* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: at 0℃; Inert atmosphere Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 2 h; Inert atmosphere
A solution of benzophenone (1.82g, 10 mmol) and diethyl 4-bromobenzylphosphonate (3.1 g, 10 mmol) in anhydrous THF (40 mL) was stirred under argon atmosphere at 0 ºC. Potassium tert-butoxide (1.1 g, 10 mmol) was added quickly and the mixture was stirred for 2 h at room temperature. The reaction mixture was poured into ethanol and a solid precipitated out. The precipitate was filtered and washed with ethanol (3×10 mL) to afford product 6 as a white powder (2.41g, 72percent). Mp 52−54 ºC; IR (KBr, cm-1): 3032, 1610, 1484; 1H NMR (300 MHz, CDCl3): δ 7.25−7.18 (m, 3H), 7.16–7.06 (m, 5H), 7.05−6.94 (m, 4H), 6.92−6.82 (m, 3H); MS (EI): m/z 335, 337 (M+, M++2, 95, 100percent).
72%
With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 2 h; Inert atmosphere
A solution of benzophenone (1.82 g, 10 mmol) and diethyl 4-bromobenzylphosphonate (3.1 g, 10 mmol) in anhydrous THF (40 mL) was stirred under argon atmosphere at 0°C. Potassium tert-butoxide (1.1 g, 10 mmol) was added quickly and the mixture was stirred for 2 h at room temperature. The reaction mixture was poured into ethanol (10 mL) and a solid precipitated out. The precipitate was filtered and washed with ethanol (310 mL) to afford 1 as a white powder (2.41 g, 72percent). Mp 52-54 °C; IR (KBr, cm-1): 3032, 1610, 1484; 1H NMR (300 MHz, CDCl3): δ 7.25-7.18 (m, 3H), 7.16-7.06 (m, 5H), 7.05-6.94 (m, 4H), 6.92-6.82 (m, 3H); LCMS(EI): m/z 335 (MH+, 100percent).
Reference:
[1] Journal of the American Chemical Society, 2000, vol. 122, # 24, p. 5695 - 5709
[2] Tetrahedron Letters, 2012, vol. 53, # 50, p. 6838 - 6842
[3] Dyes and Pigments, 2013, vol. 99, # 3, p. 740 - 747
[4] Patent: WO2009/51390, 2009, A2, . Location in patent: Page/Page column 64-65; 70-72
[5] Journal of Materials Chemistry, 2012, vol. 22, # 35, p. 18505 - 18513
[6] Chemistry - An Asian Journal, 2011, vol. 6, # 6, p. 1470 - 1478
2
[ 19350-68-6 ]
[ 762-04-9 ]
[ 38186-51-5 ]
Yield
Reaction Conditions
Operation in experiment
73%
With copper(l) iodide; caesium carbonate In 1,2-dimethoxyethane at 85℃; for 3 h; Inert atmosphere
General procedure: Under an argon atmosphere, the carbonyl compounds (0.40 mmol), TsNHNH2 (0.42 mmol, 1.05 eq) and DME (1.0 mL) were successively added to a flame-dried Schlenk flask. The reaction was heated at 60 ºC with stirring for 30 minutes. After the solution cooled down to room temperature H-Phosphonate 1b (0.40 mmol, 1.0 eq), Cs2CO3 (0.60 mmol, 1.5 eq), and CuI(0.04 mmol, 10 mol percent) were sequentially added to the system. The mixture was stirred to 85oC. When the reaction was considered complete, as determined by TLC analysis, the reaction mixture was cooled to room temperature and filtered through a short plug of silica gel [washed with EtOAc]. Solvent was then removed in vacuo to provide a crude mixture, which was purified by silica gel column chromatography to afford pure product.
Reference:
[1] Advanced Synthesis and Catalysis, 2012, vol. 354, # 14-15, p. 2659 - 2664
[2] Tetrahedron, 2013, vol. 69, # 3, p. 1065 - 1068
[3] Angewandte Chemie - International Edition, 2018, vol. 57, # 22, p. 6624 - 6628[4] Angew. Chem., 2018, vol. 130, # 22, p. 6734 - 6738,5
3
[ 873-75-6 ]
[ 122-52-1 ]
[ 38186-51-5 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 120℃; for 24 h; Inert atmosphere
To a 20 mL tubular reactor was added 4-bromobenzyl alcohol (93.0 mg, 0.50 mmol)(3.8 mg, 0.01 mmol, 2 molpercent), protected by vacuum nitrogen and then heated to 120 ° C under solvent-free conditions 24h After the TLC monitoring reaction was complete, the product was purified by column chromatography and the yield was 90percent.
Reference:
[1] Patent: CN106543221, 2017, A, . Location in patent: Paragraph 0030; 0031; 0032; 0033
[2] Green Chemistry, 2018, vol. 20, # 15, p. 3408 - 3413
4
[ 589-15-1 ]
[ 122-52-1 ]
[ 38186-51-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 100℃; for 24 h;
A solution of 25 g (0.1 mol) of 4-bromobenzyl bromide and 19 ml (0.11 mol) of triethylphosphite is heated at 100° C. for 24 hours. At room temperature, the residue is purified on a silica column (dichloromethane and then ethyl acetate). [00400] Yellow oil. m=31 g. Y=100percent. 1H NMR (CDCl3): 1.22-1.28 (6H, t), 3.05-3.13 (2H, d), 3.96-4.08 (4H, q), 7.15-7.19 (2H, dd, J=6 Hz, J'=2.4 Hz), 7.42-7.45 (2H, d, J=8 Hz).
99%
at 150℃; for 12 h; Inert atmosphere
Preparing Example 2 Preparation Of Diethyl 4-Bromobenzyl-Phosphonate (Compound A) 1-bromo-4-(bromomethyl)benzene (5.00 g, 20.0 mmol) was in a two-neck bottle. after introducing nitrogen gas by vacuum pumping, anhydrous toluene (80.0 mL) and triethyl phosphite (10.4 mL, 60.0 mmol) were added and heated to 150° C. for twelve hours. After the reaction finished, the solvent was removed by the rotary concentrator to obtain yellow liquid of 6.08 g (compound A) with a yield of 99percent. 1H NMR (400 MHz, CDCl3, δ): 7.39-7.37 (m, 2H), 7.12 (dd, J=8.4 Hz, J=2.4 Hz, 2H), 3.99-3.94 (m, 4H), 3.04 (d, J=21.6 Hz, 2H), 1.21-1.18 (m, 6H)13C NMR (100 MHz, CDCl3, 5): 131.5, 131.5, 131.4, 131.3, 130.7, 130.6, 120.8, 120.8, 62.2, 62.1, 33.8, 32.4, 16.3, 16.2.
98%
at 90℃; for 19 h;
Example lj. Diethyl 4-bromobenzylphosphonate (16).; l-bromo-4-(bromomethyl) benzene (5.0 g, 20 mmol) and triethyl phosphite (51 mL, 300 mmol) were mixed in a round bottom flask and refluxed at 90 °C for 19 hours. Excess triethyl phosphite was removed under reduced pressure and the product purified by flash chromatography (1 : 1 Hexane/ EtOAc) to give compound 16. 16: 98 percent yield ; colorless liquid; 1H NMR (400 MHz, CDC13) δ 7.30 (d, 2H, J= 7.5 Hz), 7.05 (d, 2H, J= 7.6 Hz), 3.99- 3.88 (m, 4H), 2.99 (s, IH), 2.94 (s, IH), 1.12 (t, 6H, J= 6.9 Hz); 13C NMR (100 MHz, CDC13) δ 131.7, 131.6, 131.5, 121.0, 62.3, 34.0, 32.0, 16.5; HRMS Calc for CnHi6Br03P ( M+H)+ 307.0097 found 307.0093.
98%
at 160 - 170℃; Inert atmosphere
General procedure: Organohalogen compound and anhydrous NiBr2(5–10 molpercent) as catalyst were charged into a two-necked round bottom flask equipped with a dropping funnel and short distillation column (no catalyst was used in the cases of benzyl derivatives). The mixture was degassed by bubbling the solution with dry N2gas for 30 min and then heated at 160–170°C. P(OEt)3(1.2 equiv. relative to the organohalogen compound) was slowly added through the dropping funnel. The mixture was stirred and heated at 160–170°Covernight. The crude product was purified by silica gel column chromatography using dichloromethane as an eluent. The product was dried at 70°Cunder reduced pressure for 2 h.Benzyl derivatives were purified by distillation under reduced pressure without column chromatography. Diethyl organophosphonate (ArP(O)(OEt)2) was obtained as colorless liquid.
92%
at 160℃; for 2 h;
A mixture of triethyl phosphite (2.54 g, 15.3 mmol) and 4-bromobenzyl bromide (2.00 g, 10.2 mmol) was stirred at 160° C. for 2 h. During this period ethyl bromide was distilled from the reaction mixture. Subsequently, the mixture was cooled to 70° C. and the excess of triethyl phosphite was removed by distillation under reduced pressure. The product was used without further purification, yielded 92percent product. 1H NMR (400 MHz, CDCl3): δ 1.25 (t, 6H, J=7.2 Hz), 3.06, 3.11 (s, 2H), 4.01 (m, 4H), 7.16 (d, 2H, J=8.4 Hz), 7.42 (d, 2H, I=8.4 Hz).
92.5%
at 140℃; for 2 h;
General procedure: Diethyl benzylphosphonate as the basis compound for thesynthesis of the t-APE isomers was prepared according to literature[18,19]. Benzyl bromide (1.50 g, 8.8 mmol) was suspended in 5 mLof toluene, containing triethylphosphite (6.00 g, 35 mmol). The mixture was refluxed at 140 °C for 2 h. Excess triethylphosphite and toluene were removed by distillation to give the required product as a yellow oil (1.80 g, 89.9percent).
