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Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
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USD 80+
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Structure of 402-67-5 * Storage: {[proInfo.prStorage]}
* 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 caesium carbonate In 1-methyl-pyrrolidin-2-one at 100℃; for 17 h;
A mixture of 3-fluoronitrobenzene (1.0 g, 7.1 mmol), pyrazole (0.58 g, 8.5 mmol), and cesium carbonate (2.8 g, 8.5 mmol) in 4 mL of N-methylpyrrolidinone was heated to 100°C for 17 h. After cooling to rt, the mixture was diluted with water (75 mL) and extracted with ethyl acetate (3 x 75 mL) and the combined extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 1.7 g (71 percent) of 110A as a dark red oil. LCMS (M+H+) = 190.1. HPLC Ret. time: 2.42 min.
Reference：
[1] Patent: WO2003/90912, 2003, A1, . Location in patent: Page/Page column 85-86
[2] Australian Journal of Chemistry, 1993, vol. 46, # 4, p. 417 - 425
2
[ 110-85-0 ]
[ 402-67-5 ]
[ 54054-85-2 ]
Yield
Reaction Conditions
Operation in experiment
72%
With potassium carbonate In dimethyl sulfoxide at 100℃; for 24 h;
A mixture of piperazine (12 g, 138 mmol), 1-fluoro-3-nitrobenzene (4 ml, 34 mmol) and potassium carbonate (9.60 g, 69 mmol) in DMSO (40 mL) is heated at 100°C for 24 h. The reaction is quenched with H2O (60 mL) and extracted with Et2O (3 x 20 mL). The organic layer is washed with brine (20 mL) and dried over Na2SO4 and concentrated in vacuo. The residue is chromatographied on silica gel eluting with CH2Cl2/ MeOH (94 / 6) to yield the title compound (5.15 g, 72percent) as an orange solid. This solid was dissolved in CH2Cl2 and Boc2O (6 g, 130 mmol) was added. The mixture was stirred overnight. The solvent was evaporated and the residual solid was crystallized in heptane (6.80 g, 93percent, mp 86°C). 1H NMR (200 MHz, CDCl3) δ 1.49 (s, 9 H), 3.22-3.27 (m, 4 H), 3.58-3.63 (m, 4 H), 7.16-7.71 (m, 4 H).
71%
at 70℃; for 120 h;
A suspension of 3-fluoronitrobenzene (23 ml ; 0.21 mol) and piperazine (55.5 G ; 0.64 mol) in anhydrous NMP (30 ml) was heated to 70°C for five days. The cooled mixture was diluted with water (250 ML) and extracted with dichloromethane. The combined extracts were dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column-chromatography on silica gel eluting subsequently with mixtures of ethyl acetate and methanol (4: 1 v/v) and (1: 1 V/V) to leave the desired product as oily crystals (30. 7 G ; 71percent).
65%
at 100℃; for 60 h;
1-(3-nitrophenyl)piperazine 28.4 g (0.33 mol, 5.5 eq) of piperazine is dissolved in 50 ml of DMSO. 6.4 ml (60 mmol) of 2-fluoronitrobenzene is added. The mixture is heated at 100° C. for 60 hours. After cooling, the reaction mixture is transferred into 530 ml of water. The precipitate formed is filtered and the filtrate extracted with Et2O. After drying on MgSO4 and concentration under vacuum, the crude product is purified by column chromatography (eluent CH2Cl2/MeOH 9:1) to produce 8.04 g of the expected compound in the form of an orange oil which crystallizes at room temperature (yield: 65percent). C10H13N3O2 M=207.26 g/mol 1H NMR (CDCl3) δ (ppm): 7.70 (t, Jm=2 Hz, 1H, CH(2')); 7.64 (ddd, Jo=8 Hz, Jm=2 Hz, Jm=0.6 Hz, 1H, CH(4')); 7.36 (t, Jo=8 Hz, 1H, CH(5')), 7.17 (ddd, Jo=8 Hz, Jm=2 Hz, Jm=0.6 Hz, 1H, CH(6')); 3.30-3.18 (m, 4H, CH2(3), CH2(5)); 3.09-2.97 (m, 4H, CH2(2), CH2(6)),
65%
at 100℃; for 60 h;
EXAMPLE 1 1-(3-nitrophenyl)piperazine 28.4 g (0.33 mol, 5.5 eq) of piperazine were dissolved in 50 ml of DMSO, then 6.4 ml (60 mmol) of 3-fluoronitrobenzene were added. The mixture was heated at 100° C. for 60 h. After cooling, the reaction medium was poured in 530 ml of water. The resulting precipitate was filtered and the filtrate extracted with Et2O. After drying on MgSO4 and vacuum concentration, the crude product was purified by column chromatography (eluent: CH2Cl2/MeOH 9:1) to give 8.04 g of the expected compound in the form of an orange oil which crystallized at room temperature (yield: 65percent). 1H NMR (CDCl3) δ (ppm): 7.70 (t, Jm=2 Hz, 1H, CH(2')); 7.64 (ddd, Jo=8 Hz, Jm=2 Hz, Jm=0.6 Hz, 1H, CH(4')); 7.36 (t, Jo=8 Hz, 1H, CH(5')), 7.17 (ddd, Jo=8 Hz, Jm=2 Hz, Jm=0.6 Hz, 1H, CH(6')); 3.30-3.18 (m, 4H, CH2(3), CH2(5)); 3.09-2.97 (m, 4H, CH2(2), CH2(6)).
Reference：
[1] Journal of Organic Chemistry, 1990, vol. 55, # 17, p. 4979 - 4981
4
[ 402-67-5 ]
[ 403-19-0 ]
Reference：
[1] Journal of Organic Chemistry, 1998, vol. 63, # 13, p. 4199 - 4208
5
[ 402-67-5 ]
[ 1526-17-6 ]
[ 403-19-0 ]
Reference：
[1] Journal of Organic Chemistry, 1990, vol. 55, # 17, p. 4979 - 4981
6
[ 98-95-3 ]
[ 402-67-5 ]
[ 19064-24-5 ]
[ 350-46-9 ]
[ 1493-27-2 ]
Reference：
[1] Journal of Fluorine Chemistry, 1981, vol. 18, p. 363 - 374
[2] Journal of Fluorine Chemistry, 1981, vol. 18, p. 363 - 374
[3] Journal of Fluorine Chemistry, 1981, vol. 18, p. 363 - 374
7
[ 98-95-3 ]
[ 402-67-5 ]
[ 19064-24-5 ]
[ 446-35-5 ]
[ 2265-94-3 ]
[ 350-46-9 ]
[ 1493-27-2 ]
Reference：
[1] Journal of Fluorine Chemistry, 1981, vol. 18, p. 363 - 374
8
[ 98-95-3 ]
[ 402-67-5 ]
[ 446-35-5 ]
[ 350-46-9 ]
[ 1493-27-2 ]
Reference：
[1] Journal of Fluorine Chemistry, 1981, vol. 18, p. 363 - 374
9
[ 98-95-3 ]
[ 402-67-5 ]
[ 19064-24-5 ]
[ 446-35-5 ]
[ 2265-94-3 ]
[ 350-46-9 ]
[ 1493-27-2 ]
Reference：
[1] Journal of Fluorine Chemistry, 1981, vol. 18, p. 363 - 374
10
[ 402-67-5 ]
[ 364-78-3 ]
[ 17809-36-8 ]
[ 369-35-7 ]
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 2, p. 442 - 443
[2] Journal of Organic Chemistry, 1996, vol. 61, # 9, p. 2934 - 2935
[3] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 11, p. 1437 - 1444
11
[ 98-95-3 ]
[ 402-67-5 ]
[ 369-34-6 ]
[ 364-74-9 ]
[ 350-46-9 ]
[ 1493-27-2 ]
Yield
Reaction Conditions
Operation in experiment
0.05 mmol
at 0 - 25℃; Cooling with ice
General procedure: A FEP or PFA reactor equipped with a Teflon-lined magnetic stir bar and connected to a gas-washing bottle was charged with substituted benzene (0.95–1.10 mmol), 1,1,1,3,3-pentafluorobutane (1–2 mL per mmol of C6H5R), and BF3 · Et2O (1.3–1.5 mmol per mmol of C6H5R). The mixture was stirred for 10–15 min at 0–5°C (ice bath), and XeF2 (1.2–1.3 mmol per mmol of C6H5R) was added in portions. After addition of each portion, the mixture was stirred for 3–5 min at 22–25°C and cooled again. When the addition was complete the dark solution was stirred for 15–30 min at 22–25°C, 10percent aqueous KHCO3 was added, and the upper organic layer was separated, passed through a short column charged with silica gel (40–60 μm), and dried over MgSO4. The solution was analyzed by 19F NMR and GC/MS. The main products are given in table, and the others are listed below (GC/MS data).
Reference：
[1] Russian Journal of Organic Chemistry, 2016, vol. 52, # 10, p. 1400 - 1407[2] Zh. Org. Khim., 2016, vol. 52, # 10, p. 1412 - 1419,8
12
[ 402-67-5 ]
[ 21397-07-9 ]
Yield
Reaction Conditions
Operation in experiment
79.8%
With hexachloroethane; lithium tert-butoxide In N,N-dimethyl-formamide at 60℃; for 4 h; Inert atmosphere
A solution of 1-fluoro-3-nitrobenzene (1.41g, 10mmol), t-BuOLi (2.00g, 25mmol) and C2Cl6 (4.73g, 20 mmol) in 15ml dry DMF was stirred for 4h at 60°C under N2 atmosphere. Ethyl acetate was added and the resulting organic solution was washed by 1M HCl, saturated NaHCO3 and brine successively. The solvent was removed under reduced pressure and the residue was purified on column chromatography (eluted by 0.5percent ethyl acetate in petroleum ether) to obtain 6 as a colorless oil. Yield: 79.8percent, 1H NMR (400 MHz, CDCl3) δ 7.77–7.69 (m, 1H, Ph-H), 7.48–7.41 (m, 2H, Ph-H).
9.2%
With hydrogenchloride; N-chloro-succinimide In tetrahydrofuran; ethyl acetate
a 2-chloro-3-fluoronitrobenzene To a -78° C. solution of 3-fluoronitrobenzene (2 g, 14.2 mmol) in THF (30 mL) was added N-chlorosuccinimide (5.69 g, 42.6 mmol) in THF (20 mL), NaHMDS (1 M in THF, 28.4 mL, 28.4 mmol) was then added dropwise to maintain an internal temperature below -75° C. The resulting mixture was stirred for 30 min at -78° C. Then it was partitioned between 5percent of HCl and ethyl acetate. The combined organic layer is dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (20percent Ethyl acetate Hexane) gave the desired product(231 mg, 9.2percent). EI-MS m/z 176.5 (M+).
9.6%
With N-Bromosuccinimide In tetrahydrofuran; ethyl acetate
a 2-chloro-3-fluoronitrobenzene To a -78° C. solution of 3-fluoronitrobenzene (2 g, 14.2 mmol) in THF (30 mL) was added N-bromosuccinimide (7.58 g, 42.6 mmol) in THF (20 mL), NaHMDS (1 M in THF, 28.4 mL, 28.4 mmol) was then added dropwise to maintain an internal temperature below -75° C. The resulting mixture was stirred for 30 min at -784C. Then it was partitioned between 5percent of HCL and ethyl acetate.. The combined organic layer is dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (20percent Ethyl acetate/Hexane) gave the desired product (300 mg, 9.6percent). EI-MS m/z 221 (M+).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 15, p. 3365 - 3369
[2] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3416 - 3437
[3] Patent: US6500863, 2002, B1,
[4] Patent: US6500863, 2002, B1,
13
[ 402-67-5 ]
[ 59255-94-6 ]
Reference：
[1] Organic Letters, 2009, vol. 11, # 2, p. 421 - 423
[2] Journal of Organic Chemistry, 2009, vol. 74, # 21, p. 8309 - 8313
[3] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3416 - 3437
14
[ 402-67-5 ]
[ 364-53-4 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 982 - 994
[2] Tetrahedron Letters, 2000, vol. 41, # 22, p. 4277 - 4279
[3] Journal of the Chemical Society, 1953, p. 3042
15
[ 402-67-5 ]
[ 399-96-2 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1964, vol. 259, p. 3030 - 3032
[2] Bulletin de la Societe Chimique de France, 1966, p. 1848 - 1858
16
[ 402-67-5 ]
[ 18645-88-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 2, p. 588 - 597
17
[ 402-67-5 ]
[ 364-78-3 ]
[ 17809-36-8 ]
[ 369-35-7 ]
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 2, p. 442 - 443
[2] Journal of Organic Chemistry, 1996, vol. 61, # 9, p. 2934 - 2935
[3] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 11, p. 1437 - 1444
18
[ 402-67-5 ]
[ 17809-36-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 2015, vol. 58, # 2, p. 588 - 597
19
[ 402-67-5 ]
[ 369-35-7 ]
Reference：
[1] Journal of Organic Chemistry, 1998, vol. 63, # 15, p. 4878 - 4888
[2] Journal of Organic Chemistry, 1986, vol. 51, # 25, p. 5039 - 5040
[3] Journal of Heterocyclic Chemistry, 1994, vol. 31, # 6, p. 1513 - 1520
20
[ 402-67-5 ]
[ 364-78-3 ]
[ 17809-36-8 ]
[ 369-35-7 ]
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 2, p. 442 - 443
[2] Journal of Organic Chemistry, 1996, vol. 61, # 9, p. 2934 - 2935
[3] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 11, p. 1437 - 1444
21
[ 402-67-5 ]
[ 21397-08-0 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3416 - 3437
22
[ 402-67-5 ]
[ 27126-93-8 ]
[ 34470-17-2 ]
Reference：
[1] Journal of the American Chemical Society, 1986, vol. 108, # 18, p. 5453 - 5459
23
[ 402-67-5 ]
[ 111721-75-6 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3416 - 3437
24
[ 402-67-5 ]
[ 148546-99-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 26, p. 8261 - 8269
[2] Patent: WO2004/101533, 2004, A1, . Location in patent: Page 95
[3] Patent: WO2014/125410, 2014, A1,
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 12, p. 5099 - 5119
With palladium 10% on activated carbon; hydrazine hydrate monohydrate In ethanol at 20℃; for 12h; Schlenk technique;
2. The Typical Procedure for Pd/C Catalyzed Transfer Hydrogenation of Nitro Compounds.
General procedure: Procedure B: A mixture of nitro compounds 1 (0.50 mmol) and Pd/C (10 wt% palladium on activated carbon paste and 50 % moisture, 5 wt% wet Pd/C based on starting material 1) in EtOH (3 mL) was added into a Schlenk flask (25 mL) and stirred at room temperature. Followed by addition of H2NNH2·H2O (50 mg, 1.0 mmol, 2.0 equiv) and the mixture was stirred at room temperature until the reaction was finished. Then the solvent was evaporated under reduced pressure and the residue was purified by column chromatography.
99%
With hydrogen In ethanol; water monomer at 130℃; for 3h; Autoclave;
97%
With sodium tetrahydridoborate In water monomer at 25℃; for 1h; Sealed tube;
2.4.1 Conversion of nitroaromatic compounds into aromatic amines
General procedure: Nitrobenzene (1mmol, 123.1mg), NaBH4 (2mmol, 76mg), H2O(3mL) and catalyst (50mg) were added to the 50mL reaction tube. The reaction system was sealed at 25°C for 1h. The progress of the reaction was monitored by TLC (monitored by thin layer chromatography). After the reaction was completed, the catalyst was separated with an external magnet and washed with H2O and EtOH three times respectively. The reaction mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure on a rotary evaporator. The crude product is purified by column chromatography.
