Dibromobenzene (50g, 0.21mol), morpholine (15.89mL, 0.19mol) and anhydrous toluene (200mL) were added to a flask by syringe under argon. The solution was thoroughly mixed before R-BINAP (1.32g, 0.0021mol) and ira(dibenzylideneacetone) palladium (0) (0.640g, 0.006mol) were added and finally DBU (25.8mL, 0.17mol) was added via syringe. The reaction mixture was stirred at 60°C. Sodium ie/t-butoxide (30.55 g, 0.32mol) was added and the reaction was heated to 100°C overnight. The suspension was diluted with ethyl acetate, filtered through Celite and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica eluting with ethyl acetate:hexane, 1: 1, to afford 4-(3-bromophenyl)morpholine as yellow oil (36.5g, 71 ).Mass: (ES+) 242 (M+H)+
60%
Stage #1: With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 60℃; Inert atmosphere Stage #2: With sodium t-butanolate In toluene at 100℃;
Intermediate 5: 3-Morpholin-4- lphenyl boronic acid1,3-Dibromobenzene (50g, 0.212mol), morpholine (15.88mL, 0.191mol) and anhydrous toluene (200mL) were added to a flask by syringe under argon. The solution was thoroughly mixed before R-BINAP (1.32g, 0.0021mol) and iris (dibenzylideneacet one) palladium (0) (0.640g, 0.006mol) were added and finally DBU (25.83 mL, 0.1726) was added via syringe. The reaction mixture was stirred at 60°C. Sodium te/t-butoxide (30.55 g, 0.3178 mol) was added and the reaction was heated to 100°C overnight. The suspension was diluted with ethyl acetate, filtered through Celite and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica (ethyl acetate:hexane, 1: 1) to afford 4- (3-bromophenyl) morpholine as yellow oil (31g, 60percent). Mass: (ES+) 242 (M+H)+
Reference：
[1] Patent: WO2011/144578, 2011, A1, . Location in patent: Page/Page column 28
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5522 - 5537
[3] Tetrahedron, 2008, vol. 64, # 13, p. 2938 - 2950
[4] Patent: WO2011/144577, 2011, A1, . Location in patent: Page/Page column 25-26
64
[ 123-75-1 ]
[ 108-36-1 ]
[ 219928-13-9 ]
Yield
Reaction Conditions
Operation in experiment
99%
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 80℃; for 4.5 h; Sealed tube
Commercial 1,3-dibromobenzene 1 (200.0mg, 0.85mmol), 12 pyrrolidine (60.5mg, 0.85mmol) and 157.0mg of a reagent constituted by 13 tris(dibenzylideneacetone)dipalladium(0), 14 BINAP and 15 t-BuONa (mol ratio: 0.05:0.15:2) were suspended in 16 toluene (2.5mL) and allowed to react in a sealed tube, at 80°C for 4.5h, under magnetic stirring. After cooling to room temperature, the mixture was filtered under reduced pressure and the resulting solution evaporated in vacuo. The residue was dissolved in CHCl3 and washed with a 10percent aqueous solution of 60 NaOH. The organic phase was dried over anhydrous Na2SO4, filtered, evaporated in vacuo, and purified by flash column chromatography on silica gel (petroleum ether), obtaining the intermediate 2 as a transparent oil (190.5mg, 0.84mmol). Yield: 99percent. 1H NMR (CDCl3, 400MHz) δ (ppm): 7.05 (t, 1H, J=8.0Hz), 6.76–6.74 (m, 1H), 6.68 (m, 1H), 6.46 (m, 1H), 3.27–3.24 (m, 4H), 2.05–1.99 (m, 4H).
54%
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene for 4 h; Reflux
1,3-Dibromobenzene (1.0 g, 4.24 mmol), pyrrolidine (0.43 mL, 5.0 mmol), sodium tert-butoxide (1.14 g, 11.87mmol) and BINAP (0.2 g, 0.32 mmol) were dissolved in 17 mL of toluene. Pd2(dba)3 (0.097 g, 0.1 mmol) was addedthereto, and the mixture was stirred 4 hours under reflux. Solids were filtered through Celite and purified by columnchromatography to obtain the title compound (0.52 g, 54percent).1H-NMR (CDCl3) δ 7.05 (1H, t), 6.75 (1H, d), 6.67 (1H, m), 6.45 (1H, m), 3.26 (4H, m), 2.00 (4H, m)
45%
With caesium carbonate In toluene at 120℃;
Synthesis of 1-(3-bromophenyl)pyrrolidine Into a 500 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1,3-dibromobenzene (20 g, 84.78 mmol, 1.00 equiv) in toluene (300 mL). To this was added pyrrolidine (6.03 g, 84.80 mmol, 1.00 equiv). Addition of Pd(OAc)2 (190 mg, 0.85 mmol, 0.01 equiv) was next. This was followed by the addition of BINAP (760 mg, 2.53 mmol, 0.03 equiv). To the mixture was added Cs2CO3 (69.1 g, 211.96 mmol, 2.50 equiv). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 120° C. in a bath of oil. The reaction progress was monitored by TLC (EtOAc/PE=1:5). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The residue was purified by eluding through a column with a PE solvent system. This resulted in 8.51 g (45percent) of 1-(3-bromophenyl)pyrrolidine as a light yellow liquid. LC-MS (ES, m/z): [M+H]+ calcd for C10H13BrN 226, found 226
45%
With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 120℃;
Synthesis of 1-3-bromophenyl)pyrrolidine Into a 500 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1,3-dibromobenzene (20 g, 84.78 mmol, 1.00 equiv) in toluene (300 mL). To this was added pyrrolidine (6.03 g, 84.80 mmol, 1.00 equiv). Addition of Pd(OAc)2 (190 mg, 0.85 mmol, 0.01 equiv) was next. This was followed by the addition of BINAP (760 mg, 2.53 mmol, 0.03 equiv). To the mixture was added Cs2CO3 (69.1 g, 211.96 mmol, 2.50 equiv). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 120° C. in a bath of oil. The reaction progress was monitored by TLC (EtOAc/PE=1:5). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The residue was purified by eluding through a column with a PE solvent system. This resulted in 8.51 g (45percent) of 1-(3-bromophenyl)pyrrolidine as a light yellow liquid. LC-MS (ES, m/z): [M+H]+ calcd for C10H13BrN 226, found 226
Reference：
[1] Chemical Communications, 2008, # 7, p. 889 - 890
[2] Patent: US2009/289547, 2009, A1, . Location in patent: Page/Page column 47
[3] Patent: US2011/155955, 2011, A1, . Location in patent: Page/Page column 7-8
66
[ 108-36-1 ]
[ 4422-32-6 ]
Yield
Reaction Conditions
Operation in experiment
64%
With sodium carbonate In diethyl ether; ethanol; hexane; toluene
EXAMPLE 38 3-[3-(Pyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine A mixture of 1,3-dibromobenzene (8.7 g, 36.8 mmol) and pyridine-3-boronic acid-1,3-propanediol cyclic ester (4.0 g, 24.5 mmol) in EtOH (60 ml) and toluene (60 ml) together with 2N Na2CO3 solution (24.5 ml) was degassed with a stream of N2 for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.22 mmol) was added and the reaction heated at reflux for 14 h. The mixture was concentrated under reduced pressure to remove the organic solvents. The organics were extracted with EtOAc (2*125 ml) and then washed with brine (75 ml), dried (MgSO4), and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography on silica, using 80percent diethyl ether in hexane as the eluent, to yield 3-(3-bromophenyl)pyridine (3.66 g, 64percent): δH(360 MHz, CDCl3) 7.30-7.42 (2H, m), 7.47-7.60 (2H, m), 7.72 (1H, s), 7.84 (1H, dt, J 8 and 2), 8.62 (1H, dd, J 4.8 and 1.5), 8.83 (1H, s).
Reference：
[1] Patent: US2003/176449, 2003, A1,
67
[ 108-36-1 ]
[ 89878-14-8 ]
[ 265644-07-3 ]
[ 4422-32-6 ]
Yield
Reaction Conditions
Operation in experiment
70%
With tetra(n-butyl)ammonium hydroxide; sodium carbonate In 1,2-dimethoxyethane; diethyl ether; water
Part A 3-[3-(Tri-n-butylstannanyl)phenyl]Pyridine A mixture of 1,3-dibromobenzene (105.0 g, 0.45 mol), diethyl(3-pyridyl)borane (30.0 g, 0.204 mol) and tetrabutylammonium hydroxide (2 ml of a 40 wt percent solution in water) in 1,2-dimethoxyethane (200 ml) and sodium carbonate (100 ml of a 2M solution) was degassed with nitrogen for 15 min before addition of tetrakis(triphenylphosphine)palladium(0) (4.5 g, 3.9 mmol). The mixture was heated at 80° C. for 18 h, cooled to room temperature, diluted with ethyl acetate and extracted with 1M hydrochloric acid (4*250 ml). The combined aqueous phases were made basic with solid sodium hydroxide and then extracted with diethyl ether. The organic layer was washed with water, brine, dried over sodium sulphate and concentrated to give a yellow oil. Purification by silica gel chromatography eluding with isohexane on a gradient of diethyl ether (10percent to 50percent) gave 3-(3-bromophenyl)pyridine (33.5 g, 70percent) as a colourless oil. 1H NMR (400 MHz, CDCl3) δH 7.28-7.40 (2H, m), 7.48-7.57 (2H, m), 7.73 (1H, t, J 2), 7.82-7.87 (1H, m), 8.62 (1H, s), 8.80 (1H, s).
