* 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.
Reference：
[1] Organic Process Research and Development, 2008, vol. 12, # 1, p. 116 - 119
[2] European Journal of Organic Chemistry, 2002, # 16, p. 2844 - 2854
[3] Justus Liebigs Annalen der Chemie, 1971, vol. 751, p. 17 - 26
[4] Journal of Organic Chemistry, 1994, vol. 59, # 6, p. 1381 - 1388
[5] Chemische Berichte, 1884, vol. 17, p. 1233
4
[ 769-92-6 ]
[ 3282-56-2 ]
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 10, p. 3320 - 3326
5
[ 769-92-6 ]
[ 253185-03-4 ]
[ 23132-52-7 ]
[ 3282-56-2 ]
[ 1625-91-8 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1995, vol. 114, # 7, p. 311 - 316
6
[ 4627-22-9 ]
[ 98-54-4 ]
[ 3282-56-2 ]
[ 769-92-6 ]
Reference：
[1] Russian Chemical Bulletin, 1994, vol. 43, # 10, p. 1651 - 1656[2] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1994, # 10, p. 1746 - 1751
7
[ 558-17-8 ]
[ 98-95-3 ]
[ 937-33-7 ]
[ 3282-56-2 ]
[ 769-92-6 ]
[ 1127-42-0 ]
Reference：
[1] Russian Journal of Organic Chemistry, 1995, vol. 31, # 9, p. 1276 - 1283[2] Zhurnal Organicheskoi Khimii, 1995, vol. 31, # 9, p. 1414 - 1421
[3] Russian Journal of Organic Chemistry, 1993, vol. 29, # 10, p. 1654 - 1662[4] Zhurnal Organicheskoi Khimii, 1993, vol. 29, # 10, p. 1987 - 1998
8
[ 558-17-8 ]
[ 98-95-3 ]
[ 937-33-7 ]
[ 3282-56-2 ]
[ 769-92-6 ]
[ 1127-42-0 ]
[ 62-53-3 ]
Reference：
[1] Russian Journal of Organic Chemistry, 1993, vol. 29, # 10, p. 1654 - 1662[2] Zhurnal Organicheskoi Khimii, 1993, vol. 29, # 10, p. 1987 - 1998
9
[ 253185-03-4 ]
[ 5369-19-7 ]
[ 769-92-6 ]
[ 6310-21-0 ]
Reference：
[1] Journal of Organic Chemistry, 1984, vol. 49, # 23, p. 4479 - 4482
[2] Journal of Organic Chemistry, 1984, vol. 49, # 23, p. 4479 - 4482
10
[ 769-92-6 ]
[ 6310-19-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 25, p. 4906 - 4916
[2] Patent: WO2011/47315, 2011, A1,
[3] Journal of the American Chemical Society, 2012, vol. 134, # 3, p. 1528 - 1535
11
[ 3972-65-4 ]
[ 769-92-6 ]
[ 4627-22-9 ]
Yield
Reaction Conditions
Operation in experiment
72%
With tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene at 90 - 110℃; for 12 h; Inert atmosphere
4-tert-Butyl-1-aniline (14.9 g, 100 mmol),Tert-butyl-1-bromobenzene (21.2 g, 100 mmol),Bis (dibenzylideneacetone) palladium (1.7 g, 3 mmol),Tri-tert-butylphosphine (1.2 g, 6 mmol) was added to toluene (200 ml)And the resulting toluene solution was heated to 90 ° C under a stream of argon;Then sodium tert-butoxide (0.6 g, 6 mmol) was added,Heated to 110 ° C under an argon atmosphere,The reaction was stirred for 12 hours.The reaction mixture was cooled to room temperature,Add water to separate.The solvent of the obtained organic layer was concentrated,Get solid,The resulting solid was purified by silica gel column chromatography,The target product Intermediate 5 (20.2 g, 72 mmol) was obtained,Yield 72percent.
72%
With tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene at 90 - 110℃; for 12 h; Inert atmosphere
4-tert-butyl-1-aniline (14.9 g, 100 mmol),4-tert-butyl-1-bromobenzene (21.2 g, 100 mmol),Bis(dibenzylideneacetone)palladium (1.7 g, 3 mmol),Tri-tert-butylphosphine (1.2 g, 6 mmol) was added to toluene (200 ml). Heat to 90°C under a stream of argon gas,Then add sodium tert-butoxide (0.6 g, 6 mmol).Heating was continued to 110°C under an argon atmosphere and the reaction was stirred for 12 hours.The reaction solution was cooled to room temperature, and water was added for liquid separation.The resulting organic layer is concentrated, The resulting solid was purified by silica gel column chromatography.Intermediate 9 (20.2 g, 72 mmol) was obtained in 72percent yield.
72%
With tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene at 90 - 110℃; for 12 h; Inert atmosphere
4-tert-butyl-1-aniline (14.9 g, 100 mmol), 4-tert-butyl-1-bromobenzene (21.2 g, 100 mmol), bis(dibenzylideneacetone) palladium (1.7 g, 3) A mixture of mmol), tri-tert-butylphosphine (1.2 g, 6 mmol) and toluene (200 ml) was heated under a stream of argon gas to 90°C, and sodium tert-butoxide (0.6 g, 6 mmol) was added to the solution in argon. Heat to 110°C in a gas atmosphere and stir the reaction for 12 hours. The reaction mixture was cooled to room temperature and water was added for liquid separation. The solvent of the resulting organic layer was concentrated, and the resulting solid was purified by silica gel column chromatography to give Intermediate 5 (20.2 g, 72 mmol) in 72percent yield.
Reference：
[1] Bulletin of the Chemical Society of Japan, 2000, vol. 73, # 4, p. 1021 - 1027
[2] Patent: CN107286027, 2017, A, . Location in patent: Paragraph 0052; 0064; 0065; 0066
[3] Patent: CN107573306, 2018, A, . Location in patent: Paragraph 0030; 0038
[4] Patent: CN107573357, 2018, A, . Location in patent: Paragraph 0039; 0040
[5] Tetrahedron Letters, 2001, vol. 42, # 27, p. 4421 - 4424
[6] Patent: WO2005/90291, 2005, A1, . Location in patent: Page/Page column 82
12
[ 3972-65-4 ]
[ 4627-22-9 ]
[ 769-92-6 ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: With ammonia; sodium t-butanolate In 1,2-dimethoxyethane at 90℃; for 24 h; Stage #2: With hydrogenchloride In 1,2-dimethoxyethane; water at 20℃; for 0.0833333 h; Stage #3: With sodium hydrogencarbonate In 1,2-dimethoxyethane; water
CyPF-t-Bu)PdCl2 (7.30 mg, 1.00 x 10'2 mmol), NaOrBu (0.192 g, 2.00 mrnol) and 4-t-butyl-l-bromobenzene (0.213 g, 1.00 mmol) were weighed into a Parr Bomb inside a dry box. DME (20.0 mL) was then added. The Parr bomb was closed and removed from the dry box. Ammonia was added with stirring by connecting to an ammonia tank and maintaining the pressure at 80 psi for 30 min." The resulting reaction mixture was allowed to stir for 24 h at 90 0C. Pressure was built up to 200 psi during the reaction. The reaction mixture was then cooled to room temperature before being poured into ice water (20.0 mL). To this mixture was added HCI aqueous solution (10.0 mL, 1.0 M)). The mixture was stirred at room temperature for 5 min and was then neutralized with a saturated solution of NaHCO3 (5.00-10.0 mL). After extraction with CH2Cl2 (3 x 20.0 mL), the organic layer was separated and dried over MgSO4. The solvent was evaporated, and the crude product isolated by eluting with hexane/ethyl acetate (70/30) to give 128.1 mg (86percent) of 4-t-butylaniline as a pale yellow liquid. 1H NMR (CDCl3) δ 7.05 (d, J= 8.4 Hz, 2 H), 6.55 (d, J= 8.8 Hz, 2 H), 3.44 (s, br, 2 H), 1.20 (s, 9 H); 13C NMR (CDCl3) δ 143.74, 141.32, 125.98, 114.86, 33.85, 31.49.
