* 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] Journal of Organic Chemistry, 1984, vol. 49, # 23, p. 4479 - 4482
[2] Journal of Organic Chemistry, 1984, vol. 49, # 23, p. 4479 - 4482
2
[ 6310-21-0 ]
[ 7073-99-6 ]
Yield
Reaction Conditions
Operation in experiment
41%
Stage #1: With hydrogen bromide In water at 20℃; for 0.333333 h; Stage #2: With sodium nitrite In diethyl ether; water at -56 - -8℃; for 2.58333 h;
176 ml of 48percent HBr solution (1.57 mol) are slowly added to 30.5 g (0.20 mol) of2-tert-butylaniline at room temperature during 20 minutes. The beige suspension is cooleddown to -56°C and 23.8 g (0.34 mol) of sodium nitrite are added in small portions during 20 minutes and stirring continued at the same temperature during one hour. 250 ml of ice-cold diethyl ether are slowly added during 15 minutes and the temperature let slowly rising to-8°C during two hours until no more gas evolved. The temperature is decreased again to-56°C and 25 ml of water are added first followed by the addition of 118.5 g (0.41 mol) ofsodium carbonate decahydrate giving a brown suspension. The temperature is let raising toroom temperature during three hours with evolution of gas starting at -28°C. The resulting brown suspension is further stirred at room temperature during 16 hours. The water phase is separated and the organic phase three times washed with water, dried over sodium sulfate and concentrated under vacuum giving a brown oil. Further purification is done bychromatography (silica gel, heptane), followed by distillation of resulting oil under vacuum (97°C, 16 mbbar), giving the title product as colorless oil (yield: 17.9 g (41percent)).1HNMR (400 MHz, CDCI3): = 1.58 (s, 9 H), 7.07 (dt, I H), 7.29 (dt, I H), 7.50 (dd, I H),7.64 (dd, I H).
30%
Stage #1: With hydrogen bromide; sodium nitrite In water at 0℃; for 2 h; Stage #2: With copper In water at 0 - 50℃; for 0.5 h;
To a solution of 2-tert-butylphenylamine (7.5 g, 50 mmol) in 48percent HBr (13 mL) at 0°C was added a solution of sodium nitrite (7.6 g, 0.11 mol) in water (10 mL). The solution was kept at 0°C for 2 h until the addition of 0.20 g of copper powder. The resulting solution was stirred at 0°C until bubbling stopped, and finally heated to 50°C for 30 min. The reaction mixture was diluted with water (40 mL), extracted with diethyl ether (3 x 50 mL) and combined organic layers were washed with an aqueous solution of potassium hydroxide (10percent). The product was purified by chromatography (silica gel; eluent:hexane) to afford a light brown liquid (3.1 g, 30percent). 1H NMR: δ 7.65(d, J 7.8 Hz, ArZH, 1H), 7.54 (d, J 8.0 Hz, ArZH,1H), 7.34 (t, J 7.1 Hz, ArZH, 1H), 7.11 (t, J 8.7 Hz,ArZH, 1H), 1.53 (s, (CH3)2, 9H) ppm.
27%
Stage #1: With hydrogen bromide; sodium nitrite In water at 5 - 10℃; for 2 h; Stage #2: With copper In water
Synthesis of 5-(2-tert-butylbenzyloxy)methyl-2′-deoxyuridine-5′-triphosphate 1-Bromo-2-tert-butylbenzene: To a solution of 2-tert-butylaniline (7.46 g, 50 mmol 15.6 mL) in hydrobromic acid (40percent w/w, 15 mL) cooled at <5° C. (ice/salt bath), a solution of 7.55 g (0.11 mol) of sodium nitrite in 10 mL of water was added at a rate that the temperature did not exceed 10° C. (ca two hour addition time). When the diazotization was completed, 0.20 g of copper powder was added. (CAUTION: the solution was refluxed very cautiously because of vigorous gas evolution). When the vigorous evolution of nitrogen subsided, the system was kept at 50° C. for 30 minutes and was then diluted with 80 mL of water and extracted three times with diethyl ether (100 mL each). The organic layer was washed with 10percent solution of KOH; dried over Na2SO4, concentrated in vacuo, and purified by chromatography on silica gel chromatography. The product obtained was further distilled at 85° C. (3 mm Hg) to yield 1-bromo-2-tert-butylbenzene (2.88 g, 27percent). 1H NMR (400 MHz, CDCl3): δ 7.58 (m, 1 H, Ph-H), 7.45 (m, 1 H, Ph-H), 7.24 (m, 1 H, Ph-H), 7.02 (m, 1 H, Ph-H), 1.51 (s, 9 H, C(CH3)3).
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 40, p. 12288 - 12291[2] Angew. Chem., 2017, vol. 129, p. 12456 - 12459,4
[3] Patent: WO2015/14835, 2015, A1, . Location in patent: Page/Page column 171
[4] Heteroatom Chemistry, 2010, vol. 21, # 5, p. 355 - 360
[5] Supramolecular Chemistry, 2014, vol. 26, # 9, p. 632 - 641
[6] Patent: US9200319, 2015, B2, . Location in patent: Page/Page column 137; 138
[7] Journal of Organic Chemistry, 2004, vol. 69, # 4, p. 1186 - 1195
[8] Organic Letters, 2005, vol. 7, # 7, p. 1291 - 1294
[9] Journal of Organic Chemistry, 2006, vol. 71, # 15, p. 5474 - 5481
[10] Heteroatom Chemistry, 2010, vol. 21, # 4, p. 265 - 270
[11] Journal of Organometallic Chemistry, 2011, vol. 696, # 18, p. 2993 - 2999
3
[ 1886-57-3 ]
[ 6310-21-0 ]
Reference：
[1] Journal of the American Chemical Society, 1988, vol. 110, # 20, p. 6818 - 6825
[2] Bulletin de la Societe Chimique de France, 1949, p. 134,144
[3] Chemische Berichte, 1890, vol. 23, p. 2413
[4] Journal of the Chemical Society, 1928, p. 2336
[5] Journal of the Chemical Society. Perkin transactions 1, 1976, # 5, p. 465 - 470
[6] Chemische Berichte, 1962, vol. 95, p. 1921 - 1942
[7] Tetrahedron, 1960, vol. 9, p. 210 - 229
[8] Journal of the Chemical Society, 1961, p. 611 - 618
[9] Journal of Organic Chemistry, 1980, vol. 45, p. 4844
4
[ 1634-04-4 ]
[ 62-53-3 ]
[ 6310-21-0 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 165℃; for 4 h; Autoclave; Inert atmosphere
Weigh 1118 g (0.012 mol) of aniline, 0.48 mol of methyl t-butyl ether, 3.83 g of commercially available montmorillonite was added to 100 ml In the autoclave, the inside of the kettle was continuously replaced with nitrogen for 5 times. After heating the reaction solution to 165 ° C, the mechanical stirring was turned 900 rpm, the reaction is started and the reaction temperature is maintained within ± 1 ° C of the desired reaction temperature. After 4 hours of reaction, turn off The reaction mixture was cooled and cooled, and the catalyst was separated by centrifugation. By distillation and chromatography to obtain a purity of 98percent O-tert-butylaniline.
