* 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.
General procedure: A 1N HCl solution (82.5 mL) was added to the aniline (~1 mmol) in a round bottom flask. To this was added acrolein diethyl acetal (2.5 mmol). The resulting solution was refluxed at 111 °C for 24 hours. After cooling to room temperature, the solution was neutralized (pH 7−8) by addition of solid Na2CO3. The product was then extracted into dichloromethane (3 x 100 mL), and the combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude residue was then purified by column chromatography (elution mixture of hexane with ethyl acetate or 15percent ethyl acetate/cyclohexane with methanol) to give the desired quinoline product.
Reference:
[1] Chinese Chemical Letters, 2014, vol. 25, # 5, p. 779 - 782
4
[ 109-97-7 ]
[ 540-37-4 ]
[ 52768-17-9 ]
Reference:
[1] Journal of Organic Chemistry, 2007, vol. 72, # 23, p. 8943 - 8946
[2] Letters in Organic Chemistry, 2010, vol. 7, # 3, p. 212 - 218
[3] Advanced Synthesis and Catalysis, 2008, vol. 350, # 9, p. 1253 - 1257
5
[ 13331-23-2 ]
[ 540-37-4 ]
[ 59147-02-3 ]
Yield
Reaction Conditions
Operation in experiment
92%
With C7H10N2*Pd(2+)*2Cl(1-); potassium carbonate In methanol; water for 0.166667 h; Reflux; Schlenk technique
General procedure: A 20mL Schlenk tube with a magnetic stir bar was charged with aryl halide (2mmol), arylboronic acid (2.4mmol), K2CO3 (5mmol), 10mL of solvent [H2O, H2O–MeOH (1:1), H2O–EtOH (1:1), H2O–EG (1:1)] and an aliquot of 0.01M solution of palladium complexes PdCl2(L)2 or Pd[(L)4]Cl2 in MeOH (0.001–0.2molpercent) under air atmosphere. The reaction mixture was placed in a preheated oil bath: at 100°C for MeOH–H2O, at 110°C for EtOH–H2O, at 140°C for H2O and at 160°C for EG–H2O; and stirred under reflux for the given time. After this time, the mixture was cooled, acidified by 5M HCl (in the case of acids) and diluted with 10mL of H2O and 10mL of Et2O (or EtOAc). The organic phase was separated, and the aqueous layer was extracted with Et2O EtOAc) (2×10mL). The combined organic layers were washed with H2O (10mL), brine (10mL), and dried over Na2SO4. The pure products were obtained by a simple filtration of ether solution through silica gel pad and evaporation of a solvent.
Reference:
[1] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 11, p. 4755 - 4763
11
[ 3034-53-5 ]
[ 540-37-4 ]
[ 193017-26-4 ]
Reference:
[1] Synthesis, 2001, # 1, p. 128 - 134
12
[ 333-20-0 ]
[ 540-37-4 ]
[ 16582-58-4 ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: at 20℃; Cooling with ice Stage #2: With ammonium hydroxide In water
General procedure: A mixture of 0.1 mol of 4-substituted aniline and 0.1 mol of Potassium thiocyanate (KCNS) in 100 ml glacial acetic acid (AcOH) was cooled in an ice bath and stirred for 10-20 min, and then 0.1 mol bromine in glacial acetic acid was added dropwise at such a rate to keep the temperature below 10 °C throughout the addition. The reaction mixture was stirred at room temperature for 2-4 h, the hydrobromide (HBr) salt thus separated out was filtered, washed with acetic acid, dried, dissolved in hot water and basified to pH 11.0 with ammonia solution (NH4OH) and the resulting precipitate was filtered, washed with water and dried to get the desired product 3a-k. The progress of the reaction was monitored by Thin Layer Chromatography using toluene: acetone (8:2) solvent system.
Reference:
[1] European Journal of Medicinal Chemistry, 2012, vol. 53, p. 41 - 51
[2] Heteroatom Chemistry, 2012, vol. 23, # 4, p. 399 - 410
[3] European Journal of Medicinal Chemistry, 2014, vol. 71, p. 24 - 30
[4] Medicinal Chemistry, 2013, vol. 9, # 4, p. 596 - 607
[5] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5561 - 5565
13
[ 1147550-11-5 ]
[ 540-37-4 ]
[ 16582-58-4 ]
Reference:
[1] European Journal of Organic Chemistry, 2011, # 31, p. 6206 - 6217
14
[ 540-37-4 ]
[ 16582-58-4 ]
Reference:
[1] Medicinal Chemistry Research, 2013, vol. 22, # 1, p. 195 - 210
[2] Journal of Chemical Research, 2014, vol. 38, # 10, p. 611 - 616
[3] Patent: US2016/2600, 2016, A1,
15
[ 540-72-7 ]
[ 540-37-4 ]
[ 16582-58-4 ]
Reference:
[1] Die Pharmazie, 1967, vol. 22, # 6, p. 229 - 233
16
[ 15192-76-4 ]
[ 540-37-4 ]
[ 16582-58-4 ]
Reference:
[1] Bulletin de la Societe Chimique de France, 1956, p. 1701
17
[ 540-37-4 ]
[ 20780-76-1 ]
Reference:
[1] European Journal of Pharmacology, 2007, vol. 556, # 1-3, p. 200 - 206
[2] Tetrahedron, 2005, vol. 61, # 25, p. 6082 - 6087
[3] Chemische Berichte, 1924, vol. 57, p. 1773
[4] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 292 - 302
[5] Medicinal Chemistry, 2016, vol. 12, # 5, p. 489 - 498
18
[ 302-17-0 ]
[ 540-37-4 ]
[ 20780-76-1 ]
Reference:
[1] Pharmazie, 1980, vol. 35, # 1, p. 14 - 16
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 8, p. 1882 - 1885
With copper(l) chloride; sodium hydroxide; 3-(diphenylphosphino)propionic acid In dimethyl sulfoxide at 120℃; for 14 h; Inert atmosphere; Sealed tube
General procedure: NH-containing heterocycle (1.4 mmol) and DMF (2.0 mL) were added to a mixture of CuCl (15.0 molpercent) and ligand 1 (20.0 molpercent) in DMF (2.0 mL), aryl iodide (1.0 mmol), NaOH (2.0 mmol). The mixture was vigorously stirred at 120 °C for 14 h under a dry nitrogen atmosphere. After completion of the reaction (as monitored by TLC), H2O was added and the organic layer was extracted with EtOAc, washed with brine and dried over MgSO4. The solution was filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography. The purity of the compounds was checked by 1H NMR and yields are based on aryl iodide. All the products are known and the spectroscopic data (FT‑IR and NMR) and melting points were consistent with those reported in the literature.
80 %Chromat.
With C16H12ClN3OPdS; potassium hydroxide In dimethyl sulfoxide at 110℃; for 10 h;
General procedure: Arylhalide (1.0 mM), nitrogen-containing heterocycle (1.2 mM), KOH (2 mM), and the catalyst (0.75 Mpercent) were stirred in dimethyl sulfoxide (DMSO) (4 mL) at 110 °C for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate(70 : 30) as eluent to afford the desired product. The products have been characterized by 1H NMR spectroscopy.
Reference:
[1] Green Chemistry, 2013, vol. 15, # 2, p. 336 - 340
[2] Journal of the Chinese Chemical Society, 2013, vol. 60, # 8, p. 1007 - 1013
[3] RSC Advances, 2014, vol. 4, # 14, p. 7321 - 7329
[4] New Journal of Chemistry, 2015, vol. 39, # 4, p. 2901 - 2907
[5] Chemistry - An Asian Journal, 2014, vol. 9, # 12, p. 3418 - 3430
[6] Journal of Chemical Research, 2014, vol. 38, # 2, p. 128 - 129
[7] Journal of Organic Chemistry, 2009, vol. 74, # 5, p. 2200 - 2202
[8] RSC Advances, 2015, vol. 5, # 2, p. 1522 - 1528
[9] Tetrahedron, 2006, vol. 62, # 18, p. 4435 - 4443
[10] Journal of Medicinal Chemistry, 1988, vol. 31, # 11, p. 2136 - 2145
[11] RSC Advances, 2014, vol. 4, # 29, p. 15122 - 15130
[12] Journal of Coordination Chemistry, 2015, vol. 68, # 19, p. 3537 - 3550
24
[ 540-37-4 ]
[ 13939-06-5 ]
[ 71-36-3 ]
[ 94-25-7 ]
Yield
Reaction Conditions
Operation in experiment
90%
With C35H20F34NO3(1-)*Pd(2+)*Cl(1-); N-ethyl-N,N-diisopropylamine In neat (no solvent) at 130℃; for 0.2 h; Microwave irradiation
General procedure: A mixture of the aryl halide (1.0 mmol), alcohol (5.0 equiv), Mo(CO)6 (0.5 equiv), DIPEA (1.5 equiv) and palladacycle 1 (1 mol percent Pd) was heated in a pressure tube at 130 °C under microwave irradiation. The reaction was monitored by TLC. When the reaction has completed, the reaction mixture was cooled to room temperature and the alcohol was removed. The crude mixture was subjected to F-SPE to remove palladacycle 1 (see general procedure for the recycling of palladacycle 1) and the solution of crude product was concentrated, diluted with EtOAc (20 mL) and washed successively with 2 M HCl (210 mL) and water (10 mL). The organic layer was driedover anhydrous MgSO4, filtered and concentrated to give pure 6.