96%
With potassium fluoride; PMHS; palladium diacetate In tetrahydrofuran; water monomer at 20℃; for 0.5h;
96%
With potassium fluoride; PMHS In tetrahydrofuran at 20℃; for 0.5h;
94%
With 1,3-dimethyl-2-imidazolidinone; sodium trimethylsilanethiolate at 185℃; for 24h;
94.6%
With molybdenum(IV) oxide; hydrazine monohydrate; pyrographite In ethanol at 20℃; for 4.5h; Green chemistry;
7 Preparation of m-fluoroaniline
Example 7 Preparation of m-fluoroaniline 1.41 g (10 mmol) of m-nitrofluorobenzene, 25.6 mg (0.2 mmol) of MoO2, 76.8 mg of activated carbon and 30 mL of ethyl alcohol were added into a 50 ml flask. Then 1.92 g (20 mmol) of hydrazine hydrate (50%) was added dropwise at room temperature and reacted at room temperature for 4.5 hours until TLC analysis showed the raw materials were reacted completely and then filtered, concentrated filtrate, extracted with 20 mL of ethyl acetate and 10 mL of water, the obtained organic phase was washed and concentrated, finally, get 1.05 g of light yellow liquid, the molar yield was 94.6%, HPLC purity was 98.9%. 1HNMR data: 1HNMR (400 MHz, CDCl3) δ: 7.10-7.13 (m, 1H), 7.93-7.96 (m, 1H), 6.65-6.68 (m, 1H), 6.54-6.57 (m, 1H), 5.30 (s, 2H).
94.6%
With molybdenum(IV) oxide; pyrographite; hydrazine hydrate monohydrate In ethanol at 20℃; for 4.5h;
7 Example 7: Synthesis of m-fluoroaniline
A 50 ml three-necked flask was charged with 1.41 g (10 mmol) of m-fluoronitrobenzene, 25.6 mg (0.2 mmol) of molybdenum dioxide, 76.8 mg of activated carbon, and 30 ml of anhydrous ethanol, and hydrazine hydrate (50%) 1.92 g (20 mmol) was added dropwise at room temperature. After the dropwise addition to room temperature for 4.5 h, TLC monitoring showed that the reaction was completed, filtered, and the filtrate was concentrated, then ethyl acetate (20 mL) and water (10 ml) were added and extracted. The organic phase was washed with water and concentrated to give the object product, 1.05 g of pale yellow liquid, yield 94.6%, HPLC purity 98.9%.
93%
With hydrazine hydrate monohydrate In ethanol 1) 70 deg C, 1 h, 2) reflux, 8 h;
92%
With graphitic carbon nitride; hydrazine hydrate monohydrate In water monomer at 70℃; for 32h; Irradiation; Sealed tube; Green chemistry; chemoselective reaction;
88%
With sodium tetrahydridoborate; copper(II) oxide In water monomer at 30℃; for 1.6h;
With methanol; nickel Hydrogenation;
With methanol; platinum Hydrogenation;
With hydrogenchloride; stannous chloride
With hydrogenchloride; iron(0)
With sulfuric acid at 25℃; (electrochemical reduction);
With hydrogenchloride; stannous chloride In ethanol; water monomer at 30℃;
With hydrogenchloride; iron(0) In ethanol
With hydrogen In methanol at 20℃; for 0.5h; chemoselective reaction;
With palladium on activated charcoal; hydrogen In tetrahydrofuran
With hydrogen In methanol at 79.84℃; Autoclave;
98 %Chromat.
With formic acid In 1,4-dioxane; water monomer at 50℃; for 1.5h;
With hydrogen In methanol at 20℃; for 8h; Flow reactor;
2.15 mg
With hydrogenchloride; hydrogen; iron(0)
1.6
6) 3-fluoronitrobenzene 10 (2.8g, 1.3mol) was added to hydrogen and hydrogen chloride, and iron catalyst was added to reduce the reaction to yield 3-fluoroaminobenzene 11 (2.15g, 0.8mol);
With hydrogen In methanol at 110℃; for 3h; Autoclave;
With formic acid In ethanol; water monomer at 90℃; for 4h;
With 2C32H16O4(2-)*3Zn(2+)*2HO(1-)*3C5H11NO; hydrazine hydrate monohydrate In decane; ethanol for 5h; Irradiation; Green chemistry;
With hydrogen In ethanol at 90℃; for 1h; chemoselective reaction;
99 %Chromat.
With hydrazine monohydrate In ethanol at 75℃; for 3h; Inert atmosphere;
2.4. The process for the hydrogenation of nitroarenes
General procedure: To an 10 mL glass reactor was added 1 mmol of nitro compound, 0.1mmol of FeO(OH)/C nanoparticles, 2 mL of ethanol and 2 mmol of 80%N2H4.H2O at N2 atmosphere. Next, the reactant was stirred at 75 C forabout 2-12 h. After the reaction was finished, the catalyst was filteredoff and washed with dichloromethane or ethyl acetate, the solvents wereremoved in vacuo, and the target product was purified by columnchromatography or directly dried over in vacuo
With hydrazine monohydrate; FeMo1.1S3.2 In ethanol at 30℃; for 1.5h; Inert atmosphere; chemoselective reaction;
With 5% rhodium-on-charcoal; hydrazine hydrate In tetrahydrofuran at 0℃; for 1h; Inert atmosphere;
100%
With 5% rhodium-on-charcoal; hydrazine hydrate In tetrahydrofuran at 0℃; Inert atmosphere;
N-(3-fluorophenyl)hydroxylamine
Under N2 atmosphere, a suspension of 1-fluoro-3-nitrobenzene ( 1.00 g, 7.09 mmol, 1.00 equiv) and 5% Rh/C (50.0 mg, 0.30 mol%Rh) in THF (25.00 mli, 0.284 M) was cooled to 0 °C. Hydrazine monohydrate (0.390 g, 7.80 mmol, 1.10 equiv) was added dropwise. The reaction mixture stirred at 0°C for lh. The reaction mixture was filtered through a short pad of celite. The celite was washed with EtOAc and the combined organic layers wereconcentrated in vacuo to afford the title compound as a5 white solid (0.870g, 7.12mmol, quant yield). Rf= 0.28 (hexanes/EtOAc 4:1 (v/v)). XH NMR (400MHz, (CD3)2SO, δ) : 8.50 (s, 1H) , 8.45 (d, J= 2.1Hz, 1H) , 7.17-7.14 (m, 1H) , 6.61-6.58 (m, 2H) , 6.5O-6.48 (m, 1H) . 13C NMR (100MHz, (CD3)2SO, δ) : 163.0 (d, J= 238.8 Hz), 154.4 (d, J= 10.2 Hz), 130.0(d, J= 9.6 Hz), 108.7 (d, J= 2.3 Hz), 105. l(d, J= 21.4Hz), 99.3(d, J= 25.5Hz). 19F NMR (376 MHz, (CD3)2SO, 25°C, δ) : -117.3(s). Mass Spectrometry: HRMS (ESI-TOF) (m/z) : calcd for CeHiNOF ( [M + H] +) , 128.0512, found, 128.0513.
97%
With rhodium contaminated with carbon; hydrazine hydrate In tetrahydrofuran at 0℃; for 1h; Inert atmosphere;
With ammonium chloride; zinc
With sulfuric acid (electrochemical reduction);
With sulfuric acid at 15℃; (electrochemical reduction);
With ammonium chloride; zinc In ethanol; water at 65℃;
With rhodium contaminated with carbon; hydrazine In tetrahydrofuran at 0℃; for 3h; Inert atmosphere;
With 5% rhodium-on-charcoal; hydrazine hydrate In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
With rhodium on carbon; hydrazine hydrate In tetrahydrofuran at 0 - 23℃;
With 5% rhodium-on-charcoal; hydrazine hydrate In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
General procedure for the synthesis of protected N-aryl-N-hydroxylamines. General procedure A
General procedure: Under nitrogen atmosphere, a suspension of nitroarene S1 (1.00 eq.) and 5% Rh/C (0.30 mol% Rh) in THF (0.324 M) was cooled to 0 °C. Hydrazine monohydrate (1.20 eq.) was added dropwise. The reaction mixture was stirred at 0 °C for 1 hour and then slowly warmed up to r.t. and stirred at r.t. for 3 hours. The reaction mixture was filtered through a short pad of celite and concentrated in vacuo. Recrystallization from DCM/PE afforded the title compound S2. The resulting crude residue was used directly for the next step.
With ethanol; sodium hydroxide at 80℃; for 24h; chemoselective reaction;
65%
With 1,3-bis(N',N'-dimethyl-4-aminopyridinium)propane diiodide; sodium hydride In N,N-dimethyl-formamide; paraffin oil at 20℃; for 0.25h; Inert atmosphere;
58%
With cerium(IV) oxide; hydrogen In toluene at 90℃; chemoselective reaction;
With lithium aluminium tetrahydride; diethyl ether
Stage #1: 3-nitro-aniline With tetrafluoroboric acid; 1-ethyl-3-methylimidazolium tetrafluoroborate; sodium nitrite at 0 - 20℃; for 12.5h;
Stage #2: at 50℃;
93%
With pyridine hydrogenfluoride; sodium nitrite 1.) O deg C, 20 min, 2.) 120 deg C, 1 h;
34%
Stage #1: 3-nitro-aniline With hydrogenchloride; fluoroboric acid; sodium nitrite In water at 25℃; for 0.00555556h;
Stage #2: In 1,2-dichloro-benzene at 200℃; for 0.0166667h;
Typical continuous fluorodediazoniation procedure:
General procedure: 14 Typical continuous diazotization procedure: Material A (50 mL of aqueous solution containing amine (100 mmol), fluoroboric acid (120 mmol), hydrochloric acid (180 mmol)), and material B (50 mL of aqueous solution containing sodium nitrite (105 mmol)) were pumped into the T-joint at 4 mL/min, respectively, after a residence time of about 15 s at 25 °C in a reacting tube, the mixture flowed through the outlet and accumulated in the cooling vessel. Vigorous stirring was maintained. The solid was filtered with suction after the slurry was cooled to -5 °C. The solid was washed with methanol and then dried in vacuo to yield the corresponding diazonium tetrafluoroborate. 15 Typical continuous fluorodediazoniation procedure: Slurry of the diazonium tetrafluoroborate prepared as above in 300 mL of cosolvent was introduced into a reacting tube continuously at a flow rate of 4 mL/min. The mixture was maintained for 1 min at setting temperature and then cooled in the tandem tube. The collected liquid was washed with aqueous NaOH and water, nearly colorless liquid was obtained.
With potassium carbonate In dimethyl sulfoxide at 90℃; for 40h;
742 mg
In N,N-dimethyl-formamide at 100℃;
4-(4-Nitrophenyl)morpholine (S2)
1-Chloro-4-nitrobenzene (500 mg, 3.17 mmol) and K2CO3 (526 mg, 3.8 mmol, 1.2 equiv.) were added together with DMF (10 mL) and stirred at RT. Morpholine (440 µL, 5.1 mmol, 1.6 equiv.) was added to the reaction mixture which was heated at 100 °C overnight. After cooling down to RT, the mixture was extracted with EA. The EA layer was washed with DI-water three times and the combined water layers were back-extracted with EA three times. The combined EA extracts were dried (Na2SO4) and all solvent was evaporated under vacuum. The residue was purified by flash chromatography (elution system - EA : Hexane = 1 : 1 ) to give the title compound as a yellow solid (294 mg, 1.41 mmol). Rf = 0.35 (EA/Hexane = 1 : 1); 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 9.4 Hz, 2H), 6.84 (d, J = 9.4 Hz, 2H), 3.92 - 3.82 (m, 4H), 3.41 - 3.34 (m, 4H).
With potassium carbonate In dimethyl sulfoxide at 100℃; for 2h; Green chemistry;
Substrate preparation:
General procedure: A mixture of morpholine (2.62 g, 30mmol), potassium carbonate (4.14g, 30 mmol) and 4-fluoronitrobenzene(2.82 g, 20 mmol) in DMSO (10 mL) was stirred at 100 for 2h. After completion of thereaction, the mixture was allowed to cool to room temperature, and water (50 mL) was added. The solidswere collected by filtration, washed by water, and dried, 4.08g of 1a was obtained as a yellow solid (98%yield).
94%
With potassium carbonate In dimethyl sulfoxide at 90℃; for 24h;
94%
With potassium carbonate In dimethyl sulfoxide
2 4-(3-nitro-phenyl)-morpholine (27b)
To a mixture of 3-fluor nitro benzene 20b (425 mg, 3.01 MMOL) and K2CO3 (623 mg, 4.52 MMOL) in dimethyl sulfoxide (3 mL) was added morpholine (0.52 mL, 6.02 MMOL) and the reaction continued as described above to afford amine 589 mg of 27b in 94% YIELDS. H- NMR (300 MHz, CDC13) : 6 3.27 (4Hs, t, J = 4.83 Hz), 3.9 (4Hs, t, J = 4.95 Hz), 7.21 (1 H, ddd, J = 1. 03,2. 25,9. 06 Hz), 7.42 (1 H, t, J = 8. 19 Hz), 7.68-7. 76 (2Hs, m); ESI-MASS : 231.0 (M+23).
92%
In dimethyl sulfoxide at 110℃; for 36h;
97.A
A mixture of 3-fluoronitrobenzene (10.0 g, 71 mmol), morpholine (27 mL), and DMSO (118 mL) was stirred at 110°C for 36 h then cooled to rt and poured into 800 mL of water. The resulting mixture was stirred for 20 min and the solid was collected by vacuum filtration and dried in vacuo to afford 13.6 g (92%) of 97A as a bright yellow solid. ). LCMS (M+H+) = 209.1. HPLC Ret. time: 1. 48 min.
90%
In dimethyl sulfoxide at 100℃; for 60h;
80%
With potassium carbonate In dimethyl sulfoxide for 3h; Heating; Inert atmosphere;
79%
In dimethyl sulfoxide at 110℃; for 72h;
30.a
REFERENCE EXAMPLE 30; 4-(3-Aminophenyl)morpholine; a) 4-(3-Nitrophenyl)morpholine; To a solution of morpholine (6.8 mL, 77.9 mmol) in DMSO (25 mL), 1-fluoro-3- nitrobenzene (2.0 g, 14.2 mmol) was added and the mixture was heated at 110 0C for 48 h. Additional morpholine (3.4 mL, 38.9 mmol) was added and stirring at 110 0C was continued for another 24 h. The reaction mixture was then poured over water, and the precipitate thus obtained was filtered and dried in a vacuum oven to afford 2.35 g of the title compound (yield: 79%). LC-MS (method 1): tR = 7.18 min; m/z = 209.1 [M+H]+.
77%
In acetonitrile at 62℃; for 50h;
74%
In dimethyl sulfoxide at 100℃; for 18h;
63.6%
With potassium carbonate In dimethyl sulfoxide at 140℃; for 2h;
2.2 2. Synthesis of 4- (3-nitrophenyl) morpholine (Compound 6a)
A mixture of 3-fluoronitrobenzene (319.5 μL, 3.0 mmol), morpholine (528.0 μL, 6.0 mmol) and potassium carbonate (1.382 g, 10.0 mmol) dissolved in DMSO (3 mL) was stirred at 140 ° C. for 2 hours . The mixture was diluted with ethyl acetate, filtered and concentrated in vacuo. The thus-obtained crude product was purified by flash column chromatography (CHCl3) to obtain Compound 6a (397.3 mg, 1.908 mmol, 63.6%) as a yellow solid.