Reference：
[1] Patent: CN105218381, 2016, A, . Location in patent: Paragraph 0012; 0013; 0014
5
[ 88-18-6 ]
[ 6310-21-0 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 2, p. 387 - 392
6
[ 21367-80-6 ]
[ 6310-21-0 ]
Reference：
[1] Journal of Chemical Research, 2013, vol. 37, # 1, p. 55 - 56
7
[ 6310-20-9 ]
[ 6310-21-0 ]
Reference：
[1] Journal of Organic Chemistry, 1980, vol. 45, p. 4844
2-t-Butylaniline (13.35 g, 89.4 mmol) was diazotized in sulfuric acid (25% w/w, 110 mL) with sodium nitrite (9.34 g) in water (18 mL) at -20 C. The diazonium salt was transferred to a solution of potassium iodide (67 g) in water 20 mL, and after 18 hours, a solution of sodium hydroxide (25 g) in water (100 mL) was added. The mixture was extracted with hexanes, hexane extracts passed through a column of silica gel, and concentrated. The product was obtained as a liquid, 13.77 g (59%). Mass spec: m/z 260 (M+). 1H NMR (CDCl3) δ ppm: 1.53 (s, 9H), 6.82 (td, 1H, 1.68 and 7.68 Hz), 7.27 (td, 1H, 1.4 and 7.32 Hz), 7.43 (dd, 1H, 1.64 and 8.0 Hz), 7.99 (dd, 1.4 and 7.8 Hz).
45%
With toluene-4-sulfonic acid; potassium iodide; sodium nitrite; In water; tert-butyl alcohol; at -3 - 20℃; for 17.5h;
28.7g (151mmol) of p-toluenesulfonic acid monohydrate were dissolved in 75ml of tert- butanol.5.0g (33.5mmol) of 2-(tert-butyl)aniline were added, and the final white suspension was cooled to -3C. A solution of 6.93g (101mmol) of sodium nitrite and 20.86g (126mmol) of potassium iodide in 30ml of water was added within 30 minutes. It was warmed up to room temperature and stirred for 17 hours.27.4g (174mmol) of sodium sulfurothioate were dissolved in 100ml of water and added to the reaction mixture.11.26g (134mmol) of sodium bicarbonate were dissolved in 100ml of water and added, then the mixture was stirred for 30 minutes. The reaction mixture was diluted with 200ml of cyclohexane, the phases were separated and the water phase was extracted with cyclohexane. The combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography (heptane/ethyl acetate) to give 5.36g (45% yield) of Intermediate 47-1. 1H NMR (400 MHz, Methylene Chloride-d2) d 8.00 (dd, J = 7.8, 1.5 Hz, 1H), 7.46 (dd, J = 8.0, 1.7 Hz, 1H), 7.36- 7.23 (m, 1H), 6.89- 6.78 (m, 1H), 1.54 (s, 9H).
With tetra-N-butylammonium tribromide; In tetrahydrofuran; at 0 - 20℃; for 0.166667h;
25 g of 2 ferf-butylaniline (168 mmol) are dissolved in 250 mL of THF; the reaction mixture is stirred and cooled to O0C, and 81 g of tetrabutylammonium bromide (TBA-Br3) (168 mmol) are then added portionwise while maintaining the temperature between 00C and 5C. The temperature is then allowed to rise to about room temperature and the mixture is stirred for 10 minutes. The reaction is stopped by adding 250 mL of water and is then extracted with 250 mL of ethyl acetate. The organic phases are washed with 1 L of saturated Na2S2O5 solution and EPO <DP n="21"/>then dried over magnesium sulfate. The solvents are evaporated off and the residue is filtered through a pad of silica (pure heptane, then a 3/7 heptane/ethyl acetate mixture). 43.6 g of 4-bromo-2-te/?-butylaniline (yield = 100%) are obtained in the form of a white solid.
100%
With tetra-N-butylammonium tribromide; In tetrahydrofuran; at 5℃; for 1.25h;Product distribution / selectivity;
Example 703-(1-[6-cyclopropyl-4-(1,1-dimethylethyl)-1-methyl-1H-benzimidazopiperidinyl)-1,3-oxazolidin-2-oneStep A[4-bromo-2-( 1, 1-dimethylethyl)phenyl]amine[00330] To a solution of 2-tert-butylaniline (52.2 mL, 335 mmol) in THF (618 mL) at 5 C (ice-water bath) was added tetrabutylammonium tribromide (146 g, 303 mmol) in THF (200 mL) dropwise over 45 minutes. After 30 minutes, the mixture was quenched with water (100 mL) and stirred for 15 minutes. The mixture was diluted with diethyl ether (1 L) and washed with saturated aqueous NaHC03 (400 mL), then brine (400 mL), dried (Na2S04), filtered and concentrated to give [4-bromo-2-(1 ,1-dimethylethyl)phenyl]amine (78.40 g, 344 mmol, quantitative yield) as brown oil. This was used for next step. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.30 (s, 9 H), 4.98 (s, 2 H), 6.57 - 6.62 (m, 1 H), 7.02 (dd, J=8.5, 2.3 Hz, 1 H), 7.09 (d, J=2.3 Hz, 1 H); MS(ESI) m/z: 228.1 , 230.2 (MH+).