With 1,8-diazabicyclo[5.4.0]undec-7-ene In 1-methyl-pyrrolidin-2-one at 250℃; for 0.2 h; Flow reactor
General procedure: Selective N-monomethlyation reactions were performed in a Vapourtec E-series continuous flow system equipped with a high temperature tube reactor (10 mL, stainless steel, 0.03'' i.d., Fig. 2 ) and a membrane back pressure regulator (Zaiput). Stock solutions of aniline (20 mmol, 1.0 equiv, 2 M), DMC (5.05 mL, 60 mmol, 3.0 equiv, 6 M), and DBU (4.47 mL, 30 mmol, 1.5 equiv, 3 M) were prepared in oven-dried 10 mL volumetric flasks using NMP as the solvent. The solutions were transferred to screw-thread vials with septum caps and reagents were pumped directly from the vials. After the high temperature coiled tube reactor was heated to 250 °C, peristaltic pumps (Vapourtec V-3) were used to pump the reactant solutions into the system (0.277 mL/min each for a 12 min residence time). The solutions were mixed with a cross-mixer (0.4″ i.d.), passed though the high temperature coiled tube reactor. Upon exiting the reactor, the reaction stream was passed through a short segment of stainless steel tubing to enable the reaction to cool and then exited the system by passage through the back pressure regulator (Note: PFA fittings should not be used at the exit of the reactor as they will deform due to the high temperature of the reaction stream and cause leaks in the system. Stainless steel connectors and tubing (12'') were used in our system.). After the flow system was equilibrated for 18 min, the product stream was collected for 5 min (2.77 mmol of aniline). The crude mixture was dissolved in ethyl acetate and washed with brine. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 25 g Ultra-sil, 3–15percent ethyl acetate in hexanes) to afford the desired product.
With sodium hydrogencarbonate In N,N-dimethyl-formamide at 20℃; for 48 h;
4-Iodobenzenamine (1327 mg, 6.06 mmol), NaHCO3 (1140 mg, 13.57 mmol), and DMF (4 mL) were added into the 25 mL flask, the resulting mixture was stirred at rt, iodomethane (2415 mg, 17.00 mmol) was added dropwise via a dropping funnel. After the complete conversion of the starting material as monitored by TLC (eluent: petroleum ether/ethyl acetate = 2/1), the mixture was poured into cold water (10 mL), the organic layer was separated, the aqueous phase was extracted with ethyl acetate (10 mL × 3), the organic phase was combined and washed with a saturated aqueous solution of NaCl, and dried over anhydrous MgSO4. The solvent was evaporated. Flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10/1) afforded 4-iodo-N,N-dimethylbenzenamine as a pale yellow solid (508 mg, 34percent).
Reference:
[1] Organometallics, 2014, vol. 33, # 13, p. 3251 - 3264
[2] Journal of Physical Organic Chemistry, 2005, vol. 18, # 5, p. 468 - 472
[3] Bulletin of the Chemical Society of Japan, 2005, vol. 78, # 2, p. 344 - 348
[4] European Journal of Inorganic Chemistry, 2014, vol. 2014, # 31, p. 5322 - 5330
[5] Chinese Chemical Letters, 2016, vol. 27, # 11, p. 1683 - 1685
39
[ 50-00-0 ]
[ 540-37-4 ]
[ 698-70-4 ]
Reference:
[1] Tetrahedron Letters, 2004, vol. 45, # 38, p. 7061 - 7064
[2] Advanced Synthesis and Catalysis, 2015, vol. 357, # 16-17, p. 3424 - 3428
[3] Journal of Organic Chemistry, 2018, vol. 83, # 2, p. 656 - 663
[4] Organic Letters, 2017, vol. 19, # 19, p. 5114 - 5117
[5] Journal of Organic Chemistry, 2011, vol. 76, # 24, p. 10229 - 10235
[6] Catalysis Today, 2012, vol. 198, # 1, p. 35 - 44
[7] European Journal of Organic Chemistry, 2014, vol. 2014, # 35, p. 7839 - 7849
[8] Journal of Chemical Sciences, 2016, vol. 128, # 9, p. 1469 - 1473
40
[ 540-37-4 ]
[ 74-88-4 ]
[ 60577-34-6 ]
[ 698-70-4 ]
Reference:
[1] Chemical Communications, 2010, vol. 46, # 20, p. 3538 - 3540
41
[ 540-37-4 ]
[ 29632-73-3 ]
Yield
Reaction Conditions
Operation in experiment
44%
at 20℃;
To a solution of 4-iodo aniline (1.1 g, 5.0 mmol), in 6 mL of HO Ac, was added a solution of Br2 (250 μ., 4.8 mmol) and the mixture stirred overnight at room temperature. The reaction mixture was washed with brine, saturated aqueous NaHC03 and extracted with Et20, dried (Na2S04), filtered and concentrated. Purification by column chromatography (Hexane:EtOAc = 9: 1, 4: 1, 2: 1) provided the title compound as a brown oil (570 mg, 1.9 mmol, 44 percent) Rf: 0.46 (Hexane:EtOAc, 4: 1). 1H NMR (400 MHz; CDC13): δ 6.54 (1H, d, J = 8.2 Hz, ArCH), 7.37 (1H, d, J = 8.4 Hz, ArCH), 7.70 (1H, s, ArCH). 13C NMR (100 MHz; CDC13): δ 110.0, 117.3, 131.1, 134.4, 136.9, 139.9, 143.8.
Reference:
[1] Organic Letters, 2006, vol. 8, # 8, p. 1713 - 1716
[2] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 8, p. 774 - 779
[3] Patent: WO2018/148721, 2018, A1, . Location in patent: Page/Page column 83
[4] Zhurnal Obshchei Khimii, 1934, vol. 4, p. 557,559[5] Chem. Zentralbl., 1935, vol. 106, # II, p. 505
[6] Chemistry - A European Journal, 2011, vol. 17, # 49, p. 13665 - 13669
Reference:
[1] Journal of the American Chemical Society, 2002, vol. 124, # 29, p. 8661 - 8666
[2] Journal of Organic Chemistry, 2015, vol. 80, # 2, p. 882 - 896
45
[ 624-92-0 ]
[ 540-37-4 ]
[ 35371-03-0 ]
Reference:
[1] Chemical Communications, 2013, vol. 49, # 48, p. 5507 - 5509
With hemicucurbituril supported [Bmim]Cl In toluene for 10 h; Reflux
General procedure: A mixture of aryl halide (1 mmol) and sodium alkoxide(3.0 mmol) was refluxed in the presence of 200 mg ofHmCucSILP catalyst in toluene (5 mL) for an appropriatetime as indicated in Table 2. After completion of thereaction, the reaction mixture was filtered and solvent wasevaporated in vacuo to give the crude product, which waspurified by column chromatography over silica gel usinghexane/EtOAc as the eluent.
EXAMPLE 40; 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid [4-(2-methoxy-ethoxy)-phenyl]-amide; a. 4-(2-Methoxy-ethoxy)-phenylamine; A mixture of 4-iodoaniline (219 mg, 1.0 mmol), 2-methoxyethanol (152 mg, 2.0 mmol), copper iodide (19.0 mg, 0.1 mmol), cesium carbonate (554 mg, 1.7 mmol) and 1,10-phenanthroline (36.0 mg, 0.2 mmol) was stirred in toluene (0.5 mL) at 110° C. overnight. The reaction was then cooled to RT and filtered through silica gel and washed with diethyl ether. The ether was removed in vacuo to obtain a crude solid. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a solid (8.9 mg, 5.3percent). 1H NMR (300 MHz, CDCl3) δ 6.82-6.72 (m, 4H), 4.06 (t, 2H), 3.72 (t, 2H), 3.45 (s, 3H).
With palladium diacetate; triethylamine In neat (no solvent) at 100℃; for 4 h; Sealed tube
General procedure: In a typical reaction, aryl halide (1.0 mmol), olefin (1.5 mmol),Et3N (2 mmol), Pd(OAc)2 (0.01 mmol) and [HQ-PEG1000-DIL][BF4](0.1 mmol) were added to a tube and sealed. The reaction mixture was stirred at 100 C for a certain time. At the end of the reaction, the final mixture was cooled to room temperature and extracted with diethyl ether. The combined organic extracts were dried over anhydrous MgSO4 and concentrated to give the crude product, which was purified by column chromatography on silica gel (200-300 mesh) using ethyl acetate/petroleum ether as eluent to afford the desired product in high purity. Only the trans-products were selectively obtained and characterized by comparison of 1H NMR data in the literature. The catalyst left in the reaction vessel was dried in vacuo for 2 h.The residue was subjected to a second run by charging the reaction tube with fresh starting materials without further addition of Pd(OAc)2 and [HQ-PEG1000-DIL][BF4].
75%
With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 6 h; Inert atmosphere
General procedure: A mixture of 4-iodotoluene (5 g, 22.93 mmol), ethyl acrylate (4.587 g, 45.87 mmol) and potassium carbonate (6.330 g, 45.87 mmol) was taken in DMF (15 ml) and then added SS-Pd (10.27 g, 2 molpercent Pd). The reaction mixture was heated at 100 oC for 6 h under nitrogen atmosphere. After cooling the reaction mixture was diluted with 15ml of ethyl acetate and washed with cold water. The organic layer was finally washed with brine and dried over anhydrous Na2SO4. The crude mixture was purified by column chromatography (EtOAc:Hexane, 1:99), afforded (E)-ethyl 3-p-tolylacrylate 1 as colourless liquid (4.051g, 93percent yield)
60%
With potassium phosphate In N,N-dimethyl-formamide at 100℃; for 5 h;
General procedure: A mixture of aryl halide (1 mmol), ethylacrylate (1 mmol), K3PO4 (1 mmol), nano-Pd/Fe3O4/ZnO (0.003 g), and DMF (1.0 mL) was put into a preheated oil bath at 100 °C foran appropriate period of time. Then, the reaction mixture was diluted with EtOAc and the catalyst was removed by a magnet. The filtrate was extracted with water and the organic layer dried over CaCl2 and evaporated under reduced pressure. Resulting products were purified by column chromatography over silica gel using n-hexane/ethylacetate (5:1) as eluent to give the desired pure product with excellent yield.