52%
In dimethyl sulfoxide at 110℃; for 6h;
45.5%
In dimethyl sulfoxide at 110℃; for 7h;
AA.1 Step 1: 4-(3-nitrophenyl)morpholine
A solution of l-fluoro-3-nitrobenzene (1.5 g, 0.0106 mol) and morpholine (4.6 g, 0.0530 mol) in DMSO (15 mL) was heated at 110°C for 7 h. After completion of starting materials, as evidenced by TLC, the mixture was quenched with ice and poured into ice cold water. The aqueous layer was extracted with ethyl acetate (3 x 250 mL). The organic layer was washed with water (3 x 100 mL), dried over Na2S04 and concentrated to obtain crude material which was filtered after trituration with pentane (10 mL) to obtain 4-(3- nitrophenyl)morpholine (1.0 g, 45.5%) as yellow solid. LCMS calculated for (M) 208.04 and found (M+H) 209.06, LCMS showed 99.42% purity
28%
In various solvent(s) at 180℃; for 5h; Irradiation;
In acetonitrile
R.18 4-(3-Nitro-phenyl)-morpholine.
4-(3-Nitro-phenyl)-morpholine. 3-Fluoronitrobenzene (10 g, 71 mmol) was dissolved in acetonitrile (100 mL). Morpholine (30 mL, 350 mmol) was added and the mixture was reacted 18 h at 150° C./80 psi in a pressure reactor. The reaction was cooled to room temperature, concentrated under vacuum and 5 g of the total mixture was purified by column chromatography on silica eluted with CH2Cl2. The product (3.6 g) was isolated as a bright yellow oil.
In acetonitrile
R.18 4-(3-Nitro-phenyl)-morpholine
4-(3-Nitro-phenyl)-morpholine 3-Fluoronitrobenzene (10 g, 71 mmol) was dissolved in acetonitrile (100 mL). Morpholine (30 mL, 350 mmol) was added and the mixture was reacted 18 h at 150° C./80 psi in a pressure reactor. The reaction was cooled to room temperature, concentrated under vacuum and 5 g of the total mixture was purified by column chromatography on silica eluted with CH2Cl2. The product (3.6 g) was isolated as a bright yellow oil.
With potassium carbonate In dimethyl sulfoxide
Scheme 2
4-(3-Nitro-phenyl)-morpholine (27b). To a mixture of 3-fluoro nitro benzene 20b (425 mg, 3.01 mmol) and K2CO3 (623 mg, 4.52 mmol) in dimethyl sulfoxide (3 mL) was added morpholine (0.52 mL, 6.02 mmol) and the reaction continued as described above to afford amine 589 mg of 27b in 94% yields. 1H-NMR (300 MHz, CDCl3): δ 3.27 (4Hs, t, J=4.83 Hz), 3.9 (4Hs, t, J=4.95 Hz), 7.21 (1H, ddd, J=1.03, 2.25, 9.06 Hz), 7.42 (1H, t, J=8.19 Hz), 7.68-7.76 (2Hs m); ESI-MASS: 231.0 (M+23).
In dimethyl sulfoxide at 110℃; for 60h;
2
3-Fluoronitrobenzene (lOg, 71mmol) was added to a solution of morpholine (34ml, 390mmol) in dimethylsulfoxide (120ml) and heated at 110°C for 60 hours. The reaction was cooled and poured onto water (800ml). The desired product precipitated and was collected by filtration. The orange solid was dried in vacuo and used in subsequent reactions without further purification (13. 7g, 66mmol). NMR: 8H [2H6]-DMSO 7.68 (1H, dd), 7.62 (1H, dd), 7.49 (1H, t), 7.42 (1H, dd), 3.76 (4H, dd), 3.24 (4H, dd) ppm.
In dimethyl sulfoxide at 110℃; for 60h;
7
3-Fluoronitrobenzene (lOg) was added to a solution of morpholine (34ml) in DMSO (120ml) and heated at 110°C for 60h. The reaction mixture was cooled and poured onto water (800ml). The precipitate was collected by filtration and the orange solid was dried under vacuum and used in subsequent reactions without further purification (13.7g). NMR: 8H [d6-DMSO] 7.68 (1H, dd), 7.62 (1H, dd), 7.49 (1H, t), 7.42 (1H, dd), 3.76 (4H, dd), 3.24 (4H, dd).
at 140℃; for 48h;
1
Step 1 A mixture of 1-Fluoro-3-nitrobenzene (3.0 g, 21 mmol) in morpholine (12.0 mL, 138 mmol) was heated to 140°C for 48 h. Upon cooling to room temperature, the mixture was concentrated under reduced pressure and purified by column chromatography on silica gel(hexanes/ethyl acetate, 0-100%) to afford 4-(3 -Nitrophenyl)morpholine.
at 140℃; for 48h;
1 Intermediate 4: Tert-butyl 8-morpholino-5H-benzo[blpyrido[2,3-el[ 1 ,4"|diazepine- 11 (6H)- carboxylate Step 1:
A mixture of l-Fluoro-3 -nitrobenzene (3.0 g, 21 mmol) in morpholine (12.0 mL, 138 mmol) was heated to 140 °C for 48 h. Upon cooling to room temperature, the mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (hexanes/ethyl acetate, 0-100%) to afford 4-(3-Nitrophenyl)morpholine.
8.25 g
for 12h; Inert atmosphere; Reflux;
2 (1-2) Synthesis Example 2 (Synthesis of Squarylium Compound 2)
7.06 g (0.050 mol) of 3-fluoronitrobenzene and 13.07 g (0.150 mol) of morpholine were charged into a 200 mL two-necked flask, and while stirring with a magnetic stirrer under nitrogen flow (5 mL / min) , And reacted under reflux for 12 hours. After completion of the reaction, the reaction solution was cooled to room temperature, then the reaction solution was added to ion exchanged water, and the extraction operation was carried out with ethyl acetate. The obtained organic phase was concentrated with an evaporator, and the concentrate was purified by column chromatography on silica gel (developing solvent: ethyl acetate)8.25 g of Intermediate 2-1 (1- (3-nitrophenyl) morpholine) was obtained. The yield based on 3-fluoronitrobenzene was 79.2 mol%. 8.25 g (0.040 mol) of Intermediate 2-1, 40.91 g (0.181 mol) of tin chloride.dihydrate and 204 g of concentrated hydrochloric acid were placed in a 200 mL two-necked flask, and under nitrogen flow (5 mL / min), while stirring with a magnetic stirrer, the temperature in the flask was maintained at 100 ° C. and the reaction was carried out for 30 minutes. After completion of the reaction, the reaction solution was cooled to room temperature and filtered to obtain white crystals. The obtained crystals were added to a 20 mass% sodium hydroxide aqueous solution for neutralization, and then ethyl acetate was added to carry out the extraction operation. The obtained organic phase was concentrated with an evaporator, and the concentrate was purified by column chromatography on silica gel (developing solvent: ethyl acetate) to give Intermediate 2-2 (1- (3-aminophenyl) morpholine). 2.28 g was obtained.The yield based on the intermediate 2-1 was 32.3 mol%. Then, in a 200 mL two-necked flask, 1.38 g (0.008 mol) of Intermediate 2-2, 3.19 g (0.015 mol) of trifluoroacetic anhydride, 1.74 g (0.017 mol) of triethylamine, 40 g And the mixture was allowed to react at room temperature for 12 hours while stirring with a magnetic stirrer under nitrogen flow (5 mL / min). After completion of the reaction, the reaction solution was added to ion-exchanged water and extraction operation was performed with ethyl acetate. The obtained organic phase was concentrated with an evaporator, and the concentrate was purified by column chromatography on silica gel (eluent: ethyl acetate) to give Intermediate 2-3 (2,2,2-trifluoro-N- ( 3-morpholinophenyl) acetamide) was obtained. The yield based on the intermediate 2-2 was 96.0 mol%. Subsequently, 2.0 g (0.007 mol) of Intermediate 2-3, 0.43 g (0.004 mol) of squaric acid, 23 g of 1-butanol and 23 g of toluene were added to a 300 mL three-necked flask, and under nitrogen flow / Min), the mixture was stirred using a magnetic stirrer, and reacted under reflux for 3 hours while removing water eluted using a Dean-Stark apparatus. After completion of the reaction, the reaction solution was concentrated with an evaporator, the solvent was distilled off, 50 g of methanol was added thereto for crystallization. Precipitated crystals were obtained by filtration, and the obtained crystals were rinsed with methanol to obtain a wet cake. This wet cake was dried at 60 ° C. for 12 hours using a vacuum dryer to obtain 0.64 g of squarylium compound 2 shown in Table 1. The yield based on squaric acid was 23.7 mol%
In dimethyl sulfoxide
a a.
a. Meta-morpholino nitrobenzene Using 1-fluoro-3-nitrobenzene (10 g, 0.07M) and morpholine (33.5 g, 0.38M) in DMSO (116 ml) is prepared using the method described by Brown G. R. et al., Tet. Lett. 40 (1999) 1219-1222. Filtration of the precipitated product yields the product; mp 113.8-115.5° C.
2.6 g
With potassium carbonate In dimethyl sulfoxide at 90℃; for 24h;
With potassium carbonate In dimethyl sulfoxide at 90℃; for 24h;
93%
With potassium carbonate In dimethyl sulfoxide
Scheme 2
1-Methyl-4-(3-nitro-phenyl)-piperazine (28b). To a mixture of 3-fluoro nitro benzene 20b (425 mg, 3.01 mmol) and K2CO3 (623 mg, 4.52 mmol) in dimethyl sulfoxide (3 mL) was added 1-methyl piperazine (0.66 mL, 6.02 mmol) and the reaction continued as described above to afford 619 mg of amine 28b in 93% yields. 1H-NMR (300 MHz, CDCl3): δ 2.38 (3Hs, s), 2.6 (4Hs, t, J=5.0 Hz), 3.32 (4Hs, t, J=5.14 Hz), 7.2 (1H, dd, J=2.16, 8.26 Hz), 7.39 (1H, t, J=8.14 Hz), 7.67 (1H, dd, J=1.43, 8.01 Hz); ESI-MASS: 222.4 (M+1).
93%
With potassium carbonate In dimethyl sulfoxide
2 1-methyl-4-(3-nitro-phenyl)-piperazine (28b)
To a mixture of 3-fluoro nitro benzene 20b (425 mg, 3.01 MMOL) and K2CO3 (623 mg, 4.52 MMOL) in dimethyl sulfoxide (3 mL) was added 1-methyl piperazine (0.66 mL, 6.02 MMOL) and the reaction continued as described above to afford 619 mg of amine 28b in 93% YIELDS. 1H-NMR (300 MHz, CDCI3) : J 2. 38 (3Hs, s), 2.6 (4Hs, t, J = 5.0 Hz), 3.32 (4Hs, t, J = 5.14 Hz), 7.2 (1H, dd, J = 2.16, 8. 26 Hz), 7.39 (1H, t, J = 8. 14 Hz), 7.67 (1 H, dd, J = 1.43, 8.01 Hz); ESI-MASS : 222.4 (M+1).
88%
In dimethyl sulfoxide at 100℃; for 60h;
59%
at 130℃; for 72h;
108.A
A mixture of 3-fluoronitrobenzene (1.0 g, 7.1 mmol) and 1-methylpiperizine (5 mL) was heated to 130°C for 3 days. After cooling to rt, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (4 x 40 mL). Concentration of the combined extracts yielded a dark red oil which was dissolved in dichloromethane (75 mL) and washed with 1 N aqueous HC1 (3 x 25 mL). The combined acidic aqueous extracts were neutralized to pH-7 by addition of 3 N aqueous potassium hydroxide solution and extracted with dichloromethane (3 x 40 mL). The combined extracts were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 0.92 g (59%) of 108A as a dark brown oil. LCMS (M+H+) = 222.1. HPLC Ret. time: 0.97 min.
48%
With potassium carbonate In dimethyl sulfoxide at 122℃; for 12h;
41%
With potassium carbonate In dimethyl sulfoxide at 100℃; for 20h;
IV.i Example-IV: Synthesis of 5-( 1 -(4-(tert-butyl)benzoyl)- 1 H-indol-4-yl)- 1 -methyl-3 -((3-(4-methyl piperazin- 1 -yl) phenyl) amino) pyrazin-2( 1 H)-one (Compound-32):
Step-(i): Synthesis of 1 -methyl-4-(3-nitrophenyl)piperazine:To a stirred solution of 3-fluoro nitrobenzene (25 g, 177.3 mmol) in DMSO (125 mL) was added K2C03 (36.67 g, 265.7 mmol) followed by N-Methyl piperizine (26.5 g, 265.9 mmol) at ambient temperature. The reaction mixture was stirred at 100°C for 20h. The reaction mixture was quenched with water, extracted with CHC13, the combined organic phases were washed withbrine dried over sodium sulphate and concentrated. The obtained crude product was purified by colunm chromatography using 100-200 mesh silica gel and 4% MeOH in DCM as eluent to give the titled product as a white solid (15 g, 4 1%); MS (ES) mlz 222 (M+1).
With potassium carbonate In N,N-dimethyl-formamide
With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 24h;
250
l-MethyI-4-(3-nitrophenyl)-piperazineN02; [715] A mixture of 1 -fluoro-3-nitrobenzene (282mg, 2.00mmol), 1 -methyl-piperazine (401mg, 4.00mmol), potassium carbonate (276mg, 2.00mmol), and DMF (3mL)was stirred and heated at 110°C for 24h. After cooling to rt, the mixture was poured intobrine (lOmL) and extracted with EtOAc (3 x lOmL). The combined organic extracts wereextracted with aqueous HC1 (1 N, 2 x 20mL). The acidic extracts were basified by aqueousNaOH until pH>10. The basified aqueous solution was extracted with EtOAc (2 x 30mL).The extracts were then washed with H2O (3 x 20mL) and brine (20mL), dried over MgSO4,filtered and concentrated in vacua to give the title compound as yellow oil. 'H NMR(CD3OD, 400 MHz): 8 = 2.22 (s, 3 H), 2.48 (t, 4 H, J= 5.0 Hz), 3.16 (t, 4 H, J= 5.2 Hz), 7.16- 7.18 (m, 1 H), 7.27 (t, 1 H, J= 8.2 Hz), 7.46 - 7.49 (m, 1 H), 7.57 (t, 1 H, J= 2.2 Hz). MS(ES+): m/z 222.26 (100) [MH+]. HPLC: fo = 1.55 min (ZQ2000, polar_5 min).
With potassium carbonate In dimethyl sulfoxide at 122℃; for 24h;
37.A
A. 3-(4-Methyl-piperazin-1-yl)-phenylamine To a suspension of 1-fluoro-3-nitrobenzene (3.77 mL, 35.4 mmol) and potassium carbonate (10 g, 71 mmol) in DMSO (30 mL) was added 1-methyl piperazine (59 mL, 53.2 mmol). The mixture was stirred at 122° C. for 24 hours. After cooing down, the mixture was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were washed with brine, dried with sodium sulfate (Na2SO4), and concentrated in vacuo to afford an orange oil. Recrystallization from EtOAc/hexanes gave 4.2 g of 1-(4-methyl-piperazin-1-yl)-3-nitrobenzene, which was reduced via hydrogenation to give the title compound (beige solid, 3 g). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.04 (t, J=8.0 Hz, 1H), 6.38 (dd, J=2.3, 8.2 Hz, 1H), 6.26 (t, J=2.2 Hz, 1H), 6.22 (dd, J=2.3, 8.2 Hz, 1H), 3.60 (br, 2H), 3.18 (t, J=4.9 Hz, 4H), 2.55 (t, J=4.9 Hz, 4H), 2.34 (s, 3H).