98%
With tetrabuthylammonium tribromide; In tetrahydrofuran; at 0℃; for 0.5h;
Reference Example 8 4-Bromo-2-tert-butylaniline To a solution of 2-tert-butylaniline (50 g, 335 mmol) in THF (500 mL) was added tetrabutylammonium tribromide (234.5 g, 335 mmol) at 0 C. After the solution was stirred for 30 minutes at that temperature, it was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated Na2S2O3 solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=100:0 to 20:80) to provide 4-bromo-2-tert-butylaniline (74.6 g, 98%) as a pink oil. 1H NMR (300 MHz, CDCl3) delta 1.39 (s, 9H), 3.81 (br. s., 2H), 6.51 (d, J=8.3 Hz, 1H), 7.11 (dd, J=8.3, 2.3 Hz, 1H), 7.30 (d, J=2.3 Hz, 1H).
83%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 1h;Product distribution / selectivity;
Step 1 : 4-Bromo-2-(tert-butyl)aniline (P25a)To a solution of 2-ferf-butylaniline (14.9 g, 100 mmol) was added a solution of NBS (17.8 g, 100 mmol) in DMF at rt. The reaction mixture was stirred for 1 h at rt, diluted with water (30 mL) and extracted with Et20 (3 x 250 mL). The organic layer was washed with brine, dried over Na2S0 , concentrated and purified by CC to give compound P25a (19 g, 83%).
83%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃;
Step 1 : 4-Bromo-2-(tert-butvuaniline (P38a) To a solution of 2-(tert-butyl)aniline (14.9 g, 100 mmol) was added a solution of NBS (17.8 g, 100 mmol) in DMF at rt. The mixture was stirred overnight at rt, diluted with water (30 mL) and extracted with Et20 (3x 250 mL). The organic layer was washed with brine, dried over Na2S04, concentrated and purified by CC to give compound P38a (19 g, 83%).
79%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 4h;
Step 1: 4-Bromo-2-tert-butylaniline (19a) To a solution of NBS (218 mg, 1 mmol) in DMF was added a solution of 2-tert-butylaniline (149 mg, 1 mmol) in DMF at rt. The reaction mixture was stirred for 4 h at rt. After the reaction was completed (monitored by LC-MS), water (30 mL) was added and the reaction mixture was extracted with EA (150 mL). The organic layer was washed with brine and dried over Na2SO4, concentrated in vacuo and purified by CC (hexane/EA = 3:1) to give the title compound 19a (180 mg, 79%).
79%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 4h;
Step 1: 4-Bromo-2-tert-butylaniline (Pla) To a solution of NBS (218 mg, 1 mmol) in DMF was added a solution of 2-tert-butylaniline(149 mg, 1 mmol) in DMF at rt. The reaction mixture was stirred for 4 h at ii, then water (30mL) was added and the mixture was extracted with EA (150 mL). The organic layer waswashed with brine and dried over Na2SO4, concentrated and purified by CC (hexane/EA = 3/1)to give compound Pla (180 mg, 79%).
79%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 4h;
Step 1 : 4-Bromo-2-ferf-butylaniline (P1a) To a solution of NBS (218 mg, 1 mmol) in DMF was added a solution of 2-tert-butylaniline (149 mg, 1 mmol) in DMF at rt. The reaction mixture was stirred for 4 h at rt, then water (30 mL) was added and the mixture was extracted with EA (150 mL). The organic layer was washed with brine and dried over Na2S04, concentrated and purified by CC (hexane/EA = 3/1) to give compound P1a ( 80 mg, 79%).
79%
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 2h;
To a solution of 2-tert-butyl- (10 mL, 67 mmol) in DMF (130 mL) was added N-bromosuccinimide (6.9 g, 80 mmol). The reaction was stirred at rt for 2 h and then partitioned between water and EtOAc. The aqueous phase was washed with additional EtOAc and the organic phases were combined, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: 10-100% EtOAc/heptane) to provide 4-bromo-2-(tert-butyl)aniline (12 g, 53 mmol, 79% yield). 1H NMR (400 MHz, DMSO-d6) delta ppm 7.10 (d, J=2.5 Hz, 1H), 7.03 (dd, J=8.5, 2.3 Hz, 1H), 6.61 (d, J=8.5 Hz, 1H), 4.97 (s, 2H), 1.31 (s, 9H). m/z (ESI, +ve ion): 229.8 (M+H)+.
71%
Example 1; Synthesis of 4-[2-(3-tert-Butyl-4-diethylaminophenyl)-2-hydroxyiminoethoxy]benzoic acid:; a. Preparation of 4-Bromo-2-tert-butylaniline:; 51.8 g (347 mmol) of 2-tert-butylaniline (commercial product marketed especially by the company Aldrich) are dissolved in 600 ml of glacial acetic acid. 900 ml of aqueous 48% hydrobromic acid are then added, and the reaction medium is then cooled to 0 C. 300 ml of DMSO are then added dropwise, after which the reaction medium is warmed to room temperature. After stirring for 4 hours, 250 ml of ethyl acetate are added, followed by 400 ml of 5N sodium hydroxide, and then 1.75 l of 10N sodium hydroxide, to bring the pH to 8. 250 ml of ethyl acetate are added and the medium is separated by settling of the phases. The aqueous phase is then re-extracted with 500 ml of ethyl acetate. The combined organic phases are then rinsed with 1 l of water, and then concentrated under reduced pressure. The residue obtained is purified by chromatography (eluent: 95/5 heptane/ethyl acetate). An orange-colored oil is obtained (m=56.2 g, yield=71%).