Reference：
[1] Patent: US2002/188000, 2002, A1,
68
[ 108-36-1 ]
[ 73183-34-3 ]
[ 196212-27-8 ]
Yield
Reaction Conditions
Operation in experiment
86%
With potassium acetate In 1,4-dioxane at 85℃; for 18 h; Inert atmosphere
1,3-dibromobenzene (2.5 g, 10.6 mmol), bis(pinacolato)diboron (6.0 g, 23.5 mmol), Pd(dppf)2Cl2 (0.9 g, 1.2 mmol), and potassium acetate (7.1 g, 72.1 mmol) were dissolved in 50 mL of 1,4-dioxane. The reaction mixture was degassed with argon and then heated to 85° C. under argon for 18 hours. The reaction mixture was filtered and an extraction was performed in ethyl acetate. The organic phase was washed with water and brine. The extract was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by a silica gel column with 1:9 ethyl acetate:hexanes as the eluent. The solvents were removed and the product was recrystallized from dichloromethane/methanol to yield the product as an off-white solid 4 (3.008 g, 86percent yield).
Reference：
[1] New Journal of Chemistry, 2018, vol. 42, # 6, p. 4728 - 4734
[2] Patent: US2012/226046, 2012, A1, . Location in patent: Page/Page column 18; 19
[3] Organic Letters, 2007, vol. 9, # 4, p. 559 - 562
[4] Angewandte Chemie - International Edition, 2016, vol. 55, # 37, p. 11247 - 11250[5] Angew. Chem., 2016, vol. 128, # 37, p. 11413 - 11417,5
[6] Patent: EP2266982, 2010, A1, . Location in patent: Page/Page column 27-29
First, 1 times the equivalent of carbazole,1 to 1.5 equivalents of dihalogenated benzene, such as m-dibromobenzene,0.44 times the equivalent of Cu (electrolytic refined copper),4.04 times the equivalent of K2CO3 into the reaction vessel,Nitrobenzene as the reaction solvent,Nitrogen protection under 120 ~ 160 reaction 12 ~ 48h,The reaction solution was distilled under reduced pressure to obtain a crude product,The pure product was obtained by column chromatography,The yield was 75-85percent.
83%
With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 24 h; Inert atmosphere
To a 500 mL reaction flask was charged 20 g (84.7 mmol) of m-dibromobenzene,14 g (84.7 mmol) of carbazole, 1.6 g (8.77 mmol)Cuprous iodide,1.5 g (16.9 mmol)ofN-dimethyl-1,2-ethanediamine, 117 g (0.847 mol) of potassium carbonate and 300 ml of solvent xylene,Nitrogen protection Heating to 120 ° C,Insulation reaction for 24 hours.The water bath was cooled to 80 ° C and filtered while hot. The filter cake was washed with toluene and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column eluting with petroleum ether / dichloromethane to give 22.6 g of a white solid product. Yield: 83percent
71%
With copper; potassium carbonate In N,N-dimethyl-formamide at 130℃; Inert atmosphere
see Kido, J.; Su, S. -J.; Sasabe, H.; Takeda, T.; Chem. Mater. 2008, 20(5), 1691-1693, which is incorporated by reference herein for its relevant teachings) was prepared as follows: a mixture of carbazole (4.000 g, 23.92 mmol), 1,3-dibromobenzene (14.11 g, 59.81 mmol), K2CO3 (9.919 g, 71.77 mmol), copper powder (4.561 g, 71.77 mmol) and anhydrous N,N-dimethylformamide (DMF) (120 mL) was degassed with argon for 1 h. while stirring. The reaction mixture was then maintained under argon at 130° C. while stirring for 4 days until TLC (SiO2, 4:1 hexanes-dichloromethane) indicated consumption of the starting material. Upon cooling to RT, about 300 mL dichloromethane was added, the crude mixture filtered, the filtrant wash with an additional 200 mL dichloromethane, and the filtrate concentrated in vacuo. The resulting residue was then purified by flash chromatography (SiO2, hexanes) to yield Compound 3 (5.47 g, 71percent) as a colorless oil.
80 mmol
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; potassium <i>tert</i>-butylate In 5,5-dimethyl-1,3-cyclohexadiene for 6 h; Reflux
Step 1. Add 100 mmol of carbazole to the reaction vessel.m-dibromobenzene 100mmol,Potassium tert-butoxide 300mmol,Pd2 (dba) 3 1mmol,Ultrasonic deoxygenated xylene,Stir and dissolve,Replace the air three times,Adding ligand tri-tert-butylphosphine 4percent (4mmol, 50percent m/V),Replace the air three times,The reaction was refluxed for 6 h.Cool to room temperature,Add enough dichloromethane to completely dissolve the product.a small amount of silica gel funnel,Remove catalyst and salt.The filtrate is concentrated to a viscous state.Column chromatography,The product was obtained 3-1 80 mmol.
Reference：
[1] Patent: WO2013/12298, 2013, A1, . Location in patent: Paragraph 101-012
[2] Patent: CN106883163, 2017, A, . Location in patent: Paragraph 0036; 0037; 0038; 0039
[3] Patent: CN104497013, 2017, B, . Location in patent: Paragraph 0071-0073
[4] Patent: US9379336, 2016, B2, . Location in patent: Page/Page column 40; 41
[5] RSC Advances, 2014, vol. 4, # 101, p. 57679 - 57682
[6] Journal of Materials Chemistry C, 2015, vol. 3, # 48, p. 12529 - 12538
[7] Patent: CN107298651, 2017, A, . Location in patent: Paragraph 0009; 0010
[8] Patent: CN108264521, 2018, A, . Location in patent: Paragraph 0038; 0039; 0040; 0043; 0044; 0045
76
[ 108-36-1 ]
[ 32316-92-0 ]
[ 667940-23-0 ]
Yield
Reaction Conditions
Operation in experiment
47%
With potassium carbonate In tetrahydrofuran; water for 24 h; Heating / reflux
Example 13 : Preparation of compound 30; [196][197] 13-A. Preparation of compound 13a[198] Under N atmosphere, 1,3-dibromophenyl (10 g, 42.2 mmol), 2-naphthyl boronic acid (5.16 g, 42.2 mmol), and Pd(PPh ) (2.4 g, 2.1 mmol) were added to a 2 M aqueous solution of potassium carbonate (50 mL) and THF (300 mL). The mixture was refluxed under stirring for about 24 hours. After completing the reaction, the mixture was cooled to normal temperature. The organic layer was separated from the reaction mixture, dried over magnesium sulfate, and distilled under reduced pressure. The resultant was purified by column chromatography to prepare a compound 13a (4.6 g, 47percent). MS [M] = 233
Stage #1: Reflux Stage #2: at 110 - 150℃; for 1 h;
Sodium (0.319 gm 0.0138 mole) was added to N,N-dimethylethanolamine (2.0 g 0.0224 mole) and the mixture was allowed to reflux. After dissolution of the sodium, 1,3-dibromobenzene (5.2 g 0.0224 mol) was added at 110° C. and subsequently copper(I)bromide (0.205 g 0.0014 mol) addition the temperature rose to 150° C. and the reaction was complete within 1 h. The reaction mixture was cooled to room temperature and a solution of sodium cyanide (0.545 g) in 500 mL of water was added. The mixture was extracted with dichloromethane. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by column chromatography eluting with dichloromethane:methanol (19:1) to afford 2-(3-bromophenoxy)-N,N-dimethylethanamine as a yellow solid (2.0 g, 36percent).ES+ 245 (M+H)+
Reference：
[1] Organic Process Research and Development, 2016, vol. 20, # 12, p. 2085 - 2091
84
[ 76-86-8 ]
[ 108-36-1 ]
[ 185626-73-7 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Stage #2: at 20℃; for 12 h;
1,3-Dibromobenzene 20 g (84.77 mmol) was dissolved in THF 500 mL, and then cooled to a temperature of -78. n-BuLi 2.5M 33.9 mL(84.77 mmol) was slowly added thereinto, and then stirred at a temperature of -78 for 1 hour. Chlorotriphenylsilane ((C6H5)3SiCl) 29.9 g was dissolved in THF 100 mL, and this solution was added into the above reaction mixture. The resultant mixture was slowly warmed to room temperature, and stirred for 12 hours. Then, extraction with EA, wash with distilled water and aqueous NaCl solution, drying over MgSO4, distillation under reduced pressure, and recrystallization with MC-MeOH in the ratio of 1:10, were sequentially performed, thereby obtaining Compound 8-1 18 g(95 percent).