72%
With lithium amide In 1,2-dimethoxyethane at 80℃; for 10 h;
The optimization of the reaction conditions for the lithium amide reaction was performed, as with the ammonia reaction, using 4-/-butylphenyl bromide. The amination of 4-/-butylphenyl bromide with lithium amide catalyzed by (CyPF-Z-Bu)PdCl2 (1.0 molpercent) was performed using various amounts of lithium amide, in various solvents, at various temperatures, and for various times. The conversion and the ratio of mono- to di-arylation products were determined by 1H NMR of the crude reaction products. The results of these experiments are summarized in Table 8. The selectivites improved at higher dilution, with reactions conducted with a 0.05 M concentration of the 4-/-butylphenyl bromide giving the highest selectivity. Selectivity was also improved by the use of a greater excess of lithium amide, although using 10-fold excess gave good <n="60"/>selectivity at 0.05M. The reaction proceeded in 1,2-dimethoxyethane (DME), tetrahydrofuran (THF) and 1,4-dioxane, with 1,2-dimethoxyethane giving the best results. Finally, a detrimental effect of increased temperature was observed on selectivity, with lower selectivity being observed when the reaction was conducted at 11O0C, in contrast to better selectivity at 11O0C.Table 8. Optimiztion of the Stoichimetry for the Catalyzed Animation Reaction using 4-t-ButyIphenyI bromide and Lithium Amide.
72%
Stage #1: With lithium amide In 1,2-dimethoxyethane at 80℃; for 24 h; Sealed vial Stage #2: With hydrogenchloride In 1,2-dimethoxyethane; water at 20℃; for 0.0833333 h; Stage #3: With sodium hydrogencarbonate In 1,2-dimethoxyethane; water
(CyPF-^-Bu)PdCl2 (7.30 mg, 1.00 x W2 mmol), LiNH2 (0.230 g, 10.0 mmol) and 4-/-butyl-l-bromobenzene (0.213 g, 1.00 mmol) were weighed into a 24 mL vial. DME (20.0 mL) was then added. The vial was sealed with a cap containing a PTFE septum, and the reaction mixture was stirred for 24 h at 80 0C. The reaction mixture was allowed to cool to room temperature before pouring into ice water (20.0 mL). To this mixture was added HCl aqueous solution (10.0 mL, 1.0 M). The mixture was stirred at room temperature for 5 min and was then neutralized with a saturated solution of NaHC(>USD (5.00-10.0 mL). After extraction with CH2Cl2 (3 x 20.0 mL), the organic layer was separated and dried over MgSO4. The solvent was evaporated, and the crude product isolated by eluting with hexane/ethyl acetate (80/20) to give 107.0 mg (72percent) of 4-J-butylaniline as a pale yellow liquid.
37%
With lithium amide In 1,4-dioxane at 80℃; for 24 h;
The optimization of the reaction conditions for the lithium amide reaction was performed, as with the ammonia reaction, using 4-/-butylphenyl bromide. The amination of 4-/-butylphenyl bromide with lithium amide catalyzed by (CyPF-Z-Bu)PdCl2 (1.0 molpercent) was performed using various amounts of lithium amide, in various solvents, at various temperatures, and for various times. The conversion and the ratio of mono- to di-arylation products were determined by 1H NMR of the crude reaction products. The results of these experiments are summarized in Table 8. The selectivites improved at higher dilution, with reactions conducted with a 0.05 M concentration of the 4-/-butylphenyl bromide giving the highest selectivity. Selectivity was also improved by the use of a greater excess of lithium amide, although using 10-fold excess gave good <n="60"/>selectivity at 0.05M. The reaction proceeded in 1,2-dimethoxyethane (DME), tetrahydrofuran (THF) and 1,4-dioxane, with 1,2-dimethoxyethane giving the best results. Finally, a detrimental effect of increased temperature was observed on selectivity, with lower selectivity being observed when the reaction was conducted at 11O0C, in contrast to better selectivity at 11O0C.Table 8. Optimiztion of the Stoichimetry for the Catalyzed Animation Reaction using 4-t-ButyIphenyI bromide and Lithium Amide.
71 - 88 %Spectr.
With ammonia; sodium t-butanolate In 1,2-dimethoxyethane at 20 - 90℃; for 20 - 24 h; Sealed tube; Parr bomb
The animation of 4-λ-butylphenyl bromide with ammonia catalyzed by (CyPF-Z-Bu)PdCl2 (1.0 molpercent), in the presence of sodium /-butoxide (3eq.) in DME was performed at various concentrations. The reaction was performed in a Parr bomb with the reaction mixture saturated with ammonia by stirring at ambient temperature for 30min under 80 p.s.i. of ammonia before commencing heating. The reaction mixture was then heated at 900C. The conversion and amount of mono- and di-arylation products determined by 1H NMR of the crude reaction products. The results of the experiments are summarized in Table 5. The results show that the reaction selectivity was optimized by increasing the dilution of the reaction. However, this was not necessary for hindered substrates, which underwent the amination reaction with excellent selectivity (see Table 1 above).
