* 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.
With potassium carbonate; hydrazine hydrate In water; N,N-dimethyl-formamide at 80℃; for 9 h;
General procedure: Aryl halide (1.0 mmol), phenylboronic acid (1.1 mmol),K2CO3(2.0 mmol), Ni7–Pd3BIHPS (0.03 g) and H2O/DMF (2:1, 3 mL) were mixed and heated at 80 °C for anappropriate time (monitored by TLC). Then, hydrazinehydrate (80 wtpercent, 6 eq) was added to the reaction vessel.After completion of the reduction process, the mixturewas filtered and washed with water. The organic layer wasextracted with ethyl acetate (3 × 15 mL) and dried overMgSO4.Then the organic solution was concentrated andpurified by column chromatography to obtain the finalproduct.
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 17, p. 7410 - 7424
3
[ 13331-27-6 ]
[ 57976-57-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 2002, vol. 45, # 18, p. 3865 - 3877
4
[ 13331-27-6 ]
[ 607-34-1 ]
Reference：
[1] Chinese Chemical Letters, 2014, vol. 25, # 5, p. 779 - 782
5
[ 13331-27-6 ]
[ 75-05-8 ]
[ 121-89-1 ]
Yield
Reaction Conditions
Operation in experiment
70%
With 1,10-Phenanthroline; nickel(II) bromide 2-methoxyethyl ether; sodium hydrogencarbonate In water at 100℃; for 5 h; Autoclave
General procedure: The reaction was carried out in an autoclave containing a 10 mL Teflon reactiontube. NiBr2·diglyme (5 molpercent), 1,10-phen (10 molpercent) and a magnetic stir bar wereplaced in the tube. Then, arylboronic acid (1.0 mmol), NaHCO3 (2.0 equiv), H2O (2.0mmol) and alkyl nitrile (1.0 mL) were added to the tube. After that the autoclave wascapped with a stopper. The autoclave was cool down by liquid nitrogen, then createdvacuum at this temperature and added HCFC-244bb (2.0 mL, 2.6 g) by self-suction.Finally the autoclave was wormed in an oil bath at 100 °C for 5 h. After the reaction,the autoclave was cooled to room temperature and vented the excess HCFC-244bb carefully. Water (30 mL) was added to the mixture, and the mixture was extractedwith dichloromethane (3 x 15 mL). The organic layers were washed with brine, driedover Na2SO4, and evaporated the organic solvent by rotatory evaporator. The crudeproduct was then purified by column chromatography.
Reference：
[1] Chemical Communications, 2001, # 22, p. 2316 - 2317
7
[ 13331-27-6 ]
[ 105-56-6 ]
[ 121-89-1 ]
Reference：
[1] New Journal of Chemistry, 2015, vol. 39, # 11, p. 8763 - 8770
8
[ 13331-27-6 ]
[ 75072-07-0 ]
[ 657-15-8 ]
Reference：
[1] Journal of the American Chemical Society, 2000, vol. 122, # 45, p. 11260 - 11261
9
[ 1292766-17-6 ]
[ 13331-27-6 ]
[ 75072-07-0 ]
[ 657-15-8 ]
[ 52403-06-2 ]
Reference：
[1] Journal of the American Chemical Society, 2000, vol. 122, # 45, p. 11260 - 11261
10
[ 13331-27-6 ]
[ 79-10-7 ]
[ 1664-57-9 ]
Reference：
[1] Synlett, 2011, # 17, p. 2517 - 2520
11
[ 13331-27-6 ]
[ 105-36-2 ]
[ 14318-64-0 ]
Reference：
[1] Chemical Communications, 2001, # 7, p. 669 - 670
12
[ 13331-27-6 ]
[ 30418-59-8 ]
Yield
Reaction Conditions
Operation in experiment
83%
Stage #1: With hydrogenchloride; 1,1,1,3',3',3'-hexafluoro-propanol; iron In water at 20℃; for 0.5 h; Stage #2: With sodium hydrogencarbonate In water
General procedure: The nitro compound (1 equiv), HFIP (10 equiv), Fe powder (5 equiv) were mixed in a tube. Then 2 N HCl aqueous solutions was added to the reaction mixture. After stirring at room temperature for 30 min, the reaction mixture was neutralized with sat. NaHCO3 (aq.) and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was then purified by column chromatography on silica gel to furnish the desired amine product.