87%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: at 20℃; for 24 h;
Preparation of Compound 2-3 After 1,3-dibromobenzene (11.2 g, 47 mmol) was dissolved in THF (200 mL), the mixture was cooled to -78 °C. After slowly adding n-BuLi (19 mL, 2.5M in hexane, 70.5 mmol), the mixture was stirred for 1 hour. Solution that TPS-Cl (20 g, 56.8 mmol) was dissolved in THF (25 mL) was slowly added. After slowly increasing temperature, the mixture was stirred at room temperature for one day. Upon completion of the reaction, H2O was added and the mixture was extracted with EA/H2O. After removing moisture with MgSO4 and performing distillation under reduced pressure, Compound 2-3 (17 g, 87percent) was obtained by column(MC/Hexane) separation.
63%
Stage #1: at -78℃; for 0.166667 h; Inert atmosphere Stage #2: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Stage #3: at 20℃; for 12 h;
1,3-dibromobenzene (20g, 84. 77mmol) was added to the reaction vessel, and nitrogen atmosphere was created in a vacuum state. After addition of tetrahydrofuran (500mL), the mixture was stirred at -78 ° C for 10 min. After slowly added N-BuLi (2. 5M) (33. 9mL, 84. 77mmol), the mixture was stirred at -78 ° C for 1 hour. Chloro triphenylsilyl(29. 9g, 107. 72mmol) was dissolved THF (lOOmL) in, and slowly added the mixture. After stirring for 12 hours at room temperature, the reaction was complete and the mixture was washed with distilled water. Extracted with EA, and the organic layer was dried with MgS04, using a rotary evaporatorAnd slowly added to the solvent. To give compound A-4 (62g, 63percent) was recrystallized from MC and Μ0Η
63%
Stage #1: at -78℃; for 0.166667 h; Inert atmosphere Stage #2: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere Stage #3: at 20℃; for 12 h; Inert atmosphere
20g (84.77mmol) 1,3-dibromobenzene in a reaction vessel to create a vacuum with nitrogen atmosphere was added 500mL THF was stirred at -78 °C 10 minutes. 33.9 mL (84.77 mmol) of n-BuLi (2.5 M) was slowly added thereto, followed by stirring at -78 °C for 1 hour. 29.9 g (107.72 mmol) of chlorotriphenylsilane was dissolved in 100 mL of THF and then slowly added. After stirring for 12 hours at room temperature, the reaction mixture was washed with distilled water and extracted with EA. The organic layer was dried over MgSO4. The solvent was removed by a rotary evaporator and the residue was recrystallized from MC and MeOH to obtain 62 g (63percent) of Compound A-4.
Stage #1: With n-butyllithium In tetrahydrofuran-d8 at -78℃; for 1 h; Stage #2: at 20℃; for 5 h;
1,3-Dibromobenzene 28 g(0.119 mol) was dissolved in THF 600 mL, and then n-BuLi 47.5 mL was slowly added dropwise thereto at -78°C, followed by stirring for 1 hour. 2-Chloro-4,6-diphenyl-1,3,5-triazine 47.5 mL was slowly added dropwise thereto, and the resultant mixture was stirred at room temperature for 5 hours after the temperature was slowly raised. After the reaction is completed, extraction with EA and distilled water and column separation were sequentially performed, thereby obtaining Compound 9-1 15.7 g (40.43 mmol, 40.4percent).
28%
With n-butyllithium In tetrahydrofuran at -78 - 20℃; for 12 h;
1,3-dibromobenzene was dissolved in THF and cooled into the temperature of —78° C. n-l3uLi (60 mE, 2.5M) was slowly dropped into the solution, and 2-chioro-4,6-diphenyl-1,3,5-triazine (40 g, 149.7 mmol), whichdissolved in THF, was slowly dropped. The solution was slowly heated up to the room temperature and stirred forhours. After completion of the reaction, the resultant was re-precipitated by THF/MeOH and MC (methylenechloride)/hexane such that 2-(3-bromophenyl)-4,6-diphenyl-15-triazine (16 g, yield: 28percent) was obtained.
Reference：
[1] Patent: EP2857395, 2015, A1, . Location in patent: Paragraph 0076
[2] Patent: US2018/130953, 2018, A1, . Location in patent: Paragraph 0211; 0212
[3] Patent: JP2016/108255, 2016, A, . Location in patent: Paragraph 0087-0089
With n-butyllithium; diisopropylamine; In tetrahydrofuran; at -78℃; for 1.83333h;Inert atmosphere;
2,6-dibromobenzoic acid was synthesized according to literature procedure. See, e.g., Varcoe, J.R. et al., Chem. Mater. 2007, 19, 2686-2693, incorporated herein in its entirety. More specifically, dry tetrahydrofuran (THF, 400 mL) in a 2-neck round- bottom flask under argon was cooled to 0 C in an ice-water bath. n-Butyllithium (2.5 M in hexanes, 117 mL) was added followed by a slow addition of diisopropylamine (45 mL) at 0 C to form lithium diisopropylamide (LDA). The mixture was stirred for 45 min and then cooled to -78 C in a dry ice/acetone bath. While at this temperature, 1,3-dibromobenzene (50.0 g, 0.212 mol) was added drop-wise over 5 min and stirred for 1 h. Dry ice was then closed in a glass container and connected by syringe into the reaction mixture. After bubbling the mixture with the evolved gaseous CO2 for 45 min, pieces of dry ice were added into the mixture. The mixture was allowed to slowly warm up to room temperature. Aqueous sodium hydroxide (0.5 M) and ethyl acetate (400 mL) were added until all of the solid was dissolved. The aqueous layer was washed with ethyl acetate and then acidified with concentrated hydrochloric acid until approximately pH=1. The precipitate was dissolved in fresh ethyl acetate, washed with brine, dried over MgSO4, filtered, and the solvent was evaporated at 40 C under vacuum. The oil was cooled to room temperature, resulting in crystallization. The solid was boiled in hexanes (2 L) for 1 h and then cooled to room temperature. The solid was collected, washed with hexanes, and dried under vacuum at 80 C, resulting in 1 (39.3 g, 66%) as an off-white powder. 1H NMR (500 MHz, DMSO-d6, delta 7.70 (d, J = 8.1 Hz, 2H), 7.29 (t, J = 8.1 Hz, 1H).13C NMR (125 MHz, DMSO-d6, delta 166.87, 138.67, 131.87, 131.65.
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 85℃; for 18h;Inert atmosphere;
1,3-dibromobenzene (2.5 g, 10.6 mmol), bis(pinacolato)diboron (6.0 g, 23.5 mmol), Pd(dppf)2Cl2 (0.9 g, 1.2 mmol), and potassium acetate (7.1 g, 72.1 mmol) were dissolved in 50 mL of 1,4-dioxane. The reaction mixture was degassed with argon and then heated to 85 C. under argon for 18 hours. The reaction mixture was filtered and an extraction was performed in ethyl acetate. The organic phase was washed with water and brine. The extract was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by a silica gel column with 1:9 ethyl acetate:hexanes as the eluent. The solvents were removed and the product was recrystallized from dichloromethane/methanol to yield the product as an off-white solid 4 (3.008 g, 86% yield).
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 9h;Inert atmosphere;
Synthesis Example 3; Compound A-3 was synthesized by the method illustrated in Scheme 3.; To 7 ml of 1,4-dioxane (produced by Wako Pure Chemical Industries, Ltd.) were added 0.34 g of compound (3-a) (produced by Tokyo Chemical Industry Co., Ltd.), 0.85 g of bis (pinacolato) diboron (produced by BASF Japan Ltd.) and 0.86 g of potassium acetate (produced by Wako Pure Chemical Industries, Ltd.). Under a nitrogen atmosphere, 0.21 g of [bis(diphenylphosphino)ferrocene]dichloropalladium (produced by Aldrich Chemical Company, Inc.) was added and the resulting mixture was stirred at 80C for 9 hours. To the resulting solution were added 100 ml of water and 100 ml of ethyl acetate. Then, an organic layer was fractionated, washed with 100 ml of water, and then dried with magnesium sulfate. The resulting solution was purified by column chromatography (filler: silica gel, eluent: dichloromethane) to obtain 167 mg of compound (3-b).
Preparation 14 5.0 g of <strong>[876-53-9]1,3-dibromoadamantane</strong>, 2.3 g of aluminium bromide and 100 ML of 1,3-dibromobenzene were placed into a 300 ML four-necked flask, and the mixture was stirred overnight while maintaining at 0 C. with an ice bath.Thereafter, a temperature was retained at 60 C. for 4 hours.After cooling, 100 ML of 1N hydrochloric acid was placed, the mixture was stirred well, and the organic layer was taken out, and washed with 100 ML of water.About 400 ML of methanol was added to the organic layer, the precipitated crystals were filtered and dried to obtain 6.8 g of 1,3-bis(3,5-dibromophenyl)adamantane.