Reference：
[1] Journal of the American Chemical Society, 2006, vol. 128, # 31, p. 10028 - 10029
[2] Patent: WO2007/109365, 2007, A2, . Location in patent: Page/Page column 44; 45; 46
[3] Patent: WO2007/109365, 2007, A2, . Location in patent: Page/Page column 58-59
[4] Patent: WO2007/109365, 2007, A2, . Location in patent: Page/Page column 48-49; 50
[5] Patent: WO2007/109365, 2007, A2, . Location in patent: Page/Page column 58-59
[6] Patent: WO2007/109365, 2007, A2, . Location in patent: Page/Page column 59-60
[7] Patent: WO2007/109365, 2007, A2, . Location in patent: Page/Page column 59-60
[8] Patent: WO2007/109365, 2007, A2, . Location in patent: Page/Page column 58-59
[9] Patent: WO2007/109365, 2007, A2, . Location in patent: Page/Page column 58-59
[10] Patent: WO2007/109365, 2007, A2, . Location in patent: Page/Page column 56-57
[11] Patent: WO2007/109365, 2007, A2, . Location in patent: Page/Page column 54-55
[12] Patent: WO2007/109365, 2007, A2, . Location in patent: Page/Page column 54-55
[13] Patent: WO2007/109365, 2007, A2, . Location in patent: Page/Page column 55-56
[14] Patent: WO2007/109365, 2007, A2, . Location in patent: Page/Page column 53-55
[15] Patent: WO2007/109365, 2007, A2, . Location in patent: Page/Page column 56-57
13
[ 769-92-6 ]
[ 123324-71-0 ]
[ 4627-22-9 ]
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 51, p. 12575 - 12584
14
[ 937-07-5 ]
[ 769-92-6 ]
[ 4627-22-9 ]
Reference：
[1] Chemical Communications, 2018, vol. 54, # 69, p. 9679 - 9682
15
[ 98-54-4 ]
[ 4627-22-9 ]
[ 769-92-6 ]
Reference：
[1] Chemische Berichte, 1887, vol. 20, p. 1255
16
[ 769-92-6 ]
[ 36637-47-5 ]
[ 4627-22-9 ]
Reference：
[1] Journal of the American Chemical Society, 1935, vol. 57, p. 195,196
Reference：
[1] Journal of Organic Chemistry, 1984, vol. 49, # 23, p. 4479 - 4482
[2] Journal of Organic Chemistry, 1984, vol. 49, # 23, p. 4479 - 4482
20
[ 62-53-3 ]
[ 75-65-0 ]
[ 769-92-6 ]
[ 6310-21-0 ]
[ 2909-84-4 ]
Reference：
[1] Journal of Nanoscience and Nanotechnology, 2018, vol. 18, # 11, p. 7960 - 7968
21
[ 75-28-5 ]
[ 62-53-3 ]
[ 937-33-7 ]
[ 769-92-6 ]
[ 6310-21-0 ]
Reference：
[1] Journal of the American Chemical Society, 1983, vol. 105, # 5, p. 1122 - 1126
22
[ 769-92-6 ]
[ 103273-01-4 ]
Yield
Reaction Conditions
Operation in experiment
87%
With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 20℃; for 18.5 h; Darkness
To a solution of 4-tert-butylaniline (10 g, 68 mmol) in DMF (150 mL) cooled to 0 °C was added NBS (12.1 g, 68 mmol) under strictly exclusion of light, and the mixture was stirred for 30 min at the same temperature. Then the ice-bath was removed and the stirring was continued at rt overnight (18 h). The mixture was poured into water (300 mL) and extracted with CH2Cl2, the combined organic phase was over MgSO4 and filtered. he filtrate was evaporated to give a black-brown tar which was purified by column chromatography (PE : EtOAc = 20 : 1) to obtain a colorless oil (13.5 g, 87 percent); Rf = 0.69 (PE : EtOAc = 5 : 1); 1H-NMR (CDCl3, 300 MHz) δ: 7.43 (t, J = 1.2 Hz, 1H), 7.14 (m, 1H), 6.72 (d, J = 8.1 Hz,1H), 3.96 (br, 2H), 1.30 (s, 9H).
68%
With N-Bromosuccinimide In chloroform at 0 - 20℃; for 5 h; Inert atmosphere
Prepared according to a literature procedure. To a solution of 4-(tertbutyl)aniline (5.50 mL, 34.5 mmol, 1.0 eq.) in chloroform (200 mL) at 0 °C wasadded N-bromosuccinimide (6.76 g, 37.9 mmol, 1.1 eq.). The reaction was warmed to room temperature and stirred for 5 hours, then washed with water and extracted into chloroform. The organic phase was dried over sodium sulphate and the solvent removed under reduced pressure. Purification by flash chromatography on silica gel (SiO2, hexane)afforded the title compound as a brown oil (5.35 g, 23.5 mmol, 68 percent yield).
Reference：
[1] Heterocycles, 2006, vol. 68, # 12, p. 2635 - 2645
[2] Angewandte Chemie - International Edition, 2014, vol. 53, # 1, p. 178 - 183[3] Angew. Chem., 2014, vol. 126, # 1, p. 182 - 187,6
[4] Tetrahedron Letters, 2012, vol. 53, # 39, p. 5248 - 5252
[5] Journal of Fluorine Chemistry, 2015, vol. 180, p. 33 - 39
[6] Journal of the American Chemical Society, 2005, vol. 127, # 25, p. 9071 - 9078
[7] Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7360 - 7377
[8] Tetrahedron, 2001, vol. 57, # 38, p. 8075 - 8083
[9] Patent: WO2008/147952, 2008, A1, . Location in patent: Page/Page column 53
[10] Patent: WO2009/36412, 2009, A1, . Location in patent: Page/Page column 66
[11] Patent: WO2010/53471, 2010, A1, . Location in patent: Page/Page column 49
[12] Patent: US2011/98311, 2011, A1,
[13] Patent: US2011/98311, 2011, A1,
[14] Patent: US2012/309758, 2012, A1, . Location in patent: Page/Page column 76
[15] Angewandte Chemie - International Edition, 2014, vol. 53, # 19, p. 4945 - 4949
[16] Patent: US2015/231142, 2015, A1, . Location in patent: Paragraph 0459; 1959
[17] Journal of the American Chemical Society, 2016, vol. 138, # 40, p. 13147 - 13150
[18] Chinese Journal of Chemistry, 2018, vol. 36, # 9, p. 815 - 818
With N-chloro-succinimide In chloroform at 0 - 20℃; for 5 h; Inert atmosphere
To a solution of 4-(tert-butyl)aniline (5.00 ml, 31.4 mmol, 1.0 eq.) in chloroform (200 mL) at 0 °C was added N-chlorosuccinimide (4.61 g, 34.5 mmol, 1.1 eq.).The reaction was warmed to room temperature and stirred for 5 hours, thenwashed with water and extracted into chloroform. The organic phase was dried over magnesium sulphate and the solvent removed under reduced pressure. Purification by flash chromatography on silica gel (SiO2, petroleum ether 30-40: EtOAc 9:1) afforded the title compound as a brown oil (1.43 g, 9.82 mmol, 31 percent yield).
Reference：
[1] Journal of Fluorine Chemistry, 2015, vol. 180, p. 33 - 39
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 12, p. 3362 - 3366
25
[ 769-92-6 ]
[ 68176-57-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 25, p. 4906 - 4916
26
[ 769-92-6 ]
[ 129316-09-2 ]
Reference：
[1] Physical Chemistry Chemical Physics, 1999, vol. 1, # 8, p. 1699 - 1706
[2] Journal of the American Chemical Society, 1991, vol. 113, # 11, p. 4238 - 4241
[3] European Journal of Organic Chemistry, 2012, # 7, p. 1448 - 1454
[4] Tetrahedron, 2013, vol. 69, # 19, p. 3934 - 3941
[5] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 1107 - 1117
27
[ 769-92-6 ]
[ 10546-67-5 ]
Yield
Reaction Conditions
Operation in experiment
89.5%
at 85℃; for 5 h; Inert atmosphere
p-tert-Butylaniline (24.2 g, 0.162 mol) was dissolved in 250 mL AcOH. To this solution was added Br2 (17 mL, 0.324 mol) in AcOH (30 mL) dropwise over 3.5 h with vigorous stirring. The mixture was then heated at 85 °C for 1.5 h, cooled to r.t., and poured into ice water (300 mL). The resultant mixture was treated with a diluted aqueous solution of NaHCO3 and ethyl acetate (500 ml). The organic layer was separated, washed with water and dried over anhydrous Na2SO4. The concentrated product was passed through a short column (silica-gel/ petroleum ether) to give 44.5 g (89.5 percent) of titled compound.1H NMR (DMSO-d6, 500 MHz, ppm): δ 7.38 (s, 2H, Ar-H), 5.13 (s, 2H, NH2-H), 1.20 (s, 9H, C(CH3)3-H); 13C NMR (DMSO-d6, 125 MHz, ppm): δ 141.46, 140.36, 128.64, 107.68, 33.68, 30.92 ppm. HRMS (ESI): m/z calcd [M+H+] C10H14Br2N: 307.9407; Found: 307.9307.