Reference：
[1] Tetrahedron Letters, 2017, vol. 58, # 37, p. 3646 - 3649
[2] Journal of the American Chemical Society, 1932, vol. 54, p. 4415,4418
[3] Journal of Organic Chemistry, 1937, vol. 2, p. 522,533
[4] Journal of the American Chemical Society, 1931, vol. 53, p. 713
[5] Patent: US2007/209123, 2007, A1, . Location in patent: Page/Page column 7
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, p. 715 - 720
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 23, p. 5612 - 5615
15
[ 13675-18-8 ]
[ 99-09-2 ]
[ 13331-27-6 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6608 - 6612
16
[ 585-79-5 ]
[ 13331-27-6 ]
Reference：
[1] Journal of Organic Chemistry, 2002, vol. 67, # 15, p. 5394 - 5397
17
[ 98-80-6 ]
[ 13331-27-6 ]
[ 5570-19-4 ]
Reference：
[1] Journal of the American Chemical Society, 1931, vol. 53, p. 713
[2] Journal of the Chemical Society, 1930, p. 2171,2176
18
[ 13675-18-8 ]
[ 586-36-7 ]
[ 13331-27-6 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6608 - 6612
19
[ 7732-18-5 ]
[ 13331-27-6 ]
Reference：
[1] Journal of the American Chemical Society, 2012, vol. 134, # 17, p. 7431 - 7441
20
[ 99-09-2 ]
[ 13331-27-6 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6608 - 6612
21
[ 98-80-6 ]
[ 13331-27-6 ]
[ 5570-19-4 ]
Reference：
[1] Journal of the American Chemical Society, 1931, vol. 53, p. 713
[2] Journal of the Chemical Society, 1930, p. 2171,2176
22
[ 13331-27-6 ]
[ 87199-18-6 ]
Reference：
[1] Journal of the American Chemical Society, 1932, vol. 54, p. 4415,4418
23
[ 13331-27-6 ]
[ 78887-39-5 ]
Reference：
[1] Journal of the American Chemical Society, 1931, vol. 53, p. 713
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 90℃; for 24h;
A solution of 2,3-dichloro-iodobenzene (6.00 G, 22. 0 mmol) in 60 mL toluene and 20 mL eth- anol was treated with 3-nitro-phenylboron. ic acid (4. 22 G, 25. 3 mmol) and NA2CO3 (2 N in H20, 30. 0 ML). Then mixture was purged with N2 for 5 min and Pd- (PPH3) (1. 02 G, 0. 879 mmol) was added. The mixture was heated to 90°C for 24 h and cooled to ambient temperature and concentrated in vacuo. The residual oil was partitioned with Et2O (80 M. L) and washed with dilute brine solution (3x50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting white solid was recrystallized from hexane and to give the title compound (2.30 g, 39percent) as a fluffy white SOLID. 1H NMR (CDC13,400 MHz) 5 8.29 (m, 2H), 7.76 (m, 1H), 7.63 (t, J=7. 61 Hz, 1H), 7. 55 (m, 1H), 7. 31 (t, J=7.81 HZ, 1H), 7.26 (m, 1H.)
1.2 g of Wang polystyrene resin (Rapp-Polymere, Tuebingen; loading 1.08 mmol/g) are swollen in dimethylformamide (DMF). The solvent is filtered off with suction and a solution of 1005 mg of Fmoc-phenylalanine (amino acid reagent) in 10 ml of dimethylformamide (DMF) is added. After shaking at room temperature for 15 min, the suspension is treated with 345 mul of pyridine and 543 mg of 2,6-dichlorobenzoyl chloride. It is shaken overnight at room temperature. The resin is then washed with dimethylformamide (DMF), methanol and dichloromethane. The resin is treated with 15 ml of a 20% strength piperidine solution dimethylformamide (DMF) and shaken at room temperature for 10 min. It is then washed 3 times with dimethylformamide (DMF) and a further 15 ml of a 20% strength piperidine solution in dimethylformamide (DMF) are added. After shaking for 20 min, it is washed with dimethylformamide (DMF) and tetrahydrofuran (THF). The resin is treated with a solution of 452 ml of diisopropylethylamine in 5 ml of tetrahydrofuran (THF) and a solution of 431 mg of 3-bromobenzenesulfonyl chloride in 5 ml of tetrahydrofuran (THF). It is shaken overnight at room temperature. The resin is then washed with dimethylformamide (DMF), methanol and tetrahydrofuran (THF). The resin is suspended in 7 ml of xylene, treated with 1.08 g of 3-nitrobenzeneboronic acid and a solution of 1.37 g of sodium carbonate in 6 ml of water and shaken for 5 min at room temperature. 227 mg of bis-(triphenylphosphane)-palladium(II) chloride and 170 mg of triphenylphosphane are then added and the mixture is stirred overnight at 85C. The resin is then washed with tetrahydrofuran (THF)/water 1:1, 0.25 M aqueous hydrochloric acid, water, dimethylformamide (DMF), methanol, tetrahydrofuran (THF) and dichloromethane. The resin is treated with a solution of 5.4 g of tin(II) chloride dihydrate in 12 ml of N-methylpyrrolidone (NMP) and shaken overnight at room temperature. The resin is then washed with N-methylpyrrolidone (NMP), methanol, tetrahydrofuran (THF) and dichloromethane. The resin is treated with a solution of 1.45 g 2-furanyl-carboxylic acid (acid reagent) in 20 ml dimethylformamide (DMF). After shaking for 1 minute a solution of 2.64 ml diisopropylcarbodiimide in 5 ml dimethylformamide (DMF) is added and the mixture is shaken for 3 hours at room temperature. The resin is then washed with dimethylformamide (DMF) and is treated with 1.45 g 2-furanyl-carboxylic acid in 20 ml dimethylformamide (DMF) and 2.64 ml diisopropylcarbodiimide in 5 ml dimethylformamide (DMF) again. After shaking for 3 hours the resin is washed with dimethylformamide (DMF), methanol, tetrahydrofurane (THF) and dichloromethane. For removal of the product, the resin is shaken with 10 ml of trifluoroacetic acid (TFA)/dichloromethane 1:1 for 1 hour, filtered off. The filtrate is concentrated in vacuo and purified on silica gel. 201 mg of the title compound are obtained. Mass spectrometry (ESI): 491. Retention time (HPLC): Rt = 9,6.1H-NMR (400 MHz, methanol) delta = 7,99 (s, 1H), 7,91 (s, 1H), 7,81 (d, 1H), 7,75 (m, 2H), 7,66 (m, 1H), 7,52 - 7,43 (m, 2H), 7,41 (d, 1H), 7,29 (d, 1H), 7,11 (s, 5H), 7,68 (m, 1H), 4,10 (dd, 1H, J =5,6 Hz, J = 10,8 Hz, H-2), 3,06 (dd, 1H, J = 5,6 Hz, J = 13,8 Hz, H-3a), 2,85 (dd, 1H, J = 10,8 Hz, J = 13,8 Hz, H-3b).