With sodium carbonate;tetrakis(triphenylphosphine)palladium (0); In diethyl ether; ethanol; hexane; toluene;
EXAMPLE 38 3-[3-(Pyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-alpha]pyrimidine A mixture of 1,3-dibromobenzene (8.7 g, 36.8 mmol) and pyridine-3-boronic acid-1,3-propanediol cyclic ester (4.0 g, 24.5 mmol) in EtOH (60 ml) and toluene (60 ml) together with 2N Na2CO3 solution (24.5 ml) was degassed with a stream of N2 for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.22 mmol) was added and the reaction heated at reflux for 14 h. The mixture was concentrated under reduced pressure to remove the organic solvents. The organics were extracted with EtOAc (2*125 ml) and then washed with brine (75 ml), dried (MgSO4), and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography on silica, using 80% diethyl ether in hexane as the eluent, to yield 3-(3-bromophenyl)pyridine (3.66 g, 64%): deltaH(360 MHz, CDCl3) 7.30-7.42 (2H, m), 7.47-7.60 (2H, m), 7.72 (1H, s), 7.84 (1H, dt, J 8 and 2), 8.62 (1H, dd, J 4.8 and 1.5), 8.83 (1H, s).
With tetra(n-butyl)ammonium hydroxide; sodium carbonate;tetrakis(triphenylphosphine)palladium (0); In 1,2-dimethoxyethane; diethyl ether; water;
Part A 3-[3-(Tri-n-butylstannanyl)phenyl]Pyridine A mixture of 1,3-dibromobenzene (105.0 g, 0.45 mol), diethyl(3-pyridyl)borane (30.0 g, 0.204 mol) and tetrabutylammonium hydroxide (2 ml of a 40 wt % solution in water) in 1,2-dimethoxyethane (200 ml) and sodium carbonate (100 ml of a 2M solution) was degassed with nitrogen for 15 min before addition of tetrakis(triphenylphosphine)palladium(0) (4.5 g, 3.9 mmol). The mixture was heated at 80 C. for 18 h, cooled to room temperature, diluted with ethyl acetate and extracted with 1M hydrochloric acid (4*250 ml). The combined aqueous phases were made basic with solid sodium hydroxide and then extracted with diethyl ether. The organic layer was washed with water, brine, dried over sodium sulphate and concentrated to give a yellow oil. Purification by silica gel chromatography eluding with isohexane on a gradient of diethyl ether (10% to 50%) gave 3-(3-bromophenyl)pyridine (33.5 g, 70%) as a colourless oil. 1H NMR (400 MHz, CDCl3) deltaH 7.28-7.40 (2H, m), 7.48-7.57 (2H, m), 7.73 (1H, t, J 2), 7.82-7.87 (1H, m), 8.62 (1H, s), 8.80 (1H, s).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃;Inert atmosphere;
Example 31; Synthesis of Compound 43; 3-Pyridineboronic acid pinacol ester (8.7 g, 42.4 mmol) and 1,3-dibromo benzene (50.04 g, 212 mmol) were added to a 500 mL of three-neck round bottom flask. To this flask, dioxane (250 mL) and aqueous K2CO3 (2 N, 125 mL) was added. The mixture was stirred and degassed with a steam of argon for 30 minutes. Then under argon atmosphere 1 g of Pd(PPh3)4 was added. The mixture was brought to 80 C. and stirred overnight. The next day, solvent was removed by roto-evaporation and residue was suspended into an equal amount of water (200 mL) and CH2Cl2 (200 mL). The organic layer was separated from aqueous layer and washed with water (100 mL) and brine solution (100 mL). After dried over Na2SO4, and removal of drying agent, some silica gel was added to flask and the mixture was evaporated down to dryness. This silica gel absorbed with mixture of starting material and product was transferred to a medium frit preload with a bed of fresh silica gel. Hexane (1 L) was used to rinsed the bed afford un-reacted starting material. Ethyl acetated (1 L) was rinsed to the silica gel bed, afford 9 g of product. 1H NMR (CDCl3) delta 8.83 (dd, 1H), 8.64 (dd, 1H), 7.86 (dt, 1H), 7.74 (t, 1H), 7.55 (dt, 1H), 7.52 (dt, 1H), 7.39(dd, 1H), 7.37(t, 1H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃;Inert atmosphere;
Example 4Synthesis of Compound 3 3-Pyridineboronic acid pinacol ester (8.7 g, 42.4 mmol) and 1,3-dibromo benzene (50.04 g, 212 mmol) were added to a 500 mL of three neck round bottom flask. To this flask, dioxane (250 mL) and aqueous K2CO3 (2 N, 125 mL) were added. The mixture was stirred and degassed with a steam of argon for 30 minutes. Then under, argon atmosphere, 1 g of Pd(PPh3)4 was added. The mixture was brought to 80 C. and stirred overnight. The next day, solvent was removed by roto-evaporation and residue was suspended into an equal amount of water (200 mL) and CH2Cl2 (200 mL). The organic layer was separated from aqueous layer and washed with water (100 mL) and brine solution (100 mL). After dried over Na2SO4, and removal of drying agent, some silica gel was added to the flask and the mixture was evaporated down to dryness. This silica gel absorbed with mixture of starting material and product was transferred to a medium fit preloaded with a bed of fresh silica gel. Hexane (1 L) was used to rinse the bed to afford un-reacted starting material. 1 L of ethyl acetated was rinsed to the silica gel bed, affording 9 g of product. 1H NMR (CDCl3) delta 8.83 (dd, 1H), 8.64 (dd, 1H), 7.86 (dt, 1H), 7.74 (t, 1H), 7.55 (dt, 1H), 7.52 (dt, 1H), 7.39 (dd, 1H), 7.37 (t, 1H).
4-[1-(3-Bromo-phenyl)-vinyl]-1-trifluoromethoxy-benzene A solution of n-butyllithium (1.6 M in hexane, 17.8 mL, 28.4 mmol, 1.16 eq.) was added dropwise over 20 min to a solution of 1,3-dibromobenzene (3.26 mL, 26.95 mmol, 1.1 eq) in 25 mL of dry tetrahydrofuran at -78° C. and under an inert atmosphere. The white suspension formed was stirred at -78° C. for 30 min. A solution of 4-(trifluoromethoxy)-acetophenone (5 g, 24.5 mmol, 1.0 eq.) in 25 mL of tetrahydrofuran was then added dropwise and the reaction stirred for 1 h. The reaction mixture was examined by LC-MS which showed the complete formation of tertiary alcohol. The solution was quenched with a saturated solution of ammonium chloride and water. 2 N HCl was then added to reach pH=5. The two phases were separated; the organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual material (tertiary alcohol) was dissolved in a mixture of acetic acid/sulfuric acid (10 mL of acetic acid, 0.3 mL of sulfuric acid) and the reaction mixture was stirred for 3 h at room temperature; then it was examined by LC-MS which showed the complete formation of desired product. The solution was quenched with ice and dichloromethane (20 mL) was added. The two phases formed and were separated. The organic layer was washed with a saturated solution of sodium bicarbonate and brine. It was then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crude was purified by flash chromatography eluding with petroleum ether to give the desired product as a colourless liquid (3.60 g, Yield: 43percent). Mass (calculated) C15H10BrF3O [343]; [M+H+] not observed LC Rt=3.20 min (5 min method) 1H-NMR (CDCl3): 5.49 (s, 2H); 7.21 (m, 4H); 7.34 (m, 2H); 7.49 (m, 2H)
Preparations; Preparation 1.; (4- (3-Bromo-phenyl)-cyclohex-3-enyl)-dimethyl-amine; Combine 1,3-dibromobenzene (6.708 g, 28.4 mmol) and anhydrous ether (90 mL) and cool to-25C. Add n-BuLi (1.6M solution in hexanes, 19.4 mL, 3.0 mmol) to the above solution and stir for 10 min. Then add a solution of 4-dimethylamino- cyclohexanone (3.65 g, 25.8 mmol) in anhydrous ether (10 mL) through a cannula. Stir the mixture for 1.5 hr. at-10C and then quench with saturated NaHCO3 solution. Separate the organic layer, extract the aqueous layer three times. Combine the organic layers, dry over sodium sulfate, filter and concentrate to give a residue. Purify the residue by chromatography (silica gel, 7% 2M NH3/MeOH in DCM) to provide the alcohol intermediate as a mixture of two diastereomers (6.01 g). Dissolve the above alcohol in trifluoroacetic acid (15.5 mL, 0.20 mol) and heat at 50C for 5 hr. Remove volatiles under reduced pressure, partition the residue in DCM/water, adjust pH>l 1 with 1N NaOH solution. Extract the aqueous layer three times with DCM, combine the organic layers, dry over sodium sulfate, filter and concentrate to give a residue. Purify by chromatography (silica gel, 7% 2M NH3/MeOH in DCM) to provide the title compound (3.41 g, 47. 1% two-step yield). Separate the two enantiomers by chiral HPLC (Chiralpak AD 4.6 x 250 mm, eluting with 0.2% dimethethylamine in acetonitrile, flow rate: 1 mL/min.) to provide two enantiomers: isomer 1A (tR = 13. 0 min), isomer 1B (tR = 16. 1 min), MS (ES): m/z = 280.0 (M+H) +, 1H NMR (CDC13) : 8 7.54 (br, 1H), 7. 38-7. 29 (m, 2H), 7.22-7. 16 (m, 1H), 6.10 (br, 1H), 2.55-2. 41 (m, 4H), 2.37 (s, 6H), 2.27-2. 13 (m, 2H), 1.58 (m, 1H).