65%
25 g (168 mmol) of 2-tert-butylaniline are placed in 300 ml of acetic acid. 450 ml of aqueous HBr at 48% are added and the mixture is then cooled to 0 C. 150 ml of DMSO are added dropwise, the mixture having been brought back to ambient temperature is stirred for 2 hours and it is then poured into ice-cold water and basified to pH 10 with 5N NaOH. It is extracted with diethyl ether and the organic phase is then dried and concentrated to dryness. The residue is column-purified (95/5 heptane/EtOAc). 25.2 g of 4-bromo-2-tert-butylphenylamine are obtained in the form of a yellow oil (yield=65%).
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0 - 20℃;
To a solution of 2-t-butylaniline (45 g, 0.3 mol, 1 eq) in DMF (250 mL) was added NBS (53.6 g, 0.3 mmol, 1 eq) portionwise at 0 oC. The mixture was stirred at rt overnight, TLC indicated completion. The reaction was poured into ice-water (500 mL), extracted with EA (200 mL x 3). The combined organic layers were washed with brine (200 mLx3), dried over sodium sulfate, concentrated affording 4-bromo-2-t-butylaniline (75 g, crude, containing DMF) which was used in next step directly. 1HNMR (300 MHz, CDCl3): G 7.32 (s, 1 H), 7.14- 7.11 (d, J = 10.5 Hz, 1 H), 6.53 (d, J = 8.4 Hz, 1 H), 3.74 (br, 2 H), 1.41 (s, 9 H).^
223.A Part A
Part A Methyl 2-(2-tert-Butylphenylamino)-2-oxoacetate A 3-L, 3-necked round-bottomed flask, equipped with a mechanic stirrer and a thermal probe (under nitrogen) was charged with 2-tert-Butylaniline (109 g, 114 mL, 732 mmoles), triethylamine (81.4 g, 112 mL, 804 mmoles, 1.1 equiv.) and toluene (600 mL). The resulting mixture was stirred at a moderate speed at -30° C. An additon funnel was charged with Methyl chlorooxoacetate (100 g, 816 mmoles, 1.11 equiv.) with toluene (200 mL), and the mixture added to the reaction mixture at such a rate that the internal batch temperature is less than -20° C. After addition, the reaction was warmed to room temperature for an hour, quenched with water, then partitioned between E,tOAc/water. The aqueous phase was extracted with EtOAc (200 mL), and the combined organic layers were washed successively with KHSO4 (200 mL), NaHCO3 (sat'd) (200 mL) and brine (200 mL), then dried the organic over MgSO4. The organic phase was concentrated by rotary evaporation, yielding the title compound as a pale yellow solid [Methyl 2-(2-tert-Butylphenylamino)-2-oxoacetate, 160 g, 93.1%]. MP 61.7-63.6° C. IR (KBr) 3409, 2954, 1736, 1724, 1530, 1299, 1166, 766 cm-1; 1H NMR (300 MHz, CDCl3): δ (ppm): 9.20 (br, 1H), 7.97 (dd, J=7.8 Hz, J'=1.8 Hz, 1H), 7.43 (dd, J=7.8 Hz, J'=1.8 Hz, 1H), 7.31-7.16 (m, 2H), 4.00 (s, 3H), 1.47(s, 9H). The product thus obtained can be used directly for the subsequent reaction.
88.8%
Stage #1: 2-(1,1-dimethylethyl)-benzenamine With triethylamine In dichloromethane at 0 - 5℃; for 0.25h;
Stage #2: monomethyl oxalyl chloride In dichloromethane at 10 - 20℃; for 16h;
1.1 Step 1: synthesis of compound 1-c
Compound 1-a (10.00 g, 67.01 mmol, 1.00 eq) and triethylamine (7.46 g, 73.71 mmol, 1.10 eq) were added to dichloromethane (100 mL) and stirred at 0-5°C for 15 min. Compound 1-b (9.03 g, 73.71 mmol, 1.10 eq) was then added to the above solution, and stirred at 10-20°C for 16 hours. After the reaction was completed, 100 mL of water was added thereto and then separated. The aqueous phase was further extracted with dichloromethane (200 mL 3 2). The organic phases were combined, and washed with dilute hydrochloric acid (0.1 M, 150 mL) and water (100 mL). The organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, to give the product of compound 1-c (14.0 g, yield: 88.8%). 1H NMR (400 MHz, CHLOROFORM-d)hδ=9.04-9.31 (m, 1H), 7.97 (d, J=8.03 Hz, 1H), 7.43 (d, J=7.53 Hz, 1H), 7.25-7.32 (m, 1H), 7.15-7.22 (m, 1H), 4.00 (s, 3H), 1.47 (s, 9H).
81%
With triethylamine In tetrahydrofuran at 20℃; for 3h;
70%
With triethylamine In dichloromethane at 0 - 20℃; for 1h;
70%
With triethylamine In dichloromethane at 0℃; for 1.33333h; Inert atmosphere;
1.A Part A: Methyl 2-[N-(2-tert-Butylphenylamino)]-2-oxoacetate
Part A: Methyl 2-[N-(2-tert-Butylphenylamino)]-2-oxoacetate (0157) A solution of 2-tert-butylaniline (57 mL, 54.5 g, 366 mmol), triethylamine (56 mL, 402 mmol), and methylene chloride (370 mL) was cooled to 0° C. (ice bath) and stirred under nitrogen. An addition funnel was charged with methyl 2-chloro-2-oxoacetate (50 g, 408 mmol) which was then added dropwise over 20 minutes to the stirred solution causing a significant exotherm. After addition complete, the resulting suspension was stirred for 1 hr. The suspension was then concentrated under vacuum, which is then taken up in ethyl acetate and partitioned with water. The aqueous layer was washed twice with ethyl acetate, and the combined organic layers were then extracted with 5% aqueous potassium bisulfate, followed by saturated sodium chloride, and then dried over magnesium sulfate and concentrated under reduced pressure. The resulting oil was then dried overnight, then recrystallized from 3:1 hexanes/toluene (two crops) to give the title compound as a white crystalline solid (60.43 g, 70%)
70%
With triethylamine In dichloromethane at 0℃; for 1.33333h; Inert atmosphere;
1.A Methyl 2-[N-(2-tert-Butylphenylamino)]-2-oxoacetate
A solution of 2-tert-butylaniline (57 mL, 54.5 g, 366 mmol), triethylamine (56 mL,402 mmol), and methylene chloride (370 mL) was cooled to Ooc (ice bath) and stirred undernitrogen. An addition funnel was charged with methyl 2-chloro-2-oxoacetate (50 g, 408 mmol) which was then added dropwise over 20 minutes to the stirred solution causing a significant exotherm. After addition complete, the resulting suspension was stirred for 1 hr. The suspension was then concentrated under vacuum, which is then taken up in ethyl acetate and partitioned withwater. The aqueous layer was washed twice with ethyl acetate, and the combined organic layers were then extracted with 5% aqueous potassium bisulfate, followed by saturated sodium chloride, and then dried over magnesium sulfate and concentrated under reduced pressure. The resulting oil was then dried overnight, then recrystallized from 3:1 hexanes/toluene (two crops) to give the title compound as a white crystalline solid (60.43 g, 70 %).