With sodium carbonate; In 1,2-dimethoxyethane; hexane; dichloromethane;
Preparation 30 To a suspension of <strong>[89488-29-9]2-bromo-4-methoxypyridine</strong> (483 mg), 3-nitrophenylboronic acid (643 mg) and tetrakis(triphenylphosphine)-palladium (148 mg) in 1,2-dimethoxyethane (10 ml) was added 2M aqueous solution of sodium carbonate (2.78 ml). The mixture was stirred at 90 C. for 6 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with dichloromethane. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 40 g, 50-100% dichloromethane in n-hexane) to give 3-(4-methoxypyridin-2-yl)-nitrobenzene (365 mg). 1H-NMR (CDCl3): delta3.95(3H,s), 6.87(1H,dd,J=5.7 Hz,2.4 Hz), 7.31(1H,d,J=2.4 Hz), 7.64(1H,t,J=8.0 Hz), 8.2-8.4(2H,m), 8.56(1H,d,J=5.7 Hz), 8.82(1H,s)
With sodium carbonate; In 1,2-dimethoxyethane; hexane; ethyl acetate;
Preparation 36 To a suspension of <strong>[17117-13-4]2-bromo-4-ethoxypyridine</strong> (879 mg), 3-nitrophenylboronic acid (944 mg) and tetrakis(triphenylphosphine)-palladium (251 mg) in 1,2-dimethoxyethane (20 ml) was added 2M aqueous solution of sodium carbonate (5.66 ml). The mixture was stirred at 90 C. for 8 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 40 g, 25% ethyl acetate in n-hexane) to give 3-(4-ethoxypyridin-2-yl)nitrobenzene (887 mg). 1H-NMR (CDCl3): delta1.49(3H,t,J=7.0 Hz), 4.18(2H,q,J=7.0 Hz), 6.83(1H,dd,J=5.7 Hz,2.4 Hz), 7.29(1H,d,J=2.4 Hz), 7.63(1H,t,J=8.0 Hz), 8.2-8.4(2H,m), 8.54(1H,d,J=5.7 Hz), 8.81(1H,t,J=2.0 Hz)
bis(dibenzylideneacetone)-palladium(0); In tetrahydrofuran; ethyl acetate;
C. 6-amino-8-(3-nitrophenyl)-1,7-naphthyridine To a stirred solution of <strong>[5912-35-6]6-amino-8-bromo-1,7-naphthyridine</strong> (4 g, 0.018 mol) in a mixture of tetrahydrofuran (80 ml) and aqueous Na2 CO3 (34 ml, 2N) is added bis(dibenzylideneacetone)palladium (0.40 g, 0.0007 mol), triphenylphosphene (0.37 g, 0.0014 mol) and 3-nitrophenylboronic acid (3.7 g, 0.022 mol). The mixture is stirred for 16 h at 80 C. The mixture is filtered, ethyl acetate added and the mixture washed with 2N NaOH and water. The organic solvent is removed and the residue suspended in ether. Filtration affords the title compound. Mass M+H 267. mp 221-223 C.
EXAMPLE 197 5,8-Difluoro-1,2-dihydro-6-(3-nitrophenyl)-2,2,4-trimethylquinoline (Compound 297, structure 83 of Scheme XXI, where R1 =R3-5 =R7 =R9 =H, R2 =nitro, R6 =R8 =fluoro) This compound was prepared by the same procedure as described in the synthesis of Compound 291 (EXAMPLE 191) from <strong>[112279-60-4]4-bromo-2,5-difluoroaniline</strong> (32 mg, 0.13 mmol) and 3-nitrobenzeneboronic acid (167 mg, 1.0 mmol) to afford 3 mg (10%) of Compound 297 as a colorless oil. Data for Compound 297: 1 H-NMR(400 MHz, CDCl3) 8.33 (t, J=1.6, 1H), 8.14 (dd, J=8.0, 1.6, 1H), 7.78 (d, J=8.0, 1H), 7.57 (t, J=8.0, 1H), 6.94 (dd, J=10.8, 6.3, 1H), 5.37 (s, 1H), 4.16 (bs, 1H), 2.17 (dd, J=7.0, 1.3, 3H), 1.34 (s, 6H).
3 mg (10%)
EXAMPLE 197 5,8-Difluoro-1,2-dihydro-6-(3-nitrophenyl)-2,2,4-trimethylquinoline (Compound 297, Structure, 83 of Scheme XXI, where R1 =R3-5 =R7 =R9 =H, R2 =nitro, R6 =R8 =fluoro) This compound was prepared by the same procedure as described in the synthesis of Compound 291 (EXAMPLE 191) from <strong>[112279-60-4]4-bromo-2,5-difluoroaniline</strong> (32 mg, 0.13 mmol) and 3-nitrobenzeneboronic acid (167 mg, 1.0 mmol) to afford 3 mg (10%) of Compound 297 as a colorless oil. Data for Compound 297: 1 H NMR (400 MHz, CDCl3) 8.33 (t, J=1.6, 1 H), 8.14 (dd, J=8.0, 1.6, 1 H), 7.78 (d, J=8.0, 1 H), 7.57 (t, J=8.0, 1 H), 6.94 (dd, J=10.8, 6.3, 1 H), 5.37 (s, 1 H), 4.16 (bs, 1 H), 2.17 (dd, J=7.0, 1.3, 3 H), 1.34 (s, 6 H).