With triethylamine In N,N-dimethyl-formamide at 20℃; for 24h;
General procedure for the synthesis of compound 4a-4b
General procedure: To a stirring solution of 4-fluoronitrobenzene (1.41g, 10mmol) in anhydrous DMF (25mL) were added 1-methylpiperazine (1.01g, 10.00mmol) and triethylamine (1.01g, 10mmol). Reaction was stirred at r.t. for 24h. Upon completion, the residue was taken up in ice water (60mL). The pH was adjusted to 8 with saturated sodium carbonate solution, and the aqueous phase was extracted with ethyl acetate (40mL×3). The combined organic phase was washed twice with saturated brine (30mL×2) and dried over anhydrous MgSO4. After filtering out MgSO4, the solvent of filtrate was removed in vacuo and the residue was purified by silica gel column chromatography (PE : EA=1 : 1) to afford compound 4a as an orange solid.
With caesium carbonate In 1-methyl-pyrrolidin-2-one at 100℃; for 17h;
110.A
A mixture of 3-fluoronitrobenzene (1.0 g, 7.1 mmol), pyrazole (0.58 g, 8.5 mmol), and cesium carbonate (2.8 g, 8.5 mmol) in 4 mL of N-methylpyrrolidinone was heated to 100°C for 17 h. After cooling to rt, the mixture was diluted with water (75 mL) and extracted with ethyl acetate (3 x 75 mL) and the combined extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 1.7 g (71 %) of 110A as a dark red oil. LCMS (M+H+) = 190.1. HPLC Ret. time: 2.42 min.
29%
With potassium carbonate In dimethyl sulfoxide for 8h;
With potassium carbonate In dimethyl sulfoxide at 105 - 110℃; for 25.5h;
24%
With potassium carbonate In dimethyl sulfoxide for 8h;
With potassium carbonate In dimethyl sulfoxide at 130℃; for 5h;
18.1
[0431] Experimental Details: A solution of 10 g (70.92mmol) of 3-fluoro- nitrobenzene, leq imidazole and 2eq K2CO3 in 100ml of DMSO was heated at 130°C for 5 hours. The reaction was monitored by LC-MS. Then 50OmL of water was added and the precipitate was filtered and the solid was washed with water and dried to afford compound 2 without further purification.
With potassium carbonate In dimethyl sulfoxide at 130℃; for 5h;
16.1
Example 16 Experimental Details: A solution of 10 g (70.92 mmol) of 3-fluoro-nitrobenzene, 1 eq imidazole and 2 eq K2CO3 in 100 ml of DMSO was heated at 130° C. for 5 hours. The reaction was monitored by LC-MS. Then 500 mL of water was added and the precipitate was filtered and the solid was washed with water and dried to afford compound 2 without further purification.
To a mixture of 3-fluoro nitro benzene 20b (425 mg, 3.01 MMOL) and K2CO3 (623 mg, 4.52 MMOL) in dimethyl sulfoxide (3 mL) was added 1-benzyl piperazine (1.04 mL, 6.02 MMOL) and the reaction continued as described above to afford amine 805 mg of 29b in 90% YIELDS. H-NMR (300 MHz, CDCl3) : (52. 64 (4Hs, t, J = 5.0 Hz), 3.31 (4Hs, t, J = 5.14 Hz), 3.6 (2Hs, s), 7.18 (1H, dd, J = 1.95, 8. 33 Hz), 7.26-7. 42 (6Hs, m), 7.66 (1H, ddd, J = 0.63, 2.02, 8.0 Hz), 7.72 (1H, t, J = 2.32 Hz); ESt-MASS : 298. 1 (M+1).
With potassium carbonate; In methanol; chloroform; dimethyl sulfoxide;
EXAMPLE I 1-Benzyl-4-(3-nitrophenyl)-piperazine A mixture of <strong>[2759-28-6]1-benzylpiperazine</strong> (8.8 g, 50 mmol), 1-fluoro-3-nitrobenzene (5.3 g, 37.5 mmol) and potassium carbonate (13.8 g, 0.1 mol) in dimethyl sulfoxide (50 mL) was stirred at 100 C. for 24 hrs. The reaction mixture was cooled to room temperature, poured into ice water (150 mL) and extracted with diethyl ether (3*50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum. Purification by chromatography (240 g. silica gel, 2% methanol in chloroform) afforded 5.4 g (48%) as an orange oil, which was analyzed using NMR (CDCl3) spectroscopy; the resulting NMR spectrum contained the following peaks: delta2.61 (4H, t), delta3.27 (4H, t), delta3.56 (2H, s), delta7.15 (1H, ddd), delta7.24-7.37 (6H, m), delta7.62 (1H, ddd), delta7.68 (1H, t), confirming the presence of 1-benzyl-4-(3-nitrophenyl)-piperazine.
With potassium carbonate; In dimethyl sulfoxide;
1-Benzyl-4-(3-nitro-phenyl)-piperazine (29b). To a mixture of 3-fluoro nitro benzene 20b (425 mg, 3.01 mmol) and K2CO3 (623 mg, 4.52 mmol) in dimethyl sulfoxide (3 mL) was added 1-benzyl piperazine (1.04 mL, 6.02 mmol) and the reaction continued as described above to afford amine 805 mg of 29b in 90% yields. 1H-NMR (300 MHz, CDCl3): delta 2.64 (4Hs, t, J=5.0 Hz), 3.31 (4Hs, t, J=5.14 Hz), 3.6 (2Hs, s), 7.18 (1H, dd, J=1.95, 8.33 Hz), 7.26-7.42 (6Hs, m), 7.66 (1H, ddd, J=0.63, 2.02, 8.0 Hz), 7.72 (1H, t, J=2.32 Hz); ESI-MASS: 298.1(M+1).
With potassium carbonate In dimethyl sulfoxide at 100℃; for 24h;
2-1; 3.1
A mixture of piperazine (12 g, 138 mmol), 1-fluoro-3-nitrobenzene (4 ml, 34 mmol) and potassium carbonate (9.60 g, 69 mmol) in DMSO (40 mL) is heated at 100°C for 24 h. The reaction is quenched with H2O (60 mL) and extracted with Et2O (3 x 20 mL). The organic layer is washed with brine (20 mL) and dried over Na2SO4 and concentrated in vacuo. The residue is chromatographied on silica gel eluting with CH2Cl2/ MeOH (94 / 6) to yield the title compound (5.15 g, 72%) as an orange solid. This solid was dissolved in CH2Cl2 and Boc2O (6 g, 130 mmol) was added. The mixture was stirred overnight. The solvent was evaporated and the residual solid was crystallized in heptane (6.80 g, 93%, mp 86°C). 1H NMR (200 MHz, CDCl3) δ 1.49 (s, 9 H), 3.22-3.27 (m, 4 H), 3.58-3.63 (m, 4 H), 7.16-7.71 (m, 4 H).
71%
In methanol; ethyl acetate
6.b Example 6b
Example 6b 1-(3-Nitrophenyl)-piperazine. A suspension of 3-fluoronitrobenzene (23 ml; 0.21 mol) and piperazine (55.5 g; 0.64 mol) in anhydrous NMP (30 ml) was heated to 70° C. for five days. The cooled mixture was diluted with water (250 ml) and extracted with dichloromethane. The combined extracts were dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column-chromatography on silica gel eluding subsequently with mixtures of ethyl acetate and methanol (4:1 v/v) and (1:1 v/v) to leave the desired product as oily crystals (30.7 g; 71%).
71%
In 1-methyl-pyrrolidin-2-one at 70℃; for 120h;
1.A 1-(3-nitrophenyl)-piperazine;
A suspension of 3-fluoronitrobenzene (23 ml ; 0.21 mol) and piperazine (55.5 G ; 0.64 mol) in anhydrous NMP (30 ml) was heated to 70°C for five days. The cooled mixture was diluted with water (250 ML) and extracted with dichloromethane. The combined extracts were dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column-chromatography on silica gel eluting subsequently with mixtures of ethyl acetate and methanol (4: 1 v/v) and (1: 1 V/V) to leave the desired product as oily crystals (30. 7 G ; 71%).
65%
In dimethyl sulfoxide at 100℃; for 60h;
17 1-(3-nitrophenyl)piperazine
1-(3-nitrophenyl)piperazine 28.4 g (0.33 mol, 5.5 eq) of piperazine is dissolved in 50 ml of DMSO. 6.4 ml (60 mmol) of 2-fluoronitrobenzene is added. The mixture is heated at 100° C. for 60 hours. After cooling, the reaction mixture is transferred into 530 ml of water. The precipitate formed is filtered and the filtrate extracted with Et2O. After drying on MgSO4 and concentration under vacuum, the crude product is purified by column chromatography (eluent CH2Cl2/MeOH 9:1) to produce 8.04 g of the expected compound in the form of an orange oil which crystallizes at room temperature (yield: 65%). C10H13N3O2 M=207.26 g/mol 1H NMR (CDCl3) δ (ppm): 7.70 (t, Jm=2 Hz, 1H, CH(2')); 7.64 (ddd, Jo=8 Hz, Jm=2 Hz, Jm=0.6 Hz, 1H, CH(4')); 7.36 (t, Jo=8 Hz, 1H, CH(5')), 7.17 (ddd, Jo=8 Hz, Jm=2 Hz, Jm=0.6 Hz, 1H, CH(6')); 3.30-3.18 (m, 4H, CH2(3), CH2(5)); 3.09-2.97 (m, 4H, CH2(2), CH2(6)),
65%
In dimethyl sulfoxide at 100℃; for 60h;
1 1-(3-nitrophenyl)piperazine
EXAMPLE 1 1-(3-nitrophenyl)piperazine 28.4 g (0.33 mol, 5.5 eq) of piperazine were dissolved in 50 ml of DMSO, then 6.4 ml (60 mmol) of 3-fluoronitrobenzene were added. The mixture was heated at 100° C. for 60 h. After cooling, the reaction medium was poured in 530 ml of water. The resulting precipitate was filtered and the filtrate extracted with Et2O. After drying on MgSO4 and vacuum concentration, the crude product was purified by column chromatography (eluent: CH2Cl2/MeOH 9:1) to give 8.04 g of the expected compound in the form of an orange oil which crystallized at room temperature (yield: 65%). 1H NMR (CDCl3) δ (ppm): 7.70 (t, Jm=2 Hz, 1H, CH(2')); 7.64 (ddd, Jo=8 Hz, Jm=2 Hz, Jm=0.6 Hz, 1H, CH(4')); 7.36 (t, Jo=8 Hz, 1H, CH(5')), 7.17 (ddd, Jo=8 Hz, Jm=2 Hz, Jm=0.6 Hz, 1H, CH(6')); 3.30-3.18 (m, 4H, CH2(3), CH2(5)); 3.09-2.97 (m, 4H, CH2(2), CH2(6)).
In dimethyl sulfoxide at 100℃;
In 1,2-dimethoxyethane for 48h; Heating / reflux;
A suspension of 1-fluoro-3- nitrobenzene (54ml, O.?Omol) and piperazine (129g, 1.5mol) in dimethoxyethane (100ml) was stirred at reflux under nitrogen for two days. After cooling, the solvent was removed in vacuo and the residue was partitioned between water (600ml) and ethyl acetate (two times 400ml). The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The filtrate was diluted with ethyl acetate to a final volume of 1500ml and 1-(3-nitrophenyl)-piperazine, hydro chloride precipitated upon addition of ethanolic hydrogen chloride (170ml, 3M). The precipitate was filtered off, washed with ethyl acetate and dried in the air to yield 103.3g (85%).
With potassium carbonate In N,N-dimethyl-formamide at 130℃; for 48h; Inert atmosphere;
37.1 Step 1: 3-(3-Nitrophenoxy)pwidine (37.3)
[00495] K2CO3 (1.96 g, 14.17 mmol) and intermediate 37.2 (0.76 mL, 7.09 mmol) were sequentially added to a stirred solution of intermediate 37.1 (674 mg, 7.09 mmol) in dry DMF (10 mL) maintained under N2 atmosphere, and stirring was continued at 130 °C for 48 h. The mixture was poured into H2O (150 mL) and extracted with CH2CI2 (3 x 30 mL). The combined organic layers were washed with H2O (80 mL) and brine (500 mL), dried over anhydrous Na2SC>4, and evaporated to dryness. After purification by flash chromatography (PET/EtOAc, from 100% PET to 1:1 v/v PET/EtOAc) the desired intermediate 37.3 (805 mg, 3.72 mmol) was obtained as a brown oil. Yield: 53%. MS-ESI(+) m/z: 217.0 (M+H).
With potassium carbonate In N,N-dimethyl-formamide at 80 - 150℃;
With copper(l) iodide; caesium carbonate; potassium iodide In N,N-dimethyl-formamide at 90℃;
15.a Step a:
To a solution of l-fluoro-3 -nitrobenzene (1.41 g, 10 mmol), pyridin-4-ol (950 mg 10 mmol), CS2CO3 (6.5 g, 20mmol) in DMF (20 mL) was added KI (1.6 g ,10 mmol) and Cul (190 mg, 1 mmol). The mixture was stirred at 90 °C overnight. The reaction was filtered, poured into water (100 mL), and extracted using EA (3 x 100 mL). The organic layers were combined, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 10:1) to Compound 15-1 (2 g, 92%).
22%
With potassium carbonate In N,N-dimethyl-formamide at 125℃; for 18h; Inert atmosphere;
52.1 Step 1: 4-(3-Nitrophenoxy)pwidine (52.2)
[00551] A mixture of intermediate 47.1 (1.00 g, 7.09 mmol), intermediate 52.1 (0.67 g, 7.09 mmol), and K2CO3 (1.96 g, 14.17 mmol) in DMF (7 mL) was stirred at 125 °C for 18 h. Once cooled to r.t., the reaction was poured into EtOAc (40 mL), washed with H2O (2 x 30 mL), brine (30 mL), dried over Na2S04, and concentrated under reduced pressure. After chromatographic purification (PET/EtOAc from 90:10 to 50:50, v/v), intermediate 52.2 was obtained in 22% yield as yellow solid. [00552] MS-ESI(+) m/z: 217.3 (M+H).
With potassium carbonate In N,N-dimethyl-formamide at 80 - 150℃;
[0250] The title compound was obtained by the method used in the preparation of 3- {2- [5-CYCLOHEXYL-L- (3, 3-DIMETHYL-2-OXO-BUTYL)-2-OXO-1, 2-DIHYDRO-3H-1, 3,4-benzotriazepin-3-yl]- acetylamino}-benzoic acid methyl ester (Example 1) except that 3-MORPHOLIN-4-YL-PHENYLAMINE (prepared in two steps from 3-FLUORO-1-NITROBENZENE) was used instead of 3-amino-benzoic acid methyl ester in step E. 1H NMR (CDC13) 8.22 (1H, br s), 7.50-7. 44 (2H, m), 7.29-7. 12 (3H, m), 7.03 (1H, d, 8.1), 6.75 (1H, d, 8.1), 6.63-6. 60 (1H, m), 4.77 (1H, d, 17.7), 4.65 (1H, d, 17.7), 4.34 (1H, d, 16.8), 4.19 (1H, d, 16.8), 3. 84 (4H, t, 4.8), 3.15 (4H, t, 4.8), 2.82-2. 75 (1H, m), 2.05- 1.74 (6H, m), 1.36-1. 24 (13H, m). Found: C 68.18, H 7.42, N 12.29% ; C32H4LNS04*0. 3H20 requires: C 68.10, H 7.42, N 12.41%.