91%
at 150℃; for 3 h;
Intermediate 1 Diethyl 4-bromobenzylphosphonate 4-Bromoben2yl bromide (22.5g, 90mmol) and triethylphosphite (16.45g, 99mmol) were heated to 150°C for 3 h. The mixture was purifed by flash chromatography (1/4 EtOAc/hexane) to give diethyl 4-bromobenzylphosphonate (25.2g, 91percent). Ή NMR (300 MHz, CDCI3) δ ?7.45 (m, 2H), 7.15 (m, 2H), 4.00 (m, 4H), 3.05 (m, 2H), 1.25 (m, 6H)
81%
for 24 h; Heating / reflux
4-bromobenzylbromide (10. Og, 40.0mmol) was dissolved in triethylphosphite (8.4mL, 48.0mmol) under a nitrogen atmosphere, and the reaction solution was refluxed and stirred for 24 hours. The reaction solution was passed through a silica gel column by using hexane-ethylacetate 7:3 as an eluant. After the solvent was removed, the residue material was dried in vacuum to thereby obtain pale yellow oil (10. Og, yield: 81percent) .
Reference:
[1] Patent: US6689922, 2004, B1, . Location in patent: Page column 23
[2] Chemistry - A European Journal, 2012, vol. 18, # 24, p. 7473 - 7485
[3] Synthetic Communications, 2011, vol. 41, # 2, p. 206 - 218
[4] Patent: US2013/41153, 2013, A1, . Location in patent: Paragraph 0041; 0042; 0043; 0044
[5] ChemMedChem, 2010, vol. 5, # 1, p. 56 - 60
[6] Patent: WO2011/72257, 2011, A2, . Location in patent: Page/Page column 38-39; 42
[7] Polyhedron, 2018, vol. 147, p. 1 - 8
[8] Organic Letters, 2003, vol. 5, # 7, p. 1131 - 1134
[9] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 22, p. 7724 - 7730
[10] Tetrahedron, 1998, vol. 54, # 9, p. 1691 - 1714
[11] Patent: US7449578, 2008, B1, . Location in patent: Page/Page column 6
[12] Organic Electronics: physics, materials, applications, 2017, vol. 50, p. 228 - 238
[13] Patent: WO2013/27001, 2013, A1, . Location in patent: Page/Page column 33
[14] Journal of Medicinal Chemistry, 2013, vol. 56, # 24, p. 9982 - 10002
[15] Tetrahedron Letters, 2004, vol. 45, # 1, p. 125 - 128
[16] Patent: WO2008/91130, 2008, A1, . Location in patent: Page/Page column 12
[17] Journal fuer Praktische Chemie/Chemiker-Zeitung, 1998, vol. 340, # 8, p. 744 - 754
[18] Tetrahedron Letters, 1996, vol. 37, # 42, p. 7611 - 7614
[19] Journal of Organic Chemistry, 2004, vol. 69, # 3, p. 719 - 726
[20] Tetrahedron, 1999, vol. 55, # 9, p. 2671 - 2686
[21] Journal of Physical Organic Chemistry, 2000, vol. 13, # 10, p. 587 - 590
[22] Organic Letters, 2005, vol. 7, # 15, p. 3199 - 3202
[23] New Journal of Chemistry, 2006, vol. 30, # 11, p. 1606 - 1613
[24] Journal of the American Chemical Society, 2002, vol. 124, # 11, p. 2518 - 2527
[25] Patent: WO2008/99986, 2008, A1, . Location in patent: Page/Page column 27; 30
[26] Patent: EP1182183, 2002, A1, . Location in patent: Page 35
[27] Patent: EP1182183, 2002, A1, . Location in patent: Page 38
[28] Patent: WO2009/51390, 2009, A2, . Location in patent: Page/Page column 64-65; 70-72
[29] Patent: WO2009/128559, 2009, A1, . Location in patent: Page/Page column 40
[30] Tetrahedron Letters, 2010, vol. 51, # 15, p. 1985 - 1988
[31] Patent: WO2007/87441, 2007, A2, . Location in patent: Page/Page column 76
[32] Central European Journal of Chemistry, 2011, vol. 9, # 4, p. 610 - 618
[33] Reactive and Functional Polymers, 2013, vol. 73, # 9, p. 1207 - 1212
[34] European Journal of Organic Chemistry, 2015, vol. 2015, # 27, p. 5987 - 5994
[35] Chemistry of Materials, 2015, vol. 27, # 19, p. 6543 - 6549
[36] Patent: CN103450883, 2016, B, . Location in patent: Paragraph 0051; 0055
[37] Patent: CN106905169, 2017, A, . Location in patent: Paragraph 0092
[38] Journal of Organic Chemistry, 2017, vol. 82, # 18, p. 9435 - 9451
[39] Journal of Materials Chemistry B, 2018, vol. 6, # 37, p. 5986 - 5991
5
[ 1067-71-6 ]
[ 589-87-7 ]
[ 38186-51-5 ]
Reference:
[1] Advanced Synthesis and Catalysis, 2011, vol. 353, # 18, p. 3340 - 3346
6
[ 78-40-0 ]
[ 589-15-1 ]
[ 38186-51-5 ]
Reference:
[1] Advanced Materials, 2013, vol. 25, # 20, p. 2837 - 2843
[2] Journal of Polymer Science, Part A: Polymer Chemistry, 2016, vol. 54, # 17, p. 2722 - 2730
[3] Patent: CN105712917, 2016, A, . Location in patent: Paragraph 0021
7
[ 1122-91-4 ]
[ 122-52-1 ]
[ 38186-51-5 ]
Reference:
[1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 15, p. 2934 - 2936
8
[ 762-04-9 ]
[ 589-15-1 ]
[ 38186-51-5 ]
Reference:
[1] New Journal of Chemistry, 2010, vol. 34, # 5, p. 967 - 975
[2] Journal of the American Chemical Society, 1994, vol. 116, # 15, p. 6631 - 6635
9
[ 1122-91-4 ]
[ 38186-51-5 ]
Reference:
[1] Advanced Synthesis and Catalysis, 2012, vol. 354, # 14-15, p. 2659 - 2664
[2] Tetrahedron, 2013, vol. 69, # 3, p. 1065 - 1068
[3] Angewandte Chemie - International Edition, 2018, vol. 57, # 22, p. 6624 - 6628[4] Angew. Chem., 2018, vol. 130, # 22, p. 6734 - 6738,5
10
[ 106-38-7 ]
[ 38186-51-5 ]
Reference:
[1] Journal of Polymer Science, Part A: Polymer Chemistry, 2016, vol. 54, # 17, p. 2722 - 2730
[2] Patent: CN105712917, 2016, A,
11
[ 589-17-3 ]
[ 122-52-1 ]
[ 38186-51-5 ]
Reference:
[1] Bulletin de la Societe Chimique de France, 1974, p. 1506 - 1508
[2] Journal of Physical Organic Chemistry, 2017, vol. 30, # 12,
General procedure: Organohalogen compound and anhydrous NiBr2(5-10 mol%) as catalyst were charged into a two-necked round bottom flask equipped with a dropping funnel and short distillation column (no catalyst was used in the cases of benzyl derivatives). The mixture was degassed by bubbling the solution with dry N2gas for 30 min and then heated at 160-170C. P(OEt)3(1.2 equiv. relative to the organohalogen compound) was slowly added through the dropping funnel. The mixture was stirred and heated at 160-170Covernight. The crude product was purified by silica gel column chromatography using dichloromethane as an eluent. The product was dried at 70Cunder reduced pressure for 2 h.Benzyl derivatives were purified by distillation under reduced pressure without column chromatography. Diethyl organophosphonate (ArP(O)(OEt)2) was obtained as colorless liquid.
A solution of 25 g (0.1 mol) of 4-bromobenzyl bromide and 19 ml (0.11 mol) of triethylphosphite is heated at 100 C. for 24 hours. At room temperature, the residue is purified on a silica column (dichloromethane and then ethyl acetate). [00400] Yellow oil. m=31 g. Y=100%. 1H NMR (CDCl3): 1.22-1.28 (6H, t), 3.05-3.13 (2H, d), 3.96-4.08 (4H, q), 7.15-7.19 (2H, dd, J=6 Hz, J'=2.4 Hz), 7.42-7.45 (2H, d, J=8 Hz).
99%
In toluene; at 150℃; for 12h;Inert atmosphere;
Preparing Example 2 Preparation Of Diethyl 4-Bromobenzyl-Phosphonate (Compound A) 1-bromo-4-(bromomethyl)benzene (5.00 g, 20.0 mmol) was in a two-neck bottle. after introducing nitrogen gas by vacuum pumping, anhydrous toluene (80.0 mL) and triethyl phosphite (10.4 mL, 60.0 mmol) were added and heated to 150 C. for twelve hours. After the reaction finished, the solvent was removed by the rotary concentrator to obtain yellow liquid of 6.08 g (compound A) with a yield of 99%.1H NMR (400 MHz, CDCl3, delta): 7.39-7.37 (m, 2H), 7.12 (dd, J=8.4 Hz, J=2.4 Hz, 2H), 3.99-3.94 (m, 4H), 3.04 (d, J=21.6 Hz, 2H), 1.21-1.18 (m, 6H)13C NMR (100 MHz, CDCl3, 5): 131.5, 131.5, 131.4, 131.3, 130.7, 130.6, 120.8, 120.8, 62.2, 62.1, 33.8, 32.4, 16.3, 16.2.
98%
at 90℃; for 19h;
Example lj. Diethyl 4-bromobenzylphosphonate (16).; l-bromo-4-(bromomethyl) benzene (5.0 g, 20 mmol) and triethyl phosphite (51 mL, 300 mmol) were mixed in a round bottom flask and refluxed at 90 C for 19 hours. Excess triethyl phosphite was removed under reduced pressure and the product purified by flash chromatography (1 : 1 Hexane/ EtOAc) to give compound 16. 16: 98 % yield ; colorless liquid; 1H NMR (400 MHz, CDC13) delta 7.30 (d, 2H, J= 7.5 Hz), 7.05 (d, 2H, J= 7.6 Hz), 3.99- 3.88 (m, 4H), 2.99 (s, IH), 2.94 (s, IH), 1.12 (t, 6H, J= 6.9 Hz); 13C NMR (100 MHz, CDC13) delta 131.7, 131.6, 131.5, 121.0, 62.3, 34.0, 32.0, 16.5; HRMS Calc for CnHi6Br03P ( M+H)+ 307.0097 found 307.0093.