3 mg (10%)
EXAMPLE 197 5,8-Difluoro-1,2-dihydro-6-(3-nitrophenyl)-2,2,4-trimethylquinoline (Compound 297, structure 83 of Scheme XXI, where R1 =R3-5 =R7 =R9 =H, R2 =nitro, R6 =R8 =fluoro) This compound was prepared by the same procedure as described in the synthesis of Compound 291 (EXAMPLE 191) from <strong>[112279-60-4]4-bromo-2,5-difluoroaniline</strong> (32 mg, 0.13 mmol) and 3-nitrobenzeneboronic acid (167 mg, 1.0 mmol) to afford 3 mg (10%) of Compound 297 as a colorless oil. Data for Compound 297: 1 H NMR (400 MHz, CDCl3) 8.33 (t, J=1.6, 1H), 8.14 (dd, J=8.0, 1.6, 1H), 7.78 (d, J=8.0, 1H), 7.57 (t, J=8.0, 1H), 6.94 (dd, J=10.8, 6.3, 1H), 5.37 (s, 1H), 4.16 (bs, 1H), 2.17 (dd, J=7.0, 1.3, 3H), 1.34 (s, 6H).
EXAMPLE 211 8-Chloro-1,2-dihydro-2,2,4-trimethyl-6-(3-nitrophenyl)quinoline (Compound 311, structure 83 of Scheme XXI, where R1 =R3-7 =R9 =H, R2 =nitro, R8 =chloro) 3-Chloro-4-amino-3'-nitrobiphenyl (structure 82 of Scheme XXI, where R1 =R3-7 =H, R2 =nitro, R8 =chloro). This compound was prepared by General Method 14 (EXAMPLE 191) from 3-nitrobenzeneboronic acid (0.25 g, 1.5 mmol), 4-bromo-2-chloroaniline (0.21 g, 1.0 mmol), and (PPh3)4 Pd (35 mg, 0.030 mmol) to afford a crude material which was used directly in the next step. 8-Chloro-1,2-dihydro-2,2,4-trimethyl-6-(3-nitrophenyl)quinoline (Compound 311, structure 83 of Scheme XXI, where R1 =R3-7 =R9 =H, R2 =nitro, R8 =chloro). This compound was prepared by General Method 8 (EXAMPLE 138) from the crude biphenyl amine obtained above to afford 2 mg (1%) of Compound 311 as an orange solid. Data for Compound 311: 1 H NMR (400 MHz, acetone-d6) 8.48 (d, J=2.0, 1H), 8.11 (dd, J=8.0, 2.0, 1H), 8.04 (dd, J=6.6, 1.6, 1H), 7.67 (t, J=8.0, 1H), 7.55 (d, J=2.0, 1H), 7.40 (d, J=2.0, 1H), 5.43 (s, 1H), 1.99 (s, 3H), 1.29 (s, 6H).
2 mg (1%)
EXAMPLE 211 8-Chloro-1,2-dihydro-2,2,4-trimethyl-6-(3-nitrophenyl)quinoline (Compound 311, structure 83 of Scheme XXI, where R1 =R3-7 =R9 =H, R2 =nitro, R8 =chloro) 3-Chloro-4-amino-3'-nitrobiphenyl (structure 82 of Scheme XXI, where R1 =R3-7 =H, R2 =nitro, R8 =chloro) This compound was prepared by General Method 14 (EXAMPLE 191) from 3-nitrobenzeneboronic acid (0.25 g, 1.5 mmol), 4-bromo-2-chloroaniline (0.21 g, 1.0 mmol), and (PPh3)4 Pd (35 mg, 0.030 mmol) to afford a crude material which was used directly in the next step. 8-Chloro-1,2-dihydro-2,2,4-trimethyl-6-(3-nitrophenyl)quinoline (Compound 311, structure 83 of Scheme XXI, where R1 =R3-7 =R9 =H, R2 =nitro, R8 =chloro) This compound was prepared by General Method 8 (EXAMPLE 138) from the crude biphenyl amine obtained above to afford 2 mg (1%) of Compound 311 as an orange solid. Data for Compound 311: 1 H NMR (400 MHz, acetone-d6) 8.48 (d, J=2.0, 1H), 8.11 (dd, J=8.0, 2.0, 1H), 8.04 (dd, J=6.6, 1.6, 1H), 7.67 (t, J=8.0, 1H), 7.55 (d, J=2.0, 1H), 7.40 (d, J=2.0, 1H), 5.43 (s, 1H), 1.99 (s, 3H), 1.29 (s, 6H).