With copper; potassium carbonate; In dimethyl sulfoxide; at 180℃; for 4h;
Another reaction vessel was charged with 17.2 ml of 1,3-dibromobenzene, 6.0 g of 5H-pyrido[4,3-b]indole, 1.1 g of copper powder, 9.9 g of potassium carbonate, and 0.6 ml of dimethyl sulfoxide, followed by heating and stirring at 180C for 4 hours. After cooling to room temperature, 50 ml of chloroform was added thereto, the insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (carrier: silica gel, eluent: hexane/chloroform) to obtain 7.1 g (yield 62%) of 5-(3-bromophenyl)-5H-pyrido[4,3-b]indole as a white powder.
Example 9ii (3-BromophenyI)(tetrahydro-2H-pyran-4-yI)methanimine 1,3-Dibromobenzene (3.04 mL, 25.2 mmol) was dissolved in Et2O (60 mL) and cooled to - 78 0C. n-Butyllithium (10.1 mL, 25.25 mmol) was added and the the solution stirred for 30 min. Tetrahydro-2H-pyran-4-carbonitrile (2.80 g, 25.20 mmol) was added in Et2O (20 mL) is at -78 0C and the reaction was stirred for 30 min. The reaction was then allowed to warm to room temperature over 30 min. MeOH (20 mL) containing ammonium acetate (2 g, 25.95 mmol) was added. The solvents were evaporated and the residue taken up in DCM and water. The organic layer was separated and the aqueous phase extracted with DCM. The combined organic phases were shaken with brine and dried over MgSO4. The mixture was20 filtered and the solvent evaporated to yield 4.64 g (69% yield) of the title compound: MS (ES+) m/z 268, 270 [M+H]+.
General procedure: To degassed DMF (8.0 mL) was added Pd(dppf)Cl2 (73 mg, 0.10 mmol), bis(pinacolato)diboron (508 mg, 2.0 mmol), potassium acetate (589 mg, 6.0 mmol), and 2,6-dibromobenzene (0.121 mL, 236 mg, 1.0 mmol) in order at room temperature. The mixture was heated to 130 C for 1 hour to complete formation of the boronic ester. Then 3-bromopyridine (0.289 mL, 474 mg, 3.0 mmol) and degassed aqueous sodium hydroxide (2.00 mL, 3.0 M, 6.0 mmol) were sequentially added to the hot reaction, and heating at 130 C was continued for another 3 hours when the reaction was complete (by GCMS). The reaction was cooled and evaporated to a residue in vacuo. The residue was extracted with chloroform, and the combined extracts were concentrated and applied to preparative silica TLC plates. After development by 1:1 THF:EtOAc the product bands were removed and extracted with DME. Evaporation of extract solutions resulted in the yields. The products could be purified by sublimation at 180 C and 10 mmHg if needed.
1,3-Dibromobenzene 20 g (84.77 mmol) was dissolved in THF 500 mL, and then cooled to a temperature of -78. n-BuLi 2.5M 33.9 mL(84.77 mmol) was slowly added thereinto, and then stirred at a temperature of -78 for 1 hour. Chlorotriphenylsilane ((C6H5)3SiCl) 29.9 g was dissolved in THF 100 mL, and this solution was added into the above reaction mixture. The resultant mixture was slowly warmed to room temperature, and stirred for 12 hours. Then, extraction with EA, wash with distilled water and aqueous NaCl solution, drying over MgSO4, distillation under reduced pressure, and recrystallization with MC-MeOH in the ratio of 1:10, were sequentially performed, thereby obtaining Compound 8-1 18 g(95 %).
87%
Preparation of Compound 2-3 After 1,3-dibromobenzene (11.2 g, 47 mmol) was dissolved in THF (200 mL), the mixture was cooled to -78 C. After slowly adding n-BuLi (19 mL, 2.5M in hexane, 70.5 mmol), the mixture was stirred for 1 hour. Solution that TPS-Cl (20 g, 56.8 mmol) was dissolved in THF (25 mL) was slowly added. After slowly increasing temperature, the mixture was stirred at room temperature for one day. Upon completion of the reaction, H2O was added and the mixture was extracted with EA/H2O. After removing moisture with MgSO4 and performing distillation under reduced pressure, Compound 2-3 (17 g, 87%) was obtained by column(MC/Hexane) separation.
63%
1,3-dibromobenzene (20g, 84. 77mmol) was added to the reaction vessel, and nitrogen atmosphere was created in a vacuum state. After addition of tetrahydrofuran (500mL), the mixture was stirred at -78 C for 10 min. After slowly added N-BuLi (2. 5M) (33. 9mL, 84. 77mmol), the mixture was stirred at -78 C for 1 hour. Chloro triphenylsilyl(29. 9g, 107. 72mmol) was dissolved THF (lOOmL) in, and slowly added the mixture. After stirring for 12 hours at room temperature, the reaction was complete and the mixture was washed with distilled water. Extracted with EA, and the organic layer was dried with MgS04, using a rotary evaporatorAnd slowly added to the solvent. To give compound A-4 (62g, 63%) was recrystallized from MC and Mu0Eta
63%
20g (84.77mmol) 1,3-dibromobenzene in a reaction vessel to create a vacuum with nitrogen atmosphere was added 500mL THF was stirred at -78 C 10 minutes. 33.9 mL (84.77 mmol) of n-BuLi (2.5 M) was slowly added thereto, followed by stirring at -78 C for 1 hour. 29.9 g (107.72 mmol) of chlorotriphenylsilane was dissolved in 100 mL of THF and then slowly added. After stirring for 12 hours at room temperature, the reaction mixture was washed with distilled water and extracted with EA. The organic layer was dried over MgSO4. The solvent was removed by a rotary evaporator and the residue was recrystallized from MC and MeOH to obtain 62 g (63%) of Compound A-4.
60%
Under a nitrogen atmosphere,1,3-Dibromobenzene (5.12 ml, 42.39 mmol) was dissolved in THF (200 mL).The reaction temperature was lowered to about -78 C.N-BuLi (2.5 M in hexanes, 17 ml, 42.5 mmol) was slowly added dropwise to the reaction mixture.It was then stirred at the same temperature for about 1 hour.A solution of triphenylsilyl chloride (15 g, 50.87 mmol, THF (50 ml)) was slowly added dropwise to the reaction mixture.Stir at about -78 C for about 1 hour,Then, the reaction mixture was stirred at room temperature for about 12 hours.A 20% NH4Cl solution was added to the reaction mixture to terminate the reaction.The reaction mixture was extracted with EA.The organic layer was separated, dried over MgSO 4 to remove water and separated by column chromatography (hexane).To give the intermediate compound (12) (10.57g, 60% yield).
(R)-tert-butyl (1-(3-bromophenyl)pyrrolidin-3-yl)methylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 80℃; for 16h;
Step 1: (R)-tert-Butyl 2-(3-(3-(butyloxycarbonylaminomethyl)pyrrolidin-1-yl)phenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate 1,3-Dibromobenzene (0.2 g, 0.85 mmol), <strong>[173340-25-5](R)-tert-butyl pyrrolidin-3-ylmethylcarbamate</strong> (0.17 g, 0.85 mmol), Pd2(dba)3 (39 mg, 0.04 mmol), BINAP (40 mg, 0.06 mmol) and sodium tert-butoxide (98 mg, 1.02 mmol) were suspended in toluene (2 mL). The mixture was heated at 80 C. for 16 hr. The mixture was cooled and diluted with water and EtOAc. The organic layer was separated, passed through a phase separator cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (R)-tert-butyl (1-(3-bromophenyl)pyrrolidin-3-yl)methylcarbamate as a yellow oil (0.179 g, 59%).