Reference：
[1] Synthesis, 1995, # 11, p. 1419 - 1422
[2] Tetrahedron, 2009, vol. 65, # 22, p. 4429 - 4439
[3] Chemistry - A European Journal, 2013, vol. 19, # 27, p. 8937 - 8947
[4] Chemistry Letters, 1994, # 11, p. 2127 - 2130
[5] European Journal of Organic Chemistry, 2012, # 7, p. 1448 - 1454
[6] Journal of the American Chemical Society, 1995, vol. 117, # 43, p. 10662 - 10671
[7] Tetrahedron, 2013, vol. 69, # 19, p. 3934 - 3941
[8] Physical Chemistry Chemical Physics, 1999, vol. 1, # 8, p. 1699 - 1706
[9] Chemical Communications, 2014, vol. 50, # 16, p. 2055 - 2057
[10] Organic Letters, 2014, vol. 16, # 22, p. 5866 - 5869
[11] Journal of the American Chemical Society, 2003, vol. 125, # 39, p. 11911 - 11924
[12] Journal of the American Chemical Society, 1991, vol. 113, # 11, p. 4238 - 4241
[13] Patent: WO2007/64553, 2007, A2, . Location in patent: Page/Page column 41
[14] Patent: WO2009/42694, 2009, A1, . Location in patent: Page/Page column 113
[15] RSC Advances, 2015, vol. 5, # 85, p. 69453 - 69457
[16] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 1107 - 1117
With bromine; In methanol; dichloromethane; at 20℃; for 24h;
17.2 mL (335.1 mmol) of bromine (Br2) was added to a solution of 20.0 g (134.0 mmol) of 3-tert-butyl aniline in 100 mL of methanol and 100 mL of dichloromethane (DCM) DCM), and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solvent was distilled off under reduced pressure, neutralized with 20% NaOH, and extracted with dichloromethane (DCM). The extracted organic layer was washed once with saturated brine and then distilled under reduced pressure. The residue was purified by column chromatography (CHCl3: HEX) to obtain 41.0 g (yield: 99.6%) of a yellow liquid compound (Intermediate (14)).
99.6%
With bromine; In methanol; dichloromethane; at 0 - 20℃; for 24h;
To a solution obtained by dissolving 20.0 g (134.0 mmol) of 4-tert-butylaniline in 100 ml of methanol and 100 ml of dichloromethane (DCM), a solution obtained by diluting 17.2 ml (335.1 mmol) of bromine (Br2) in 50 ml of methanol and 50 ml of dichloromethane (DCM) at about 0 C. was slowly added dropwisely, followed by stirring at room temperature for about 24 hours. After finishing the reaction, reaction solvents were distilled under a reduced pressure, and the resultant product was neutralized with 20% NaOH and then, extracted with dichloromethane (DCM). The extracted organic layer was washed with a saturated saline solution once and distilled under a reduced pressure. The crude product was separated by column chromatography (CHCl3:HEX) to obtain 41.0 g (yield: 99.6%) of a yellow liquid compound (Intermediate 3).
89.5%
With bromine; acetic acid; at 85℃; for 5h;Inert atmosphere;
p-tert-Butylaniline (24.2 g, 0.162 mol) was dissolved in 250 mL AcOH. To this solution was added Br2 (17 mL, 0.324 mol) in AcOH (30 mL) dropwise over 3.5 h with vigorous stirring. The mixture was then heated at 85 C for 1.5 h, cooled to r.t., and poured into ice water (300 mL). The resultant mixture was treated with a diluted aqueous solution of NaHCO3 and ethyl acetate (500 ml). The organic layer was separated, washed with water and dried over anhydrous Na2SO4. The concentrated product was passed through a short column (silica-gel/ petroleum ether) to give 44.5 g (89.5 %) of titled compound. 1H NMR (DMSO-d6, 500 MHz, ppm): delta 7.38 (s, 2H, Ar-H), 5.13 (s, 2H, NH2-H), 1.20 (s, 9H, C(CH3)3-H); 13C NMR (DMSO-d6, 125 MHz, ppm): delta 141.46, 140.36, 128.64, 107.68, 33.68, 30.92 ppm. HRMS (ESI): m/z calcd [M+H+] C10H14Br2N: 307.9407; Found: 307.9307.
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃;
The aniline (75 g, 67 mol) was dissolved in DMF (37 mL), NBS added (25 grams; 142 mrnol) and the solution stirred at RT overnight. The solution was diluted with aqueous NaOH (I N, 370 mL) followed by aqueous/EtOAc work-up to afford the titled compound. The crude oil was dissolved in DMF (24 mL), added dropwise to a 70 0C solution of isoamyl nitrite (1 1.8 g, 101 mmol) in DMF (24 mL) and stirred for 30 minutes. The solution was cooled to RT, diluted with water (700 mL), acidified with AcOH, followed by aqueous/EtOAc work-up and silica gel chromatography (hexanes, neat) to afford the titled compound.
Example 1.1.75: 3-(aminomethyl)-5-tert-butylphenol; To a stirring solution of 5.0 g (33.5 mmol) of 4-tert-butylaniline in 250 rnL of CH2Cl2 at 0 0C was added 6 rnL of Br2 in 30 rnL of CH2Cl2 dropwise until a dark orange color persisted. The organic layer was washed with 100 rnL of water, 100 mL of sat . NaHCO3, and 100 mL of brine. It was dried over Na2SO4, filtered, and concentrated to form 2,6- dibromo-4-tert-butylaniline which was used in the next reaction without further purification.
With bromine; acetic acid; at 85℃; for 6h;
General procedure: To a solution of 4-isopropylaniline (20.3 g, 150 mmol)in acitic acid (200 mL) was added dropwise the solution of bromide in aciticacid (15.4 mL/ 30 mL). The reaction mixture was stirred for 6 hrs at 85 C.When TLC showed complete disappearance of aniline, ice water was poured intothe system and nuetralized by aquous NaHCO3 and then extracted by ethylacetate for three times. The organic layer was concentrated under vacuum andthe residue subjected to column chromatography on silica gel to afford compound2,6-dibromo-4-isopropylaniline (33.2 g, 76 %).
With bromine; In dichloromethane; for 2h;
10 g of p-tert-butylaniline was dissolved in dichloromethane, and 2.2 parts of bromine in dichloromethane was added dropwise at room temperature, stirred for 2 hours, the solvent was evaporated, then 100 mL of 20% aqueous sodium hydroxide solution was added, and extracted with diethyl ether. dry. The solvent was evaporated under reduced pressure, and silica gel column was evaporated to give white crystals (2,6-dibromo-4-tert-butylaniline).
General procedure: dissolve the substituted anline (3 mmol) in HCl aq (6 M) at -5 C,and slowly added an aqueous solution of NaNO2 (0.23 g, 3.3 mmol).The mixture was stirred for further 0.5 h, a solution of SnCl2 (1.7 g,7.5 mmol) dissolved in concentrated HCl was added dropwise, then the resulting mixture was moved to room temperature and stirred for further1 h. The muddy mixture was filtered out, washed with a small amount of HCl solution and dried in vacuum. This desired phenylhydrazine hydrochloride intermediate was used directly without additional purification.To a solution of substituted benzyl halide 3 mmol in EtOH was added the hydrazine hydrate 30 mmol, and the mixture was stirred atroom temperature overnight till the reaction was completed monitored by TLC. The reaction mixture was concentrated to dryness, and redissolvedin a little EtOH, then added an aqueous HCl (12 M) andstirred for a while at 0 C. The resulting precipitate was collected byfiltration and dried. This desired benzylhydrazine hydrochloride intermediatewas used directly without additional purification.