3-Chloro4-amino-3'-nitrobiphenyl (Structure 82 of Scheme XXI, where R1 =R3-7 =H, R2 =nitro, R8 =chloro) This compound was prepared by General Method 14 (EXAMPLE 191) from 3-nitrobenzeneboronic acid (0.25 g, 1.5 mmol), 4-bromo-2-chloroaniline (0.21 g, 1.0 mmol), and (PPh3)4 Pd (35 mg, 0.030 mmol) to afford a crude material which was used directly in the next step.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 50℃; for 16h;
EXAMPLE 2 2,2,2-trifluoro-N-(pyrimidin-5-ylmethyl)-N-{3-[2- (trifluoromethyl)benzyl]phenyl} ethanesulfonamideA heterogeneous solution of l-(bromomethyl)-2-(trifluoromethyl)benzene (1.0 g, 4.2 mmol) and 3-nitrophenyl boronic acid (1.1 g, 6.3 mmol) in dimethoxyethane (38 mL) and 2M solution of sodium carbonate (12.7 mL, 25.5 mmol) was purged with nitrogen for 5 min. Palladium triphenylphosphine (155 mg, 0.13 mmol) was then added to the biphasic mixture. The reaction mixture was heated to 50 0C for 16hr, cooled to room temperature, and quenched by addition of water and ethyl acetate. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified via column chromatography on silica gel (eluting 15-80% ethyl acetate/hexanes) to give 1.16 g (98%) of l-(3-nitrobenzyl)-2-(trifluoromethyl)benzene as a clear, colorless oil. Hydrazine monohydrate (2 mL, 41.2 mmol) and a catalytic amount of palladium on carbon was added to a solution of l-(3-nitrobenzyl)-2-(trifluoromethyl)benzene (1.16 g, 4.1 mmol) in ethyl alcohol (200 mL) at ambient temperature. The resulting mixture was heated to reflux for 16 hr. The reaction was cooled to room EPO <DP n="20"/>temperature and filtered over Celite. The filtrate was concentrated in vacuo to give 0.95 g (92%) of 3-[2- (trifluoromethyl)benzyl]aniline.A solution of pyrimidine aldehyde (230 mg, 2.1 mmol) and 3-[2-(trifluoromethyl)benzyl]aniline (450 mg, 1.8 mmol) in methanol (4.5 mL) was refluxed for 2 hr. The resulting mixture was cooled to 00C and then allowed to warm back to room temperature after the addition of sodium borohydride (170 mg, 4.5 mmol). After stirring for an additional 16h at room temperature, the mixture was rotovapped in vacuo to remove volatile solvents. The residue was directly purifed by silica gel chromatography (eluting first with 20-100% ethyl acetate/hexanes followed by 0- 20% MeOH/dichloromethane) to give 141 mg of N-(pyrimidin-5-ylmethyl)-3-[2-(trifluoromethyl)- benzyl] aniline. A neat solution of 2,2,2-trifluoroethanesulfonyl chloride (64 uL, 0.58 mmol) was added dropwise to a solution of N-(pyrimidin-5-ylmethyl)-3-[2-(trifluoromethyl)benzyl]aniline (141 mg, 0.41 mmol) in dichloroethane (1.6 mL) and pyridine (0.8 mL) at 00C. The reaction mixture was allowed to gradually warm to room temperature and stirred at room temperature until TLC indicated completion of reaction. Volatile solvents were removed using a rotary evaporator. The residue was directly purified via column chromatography on silica gel (eluting with 0-100% ethyl acetate/dichloromethane) to give 2,2,2- trifluoro-N-(pyrimidin-5-ylmethyl)-N- {3-[2-(trifluoromethyl)benzyl]phenyl} ethanesulfonamide as solid. 1H NMR (CDCl3, 500MHz), delta 9.12 (s, IH), 8.55 (s, 2H), 7.70-7.68 (d, IH), 7.48-7.47 (m, IH), 7.39-7.29 (m, 3H), 7.18-7.17(d, IH), 7.12-7.09 (m, IH), 6.94 (s, IH), 4.85 (s, 2H), 4.16 (s, 2H), 3.82-3.77 (m, 2H). MS (ESI): 490 (M+ + H).
tetrakis(triphenylphosphine)palladium (0); In 1,2-dimethoxyethane; hexane;
Preparation 94 To a suspension of <strong>[89640-55-1]3-iodo-4-methoxypyridine</strong> (0.62g), 3-nitrophenylboronic acid (0.57g) and tetrakis(triphenylphosphine)palladium(0) (152mg) in dimetoxyethane (10ml) was added aqueous sodium carbonate (2M, 3.43ml) and the mixture was stirred at 60C for 6 hours. The mixture was diluted with ethyl acetate and washed with aqueous sodium hydroxide (1N) and brine. The separated organic layer was dried over magnesium sulfate and evaporated. The residue was purified with silica gel (25g) column chromatography and eluted with 40-80% ethyl acetate in n-hexane to give 3-(4-methoxypyridin-3-yl)nitrobenzene (84mg). APCI-mass;m/z231(M+H+) 1H-NMR(DMSO-d6): delta;3.90(3H,s), 7.24(1H,d,J=5.8Hz), 7.75(1H,t,J=8.0Hz), 8.00 (1H,d,J=8.0Hz), 8.24(1H,dt,J=8.2Hz,1.1Hz), 8.35(1H,t,J=1.0Hz), 8.48(1H,s), 8.53(1H, d,J=7.6Hz)
0.14 g of tetrakistriphenylphosphine palladium was added at room temperature to a solution having 0.9 g of 1-brom-2, 6-dichlorobenzene dissolved in 50 ml of toluene, followed by stirring for 10 minutes. 0.8 g of 3- nitrophenyl boronic acid, 5 ml of ethanol and 4.2 ml of a . 2M sodium carbonate aqueous solution were added thereto, and the reaction system was flushed with nitrogen, followed by stirring for 15 hours under reflux under heating. After cooling, the reaction solution was filtered through celite, followed by washing thoroughly with ethyl acetate from above. Cold water was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel (Silica gel 60N; spherical and neutral, manufactured. by Kanto Kagaku) column chromatography to obtain 0.98 g of 3- (2, 6- dichlorophenyl) nitrobenzene as an oily substrate. Further, NMR of this compound was as follows. 1H-NMR 5 (ppm) 7.30 (t, lH ; J =8. 1 Hz), 7.42 (d, 2H; J =8. 1 Hz), 7.61 (d, lH ; J =7.8 Hz), 7.65 (t, lH; J =7. 8 Hz), 8.18 (s, lH), 8. 29 (d, lH ; J =7.8 Hz)
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,2-dimethoxyethane; water; for 16h;Reflux; Inert atmosphere;