With triethylamine at 0 - 20℃;
With triethylamine In dichloromethane at 0℃; Heating;
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 18h;
With EDAC; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In dichloromethane;
EXAMPLE 154 Step A-Preparation of N-(4-tert-butyl-phenyl)-2,6-difluoro-nicotinamide A solution of <strong>[171178-50-0]2,6-difluoropyridine-3-carboxylic acid</strong> (3.2 g, 20 mmol), t-butylaniline (3.0 g, 20 mmol), HOBt (2.6 g, 20 mmol), EDAC (8 g, 40 mmol), and DIEA (8 mL) in CH2Cl2 (80 mL) was stirred at RT for 1 h. The mixture was washed with aq. NaHCO3 and brine. The organic solution was dried over Na2SO4 and concentrated in vacuo. The residue was purified via flash chromatography on silica (Hex:EtOAc=4:1) to give a light yellow flaky crystal as desired product.
With EDAC; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In dichloromethane;
Step A-Preparation of N-(4-tert-butyl-phenyl)-2,6-difluoro-nicotinamide A solution of <strong>[171178-50-0]2,6-difluoropyridine-3-carboxylic acid</strong> (3.2 g, 20 mmol), t-butylaniline (3.0 g, 20 mmol), HOBt (2.6 g, 20 mmol), EDAC (8 g, 40 mmol), and DIEA (8 mL) in CH2Cl2 (80 mL) was stirred at RT for 1 h. The mixture was washed with aq. NaHCO3 and brine. The organic solution was dried over Na2SO4 and concentrated in vacuo The residue was purified via flash chromatography on silica (Hex:EtOAc=4:1) to give a light yellow flaky crystal as desired product.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h;
Step A-Preparation of N-(4-tert-butyl-phenyl)-2,6-difluoro-nicotinamide A solution of <strong>[171178-50-0]2,6-difluoropyridine-3-carboxylic acid</strong> (3.2 g, 20 mmol), t-butylaniline (3.0 g, 20 mmol), HOBt (2.6 g, 20 mmol), EDAC (8 g, 40 mmol), and DIEA (8 mL) in CH2Cl2 (80 mL) was stirred at RT for 1 h.The mixture was washed with aq. NaHCO3 and brine.The organic solution was dried over Na2SO4 and concentrated in vacuo. The residue was purified via flash chromatography on silica (Hex:EtOAc=4:1) to give a light yellow flaky crystal as desired product.
With monopotassium carbonate; sodium iodide In diethylene glycol dimethyl ether at 170℃; for 8h;
LXVIII; CII; 125.A Preparation LXVIII 1-(2-tert-Butyl-phenyl)-4-methyl-piperazine; Preparation CII 1-[2-(tert-butyl)-5-aminophenyl]-4-methylpiperazine; N-[4-(tert-Butyl)-3-(4-methylpiperazinyl)phenyl]{2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide; Step A Preparation of 1-[2-(tert-butylphenyl]-4-methylpiperazine
Step A-Preparation of 1-[2-(tert-butylphenyl]-4-methylpiperazine A mixture of 2-tert-butylaniline (5.4 g) and N-methylbis(2-chloroethyl)amine hydrochloride (7 g) and K2CO3 (5 g) in NaI (2 g) in diglyme (150 ml) was heated at 170° C. for 8 h.The reaction was filtered and the filtrate was evaporated under high vacuum.The residue was mixed with EtOAc (200 ml) and H2O (200 ml) and extracted with EtOAc twice.The combined organic layer was washed with brine, dried over Na2SO4 and evaporated to give crude 1-[2-(tert-butylphenyl]-4-methyl-piperazine, which was used in next step without further purification.
With monopotassium carbonate; sodium iodide In diethylene glycol dimethyl ether at 170℃; for 8h;
LXVIII Preparation LXVIII 1-(2-tert-Butyl-phenyl)-4-methyl-piperazine
2-tert-Butyl-phenylamine and bis-(2-chloro-ethyl)-methylamine were mixed together with K2CO3 (25 g), NaI (10 g) and diglyme (250 mL) and heated at 170° C. for 8 h. Cooled and filtered solid and evaporated solvent. Diluted with EtOAc, washed with NaHCO3 solution, extracted twice more with EtOAc, washed with brine, dried over Na2SO4 and evaporated to give the compound as a dark solid.
With potassium carbonate; sodium iodide In diethylene glycol dimethyl ether at 170℃; for 8h;
LXVIII
2-tert-Butyl-phenylamine and bis-(2-chloro-ethyl)-methylamine were mixed together with K2C03 (25 g) , Nal (10g) and diglyme (250 mL) and heated at 170 2C for 8 h. Thereaction mixture was cooled, the solid filtered and solventevaporated. The residue was diluted with EtOAc, washed withNaHCO3 solution, extracted twice more with EtOAc, washedwith brine, dried over Na2S04 and evaporated to give thecompound as a dark solid.