98%
With nickel dibromide; at 160 - 170℃;Inert atmosphere;
General procedure: Organohalogen compound and anhydrous NiBr2(5-10 mol%) as catalyst were charged into a two-necked round bottom flask equipped with a dropping funnel and short distillation column (no catalyst was used in the cases of benzyl derivatives). The mixture was degassed by bubbling the solution with dry N2gas for 30 min and then heated at 160-170C. P(OEt)3(1.2 equiv. relative to the organohalogen compound) was slowly added through the dropping funnel. The mixture was stirred and heated at 160-170Covernight. The crude product was purified by silica gel column chromatography using dichloromethane as an eluent. The product was dried at 70Cunder reduced pressure for 2 h.Benzyl derivatives were purified by distillation under reduced pressure without column chromatography. Diethyl organophosphonate (ArP(O)(OEt)2) was obtained as colorless liquid.
98%
at 140℃; for 7h;Inert atmosphere;
A solution of 1-bromo-4-(bromomethyl)benzene (5.15 g,16.3 mmol) was stirred under argon atmosphere at 140 C for 15 min.Thereafter, triethyl phosphite (24.38 g, 146.7 mmol) was added and the mixture was stirred for 7 h. After the excess triethyl phosphite was removed by vacuum distillation, the residue was cooled to room temperature.A colorless clear liquid was obtained (5 g, 98% yield). 1HNMR (500 MHz, CDCl3) delta 7.43 (d, J=7.9 Hz, 2 H), 7.17 (dd, J=8.5,2.5 Hz, 2 H), 4.06-3.96 (m, 4 H), 3.09 (d, J=21.7 Hz, 4 H), 1.25 (t,J=7.1 Hz, 6 H); MS (EIS), m/z: 307.0093 ([M+H]+, calcd for C11H16BrO3P, 306.002).
92%
at 160℃; for 2h;
A mixture of triethyl phosphite (2.54 g, 15.3 mmol) and 4-bromobenzyl bromide (2.00 g, 10.2 mmol) was stirred at 160 C. for 2 h. During this period ethyl bromide was distilled from the reaction mixture. Subsequently, the mixture was cooled to 70 C. and the excess of triethyl phosphite was removed by distillation under reduced pressure. The product was used without further purification, yielded 92% product. 1H NMR (400 MHz, CDCl3): delta 1.25 (t, 6H, J=7.2 Hz), 3.06, 3.11 (s, 2H), 4.01 (m, 4H), 7.16 (d, 2H, J=8.4 Hz), 7.42 (d, 2H, I=8.4 Hz).
92.5%
In toluene; at 140℃; for 2h;
General procedure: Diethyl benzylphosphonate as the basis compound for thesynthesis of the t-APE isomers was prepared according to literature[18,19]. Benzyl bromide (1.50 g, 8.8 mmol) was suspended in 5 mLof toluene, containing triethylphosphite (6.00 g, 35 mmol). The mixture was refluxed at 140 C for 2 h. Excess triethylphosphite and toluene were removed by distillation to give the required product as a yellow oil (1.80 g, 89.9%).
91%
at 150℃; for 3h;
Intermediate 1 Diethyl 4-bromobenzylphosphonate 4-Bromoben2yl bromide (22.5g, 90mmol) and triethylphosphite (16.45g, 99mmol) were heated to 150C for 3 h. The mixture was purifed by flash chromatography (1/4 EtOAc/hexane) to give diethyl 4-bromobenzylphosphonate (25.2g, 91%). ? NMR (300 MHz, CDCI3) delta ?7.45 (m, 2H), 7.15 (m, 2H), 4.00 (m, 4H), 3.05 (m, 2H), 1.25 (m, 6H)
81%
for 24h;Heating / reflux;
4-bromobenzylbromide (10. Og, 40.0mmol) was dissolved in triethylphosphite (8.4mL, 48.0mmol) under a nitrogen atmosphere, and the reaction solution was refluxed and stirred for 24 hours. The reaction solution was passed through a silica gel column by using hexane-ethylacetate 7:3 as an eluant. After the solvent was removed, the residue material was dried in vacuum to thereby obtain pale yellow oil (10. Og, yield: 81%) .
at 80℃; for 17h;
A solution of 4-bromobenzyl bromide(10 g, 40 mmol) andtriethylphosphite(5 mL, 0.29 mol) was heated at 80 C for 17 hours.And then the synthesis was conducted by the same procedure of c.(colorless oil) IH NMR (CDCl3): delta 7.29 (d, JH-H= 8.4 Hz, 2H), 7.04(d, JH-H= 8.4 Hz, 2H), 3.89 (dq, 3JH-P= 12.2 Hz, JH-H= 7.5 Hz, 4H),2.96 (d, 2JH-P= 21.3 Hz, 2H), 1.14 (t, 3JH-H= 7.5 Hz, 6H); 31P NMR(CDC13): 19.99.
at 120℃; for 2h;Product distribution / selectivity;
[Exemplary embodiment 1] Synthesis of Compound 1 Compound 1[Reaction formula 1]n-BiotaiotaLiota THF Together with triethylphosphite (25g, 150mmol) , 1- bromo-4-bromomethylbenzene (5g, 20mmol) was put into an agitator to have them react to each other for two hours at 120C to thereby synthesize triethyl 4- bromobenzylphosphite . The synthesized triethyl 4- <n="66"/>bromobenzylphosphite (6.74g, 20mmol), benzophenone (5.13g, 29.16mmol) and potassium tert-butoxide (3.27g, 29.1betammol) were put into a reactor and melted by THF of 50ml to have them react to each other for four hours at 120C to thereby synthesize l-bromo-4- (2, 2-diphenylvinyl) benzene . After melted by THF 50ml, l-bromo-4- (2, 2- diphenylvinyl) benzene (6.03g, ldeltammol) was gradually added with 2Mn-BuLi (10ml, 20mmol) at -78C to be agitated for one hour at low temperatures. Again, the mixture was gradually added with (Z) -3- ( 5-bromothiophene-2-yl) -2- cyanoacrylic acid (5.1betag, 20mmol) at -78C, agitated for one hour at low temperatures and then additionally agitated for 30 minutes at 0C to complete the reaction.After extracting an organic layer from the mixture with dichloromethane and distilled water, the solvent was removed through a distiller, the organic layer was recrystallized by n-hexane, and dried and purified after filtering sediment (yield 52%) .1H NMR(CDCl3) : [ppm] = 8.04 (s, IH) , 7.67 (s, IH) , 7.60 (d, 3JHH = 3.6Hz, 2H) , 7.52 (d, 3JHH = 8.4Hz, 2H) , 7.43 (m, 3H) , 7.34 (m, 5H) , 7.19 (dd, 3JHH = 8Hz, 2H) , 7.14 (s, IH) , 7.07 (d, 3JHH = 8.4Hz, 2H) . [Exemplary embodiment 8] Synthesis of compound 142 [Compound 142][Synthesis scheme] <n="72"/>(OH)2 K2CO3 P d(PPhOl4 THF Together with triethylphosphite (25g, ldeltaOmmol), 1- bromo-4-bromomethylbenzene (5g, 20mmol) was put into an agitator to have them react to each other for two hours at 120C to thereby synthesize triethyl A- bromobenzylphosphite. The synthesized triethyl 4- bromobenzylphosphite (6.1Aq, 2OmInOl), benzophenone (5.13g, 29.1betammol) and potassium tert-butoxide (3.27g, 29.1betammol) were put into a reactor and melted by THF of 50ml to have them react to each other for four hours at 120C to thereby synthesize l-bromo-4- (2, 2- diphenylvinyl) benzene (1-1) . The synthesized-bromo-4- (2, 2- diphenylvinyl) benzene (1-1) (beta.03g, ldeltammol) was melted by THF of 50ml, gradually added with 2Mn-BuLi (10ml, 20mmol) at -78 C and agitated for one hour at low temperatures. The mixture was gradually added with triisopropyl borate <n="73"/>(3.76g, 20mmol) at -78C, agitated for one hour at low temperatures and then additionally agitated for 30 minutes at 0C to thereby synthesize 4- (2, 2- diphenylvinyl) phenylboronic acid (1-2) . The synthesized 4- (2, 2-diphenylvinyl) phenylboronic acid (4.5g, 15mmol) (l-2), K2CO3 (6.2g, 45mmol) and Pd (PPh3) 4 (0.8betag, 0.75mmol) were melted by THF (60ml), added with (E) -3- (5- bromothieno [3, 2-b] thiophene-2-yl) -2-cyanoacrylic acid(5.6g, 18mmol) , agitated for four hours at 120C to complete the reaction. After extracting an organic layer from the mixture with dichloromethane and distilled water, the solvent was removed through an evaporator and the organic layer was recrystallized by n-hexane and dried to collect the compound 142 after the sediment was filtered.
at 150℃; for 3h;
A boronate ester unit having an alkenyl group was synthesized according to Scheme 6.