Reference:
[1] Journal of Organometallic Chemistry, 2013, vol. 739, p. 1 - 5
[2] Tetrahedron Letters, 2012, vol. 53, # 52, p. 7044 - 7051
[3] Advanced Synthesis and Catalysis, 2016, vol. 358, # 23, p. 3736 - 3742
[4] Journal of the Iranian Chemical Society, 2016, vol. 13, # 1, p. 45 - 53
[5] Synlett, 2011, # 3, p. 369 - 372
[6] Organic and Biomolecular Chemistry, 2004, vol. 2, # 15, p. 2249 - 2252
[7] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2008, vol. 47, # 10, p. 1549 - 1554
53
[ 13675-18-8 ]
[ 540-37-4 ]
[ 5122-99-6 ]
Reference:
[1] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6608 - 6612
54
[ 540-37-4 ]
[ 5122-99-6 ]
Reference:
[1] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6608 - 6612
55
[ 5720-06-9 ]
[ 540-37-4 ]
[ 263901-48-0 ]
Reference:
[1] European Journal of Organic Chemistry, 2007, # 32, p. 5364 - 5375
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 15, p. 3057 - 3061
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 6, p. 2648 - 2659
56
[ 1243985-65-0 ]
[ 540-37-4 ]
[ 263901-48-0 ]
Reference:
[1] European Journal of Organic Chemistry, 2013, # 13, p. 2545 - 2554
57
[ 540-37-4 ]
[ 62830-55-1 ]
Reference:
[1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 5, p. 1706 - 1712
[2] Advanced Synthesis and Catalysis, 2014, vol. 356, # 7, p. 1571 - 1576
58
[ 201230-82-2 ]
[ 540-37-4 ]
[ 75-65-0 ]
[ 120363-13-5 ]
Reference:
[1] Organic and Biomolecular Chemistry, 2017, vol. 15, # 32, p. 6715 - 6719
59
[ 540-37-4 ]
[ 134856-58-9 ]
Reference:
[1] Synthetic Communications, 2003, vol. 33, # 14, p. 2447 - 2461
[2] Tetrahedron, 2002, vol. 58, # 52, p. 10387 - 10405
[3] Journal of Organic Chemistry, 2003, vol. 68, # 6, p. 2167 - 2174
[4] Chemistry - A European Journal, 2001, vol. 7, # 21, p. 4706 - 4714
[5] Journal of the American Chemical Society, 2001, vol. 123, # 34, p. 8177 - 8188
[6] Tetrahedron, 1996, vol. 52, # 15, p. 5495 - 5504
Reference:
[1] Journal of Medicinal Chemistry, 1988, vol. 31, # 10, p. 2048 - 2056
[2] Patent: WO2012/37108, 2012, A1,
[3] Organic Process Research and Development, 2017, vol. 21, # 7, p. 1003 - 1011
63
[ 887144-94-7 ]
[ 540-37-4 ]
[ 97760-97-9 ]
Yield
Reaction Conditions
Operation in experiment
61%
With potassium carbonate; nickel(II) hydroxide In dimethyl sulfoxide at 35℃; for 2 h;
In the preparation method of the trifluoromethyl aromatic amine of the present embodiment, the aromatic amine is p-iodoaniline, and other reactions and post-treatment processes are the same as in the embodiment 28. The preparation method of the trifluoromethyl aromatic amine of the present embodiment, the aromatic amine is aniline, and the nickel compound is nickel hydroxide.The base is potassium carbonate, and the reaction process parameters are: 1-trifluoromethyl-1,2-phenyliodo-3(H)-one (0.5 mmol, 1.0 eq).Aromatic amine (1.5 mmol, 3.0 eq), nickel hydroxide 10 molpercent, potassium carbonate (1.5 mmol, 3.0 eq),DMSO (2 mL) was reacted at 35 ° C for 2 h, and the other reactions and workup procedures were the same as in Example 1.
60%
With tris[2-phenylpyridinato-C2,N]iridium(III) In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Irradiation
Under nitrogen or argon, 4-iodoaniline 0.4 mmol,0.2mmol, Ir (ppy) 3(2mg) and DMF1 ml was added to the reaction flask, followed by blueLED lights (7W) irradiation until complete conversion of trivalent iodine reagentcompletion of the reaction at room temperature. Add 10 ml of saturated Na 2CO3 Aqueoussolution, and extracted with ethyl acetate three times, the organic layer was washedwith water and once with saturated brine, dried over anhydrous Na 2SO 4The organic layerwas dried. Column chromatography (eluent: petroleum ether 60-90: ethyl acetate = 20: 1-10: 1) to give the product in 60percent yield.
Reference:
[1] Organic Letters, 2018, vol. 20, # 13, p. 3732 - 3735
[2] Patent: CN108503552, 2018, A, . Location in patent: Paragraph 0240-0244
[3] Patent: CN103553857, 2016, B, . Location in patent: Paragraph 0021-0022
[4] Organic Letters, 2014, vol. 16, # 6, p. 1768 - 1771
64
[ 2314-97-8 ]
[ 540-37-4 ]
[ 97760-97-9 ]
Yield
Reaction Conditions
Operation in experiment
90%
With fac-tris(2-phenylpyridinato-N,C2')iridium(III); potassium carbonate In 1,2-dichloro-ethane at 20℃; for 24 h; Inert atmosphere; Schlenk technique; Irradiation
General procedure: A 25 mL of Schlenk tube equipped with a magnetic stir bar were charged with aniline (1.2 mmol, 3.0 equiv) or heterocycles (0.8 mmol, 2.0 equiv), K2CO3 (0.8 mmol, 2.0 equiv) and fac-Ir(ppy)3 (2.6 mg, 0.004 mmol, 1 mol percent), under air. The vessel was evacuated and backfilled with Ar (3 times), CF3I stock solution (0.56 mL, 0.71 mmol/mL in 1,2-chloroethane or 0.36 mL, 1.11 mmol/mL in DMSO, 1.0 equiv), anhydrous 1,2-dichloroethane (3 mL) were then added. The tube was screw capped and stirred at room temperature under irradiation of blue LEDs (12 W) for 24 hours. The reaction mixture was filtered through a pad of Celite and washed with ethyl acetate (3×5 mL). The filtrate was concentrated. The residue was subjected to column chromatography on silica gel to afford the pure product.
General procedure: The reactions were carried out in a 50 mL RB flask under reduced pressure for 10 min at 80°C unless reported differently. In a typical experiment, 5 mmol of amine was added to 5 mmol of BOC anhydride, and the reaction was allowed to proceed for 10 min. The desired product was obtained in a rotary evaporator under vacuum conditions.
87%
With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 3 h;
A mixture of 4-iodoaniline 2 (9.39 g, 42.8 mmol) and Boc2O (8.78 g, 47.1 mmol) in DMF [(25] mL) and DIEA (5 mL) was stirred at RT for 3 hr, diluted with AcOEt (300 mL), and washed with [H20] (2x, each 150 mL). The organic layer was dried (MgSO4) and evaporated to give compound 3 (11.89 g, [87percent, 1H-NMR).]
73%
for 16 h; Heating / reflux
To a solution of 4-iodoaniline (10 g) in tetrahydrofuran (200 mL) was added di-tert-butyl dicarbonate (11 g), and the reaction mixture was heated under reflux for 16 hrs. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography, and tert-butyl 4-iodophenylcarbamate was obtained as crystals from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). Recrystallization from ethyl acetate-hexane gave colorless prism crystals (10.7 g, yield 73percent). melting point: 148-149°C.
70%
Stage #1: With lithium bis(trimethylsilyl)amide In tetrahydrofuran at 0 - 20℃; Stage #2: at 20℃; for 2 h;
4-IODOANILINE (3.28 g, 15 mmol) was dissolved in anhydrous THF (70 ml), cooled to 0°C and treated with lithium hexamethyldisilazide (1M in THF, 30ML, 30 mmol). After warming to room temperature di-tert-butyl dicarbonate (3.27 g, 15 mmol) in anhydrous THF (30 ml) was added dropwise and the mixture stirred for 2 h. The reaction was quenched by the addition of sat. NH4C1 solution, the organic phase was separated and washed with water. After concentration the crude product was purified by flash column chromatography (ethyl acetate/heptane 4: 1) yielding (4-iodo-phenyl) -carbamic acid tert-butyl ester as a tan solid (3.37 g, 70 percent ;-10 percent contamination with di-tert-butyl ester) MS: M = 318.0 (ESI-) 'H-NMR (400 MHz, [D6]-DMSO) : 1.47 (s, 9H), 7.29 (d, 2H), 7.57 (d, 2H), 9.46 (s, br, NH)
70%
With lithium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; for 2 h;
4-Iodoaniline (3.28 g, 15 mmol) is dissolved in anhydrous THF (70 ml), cooled to 0° C. and treated with lithium hexamethyldisilazide (1M in THF, 30 ml, 30 mmol). After warming to room temperature di-tert-butyl dicarbonate (3.27 g, 15 mmol) in anhydrous THF (30 ml) is added dropwise and the mixture stirred for 2 h. The reaction is quenched by the addition of sat. NH4Cl solution, the organic phase is separated and washed with water. After concentration the crude product is purified by flash column chromatography (ethyl acetate/heptane 4:1) yielding (4-iodo-phenyl)-carbamic acid tert-butyl ester as a tan solid (3.37 g, 70percent; 10percent contamination with di-tert-butyl ester). MS: M=318.0 (ESI-) 1H-NMR (400 MHz, [D6]-DMSO): δ=1.47 (s, 9H), 7.29 (d, 2H), 7.57 (d, 2H), 9.46 (s, br, NH)
58.2%
With dmap; triethylamine In methanol at 50℃;
To a solution of V-1 (10 g, 45.66 mmol), TEA (9.22 g, 91.23 mmol) and DMAP (50 mg) in MeOH (100 mL) was added di-tert-butyl dicarbonate (19.8 g, 50.2 mmol). The mixture was heated to 50° C. overnight. After completion of the reaction, the mixture was concentrated, the residue was purified by column chromatography (PE/EA=10/1) to afford V-2 (8.47 g, yield 58.2percent).
48%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 14 h; Cooling with ice
The 4-iodo aniline (5.0 g, 22 . 83 mmol) dissolved in DMF (50 ml) in. To the obtained by adding in a mixture of diisopropylethylamine (2.5 ml). Furthermore, under the ice, a mixture of to the resulting dropping (Boc)2O (11.0 g, 50 . 04 mmol). After the completion of the dropping, the resulting reaction mixture at room temperature for 14 hours. Then ice water into the mixture in (250 ml). The resulting mixture is extracted with methylene chloride. The resulting organic phase is concentrated to obtain crude product under reduced pressure. Under heating, the resulting crude product using normal hexane beating. The slurry is cooling, filtering to obtain 3.5 g of white solid (yield: 48.0percent).