With potassium carbonate; sodium iodide In diethylene glycol dimethyl ether at 170℃; for 8h;
LIV Preparation [LIV-1-(2-TERT-BUTYL-PHENYL)-4-METHYL-] piperazine
Preparation [LIV-1-(2-TERT-BUTYL-PHENYL)-4-METHYL-] piperazine 2-tert-Butyl-phenylamine and bis- (2-chloro-ethyl)- methylamine were mixed together with [K2CO3] (25 g), NaI (10 g) and diglyme (250 mL) and heated at [170 °C] for 8 h. Cooled and filtered solid and evaporated solvent. Diluted with EtOAc, washed with [NAHC03] solution, extracted twice more with EtOAc, washed with brine, dried over [NA2SO4] and evaporated to give the compound as a dark solid. a) [1-BROMO-2-(2-METHYL-ALLYLOXY)-4-NITRO-BENZENE] was prepared from methallyl. bromide was prepared similarly to the procedure outlined above.
Two runs were conducted each using the procedure described herein. A slurry of 2000 g of phenylamine and 200 g of an acid activated acidic montmorillonite catalyst sold as F-22 by Englehard Chemicals Inc. and having a residual acidity of 3 was introduced into a reactor via a sample line by applying a slight vacuum to the reactor. The reactor was stirred (950 RPM), purged several times using 3.445 mPa (500 psi) nitrogen and then heated to 250° C. The autogeneous pressure of phenylamine at these conditions was about 430 kPa (60 psi). Isobutylene was introduced into the reactor, in run-1 directly into the liquid and in run-2 into the vapor space above the liquid. In each instance the isobutylene was added in about 10% increments over a period of 2 hours 15 minutes in run 1 and 2 hrs and 27 minutes in run 2. Samples were withdrawn from the reactor at 2, 4 and 6 hour intervals after all the isobutylene was added. The samples were filtered to remove the catalyst and then subjected to G.C. analysis. The results obtained are given in Table 1. TABLE 1 ALKYLATION OF ANILINE WITH ISOBUTYLENE AT 250° C. (F-22-Montmorillonite Catalyst - Engelhard) FEED Aniline 2000 g 21.5 moles Clay 200 g Isobutylene 845 g 15 moles Mole Ratio: Isobutylene/Aniline = 0.7 AnilineProduct Distribution %(2) Run I.D. Time, HrConv. (%)(1) N-C4 o-C4 p-C4 Di-Substit Run 1-1 2 71.5 0.3 2.8 92.8 4.1 Run 1-2 4 88.5 0.2 1.6 94.7 3.5 Run 1-3 6 90.3 0.2 1.6 94.4 3.8 Run 2-1 2 91.6 0.2 1.4 94.8 3.6 Run 2-2 4 94.6 0.2 2.0 93.8 4.0 Run 2-3 6 92.4 0.2 1.8 94.2 3.9 (1)Based on theoretical moles of aniline for a mono alkylation reaction. (2)Based on moles of aniline reacted.
With potassium carbonate; sodium iodide; In diethylene glycol dimethyl ether; at 170℃; for 8h;
A mixture of 2-t-butylaniline (5.4 g) andmethylchlorethylamine hydrochloride (7 g) and K2C03 (5 g) inNal (2 g) in diglyme (150 m) was heated at 170 2C for 8 h.The reaction was filtered and the filtrate was evaporatedunder high vacuum. The residue was mixed with EtOAc (200 ml)and H20 (200 ml) and extracted with EtOAc twice. Thecombined organic layer was washed with brine and dried overNa2S04 and evaporated to give crude 1-[2-(tert-butylphenyl]-4-methylpiperazine. The crude 1-[2-(tert-butylphenyl]-4-methylpiperazine (260 mg) was stirred with H2S04 (3 ml) atOaC and HN03 (1.2 ml, 70%) was slowly added to the reaction.The reaction was warmed to RT, stirred for 30 min, poured onice and basified with K2C03 slowly. The solution wasextracted with EtOAc three times, washed with H20, followedby brine, dried over Na2S04 and evaporated under reducedpressure. The residue was purified by column chromatographyto give 1-[2-(tert-butyl)-5-nitrophenyl]-4-methylpiperazine(260 mg) , which was hydrogenated under H2 atmosphere to give1-[2-(tert-butyl)-5-aminophenyl]-4-methylpiperazine.