General procedure: To a mixture of aryl bromide or aryl iodide (1 eq), boronic acid (1.1 eq) in dimethoxyethane (0.1 M) was added 1M aqueous NaHCO3 solution (3 eq) followed by Pd(Ph3)4 (0.075 eq). The reaction mixture was refluxed overnight under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, washed with a saturated NaHCO3 solution and brine. The combined organic layers were dried over anhydrous Mg504 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (SiO2, ethyl acetate/hexanes) to give the desired product.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In Isopropyl acetate; toluene; at 90.0℃; for 16.0h;
<strong>[1152475-42-7]7-bromo-2-chlorothieno[3,2-d]pyrimidine</strong> (5, 0.8 g, 3.22 mmol) was taken up in a toluene (20 mL):IPA (3 mL) mixture along with 3-Nitro phenylboronic acid (0.646 g, 3.87 mmol), Pd(PPh3)4 (0.373g, 0.33 mmol), and 2 M Na2C03 (3.6 mL) to form a mixture. The mixture was heated at 90C overnight ( 16h). TLC of the reaction mixture showed complete conversion of compound 5 to compound 6. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with 10% aq. NaHC03 solution, dried over Na2S04 and concentrated. The concentrate was purified by column chromatography (Silica gel 20-30% ethyl acetate in hexane) to obtain a white solid of 2-chloro-7-(3-nitrophenyl)thieno[3,2-d]pyrimidine (6, 0.44 g, 46.9%). 'HNMR (CDC13): 9.23 (s, 1 H), 8.78 (s, 1 H), 8.42-8.40 (d, 1 H), 8.37 (s, 1H), 8.30-8.27 (d, 1H), 7.73-7.70 (t, 1 H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3h;Inert atmosphere;
A solution of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- fif]pyrimidine (15.0 g, 52.9 mmol) in N,N-dimethylformamide (200 mL) was added to Pd(dppf)Cl2 (2.2 g, 2.7 mmol), (3-nitrophenyl)boronic acid (13.3 g, 79.7 mmol) under nitrogen. A solution of sodium carbonate (6.00 g, 56.6 mmol) in water (60.0 mL) was then added and the reaction was stirred for 3 hours at 100 C. The resulting mixture was concentrated in vacuo, and the solids were filtered and extracted with dichloromethane (*3). The combined organic layers were washed with H20, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was then purified by chromatography using silica gel, eluting with 0-33% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford 4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-£ lpyrirnidine as a yellow solid. LRMS (ESI) calc'd for [M+H]+: 371, found 371.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In N,N-dimethyl-formamide; at 115℃; for 1.5h;Inert atmosphere;
To ethyl 4-chloro-7H-pyrrolo[2,3-if]pyrimidine-5-carboxylate (10.0 g, 44.3 mmol), (3-nitrophenyl)boronic acid (1 1.8 g, 70.9 mmol), PdCl2(dppf)-CH2Cl2 (3.62 g, 4.43 mmol) and aqueous sodium carbonate (2 M solution, 55.4 mL, 111 mmol) in a flask was added DMF (148 mL). The mixture was degassed for 10 minutes then heated at 1 15 C for 1.5 hours. The reaction was cooled to ambient temperature, then water was added and the mixture was extracted with DCM (*3) and EtOAc (*1). The combined organics were concentrated, diluted with EtOAc (300 mL) and washed with sorbitol/Na2C03 solution to remove excess boronic acid. The aqueous layer was extracted with EtOAc (x4). The combined organics were concentrated after which EtOAc and hexanes were added with stirring. The resulting precipitate was filtered to give solid product that was further triturated with DCM and hexanes to give ethyl 4-(3-nitrophenyl)-7H-pyrrolo[2,3- < ]pyrimidine-5-carboxylate. The combined organic fractions were concentrated under reduced pressure to give a residue containing product and DMF. Addition of MeOH and water led to formation of a precipitate which was filtered to afford additional ethyl 4-(3- nitrophenyl)-7H-pyrrolo[2,3-i ]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C,5Hi3N404 [M+H]+: 313, found 313. NMR (600 MHz, DMSO-D6) delta 13.17 (s, 1H), 8.99 (s, 1H), 8.43 (s, 1H), 8.39-8.36 (m, 2H), 8.12 (d, J= 7.8 Hz, 1H), 7.79 (t, J= 7.8 Hz, 1H), 3.93 (q, J= 7.2 Hz, 2H), 0.95 (t, J= 7.2 Hz, 3H).
With oxygen; sodium hydroxide; copper dichloride; In methanol; for 31h;Reflux;
General procedure: A mixture of 1.6 mmol of C-nitro-NH-azole (1a-e), 2.6 mmol of arylboronic acid (2a-n), 1.6 mmol of sodium hydroxide, 0.2 mmol of CuCl2 and methanol (15 mL) was refluxed while air was bubbled through the reaction mixture. After completion of the reaction, determined on the basis of TLC analysis, the solvent was removed under reduced pressure using a rotary evaporator. The obtained crude product was purified by silica gel column chromatography with 5:95 v/v MeOH/CHCl3 as an eluent to give corresponding N-aryl-C-nitroazole. The product was crystallized from methanol/water.
With tetrabutylammomium bromide; palladium diacetate; potassium carbonate; In water; at 70℃; for 3.33h;Inert atmosphere;
General procedure: Mixtures of the aryl bromides 24 or 30 (2.65mmol), the boronic acids 23a or 23b (2.23mmol), tetrabutylammonium bromide (796mg, 2.47mmol), and K2CO3 (2.9g, 21mmol) were suspended in distilled water (10mL) under argon for 20min. Then Pd(OAc)2 (9.2mg, 0.04mmol) was added, and the resulting suspensions were heated to 70C and stirred under argon for 3h. After cooling down, the solutions were diluted with distilled water (10mL) and extracted with CH2Cl2 (3×15mL). The combined organic layers were dried over Na2SO4 and the solvents were evaporated. The crude residues were further purified by silica gel column chromatography, eluting with hexane-ethyl acetate 8:2, to provide the products 25a-b or 25d.