In toluene; at 130℃; for 3h;
The mixed solution of 4-bromobenzyl bromide (1 g, 4.0 mmol) and triethyl phosphite (3.5 mL) in toluene (10 mL) was heated to 1300C in a sealed tube for 3 hr. The solvent was removed and the crude product 2 was ready for the next step. To a solution of crude 2 (300 mg, 0.97 mmol) in THF (5 mL) was added <n="78"/>NaHMDS (1 N, 1 ml_) at -780C. After 5 min, 2,6-difluorobenzyl aldehyde (100 mul_, 0.93 mmol) was added. After 20 min, the solution was allowed to warm up to room temperature slowly and then quenched with aqueous NH4CI (10 ml_). The organic phase was collected, dried, and concentrated. Column chromatography afforded olefin 3. Compound 2 was obtained following general Suzuki coupling conditions.1H NMR (300 MHz1 CDCI3) delta 7.95 (s, 1 H), 7.92 (d, J = 2.1 Hz, 1 H), 7.70-7.36 (m, 5 H), 7.28-7.17 (m, 5 H), 6.96-6.90 (m, 2 H), 2.35 (s, 3 H); ESMS cacld (C24H17F2NO): 373.1 ; found: 374.2 (M+H).
for 2h;Reflux;
To a 500 ml single-neck flask, was added 25 g p-bromobenzyl bromide and 49.8 ml triethyl phosphite (1-2). The mixture was refluxed for 2 hours, then the excess triethyl phosphate was removed. 23.4 g intermediate 1-1, 250 ml DMF, and 16.8 g potassium tert-butoxide were added into the flask in an ice bath. The resulting mixture was allowed to warm to the room temperature, and stirred overnight. The reaction mixture was poured into distilled water, filtered, and the precipitate was recrystallized from ethanol to yield 31.8 g product (83%).
at 20 - 70℃; for 25h;Inert atmosphere;
1. Under the protection of argon, bromobromobenzyl chloride was added to the twin-necked round bottom flask, and triethyl phosphite was slowly added dropwise at room temperature. The mixture was stirred at room temperature and heated to 70 C for 25 hours. The reaction mixture was allowed to cool to room temperature, and a saturated ammonium chloride solution was poured into the reaction solution. The extract was repeatedly extracted three times with ethyl acetate solvent, dried over anhydrous magnesium sulfate and filtered to obtain an organic layer. The solvent was removed by vacuum distillation under reduced pressure After the crude product.And further purified by silica gel column chromatography (dichloromethane: petroleum ether = 1: 1, v / v) to give the title compound (1) as a colorless oil.
at 140℃; for 7h;Inert atmosphere;
Add p-bromobenzyl bromide (5.15 g, 20.36 mmol) to a 50 mL three-necked flask equipped with a reflux apparatus and argon.The mixture was heated to 140 C and stirred for melting. After 15 minutes of aeration, triethyl phosphite (24.38 g, 143.79 mmol) was added and the reaction was stirred for 7 h.After distillation, the excess of triethyl phosphite is distilled off, and cooled to room temperature to obtain compound 1;
In ethanol;Reflux;
Add 50g of triethyl phosphite to a 1000ml single-mouth bottle, 25g of p-bromobenzyl bromide, dissolved by heating, and it is transparent. It starts to reflux. It is estimated to produce ethanol. Turn off the reflux condensate and evaporate the ethanol. After 3 hours, The reaction was stopped, and the remaining triethyl phosphite was removed under reduced pressure. Add it to a 500 ml four-necked flask, add 300 ml of DMF, and add M3.(16.8 g), cooled to 0 C, potassium tert-butoxide (16.84 g) was added and stirred overnight. The reaction solution was poured into ice water, filtered, and the filter cake was beaten twice with methanol to give an off-white solid, yield 82%
A solution of benzophenone (1.82g, 10 mmol) and diethyl 4-bromobenzylphosphonate (3.1 g, 10 mmol) in anhydrous THF (40 mL) was stirred under argon atmosphere at 0 ºC. Potassium tert-butoxide (1.1 g, 10 mmol) was added quickly and the mixture was stirred for 2 h at room temperature. The reaction mixture was poured into ethanol and a solid precipitated out. The precipitate was filtered and washed with ethanol (3×10 mL) to afford product 6 as a white powder (2.41g, 72%). Mp 52-54 ºC; IR (KBr, cm-1): 3032, 1610, 1484; 1H NMR (300 MHz, CDCl3): delta 7.25-7.18 (m, 3H), 7.16-7.06 (m, 5H), 7.05-6.94 (m, 4H), 6.92-6.82 (m, 3H); MS (EI): m/z 335, 337 (M+, M++2, 95, 100%).
72%
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere;
A solution of benzophenone (1.82 g, 10 mmol) and diethyl 4-bromobenzylphosphonate (3.1 g, 10 mmol) in anhydrous THF (40 mL) was stirred under argon atmosphere at 0C. Potassium tert-butoxide (1.1 g, 10 mmol) was added quickly and the mixture was stirred for 2 h at room temperature. The reaction mixture was poured into ethanol (10 mL) and a solid precipitated out. The precipitate was filtered and washed with ethanol (310 mL) to afford 1 as a white powder (2.41 g, 72%). Mp 52-54 C; IR (KBr, cm-1): 3032, 1610, 1484; 1H NMR (300 MHz, CDCl3): delta 7.25-7.18 (m, 3H), 7.16-7.06 (m, 5H), 7.05-6.94 (m, 4H), 6.92-6.82 (m, 3H); LCMS(EI): m/z 335 (MH+, 100%).
With potassium tert-butylate; In tetrahydrofuran;Heating / reflux;Product distribution / selectivity;
[Exemplary embodiment 1] Synthesis of Compound 1 Compound 1[Reaction formula 1]n-BiotaiotaLiota THF Together with triethylphosphite (25g, 150mmol) , 1- bromo-4-bromomethylbenzene (5g, 20mmol) was put into an agitator to have them react to each other for two hours at 120C to thereby synthesize triethyl 4- bromobenzylphosphite . The synthesized triethyl 4- <n="66"/>bromobenzylphosphite (6.74g, 20mmol), benzophenone (5.13g, 29.16mmol) and potassium tert-butoxide (3.27g, 29.1betammol) were put into a reactor and melted by THF of 50ml to have them react to each other for four hours at 120C to thereby synthesize l-bromo-4- (2, 2-diphenylvinyl) benzene . After melted by THF 50ml, l-bromo-4- (2, 2- diphenylvinyl) benzene (6.03g, ldeltammol) was gradually added with 2Mn-BuLi (10ml, 20mmol) at -78C to be agitated for one hour at low temperatures. Again, the mixture was gradually added with (Z) -3- ( 5-bromothiophene-2-yl) -2- cyanoacrylic acid (5.1betag, 20mmol) at -78C, agitated for one hour at low temperatures and then additionally agitated for 30 minutes at 0C to complete the reaction.After extracting an organic layer from the mixture with dichloromethane and distilled water, the solvent was removed through a distiller, the organic layer was recrystallized by n-hexane, and dried and purified after filtering sediment (yield 52%) .1H NMR(CDCl3) : [ppm] = 8.04 (s, IH) , 7.67 (s, IH) , 7.60 (d, 3JHH = 3.6Hz, 2H) , 7.52 (d, 3JHH = 8.4Hz, 2H) , 7.43 (m, 3H) , 7.34 (m, 5H) , 7.19 (dd, 3JHH = 8Hz, 2H) , 7.14 (s, IH) , 7.07 (d, 3JHH = 8.4Hz, 2H) . [Exemplary embodiment 8] Synthesis of compound 142 [Compound 142][Synthesis scheme] <n="72"/>(OH)2 K2CO3 P d(PPhOl4 THF Together with triethylphosphite (25g, ldeltaOmmol), 1- bromo-4-bromomethylbenzene (5g, 20mmol) was put into an agitator to have them react to each other for two hours at 120C to thereby synthesize triethyl A- bromobenzylphosphite. The synthesized triethyl 4- bromobenzylphosphite (6.1Aq, 2OmInOl), benzophenone (5.13g, 29.1betammol) and potassium tert-butoxide (3.27g, 29.1betammol) were put into a reactor and melted by THF of 50ml to have them react to each other for four hours at 120C to thereby synthesize l-bromo-4- (2, 2- diphenylvinyl) benzene (1-1) . The synthesized-bromo-4- (2, 2- diphenylvinyl) benzene (1-1) (beta.03g, ldeltammol) was melted by THF of 50ml, gradually added with 2Mn-BuLi (10ml, 20mmol) at -78 C and agitated for one hour at low temperatures. The mixture was gradually added with triisopropyl borate <n="73"/>(3.76g, 20mmol) at -78C, agitated for one hour at low temperatures and then additionally agitated for 30 minutes at 0C to thereby synthesize 4- (2, 2- diphenylvinyl) phenylboronic acid (1-2) . The synthesized 4- (2, 2-diphenylvinyl) phenylboronic acid (4.5g, 15mmol) (l-2), K2CO3 (6.2g, 45mmol) and Pd (PPh3) 4 (0.8betag, 0.75mmol) were melted by THF (60ml), added with (E) -3- (5- bromothieno [3, 2-b] thiophene-2-yl) -2-cyanoacrylic acid(5.6g, 18mmol) , agitated for four hours at 120C to complete the reaction. After extracting an organic layer from the mixture with dichloromethane and distilled water, the solvent was removed through an evaporator and the organic layer was recrystallized by n-hexane and dried to collect the compound 142 after the sediment was filtered.
Stage #1: diethyl (4-bromobenzyl)phosphonate With sodium hydride In N,N-dimethyl-formamide for 0.333333h; cooling;
Stage #2: benzaldehyde In N,N-dimethyl-formamide for 12h; Further stages.;
59%
With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 0 - 20℃;
With potassium tert-butylate; In tetrahydrofuran; for 0.5h;Inert atmosphere; Cooling with ice;
Preparing Example 3 Preparation Of (E)-1,2-Bis(P-Phenyl-Bromide)Ethene) (Compound B) Potassium tert-butoxide (4.08 g, 36.4 mmol) was in a one-neck bottle. After introducing nitrogen gas by vacuum pumping, anhydrous tetrahydrofuran (25.0 mL) was added. Then, compound A (6.30 g, 20.0 mmol) and 4-bromobenzaldehyde (3.37 g, 18.2 mmol) were in another two-neck bottle. After introducing nitrogen gas by vacuum pumping, anhydrous tetrahydrofuran (25.0 mL) was added. The said potassium tert-butoxide and solution was added slowly under ice bath for 30 minutes. After the reaction finished and was back to room temperature, the organic layer was exacted with ethyl acetate and water respectively and collected, then removing water with magnesium sulphate and condensing. After column chromatography with n-hexane, white solids of 6.09 g with a yield of 99% were obtained. 1H NMR (400 MHz, CDCl3, delta): 7.46 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.00 (s, 1H). 13C NMR (100 MHz, CDCl3, delta): 135.9, 131.8, 128.1, 128.0, 121.6.