Reference:
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 22, p. 5864 - 5869
[2] Research on Chemical Intermediates, 2017, vol. 43, # 3, p. 1355 - 1363
[3] Chemical Communications, 2013, vol. 49, # 61, p. 6909 - 6911
[4] Patent: WO2004/12736, 2004, A1, . Location in patent: Page/Page column 24
[5] Organic Letters, 2018, vol. 20, # 7, p. 1693 - 1697
[6] Chemistry - An Asian Journal, 2013, vol. 8, # 1, p. 113 - 120
[7] Patent: EP1486490, 2004, A1, . Location in patent: Page 47
[8] Patent: WO2004/96796, 2004, A1, . Location in patent: Page 42
[9] Patent: US2005/197370, 2005, A1, . Location in patent: Page/Page column 15
[10] Angewandte Chemie - International Edition, 2014, vol. 53, # 41, p. 11046 - 11050[11] Angew. Chem., 2014, vol. 126, # 41, p. 11226 - 11230,5
[12] Patent: US2014/200215, 2014, A1, . Location in patent: Paragraph 0965; 0966
[13] Patent: CN105384739, 2016, A, . Location in patent: Paragraph 0242; 0243; 0244
[14] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 6, p. 1203 - 1212
[15] Journal of Medicinal Chemistry, 2003, vol. 46, # 23, p. 5055 - 5063
[16] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 24, p. 4293 - 4297
[17] Patent: US2002/38025, 2002, A1,
[18] Patent: US5407959, 1995, A,
[19] Patent: US5726319, 1998, A,
[20] MedChemComm, 2013, vol. 4, # 12, p. 1562 - 1570
[21] Angewandte Chemie - International Edition, 2016, vol. 55, # 52, p. 16101 - 16105[22] Angew. Chem., 2016, vol. 128, # 52, p. 16335 - 16339,5
[23] Chemistry - A European Journal, 2017, vol. 23, # 4, p. 917 - 925
Reference:
[1] Patent: US5346914, 1994, A,
[2] Patent: US5432194, 1995, A,
70
[ 540-37-4 ]
[ 214360-60-8 ]
Reference:
[1] Patent: WO2014/117090, 2014, A1,
71
[ 540-37-4 ]
[ 57260-71-6 ]
[ 170911-92-9 ]
Yield
Reaction Conditions
Operation in experiment
43%
With potassium phosphate; copper(l) iodide In ethylene glycol; isopropyl alcohol at 80℃; for 30 h;
A mixture of 4-iodoaniline (0.654 g, 3 mmol), piperazine-1-carboxylic acid tert-bvyl ester (0.67 g, 3.6 mmol), potassium phosphate (1.272 g, 6 mmol), ethylene glycol (0.33 ml) and copper iodide (0.03 g, 0.15 mmol) in 2-propanol (3 ml) was placed under argon in a sealed-tube and heated to 8O0C for 30 hours. After being cooled to room temperature, the medium was washed with water (50 ml) and extracted with ethyl acetate (100 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane: acetone, 70:30) to yield 43a (0.36 g, 1.3 mmol, 43percent) as a yellow powder.
Reference:
[1] Patent: WO2006/124118, 2006, A1, . Location in patent: Page/Page column 59
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 7, p. 2779 - 2796
72
[ 142-08-5 ]
[ 540-37-4 ]
[ 13143-47-0 ]
Yield
Reaction Conditions
Operation in experiment
95%
With 8-quinolinol; potassium carbonate In N,N-dimethyl-formamideInert atmosphere; Reflux; Large scale
In a 3000L reactor, iodoaniline 438kg, 2-hydroxypyridine 190kg, 8-hydroxyquinoline 58kg, potassium carbonate 207kg, N,N-dimethylformamide (DMF) 1500kg, nitrogen protection, stirring is turned on. The mixture was warmed to reflux and reacted overnight. Chromatography was followed up to the end of the reaction. The potassium iodide was removed by filtration. Part of the DMF was recovered under reduced pressure, cooled to 50° C., and filtered to give crude 1-(4-aminophenyl)-1H-pyridin-2-one. The crude product was added with 740 kg of ethanol, heated and dissolved, and 55 kg of activated carbon was added for decoloration. The solution was filtered while hot, and the filtrate was cooled and crystallized. The product was filtered, dried and packaged to give 1-(4-aminophenyl)-1H-pyridin-2-one with a yield of 95. percent,The purity is 99percent.
70%
With copper(l) iodide; 8-quinolinol; caesium carbonate In 1,4-dioxane; dimethyl sulfoxide at 120℃; for 15 h; Sealed tube
11128] In a similar manner as described in Example 114,(R)-5-(3-(4-methoxybenzamido)piperidin- 1 -yl)-3-(4-(2-ox-opyridin- 1 (2H)-yl)phenylamino)pyrazine-2-carboxamide(154) was prepared using 1 -(4-aminophenyl)pyridin-2(1H)-one. MS found for C29H29N704 as (M+H) 540.1, (M—H)538.3. UV: X=260, 285, 308, 346, 369 nm Synthesis of i-(4-aminophenyl)pyridin-2(1H)-one: The mixture of 4-iodoa-niline (1.00 g, 4.56 mmol), 2-hydroxypyridine (650 mg, 6.84mmol), fine powder Cs2CO3 (2.97 g, 9.12 mmol), fine powderCul (180mg, 0.92 mmol), 8-hydroxyquinoline (140mg, 0.92mmol) in 6 mE DMSO and 10 mE dioxane was stirred in asealed tube at 120° C. for 15 h. The mixture was diluted with300 mE EtOAc, filtered through celite, washed with brine,dried, concentrated and subjected to flash column with 0 to7percent MeOR in dichioromethane to isolate this compound (590mg, yield 70percent).
53.45%
With copper(l) iodide; 8-quinolinol; potassium carbonate In dimethyl sulfoxide at 130℃; for 12 h; Inert atmosphere
General procedure: Compound 1 (5g, 22.83mmol) was dissolved in DMSO (120mL), followed by the addition of 2-Piperidinone (4.53g, 45.66mmol), CuI (0.43g, 2.28mmol), 8-hydroxy-quinoline (0.66g, 4.57mmol) and K2CO3 (9.46g, 68.49mmol). The mixture was heated to 130°C under N2 for 12h, cooled, and quenched with water (120mL). The organics were extracted with ethyl acetate (2×150mL) and dried (Na2SO4). Purification by silica gel column chromatography (n-hexane/ethyl acetate, 5/1 to 3/1, as eluent) afforded compound 2 as faint yellow (2.80g, 64.47percent).
39.8%
With copper(l) iodide; 8-quinolinol; caesium carbonate In dimethyl sulfoxide at 120℃;
A mixture of pyridin-2-ol (2.00 g, 21.0 mmol), 4-iodoaniline (4.61 g, 21.0 mmol), 8-quinolinol (0.61 g, 4.2 mmol), Cul (0.80 g, 4.2 mmol) and Cs2C03 (10.26 g, 31.5 mmol) in DMSO (50 mL) was stirred at 120°C for overnight. After filtration, the filtrate was partitioned between EA and water and the aqueous layer was further extracted with EA. The combined organic layers was washed with water and brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound as a green solid (1.56 g, 39.8 percent yield). MS (m/z): 186.9 (M+H)+.
39.8%
With copper(l) iodide; 8-quinolinol; caesium carbonate In dimethyl sulfoxide at 120℃;
A mixture of pyridin-2-ol (2.00 g, 21.0 mmol), 4-iodoaniline (4.61 g, 21.0 mmol), 8-quinolinol (0.61 g, 4.2 mmol), Cul (0.80 g, 4.2 mmol) and Cs2C03 (10.26 g, 31.5 mmol) in DMSO (50 mL) was stirred at 120°C for overnight. After filtration, the filtrate was partitioned between EA and water and the aqueous layer was further extracted with EA. The combined organic layers was washed with water and brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound as a green solid (1.56 g, 39.8 percent yield). MS (m/z): 186.9 (M+H)+.
Reference:
[1] Patent: CN107382836, 2017, A, . Location in patent: Paragraph 0021; 0022
[2] Patent: US2015/158865, 2015, A1, . Location in patent: Paragraph 1127; 1128
[3] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 411 - 422
[4] Patent: WO2014/139145, 2014, A1, . Location in patent: Page/Page column 37
[5] Patent: WO2014/139465, 2014, A1, . Location in patent: Page/Page column 38
[6] Patent: WO2006/55951, 2006, A2, . Location in patent: Page/Page column 59
[7] Patent: WO2008/86226, 2008, A2, . Location in patent: Page/Page column 123-124
[8] Patent: WO2005/32468, 2005, A2, . Location in patent: Page/Page column 158
[9] Patent: WO2006/63113, 2006, A2, . Location in patent: Page/Page column 118
[10] Patent: WO2006/63293, 2006, A2, . Location in patent: Page/Page column 48-49
[11] Patent: WO2005/32468, 2005, A2, . Location in patent: Page/Page column 158
73
[ 4509-90-4 ]
[ 540-37-4 ]
[ 385425-15-0 ]
Yield
Reaction Conditions
Operation in experiment
81%
Stage #1: With triethylamine In tetrahydrofuran at 0 - 20℃; Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃;
Part A. 4-iodoaniline (45.82 g, 209.2 mmol) and triethylamine (65.61 ml, 470.7 mmol) were dissolved into THF (800 mL) and cooled to 0° C. 5-Bromovaleryl chloride (50.0 g, 251.1 mmol) dissolved in THF (200 mL) was added dropwise to the reaction. The reaction was warmed to room temperature and stirred overnight. Reaction was cooled to 0° C. and potassium tert-butoxide (70.43 g, 627.6 mmol) was slowly added. The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated and then re-dissolved in ethyl acetate (500 mL) and 3N HCl (500 mL), extracted with ethyl acetate (2.x.250 mL), washed with 1N HCl (3.x.250 mL), washed with brine (1.x.250 mL), and dried (Na2SO4). Purification by silica gel chromatography using 0percent-100percentethyl acetate/hexane gradient as eluent to afford 51.03 g (81percent): 1H NMR (CDCl3) δ 7.70 (d, j=8.4 Hz, 2H), 7.03 (d, j=8.8 Hz, 2H), 3.62 (t, j=5.9 Hz, 2H), 2.56 (t, j=5.7 Hz, 2H), 2.50-1.88 (m, 4H) ppm.