To 1,3-dibromobenzene (807 mg, 3.42 mmol) was added 5-chloro-2-fluoropyridin-4- ylboromc acid (300 mg, 1.711 mmol), PdC12(dppf).CH2C12 adduct (140 mg, 0.171 mmol), DME (7 ml) and then last 2M sodium carbonate (2.57 ml, 5.13 mmol). The reaction was stirred at 85-90 C for 2 hr. The reaction was followed by LCMS. The reaction was cooled, 20 ml of ethyl acetate was added, filtered and concentrated to crude product. The crude was purified by silica gel chromatography using 40g column eluting with 0-15% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 252 mg of the titled compound as free base used without further purification. In addition 12 mg was further purified by prep LC and lyophilized to give 3.1 mg of title compound as TFA salt. LCMS (m/z): 286.1/288.0 (MH+), rt = 1.17 min.
With copper; potassium carbonate; nitrobenzene; at 120 - 160℃;Inert atmosphere;
First, 1 times the equivalent of carbazole,1 to 1.5 equivalents of dihalogenated benzene, such as m-dibromobenzene,0.44 times the equivalent of Cu (electrolytic refined copper),4.04 times the equivalent of K2CO3 into the reaction vessel,Nitrobenzene as the reaction solvent,Nitrogen protection under 120 ~ 160 reaction 12 ~ 48h,The reaction solution was distilled under reduced pressure to obtain a crude product,The pure product was obtained by column chromatography,The yield was 75-85%.
83%
With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 5,5-dimethyl-1,3-cyclohexadiene; at 120℃; for 24h;Inert atmosphere;
To a 500 mL reaction flask was charged 20 g (84.7 mmol) of m-dibromobenzene,14 g (84.7 mmol) of carbazole, 1.6 g (8.77 mmol)Cuprous iodide,1.5 g (16.9 mmol)ofN-dimethyl-1,2-ethanediamine, 117 g (0.847 mol) of potassium carbonate and 300 ml of solvent xylene,Nitrogen protection Heating to 120 C,Insulation reaction for 24 hours.The water bath was cooled to 80 C and filtered while hot. The filter cake was washed with toluene and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column eluting with petroleum ether / dichloromethane to give 22.6 g of a white solid product. Yield: 83%
71%
With copper; potassium carbonate; In N,N-dimethyl-formamide; at 130℃;Inert atmosphere;
see Kido, J.; Su, S. -J.; Sasabe, H.; Takeda, T.; Chem. Mater. 2008, 20(5), 1691-1693, which is incorporated by reference herein for its relevant teachings) was prepared as follows: a mixture of carbazole (4.000 g, 23.92 mmol), 1,3-dibromobenzene (14.11 g, 59.81 mmol), K2CO3 (9.919 g, 71.77 mmol), copper powder (4.561 g, 71.77 mmol) and anhydrous N,N-dimethylformamide (DMF) (120 mL) was degassed with argon for 1 h. while stirring. The reaction mixture was then maintained under argon at 130 C. while stirring for 4 days until TLC (SiO2, 4:1 hexanes-dichloromethane) indicated consumption of the starting material. Upon cooling to RT, about 300 mL dichloromethane was added, the crude mixture filtered, the filtrant wash with an additional 200 mL dichloromethane, and the filtrate concentrated in vacuo. The resulting residue was then purified by flash chromatography (SiO2, hexanes) to yield Compound 3 (5.47 g, 71%) as a colorless oil.
With copper(l) iodide; calcium carbonate; at 158℃;Inert atmosphere;
(1) carbazole, m-dibromobenzene and calcium carbonate are placed in a reactor at a molar ratio of 1: 1.2: 2.5, stirred in a water bath at 33 C., purged with nitrogen, and added with cuprous iodide, L- Amino acid,Heated to 158 reaction, TCL test to determine the absence of raw materials after the reaction was terminated by water,The product was cooled to room temperature via an ice-water bath, the solid was precipitated by stirring and the resulting solid was filtered off with suction to give 9- (3-bromophenyl) carbazole.
80 mmol
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; potassium tert-butylate; In 5,5-dimethyl-1,3-cyclohexadiene; for 6h;Reflux;
Step 1. Add 100 mmol of carbazole to the reaction vessel.m-dibromobenzene 100mmol,Potassium tert-butoxide 300mmol,Pd2 (dba) 3 1mmol,Ultrasonic deoxygenated xylene,Stir and dissolve,Replace the air three times,Adding ligand tri-tert-butylphosphine 4% (4mmol, 50% m/V),Replace the air three times,The reaction was refluxed for 6 h.Cool to room temperature,Add enough dichloromethane to completely dissolve the product.a small amount of silica gel funnel,Remove catalyst and salt.The filtrate is concentrated to a viscous state.Column chromatography,The product was obtained 3-1 80 mmol.
With tris-(dibenzylideneacetone)dipalladium(0); johnphos; sodium t-butanolate; In toluene; for 1h;Inert atmosphere;
General procedure: A round-bottomed flask was charged with Pd2(dba)3 (5 mol percent ), ligand (10 molpercent), aryl halide (1mmol), appropriate isoquinolinamine (1 mmol), base (1.5 mmol) and dry solvent (5 mL). Theflask was flushed with argon for 5 min. The mixture was heated at reflux under magnetic stirring.After cooling down to room temperature, the reaction mixture was concentrated and the residuewas purified by flash column chromatography on silica gel.
With bromotris(triphenylphosphine)copper(I); potassium carbonate; In N,N-dimethyl-formamide; toluene; at 140 - 145℃; for 12 - 18h;Inert atmosphere; Dean-Stark;
In a procedure analogous to resin 6a, bisphenol A6F (2b) (100g, 297mmol), 1,3-dibromobenzene (3) (35.0g, 148mmol), (PPh3)3CuBr (1.4g, 1mol% to 3), powdered anhydrous K2CO3 (61.05g, 446mmol), and 4-nitrophthalonitrile (5) (52.3g, 302mmol) were reacted in toluene (50mL), and N,N-dimethylformamide (DMF) (500mL) to yield 1b (147.2g, 98%) after workup and vacuum drying as an amber colored glassy solid. 1H NMR (300MHz, CDCl3): delta 7.80-7.72 (m, aromatic-H), 7.55-7.43 (m, aromatic-H), 7.40-7.26 (m, aromatic-H), 7.15-6.92 (m, aromatic-H), 6.89-6.76 (m, aromatic-H). 13C NMR (75MHz, CDCl3): delta 160.47, 160.41, 157.48, 151.29, 157.10, 157.08, 154.34, 154.16, 135.44, 132.31, 131.85, 131.71, 131.50, 130.70, 130.61, 130.24, 128.56, 128.40, 127.60, 127.21, 122.09, 122.05, 119.89, 119.74, 117.64, 117.55, 117.40, 117.39, 115.12, 115.00, 114.91, 114.72, 111.04, 110.98, 109.37, 109.30 (aromatic). IR [cm-1]: nu 3042 (C=CH), 2232 (CN), 1592 (C=C), 1498 (aromatic), 1308 (aromatic), 1278 (C-O), 1242 (-CF3), 1160 (C-O), 927 (C-O), 837 (aromatic). Calc. For M+(C52H26F12N4O4) 998.18 (n=1); Mass calculated from observed ESI-MS m/z ratio was 998.17, corresponding to n=1.
With potassium phosphate monohydrate; palladium dichloride; 3-(diphenylphosphino)propionic acid; In dimethyl sulfoxide; at 100℃; for 12h;Schlenk technique;
General procedure: The Schlenk tube (5 mL) equipped with a stir bar was charged with PdCl2 (1.0 mol%), Ph2P(CH2)2COOH (2.0 mol%), and K3PO4 ·H2O (4.0 equiv.), then 1,4-dibromobenzene (0.5 mmol), phenylboronic acid (1.20 mmol), and DMSO (2.0 ml) were added, and the mixture was stirred at 100 C until the substrate was completely consumed. After cooling to room temperature, the solution was quenched with water and extracted with EtOAc (3 × 10 mL). The combined EtOAc extracts were dried over anhydrous Na2SO4 and filtrated and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel with PE as the eluent to obtain the desired products.
N1,N3-bis(4-hexylphenyl)benzene-1,3-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; hexane; water;
Example 1-4 Preparation of N1,N3-bis(4-hexylphenyl)benzene-1,3-diamine 1,3-Dibromobenzene (0.5 g, 2.1 mmol) was dissolved in 1,4-dioxane, mixed with <strong>[33228-45-4]4-hexylaniline</strong> (0.88 mL, 4.5 mmol), Pd2(dba)3 (0.061 mg, 0.1 mmol), XPhos (0.1 g, 0.21 mmol) and t-BuONa (0.6 g, 6.4 mmol) and then heated at 100 C. for 18 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and water was added. The mixture was extracted with MC, dried with Na2SO4, concentrated and suspended in n-hexane to obtain the target compound (0.42 g, yield: 47%) (compound 1d). 1H NMR (400 MHz, CDCl3): delta 7.100-7.073 (m, 5H), 7.028-7.007 (m, 4H), 6.682-6.672 (t, 1H), 6.560-6.534 (m, 2H), 5.568 (s, 2H), 2.572-2.533 (t, 4H), 1.612-1.576 (m, 4H), 1.322-1.318 (m, 12H), 0.911-0.877 (t, 6H).