1,3-diisopropyl-2-(3-nitrophenyl)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate monohydrate; palladium diacetate; In toluene; for 27h;Inert atmosphere; Reflux;
4.07 g (24.4 mmol) of 3-nitrobenzeneboronic acid, 5.0 g (20.7 mmol) of2-bromo-1,3-diisopropyl-benzene, 21.3 g (0.10 mol) of tripotassium phosphate, 248 mg (0.60 mmol) of 2-dicyclohexylphosphino-2? ,6? -dimethoxybiphenyl, and 45 mg (0.20 mmol) of palladium(ll) acetate are suspended in 50 ml of toluene, and three times evacuated and backfilled with argon. The beige suspension is heated under reflux during19 hours and 0.75 ml of water are added. Heating is continued under reflux during eight hours and the hot suspension filtered through a 3 cm layer of Hyflo filter aid followed by rinsing the filter aid with 200 ml of toluene. The filtrate is three times extracted with 200 ml of water, the organic phase dried over sodium sulfate, and concentrated under vacuum. The resulting solid is suspended in heptane, filtered and dried under vacuum, and furtherpurified by chromatography (silica gel, heptane/ethyl acetate 95:5), giving the title product as a light yellow solid (yield: 3.8 g (67%)).1HNMR (400 MHz, CDCI3): = 1.11 (d, 6 H), 1.13 (d, 6 H), 2.45-2.57 (m, 2 H), 7.27 (d, 2 H), 7.40-7.46 (m, I H), 7.53-7.58 (m, I H), 7.61-7.67 (m, I H), 8.09-8.13 (m, I H), 8.25-8.30 (m, I H).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; for 16h;Inert atmosphere; Reflux;
To a solution of 3-nitrophenylboronic acid 2 (5.19 g, 30 mmol), CS2CO3 (19.56 g, 60 mmol) and <strong>[40381-90-6]2,6-dichloronicotinonitrile</strong> 1 (5.51 g, 33 mmol) in dry 1,4-dioxane (100 mL) was added Pd(dppf)Cl2'DCM (2.4 g, 3.0 mmol) under nitrogen atmosphere, and the mixture was degassed with nitrogen 6 times, then refluxed for 16 h under nitrogen atmosphere. After cooling to room temperature, the solvent was evaporated and the residue was purified by flash chromatography, eluting with 20: 1 to 3: 1 PE/EA to afford the title compound as a yellow solid (1.6 g, 21%).
With potassium carbonate; In water; at 50℃; for 1.5h;
General procedure: In a test tube equipped with a magnetic stirrer bar, thearyl halide 1 (1 mmol) was mixed with phenyl boricacid 2 (1.2 mmol), K2CO3(2 mmol), and the Pd-catalyst(0.1mol% Pd) in 2 ml of H2Oin air. The reaction mixturewas then stirred at 50 C for appropriate time. After completionof the reaction, the catalyst was removed by magnetand washed with ethanol and water (3 × 5 ml). The aqueouslayer was extracted with chloroform, then organic layerdried over anhydrous MgSO4.The solvent was evaporatedunder reduced pressure to give the corresponding biarylcompounds. All the products were previously reported [5,8-12] and were confirmed by the spectroscopic methodusing 1H and 13C NMR (see supporting information).
93%
With 0.1 % Cu/C; potassium carbonate; In water; at 50℃; for 2.5h;Green chemistry;
General procedure: In a test tube, 1.0 mmol of aryl halides 1, 1.2 mmol of phenylboronic acid 2 were mixed together and then 2.0 mmol of K2CO3, and the Cu/Cnano-catalyst (0.1 mol % Cu) in 2 mL of H2O, were added in air. The reaction mixture was then stirred at 50 C for appropriate time. After completion of the reaction (monitored by TLC), the catalyst was removed by simple filtration. The recycled catalyst was was hed with ethanol and water (3 × 5 mL) and dried at 60 C in oven for further use. The aqueous layer was extracted with ethyl acetate, and organic layer dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure to give the corresponding biaryl compounds.
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,4-dioxane; at 95℃;Inert atmosphere;
A stirred solution of <strong>[3993-78-0]2-amino-4-chloropyrimidine</strong> (Intermediate 3, ALDRICH, 1.0 g, 7.75 mmol) and 3-nitrophenylboronic acid (ALDRICH, 1.2 g, 7.75 mmol) in 1,4-dioxane (50mL) and saturated NaHC03 (12.5mL) was degassed for 10 minutes with nitrogen. Pd(PPh3)4 (ALDRICH, 0.447 g, 0.38 mmol) was then added, and the reaction was heated at 95C overnight. The reaction was allowed to cool to room temperature and then poured onto water and EtOAc. The organic layer was separated, dried (Na2S04), filtered and evaporated under reduced pressure. Flash chromatography of the residue (SNAP 55 KP-NH, 100% DCM) afforded the title compound (1.5g, 93% yield) as a yellow solid. *H NMR (400 MHz, DMSO-d6): delta 8.92 (1H, m), 8.51 (1H, dt), 8.41 (1H, d), 8.36 (1H, ddd), 7.81 (1H, t), 7.29 (lH,d), 6.87 (2H, s,b). m/z= 217 (M+H)
methyl 5-bromo-1-(3-nitrophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
168 mg
With pyridine; copper diacetate; at 80℃; for 1h;
Methyl 5-bromo-6-oxo-1,6-dihydropyridine-3-carboxylate (450 mg)(3-nitrophenyl) boronic acid (400 mg),A mixture of copper (II) acetate (400 mg) and pyridine (10 ml)And the mixture was stirred at 80 C. for 1 hour. The mixture was cooled to room temperature and extracted with ethyl acetate and water. The obtained organic layer was washed with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (168 mg).