81%
Stage #1: With triethylamine In tetrahydrofuran at 0 - 20℃; Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃;
Part A. 4-iodoaniline (45.82 g, 209.2 mmol) and triethylamine (65.61 mL, 470.7 mmol) were dissolved into THF (800 mL) and cooled to 0° C. 5-Bromovaleryl chloride (50.0 g, 251.1 mmol) dissolved in THF (200 mL) was added dropwise to the reaction. The reaction was warmed to rt and stirred overnight. Reaction was cooled to 0° C. and potassium tert-butoxide (70.43 g, 627.6 mmol) was slowly added. The reaction was warmed to rt and stirred overnight. The reaction was concentrated and then redissolved in ethyl acetate (500 mL) and 3N HCl (500 mL), extracted with ethyl acetate (2×250 mL), washed with 1N HCl (3×250 mL), washed with brine (1×250 mL), and dried (Na2SO4). Purification by silica gel chromatography using 0percent-100percent ethyl acetate/hexane gradient as eluent to afford 51.03 g (81percent): 1H NMR (CDCl3)□ δ 7.70 (d,j=8.4 Hz, 2H), 7.03 (d,j=8.8 Hz, 2H), 3.62 (t,j=5.9 Hz, 2H), 2.56 (t,j=5.7 Hz, 2H), 2.50-1.88 (m, 4H) ppm.
48.5%
Stage #1: With triethylamine In tetrahydrofuran at 0 - 20℃; for 16.5 h; Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; Stage #3: With hydrogenchloride; water In tetrahydrofuran
EXAMPLE 1; l-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxo-l-piperidinyl)phenyl)-4,5,6,7- tetrahydro-lH-pyrazole- [3,4-c] pyridine-3-carboxamide; l-(4-Iodophenyl) piperidin-2-one:; Triethylamine (31.10 g, 307.38 mmol) was added to a solution of 4-iodoaniline (30.0 g, 136.98 mmol) in tetrahydrofuran (80OmL). After cooling the mixture to about 0 0C, a solution of 5- bromo-pentanoyl chloride (32.7g, 163.90 mmol) in tetrahydrofuran (20OmL) was slowly added to the mixture over a period of about 30 minutes. The mixture was stirred at ambient temperature for about 16 hours. The mixture was then cooled to about 0 0C, and potassium tert-butoxide (46.0 g, 410 mmol) was slowly added. The mixture was stirred at ambient temperature for about 18 hours. Evaporation of the solvent in vacuo afforded a thick oily mass which was acidified to a pH of about 2.0 by adding a 3 N hydrochloric acid solution. Following standard extractive workup with ethyl acetate (3 x 500 mL), the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane, 0percent-100percent) to give the title product as an off-white solid (20.0 g, yield = 48.5percent). mp: 108-1100C. 1H NMR (400 MHz, CDCl3) δ 1.93-1.95 (m, 4H), 2.55 (t, J=6.2 Hz, 2H), 3.62 (t, J=5.2 Hz, 2H), 7.02 (d, J= 8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H); IR (KBr) υ 3256, 3049, 2936, 2864, 1634, 1576, 1482, 1434, 1164, 1000, 819, 709 cm"1; MS 302 (M + 1).
Reference:
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 22, p. 5339 - 5356
[2] Patent: US2003/232804, 2003, A1, . Location in patent: Page 94
[3] Patent: US2017/50964, 2017, A1, . Location in patent: Paragraph 0699
[4] Patent: WO2010/30983, 2010, A2, . Location in patent: Page/Page column 28
With C12H18ClCuN4O(1+)*ClO4(1-); caesium carbonate; In acetonitrile; at 80℃; for 24h;Inert atmosphere;
General procedure: In a flame-driedvessel, equipped with a magnetic stirrer, under argon atmosphere,were added 0.3 mL of anhydrous acetonitrile, the nucleophile (imidazoleor benzimidazole - 0.75 mmol, 1.5 eq.), the electrophile(alkyl or aryl iodide - 0.5 mmol, 1 eq.), the base (1 mmol, 2 eq.),and the copper catalyst (0.05 mmol - 10% loading). The reactionvessel was heated to 80 C and left under stirring for 24 h. Thereaction mixture was then allowed to cool to room temperature,diluted with dichloromethane (5 mL) and filtered through celite. The celitepad was further washed with dichloromethane(2 x 5 mL). The combined organic phases were washed with water(2 x 5 mL) and brine (2 x 5 mL). The organic solvents were thenremoved in vacuo to yield the crude product, which was purifiedby flash column chromatography on silica gel using a gradient mixtureof ethyl acetate/petroleum ether as eluent. The 1H and 13CNMR spectral data for all N-arylatedimidazoles and benzimidazolesare in full agreement with those reported to literature [57-61].
75%
With copper(l) chloride; sodium hydroxide; 3-(diphenylphosphino)propionic acid; In dimethyl sulfoxide; at 120℃; for 14h;Inert atmosphere; Sealed tube;
General procedure: NH-containing heterocycle (1.4 mmol) and DMF (2.0 mL) were added to a mixture of CuCl (15.0 mol%) and ligand 1 (20.0 mol%) in DMF (2.0 mL), aryl iodide (1.0 mmol), NaOH (2.0 mmol). The mixture was vigorously stirred at 120 C for 14 h under a dry nitrogen atmosphere. After completion of the reaction (as monitored by TLC), H2O was added and the organic layer was extracted with EtOAc, washed with brine and dried over MgSO4. The solution was filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography. The purity of the compounds was checked by 1H NMR and yields are based on aryl iodide. All the products are known and the spectroscopic data (FT-IR and NMR) and melting points were consistent with those reported in the literature.
80%Chromat.
With C16H12ClN3OPdS; potassium hydroxide; In dimethyl sulfoxide; at 110℃; for 10h;
General procedure: Arylhalide (1.0 mM), nitrogen-containing heterocycle (1.2 mM), KOH (2 mM), and the catalyst (0.75 M%) were stirred in dimethyl sulfoxide (DMSO) (4 mL) at 110 C for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate(70 : 30) as eluent to afford the desired product. The products have been characterized by 1H NMR spectroscopy.
In neat (no solvent); at 80℃; for 0.166667h;Green chemistry;
General procedure: The reactions were carried out in a 50 mL RB flask under reduced pressure for 10 min at 80C unless reported differently. In a typical experiment, 5 mmol of amine was added to 5 mmol of BOC anhydride, and the reaction was allowed to proceed for 10 min. The desired product was obtained in a rotary evaporator under vacuum conditions.
87%
With N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 3h;
A mixture of 4-iodoaniline 2 (9.39 g, 42.8 mmol) and Boc2O (8.78 g, 47.1 mmol) in DMF [(25] mL) and DIEA (5 mL) was stirred at RT for 3 hr, diluted with AcOEt (300 mL), and washed with [H20] (2x, each 150 mL). The organic layer was dried (MgSO4) and evaporated to give compound 3 (11.89 g, [87%, 1H-NMR).]
73%
In tetrahydrofuran; for 16h;Heating / reflux;
To a solution of 4-iodoaniline (10 g) in tetrahydrofuran (200 mL) was added di-tert-butyl dicarbonate (11 g), and the reaction mixture was heated under reflux for 16 hrs. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography, and tert-butyl 4-iodophenylcarbamate was obtained as crystals from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). Recrystallization from ethyl acetate-hexane gave colorless prism crystals (10.7 g, yield 73%). melting point: 148-149C.
70%
4-IODOANILINE (3.28 g, 15 mmol) was dissolved in anhydrous THF (70 ml), cooled to 0C and treated with lithium hexamethyldisilazide (1M in THF, 30ML, 30 mmol). After warming to room temperature di-tert-butyl dicarbonate (3.27 g, 15 mmol) in anhydrous THF (30 ml) was added dropwise and the mixture stirred for 2 h. The reaction was quenched by the addition of sat. NH4C1 solution, the organic phase was separated and washed with water. After concentration the crude product was purified by flash column chromatography (ethyl acetate/heptane 4: 1) yielding (4-iodo-phenyl) -carbamic acid tert-butyl ester as a tan solid (3.37 g, 70 % ;-10 % contamination with di-tert-butyl ester) MS: M = 318.0 (ESI-) 'H-NMR (400 MHz, [D6]-DMSO) : 1.47 (s, 9H), 7.29 (d, 2H), 7.57 (d, 2H), 9.46 (s, br, NH)
70%
With lithium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃; for 2h;
4-Iodoaniline (3.28 g, 15 mmol) is dissolved in anhydrous THF (70 ml), cooled to 0 C. and treated with lithium hexamethyldisilazide (1M in THF, 30 ml, 30 mmol). After warming to room temperature di-tert-butyl dicarbonate (3.27 g, 15 mmol) in anhydrous THF (30 ml) is added dropwise and the mixture stirred for 2 h. The reaction is quenched by the addition of sat. NH4Cl solution, the organic phase is separated and washed with water. After concentration the crude product is purified by flash column chromatography (ethyl acetate/heptane 4:1) yielding (4-iodo-phenyl)-carbamic acid tert-butyl ester as a tan solid (3.37 g, 70%; 10% contamination with di-tert-butyl ester). MS: M=318.0 (ESI-) 1H-NMR (400 MHz, [D6]-DMSO): delta=1.47 (s, 9H), 7.29 (d, 2H), 7.57 (d, 2H), 9.46 (s, br, NH)
70%
In tetrahydrofuran; at 65℃; for 18h;Schlenk technique; Inert atmosphere;
Boc2O (5.00 g, 22.9 mmol) was added to a solution of 4-iodoaniline (5.00 g, 22.8 mmol) in THF (20 mL). Theresulting mixture was stirred for 18 h at 65 C. Then thesolvent was removed in vacuo and the resulting residuewas recrystallised from CH2Cl2/petroleum ether affordingthe aryl carbamate as a white solid (5.11 g, 70%). Theproduct did not require further purification. 1H NMR(500 MHz, CDCl3), delta 7.55 (2H, d, 3J 8.5 Hz, ArH), 7.14 (2H,d, 3J 8.5 Hz, ArH), 6.62 (1H, s, NH), 1.49 (9H, s, CH3). NMRspectroscopic data are consistent with those of the literature[28].