72%
With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 5h;
2.1.2 (E)-1,2-Bis(4-bromophenyl)ethane (2) A mixture of (4-bromobenzyl)phosphonic acid diethyl ester (2.71 g, 11.0 mmol) and potassium tert-butoxide (3.37 g, 30.0 mmol) in THF (20 mL) was stirred in an ice-water bath for several minutes and then 4-bromobenzaldehyde (1.85 g, 10.0 mmol) was added. The solution was maintained at 0 C and stirred continuously for a further 5 h. Then, the reaction was quenched through the addition of ice water. The mixture was partitioned between DCM and water and then the organic phase was collected, dried (MgSO4), filtered, and evaporated to dryness. The residue was recrystallized (MeOH/THF) to provide a white solid (2.43 g, 72%). 1H NMR (400 MHz, CDCl3) delta (ppm): 7.09 (s, J = 7.4 Hz, 2 H), 7.24 (d, J = 7.4 Hz, 4 H), 7.45 (d, 4 H). EIMS (m/z): calcd for C14H10Br2, 338.3; found: 338.1. Anal. Calcd for C14H10Br2: C, 44.20; H 2.96. Found: C, 44.32; H, 2.975.
With sodium methylate; In N,N-dimethyl-formamide; at 25℃; for 24h;
Example lk. (E)-4-(4-bromostyryl)-N,N-dimethylaniline (17).; DMF (anhydrous) (10.5 mL) was added to sodium methoxide (176 mg, 3.26 mmol) and the color was changed to pink. To the above solution <strong>[38186-51-5]diethyl 4-bromobenzylphosphonate</strong> (1.0 g, 3.26 mmol) in DMF (6.5 ml) was added dropwise over 2 minutes, followed by 4 (dimethylamino)benzaldehyde (486 mg, 3.26 mmol). The reaction mixture was stirred at room temperature for 24 hours. Deionized water (17 mL) was added. The product was filtered out through vacuum filtration and recrystallized with DCM/ hexane to give compound 17. 17: 74%. Yield; tan solid; 1H NMR (400 MHz, CDC13) delta 7.47- 7.32 (m, 6H), 7.04 (d, IH, J= 12.5 Hz), 6.83 (d, IH, J= 16.3 Hz), 6.71 (d, 2H, J= 8.9 Hz), 2.99 (s, 6H); 13C NMR (100 MHz, CDC13) delta 150.5, 137.4, 136.1 , 132.1 , 131.8, 129.7, 128.3, 128.2, 127.9, 127.7, 125.5, 123,2, 120.3, 1 12.6, 40.7; HRMS Calc for Ci6Hi6BrN 302.0541 found 302.0539.
Stage #1: diethyl (4-bromobenzyl)phosphonate With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h;
Stage #2: tris(4-formylphenyl)amine In N,N-dimethyl-formamide at 20 - 90℃; for 97h;
55.6 %
Stage #1: diethyl (4-bromobenzyl)phosphonate With tetrabutylammomium bromide; sodium hydroxide In toluene at 45℃;
Stage #2: tris(4-formylphenyl)amine In toluene at 45℃;
3-2 Example 3-2: Preparation of tris(4-((E)-4-bromostyryl)phenyl)amine / Preparation of compound D-2
To a 250 mL round bottom flask equipped with a condenser, diethyl 4-bromobenzylphosphonate (14.0 g, 45.6 mmol) and tetra n-butylammonium bromide (TBAB, 1.47 g, 4.56 mmol) were added to anhydrous water. Toluene (150 mL) was added and dissolved. After adding 50wt% NaOH and stirring at 45° C. for 30 minutes, compound D-1 (5.0 g, 15.2 mmol) dissolved in toluene was added. After stirring at 45 °C for 24 hours, the reaction was terminated by adding HCl aqueous solution. After fractional distillation through ethyl acetate, remaining water was removed with anhydrous magnesium sulfate, the solvent was evaporated, and purified through column chromatography to obtain pu
With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 8h;
In a stream of argon, 61.6 g (0.2 mol) of 4-bromo-benzylphosphonic acid diethyl ester, 37 g (0.2 mol) of 4-bromobenzaldehyde, 23.5 g (0.21 mol) of t-butoxypotassium, and 500 mL of THF were added to a 1-L three-necked flask provided with a cooling pipe, and the whole was stirred at room temperature for 8 hours. After the completion of the reaction, 500 mL of water were charged into the resultant, and the precipitated crystal was taken by filtration and washed with 500 mL of hexane, whereby 64 g of a white powder were obtained (in 95% yield).
5-tert-butoxycarbonylamino-5-[(E)-(4-bromophenyl)ethenyl]-2,2-dimethyl-1,3-dioxane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃;
Example 1Synthesis of 5-tert-Butoxycarbonylamino-5-[(E)-(4-bromophenyl)ethenyl]-2,2-dimethyl-1,3-dioxane (17)To a solution of aldehyde 16 (0.82 g, 3.14 mmol) and phosphonate 15 (1.45 g, 4.7 mmol) in dry THF (10 mL) was added potassium tert-butoxide (1.58 g, 14.1 mmol) slowly at 0 C. After the mixture was stirred at 0 C. for 3 h and at room temperature overnight, ice-water (20 mL) was added and the suspension was extracted with CH2Cl2 (3×30 mL). The combined organic layer was washed with water (2×20 mL) and brine (2×20 mL), dried (Na2SO4), and concentrated under vacuum. The residue was purified by chromatography with gradient elution (hexanes/EtOAc 20:1 to 8:1) to give 17 (0.80 g, 62%). 1H NMR delta 7.37 (d, 2H, J=8.4 Hz), 7.19 (d, 2H, J=8.4 Hz), 6.46 (d, 1H, J=16.4 Hz), 6.21 (d, 1H, J=16.4 Hz), 5.42 (s, 1H), 3.97 (d, 2H, J=11.2 Hz), 3.88 (d, 2H, J=11.2 Hz), 1.50-1.39 (m, 15H); 13C NMR delta 154.5, 135.3, 131.2, 129.0, 128.7, 127.6, 121.1, 97.9, 79.1, 65.6, 52.7, 28.1, 27.0, 19.5. HRMS m/z: calcd for C19H27BrNO4 (MH+), 412.1118; found, 412.1120.
With tris(o-tolyl)phosphine; triethylamine In toluene mixed, heated at 115°C with stirring for 48 h; cooled to room temp., filtered, evapd., chromy.(silica-diethyl ether), evapd., elem. anal.;
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 25h;
Example 13 Synthesis of 2-[2-(4'-bromophenyl)]vinyl-1H-pyrrole (compound 13) To a solution of 1H-pyrrole-2-carboxaldehyde (0.95 g, 10 mmol) and <strong>[38186-51-5](4-bromobenzyl)phosphonic acid diethyl ester</strong> (3.69 g, 12 mmol) in dry THF (20 mL), was added potassium tert-butoxide (3.37 g, 30 mmol) at 0 C. with vigorous stirring. The mixture was stirred at 0 C. for 1 h and then allowed to warm to room temperature. After the mixture was stirred at room temperature for 1 day, water (20 mL) was added. The mixture was extracted with CH2Cl2 (3*50 mL), and the combined organic solution was washed with water (2*50 mL), and then dried over anhydrous Na2SO4. The solvent was removed under vacuum and the residue was purified by chromatography on silica gel (elution with hexane/ethyl acetate, 10:1) to give compound 13 (1.72 g, 69%) as a blue solid.
(E)-2-bromo-6-(4-bromostyryl)naphthalene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With potassium tert-butylate; In dimethyl sulfoxide; at 0 - 20℃; for 12h;
beta-bromo-2-naphthaldehyde (4.Og, 17. lmmol) and diethyl-4- bromobenzylphosphonate (6.3g, 20.5mmol) were dissolved in purified dimethylsulfoxide (10OmL) under a nitrogen atmosphere, the reaction solution was cooled down to 0C, and then potassium t-butoxide (2.5g, 20.5mmol) was slowly added thereto. The reaction mixture solution was stirred at room temperature for 12 hours. The reaction mixture solution was subjected to extraction with water and dichloromethane to thereby remove the solvent. The extracted material was sufficiently washed with methanol, and was dried in vacuum to thereby obtain a white solid (6.Og, yield: 91%).
With sodium t-butanolate; In tetrahydrofuran; at 0 - 20℃; for 12h;Cooling with ice;
To,(4-bromobenzyl)diethyl phosphonate (0.025 mol) in 100 ml of dry THF was added sodium tert-butoxide (0.05 mol). The reaction mixture was cooled to 0 C. in an ice bath. Formyl-N,N-dihexylaniline (0.02 mol) were added to the solution, the ice bath was removed and the mixture was stirred at room temperature for 12 h. The product was poured into 200 ml of water and then THF was removed. The crude product (8.0 g, 90% yield) was collected by filtration. 1H NMR (400 MHz, CDCl3): delta 7.41 (d, 2H, J=8.8 Hz), 7.35 (d, 4H, J=8.4 Hz), 7.31 (d, 2H, J=8.4 Hz), 6.99 (d, 1H, J=16.0 Hz), 6.78 (d, 1H, J=16.0 Hz), 6.61 (d, 2H, J=8.8 Hz), 3.27 (t, 4H, J=7.6 Hz), 1.56 (m, 4H), 1.32 (m, 12H), 0.90 (t, 6H, J=6.4 Hz), HRMS calcd. for C26H36BrN 441.2026, found 441.2021.
In an argon stream, a 300 mL-recovery flask was charged with 8.40 g of diethyl(4-bromobenzyl)phosphate and 50 mL of THF. After cooling the resultant to -68C, 6.16 g of potassium tert-butoxide was added, and the resultant was allowed to react for 90 minutes. Subsequently, a THF solution (60 mL) of 6.90 g of the intermediate 2 was added dropwise, and the resultant was allowed to react for 2 hours. Then, the reaction mixture was heated to room temperature for 1 hour while stirring, and allowed to react for 2 hours at room temperature. Separation was conducted by adding clean water and toluene, and an aqueous phase was extracted with toluene. An organic phase thus obtained was washed with clean water and saturated saline, dried with sodium sulfate. Solids obtained after concentration were re-crystallized from toluene, and solids thus obtained were dried under reduced pressure, whereby 7.00 g of yellowish white solids were obtained. As a result of the measurement by FD-MS (field desorption mass spectrometry), the compound was confirmed to be intermediate 3.