[0256] The title compound was obtained by the method used in the preparation of 3- {2- [5-CYCLOHEXYL-1- (3, 3-dimethyl-2-oxo-butyl) -2-oxo-1, 2-dihydro-3H-1, 3,4-benzotriazepin-3-yl]- acetylamino}-benzoic acid methyl ester (Example 1), except that 3- (4-METHYL-PIPERAZIN-1-YL)- phenylamine (prepared in two steps from 3-fluoro-1-nitrobenzene) was used instead of 3-amino- benzoic acid methyl ester in step E. 1H NMR (CDC13) 8.17 (1H, br s), 7.50-7. 44 (2H, M), 7.29- 7.27 (1H, M), 7.16-7. 09 (2H, M), 7.04 (1H, d, 8. 1), 6. 78-6. 75 (1H, M), 6.64-6. 61 (1H, M), 4.76- 4.60 (2H, M), 4.36-4. 12 (2H, M), 3.21-3. 18 (4H, M), 2.82-2. 74 (1H, M), 2.57-2. 54 (4H, M), 2.35 (3H, s), 2.04-1. 60 (6H, M), 1.45-1. 23 (13H, M). Found: C 68. 32, H 7.55, N 14.16% ; C33H44N603O0. 5H2O requires: C 68. 19, H 7.79, N 14.46%.
1-(3-nitrophenyl)piperazine monohydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: piperazine; 3-fluoro-1-nitrobenzene In 1,2-dimethoxyethane for 48h; Heating / reflux;
Stage #2: With hydrogenchloride In ethanol; ethyl acetate
A suspension of 1-fluoro-3-nitrobenzene (54 ml, 0.50 mol) and piperazine (129 g, 1.5 mol) in dimethoxyethane (100 ml) was stirred at reflux under nitrogen for two days. After cooling, the solvent was removed in vacuo and the residue was partitioned between water (600 ml) and ethyl acetate (two times 400 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The filtrate was diluted with ethyl acetate to a final volume of 1500 ml and 1-(3-nitrophenyl)-piperazine, hydro chloride precipitated upon addition of ethanolic hydrogen chloride (170 ml, 3M). The precipitate was filtered off, washed with ethyl acetate and dried in the air to yield 103.3 g (85%).
With hydrogenchloride In water; dimethyl sulfoxide; ethyl acetate at 100℃; for 18h;
13 Preparation of 1-(3-nitrophenyl)piperazine hydrochloride
Reference Example 13 Preparation of 1-(3-nitrophenyl)piperazine hydrochloride: A solution of 3-fluoronitrobenzene (250 g) and piperazine (900 g) in dimethylsulfoxide (1.5 L) is stirred at 100°C for 18 hours.. The reaction solution is diluted with water and ethyl acetate, and the organic layer is successively washed with water and saturated brine, and a 4M solution of hydrogen chloride in ethyl acetate is added to the organic layer.. The resulting precipitates are collected by filtration to give the title compound (408 g).
Stage #1: piperazine; 3-fluoro-1-nitrobenzene In dimethyl sulfoxide at 100℃;
Stage #2: With hydrogenchloride In ethyl acetate
With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1.25h;
26.1 STEP 1. PREPARATION OF 1-TERT-BUTHYLY(2-FLUORO-4-NITROPHENYL)-1, 4-PIPERIDINEDICARBOXYLATE
To a solution OF N-BOC-PIPERIDINE-4-CARBOXYLIC acid ethyl ester (2.0 g, 8.3 mmol) in 100 mL THF AT-78°C was added LDA (5.0 INL of 2M in THF, 10 mmol) over 15 minutes. The solution was stirred AT-78°C for another 15 minutes, followed by addition of a solution of 1-fluoro-3- nitrobenzene (1.2 g, 8.2 mmol) in 20 ML THF over 15 minutes. The solution was stirred AT-78°C for 30 minutes, and then the flask was immersed in an ice-water bath and slowly warmed to rt overnight, followed by treatment of saturated NH4CL at 0°C. The mixture was extracted by ethyl acetate (3x). The extracts were combined, washed with water and brine, dried over MGS04, and concentrated in vacuo. The residue was purified by column chromatography (85% HEXANE/15% EtOAc) to yield the desired product (1.5 g. 48%). LC-MS M+H 383.
With hexachloroethane; lithium tert-butoxide; In N,N-dimethyl-formamide; at 60.0℃; for 4.0h;Inert atmosphere;
A solution of 1-fluoro-3-nitrobenzene (1.41g, 10mmol), t-BuOLi (2.00g, 25mmol) and C2Cl6 (4.73g, 20 mmol) in 15ml dry DMF was stirred for 4h at 60C under N2 atmosphere. Ethyl acetate was added and the resulting organic solution was washed by 1M HCl, saturated NaHCO3 and brine successively. The solvent was removed under reduced pressure and the residue was purified on column chromatography (eluted by 0.5% ethyl acetate in petroleum ether) to obtain 6 as a colorless oil. Yield: 79.8%, 1H NMR (400 MHz, CDCl3) delta 7.77-7.69 (m, 1H, Ph-H), 7.48-7.41 (m, 2H, Ph-H).
9.2%
With hydrogenchloride; N-chloro-succinimide; In tetrahydrofuran; ethyl acetate;
a 2-chloro-3-fluoronitrobenzene To a -78 C. solution of 3-fluoronitrobenzene (2 g, 14.2 mmol) in THF (30 mL) was added N-chlorosuccinimide (5.69 g, 42.6 mmol) in THF (20 mL), NaHMDS (1 M in THF, 28.4 mL, 28.4 mmol) was then added dropwise to maintain an internal temperature below -75 C. The resulting mixture was stirred for 30 min at -78 C. Then it was partitioned between 5% of HCl and ethyl acetate. The combined organic layer is dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (20% Ethyl acetate Hexane) gave the desired product(231 mg, 9.2%). EI-MS m/z 176.5 (M+).
9.6%
With N-Bromosuccinimide; In tetrahydrofuran; ethyl acetate;
a 2-chloro-3-fluoronitrobenzene To a -78 C. solution of 3-fluoronitrobenzene (2 g, 14.2 mmol) in THF (30 mL) was added N-bromosuccinimide (7.58 g, 42.6 mmol) in THF (20 mL), NaHMDS (1 M in THF, 28.4 mL, 28.4 mmol) was then added dropwise to maintain an internal temperature below -75 C. The resulting mixture was stirred for 30 min at -784C. Then it was partitioned between 5% of HCL and ethyl acetate.. The combined organic layer is dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (20% Ethyl acetate/Hexane) gave the desired product (300 mg, 9.6%). EI-MS m/z 221 (M+).
4-Nitro-1-(3-nitrophenyl)benzimidazole was prepared analogueously to 3 g from <strong>[10597-52-1]4-nitrobenzimidazole</strong> and 1-fluoro-3-nitrobenzene. Mp 260-262 C. 1-(3-Aminophenyl)-<strong>[10597-52-1]4-nitrobenzimidazole</strong> was prepared from 4-nitro-1-(3-nitrophenyl)benzimidazole as described in Example 3a. Mp 159-161 C.
Stage #1: 1H-imidazole With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 1h;
Stage #2: 3-fluoro-1-nitrobenzene In N,N-dimethyl-formamide at 100℃;
21
To a solution of sodium hydride (1.42 g, 35.3 mmol) in N,N-dimethylformamide (20 mL) was added dropwise a solution of imidazole (2.00 g, 29.4 mmol) in N,N-dimethylformamide (10 mL) at 00C, and the mixture was stirred at room temperature for 1 hr. l-Fluoro-3-nitrobenzene (4.15 g, 29.4 mmol) was added to the reaction mixture and the mixture was stirred at 1000C. The reaction mixture was diluted with water, and extracted with ethyl, acetate (χ3) . The organic layer was washed with saturated brine, dried over anhydrous magnesium, sulfate, and filtrated. The filtrate was concentrated under reduced pressure,, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50) to give the title compound (3.05 g, 55%) as a yellow solid.1H-NMR (DMSO-d6, 300 MHz) δ 7.14 (IH, s) , 7.79 (IH, t, J = 8.4 Hz), 7.94 (IH, s), 8.13 - 8.19 (2H, m) , 8..45 (IH, s) , 8.48 (IH, t,- J = 2.1 Hz) .
Stage #1: Methyl imidazole-4-carboxylate With sodium hydride In methanol
Stage #2: 3-fluoro-1-nitrobenzene In methanol at 150℃; for 16h;
1
1H- lmidazole-4-carboxylic acid methyl ester (1 g, 7.9 mmol) was dissolved in MeOH and NaH (348 mg, 8.7 mmol) was added slowly. When the gas evolution had ceased 1-fluoro-3-nitro benzene (926 uL, 8.7 mmol) was added, and the mixture was heated to 1500C under N2 for 16 h. After cooling to room temperature the precipitation was isolated by suction filtration, washed with MeOH, and dried under vacuum to afford 1.3 g (67%) of 1. HRMS (ESI+): m/z=247.2091 [M+H]
67%
Stage #1: Methyl imidazole-4-carboxylate With sodium hydride In methanol
Stage #2: 3-fluoro-1-nitrobenzene In methanol at 150℃; for 16h;
7
[1-(3-Nitro-phenyl)-1 H-imidazole-4-carboxylic acid methyl ester] (20)1/-/-lmidazole-4-carboxylic acid methyl ester (1 g, 7.9 mmol) was dissolved in MeOH and NaH (348 mg, 8.7 mmol) was added slowly. When the gas evolution had ceased 1-fluoro-3-nitro benzene (926 uL, 8.7 mmol) was added, and the mixture was heated to 5 1500C under N2 for 16 h. After cooling to room temperature the precipitation was isolated by suction filtration, washed with MeOH, and dried under vacuum to afford 1.3 g (67%) of 20. HRMS (ESI+): m/z=247.2091 [M+H]
General procedure: A mixture ofdifferent fluoro substituted 2-nitrobenzoate (1.5 mmol) and various amines (7.5 mmol) in DMF (3 mL) was stirred atroom temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine. After dried by sodium sulfate and concentration, the residue was purified by chromatography on silica gel to give as yellowish solid.
54%
for 48h;Reflux;
A mixture of 1-ethylpiperazine (3.23 g, 0.0283 mol) and l -fluoro-3 -nitrobenzene (2.0 g, 0.0142 mol) was heated at reflux for 2 days. The resulting mixture was cooled and concentrated in vacuo. The residue was poured into water (50 mL), extracted with EA (2*50 mL). The combined extracts were washed with brine, concentrated in vacuo. The residue was purified via ISCO (eluted with EA in PE 0 - 70%) to give a yellow solid (1.80 g, 54.0% yield). MS (m/z): 236.1 (M+H)+.(B) 3-(4-ethylpiperazin-l-yl)aniline A mixture of l-ethyl-4-(3-nitrophenyl)piperazine (1.8 g, 0.00765 mol) and Rany-Ni (1.0 g) in MeOH (20 mL) was stirred under 1 atm of H2 at room temperature for 6 h. The resulting mixture was filtered and the filtrate was concentrated in vacuo to give a grey slurry (1.5 g, 95.5% yield). MS (m/z): 206.2 (M+H)+.
54%
for 48h;Reflux;
A mixture of 1-ethylpiperazine (3.23 g, 0.0283 mol) and l-fluoro-3 -nitrobenzene (2.0 g, 0.0142 mol) was heated at reflux for 2 days. The resulting mixture was cooled and concentrated in vacuo. The residue was poured into water (50 mL), extracted with EA (2*50 mL). The combined extracts were washed with brine, concentrated in vacuo. The residue was purified via ISCO (eluted with EA in PE 0 - 70%) to give a yellow solid (1.80 g, 54.0% yield). MS (m/z): 236.1 (M+H)+.
for 117h;Heating / reflux;
1-Ethyl-4-(3-nitro-phenyl)-piperazineA mixture of 1-fiuoro-3-nitrobenzene (3.2 mL, 29.7 mmol) and N-ethyl-piperazine (7.6 mL, 59.4 mmol, 2 equiv) is heated to reflux and stirred for 117h. The reaction mixture is allowed to cool to RT and diluted with H2O (40 mL) and DCM/MeOH (9:1 , 80 mL). The aqueous layer is separated and extracted with DCM/MeOH (9:1). The organic phase is washed with <n="73"/>brine, dried (Na2SO4), filtered and concentrated. Purification of the crude product by silica gel column chromatography (DCM/MeOH, 1 :0 ? 95:5) affords the title compound as a brown oil: ESI-MS: 236.0 [MH]+; tR= 2.49 min (purity: 99%, system 1 ); TLC: R, - 0.26 (DCM/MeOH, 95:5).
With potassium carbonate; In N,N-dimethyl-formamide; at 185℃; for 78h;
1.0 ml (9.4 mmol) 3-fluoronitrobenzene, 2 g (14.1 mmol) potassium carbonate and 1.2 ml (9.4 mmol) <strong>[5308-25-8]N-ethylpiperazin</strong>e in 20 ml DMF were refluxed for 48 h at 185 C. Then another 1.2 ml (9.4 mmol) <strong>[5308-25-8]N-ethylpiperazin</strong>e was added and the mixture was refluxed for a further 30 h. Then the carbonate was filtered off and the filtrate was evaporated down. The residue was purified by preparative HPLC (method 10).C12H17N3O2 (235.28)[M+H]+=236analytical HPLC (method 3): retention time=0.77 min
for 117h;Reflux;
A mixture of 2-fluoro-4-nitrobenzene (3.2 mL, 29.7 mmol) and 1-ethylpiperazine (7.6 mL, 59.4 mmol, 2 equiv) was heated to reflux for 1 17 h. After cooling to rt, the reaction mixture was diluted with H2O and DCM/MeOH, 9:1. The aqueous layer was separated and extracted with DCM/MeOH, 9:1. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH, 1 :0 ? 95:5) afforded 6 g of the title compound as a brown oil: ESI-MS: 236.0 [M+H]+; tR= 2.49 min (System 1 ); TLC: Rf = 0.26 (DCM/MeOH, 95:5).
Stage #1: 3-HYDROXYPYRIDINE With sodium hydride In dimethyl sulfoxide at 20℃; for 0.5h;
Stage #2: 3-fluoro-1-nitrobenzene In dimethyl sulfoxide at 80℃; for 72h;
A9
To a solution of 3-hydroxypyridine (5.01 g, 52.7 mmol) in DMSO (60 mL) was added NaH (1.39 g, 57.9 mmol, 2.31 g of 60% suspended in oil) and stirred for 30 min at RT. To the slurry was added l-fluoro-3- nitrobenzene (9.66 g, 68.5 mmol) and mixture was heated to 80 °C for 72h. The mixture was poured into satd NH4Cl solution (200 mL), and extracted with EtOAc (3x125 mL). The combined organic extracts were washed with H2O (75 mL), brine, dried (Na2SO4) and concentrated to yield a crude residue which was purified by column chromatography afford (4.43 g, 39% yield) pure 3-(3-nitrophenoxy)pyridine as a syrup.