58.2%
With dmap; triethylamine; In methanol; at 50℃;
To a solution of V-1 (10 g, 45.66 mmol), TEA (9.22 g, 91.23 mmol) and DMAP (50 mg) in MeOH (100 mL) was added di-tert-butyl dicarbonate (19.8 g, 50.2 mmol). The mixture was heated to 50 C. overnight. After completion of the reaction, the mixture was concentrated, the residue was purified by column chromatography (PE/EA=10/1) to afford V-2 (8.47 g, yield 58.2%).
48%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 14h;Cooling with ice;
The 4-iodo aniline (5.0 g, 22 . 83 mmol) dissolved in DMF (50 ml) in. To the obtained by adding in a mixture of diisopropylethylamine (2.5 ml). Furthermore, under the ice, a mixture of to the resulting dropping (Boc)2O (11.0 g, 50 . 04 mmol). After the completion of the dropping, the resulting reaction mixture at room temperature for 14 hours. Then ice water into the mixture in (250 ml). The resulting mixture is extracted with methylene chloride. The resulting organic phase is concentrated to obtain crude product under reduced pressure. Under heating, the resulting crude product using normal hexane beating. The slurry is cooling, filtering to obtain 3.5 g of white solid (yield: 48.0%).
31.0 g (97%)
In tetrahydrofuran;
18.1 A solution of 21.9 g (100 mmol) 4-iodoaniline and 22.9 g (105 mmol) of di-tert-butyl dicarbonate in 300 ml THF was heated for 30 h at 80 C. The solution was evaporated and extracted with aqueous 10% KHSO4 /Et2O (3x). The organic phase was washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 31.0 g (97 %) of (4-Iodo-phenyl)-carbamic acid tert-butyl ester, MS: 320 (MH+).
In sodium hydroxide;
Step 1. Preparation of N-t-Boc-4-iodoaniline The desired compound was prepared by heating a solution of 4-iodoaniline and di-tert-butyldicarbonate in 2M aqueous sodium hydroxide at reflux, followed by cooling to ambient temperature and extraction of N-t-Boc-4-iodoaniline with ethyl acetate. mp 140-141 C. 1 H NMR (300 MHz, CDCl3) delta 7.57 (2H, d, J=9 Hz), 7.13 (2H, d, J=9 Hz), 6.43 (1H, br s), 1.52 (1H, br s). MS m/e 320 (M+H)+, 337 (M+NH4)+.
In dichloromethane;
Step A 4-(t-Butoxycarbonylamino)iodobenzene 4-Iodoaniline (6 g; 27.4 mmol) and di-t-butyl dicarbonate (7.5 g; 34.4 mmol) were dissolved in methylene chloride (50 ml) and the reaction mixture stirred at room temperature for 19 h. The volatiles were removed under reduced pressure and the residues crystallized from ethyl acetate and hexanes 9:1 v/v to give 4.42 g of product. The mother liquors were evaporated under reduced pressure and then were chromatographed on silica gel using a solvent system comprising ether and hexanes 1:3 v/v. Chromatography afforded a further 2.75 g of product. A total yield of 7.17 g (82%) was obtained in the reaction. FAB-MS:- calculated for C11 H14 NO2 I 319.0 found 319.8 (M).
With sodium cyanoborohydride; In acetic acid;Inert atmosphere;
General procedure: To a solution of aniline (1 mmol) in glacial acetic acid (7 mL) under argon was added paraformaldehyde (10 mmol) and sodium cyanoborohydride (5 mmol). After stirring overnight, the reaction mixture was poured into ice cooled water (?100 mL) containing NaOH (7 g). This mixture (pH 14) was extracted thrice with CH2Cl2 (3 × 350 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product. Flash chromatographic purification of the crude product using silica gel and a mixture of hexane and ethyl acetate as the eluent provided the pure product.
General procedure: 4-Ethyl aniline (8.252 mmol) was dissolved in 50 mL of glacial acetic acid under inert N2 condition. Paraformaldehyde (80.871 mmol) was added and the contents were stirred for 15 min. Sodium cyanoborohydride (38.785 mmol) was added as the next step and it was stirred overnight at room temperature. The reaction mixture was poured in the saturated Sodium hydroxide solution, which contained crushed ice. Ethyl acetate was added later and the upper layer was collected which contained the compound and was further subjected to solvent evaporation.
With palladium diacetate; triethylamine; In neat (no solvent); at 100℃; for 4h;Sealed tube;
General procedure: In a typical reaction, aryl halide (1.0 mmol), olefin (1.5 mmol),Et3N (2 mmol), Pd(OAc)2 (0.01 mmol) and [HQ-PEG1000-DIL][BF4](0.1 mmol) were added to a tube and sealed. The reaction mixture was stirred at 100 C for a certain time. At the end of the reaction, the final mixture was cooled to room temperature and extracted with diethyl ether. The combined organic extracts were dried over anhydrous MgSO4 and concentrated to give the crude product, which was purified by column chromatography on silica gel (200-300 mesh) using ethyl acetate/petroleum ether as eluent to afford the desired product in high purity. Only the trans-products were selectively obtained and characterized by comparison of 1H NMR data in the literature. The catalyst left in the reaction vessel was dried in vacuo for 2 h.The residue was subjected to a second run by charging the reaction tube with fresh starting materials without further addition of Pd(OAc)2 and [HQ-PEG1000-DIL][BF4].
75%
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 6h;Inert atmosphere;
General procedure: A mixture of 4-iodotoluene (5 g, 22.93 mmol), ethyl acrylate (4.587 g, 45.87 mmol) and potassium carbonate (6.330 g, 45.87 mmol) was taken in DMF (15 ml) and then added SS-Pd (10.27 g, 2 molpercent Pd). The reaction mixture was heated at 100 oC for 6 h under nitrogen atmosphere. After cooling the reaction mixture was diluted with 15ml of ethyl acetate and washed with cold water. The organic layer was finally washed with brine and dried over anhydrous Na2SO4. The crude mixture was purified by column chromatography (EtOAc:Hexane, 1:99), afforded (E)-ethyl 3-p-tolylacrylate 1 as colourless liquid (4.051g, 93percent yield)
60%
With potassium phosphate; In N,N-dimethyl-formamide; at 100℃; for 5h;
General procedure: A mixture of aryl halide (1 mmol), ethylacrylate (1 mmol), K3PO4 (1 mmol), nano-Pd/Fe3O4/ZnO (0.003 g), and DMF (1.0 mL) was put into a preheated oil bath at 100 °C foran appropriate period of time. Then, the reaction mixture was diluted with EtOAc and the catalyst was removed by a magnet. The filtrate was extracted with water and the organic layer dried over CaCl2 and evaporated under reduced pressure. Resulting products were purified by column chromatography over silica gel using n-hexane/ethylacetate (5:1) as eluent to give the desired pure product with excellent yield.
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 20℃; for 48h;
4-Iodobenzenamine (1327 mg, 6.06 mmol), NaHCO3 (1140 mg, 13.57 mmol), and DMF (4 mL) were added into the 25 mL flask, the resulting mixture was stirred at rt, iodomethane (2415 mg, 17.00 mmol) was added dropwise via a dropping funnel. After the complete conversion of the starting material as monitored by TLC (eluent: petroleum ether/ethyl acetate = 2/1), the mixture was poured into cold water (10 mL), the organic layer was separated, the aqueous phase was extracted with ethyl acetate (10 mL × 3), the organic phase was combined and washed with a saturated aqueous solution of NaCl, and dried over anhydrous MgSO4. The solvent was evaporated. Flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 10/1) afforded 4-iodo-N,N-dimethylbenzenamine as a pale yellow solid (508 mg, 34%).
Part A. 4-iodoaniline (45.82 g, 209.2 mmol) and triethylamine (65.61 ml, 470.7 mmol) were dissolved into THF (800 mL) and cooled to 0 C. 5-Bromovaleryl chloride (50.0 g, 251.1 mmol) dissolved in THF (200 mL) was added dropwise to the reaction. The reaction was warmed to room temperature and stirred overnight. Reaction was cooled to 0 C. and potassium tert-butoxide (70.43 g, 627.6 mmol) was slowly added. The reaction was warmed to room temperature and stirred overnight. The reaction was concentrated and then re-dissolved in ethyl acetate (500 mL) and 3N HCl (500 mL), extracted with ethyl acetate (2×250 mL), washed with 1N HCl (3×250 mL), washed with brine (1×250 mL), and dried (Na2SO4). Purification by silica gel chromatography using 0%-100%ethyl acetate/hexane gradient as eluent to afford 51.03 g (81%): 1H NMR (CDCl3) delta 7.70 (d, j=8.4 Hz, 2H), 7.03 (d, j=8.8 Hz, 2H), 3.62 (t, j=5.9 Hz, 2H), 2.56 (t, j=5.7 Hz, 2H), 2.50-1.88 (m, 4H) ppm.
81%
Part A. 4-iodoaniline (45.82 g, 209.2 mmol) and triethylamine (65.61 mL, 470.7 mmol) were dissolved into THF (800 mL) and cooled to 0 C. 5-Bromovaleryl chloride (50.0 g, 251.1 mmol) dissolved in THF (200 mL) was added dropwise to the reaction. The reaction was warmed to rt and stirred overnight. Reaction was cooled to 0 C. and potassium tert-butoxide (70.43 g, 627.6 mmol) was slowly added. The reaction was warmed to rt and stirred overnight. The reaction was concentrated and then redissolved in ethyl acetate (500 mL) and 3N HCl (500 mL), extracted with ethyl acetate (2×250 mL), washed with 1N HCl (3×250 mL), washed with brine (1×250 mL), and dried (Na2SO4). Purification by silica gel chromatography using 0%-100% ethyl acetate/hexane gradient as eluent to afford 51.03 g (81%): 1H NMR (CDCl3)? delta 7.70 (d,j=8.4 Hz, 2H), 7.03 (d,j=8.8 Hz, 2H), 3.62 (t,j=5.9 Hz, 2H), 2.56 (t,j=5.7 Hz, 2H), 2.50-1.88 (m, 4H) ppm.