With palladium diacetate; tris-(o-tolyl)phosphine; sodium t-butanolate In toluene at 100℃; for 4h;
53%
With palladium diacetate; tris-(o-tolyl)phosphine; sodium t-butanolate In toluene at 100℃; for 4h;
2.2 4.2.2 2-tert-Butyl-N-(2-(4-chlorophenyl)ethynyl)phenyl)aniline (1k)
To a solution of Pd(OAc)2 (26.9mg, 0.12mmol) and (o-tol)3P (73.0mg, 0.24mmol), t-BuONa (0.43g, 4.50mmol) in toluene (10mL) were added 1-bromo-2-trimethylsilylethynylbenzene5 (0.76g, 3.0mmol) and 2-tert-butylaniline (0.47mL, 3.0mmol) at rt. After being stirred for 4h at 100°C, the mixture was poured into saturated NaHCO3 aq and extracted with AcOEt. The AcOEt extracts were washed with brine, dried over Na2SO4, and evaporated to dryness. Purification of the residue by column chromatography (hexane only) gave 2-tert-butyl-N-(2-(trimethylsilylethynyl)phenyl)aniline (510mg, 53%). To a solution of 2-tert-butyl-N-(2-(trimethylsilylethynyl)phenyl)aniline (940mg, 2.92mmol) in CH2Cl2 (1mL) and CH3OH (2mL) was added K2CO3 (525mg, 3.80mmol). After being stirred for 3h at rt, the mixture was poured into water and extracted with haxane. The hexane extracts were washed with brine, dried over Na2SO4, and evaporated to dryness. Purification of the residue by column chromatography (hexane only) gave 2-tert-butyl-N-(2-(ethynyl)phenyl)aniline (649mg, 89%). To a solution of (Ph3P)2PdCl2 (32mg, 0.04mmol) and CuI (17mg, 0.09mmol) in Et3N (2.0mL) were added 1-chloro-4-iodobenzene (542mg, 2.27mmol) and 2-tert-butyl-N-(2-(ethynyl)phenyl)aniline (567mg, 2.27mmol) in Et3N (2.0mL) at rt. After being stirred for 6h at rt, the mixture was poured into saturated NH4Cl aq and extracted with AcOEt. The AcOEt extracts were washed with brine, dried over Na2SO4, and evaporated to dryness. Purification of the residue by column chromatography (hexane only) gave 1k (761mg, 93%). 1k: yellow oil; IR (neat) 3425, 2206cm-1; 1H NMR (CDCl3) δ: 7.40-7.47 (4H, m), 7.36 (1H, dd, J=1.4, 7.8Hz), 7.30-7.33 (2H, m), 7.22 (1H, dt, J=1.4, 7.3Hz), 7.11-7.16 (2H, m), 6.82 (1H, d, J=8.7Hz), 6.73 (1H, dt, J=0.9, 7.6Hz), 6.45 (1H, br s), 1.44 (9H, s); 13C NMR (CDCl3) δ: 147.1, 144.4, 139.6, 134.3, 132.5, 132.3, 129.9, 128.8, 127.2, 126.93, 126.88, 124.9, 121.6, 117.8, 112.1, 108.2, 94.0, 87.3, 34.9, 30.6; MS (m/z) 359 (M+, 35Cl); Anal. Calcd for C24H22ClN: C, 80.10; H, 6.16; N, 3.89. Found: C, 80.24; H, 6.26; N, 3.86.
methyl 2-((2-(tert-butyl)phenyl)amino)-3-hydroxy-2-phenylpropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dirhodium tetraacetate In tetrahydrofuran at 30℃; for 13h; Overall yield = 41 %; chemoselective reaction;
4 4.2. General procedure for the reaction of diazo, aniline and aldehyde
General procedure: To a mixture of Rh2(OAc)4 (0.003 mmol), aniline 2 (0.30 mmol) and aldehyde 3 (1.80 mmol) in THF (1.0 mL) at 30 °C, diazo compound 1 in THF (1.0 mL) was added (0.36 mmol) for 1 h via a syringe pump. After the completion of the addition, the reaction mixture was stirred for additional 12 h. Solvents were removed under reduced pressure to give the crude products, the crude products were purified by flash chromatography on silica gel (ethyl acetate/petroleum ether=1:10 to 1:1) to give pure products.
General procedure: Anhydride 1 (100 mg, 0.757 mmol) was dissolved in a minimal amount of dry CH2Cl2 and corresponding aniline 2-13 (1 eq) was added in dry CH2Cl2. The solution was stirred for 24 h at room temperature. The solvent was evaporated and the monoamides 14-25 were air-dried, and used without further purification. Appropriate monoamide (14-25) (0.5 mmole) was dissolved in dry, freshly distilled THF (10 ml) at room temperature under argon. BOP (1.05 eq) was added to the mixture followed by the solution of triethylamine (TEA) (0.5 ml) in THF (1 ml). The reaction mixture was then stirred at room temperature for 20 min and another portion of BOP (0.5 eq) was added. After 40 min the solvent was evaporated. The residue was dissolved in CHCl3 and washed with 10% citric acid solution, sat. Na2CO3 solution, water and brine. Combined organic layers were dried over MgSO4, filtered and evaporated to dryness. Imides 26-37 were purified by column chromatography on silica gel using mixture hexan/EtOAc (0-15% v/v) as eluent. Yields are listed in Table 1.
With [(η5-pentamethylcyclopentadienyl)IrIIIbis-(κC-1,3-dimethylimidazol-2-ylidene)Cl]BF4; potassium <i>tert</i>-butylate In toluene at 80℃; for 12h;
4.2. General method for the N-alkylation of amines with alcohols
General procedure: To a 15 mL reaction tube in a glovebox, was added complex Ir3(0.5 mol%), KOtBu (75 mol%), the alcohol (0.5 mmol) and the amine(0.5 mmol) at room temperature. Then the tube was closed andremoved from the glovebox. The reaction mixture was stirred at 80 °C for 12 h. After cooling to room temperature, the reaction mixturewas diluted with ethyl acetate, filtered and dried under vacuum.The product was purified by column chromatography oversilica-gel (300-400 mesh) with an appropriate mixture of petroleum ether and ethyl acetate (80:1).
80%
With 1,10-Phenanthroline; tungsten hexacarbonyl; potassium <i>tert</i>-butylate In 1,4-dioxane at 130℃; for 24h;
75%
With (4-Ph)Triaz(NHP<SUP>i</SUP>Pr<SUB>2</SUB>)<SUB>2</SUB>Mn(CO)<SUB>2</SUB>Br; potassium <i>tert</i>-butylate In 2-methyltetrahydrofuran at 80℃; for 18h;
65%
With C20H26ClIrN3O(1+)*F6P(1-) In water at 110℃; for 24h; Inert atmosphere; Schlenk technique; Glovebox;
58%
With potassium <i>tert</i>-butylate; benzonitrile In 1,4-dioxane at 120℃; for 15h; Inert atmosphere; Glovebox; Sealed tube;
35%
With potassium <i>tert</i>-butylate; triphenylphosphine; manganese(ll) chloride In toluene at 130℃; for 20h; Inert atmosphere; Sealed tube;
95 %Chromat.