With potassium carbonate In dimethyl sulfoxide at 140℃; for 192h;
C-14
C-14) tert. Butyl (R)-3-(3-aminophenylamino)-pyrrolidine-l -carboxylate1.15 g (6.17 mmol, 1 eq) tert. butyl (R)-3-amino-pyrrolidine-l -carboxylate are dissolved in 5.8 mL DMSO and then 20 g (145 mmol, 23.4 eq) potassium carbonate are added. Then 657 μL (6.17 mmol, 1 eq) 4-fluoronitrobenzene are added dropwise. The reaction mixture is stirred for 8 days at 1400C, while potassium carbonate is added from time to time (total 20 g). It is thawed to RT and the reaction mixture is finally poured into 150 mL water and extracted 3 times with 50 mL EE. The combined organic phases are washed with saturated aqueous sodium chloride solution, dried and all the volatile constituents are eliminated in vacuo. 2.2 g (4.2 mmol, 68 %) tert. butyl (R)-3-(3-nitro-phenylamino)-pyrrolidine-l- carboxylate are obtained. MS-ESI+: 252 (M+H)+
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 50℃; for 5h; Inert atmosphere;
47.1 Step 1: 4-(3-Nitrophenoxy)tetrahydro-2H-pyran (47.3)
[00534] A mixture of intermediate 47.1 (1.00 mL, 9.39 mmol) and intermediate 47.2 (1.16 mL, 12.20 mmol) in DMF (10 mL) was treated with NaH 60% in mineral oil (0.75 g, 18.78 mmol) at 50 °C for 5 h. Once cooled to r.t. the reaction was poured into EtOAc (30 mL), washed with H2O (30 mL), brine (20 mL), dried over Na2S04, and concentrated under reduced pressure. After chromatographic purification (PET/EtOAc from 90:10 to 65:35, v/v), 545 mg of intermediate 47.3 were obtained. Yield: 26% [00535] MS-ESI(-) m/z: 222.1 (M-H)
With potassium carbonate In N,N-dimethyl-formamide at 90 - 140℃; for 22h;
16
Reference Example 16; 2-methyl-5- (3-nitrophenoxy) pyridine; A mixture of 6-methylpyridin-3-ol (17.6 g, 161 mmol) , 1- fluoro-3-nitrobenzene (25.0 g, 177 mmol), potassium carbonate(66.8 g, 483 mmol) and N,N-dimethylformamide (200 mL) was stirred at 9O0C for 13 hr, 1200C for 5 hr and 1400C for 4 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (x3) . The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was dried to give the title compound (28.6 g, 77%) as a yellow oil. 1H-NMR (DMSO-de, 300 MHz) δ 2.50 (3H, s) , 7.35 (IH, d, J = 8.4 Hz), 7.48 - 7.55 (2H, m) , 7.65 - 7.72 (2H, m) , 7.97 - 8.01 (IH, m) , 8.35 (IH, d, J = 3.0 Hz) .
With potassium carbonate In N,N-dimethyl-formamide at 150℃; for 15h;
5.53 N-[6-(3-Nitrophenoxy)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (32)
A mixture of 31 (3.54g, 15.1mmol), 1-fluoro-3-nitrobenzene (2.24g, 15.9mmol), potassium carbonate (6.26g, 45.3mmol), and DMF (30mL) was stirred at 150°C for 15h. The mixture was diluted with water and extracted with AcOEt. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residual solid was collected and washed with AcOEt-hexane to give 32 (1.82g, 37%) as a white solid: 1H NMR (DMSO-d6) δ 0.95-0.99 (4H, m), 1.96-2.05 (1H, m), 7.24 (1H, dd, J=8.7, 2.7Hz), 7.47-7.51 (1H, m), 7.63-7.70 (2H, m), 7.78-7.83 (2H, m), 7.94-7.99 (1H, m), 12.67 (1H, s).
37%
With potassium carbonate In N,N-dimethyl-formamide at 150℃; for 15h;
97-1
Example 97-1; N- [6- (3-nitrophenoxy) -1, 3-benzothiazol-2- yl] cyclopropanecarboxamide; A mixture of N- (6-hydroxy-l, 3-benzothiazol-2- yl) cyclopropanecarboxamide (3.54 g, 15.1 mmol), l-fluoro-3- nitrobenzene (2.24 g, 15.9 mmol), potassium carbonate (6.26 g, 45.3 mmol) and N,N-dimethylformamide (30 mL) was stirred at 1500C for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (1.82 g, 37%) as a white solid. 1H-NMR (DMSO-de, 300 MHz) δ 0.95 - 0.99 (4H, m) , 1.96 - 2.05 (IH, m), 7.24 (IH, dd, J = 8.7, 2.7 Hz), 7.47 - 7.51 (IH, m) , 7.63 - 7.70 (2H, m), 7.78 - 7.83 (2H, m) , 7.94 - 7.99 (IH, m) , 12.67 (IH, s).
36%
With 18-crown-6 ether; potassium carbonate In N,N-dimethyl-formamide at 150℃; for 14h;
A1.vi
(vi) Production of N-[6-(3-nitrophenoxy)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide; To a suspension of N-(6-hydroxy-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (1.53 g, 6.53 mmol) and potassium carbonate (3.72 g, 26.9 mmol) in N,N-dimethylformamide (50 mL) were added 1-fluoro-3-nitrobenzene (1.08 g, 7.65 mmol) and 18-crown-6 (1.07 g, 4.05 mmol), and the mixture was stirred at 150°C for 14 hr. The reaction mixture was cooled to room temperature, and added to a mixed solvent (1:1, 300 mL) of ethyl acetate and hexane. The mixture was washed with water (200 mL) and saturated brine (200 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was collected by filtration, and the residue was subjected to silica gel column chromatography using ethyl acetate and hexane (1:1) as an eluent to give the title compound (840 mg, 36%) as a pale-yellow solid. 1H-NMR (DMSO-d6, 300 MHz) δ 0.95-1.01 (4H, m), 1.97-2.09 (1H, m), 7.02 (1H, dd, J = 2.4, 8.4 Hz), 7.50 (1H, ddd, J = 0.9, 2.4, 8.4 Hz), 7.65-7.71 (2H, m), 7.79-7.83 (2H, m), 7.98 (1H, ddd, J = 0.9, 2.4, 8.4 Hz), 12.65 (1H, br s).
With potassium carbonate; In dimethyl sulfoxide; at 150℃; for 3h;
3-fluoronitrobenzene (2.00 g, 14.2 mmol) was dissolved in dimethylsulfoxide (15 ml). <strong>[35794-11-7]3,5-dimethylpiperidine</strong> (3.21 g, 28.4 mmol) and potassium carbonate (3.92 g, 28.4 mmol) were added thereto and the mixture was stirred for 3 hours at 150 C. The reactant was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulphate anhydrous. The solvent was removed under reduced pressure. Ethyl acetate and hexane were added to the residue. The precipitated crystals were collected with filtration to give the desired substituted nitrobenzene (2.05 g, 62 % yield). 1H-NMR (CDC13) deltappm: 0.76 (q, 1H, J = 12.0 Hz), 0.96 (d, 6H, J = 6.3 Hz), 1.70-1.91 (m, 3H), 2.32 (t, 2H, J = 12.0 Hz), 3.62-3.72 (m, 2H), 7.17-7.25 (m, 1H), 7.34 (t, 1H, J = 8.1 Hz), 7.59 (d, 1H, J = 8.1 Hz), 7.71 (s, 1H).
62%
With potassium carbonate; In dimethyl sulfoxide; at 150℃; for 3h;
3-Fluoronitrobenzene (2.00 g, 14.2 mmol) was dissolved in dimethylsulfoxide (15 ml). 3,5-Dimethylpiperidine (3.21 g, 28.4 mmol) and potassium carbonate (3.92 g, 28.4 mmol) were added thereto and the mixture was stirred for 3 hours at 150 C. The reactant was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulphate anhydrous. The solvent was removed under reduced pressure. Ethyl acetate and hexane were added to the residue. The precipitated crystals were collected with filtration to give the desired substituted nitrobenzene (2.05 g, 62% yield).1H-NMR (CDCl3) delta ppm: 0.76 (q, 1H, J=12.0 Hz), 0.96 (d, 6H, J=6.3 Hz), 1.70-1.91 (m, 3H), 2.32 (t, 2H, J=12.0 Hz), 3.62-3.72 (m, 2H), 7.17-7.25 (m, 1H), 7.34 (t, 1H, J=8.1 Hz), 7.59 (d, 1H, J=8.1 Hz), 7.71 (s, 1H).
Stage #1: t-butyl 4-hydroxy piperidine-1-carboxylate With sodium hydride In dimethyl sulfoxide for 0.333333h;
Stage #2: 3-fluoro-1-nitrobenzene In dimethyl sulfoxide at 20℃; for 16h;
124
To a suspension of NaH (0.165 g, 4.14 mmol, 1.1 equiv) in DMSO (4 mL) at rt was added 1-BOC-4-hydroxypiperidine (0.794 g, 3.94 mmol, 1.00 equiv) in one portion. After stirring for 20 min, 3-fluoronitrobenzene (0.62 g, 4.34 mmol, 1.10 equiv) was added dropwise and the resulting suspension was stirred an additional 16 hours at rt. The reaction mixture was quenched with the addition of saturated, aqueous NH4Cl and extracted with ethyl acetate (50 mL, 3*). The combined organic layers were washed with brine, dried with sodium sulfate and concentrated. Purification of the crude residue by chromatography (30% ethyl acetate in hexanes) afforded 4-(3-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester as a dark orange oil (0.390 g, 31%).
31%
Stage #1: t-butyl 4-hydroxy piperidine-1-carboxylate With sodium hydride In dimethyl sulfoxide at 20℃; for 0.333333h;
Stage #2: 3-fluoro-1-nitrobenzene In dimethyl sulfoxide at 20℃; for 16h;
124
Example 124 To a suspension of NaH (0.165 g, 4.14 mmol, 1.1 equiv) in DMSO (4 mL) at rt was added 1-BOC-4-hydroxypiperidine (0.794 g, 3.94 mmol, 1.00 equiv) in one portion. After stirring for 20 min, 3-fluoronitrobenzene (0.62 g, 4.34 mmol, 1.10 equiv) was added dropwise and the resulting suspension was stirred an additional 16 hours at rt. The reaction mixture was quenched with the addition of saturated, aqueous NH4Cl and extracted with ethyl acetate (50 mL, 3*). The combined organic layers were washed with brine, dried with sodium sulfate and concentrated. Purification of the crude residue by chromatography (30% ethyl acetate in hexanes) afforded 4-(3-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester as a dark orange oil (0.390 g, 31%).
Stage #1: (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester With sodium hydride In dimethyl sulfoxide at 20℃; for 0.333333h;
Stage #2: 3-fluoro-1-nitrobenzene In dimethyl sulfoxide at 20℃; for 1.5h;
122
To a suspension of NaH (0.17 g, 4.4 mmol, 1.1 equiv) in DMSO (4 mL) at rt was added (3S)-1-Boc-3-pyrrolidinol (0.75 g, 4.0 mmol, 1.00 equiv) in one portion. After stirring for 20 min, 3-fluoronitrobenzene (0.51 g, 3.6 mmol, 0.90 equiv) was added drop wise and the resulting suspension was stirred an additional 1.5 hours at rt. The reaction mixture was quenched with the addition of saturated, aqueous NH4Cl and extracted with ethyl acetate (3*). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. Purification of the crude residue by chromatography (30% ethyl acetate in hexanes) afforded 3-(3-nitro-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester as a bright yellow oil (0.676 g, 60%).
6.82 g
Stage #1: (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester With sodium hydride In dimethyl sulfoxide at 20℃; for 0.5h;
Stage #2: 3-fluoro-1-nitrobenzene In dimethyl sulfoxide at 20℃; for 2.5h;
17.A A) tert-butyl (3S)-3-(3-nitrophenoxy)pyrrolidine-1-carboxylate
To a mixture of 60% sodium hydride (1.45 g) and DMSO (40 ml) was added tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (5.92 g). The reaction mixture was stirred at room temperature for 30 min, and 1-fluoro-3-nitrobenzene (4.25 g) was added dropwise thereto. The mixture was stirred at room temperature for 2.5 hr. The mixture was poured into water, and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.82 g). MS 209.2 [M+H-Boc]+.
6.82 g
Stage #1: (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester With sodium hydride In dimethyl sulfoxide; mineral oil at 10 - 35℃; for 0.5h;
Stage #2: 3-fluoro-1-nitrobenzene In dimethyl sulfoxide; mineral oil at 20℃; for 2.5h;
26.A A) tert-butyl (3S)-3-(3-nitrophenoxy)pyrrolidine-1-carboxylate
To a mixture of 60% sodium hydride (1.45 g) and DMSO (40 ml) was added tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (5.92 g). The reaction mixture was stirred at room temperature for 30 min, and 1-fluoro-3-nitrobenzene (4.25 g) was added dropwise thereto. The mixture was stirred at room temperature for 2.5 hr. The mixture was poured into water, and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.82 g). MS 209.2 [M+H-Boc]+.
Stage #1: (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester With sodium hydride In dimethyl sulfoxide at 20℃; for 0.333333h;
Stage #2: 3-fluoro-1-nitrobenzene In dimethyl sulfoxide at 20℃; for 1.5h;
122
Example 122 To a suspension of NaH (0.17 g, 4.4 mmol, 1.1 equiv) in DMSO (4 mL) at rt was added (3S)-1-Boc-3-pyrrolidinol (0.75 g, 4.0 mmol, 1.00 equiv) in one portion. After stirring for 20 min, 3-fluoronitrobenzene (0.51 g, 3.6 mmol, 0.90 equiv) was added drop wise and the resulting suspension was stirred an additional 1.5 hours at rt. The reaction mixture was quenched with the addition of saturated, aqueous NH4Cl and extracted with ethyl acetate (3*). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. Purification of the crude residue by chromatography (30% ethyl acetate in hexanes) afforded 3-(3-nitro-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester as a bright yellow oil (0.676 g, 60%).
With 18-crown-6 ether; potassium carbonate In N,N-dimethyl-formamide at 90℃; for 24h; Inert atmosphere;
3 3-(2,4,6-Trimethylphenoxy)-1-nitrobenzene (11)
To a dried flask of 50 mL, 2,4,6-trimethylphenol (10) (10 mmol), potassium carbonate (20 mmol) and 20 mL of DMF were added. Then, 3-fluoro-1-nitrobenzene (9) (10 mmol) was added to the flask via a syringe, followed by 18-crown-6 (0.5 mmol) in continuing stirring. The reaction was heated at 90 °C under nitrogen atmosphere during 24 h. Next, the resulting reaction was extracted with diethyl ether. The organic layer was dried over anhydrous sodium carbonate, filtered and evaporated under reduced pressure before purification by medium pressure chromatography to obtain 11. Yield 54%; orange solid; mp: 65.3-70.5 °C; 1H NMR (300 MHz, CDCl3): δ 2.07 (s, 6H, CH3-7′, CH3-8′), 2.31 (s, 3H, CH3-9′), 6.93 (s, 2H, CH-3′, CH-5′), 7.12 (d, J = 8.1 Hz, 1H, CH -6), 7.41 (t, J = 8.1 Hz, 1H, CH -5), 7.56 (s, 1H, CH -2), 7.83 (d, J = 7.8, 1H, CH-4); 13C NMR (75 MHz, CDCl3): δ 16.28, 20.92, 109.71, 116.42, 121.14, 130.10, 130.37, 130.62, 135.51, 148.11, 149.61, 158.82; HR-MS calcd. for C15H15NO3 m/z 257.10519, found: 257.10419.