With N-Bromosuccinimide; In acetonitrile; at 20℃; for 24h;
35.0 g (201.03 mmol) of NBS was slowly added dropwise to a solution of 30.0 g (201.03 mmol) of 4-tert-butyl aniline in 670 mL of acetonitrile, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, water was added thereto, followed by extraction with dichloromethane (DCM). The extracted organic layer was washed once with saturated brine and then distilled under reduced pressure. The residue was purified by column chromatography (CHCl3) to obtain 45.0 g (yield: 98.0%) of a yellow liquid compound (Intermediate (21)).
98.0%
With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃; for 24h;
To a solution obtained by dissolving 30.0 g (201.03 mmol) of 4-tert-butylaniline in 670 ml of acetonitrile, 35.8 g (201.03 mmol) of NBS was slowly added dropwisely at about 0 C., followed by stirring at room temperature for about 24 hours. After finishing the reaction, water was added and extraction was performed using dichloromethane (DCM). The organic layer thus extracted was washed with a saturated saline solution once and then, distilled under a reduced pressure. The crude product was separated by column chromatography (CHCl3) to obtain 45.0 g (yield: 98.0%) of a yellow liquid compound (Intermediate 41).
87%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 20℃; for 18.5h;Darkness;
To a solution of 4-tert-butylaniline (10 g, 68 mmol) in DMF (150 mL) cooled to 0 C was added NBS (12.1 g, 68 mmol) under strictly exclusion of light, and the mixture was stirred for 30 min at the same temperature. Then the ice-bath was removed and the stirring was continued at rt overnight (18 h). The mixture was poured into water (300 mL) and extracted with CH2Cl2, the combined organic phase was over MgSO4 and filtered. he filtrate was evaporated to give a black-brown tar which was purified by column chromatography (PE : EtOAc = 20 : 1) to obtain a colorless oil (13.5 g, 87 %); Rf = 0.69 (PE : EtOAc = 5 : 1); 1H-NMR (CDCl3, 300 MHz) delta: 7.43 (t, J = 1.2 Hz, 1H), 7.14 (m, 1H), 6.72 (d, J = 8.1 Hz,1H), 3.96 (br, 2H), 1.30 (s, 9H).
78%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;Inert atmosphere; Darkness;
To a solution of 4-tert-butylaniline (1.0 g, 6.7 mmol) in N,N-dimethylformamide (15 mL) at 0 C was added N-bromosuccinimide (1.2 g, 6.7 mmol) under the exclusion of light and the mixture was stirred for 16 hours at room temperature. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (3 x 20 mL), dried over anhydrous magnesium sulfate and concentrated. The crude product was purified by flash column chromatography using ethyl acetate, hexane (1:19) as an eluent to obtain the title compound (1.2 g, 78%) as a brown oil, Rf: 0.46 (3:17 ethyl acetate, hexane); IR (vmax (film)): 3437, 3347, 2962, 1617, 1502, 1255, 824 cm-1; 1H NMR (300 MHz, CDCl3): delta 1.27 (9H, s), 3.92 (2H, bs), 6.72 (1H, d, J = 8.3 Hz), 7.14 (1H, d, J = 8.5 Hz), 7.41 (1H, s) ppm; 13C NMR (75 MHz, CDCl3): delta 31.5, 34.1, 109.4, 115.7, 125.5, 129.5, 141.6, 143.0 ppm; LRMS (+ESI) m/z: 228.0/230.0 ([M+H]+ 100%).
68%
With N-Bromosuccinimide; In chloroform; at 0 - 20℃; for 5h;Inert atmosphere;
Prepared according to a literature procedure. To a solution of 4-(tertbutyl)aniline (5.50 mL, 34.5 mmol, 1.0 eq.) in chloroform (200 mL) at 0 C wasadded N-bromosuccinimide (6.76 g, 37.9 mmol, 1.1 eq.). The reaction was warmed to room temperature and stirred for 5 hours, then washed with water and extracted into chloroform. The organic phase was dried over sodium sulphate and the solvent removed under reduced pressure. Purification by flash chromatography on silica gel (SiO2, hexane)afforded the title compound as a brown oil (5.35 g, 23.5 mmol, 68 % yield).
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃;
To a solution of 4-tert-butyl-phenylamine (447 g, 3 mol) in DMF (500 mL) was added dropwise NBS (531 g, 3 mol) in DMF (500 mL) at room temperature. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The crude product was directly used in the next step without further purification.
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃;
To a solution of 4-tert-butyl-phenylamine (447 g, 3 mol) in DMF (500 rnL) was added dropwise NBS (531 g, 3 mol) in DMF (500 mL) at room temperature. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The crude product was directly used in the next step without further purification.
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃;
To a solution of 4-rert-Butyl-phenylamine (447 g, 3.00 mol) in DMF (500 mL) was added dropwise NBS (531 g, 3.00 mol) in DMF (500 mL) at room temperature. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The crude product was directly used in the next step without further purification.
With N-Bromosuccinimide; In N,N-dimethyl-formamide;
2-Bromo-4-tert-butyl-phenylamine To a solution of 4-tert-Butyl-phenylamine (447 g, 3.00 mol) in DMF (500 mL) was added dropwise NBS (531 g, 3.00 mol) in DMF (500 mL) at room temperature. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The crude product was directly used in the next step without further purification.
With N-Bromosuccinimide; In N,N-dimethyl-formamide;
Example 3 2-Bromo-4-tert-butyl-phenylamine To a solution of 4-tert-butyl-phenylamine (447 g, 3 mol) in DMF (500 mL) was added dropwise NBS (531 g, 3 mol) in DMF (500 mL) at room temperature. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The crude product was directly used in the next step without further purification.
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃;
To a solution of 4-tert-butyl-phenylamine (447 g, 3 mol) in DMF (500 mL) was added dropwise NBS (531 g, 3 mol) in DMF (500 mL) at room temperature. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The crude product was directly used in the next step without further purification.
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃;
To a solution of 4-tert-butyl-phenylamine (447 g, 3 mol) in DMF (500 mL) was added dropwise NBS (531 g, 3 mol) in DMF (500 mL) at room temperature. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The crude product was directly used in the next step without further purification.
8.5 g
With N-Bromosuccinimide; In ethyl acetate; at 20℃;Cooling with ice;
Diluted 7.46 g of 4-t-butylaniline with 100 ml of ethyl acetate under ice cooling9.08 g of N-bromosuccinimide was added and stirred, and then stirred overnight at room temperature. Water and methyl-t-butyl ether are added to the reaction solution, and the reaction solution is separated, and the organic layer is washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is subjected to silica gel column chromatography (hexane : Ethyl acetate = 1: 0 to 10: 1),8.5 g of 2-bromo-4-t-butylaniline was obtained.
With N-chloro-succinimide; In chloroform; at 0 - 20℃; for 5h;Inert atmosphere;
To a solution of 4-(tert-butyl)aniline (5.00 ml, 31.4 mmol, 1.0 eq.) in chloroform (200 mL) at 0 C was added N-chlorosuccinimide (4.61 g, 34.5 mmol, 1.1 eq.).The reaction was warmed to room temperature and stirred for 5 hours, thenwashed with water and extracted into chloroform. The organic phase was dried over magnesium sulphate and the solvent removed under reduced pressure. Purification by flash chromatography on silica gel (SiO2, petroleum ether 30-40: EtOAc 9:1) afforded the title compound as a brown oil (1.43 g, 9.82 mmol, 31 % yield).