7.00 g
Synthesis of intermediate 3 (Synthesis Example (1-3)) [0073] A recovery flask (300 ml) was charged with 8.40 g of diethyl (4-bromobenzyl)phosphonate and 50 ml of THF under an argon stream. After cooling the mixture to -68C, 6.16 g of potassium tert-butoxide was added to the mixture. The mixture was stirred for 90 minutes. After the dropwise addition of a THF (60 ml) solution of 6.90 g of the intermediate 2, the mixture was reacted for 2 hours, heated to room temperature with stirring over 1 hour, and stirred at room temperature for 2 hours. The mixture was separated by adding water, and the aqueous layer was extracted with toluene. The organic layer was washed with water and a saturated sodium chloride solution, dried over sodium sulfate, and concentrated to obtain a solid. The solid was recrystallized from toluene, and the resulting solid was dried under reduced pressure to obtain 7.00 g of a yellowish-white solid. The yellowish-white solid was identified as the intermediate 3 by FD-MS analysis.
With copper(l) iodide; caesium carbonate; In 1,2-dimethoxyethane; at 85℃; for 3h;Inert atmosphere;
General procedure: Under an argon atmosphere, the carbonyl compounds (0.40 mmol), TsNHNH2 (0.42 mmol, 1.05 eq) and DME (1.0 mL) were successively added to a flame-dried Schlenk flask. The reaction was heated at 60 ºC with stirring for 30 minutes. After the solution cooled down to room temperature H-Phosphonate 1b (0.40 mmol, 1.0 eq), Cs2CO3 (0.60 mmol, 1.5 eq), and CuI (0.04 mmol, 10 mol %) were sequentially added to the system. The mixture was stirred to 85oC. When the reaction was considered complete, as determined by TLC analysis, the reaction mixture was cooled to room temperature and filtered through a short plug of silica gel [washed with EtOAc]. Solvent was then removed in vacuo to provide a crude mixture, which was purified by silica gel column chromatography to afford pure product.
General procedure: A solution of benzophenone (1.82g, 10 mmol) and <strong>[38186-51-5]diethyl 4-bromobenzylphosphonate</strong> (3.1 g, 10 mmol) in anhydrous THF (40 mL) was stirred under argon atmosphere at 0 ºC. Potassium tert-butoxide (1.1 g, 10 mmol) was added quickly and the mixture was stirred for 2 h at room temperature. The reaction mixture was poured into ethanol and a solid precipitated out.
tert-butyl 4-(4-bromobenzylidene)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
Method B Diethyl 4-bromobenzylphosphonate (Int 1) (1.69 g, 5.5 mmol) in THF (3 ml) was added dropwise to a stirred suspension of sodium hydride (60 % dispersion in oil, 0.32 g, 8.0 mmol) in THF (20 ml) and 15-crown-5 (2 drops) at rt. The reaction was warmed to 65 C for 15 minutes and then cooled to rt. ieri-Butyl 4-oxopiperidine-l-carboxylate (1 g, 5 mmol) was added and the reaction was warmed to 50 C for 1 h. The reaction mixture was poured onto ice water and extracted with ethyl acetate. The organic extract was washed with brine, dried over MgS04 and evaporated. Purification by column chromatography (Si02; 0-15 % EtOAc in petrol) gave te -butyl 4-(4- bromobenzylidene)piperidine-l-carboxylate as colourless oil (1.19 g, 69 %). ? NMR (400 MHz, MeOD) delta 7.41 - 7.50 (m, 2H), 7.05 - 7.17 (m, 2H), 6.35 (s, 1H), 3.45 - 3.56 (m, 2H), 3.37 - 3.45 (m, 2H), 2.39 - 2.48 (m, 2H), 2.29 - 2.38 (m, 2H), 1.39 - 1.54 (m, 9H) MS ES+ 252
With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 0.25h;Inert atmosphere;
A solution of 4- (diphenylamino) benzaldehyde (2.73 g, 10.0 mmol) and diethyl 4-bromobenzyl phosphonate (3.53 g, 11.5 mmol) was placed in a two-necked flask, evacuated and passed through nitrogen, 20 mL of anhydrous tetrahydrofuran (THF) was added; Potassium tert-butoxide (t-BuOK) (3.36 g, 30 mmole) dissolved in THF (30 mL) was slowly added and mixed at 0 C for 15 minutes under ice-cooling. The solvent was removed by concentration under reduced pressure and purified by column chromatography (n-hexane: dichloromethane = 9: 1) to give the yellow intermediate I-1 ((E) -4- (4-bromostyryl) N, N-diphenylaniline) (3.71 g, yield 87%).
87%
With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 0.25h;Inert atmosphere;
A solution of 4- (diphenylamino) benzaldehyde (2.73 g, 10.0 mmol) and diethyl 4-bromobenzyl phosphonate (3.53 g, 11.5 mmol) Placed in a two-necked flask, evacuated and passed through nitrogen, 20 m L of anhydrous tetrahydrofuran (THF) was added; Potassium tert-butoxide (t-BuOK) (3.36 g, 30 mmole) dissolved in THF (30 mL) was slowly added and mixed at 0 C for 15 minutes under ice-cooling. The solvent was removed by concentration under reduced pressure, And purified by column chromatography (n-hexane: dichloromethane = 9: 1) to give a yellow intermediate I-1 ((E)-4-(4-bromostyryl)-N, N-diphenylaniline) (3.71 g, yield 87%).
With potassium tert-butylate; In N,N-dimethyl-formamide; at 20℃;Cooling with ice;
To a 500 ml single-neck flask, was added 25 g p-bromobenzyl bromide and 49.8 ml triethyl phosphite (1-2). The mixture was refluxed for 2 hours, then the excess triethyl phosphate was removed. 23.4 g intermediate 1-1, 250 ml DMF, and 16.8 g potassium tert-butoxide were added into the flask in an ice bath. The resulting mixture was allowed to warm to the room temperature, and stirred overnight. The reaction mixture was poured into distilled water, filtered, and the precipitate was recrystallized from ethanol to yield 31.8 g product (83%).
With tetra-(n-butyl)ammonium iodide; at 120℃; for 24h;Inert atmosphere;
To a 20 mL tubular reactor was added 4-bromobenzyl alcohol (93.0 mg, 0.50 mmol)(3.8 mg, 0.01 mmol, 2 mol%), protected by vacuum nitrogen and then heated to 120 C under solvent-free conditions 24h After the TLC monitoring reaction was complete, the product was purified by column chromatography and the yield was 90%.
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 8h;Inert atmosphere;
A 100 ml round bottom flask was charged with a constant pressure dropping funnel and the flask was charged with 4- (diethoxyphosphinylmethyl) -bromobenzene(0.58 g, 5 mmol) was added to the funnel, and the mixture was poured into argon and then evacuated for three times. The dry tetrahydrofuran was added to 20 ml of a flask (1.0 g, 3 mmol) and B1 (2.54 g, 1.5 mmol) , 10 ml was placed in a separatory funnel, and the reaction flask was placed in an ice-water bath. After stirring and stirring, a solution of potassium t-butoxide in tetrahydrofuran was slowly added dropwise, and the mixture was stirred and heated at room temperature for 8 hours. The reaction solution was poured into 500 ml of ethanol and filtered to give a precipitate. The crude product was finally separated by silica gel column (eluent was stone Oleyl ether: dichloromethane = 6: 1) to give 2.0 g of a white solid in 72% yield
4-{bis[4-(3,6-bis-(3,6-di-tert-butylcarbazol-9-yl)carbazol-9-yl)phenyl]amino}benzaldehyde[ No CAS ]
C130H126BrN7[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 8h;Inert atmosphere;
A 100 ml round bottom flask was charged with a constant pressure dropping funnel and the flask was charged with 4- (diethoxyphosphinylmethyl) -bromobenzene(3.0 g, 9 mmol) and C1 (7.5 g, 4.5 mmol), potassium tert-butoxide (1.74 g, 15 mmol) was added to the funnel; Air, continuous ventilation three times; add dry tetrahydrofuran 50ml in the flask, 30ml in the separatory funnel, the reaction bottle placed in the ice Water bath, stirring dissolved, slowly dropping potassium tert-butoxide in tetrahydrofuran solution, after the natural temperature increase after dripping, stirring at room temperature 8hour. The reaction solution was poured into 500 ml of ethanol and filtered to give a precipitate. The crude product was finally separated by silica gel column (eluent was stone Oleyl ether: dichloromethane = 6: 1) to give 6.4 g of a white solid in 76% yield.
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 8h;Inert atmosphere;
A 100 ml round bottom flask was charged with a constant pressure dropping funnel and the flask was charged with 4- (diethoxyphosphinylmethyl) -bromobenzene(3.04 g, 9 mmol) and E1 (5.97 g, 4.5 mmol) were added to the funnel, potassium tert-butoxide (1.74 g, 15 mmol) was added to the funnel; rush to argon and then evacuated for 3 consecutive cycles; 50 ml of dry tetrahydrofuran , 30 ml was placed in a separatory funnel, and the reaction flask was placed in an ice-water bath. After stirring and stirring, a solution of potassium t-butoxide in tetrahydrofuran was slowly added dropwise, and the mixture was heated and stirred at room temperature for 8 hours. The reaction solution was poured into 500 ml of ethanol and filtered to give a precipitate. The crude product was finally separated by silica gel column (eluent: petroleum ether: dichloromethane = 6: 1) to give 4.9 g of a yellow solid in 73% yield.