With 2.9-dimethyl-1,10-phenanthroline; oxygen; copper (I) acetate; silver sulfate; sodium chloride; In dimethyl sulfoxide; at 160℃; for 24h;Schlenk technique;
Silak reaction tube equipped with a magnetic stirrer was charged with 6.2 mg of silver sulfate,36.3 mg of copper acetate, 12.5 mg of 2,9-dimethyl-1,10-o-phenanthroline,37 mg of <strong>[394-01-4]2-nitro-4-fluorobenzoic acid</strong>, and 17.5 mg of sodium chloride4 mL of dimethyl sulfoxide. Heat 160 C in the presence of oxygenReaction for 24 hours. After the reaction was completed, distilled water was added to quench the reaction,Extraction with ethyl acetate 3 times, each time 10mL,The combined organic phases were concentrated to give 14.7 mg of 2-nitro-4-fluorobenzene,The yield is 42%.
With indium; acetic acid In toluene at 80℃; for 10h; Inert atmosphere;
15 4.2.15. 1-(3-Fluorophenyl)-2,5-dimethyl-1H-pyrrole (17).14j
General procedure: Nitrobenzene derivative (1.0mmol) was added to a mixture of indium powder (460mg, 4.0mmol), and acetic acid (0.572mL, 10mmol) in toluene (2mL), followed by the addition of 2,5-hexadione or 1-phenyl-1,4-pentanedione (1.0mmol) in toluene (3mL). The reaction mixture was stirred at 80°C for 2,5-hexadione (or reflux for 1-phenyl-1,4-pentadione) under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (30mL), filtered through Celite, poured into 10% NaHCO3 (30mL), and then extracted with ethyl acetate (30mL×3). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was eluted with hexane for most derivatives or ethyl acetate/hexane (v/v=5:95) for benzonitrile derivatives through a neutral silica gel column to give the corresponding pyrroles. The structures of the pyrroles were characterized by 1H NMR, 13C NMR, FTIR, and GC-MS, and were mostly known compounds. If it is an unknown compound, elemental analysis data were reported additionally.
With caesium carbonate In N,N-dimethyl-formamide at 150℃; for 6h;
1.3 Preparation of 8-(3-nitrophenoxy)[l,2,4]triazolo[1,5-a]pyridin-2- amine
N,N-dimethylformamide (30 mL) was added to the compound obtained in Step 2 (3.2 g, 0.021 mol). 3-fluoronitrobenzene (2.7 mL, 0.026 mol) and cesium carbonate (13.9 g, 0.043 mol) was added to the reaction solution. The resulting mixture was stirred for 6 hours at 150°C, and then washed with dichloromethane, distilled water and an aqueous solution of ammonium chloride. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane : methanol = 60 : 1 (v:v)) to obtain the title compound (1.7 g, yield: 30%). 1H-NMR (300 MHz, DMSO-d6) δ 6.14 (s, 2H), 6.94 (t, 1H), 7.35 (d, 2H),7.47 (m, 1H), 7.64 (m 2H), 7.96 (d, 1H), 8.52 (d, 1H).
30%
With caesium carbonate In N,N-dimethyl-formamide at 150℃; for 6h;
1.3 Preparation of 8-(3-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridin-2-amine
N,N-dimethylformamide (30 mL) was added to the compound obtained in Step 2 (3.2 g, 0.021 mol). 3-fluoronitrobenzene (2.7 mL, 0.026 mol) and cesium carbonate (13.9 g, 0.043 mol) was added to the reaction solution. The resulting mixture was stirred for 6 hours at 150° C., and then washed with dichloromethane, distilled water and an aqueous solution of ammonium chloride. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane:methanol=60:1 (v:v)) to obtain the title compound (1.7 g, yield: 30%). 1H-NMR (300 MHz, DMSO-d6) δ 6.14 (s, 2H), 6.94 (t, 1H), 7.35 (d, 2H), 7.47 (m, 1H), 7.64 (m 2H), 7.96 (d, 1H), 8.52 (d, 1H)
To a solution of 20 (400 mg, 2.8 mmol) in DMI (2.4 mL), <strong>[15878-00-9]4-chloro-1H-pyrazole</strong> (440 mg, 4.3 mmol) and K2CO3 (0.78 g, 5.7 mmol) were added and stirred at 130 C for 16 h. The mixture was partitioned with EtOAc and H2O. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was chromatographed on amino silica gel with elution using (n-hexane-EtOAc) (90:10) to give 21 (583 mg, 92%) as a pale yellow solid. 1H NMR (DMSO-d6) delta 7.82 (1H, dd, J = 8.0, 8.0 Hz), 8.00 (1H, d, J = 0.4 Hz), 8.16-8.21 (1H, m), 8.27-8.32 (1H, m), 8.64 (1H, dd, J = 2.4, 2.4 Hz), 9.04 (1H, d, J = 0.4 Hz); MS (ESI) m/z 224, 226 [M+H]+.
Stage #1: C24H20O3 With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 1h;
Stage #2: 3-fluoro-1-nitrobenzene In N,N-dimethyl-formamide at 130℃; for 70h;
Compound 6.
Potassium carbonate (5.82 g, 42 mmol) was added to a solution of compound 5 (10 g, 28 mmol) in anhydrous dimethylformamide (DMF), and the solution was stirred at 80° C. After 1 h, 3-fluoronitrobenzene (5 mL, 42 mmol) was added, and stirring was continued at 130° C for 70 h. The mixture was cooled to room temperature, quenched by 1 M HCl, and extracted with EtOAc and brine. The organic layer was dried over anhydrous MgSO4. The crude product was chromatographed on silica gel column with EtOAc/CH2Cl2/hexane (1:1:10) to obtain compound 6 (8.4 g, yield= 62%).
With potassium fluoride; 18-crown-6 ether In 1-methyl-pyrrolidin-2-one; toluene at 110 - 200℃; Inert atmosphere; Large scale;
6
General procedure: 60.0KG 4-chloronitrobenzene (1.0eq), 16.6KG potassium fluoride (0.75eq), 1.5KG18 crown 6 (accounting for 2.5% of the total mass of 4-chloronitrobenzene), 150KG in the reactor N-methylpyrrolidone (250% of the total mass of 4-chloronitrobenzene),Under nitrogen protection, the temperature was raised to 110-120 ° C with stirring, the toluene was evaporated under reduced pressure and refluxed, and then the temperature was continued to rise to 150-200 ° C, and the reaction was kept for 3-6 h. When nitrobenzene=50:50, cool down to 150-180°C, carry out rectification under reduced pressure (50-100mmHg) while reacting, and adjust the reflux ratio to 1:3-5 to obtain 4-fluoronitrobenzene 39.15KG, GC Purity 99.64%. The remaining solid-liquid mixture was cooled to 60-70°C and filtered, the filter cake was washed twice with toluene, and the combined filtrate was applied to the next batch. The 2nd batch to the 9th batch: 60.0KG 4-chloronitrobenzene (1.0eq) and 16.6KG potassium fluoride (0.75eq) were added to each batch for reaction, and the above reaction and rectification process were repeated to obtain 4-fluoronitrobenzene base benzene, the filtrate was recovered and applied mechanically.The tenth batch: 51.0±1.0KG potassium fluoride (2.30±0.05eq) was added to carry out the reaction, and the above reaction and rectification process were repeated to obtain 4-fluoronitrobenzene.A total of 476.1KG of 4-fluoronitrobenzene was obtained from the reaction, the total purity was >99.6%, and the total yield was 98.2%.
64.5%
With potassium fluoride; bis(tricyclohexylphosphine)nickel(II) dichloride; tetrabutyl ammonium fluoride In N,N-dimethyl-formamide at 150℃; for 8h; Inert atmosphere;
4 Synthetic meta-fluoro-nitrobenzene
Add 0.52g (0.75mmol) of dichloro-di-dicyclohexylphosphine nickel to a 250mL three-necked flask,After adding 2.36g (15.0mmol) of meta-bromo-nitrobenzene,And add 40mL deoxygenated DMF,Start stirring under nitrogen protection,Dissolve the material.Then 1.74g (30mmol) of potassium fluoride and 0.24g (0.75mmol) of tetrabutylammonium fluoride were added. Start stirring,Heat to slight boiling (150) under nitrogen protection,Maintain at this temperature for 8 hours and then cool to room temperature naturally.Filter solids,Liquid vacuum distillation,Recover the solvent DMF,Get the product meta-fluoro-nitrobenzene 1.36g,The yield was 64.5%.
91 %Spectr.
With potassium fluoride; [COD(Pd-AlPhos)2]; silver fluoride In cyclohexane at 90℃; for 17h; Inert atmosphere; Glovebox; Sealed tube;
With potassium carbonate In N,N-dimethyl-formamide at 150℃; for 21h; Inert atmosphere;
i) Synthesis of meta-nitro 13 (Table 2).
To a solution of cyclotriguaiacylene 1 (1.63 g, 4.00 mmol) in DMF (40 mL) were addedmeta-fluoronitrobenzene (2.55 mL, 24.0 mmol) and K2CO3 (2.76 g, 20.0 mmol), and themixture was conducted at 150 C for more than 21 h with TLC monitoring. After thereaction was allowed to cool to ambient temperature, the mixture was filtered through apad of celite (eluent; CH2Cl2), and the filtrate was concentrated. The residue was dissolvedin CH2Cl2 (120 mL), and washed with water and brine, and dried over Na2SO4, andconcentrated in vacuo to give a crude product of 3.42 g. The crude was washed with coldacetonitrile (10 mL/g) at 0 C, and the following recrystallization from propionitrile (100 mL/g - 44 mL/g) yielded 13 in 1.57 g of brown needles (51 %). 1H NMR (400 MHz, CDCl3)7.87 (dd, J = 8.2, 2.3 Hz, 3H), 7.68 (dd, J = 2.3, 2.3 Hz, 3H), 7.42 (dd, J = 8.2, 8.2 Hz, 3H),7.22 (dd, J = 8.2, 2.3 Hz, 3H), 7.10 (s, 3H), 6.89 (s, 3H), 4.84 (d, J = 13.8 Hz, 3H),3.69-3.65 (m, 12H) ppm; 13C NMR (100 MHz, CDCl3) 159.3, 150.6, 149.5, 142.0, 137.9,132.5, 130.3, 123.8, 122.8, 117.3, 114.9, 111.4, 56.4, 36.8 ppm; MS (ESI) m/z: 794 ([M+Na]+); IR (neat): 2927, 1612, 1516 (NO2), 1346, 1215, 1080, 730 cm-1; HRMS (ESI) calcdfor C42H33N3O12Na 794.1956 [M + Na]+, Found 794.1982.
With potassium carbonate In N,N-dimethyl-formamide at 150℃; for 16h; Inert atmosphere;
9 Synthesis of 1-methoxy-3-(3-nitrophenoxy)benzene (9-3).
To a solution of 1- fluoro-3-nitrobenzene (1 g, 0.0071 mol) in DMF (15 mL) was added 3 -methoxy phenol (1.1458 g, 0.0092 mol) and K2CO3 (1.96 g, 0.014 mol), the reaction was stirred at 150°C for 16 hours under N2 atmosphere. The reaction was diluted with water (35 mL) and extracted with EA (3 x 15 mL). The combined organic layers were washed with brine (15 mL x 2), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (PE/EA=1%) to afford 1m-ethoxy-3-(3-nitrophenoxy)benzene (1.02 g, 59.1% yield) as a yellow oil. LCMS has no response.
59.1%
With potassium carbonate In N,N-dimethyl-formamide at 150℃; for 16h; Inert atmosphere;
9 Synthesis of 1-methoxy-3-(3-nitrophenoxy)benzene (9-3).
To a solution of 1- fluoro-3-nitrobenzene (1 g, 0.0071 mol) in DMF (15 mL) was added 3 -methoxy phenol (1.1458 g, 0.0092 mol) and K2CO3 (1.96 g, 0.014 mol), the reaction was stirred at 150°C for 16 hours under N2 atmosphere. The reaction was diluted with water (35 mL) and extracted with EA (3 x 15 mL). The combined organic layers were washed with brine (15 mL x 2), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (PE/EA=1%) to afford 1m-ethoxy-3-(3-nitrophenoxy)benzene (1.02 g, 59.1% yield) as a yellow oil. LCMS has no response.
1-(3-fluoro-4-bromophenoxy)-3-nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 12h;
Potassium carbonate (58 g, 420 mmol, 2.0 eq.) and 1-fluoro-3-nitrobenzene (29.6 g, 210 mmol, 1.0 eq.) were added to a solution of <strong>[121219-03-2]4-bromo-3-fluorophenol</strong> (40 g, 210 mmol, 1.0 eq.) in DMF (400 mL). The reaction was stirred for 12 hours at 90 C., and then concentrated under reduced pressure. The residue was diluted with water (300 mL), extracted with ethyl acetate (300 mL*3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the title compound (65 g, yield: 100%).
3,6-dinitro-9-(3-nitrophenyl)-9H-carbazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 110℃; for 24h; Inert atmosphere;
1.2 (2) Synthesis of Intermediate 3,6-dinitro-9-(3-nitrophenyl)-9H-carbazole
The 2.572g (0.01mol) 3,6-dinitro-9H-carbazole, 2.122ml (0.02mol) was added between fluoronitrobenzene and 50mlDMF three 250ml flask, with magnetic stirring and argon gas, was added 1.122g (0.01mol ) of potassium t-butoxide, the reaction temperature was raised to 110 24h; the reaction mixture was poured into ice water, suction filtration cake obtained by crystallization from ethanol twice, and dried in vacuo 80 deg.] C 24h, to give the product 3.443g, 91% yield . This intermediate structure is as follows
General procedure: 4-chloro-1H-pyrrolo[2,3-b]pyridine 9 (9.1g, 60mmol) or <strong>[74420-05-6]4-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine</strong> 10 (10.0g, 60mmol) reacted with 4-nitrophenol 11a (12.5g, 90mmol) or 2-fluoro-4-nitrophenol 11b (14.1g, 90mmol) in diphenyl ether at 190C for 1h respectively. The mixture was cooled to 60C and poured into ethyl acetate (350mL) in an ice bath for 30-50min. The mixture was filtered off and dried to give light yellow solid 12a-d.
With caesium carbonate In N,N-dimethyl-formamide at 110℃; for 1h; Inert atmosphere;
3.1 Synthesis of Compound 3-a
n a 250 ml two-neck round bottom flask under nitrogen, 2,4,6-trifluorophenol (4.00 g,1-fluoro-3-nitrobenzene (4.00 g, 28.4 mmol), cesium carbonate (cesiumcarbonate (9.24 g, 28.4 mmol) were dissolved in 120 ml of DMF and stirred at 110 ° C for 1 hour. After that,The extract was extracted with ethyl acetate and H2O and washed with brine. like thisThe obtained organic solution was added with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the above compound 3-a (6.18 g, yield: 85%).