With N-ethyl-N,N-diisopropylamine; at 20 - 70℃; for 0.666667h;Microwave irradiation;
To a solution of <strong>[61940-21-4]methyl 2-bromomethyl-6-nitro-benzoate</strong> (0.73 mmol, 1 eq.) and t-BuOH (3 mL) in a sealed reaction vial was added 4-t-butylaniline (0.73 mmol, 1 eq) and DIEA (0.38 mL, 3 eq). The reaction was stirred at RT for 30 min then heated at 170 C. for 10 min in a microwave. A yellow solid was filtered and washed with t-BuOH and H2O then dried under high-vacuum to afford 2-(4-tert-butyl-phenyl)-7-nitro-2,3-dihydro-isoindol-1-one. MS m/e 311 (M+H)+.
In a 25 mL round bottomed flask, <strong>[603-11-2]3-nitrophthalic acid</strong> (1 g, 4.7 mmol) was suspended in 1,2-dichlorobenzene (3 mL). To this was added 4-tert-butylaniline (3 mL, 18.8 mmol). The reaction was heated to 150 C., resulting in a blood red solution. The reaction was held at 150 C. for 2.5 h, then poured into a 125 mL Erlenmeyer flask. Precipitation began to occur and 50 mL of Et2O was added to the flask. The suspension was stirred for 15 h and filtered. The filtered cake was washed copiously with Et2O and dried in vacuo at 30 C. for 4 h to afford a white brittle powder. No further purification was performed on this compound. MS (ES+): 325.1(M+H)+. Calc'd for C18H16N2O4-324.33.
1 B) (4-TERT-BUTVL-PHENVL)-(6-FLUORO-ISOQUINOLIN-1-VL)-AMINE 1-CHLORO-6-FLUORO-ISOQUINOLINE (1 g, 6.13 MMOL) is dissolved in n-BuOH (20 mL) and 4-T-BUTYL-ANILINE (1. 1 g, 6.74 MMOL). 4 N HCI (1 mL) in dioxane (1 mL) is added dropwise. The resulting mixture is heated at 80C overnight. The mixture is rotary evaporated, and the residues dissolved in ethyl acetate, washed with saturated NAHC03, brine and dried over MGS04. The solute is removed and after CONCENTRATION IN VACUO, the organic layer is further purified by silica gel column (hexane 90% to 10% ethyl acetate/hexane) to afford a yellow solid (900 mg, 56%). M+H+ = 295.3. 'H NMR (300 MHz) (DMSO); 8 1.29 (s, 9H), 7.13 (d, 1H, J=6 Hz), 7.34 (d, 2H, J=8.67 Hz), 7.50 (m, 1H), 7.60 (dd, 1H, J=2.64, 9. 8 HZ) =7. 72 (d, 2H, 8.67 HZ), 7. 96 (d, 1H, 5.65 Hz), 8. 61 (dd, 1H, J=5.46, 9.23 Hz), 9.16 (s, 1H).; 21 B) (4-TERT-BUTVL-PHENVL)-(6-FLUORO-ISOQUINOLIN-1-VL)-AMINE A solution of <strong>[214045-86-0]1-chloro-6-fluoro-isoquinoline</strong> (1 g, 6.13 MMOL) and 4-tert-butyl- aniline (1. 1 g, 6.74 MMOL) in nBuOH (20 mL) and 4N HCI/DIOXANE (1 mL) is heated at 80C overnight. The mixture is concentrated and the residue is made basic with sat. NaHC03 and extracted with EtOAc. The organic layer is dried, concentrated and purified by silica gel column (Hexane to 10% ETOAC/HEXANE) to afford yellow solid (900 mg, 56%). M+H+=295. 3. H NMR (400 MHz, DMSO-D6) 5 1.29 (s, 9H), 7.13 (d, 1H, J= 6 Hz), 7.34 (d, 2H, J= 8.67 Hz), 7.50 (m, 1 H), 7.60 (dd, 1 H, J = 2.64, 9.8 Hz) 7.72 (d, 2H, J = 8.67 Hz), 7.96 (d, 1 H, J= 5.65 Hz), 8.61 (dd, 1H J=5.46, 9.23Hz), 9.16 (s, 1H).
With pyridine; In tetrahydrofuran; at 180℃; for 0.25h;Microwave irradiation;
Example 1B 7-Benzyl-N-(4-Tert-Butylphenyl)-5,6,7,8-Tetrahydropyrido[3,4-d]Pyrimidin-4-Amine A solution of Example 1A (0.744 g, 2.86 mmol), 4-tert-butylaniline (0.55 mL, 3.5 mmol), and pyridine (0.35 mL, 4.3 mmol) in tetrahydrofuran (2.9 mL) was microwave-irradiated at 180 C. for 15 min. The mixture was cooled to about 25 C., diluted with saturated, aqueous NaHCO3, extracted with dichloromethane, dried (Na2SO4), filtered and concentrated. The concentrate was chromatographed on silica gel, eluding with diethyl etherto give the title compound. 1H NMR (300 MHz, CD3OD) delta 8.24 (s, 1H), 7.26-7.49 (m, 9H), 3.75 (s, 2H), 3.52 (s, 2H), 2.87 (t, J=5.8 Hz, 2H), 2.67 (t, J=5.8 Hz, 2H), 1.32 (s, 9H). MS (m/z) 373.
Example 2 N-(4-tert-Butylphenyl)-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine A mixture of 4-tert-butylbenzenamine (0.312 mL, 1.98 mmol) and <strong>[192869-80-0]7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine</strong> (0.467 g, 1.80 mmol), prepared as described in Example 1.B. in acetonitile (2 mL) was heated in a sealed tube at 170 C. in a microwave (Emrys Optimizer model, Personal Chemistry) for five min. Upon cooling to room temperature, a precipitate formed. The mixture was diluted with hexane (5 mL) and the precipitate was collected by filtration to give 0.576 g of the title compound as a tan solid. MS: M+H=373.
In acetonitrile; at 170℃; for 0.0833333h;Microwave irradiation;
Example 2 N- (4-tert-Butylphenyl)-7-benzyl-5, 6,7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4-amine [00232] A mixture of 4-tert-butylbenzenamine (0.312 mL, 1.98 mmol) and 7-benzyl-4- chloro-5,6, 7,8-tetrahydropyrido [3,4-d] pyrimidine (0.467g, 1.80 mmol), prepared as described in Example 1. B. in acetonitile (2 mL) was heated in a sealed tube at 170C in a microwave (Emrys Optimizer model, Personal Chemistry) for five min. Upon cooling to room temperature, a precipitate formed. The mixture was diluted with hexane (5 mL) and the precipitate was collected by filtration to give 0.576 g of the title compound as a tan solid.