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 8h;Inert atmosphere;
A 100 ml round bottom flask was equipped with a constant pressure dropping funnel,The flask was charged with 4- (diethoxyphosphinylmethyl) -bromobenzene(3.1 g, 10 mmol) and Al (5.8 g, 7 mmol)(3.4g, 30mmol) was added to the funnel, rinsed with argon and then evacuated for three consecutive times. Add 70ml of dry tetrahydrofuran in a flask and 30ml in a separatory funnel and place the reaction flask in ice Water bath, stirring dissolved, slowly dropping potassium tert-butoxide in tetrahydrofuran solution, after the natural temperature increase after dripping, stirring at room temperature 8hour. The reaction solution was poured into 500 ml of ethanol and filtered to give a precipitate. The crude product was finally separated by silica gel column (eluent was stone Oleyl ether: dichloromethane = 6: 1) to give 4.6 g of a white solid in 67% yield.
(E)-3-(4-bromostyryl)-9-phenyl-9H-carbazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 0.25h;Inert atmosphere;
9-phenyl-9H-carbazole-3-carbaldehyde (3 52 g, 13 mmol) was reacted with (diethyl 4-bromobenzyl) phosphonate (4 42 g, 14.4 mmol) was placed In a two-necked flask, evacuate and pass nitrogen and add 20 m of anhydrous tetrahydrofuran (THF). Under ice bath, potassium tert-butoxide (t-BuOK X 3.36 g, 30 mmol) dissolved in THF (30 mL) Add slowly to the mixture at 0 C for 15 minutes. The solvent was removed by concentration under reduced pressure and the column was reused (N-hexane: dichloromethane = 5: 1) to give the white intermediate 1-4 ((E) -3- (4-bromostyryl) -9-phenyl-9H-carbazole) (4.52 g, yield 82%).
63%
With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 0.25h;Inert atmosphere;
9-phenyl-9H-carbazole-3-carbaldehyde (3.52 g, 13 mmol) and diethyl 4-bromobenzyl phosphonate (4.42 g, 14.4 mmol) was added to a solution placed in a two-necked flask, evacuated and passed through nitrogen, 20 m L of anhydrous tetrahydrofuran (THF) was added; Potassium tert-butoxide (t-BuOK) (3.36 g, 30 mmol) dissolved in THF (30 mL) was added slowly under ice-cooling, Reaction at 0 C for 15 minutes. The solvent was removed by concentration under reduced pressure and purified by column chromatography (n-hexane: dichloromethane = 5: 1) to give a white intermediate I-4 ((E) -3- (4-bromostyryl) -9-phenyl-9H-carbazole) (4.52 g, yield 82%).
With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 24h;Inert atmosphere;
Potassium t-butoxide (t-BuOK) (0.22 g, 2 mmol) was placed in a two-necked flask, evacuated and nitrogen was introduced, and 3 mL of anhydrous tetrahydrofuran (THF) was added. A mixture of 4- (9H-carbazol-9-yl) benzaldehyde (0.27 g, 1 mmol) and diethyl 4-bromobenzylphosphate (diethyl Bromobenzyl phosphonate (0.34 g, 1.1 mmol) was placed in a single neck flask and 3 mL of anhydrous tetrahydrofuran was added under a nitrogen atmosphere. The solution in the flask was slowly added to the two-necked flask under ice-cooling and mixed and reacted at 0 C for 1 day. The reaction solution was poured into water to precipitate a yellow solid. The precipitated yellow solid was filtered and the intermediate product I-5 ((E) -9- (4- (4-bromostyryl) phenyl) -9H-carbazole was obtained by repeatedly washing with methanol to obtain a pale yellow powder. (0.39 g, yield 93%).
93%
With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 0.25h;Inert atmosphere;
Potassium t-butoxide (t-BuOK) (0.22 g, 2 mmol) was placed in a two-necked flask, evacuated and nitrogen was introduced, and 3 mL of anhydrous tetrahydrofuran (THF) was added. A mixture of 4-(9H-carbazol-9-yl)benzaldehyde (0.27 g, 1 mmol) and diethyl 4-bromobenzyl phosphonate (0.34 g, 1.1 mmol) placed in a single neck flask, in the nitrogen environment by adding 3mL of anhydrous tetrahydrofuran. The solution in the flask was slowly added to the flask and mixed under ice bath and reacted at 0 C for 1 day. The reaction solution was poured into water to precipitate a yellow solid. The precipitated yellow solid was evacuated and filtered, and repeatedly washed with methanol to obtain the intermediate product of the pale yellow powder I-5 ((E)-9-(4-(4-bromostyryl)phenyl)-9H-carbazole (0.39 g, yield 93%).
(E)-4-(4-bromostyryl)-N,N-bis(4-fluorophenyl)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 0.25h;Inert atmosphere;
A solution of 4- (bis (4-fluorophenyl) amino) benzaldehyde (4.64 g, 15 mmol) and diethyl 4-bromobenzylphosphate (diethyl (5.07 g, 16.5 mmol) was placed in a two-necked flask, evacuated and passed through nitrogen, and then 20 mL of anhydrous tetrahydrofuran (THF) was added; under ice-cooling, Potassium butoxide (t-BuOK) (5.0 g, 45 mmol) was added slowly and the mixture was reacted at 0 C for 15 minutes. The solvent was removed by concentration under reduced pressure and purified by column chromatography (n-hexane: dichloromethane = 9: 1) to give the yellow intermediate I-2 ((E) -4- (4-bromostyryl) N, bis (4-fluorophenyl) aniline) (6.17 g, yield 89%).
89%
With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 0.25h;Inert atmosphere;
4- (bis (4-fluorophenyl) amino) benzaldehyde (4.64 g, 15 mmol) was reacted with diethyl (4-bromobenzyl) phosphonate(5.07g, 16.5mmol) Placed in a two-necked flask, evacuated and passed through nitrogen, 20 m L of anhydrous tetrahydrofuran (THF) was added; Potassium tert-butoxide (t-BuOK) (5.0 g, 45 mmol) dissolved in THF (30 mL) was slowly added to the mixture under ice-cooling, Reaction at 0 C for 15 minutes. The solvent was removed by concentration under reduced pressure and purified by column chromatography (n-hexane: dichloromethane = 9: 1) to give a yellow intermediate I-2 ((E) -4- (4-bromostyryl) -N, N-bis (4-fluorophenyl) aniline) (6.17 g, yield 89%).
4-(N-(naphthalen-1-yl)-N-phenylamino)benzaldehyde[ No CAS ]
[ 38186-51-5 ]
(E)-N-(4-(4-bromostyryl)phenyl)-N-phenylnaphthalen-1-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 0.25h;Inert atmosphere;
The 4 - (1-naphthyl (phenyl) amine) aldehyde (2.87g, 8.9mmol l) with (diethyl (4-bromobenzyl) phosphonate) (3.0g, 9.76mmol) is placed in the two-neck bottle, after vacuum and nitrogen, by adding 20 ml of anhydrous tetrahydrofuran (THF); under the ice, the dissolved THF (30 ml) for uncle butanol potassium (T-buOK) (2.24g, 20mmol) slowly adding and mixing the, 0 C 15 minutes for reaction. By means of the concentrated under reduced pressure to remove the solvent, and then the use of column chromatography (hexane: dichloromethane=9:1) purified by, get the yellow intermediate product I-3 ( (E)-N-(4-(4-bromostyryl)phenyl)-N-phenylnaphthalen-l-amine )) (2.67g, yield 63%).
63%
With potassium tert-butylate; In tetrahydrofuran; at 0℃; for 0.25h;Inert atmosphere;
A solution of 4- (1-naphthyl (1-yl) amino) benzaldehyde (2.87 g, 8.9 mmol) And diethyl 4-bromobenzyl phosphonate (3.0 g, 9.76 mmol) Placed in a two-necked flask, evacuated and passed through nitrogen, 20 m L of anhydrous tetrahydrofuran (THF) was added; Potassium tert-butoxide (t-BuOK) (2.24 g, 20 mmol) dissolved in THF (30 mL) was slowly added to the mixture under ice-cooling, Reaction at 0 C for 15 minutes. The solvent was removed by concentration under reduced pressure and purified by column chromatography (n-hexane: dichloromethane = 9: 1) to give a yellow intermediate I-3 ((E)-N-(4-(4-bromostyryl)phenyl)-N-phenylnaphthalen-1-amine (2.67 g, yield 63%).
With potassium tert-butylate; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere;
General procedure: Diethyl benzylphosphonate (1.10 g, 4.8 mmol) and 9-anthraldehyde (1.00 g, 4.8 mmol) were added into a 100 mLround-bottom flask with the protection of N2. N,N-Dimethylformamide(30 mL) was added to above flask, then cooled to0 C. The N,N-Dimethylformamide solution of t-BuOK (0.54 g,4.8 mmol) was added dropwise to above flask, stirred for 30 min at0 C, followed with stirring at room temperature until the 9-anthraldehyde was consumed completely (monitored by thinlayerchromatography). The reaction was terminated with ice water,and the product was extracted with ethyl acetate 100 mL. Afterthe solvent was evaporated, the crude product was purified bychromatography on a silica gel column (petroleum ether: ethylacetate 4:1 as eluent) to give the title compound as a pure (E)-9-styrylanthracene (1.3 g, 86.9%):
(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptane hydroiodide salt[ No CAS ]
diethyl ([4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]phenyl]methyl)phosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II); caesium carbonate; ruphos; In toluene; at 100℃;Inert atmosphere;
To a 1 00 mL round bottom Hask purged with and maintained under an inertatmosphere ofnitrogen was added (lS,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-25 oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptane hydroiodide salt l2dd (300 mg, 0.5915mmol, 1.00 equiv.), diethyl (4-bromopheny l)methyl]phosphonate 176a (267.2 mg, 0.87mmol, 1.47 equiv.), toluene (50 mL), RuPhos (67.23 mg), Rh-Phos-Precatalyst (36.9 mg), and Cs2C01 (773.5 mg, 2.37 mmo, 3.00 equiv.). The resulting mixture v.·as heated at 100Covernight with stirring. After cooling to room temperature, the solids were filtered out, andthe filtrate was concentrated under vacuum. The residue was pmitl.ed by silica gel columnchromatography eluting with ethyl acetate/petroleum ether (1:10-1:5-1:3-1:1) to furnish5 diethy l ([4-[(1 S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichloropheny l)- 1,2-oxazol-4-yl]methoxy ]-2-azabicyclo[2.2.1]heptan-2-yl]phenyl]methyl)phosphonate l76b (267 mg, 75%) as a whitesolid.