With nickel(II) iodide; 6,6'-dimethyl-2,2'-bipyridine; (dimethoxy)methylsilane In N,N-dimethyl acetamide at 0 - 50℃; for 12.1667h; Inert atmosphere; Sealed tube; regioselective reaction;
General procedure for the NiH-catalyzed remote hydroarylamination
General procedure: 6,6'-Dimethyl-2,2'-bipyridine L1 (4.1 mg, 0.022 mmol, 11 mol %) was added to an oven-dried 8 mL screw-cap vialequipped with a magnetic stir bar. The vial was introduced into a nitrogen-filled glove box, NiI2(6.3 mg, 0.020 mmol, 10 mol %), anhydrous DMPU (0.10 mL) and anhydrous DMA (0.10 mL)were added. The mixture was then stirred for 10 min, at which time DMMS(dimethoxymethylsilane, 147 μL, 1.2 mmol, 6.0 equiv) was added and the stirring was continuedfor another 10 min at room temperature before 4-phenyl-1-butene (60 μL, 0.40 mmol, 2.0 equiv)was added. The tube was sealed with a teflon-lined screw cap, removed from the glove box andstirred at 0°C before a solution of 4-nitrotoluene (27.4 mg, 0.20 mmol, 1.0 equiv) in anhydrousDMPU (0.10 mL) and anhydrous DMA (0.10 mL) was added dropwise by syringe. Then thereaction mixture was stirred at 25°C for 10 min, and then stirred at 50°C for up to 12 hr (stirred at750 rpm). After the reaction was complete, the reaction mixture was immediately filtered througha short pad of silica gel (using ethyl acetate in hexanes) to give the crude product. Tetradecane(20 μL) was added as an internal standard for GC analysis. 1, 1, 2, 2-Tetrachloroethane (10.5 μL,0.10 mmol) was added as internal standard for 1H NMR analysis of the crude material. Theproduct was purified by chromatography on silica gel for each substrate. The yields reported arethe average of at least two experiments, unless otherwise indicated.
(S)-tert-butyl 2-methyl-4-(3-nitrophenyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
With potassium carbonate In dimethyl sulfoxide at 130℃; for 16h;
34.1 Step 1: (S)-tert-butyl 2-methyl-4-(3-nitrophenyl)piperazine-l-carboxylate
A mixture of K2CO3 (8.8 g, 63.8 mmol), l-fluoro-3 -nitrobenzene (3 g, 21.3 mmol), and (S)-tert-butyl-2-methylpiperazine-l-carboxylate (4.26 g, 21.3 mmol) in DMSO (80 mL) was stirred at 130°C for 16 hrs. The mixture was then filtered and the filtrate was washed with water, extracted with EtOAc, and purified by chromatography (silica, EtOAc/PE = 1/10) to afford (,S)- tert-butyl-2-methyl-4-(3-nitrophenyl)piperazine-l-carboxylate (1.98 g, 6.18 mmol, 29%). ESI-MS (EI+, m/z): 222.2 [M-99]+.
29%
With potassium carbonate In dimethyl sulfoxide at 130℃; for 16h;
34.1 Step 1:
Step 1: (S)-tert-butyl 2-methyl-4-(3-nitrophenyl)piperazine-1-carboxylate A mixture of K2CO3 (8.8 g, 63.8 mmol), 1-fluoro-3-nitrobenzene (3 g, 21.3 mmol), and (S)-tert-butyl-2-methylpiperazine-1-carboxylate (4.26 g, 21.3 mmol) in DMSO (80 mL) was stirred at 130° C. for 16 hrs. The mixture was then filtered and the filtrate was washed with water, extracted with EtOAc, and purified by chromatography (silica, EtOAc/PE=1/10) to afford (S)-tert-butyl-2-methyl-4-(3-nitrophenyl)piperazine-1-carboxylate (1.98 g, 6.18 mmol, 29%). ESI-MS (EI+, m/z): 222.2 [M-99]+.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;Heating;
A mixture of 2-(1-methyl-5-nitro-1H-imidazol-2-yl)-ethanol (1.32 mmol) and 1-fluoro- 3 -nitrobenzene (1.67 mmol) and K2C03(465 mg, 3.36 mmol) in DMF (5 mL) was stirred 2 hours at ambient temperature followed by heating. The reaction was worked-up by extraction. The residue was purified by prep-HPLC with the following condition: column: XBridge preparative CI 8 OBD column 19x 150 mm, 5 um; mobile phase A: water (10 mmol/L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL/min; gradient elution. The product-containing fractions were collected and then lyophilized to give l-methyl-5-nitro-2-(3-nitro-phenoxymethyl)-lH- imidazole. LC-MS: (ES, m/z) 279.07 (M+H)+; analysis: C, 47.53; H, 3.69; N, 20.24; O, 28.85.
With potassium carbonate In N,N-dimethyl-formamide at 80 - 150℃; for 27h;
A mixture of p-(benzyloxy)phenol (220 mg, 1.10 mmol), m-fluoronitrobenzene(149 mg, 1.05 mmol), and potassium carbonate (173 mg,1.25 mmol) in DMF (1.5 ml) was stirred at 150 °C for 3 h, and at 80 °Cfor 24 h. It was allowed to cool to room temperature, then 1M HCl wasadded, and the mixture was extracted with ethyl acetate. The organiclayer was dried over sodium sulfate, and evaporated. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate19:1) to afford 22a (237 mg, 70%)22a: 1H NMR (600 MHz, CDCl3) δ 7.89 (ddd, J=7.8, 2.4, 0.6 Hz,1H), 7.72 (t, J=2.4 Hz, 1H), 7.43 (m, 5H), 7.35 (t, J=5.4 Hz, 1H),7.28 (ddd, J=8.4, 2.4, 0.6 Hz, 1H), 7.01 (s, 4H), 5.08 (s, 2H).
With potassium carbonate In N,N-dimethyl-formamide at 80 - 150℃; for 27h; Inert atmosphere;
O-Monobenzylresorcinol (220 mg, 1.10 mmol) was added to a solutionof m-fluoronitrobenzene (149 mg, 1.05 mmol) and potassiumcarbonate (173 mg, 1.25 mmol) in DMF (1.5 ml) under an argon atmosphere,and the mixture was stirred at 150 °C for 3 h and at 80 °C for24 h. It was allowed to cool to room temperature, then poured into 1MHCl, and extracted with ethyl acetate. The organic layer was dried oversodium sulfate, and evaporated. The residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate 19:1) to afford 24a(273 mg, 80%).24a: 1H NMR (600 MHz, CDCl3) δ 7.94 (ddd, J=8.4, 2.4, 0.6 Hz,1H), 7.81 (t, J=2.4 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.36 (m, 7H),6.84 (dd, J=8.4, 2.4 Hz, 1H), 6.67 (m, 2H), 5.06 (s, 2H).
With caesium carbonate In N,N-dimethyl-formamide at 130℃; for 8h;
2; 3
Equipped with a thermometer, mechanical agitation,Add 38g of compound 10 to the 1L three-necked bottle of the condenser.22g 3-fluoronitrobenzene,DMF500ml, stir to completely dissolve the raw materials, add 69.5g of Cs2CO3,The solution was pale yellow. After heating to 130 ° C for 8 h reaction, sample monitoring,After the raw materials are completely reacted, the mixture is cooled to room temperature for post treatment. The reaction solution is added to 3 times the volume of water.The product was stirred and filtered, and the filter cake was added to water and washed with water until neutral.After filtration, the filter cake is dried and then added toluene to dissolve completely.After purification by column and recrystallization, the title compound compound 11 was obtained as a white solid, 46 g, yield 83.3%.
With sulfuric acid; dibromohydantoin,; In dichloromethane; water; at 40℃; for 2h;
In the first step, 74.6 g (528.7 mmol, 1.0 eq) of m-nitrofluorobenzene, 1058.0 g of dichloromethane and 151.2 g (528.7 mmol, 1.0 eq) of dibromohydantoin were added to a 2 L three-necked flask, and heated under mechanical stirring. Warm up to 40 C for use. 222.2 g (1586.0 mmol, 3.0 eq) of a 70 Wt% aqueous sulfuric acid solution was added dropwise, and the mixture was diluted for 1.0 h. After the completion of the dropwise addition, the mixture was stirred for 1.0 h, and the reaction was terminated, and then returned to room temperature. In the second step, the mixture was transferred to a separatory funnel, and the dichloromethane layer was separated and placed, and washed with water (500 g × 2). After decomposing under negative pressure, the obtained residue was cooled to obtain a crude yellow solid (gas chromatographic detection, wherein 2-bromo-5-fluoronitrobenzene 96%, 2-bromo-3-fluoronitrobenzene 1%, A%), 500 g (1/1, W/W) of n-heptane/ethanol mixed solvent was added and heated under reflux for 0.5 h, and then slowly returned to room temperature, followed by filtration to obtain 2-bromo-5-fluoronitrobenzene, white solid 110.5 g. Yield 95.0% (gas phase purity > 99.0%, A%).
With carbon tetrabromide; tert.-butyl lithium; In tetrahydrofuran; N,N-dimethyl-formamide; at 60℃; for 3.5h;
2.82 g (20.0 mmol) of m-fluoronitrobenzene, 9.95 g (30.0 mmol) of carbon tetrabromide and 20.0 g of N,N-dimethylformamide were added to a 250 mL reaction flask, and the mixture was stirred under a magnetic stirring at room temperature. 60.0 mL of Adding lithium t-butoxide tetrahydrofuran solution (132.0 mmol, 2.2 M) was added dropwise for 0.5 h, and the temperature was raised to 60 C for 3 h, and then naturally returned to room temperature. The reaction solution was decomposed by a negative pressure, and 50.0 g of water was added thereto, and 50.0 g of dichloromethane was added for extraction. The oil layer was combined and washed with water (50.0 g × 5). After removing the solvent, the mixture was allowed to stand overnight to obtain a brown solid (2.22 g). Gas chromatography analysis of 2-bromo-3-fluoronitrobenzene 86% (A%), 2-bromo-5-fluoronitrobenzene 4% (A%).
To a 250 mL reaction flask, 13.2 mL of lithium diisopropylamide (26.4 mmol, 0.5 M) and 50 mL of tetrahydrofuran were added, and the mixture was placed in an ice machine and stirred to cool to -35 C for use. Then, 1.62 g (11.5 mmol) of m-nitrofluorobenzene dissolved in 25 mL of tetrahydrofuran was added dropwise thereto, and the mixture was dropped for 20 minutes, and the temperature of the dropping process was controlled at -35 to -30 C, followed by further heating and stirring for 2.0 hours. Then, 7.46 g (22.9 mmol) of 1,2-dibromotetrachloroethane dissolved in 25 mL of tetrahydrofuran was added dropwise, and the dropping temperature was controlled at -35 to -30 C, followed by further stirring for 1.0 h. The reaction solution was slowly poured into a 20.0 g beaker containing 10% ammonium chloride solution, stirred for 10 min, quenched by negative pressure, and most of the tetrahydrofuran was distilled off, and then extracted with dichloromethane (50.0 g × 2), and the oil layer was combined. After adding 50.0 g×2 of water, the solvent was removed, and the mixture was allowed to stand overnight to obtain 1.75 g of a yellow solid. Gas chromatography analysis of 2-bromo-3-fluoronitrobenzene 90% (A%), 2-bromo-5-fluoronitrobenzene 2% (A%).
With isopentyl nitrite; In tetrahydrofuran; at 120℃; under 5250.53 Torr; for 0.333333h;
General procedure: A solution of the selected heterocyclic starting material (1.00 mmol) in THF (10 mL) and a solutionof isopentyl nitrite (141 mg, 1.20 mmol) in THF (10 mL) were both pumped at a flow rate of 0.25 mLmin1 with a Vapourtech ?Easy MedChem V3? system, meeting at a PTFE T-piece and the outputflowing through a 10.0 mL coil reactor maintained at 120 C, giving a residence time of 20 min.The pressure of the system was maintained at 7 bar with a back-pressure regulator. For compoundswhere an isolated yield was reported: the output mixture was concentrated under reduced pressureto give an oil (or powder). The oil (or powder) was purified using column chromatography withvarious mixtures of ethyl acetate and hexane as the eluent, or by recrystallisation using methanol, togive isolated compounds that showed no impurities by NMR spectroscopy. For compounds where aconversion was reported (due to volatility of products), the output mixture was carefully concentratedunder a reduced pressure of 100 mbar for 10 min and the conversion was calculated by integration ofproduct peaks to a quantified internal standard (nitrobenzene).
With potassium <i>tert</i>-butylate at 130℃; for 48h; Sealed tube;
2.4 General procedure for the mono-N-methylation of nitroarenes with methanol
General procedure: Nitroarenes (1.0mmol), 2a (7.9mg, 1mol %), KOtBu (112mg, 1.0 equiv.) were charged in a 15mL pressure tube with a magnetic bar. Then, 3.5mL of methanol was added into the mixture. The reaction tube was closed with the Teflon stopper and was heated to the desired temperature (130°C) under stirring. After the desired reaction time, the reaction mixture was allowed to cool to room temperature. The solvent was removed under vacuum and then the product was purified by column chromatography and the product was analyzed by NMR spectroscopy.
4,4'-(9H-carbazole-2,7-diyl)diphenylamine[ No CAS ]
4,4'-(9-(3-nitrophenyl)-9H-carbazole-2,7-diyl)bis(N-(3-nitrophenyl)aniline)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With potassium carbonate In dimethyl sulfoxide at 150℃; for 12h; Inert atmosphere;
2.1 (1) Synthesis of 4,4'-(9-(3-nitrophenyl)-9H-carbazole-2,7-diyl)bis(N-(3-nitrophenyl)aniline):
S1. Add 3.49g (0.01mol) 4,4'-(9H-carbazole-2,7-diyl)diphenylamine,10.58g (0.075mol) m-fluoronitrobenzene and 13.8g (0.1mol) potassium carbonate are added to a 250ml three-necked flask,Add 150ml of dimethyl sulfoxide, magnetically stir and argon, heat up to 150°C,After 24 hours of reaction, the reaction solution was poured into 2000ml ice water, and the precipitate was filtered out.First wash with 50ml of 0.5mol/L hydrochloric acid, then wash with distilled water, wash three times,100ml each time; finally collect the solid.S2. The solid collected in step S1 is purified by column chromatography using dichloromethane: n-hexane=4:1 (volume ratio) as the mobile phase and silica gel as the stationary phase.The product was collected and spin-dried, and dried in vacuum at 80°C for 24 hours to obtain 4.28 g of the product.The yield was 60%.
With potassium <i>tert</i>-butylate In acetonitrile at 50℃; for 6h; Sealed tube;
4.2.1. Synthetic procedures
General procedure: Aryl fluorides (1.0 mmol), CH3SSCH3 (1.2 mmol), t-BuOK (3.0 mmol) and CH3CN (2 mL) were taken in a 25-ml sealed tube. The reaction mixture was stirred at 50 C for 6 h under air. After cooling to room temperature, the product was diluted with H2O (5 mL) and extracted with EtOAc (4 × 10 mL). The extracts were combined and washed by brine (3 × 10 mL), dried over MgSO4, filtered, and evaporated, and purified by chromatography on silica gel to obtain the desired products with ethyl acetate/hexane (v/v = 1:301:100). The products were characterized by their spectral and analytical data and compared with those of the known compounds (See supporting information).
With potassium carbonate In N,N-dimethyl-formamide at 125℃; for 24h; Inert atmosphere;
53.1 Step 1: 2-(3-Nitrovhenoxy)vwidine (53.2)
[00555] A mixture of intermediate 47.1 (1.00 g, 7.09 mmol), intermediate 53.1 (0.81 g, 8.50 mmol), and K2CO3 (1.96 g, 14.17 mmol) in DMF (10 mL) was stirred at 125 °C for 24 h. Once cooled to r.t. the reaction was poured into EtOAc (40 mL), washed with H2O (40 mL), and brine (40 mL), dried over Na2S04, and concentrated under reduced pressure. After chromatographic purification (CLhCh/MeOH from 99:1 to 96:4, v/v), 1.35 g of intermediate 53.2 were obtained. [00556] Yield: 87%. [00557] MS-ESI(+) m/z: 217.3 (M+H).
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