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium carbonate; bis(dibenzylideneacetone)-palladium(0); In water; acetonitrile; at 80℃; for 2h;Inert atmosphere; Microwave irradiation; Schlenk technique; Sealed tube;
A microwave tube was filled with quinolin-8-yl boronic acid (243 mg, 1.40 mmol), 1,3-dibromobenzene (163.5 mg, 0.695 mmol), Pd(dba)2 (14 mg, 0.025 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (22.5 mg, 0.055 mmol) and potassium carbonate (640 mg, 4.65 mmol). After addition of acetonitrile (3.75 mL) and H2O (4 mL) the tube was sealed, then evacuated and flushed with nitrogen three times. Finally, the mixture was heated at 80 C (50 W) for 2 h in a CEM Focused Microwave oven. The crude product was poured into H2O/CH2Cl2 mixture and the organic layer separated and dried over sodium sulfate. The extract was purified by column chromatography on silica gel eluting with mixtures of ethylacetate/hexanes (30 to 100%). The resultant solution was left to stand overnight in the fume chamber to yield the title compound as an off-white solid. (63 mg, 22.5%). Anal. Calcd for C24H16 N2: C, 86.72; H,4.85; N, 8.43. Found: C, 86.53; H, 4.96; N, 8.11. 1H NMR (400 MHz, CDCl3): delta = 8.98 (dd, 2H), 8.20 (dd, 2H),7.98 (t, 1H), 7.86 (dd, 2H), 7.84-7.77 (m, 4H), 7.62 (m, 3H), 7.41 (quartet, 2H). 13C NMR, delta = 149.78, 145.67,140.68, 138.69, 135.91, 132.37, 130.21, 129.62, 128.37, 127.09, 127.01, 125.98, 120.54. TOF MS-ES+, m/z:355.1215 (M + Na)+.
With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; potassium carbonate; In toluene; at 110℃;Inert atmosphere;
To a solution of 1,3-dibromobenzene (933 mg, 3.96 mmol) in toluene (2 mL), 1,3-oxazinan-2-one (200 mg, 1.978 mmol), potassium carbonate (547 mg, 3.96 mmol) and(1 R,2R)-N 1 ,N2-dimethylcyclohexane- 1 ,2-diamine (56.3 mg, 0.396 mmol) were added. The mixture was purged with nitrogen and copper(I) iodide (75 mg, 0.3 96 mmol) was added and the resulting mixture was heated at 110 C overnight. The reaction mixture was filtered, the filter cake was washed with 20 mL of DCM, and the combined filtratewas concentrated and residue was purified on silica gel eluting with a gradient of 0-10% MeOH/DCM to give 3-(3-bromophenyl)-1,3-oxazinan-2-one (342 mg, 67.5% yield). LCMS M = 256.05/25 8.05. Method G. Retention time 2.444 mm.
N-(3-(3-bromophenyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.7%
To a solution of 1,3-dibromobenzene (5.76 mL, 4.77 mmol) in THF (28.9 mL) at-78 C was added N-butyllithium (1.78 mL, 4.45 mmol, 2.5M solution in THF) dropwise and the mixture. After lh, Intermediate N8-A (557 mg, 3.18 mmol) was added dropwiseas a solution in 2 mL of THF, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction was quenched by the addition of water (10 mL) and the organic volatiles were removed in vacuo. The resulting aqueous suspension was extracted with 2x 20 mL of ethyl acetate and the organic layer was washed with brine, dried over MgSO4 and concentrated. The crude residue was purifiedby silica gel chromatography eluting with a gradient of ethyl acetate in hexanes providing N-(3 -(3 -bromophenyl)oxetan-3 -yl)-2-methylpropane-2-sulfinamide (650 mg, 1.866 mmol, 58.7% yield) as a pale yellow oil. ?H NMR (400MHz, CDC13) oe 7.57-7.52 (m, 1H), 7.50 (dt, J=7.7, 1.7 Hz, 1H), 7.39-7.28 (m, 2H), 5.17 (d, J=7.0 Hz, 1H), 5.07 (d, J=7.0 Hz, 1H), 5.03 (d, J=7.0 Hz, 1H), 4.95 (d, J=6.8 Hz, 1H), 1.24 (s, 9H).
44%
To a solution of 1,3-dibromobenzene (0.52 mL, 4.3 mmol) in THF (20 mL) at -78 C was added w-BuLi (2.5 M in hexanes, 1.6 mL, 4.0 mmol) and the resultant mixture was stirred at -78 C for 1 hour. <strong>[1158098-73-7]2-methyl-N-(3-oxetanylidene)propane-2-sulfinamide</strong> (0.50 g, 2.9 mmol) was added via cannula as a solution in THF (2 mL) and the reaction mixture was stirred at -78 C for an additional 1 hour. The reaction was quenched with saturated NH4C1 (aq) (20 mL) and extracted with EtOAc (3 X 30 mL). The combined organic extracts were washed with brine (1 X 40 mL), filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (25 g, 0 - 100% EtOAc/hexanes) to give 0.63 g (44%) of Intermediate 8A
5-(3-bromophenyl)-1-methylpyridin-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
To a solution of 5 -bromo- 1 -methylpyridin-2( 1 H)-one (400 mg, 2.127 mmol) in dioxane (10 mL) was added 4,4,4?,4?,5,5,5 ?,5?-octamethyl-2,2?-bi( 1,3 ,2-dioxaborolane) (702 mg, 2.77 mmol), potassium acetate (626 mg, 6.38 mmol), and PdC12(dppf)-CH2C12adduct (174 mg, 0.2 13 mmol). The microwave reaction vessel was degassed with N2 as described previously. The sealed reaction vessel was heated at 120 C in a microwave for 60 mm. To the cooled reaction mixture were added 1,3-dibromobenzene (602 mg, 2.55 mmol), sodium carbonate (3.16 mL, 3.16 mmol, 1 M) and additional PdC12(dppf)-CH2C12adduct (174 mg, 0.2 13 mmol). The sealed reaction vessel was degassed and heated at120 C in a microwave for 60 mm. The reaction mixture was filtered, washed with water, and extracted with ethyl acetate (20 mL x 3). The organic layers were mixed, dried, concentrated and purified by ISCO purification (12 g column, 0-10% MeOHIDCM solvent, 15 mm gradient) to provide 5-(3-bromophenyl)-1-methylpyridin-2(1H)-one (320mg, 1.21 mmol, 57% yield). LC/MS (M+H) = 264.05, 266.05 (1:1 ratio).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; for 6h;Reflux;
Compound 126-4 1g (4.1mmol), 1,3-dibromo-benzene (1,3-dibromobenzene) 1.9g (8.22mmol), Pd(PPh3)4 0.2g (0.2mmol) K2CO3 1.1g (8mmol) of toluene (toluene) 15ml, 3ml H2O, EtOH 3ml the mixture was dissolved and refluxed for 6 hours. After cooling to room temperature after completion of the reaction it was isolated by extraction with EA / H2O (Sat'd NaHCO3). The organic layer was dried over MgSO4 and evaporated under reduced pressure to remove the solvent. Separated by column chromatography to yield the desired product compound 126-3.
With tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 75℃; for 24h;Inert atmosphere;
Under a nitrogen atmosphere, to a three-necked flask was added 250ml of 1,3-dibromobenzene (24.8g, 105mmol, Aldrich), 2- pyridyl zinc bromide (0.5M in THF, 140mL, 70mmol, Aldrich), tetrakis (triphenylphosphine) palladium (2.43g, 2.1mmol, TCI), and dry tetrahydrofuran (30ml), was heated at 75 deg.] C and stirred for 24h.After completion of the reaction was allowed to cool, the reaction solution was extracted with ethyl acetate, washed with saturated brine three times, the resulting organic layer was dried over anhydrous magnesium sulfate.Filtration, the resulting filtrate was removed under reduced pressure to remove the solvent.Separation by column chromatography, the mobile phase is n-hexane / ethyl acetate = 8: 1.After the spin dry and dried under vacuum to give a colorless oily product, 3- (2-pyridyl) group bromobenzene 10.3g, yield 63percent.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; for 24h;Reflux;
In a 0.5 L reaction flask, 10.0 g (42.4 mmol) of the compound [400-1], 13.4 g (46.6 mmol) of the compound [119-4] and 1.0 g (0.8 mmol) of tetrakis triphenylphosphinevaladium ), 7.7 g (56.0 mmol) of potassium carbonate, 210 ml of 1,4-dioxane, and 42 ml of distilled water were added, followed by reflux and stirring for 24 hours. After completion of the reaction, the reaction mixture was slowly cooled to room temperature and extracted with distilled water and ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 8.1 g (48%) of intermediate compound [400-2].