48.5%
EXAMPLE 1; l-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxo-l-piperidinyl)phenyl)-4,5,6,7- tetrahydro-lH-pyrazole- [3,4-c] pyridine-3-carboxamide; l-(4-Iodophenyl) piperidin-2-one:; Triethylamine (31.10 g, 307.38 mmol) was added to a solution of 4-iodoaniline (30.0 g, 136.98 mmol) in tetrahydrofuran (80OmL). After cooling the mixture to about 0 0C, a solution of 5- bromo-pentanoyl chloride (32.7g, 163.90 mmol) in tetrahydrofuran (20OmL) was slowly added to the mixture over a period of about 30 minutes. The mixture was stirred at ambient temperature for about 16 hours. The mixture was then cooled to about 0 0C, and potassium tert-butoxide (46.0 g, 410 mmol) was slowly added. The mixture was stirred at ambient temperature for about 18 hours. Evaporation of the solvent in vacuo afforded a thick oily mass which was acidified to a pH of about 2.0 by adding a 3 N hydrochloric acid solution. Following standard extractive workup with ethyl acetate (3 x 500 mL), the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane, 0%-100%) to give the title product as an off-white solid (20.0 g, yield = 48.5%). mp: 108-1100C. 1H NMR (400 MHz, CDCl3) delta 1.93-1.95 (m, 4H), 2.55 (t, J=6.2 Hz, 2H), 3.62 (t, J=5.2 Hz, 2H), 7.02 (d, J= 8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H); IR (KBr) upsilon 3256, 3049, 2936, 2864, 1634, 1576, 1482, 1434, 1164, 1000, 819, 709 cm"1; MS 302 (M + 1).
With 8-quinolinol; potassium carbonate; In N,N-dimethyl-formamide;Inert atmosphere; Reflux; Large scale;
In a 3000L reactor, iodoaniline 438kg, 2-hydroxypyridine 190kg, 8-hydroxyquinoline 58kg, potassium carbonate 207kg, N,N-dimethylformamide (DMF) 1500kg, nitrogen protection, stirring is turned on. The mixture was warmed to reflux and reacted overnight. Chromatography was followed up to the end of the reaction. The potassium iodide was removed by filtration. Part of the DMF was recovered under reduced pressure, cooled to 50 C., and filtered to give crude 1-(4-aminophenyl)-1H-pyridin-2-one. The crude product was added with 740 kg of ethanol, heated and dissolved, and 55 kg of activated carbon was added for decoloration. The solution was filtered while hot, and the filtrate was cooled and crystallized. The product was filtered, dried and packaged to give 1-(4-aminophenyl)-1H-pyridin-2-one with a yield of 95. %,The purity is 99%.
70%
With copper(l) iodide; 8-quinolinol; caesium carbonate; In 1,4-dioxane; dimethyl sulfoxide; at 120℃; for 15h;Sealed tube;
11128] In a similar manner as described in Example 114,(R)-5-(3-(4-methoxybenzamido)piperidin- 1 -yl)-3-(4-(2-ox-opyridin- 1 (2H)-yl)phenylamino)pyrazine-2-carboxamide(154) was prepared using 1 -(4-aminophenyl)pyridin-2(1H)-one. MS found for C29H29N704 as (M+H) 540.1, (M-H)538.3. UV: X=260, 285, 308, 346, 369 nm Synthesis of i-(4-aminophenyl)pyridin-2(1H)-one: The mixture of 4-iodoa-niline (1.00 g, 4.56 mmol), 2-hydroxypyridine (650 mg, 6.84mmol), fine powder Cs2CO3 (2.97 g, 9.12 mmol), fine powderCul (180mg, 0.92 mmol), 8-hydroxyquinoline (140mg, 0.92mmol) in 6 mE DMSO and 10 mE dioxane was stirred in asealed tube at 120 C. for 15 h. The mixture was diluted with300 mE EtOAc, filtered through celite, washed with brine,dried, concentrated and subjected to flash column with 0 to7% MeOR in dichioromethane to isolate this compound (590mg, yield 70%).
53.45%
With copper(l) iodide; 8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 130℃; for 12h;Inert atmosphere;
General procedure: Compound 1 (5g, 22.83mmol) was dissolved in DMSO (120mL), followed by the addition of 2-Piperidinone (4.53g, 45.66mmol), CuI (0.43g, 2.28mmol), 8-hydroxy-quinoline (0.66g, 4.57mmol) and K2CO3 (9.46g, 68.49mmol). The mixture was heated to 130C under N2 for 12h, cooled, and quenched with water (120mL). The organics were extracted with ethyl acetate (2×150mL) and dried (Na2SO4). Purification by silica gel column chromatography (n-hexane/ethyl acetate, 5/1 to 3/1, as eluent) afforded compound 2 as faint yellow (2.80g, 64.47%).
39.8%
With copper(l) iodide; 8-quinolinol; caesium carbonate; In dimethyl sulfoxide; at 120℃;
A mixture of pyridin-2-ol (2.00 g, 21.0 mmol), 4-iodoaniline (4.61 g, 21.0 mmol), 8-quinolinol (0.61 g, 4.2 mmol), Cul (0.80 g, 4.2 mmol) and Cs2C03 (10.26 g, 31.5 mmol) in DMSO (50 mL) was stirred at 120C for overnight. After filtration, the filtrate was partitioned between EA and water and the aqueous layer was further extracted with EA. The combined organic layers was washed with water and brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound as a green solid (1.56 g, 39.8 % yield). MS (m/z): 186.9 (M+H)+.
39.8%
With copper(l) iodide; 8-quinolinol; caesium carbonate; In dimethyl sulfoxide; at 120℃;
A mixture of pyridin-2-ol (2.00 g, 21.0 mmol), 4-iodoaniline (4.61 g, 21.0 mmol), 8-quinolinol (0.61 g, 4.2 mmol), Cul (0.80 g, 4.2 mmol) and Cs2C03 (10.26 g, 31.5 mmol) in DMSO (50 mL) was stirred at 120C for overnight. After filtration, the filtrate was partitioned between EA and water and the aqueous layer was further extracted with EA. The combined organic layers was washed with water and brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound as a green solid (1.56 g, 39.8 % yield). MS (m/z): 186.9 (M+H)+.
With 8-quinolinol; potassium carbonate;copper(l) iodide; In dimethyl sulfoxide; at 130℃;
A mixture of 4-iodoaniline (1.00 g, 4.57 mmol), 2-hydroxypyridine (0.477 g, 5.02 mmol), 8-hydroxyquinoline (0.110 g, 0.759 mmol) and K2CO3 (0.945 g, 6.85 mmol) in DMSO (10 mL) was degassed with Ar before being charged with CuI (0.145 g, 0.763 mmol). The mixture in a sealed tube was then heated at 1300C overnight. Water and n-BuOH were added. The mixture was filtered. The n-BuOH phase was separated, and concentrated in vacuo to give a solid (0.666 g), which was pure enough for subsequent reactions. MS 187.3 (M+H).
With copper(l) iodide; 8-quinolinol; caesium carbonate; In 1,4-dioxane; dimethyl sulfoxide; at 120℃; for 6h;
EXAMPLE 1255-Chloro-N-(( 1 -(4-(2-oxopyridin- 1 (2H)-yl)-2-(pyridin-4-yl)phenyl)- 1 H- 1 ,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide (125); SCHEME 12 <n="125"/>Step 1 :4-Iodoaniline (12.1, 10.0 g, 45.6 mmol) was dissolved in 80 niL dioxane and 40 niL DMSO. To it were added 2-hydroxypyridine (8.68 g, 91.2 mmol), 8-hydroxyquinoline (1.32 g, 9.12 mmol), cesium carbonate (30.0 g, 91.2 mmol) and CuI (1.73 g, 9.12 mmol). The mixture was stirred at 120 0C for 6 hrs. It was filtered, concentrated, and taken into 800 mL chloroform. The organic solution washed with brine twice and concentrated to its 1A volume. The solid crashed out was isolated by filtration, washed with cold DCM, and dried in vacuo to give compound 12.2 (4.62 g, 54 %). MS found for C11H10N2O (M+H)+ 187.1.
With potassium carbonate;copper(l) iodide; 8-quinolinol; In dimethyl sulfoxide; at 130℃;Heating in a sealed tube;
EXAMPLE 137 Preparation of (2S) N-[4-(2-rhoyridon-l-yl)rhohenyl]-2-phenyl-2-(4- chlorophenylaminocarbonylamino)-acetamide; A. Preparation of 4-(2-pyridon- 1 -yl)phenylamine; [0496] A mixture of 4-iodoaniline (1.00 g, 4.57 mmol), 2-hydroxyrhoyridine (0.477 g, 5.02 mmol), 8-hydroxyquinoline (0.110 g, 0.759 mmol) and K2CO3 (0.945 g, 6.85 mmol) in DMSO (10 mL) was degassed with Ar before being charged with CuI (0.145 g, 0.763 mmol). The mixture in a sealed tube was then heated at 130 0C overnight. Water and nBuOH were added. The mixture was filtered. The nBuOH phase was separated, and concentrated in vacuo to give a solid (0.666 g), which was pure enough for subsequent reactions. MS 187.3 (M+H).
With copper(l) iodide; 8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 130℃;
A. Preparation of 4-(2-pyridon-l-yl)phenylamme; EPO <DP n="50"/>[0186] A mixture of 4-iodoaniline (1.00 g, 4.57 mmol), 2-hydroxypyridine (0.477 g, 5.02 mmol), 8-hydroxyquinoline (0.110 g, 0.759 mmol) and K2CO3 (0.945 g, 6.85 mmol) in DMSO (10 mL) was degassed with Ar before being charged with CuI (0.145 g, 0.763 mmol). The mixture in a sealed tube was then heated at 130 0C overnight. Water and nBuOH were added. The mixture was filtered. The nBuOH phase was separated, and concentrated in vacuo to give a solid (0.666 g), which was pure enough for subsequent reactions. MS 187.3 (M+H).
(1) Under an argon atmosphere, sodium hydride (100 mg) was added to a solution of 4-iodoaniline (220 mg) and <strong>[22536-63-6]<strong>[22536-63-6]2-chloro-4-methoxypyrimidin</strong>e</strong> (145 mg) in anhydrous DMF (10 ml), and the resulting mixture was stirred at 125C for 21 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extracting the resulting mixture with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate =10/1) to obtain N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg).