With sodium hydroxide; lithium carbonate; In water; benzene;
Preparation of 2-[(4-tert-Butylphenyl)amino]-6-chloro-3-nitrobenzoic acid (1d) A mixture of <strong>[55775-97-8]2,6-dichloro-3-nitrobenzoic acid</strong> (4.72 g, 0.02 mol), 4-tertbutylaniline (4.47 g, 0.03 mol), lithium carbonate (1.48 g, 0.02 mol), and 1-propanol (10 mL) was refluxed with stirring for 20 h. The solvent was evaporated and to the residue, water (30 mL) and benzene (50 mL) were added. The mixture was made strongly basic with sodium hydroxide and stirred for 1h. Orange precipitate was collected by filtration and washed with benzene and ether. Dry precipitate was dissolved in water and acidified with diluted hydrochloric acid. Resulting precipitate was collected and crystallized from acetone-water to give 4.55 (65%) of the desired product, mp 201-204 C. Anal. (C31 H27 N7 O6) C, H, N.
4-(4-tert-butylanilino)-3-methoxy-2-methylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In phenol;
Example 33 4-(4-tert-Butylanilino)-3-methoxy-2-methylpyridine 7.9 g of <strong>[107512-34-5]4-chloro-3-methoxy-2-methylpyridine</strong> and 22.4 g of 4-tert-butylaniline are heated at 120 C. for 8 hours in 20 g of phenol. After cooling, the mixture is poured into NaOH and the product is extracted using methylene chloride. After concentrating, the excess of amine is distilled off in vacuo and the residue is crystallized using hexane. 9.5 g=55% 1 H-NMR (100 MHz, CDCl3)=8.0 (d, 1H), 7.0 to 7.4 (m, 4H), 6.9 (d, 1H), 3.8 (s, 3H), 2.5 (s, 3H), 1.3 (s, 9H) ppm
Various N-substituted-6-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine derivatives are prepared using a general procedure described below. Accordingly, ethyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride is reacted with formamidine acetate to yield 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(4aH)-one, which, in turn, is reacted with POCl3 to afford the 4-chloro derivative. The intermediate chloro derivative is then condensed with substituted aniline or amine to give the desired N-substituted-6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine. Debenzylation using standard procedures known in the art followed by nucleophilic displacement of an appropriate 2-halo-pyridine yields the appropriate N-substituted-6-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine. As a representative example, synthesis of N-(4-tert-butylphenyl)-6-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine is depicted in Scheme 1.
With sodium hydroxide; sulfuric acid; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; glycerol;
EXAMPLE 28 6-(1,1-Dimethylethyl)quinoline STR34 4-(1,1-Dimethylethyl)aniline (185 g.) is added dropwise, with stirring, to 500 ml. of 75% sulfuric acid, followed by 376 g. of <strong>[127-68-4]sodium 3-nitrobenzenesulfonate</strong> in one portion, then 212 g. of glycerol over a 10 minute period. The mixture is stirred for 10 minutes, heated slowly to reflux temperature over a 2.5 hour period, then stirred and heated at reflux for 9 hours. The mixture is cooled, diluted with 400 ml. of ice water, basified with 855 ml. of 50% aqueous sodium hydroxide and warmed to 70 C. The supernatant solution is decanted and extracted with toluene. The toluene extract is in turn extracted with three 800 ml. portions of 2 N hydrochloric acid. The combined acid extract is basified with excess 50% aqueous sodium hydroxide and extracted with toluene. The toluene extract is evaporated at reduced pressure to give a residue of 6-(1,1-dimethylethyl)quinoline which is purified by distillation; b.p. 90-94 C./ 0.18 mm. By substituting an equivalent amount of the appropriately substituted aniline for the 4-(1,1-dimethylethyl)aniline in the above example, the following quinolines are obtained.
General procedure: To a 300 mL one-necked round-bottomed flask equipped with a magnetic stirring bar and areflux condenser were added <strong>[6289-46-9]dimethyl cyclohexane-2,5-dione-1,4-dicarboxylate</strong> (5.6 g, 25 mmol),aniline derivative (75 mmol), EtOH (50 mL), and AcOH (25 mL). The mixture was stirred at120 C for 2 h. The resulting mixture was allowed to cool to room temperature and EtOH (50 mL)was added. The precipitate was collected by suction filtration, washed with EtOH (150 mL), anddried under reduced pressure to give a mixture of dimethyl 2,5-di(arylamino)-3,6-dihydrotere-phthalate 3 and dimethyl 2,5-di(arylamino)terephthalate 4.A 1 L one-necked round-bottomed flask equipped with a magnetic stirring bar and refluxcondenser was charged with the crude mixture of 3 and 4, and CHCl3 (250 mL). To the flask wereadded I2 (6.35 g, 25 mmol) and EtOH (100 mL). The black solution was stirred at 80 C for 6 h.The resulting mixture was allowed to cool to room temperature and the organic solvents wereremoved under reduced pressure. The precipitate was collected by suction filtration, washed withEtOH (100 mL), and dried under reduced pressure to give 4, which was used for the next stepwithout further purification.
General procedure: To a 300 mL one-necked round-bottomed flask equipped with a magnetic stirring bar and areflux condenser were added <strong>[6289-46-9]dimethyl cyclohexane-2,5-dione-1,4-dicarboxylate</strong> (5.6 g, 25 mmol),aniline derivative (75 mmol), EtOH (50 mL), and AcOH (25 mL). The mixture was stirred at120 C for 2 h. The resulting mixture was allowed to cool to room temperature and EtOH (50 mL)was added. The precipitate was collected by suction filtration, washed with EtOH (150 mL), anddried under reduced pressure to give a mixture of dimethyl 2,5-di(arylamino)-3,6-dihydrotere-phthalate 3 and dimethyl 2,5-di(arylamino)terephthalate 4.
[00369] Dissolved 0.500 g <strong>[17823-69-7]2-cyano-3,3-bis(methylthio)acrylamide</strong> in 15 mL EtOH and added 422 mg (1.0 eq.) 4-tertbutylaniline. Stirred reaction at 75 C until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain 3-((3-(tert-butyl)phenyl)amino)-2-cyano-3-(methylthio)acrylamide a light yellow powder. Product was allowed to dry under vacuum for 1 hr. 3 -((3 -(tert-butyl)phenyl)amino)-2-cyano-3 -(methylthio)acrylamide
3,5-dichloro-N-[4-(1,1-dimethylethyl)phenyl]-4-pyridinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
180 mg
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 250℃; for 1h;Microwave irradiation;
A solution of <strong>[33216-52-3]3,4,5-trichloropyridine</strong> (400 mg, 2.2 mmol), 4-fert-butylaniline (0.71 mL, 4.5 mmol), triethylamine (0.61 mL, 4.4 mmol), and anhydrous l-methyl-2- pyrrolidinone (12 mL) was heated at 250 C in a microwave reactor (C.E.M. Discover) for 1 h. The resulting mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic phase was washed with water, saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated onto silica gel. Purification by medium pressure liquid chromatography on a silica column eluting with a gradient of 0% to 50% ethyl acetate in hexanes gave the title compound, a compound of the current invention, as an orange solid (180 mg). H NMR (CDCI3) delta 8.34 (s, 2H), 7.33 (d, 2H), 6.89 (d, 2H), 6.37 (br s, 1H), 1.32 (s, 9H).
General procedure: The round-bottom flask was charged with trans-Indole-3-acrylic acid (1.0 equiv.) or 3-Indolepropionic acid (1.0 equiv.) and the resulting mixture of DMF in CH2Cl2 (v:v, 1:3). DIPEA (1.5 equiv.) followed by HBTU (1.5 equiv.) were added to the solution. After stirring at room temperature for 30 min, amine (1.0 equiv.) was added and stirred overnight at RT. The excess solvent was evaporated and then diluted with water and EtOAc, and the two layers were separated. The aqueous solution was extracted with EtOAc. The combined organic solution was washed with water and brine, dried over magnesium sulfate, and filtered. The residue was purified by column chromatography on silica gel using 0-60% EtOAc in Hexanes as eluant to give the desired products 2a-2f.