1-(3-bromophenyl)-5-(trifluoromethyl)indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
With copper(l) iodide; potassium carbonate; pipecolic Acid; In N,N-dimethyl-formamide; at 120℃; for 48h;Inert atmosphere;
General procedure: In a 50 ml round-bottomed flask under argon, 479 mg of 3-ethylsulfanyl-5-(trifluoromethyl)-1H- indole (preparation 184; 1.95 mmol; 1 eq) were dissolved in 5 mL of DMF and the mixture was degassed with argon. 470 mul of 1,3-dibromobenzene (3.89 mmol; 1.99 eq), 540 mg of K2CO3 (3.91 mmol; 2.00 eq). 37 mg copper iodide (0.19 mmol; 0.10 eq) and 50 mg of DL-pipecolinic acid (0.39 mmol; 0.20 eq) were added. The reaction medium was stirred at 110 C. overnigh.t It was brought back to RT and 470 mul of 1,3-dibromobenzene (3.89 mmol; 1.99 eq), 37 mg copper iodide (0.19 mmol; 0.10 eq) and 50 mg of DL-pipecolinic acid (0.39 mmol; 0.20 eq) were added. The reaction medium was stirred at 120 C. for a further 24 h. It was diluted in water and extracted 3 times with EtOAc. The combined organic phases were washed with water, dried over MgSO4, filtered and evaporated to give 1.83 g of brown paste. This residue was purified by flash chromatography on silica using a cyclohexane/0% to 5% EtOAc eluent, to give 230 mg of the title compound in the form of a beige oil. The compound was synthesized according to the protocol described in preparation 185, by reacting 1 eq of <strong>[100846-24-0]5-(trifluoromethyl)-1H-indole</strong> with 2 eq of 1,3-dibromobenzene for 48 h at 120 C. to give 2.54 g of a black oil. This residue was purified by flash chromatography on silica using a cyclohexane/0% to 10% EtOAc eluent, to give 543 mg of the title compound in the form of a white solid. Yld: 39%. 1H NMR (300 MHz, DMSO-d6) deltappm 6.90 (d, J=3.4 Hz, 1H) 7.52 (dd, J=8.8, 1.7 Hz, 1H) 7.54-7.61 (m, 1H) 7.64-7.70 (m, 2H) 7.73 (d, J=8.8 Hz, 1H) 7.86 (t, J=1.9 Hz, 1H) 7.90 (d, J=3.3 Hz, 1H) 8.07-8.11 (m, 1H). LC-MS: m/z (M+H)+: 340.
5-(3-bromophenyl)-5H-pyrido[3,2-b]indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; for 24h;Inert atmosphere; Reflux;
2 g of delta-carboline, 8.5 g of dibromobenzene, 14 g of potassium carbonate, 0.7 g of cuprous iodide, 50 ml of N, N-dimethylformamide, under nitrogen, and reflux for 24 h. After completion of the reaction, the filtrate was extracted with ethyl acetate, washed with saturated brine, dried, concentrated and chromatographed to give 2.0 g of solid, 54% yield.
54%
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; for 24h;Inert atmosphere; Reflux;
2 g of delta-carboline (a2),8.5 grams of m-dibromobenzene,14 grams of potassium carbonate,0.7 grams of cuprous iodide,50 ml of N, N-dimethylformamide,Under nitrogen protection,Reflux reaction 24hAfter completion of the reaction,Filter,The filtrate was extracted with ethyl acetate,Saturated brine washing,dry,concentrate,Column chromatography,2.0 g of solid,Yield 54%.
With potassium phosphate; copper(l) iodide; trans-1,2-Diaminocyclohexane; In 1,4-dioxane; at 110℃; for 48h;Inert atmosphere;
The compound a or b (5 g, 0.03 mol), 1, 3-dibromo benzene (2.8 g, 0.012 mol), copper iodide(1.04 g, 5.46 mmol), trans-1,2-diaminocyclohexane (1.33 g,10.92 mmol), and potassium phosphate tribasic (7.64 g, 0.036 mol) were dissolved in 1,4-dioxane (100 ml) and under N2 atmosphere. The mixture was allowed to stir at 110C for 48 h. After being cooled to room temperature, the mixture was diluted with THF. The copper catalyst and inorganic were removed by filtration under reduced pressure and the residue washed with dichloromethan(CH2Cl2), The organic layer was extracted with water and then CH2Cl2 was evaporated. The residue was recrystallized by CH2Cl2. The compound 1-4 were obtained as powder. 1,3-Bis(5H-pyrido[3,2-b]indol-5-yl)benzene (mCdP) (1) Yield:47% 1H NMR (500 MHz, CDCl3, ppm) delta 7.36 (2H, dd, J = 4.5 Hz, J = 8.5 Hz), 7.42 (2H, m), 7.58(4H, m), 7.72 (2H, dd, J = 2.0 Hz, J = 8.0 Hz), 7.80 (3H, m), 7.90 (1H, t, J = 8.0 Hz), 8.46(2H, d, J = 7.5 Hz), 8.64 (2H, dd, J = 1.5 Hz, J = 4.5 Hz). 13C NMR (125 MHz, CDCl3, ppm)delta 109.8, 116.6, 120.4, 121.1, 121.4, 122.8, 124.6, 125.8, 128.3, 131.6, 134.0, 138.7, 141.2, 142.5,143.0. EI-Mass (m/z): 410 [M+]
1-(3-bromophenyl)azetidine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In 1,4-dioxane; at 95℃; for 3h;Inert atmosphere;
To a degassed (argon, 10 mm) suspension of 1,3-dibromobenzene (2.98 g, 12.65 mmol, 1.5mL), <strong>[345954-83-8]azetidine-3-carbonitrile hydrochloride</strong> (1.0 g, 8.43 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.49 g, 0.84 mmol) and sodium tert-butoxide (3.2 g, 33.70mmol) in dry 1 ,4-dioxane (70 mL) was added tris(dibenzylideneacetone)dipalladium(0) (0.39 g,0.42 mmol). The reaction mixture was stirred at 95C for 3 h and was allowed to cool to room temperature. Water (20 mL) and ethyl acetate (100 mL) were added. Layers were separated and aqueous layer was extracted with ethyl acetate (2x50 mL). Combined organic extracts were dried with sodium sulfate and solvents were removed in vacuo. Purification by flashcolumn chromatography (Method L7; 500 g; heptane, 10%-30% ethyl acetate) afforded 1.25 g(5.28 mmol; 62% of theory) of 1-(3-bromophenyl)azetidine-3-carbonitrile.GC-MS (Method A) R1 = 4.87 mm; m/z = 236/238 M1H NMR (300 MHz, DMSO-d6, Method M2) 67.14 (t, J = 8.0 Hz, 1H), 6.97-6.82 (m, 1H), 6.66(t, J = 2.0 Hz, 1H), 6.51 -6.42 (m, 1H), 4.10 (dd, J = 8.4, 7.5 Hz, 2H), 3.99 (dd, J = 7.5, 5.4 Hz,2H), 3.90-3.77 (m, 1H).
With montmorillonite K10 Clay; for 0.333333h;Microwave irradiation;
1,3-dibromobenzene (2.34g, 0.01mol) and 2,4-dibromo-phenol (2.50g, 0.01mol) was stirred in a beaker and mix, 24g of montmorillonite was added, stirred mix again into dedicated microwave reaction flask, 150w microwave heating reaction 20min, cooled. After 100mL of n-hexane was collected by washing the reaction solution was washed, evaporated under reduced pressure to give a red oil by column chromatography, to give a white solid 4.09 g, yield 85%.
(2) To be equipped with mechanical stirring, thermometer,After nitrogen substitution in the three-port reaction flask of the constant pressure dropping funnel,Add the raw materials 4a-1 (200mmol) in sequence,500.0ml tetrahydrofuran, start stirring, and cool down to -85 -90 ,Add 2mol / L n-butyllithium (210mmol) dropwise,The temperature during the dropping is maintained at -85 -90 , and the temperature is kept for 1h after the dropping is completed.A solution of the raw material <strong>[102645-33-0]2,5-dichloropyridine-4-aldehyde</strong> (200 mmol) + 140.0 ml of tetrahydrofuran was added dropwise.After the dropwise addition, the temperature was kept for 0.5h, and the temperature was naturally raised to room temperature for 3h.The reaction solution was poured into 10% aqueous ammonium chloride solution, and extracted with 320.0 ml of toluene,Separate the liquid and extract the aqueous phase once with 320.0 ml of toluene,Combine the organic phases, wash twice with 260.0 ml of water, and separate.The organic phase is dried by adding 12g of anhydrous sodium sulfate and filtered,The organic phase is concentrated (-0.08 -0.09MPa, 55 65 ) to no avail,Add 150.0ml petroleum ether and stir for 0.5h, filter, rinse the filter cake with petroleum ether,Intermediate 4a-2 (150 mmol) was obtained with a yield of 75%.
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