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In toluene; at 100℃; for 24h;Sealed tube; Inert atmosphere;
General procedure: 8-Bromo-5-nitroquinoline (45) (1 equiv.), corresponding boronic acid (1.5 equiv.), Pd(PPh3)4(0.06 equiv.) and Cs2CO3 (2 equiv.) weredissolved in dry toluene (1 mL for 1.0 mmol of 45). The reaction mixture was stirred in a sealed glass tube at 100C for 24 h under inert atmosphere. The mixture was then allowed to cool toroom temperature to which water (5 mL) was added and the product extracted intoEtOAc (3 10 mL). The combinedorganic layers were dried with Na2SO4, filtered and thesolvent was evaporated under reduced pressure. The products were purified byradial chromatography.
With potassium carbonate; hydrazine hydrate; In water; N,N-dimethyl-formamide; at 80℃; for 9h;
General procedure: Aryl halide (1.0 mmol), phenylboronic acid (1.1 mmol),K2CO3(2.0 mmol), Ni7-Pd3BIHPS (0.03 g) and H2O/DMF (2:1, 3 mL) were mixed and heated at 80 C for anappropriate time (monitored by TLC). Then, hydrazinehydrate (80 wt%, 6 eq) was added to the reaction vessel.After completion of the reduction process, the mixturewas filtered and washed with water. The organic layer wasextracted with ethyl acetate (3 × 15 mL) and dried overMgSO4.Then the organic solution was concentrated andpurified by column chromatography to obtain the finalproduct.
3-tert-butyl-3'-nitro-5-(3-nitrophenyl)-1,1'-biphenyl[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; toluene; at 20℃; for 5.5h;Inert atmosphere; Reflux;
Under nitrogen protection, 33.4 g (0.20 mol) of 3-nitrophenylboronic acid and 29.2 g (0.1 mol) of 3,5-dibromo-tert-butylThe benzene was added to a 1000 ml three-necked flask, and a mixture of 350 ml by volume of 2:1 toluene and ethylene glycol dimethyl ether was added.Solvent, 2.31 g (0.002 mol) of tetrakistriphenylphosphine palladium catalyst and 200 ml of sodium carbonate lye at a concentration of 1 mol / L, room temperatureAfter stirring for half an hour, the temperature was raised to reflux state for 5 hours, and after completion of the reaction, it was filtered, dried and further recrystallized to obtain a mediumThe interstitial compound 3,5-bis(3-nitrophenyl)-tert-butylbenzene has a yield of 91% (the mass of the intermediate compound actually obtained)Obtained from the ratio of the mass of the intermediate compound obtained theoretically).
methyl 4-[(3-nitrophenyl)methyl]-3-methoxybenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; for 24h;Microwave irradiation; Inert atmosphere; Sealed tube;
Cs2CO3 (2 eq.) was dissolved in H2O (2 mL/mmol halide) anddegassed. Halide (1 eq.), Pd(PPh3)4 (0.2 eq), and boronic acid (1 eq.)was added in that order to DME (4 mL/mmol of halide) in a microwavetube under argon gas. Cs2CO3/H2O was then added to thesolution. The microwave tube was then sealed and stirred at90-100 °C for 24 h. The organic layer was then extracted 3 H2O/DCM. The organic layer was then dried with Mg2SO4 and rotovapped.Product was purified by column chromatography. White solid; 51percent; 1H NMR (DMSO): delta 8.06 (tdd, J 3.6, 2.4, 1.1 Hz, 2H), 7.72-7.47(m, 4H), 7.38 (d, J 7.8 Hz, 1H), 4.12 (s, 2H), 3.85 (d, J 1.9 Hz, 6H);13C NMR (DMSO): delta 166.48, 157.38, 148.77, 142.78, 135.99, 134.08,131.00, 130.30, 130.04, 123.55, 122.20, 121.65, 111.45, 56.11, 52.63,35.11.
ethyl 1-methyl-5-(3-nitrophenyl)pyrazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃;
A solution of ethyl 5-bromo-l-methylpyrazole-4-carboxylate (1.0 g, 4.29 mmol), 3- nitrophenylboronic acid (859 mg, 5.15 mmol), sodium carbonate (909 mg, 8.58 mmol dissolved in 4.3 mL water), and bis(triphenylphosphine)palladium(II) dichloride (151 mg, 0.21 mmol) in DME (43 mL) was heated to 90 C overnight. After this time, General Work-up Procedure 1 was followed, and the crude residue was purified by Chromatography A to afford the title compound (710 mg, 60 % yield).
ethyl 2-(3-(3-nitrophenyl)oxetan-3-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; water; potassium hydroxide; In 1,4-dioxane; at 20℃; for 16h;
Aqueous KOH (133.0 mL, 0.20 mol) was added to a suspension of [Rh(COD)CI]2 (3.2 g, 6.5 mmol) in dioxane (100 ml) and the mixture was stirred for 30 min. Then 3-nitrophenylboronic acid (32.6 g, 0.20 mol) and <strong>[922500-91-2]ethyl 2-(oxetan-3-ylidene)acetate</strong> (WO2017107907) (18.6 g, 0.13 mol) in dioxane (40 mL) were added and The mixture was stirred at rt for 16 h under nitrogen. The reaction was quenched by the addition of HC1 (1 N) to pH = 6-7. Then General Work-up Procedure 1 was followed. The residue was purified by Chromatography A to afford the title compound (25.6 g, 74%) as a yellow solid.
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