bis(4-(6-(9H-carbazol-9-yl)hexyloxy)phenyl)methanone[ No CAS ]
C56H53BrN2O2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 12h;Inert atmosphere;
A solution of compound 1 (1.38 g, 4.5 mmol) dissolved in THF(45 mL) was stirred under an argon atmosphere at 0 C. Potassium tertbutoxide(0.05 g, 0.4 mmol) was added quickly. After fully dissolved,compound 2 (0.36 g, 0.5 mmol) was added and the mixture was stirred continuously for 12 h at room temperature. The solvent was distilled by rotary evaporation after the reaction was completed. The crude product was poured into water and extracted with dichloromethane. The organic layer was dried over sodium sulfate (MgSO4). Following filtration and evaporation of solvent under vacuum, the resulting crude product was purified on a silica gel column chromatography by dichloromethane/petroleum ether (V/V=1:2) to yield compound 3 as a light-yellow powder (0.41 g, 95% yield). 1H NMR (500 MHz, CDCl3) delta8.12 (dd, J=7.8, 0.5 Hz, 4 H), 7.51-7.40 (m, 8 H), 7.25-7.21 (m, 7 H),7.08-7.04 (m, 2 H), 6.92-6.88 (m, 2 H), 6.83-6.78 (m, 4 H), 6.73 (s,1 H), 4.34 (dd, J=15.7, 7.2 Hz, 4 H), 3.92 (td, J=6.4, 3.6 Hz, 4 H),2.02-1.87 (m, 4 H), 1.84-1.68 (m, 4 H), 1.60-1.40 (m, 9 H); MS(MALDI-TOF), m/z: 864.318 ([M]+, calcd for C56H53BrN2O2, 864.329).
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 12h;Inert atmosphere;
Compound 1 (1.38 g, 4.51 mmol) was added to a 50 mL three-necked flask equipped with a reflux apparatus and argon gas.Add 45 mL of water-depleted THF solvent and stir to dissolve, perform three water and oxygen removal operations, cool the ice bath to 0 C, and quickly add t-BuOK (0.05 g, 0.44 mmol), after fully dissolved, add compound 2 (0.36 g, 0.51 mmol), and the system was stirred at room temperature.After 12 h, after the end of the reaction, the THF was evaporated under reduced pressure, and extracted with water and DCM to give an organic phase.After overnight, filtration and washing with PE, DCM was evaporated under reduced pressure to give a pale yellow solid, ie: Compound 3;
With potassium tert-butylate; In tetrahydrofuran; at 50℃; for 12h;Inert atmosphere;
4-triphenylamine benzophenone (1.0 g, 2.35 mmol) And potassium tert-butoxide (0.20 g, 1.80 mmol) was added to a 50 ml two-necked flask. The flask was evacuated under vacuum and replaced three times in dry nitrogen. Then add and then add dissolved a solution of <strong>[38186-51-5]diethyl 4-bromobenzylphosphonate</strong> (0.72 g, 2.35 mmol) in 30 mL of THF. It was then stirred at 50 C overnight (12 hours). After cooling to room temperature, The reaction was quenched with 1 M aqueous NH 4 Cl solution. It was extracted with saturated brine and dichloromethane. Vacuum distillation, Obtained a black solid, Use silica gel powder as the stationary phase, With n-hexane as eluent, 1.22 g of a yellow solid (yield 90%) was obtained by column chromatography. The reaction equation is as follows:
With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 0.5h;Inert atmosphere;
(a) in a dry three-necked bottle,Benzaldehyde (10 mmol) and diethyl 4-bromobenzyl phosphite (10 mmol) were added to 50 mL of dry tetrahydrofuran (THF) under nitrogen.Cooled to 0-5 C in an ice bath,Potassium tert-butoxide (10 mmol) was added in portions,The color of the system turned bright yellow, and the mixture was stirred at room temperature for 30 minutes after the addition.The TLC monitors the disappearance of the raw materials, and the THF is concentrated under reduced pressure. 100 mL of deionized water is added to the system, and the precipitate is separated by filtration, dried, and then recrystallized from anhydrous ethanol.The product is a yellowish solid,The yield was 90.3%.
200.A (rac)-(6-(4-Cyclopropylbenzyl)-2-azaspiro[3.4]octan-2-yl)((1s,3s)-3-hydroxy-3-methylcyclobutyl)methanone
Step A: tert-Butyl 6-(4-bromobenzylidene)-2-azaspiro[3.4]octane-2-carboxylate. A solution of diethyl 4-bromobenzylphosphonate (818 mg, 2.66 mmol) and THF (5 mL) was added to a 0° C. mixture of NaH (107 mg, 60 wt % in mineral oil, 2.66 mmol) and THF (5 mL) under Na. The resultant mixture was stirred for 30 min before treating with a solution of tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (200 mg, 0.888 mmol) and 15-crown-5 (587 mg, 2.66 mmol) in THF (5 mL). The reaction mixture was warmed to rt and stirred overnight before being quenched with sat. NH4Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (SiO2, 0-7% EtOAc in ether) to afford the title compound (260 mg, 77%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.46-7.42 (m, 2H), 7.16-7.10 (m, 2H), 6.30 (br s, 1H), 3.86-3.78 (m, 4H), 2.76-2.66 (m, 2H), 2.61-2.50 (m, 2H), 2.00 (t, J=7.2 Hz, 1H), 1.90 (t, J=7.2 Hz, 1H), 1.45 (d, J=5.6 Hz, 9H).
Stage #1: (4-bromobenzyl)phosphonic acid diethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere;
Stage #2: tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate With benzo-15-crown-5 In tetrahydrofuran; mineral oil at 20℃; Inert atmosphere;
200.A (rac)-(6-(4-Cyclopropylbenzyl)-2-azaspiro[3.4]octan-2-yl)((1s,3s)-3-hydroxy-3-methylcyclobutyl)methanone
Step A: tert-Butyl 6-(4-bromobenzylidene)-2-azaspiro[3.4]octane-2-carboxylate. A solution of diethyl 4-bromobenzylphosphonate (818 mg, 2.66 mmol) and THF (5 mL) was added to a 0° C. mixture of NaH (107 mg, 60 wt % in mineral oil, 2.66 mmol) and THF (5 mL) under Na. The resultant mixture was stirred for 30 min before treating with a solution of tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (200 mg, 0.888 mmol) and 15-crown-5 (587 mg, 2.66 mmol) in THF (5 mL). The reaction mixture was warmed to rt and stirred overnight before being quenched with sat. NH4Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (SiO2, 0-7% EtOAc in ether) to afford the title compound (260 mg, 77%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.46-7.42 (m, 2H), 7.16-7.10 (m, 2H), 6.30 (br s, 1H), 3.86-3.78 (m, 4H), 2.76-2.66 (m, 2H), 2.61-2.50 (m, 2H), 2.00 (t, J=7.2 Hz, 1H), 1.90 (t, J=7.2 Hz, 1H), 1.45 (d, J=5.6 Hz, 9H).
77%
Stage #1: (4-bromobenzyl)phosphonic acid diethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere;
Stage #2: tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate With benzo-15-crown-5 In tetrahydrofuran; mineral oil at 20℃; Inert atmosphere;
200.A (rac)-(6-(4-Cyclopropylbenzyl)-2-azaspiro[3.4]octan-2-yl)((1s,3s)-3-hydroxy-3-methylcyclobutyl)methanone
Step A: tert-Butyl 6-(4-bromobenzylidene)-2-azaspiro[3.4]octane-2-carboxylate. A solution of diethyl 4-bromobenzylphosphonate (818 mg, 2.66 mmol) and THF (5 mL) was added to a 0° C. mixture of NaH (107 mg, 60 wt % in mineral oil, 2.66 mmol) and THF (5 mL) under Na. The resultant mixture was stirred for 30 min before treating with a solution of tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (200 mg, 0.888 mmol) and 15-crown-5 (587 mg, 2.66 mmol) in THF (5 mL). The reaction mixture was warmed to rt and stirred overnight before being quenched with sat. NH4Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (SiO2, 0-7% EtOAc in ether) to afford the title compound (260 mg, 77%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.46-7.42 (m, 2H), 7.16-7.10 (m, 2H), 6.30 (br s, 1H), 3.86-3.78 (m, 4H), 2.76-2.66 (m, 2H), 2.61-2.50 (m, 2H), 2.00 (t, J=7.2 Hz, 1H), 1.90 (t, J=7.2 Hz, 1H), 1.45 (d, J=5.6 Hz, 9H).
Stage #1: diethyl (4-bromobenzyl)phosphonate With tetrabutylammomium bromide; sodium hydroxide In toluene at 45℃;
Stage #2: 4,4'-((4-bromophenyl)azanediyl)dibenzaldehyde In toluene at 45℃;
2-3 Example 2-3: Preparation of 4-bromo-N,N-bis(4-((E)-4-bromostyryl)phenyl)aniline / Preparation of compound C-3
To a 250 mL round bottom flask equipped with a condenser, diethyl 4-bromobenzylphosphonate (11.3 g, 36.8 mmol) and tetra n-butylammonium bromide (TBAB, 1.19 g, 3.68 mmol) were added to anhydrous water. Toluene (150 mL) was added and dissolved.After adding 50wt% NaOH and stirring at 45° C. for 30 minutes, compound C-2 (7.0 g, 18.4 mmol) dissolved in toluene was added. After stirring at 45° C. for 24 hours, the reaction was terminated by adding aqueous HCl. After fractional distillation through ethyl acetate, remaining water was removed with anhydrous magnesium sulfate, the solvent was evaporated, and purified through column chromatography to obtain pure compound C-3 (14.3 g, 75.4%).