87%
General procedure: To a round bottom flask, the trans-3-indole acrylic acid (1 eq) and methylene chloride volume ratio of 1: 3 filled with. It was added DIPEA (1.5 eq.) To the solution, followed by the a HBTU (1.5 eq). After stirring for 30 minutes at room temperature (about 25 ), was added to the amine compound (1.2 eq) was stirred at room temperature overnight. To the evaporation of the excess solvent under reduced pressure, the residue was purified by silica gel column chromatography to give the following compounds in Table 1.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 120℃;Inert atmosphere;
Intermediate 2 (10.0 g, 58 mmol), 4-tert-butylphenylamine (9.5 g, 64 mmol) and 30 mL of diiso- propylethylamine are suspended in 200 mL of dimethylacetamide under argon atmosphere. The suspension is heated to 120C and stirred overnight. After cooling to room temperature, the remaining liquid is removed and the residue is taken up in methylene chloride. The organic phase is sequentially washed with hydrochloric acid (5%), a saturated sodium hydrogen carbonate solution and finally with water. The organic layer is dried over anhydrous sodium sul- fate. The remaining solution is filtered over silica, then the solvent is removed and the solid dried at 40C under vacuum. The yellow product is crystallized in ethyl acetate to give the title product as a white powder (15.5 g) in 93% yield. H-NMR (400 MHz, CDCI3): delta = 1.33 (s, 9H), 7.28 (br. s, 1 H), 7.41 (d, 2H), 7.50 (d, 2H), 7.75 (d, 1 H), 8.38 (d, 1 H).
With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; for 15h;Reflux;
3 parts of 4-tert-butylaniline,8.9 parts of <strong>[88223-35-2]2-bromo-9,9-dibutylfluorene</strong>,0.23 parts of palladium (II) acetate,1.9 parts of 2,2-bis (diphenylphosphino) -1,1'-binaphthyl and 2.9 parts of sodium tert-butoxide were added to 35 parts of toluene and reacted under heating reflux condition for 15 hours.The reaction mixture was added drop-Extraction with chloroform - water,After concentrating the chloroform phase,Separation by column chromatography (ethyl acetate - hexane)Purified,4 parts of a compound represented by the following formula (300) as a yellow solid.
dimethyl 5-(4-(tert-butyl)phenylazo)isophthalate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.84 g
In acetic acid; at 20℃; for 24.0h;
The unpurified <strong>[13290-96-5]1,3-dimethyl-5-nitrosoisophthalate</strong> (1.5 g) was dissolved in glacial acetic acid with 4-tert-butylaniline (1.0 mL, 0.94 g,6.3 mmol). The reaction was stirred at room temperature for 24 h. Ethyl acetate (EtOAc) (250 mL) was added, and the organic phase washed with copious water and sat. NaHCO3 solution then dried over MgSO4. The solvent was removed by rotary evaporation, giving an orange solid that was purified bysilica column chromatography (cyclohexane 90 : 10 EtOAc) and washed with MeOH.
2-methyl-propane-2-sulfinic acid [3-(4-tert-butyl-phenylamino)-oxetan-3-yl]-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
In methanol; at 60℃; for 5h;Inert atmosphere;
General procedure: To a stirred solution of substituted aniline (1 eq) in methanol (3 mL), <strong>[1158098-73-7]oxetan-3-tert-butylsulfinimine</strong> (1.5 eq) was added under argon atmosphere. Reaction mixture was heated at 60 C for appropriate time (Table 2). After the completion of reaction (TLC), reaction mixture was then concentrated. To the resulting residue water was added and then extracted with ethyl acetate (2 X 3 mL). Organic layer was then dried over anhydrous sodium sulphate and filtered. Solvent was removed under reduced pressure. The resulting products were then purified by chromatography using n-hexane-ethyl acetate (7:3) to afford pure 2-methyl-N-[(3-phenylamino)oxetan-3-yl]-2-propanesulfinamide derivatives. All synthesized compounds were characterized by IR, 1H-NMR, HRMS and 13C-NMR spectroscopic techniques.
General procedure: The residue mentioned above was dissolved in toluene, followed by added catalytic amounts of DMF, dropwise added SOCl2 at 0 C. After that, the reaction mixture was heated to 80 C and stirred for 12 h. The solvent was evaporated to dryness, and the residue was dissolved in toluene. The phenylamine dissolved in toluene (30 ml) was dropwise added to the resulting solution, and then the reaction mixture was stirred overnight. Then the mixture was filtered, and the filtration was washed by water for three times, which was further purified by recrystallization from toluene to give the title compound 34a as white solid (7.83g, 67% in three step).
With palladium diacetate; sodium t-butanolate; In toluene; at 120℃; for 48h;Inert atmosphere;
(1) In a 500 ml three-necked flask, 4-tert-butylaniline (14.92 g, 100 mmol) was added.<strong>[94994-62-4]2-bromo-9-phenyl-9H-carbazole</strong> (32.22 g, 100 mmol),Sodium tert-butoxide (28.83 g, 300 mmol) was added to 100 g of toluene.Palladium acetate was added under N2 protection and reacted at 120 C for 48 h. The reaction was monitored by TLC.Wash water (200ml) three times, add activated carbon to decolorize,Dry and concentrated to a gray solid, which was crystallized from ethyl acetate.Drying under vacuum to give N-(4-tert-butyl)-9-phenyl-9H-indazol-2-amine32.80 g, 84% yield.
General procedure: Xantphos (28.9 mg, 0.05 mmol), Cs2CO3 (32.6 mg, 0.10 mmol) and [Ru(p-cymene)Cl2]2 (15.3 mg, 0.025 mmol) were added to a Schlenk tube. Then the tube was evacuated and refilled with nitrogen. Dry toluene as solvent (2.0 mL)were added and the solution was stirred at room temperature under nitrogen for 30 min. Activated molecular sieves 4A (0.10 g) and triol 6a (106.1 mg, 1.00 mmol) were then added. And the solution was stirred at room temperature under nitrogen for 40 min. Subsequently, aniline 5a (46.6 mg, 0.50 mmol) was added and the solution was stirred at room temperature under nitrogen for 20 min. Then the resulting solution was heated to reflux and stirred for 48 h. The reaction was monitored by TLC. After completion, the solution was filtered through a plug of Celite and washed with EtOAc (3 mL x 3). The filtrate was concentrated under vacuum. Purification via flash column chromatography with silica gel (eluting with PE/EA = 5/1 (v/v)) yielded 4a (43.0 mg, 81% yield) as light yellow oil.
5-chloro-2-(4-isopropylphenyl)isoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With acetic acid; at 110℃; for 4h;
General procedure: The starting materials 1 and 2 were commercially available (Energy Chemical, Shanghai, China).Compound 2 (3.72 mmol) was added to a stirred solution of compound 1 (3.38 mmol) in glacial aceticacid (10 mL). The reaction mixture was then stirred at 110 C for 4 h. After completion of the reaction,the solvent was evaporated, and the residue was purified on a silica gel column chromatography andeluted with ethyl acetate/petroleum ether (bp 60-90 C) (1:3, v/v) to give compounds 3.
Chemistry
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