With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; N-(diphenylphosphino)-2,4-dimethyl-5-phenylimidazo[1,5-b]pyridazin-7-ylamine; potassium <i>tert</i>-butylate In tetrahydrofuran; diethylene glycol dimethyl ether at 70℃; for 24h; Sealed tube;
With triethylamine In 1,2-dichloro-ethane for 4h; Reflux; Inert atmosphere;
72
General procedure: 0 ° C triphosgene (2 · 97g, 1 (λ Ommol, (λ 5equiv) was dissolved in dry DCE (50mL), was added triethylamine (0. 03mL, 0. Olequiv), stirred 5min, the aromatic amine (20. Ommol) was dissolved in dry DCE (50mL) was added dropwise after, 2h completion of the dropwise, and the reaction was stirred at reflux under nitrogen for 4h, cooled to room temperature, the mixture was evaporated under reduced pressure to give a yellow solid S1.
With triethylamine In tetrahydrofuran at 60℃; for 4h;
14 Example 14 ethyl 2-[(2-tert-butylphenyl)carbamoyl]oxy} acetate
2-tert-Butylaniline (200 mg, 1.34 mmol, 1 eq.) was dissolved in anhydrous THF (10 ml) and TEA (0.224 ml, 1.61 mmol, 1.2 eq.) was added. The solution was treated with triphosgene (0.159 mg, 0.54 mmol, 0.4 eq.) and the resulting mixture was stirred at 60°C for 4 h. The reaction mixture was cooled to 0°C and ethyl glycolate (0.167 ml, 1.61 mmol, 1.2 eq.) and TEA (0.163 mg, 1.61 mmol, 1.2 eq.) were added. The reaction mixture was stirred at rt for 15 h, filtered through Celite and the filtering bed was washed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by FCC (0 to 20 % EtOAc in hexane). Y = 47 %. MS ES+ ([M+Na]+): 302.6. NMR (300 MHz, DMSO-) δ 8.94 (s, 1H), 7.42 - 7.37 (m, 1H), 7.26 - 7.15 (m, 2H), 7.13 - 6.97 (m, 1H), 4.62 (s, 2H), 4.18 - 4.12 (m, 2H), 1.34 (s, 9H), 1.21 (t, J = 7 Hz, 3H).
Stage #1: bis(trichloromethyl) carbonate With triethylamine In dichloromethane at 0℃; for 0.0833333h;
Stage #2: 2-(1,1-dimethylethyl)-benzenamine In dichloromethane at 20℃;
With beta zeolite nanocrystals; at 140℃; for 6.0h;Autoclave;Activation energy;
The test reaction, tert-butylation of aniline in the presence of beta zeolite was carried out in a 100 ml stainless steel Parr autoclave under autogenous pressure in the temperature range 140 C-170 C for 6 h. A predetermined quantity of reactants and catalyst were charged into the autoclave and the temperature was raised to the desired value. A typical experiment consisted of a reaction mixture of 0.01 mol aniline, 0.05 mol tert-butanol and 0.20 g of beta catalyst at 140 C for 6 h. The products were analyzed by gas chromatographic analysis (Hewlett Packard 5890, OV-101 column) using flame ionization detector (FID). Product identification was done by gas chromatography-mass spectrometry (GC-MS). The products were determined to be 2-tert-butylaniline (2-TBA), 4-tert-butylaniline (4-TBA) and 2,4-di-tert-butylaniline (2,4-DTBA) (Scheme 1).
N-((2-(tert-butyl)phenyl)carbamoyl)-2,5,6-trichloronicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step 1: N-((2-(tert-Butyl)phenyl)carbamoyl)-<strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> To a mixture of <strong>[142266-62-4]2,5,6-trichloronicotinamide</strong> (Intermediate P, 1.02 g, 4.5 mmol) in THF (20 mL) was added oxalyl chloride (2 M solution in DCM, 2.5 mL, 5.0 mmol). The resulting mixture was heated at 70 C. for 40 min, then heating was stopped and the reaction was allowed to cool to room temperature. 2-tert-butylaniline (0.708 mL, 4.5 mmol, Ark Pharm, Arlington Heights, Ill., USA) was added. The reaction mixture was stirred at room temperature for 10 min and then was concentrated. The residue was suspended in MeOH and filtered. The filtered solids were collected to provide N-((2-(tert-butyl)phenyl)carbamoyl)-<strong>[142266-62-4]2,5,6-trichloronicotinamide</strong>. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.43 (br s, 1H), 9.79-10.16 (m, 1H), 8.65 (s, 1H), 7.49 (br dd, J=7.5, 1.7 Hz, 1H), 7.43 (br d, J=7.7 Hz, 1H), 7.18-7.28 (m, 2H), 1.40 (s, 9H). m/z (ESI, +ve ion): 422.0 (M+Na)+.
N-[(2-tert-butylphenyl)imino]benzenimine oxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With silver(l) oxide In ethanol at 65℃; for 24h; Schlenk technique;
78%
With silver(l) oxide In dimethyl sulfoxide at 65℃; for 24h; Sealed tube;
14 Example 14 1-Phenyl-2-(2-tert-butylphenyl) oxidized azo
2-tert-butylaniline (156.0 μL, 1.0 mmol) was sequentially added to a 10 ml reaction tube, and nitrosobenzene was added.(117.8 mg, 1.1 mmol), Ag2O (254.5 mg, 1.1 mmol), DMSO (2 mL). Then, seal the tube. The reaction mixture was placed in an oil bath at 65 ° C for 24 hours, then taken out and cooled to room temperature. The reaction liquid was transferred, washed with an appropriate amount of ethyl acetate, and the mixture was mixed with a washing liquid, and concentrated and adsorbed on silica gel powder under reduced pressure. Directly separated by silica gel column chromatography to volume ratioA 100:1 mixture of petroleum ether and ethyl acetate as an eluent was separated by column chromatography to give 1-phenyl-2-(2-tert-butylphenyl) oxidized azo in a yield of 78%.
With C18H15IMnN3O3; sodium t-butanolate In toluene at 120℃; for 18h; Inert atmosphere; Schlenk technique;
43%
With 1-(2,6-diisopropylphenyl)-3-(2,4,6-trimethylphenyl)-4,5-dihydroimidazolinium chloride; bis(1,5-cyclooctadiene)nickel (0); potassium <i>tert</i>-butylate In toluene at 140℃; for 16h;
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