[Show Image] (1) Under an argon atmosphere, sodium hydride (100 mg) was added to a solution of 4-iodoaniline (220 mg) and <strong>[22536-63-6]<strong>[22536-63-6]2-chloro-4-methoxypyrimidin</strong>e</strong> (145 mg) in anhydrous DMF (10 ml), and the resulting mixture was stirred at 125C for 21 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extracting the resulting mixture with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate = 10/1) to obtain N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg).
With sodium hydride; In N,N-dimethyl-formamide; at 125℃; for 21h;
Reference Example 24 N-(4-Iodophenyl)-4-methoxy-N-methylpyrimidin-2-amine [Show Image] (1) Under an argon atmosphere, sodium hydride (100 mg) was added to a solution of 4-iodoaniline (220 mg) and <strong>[22536-63-6]<strong>[22536-63-6]2-chloro-4-methoxypyrimidin</strong>e</strong> (145 mg) in anhydrous DMF (10 ml), and the resulting mixture was stirred at 125C for 21 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extracting the resulting mixture with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate = 10/1) to obtain N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg).
With sodium hydride; In N,N-dimethyl-formamide; at 125℃; for 21h;
Under an argon atmosphere, sodium hydride (100 mg) was added to a solution of 4-iodoaniline (220 mg) and <strong>[22536-63-6]<strong>[22536-63-6]2-chloro-4-methoxypyrimidin</strong>e</strong> (145 mg) in anhydrous DMF (10 ml), and the resulting mixture was stirred at 125C for 21 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by extracting the resulting mixture with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate = 10/1) to obtain N-(4-iodophenyl)-4-methoxypyrimidin-2-amine (46 mg).
Step 1. Preparation of N-t-Boc-4-iodoaniline The desired compound was prepared according to the method of Example 4, step 1, except substituting 4-iodoaniline for 3-bromoaniline. mp 140-141 C. 1 H NMR (300 MHz, CDCl3) delta7.57 (2H, d, J=9 Hz), 7.13 (2H, d, J=9 Hz), 6.43 (1 H, br s), 1.52 (1H, br s). MS m/e 320 (M+H)+, 337 (M+NH4)+.
Step 1. Preparation of N-t-Boc-4-iodoaniline. The desired compound was prepared according to the method of Example 4, step 1, except substituting 4-iodoaniline for 3-bromoaniline. mp 140-141 C. 1 H NMR (300 MHz, CDCl3) delta7.57 (2H, d, J=9 Hz), 7.13 (2H, d, J=9 Hz), 6.43 (1H, br s), 1.52 (1H, br s). MS m/e 320 (M+H)+, 337 (M+NH4)+.
With potassium phosphate; trans-1,2-cyclohexanediamine;copper(l) iodide; In 1,4-dioxane; at 110℃; for 4h;
mixture of <strong>[34770-60-0]4-methyl-2-piperazinone</strong> (200 mg, 1.75 mmol), 4-iodoaniline (384 mg, 1.75 mmol), K3PO4 (848 mg, 4.00 mmol) and 1,2-trans-diaminocyclohexane (98 uL, 0.80 mmol) in dioxane (6 mL) was degassed with Ar before being charged with CuI (76 mg, 0.40 mmol). The mixture in a sealed tube was heated at 110 0C for 4 h. It was then purified by a silica gel prep-TLC using CH2C12/MeOH (95/5) as solvents to give the desired product (25 mg). MS 206.2 (M+H).
With 2-chloro-1,3-dimethylimidazolinium chloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;
b. To a suspension of Cpd 1b (6.21 g, 30.1 mmol) in methylene chloride (200 mL) was subsequently added diisopropylethylamine (12.0 mL, 68.9 mmol), para-iodoaniline (6.62 g, 30.2 mmol) and DMC coupling reagent (5.62 g, 33.2 mmol). The reaction was stirred at ambient temperature for 16 h, then washed twice with 1 N HCl (200 mL) and twice with saturated NaHCO3 solution (200 mL). The organics were dried with Na2SO4, filtered and evaporated in vacuo. The residue obtained was triturated with 1:1 hexanes/ethyl acetate (25 mL). The resultant solid was collected by filtration and rinsed once with 1:1 hexanes/ethyl acetate (10 mL) and dried. Compound 1c (8.31 g, 20.4 mmol) was obtained as a white crystalline powder. MS: M+H+=407.9, 1H NMR (CDCl3): delta 7.59 (d, 2H), 7.33 (d, 2H), 7.18 (t, 4H), 6.88 (br s, 1H), 3.02 (t, 2H), 2.66 (t, 2H), 1.31 (s, 9H).
With triethylamine; In acetonitrile; at 20℃; for 16h;
To a solution of 10 g of 4-iodoaniline (45.6 mmol) in 200 ml of acetonitrile there are added 6.41 ml of Et3N (45.6 mmol) and 8.47 g of morpholine-4-sulphonyl chloride (45.6 mmol). The reaction mixture is stirred for 16 hours at ambient temperature. The acetonitrile is evaporated off in vacuo, and the residue is taken up in 1N HCl and extracted with CH2Cl2. The organic phases are combined, washed with brine, dried (MgSO4) and treated with animal charcoal to yield the title product. Melting point: 91 C.
2,4-diamino-6-methyl-5-(p-iodophenylazo)-pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.5 gm (90%)
With hydrogenchloride; sodium nitrite; In ethanol; water;
EXAMPLE III 2,4-Diamino-6-methyl-5-(p-iodophenylazo) pyrimidine A solution of <strong>[1791-73-7]2,4-diamino-6-methyl pyrimidine</strong> (1.0 gm) in water (60 ml) was cooled to 0 C in ice-salt bath and stirred mechanically. p-Iodo aniline (1.84 gm) was dissolved in ethanol (30 ml) and to this solution 3 N HCl (30 ml) was added. The solution was then cooled to -5 C. A solution of sodium nitrite (0.567 gm) in water (5 ml) was also cooled to 0 C. The sodium nitrite solution was then added to the p-iodo aniline solution. After shaking thoroughly, excess sodium nitrite was decomposed with a pinch of urea. The diazotized p-iodo aniline was then added to the pyrimidine solution. After stirring for ten minutes, the pH of the combined solution was adjusted to 7.0 with 30 percent sodium hydroxide. A precipitate appeared. After stirring two hours more, the product was filtered, dried in vacuum desiccator, and crystallized from ethanol. M.P. 243-44 C. Yield: 2.5 gm (90 percent).
Step 1: Preparation of (4-Iodo-phenyl)-carbamic acid tert-butyl ester (37a): 4-iodoaniline (10.0 g, 45.6 mmol) was dissolved in THF (50 mL) in an amber flask, cooled to 0 C., and treated with tert-butoxycarbonyl anhydride. The reaction was heated to 60 C. overnight, then concentrated in vacuo to give 15.5 g (106%) of the crude product which was used without further purification. MS: 318.0 (M-1 for C11H14N1O2I1 in APCI- spectrum); TLC: SiO2, Rf0.42 (6:1 hexanes/EtOAc).
With caesium carbonate;copper(l) iodide; 1,10-Phenanthroline; In toluene; at 110℃;
EXAMPLE 40; 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid [4-(2-methoxy-ethoxy)-phenyl]-amide; a. 4-(2-Methoxy-ethoxy)-phenylamine; A mixture of 4-iodoaniline (219 mg, 1.0 mmol), 2-methoxyethanol (152 mg, 2.0 mmol), copper iodide (19.0 mg, 0.1 mmol), cesium carbonate (554 mg, 1.7 mmol) and 1,10-phenanthroline (36.0 mg, 0.2 mmol) was stirred in toluene (0.5 mL) at 110 C. overnight. The reaction was then cooled to RT and filtered through silica gel and washed with diethyl ether. The ether was removed in vacuo to obtain a crude solid. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a solid (8.9 mg, 5.3%). 1H NMR (300 MHz, CDCl3) delta 6.82-6.72 (m, 4H), 4.06 (t, 2H), 3.72 (t, 2H), 3.45 (s, 3H).
1 ,3-<strong>[3973-08-8]Thiazole-4-carboxylic acid</strong> (200 mg) was dissolved in DMF (6 ml_). HATU (650 mg) and DIPEA (0.539 ml.) were added and the reaction mixture was stirred at room temperature for 15 mins. 4-lodoaniline (508 mg) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated in vacuo and the residue was dissolved in DCM. This was washed with sodium bicarbonate solution (x 2) followed by 2N HCI (x 2). The DCM was separated, dried using a hydrophobic frit and was evaporated in vacuo to give the title compound. MS calcd for (C10H7IN2O5 + H)+: 331 <n="43"/>MS found (electrospray): (M+H)+ = 331
Synthesis of 2-(4-Iodo-phenylcarbamoyl)3-methylbutyric acid (1). A solution of <strong>[601-79-6]isopropylmalonic acid</strong> (613 mg, 4.2 mmol) and DIC (330 mul, 2.1 mmol) in chloroform (2 ml) was maintained at ambient temperature for 10 min followed by the addition of 4-iodoaniline (438 mg, 2.0 mmol). Reaction mixture was stirred at ambient temperature for additional 2 h and diluted with EtOAc (150 ml). Solution was extracted with water (30 ml x 2) and brine (30 ml), and dried over MgSO4 (anh). Solvent was evaporated in vacuum. Residue was dissolved in DCM (2 ml) and subjected to flash chromatography on CombiFlash .(R). Companion unit equipped with RediSep .(R). flash column (normal phase, 35-60 micron average particle size silicagel, 80 g, Teledyne Isco); flow rate = 60 ml/min; injection volume 2.5 ml; mobile phase A: DCM; mobile phase B: MeOH; gradient 0-60percentB in 60 min. Fractions containing the desired product were combined and concentrated in vacuum. Residue was dried in vacuum overnight to obtain target product (1) (89 mg, 13percent) as white solid. LC-MS [M+H] 348.1 (C12H14INO3+H, requires 348.16).
To a suspension of 4-iodoaniline (10.00 g, 45.66 mmol, 1.00 eq) in HCi (12 M, 30 mL) at 0 C was added dropwise a solution of NaNCh (3 15 g, 45.66 mmol, 1.00 eq) in H20 ( 13 mL), and the resulting mixture was stirred at 25 C for 1 h. Then a solution of SnCk (30.91 g, 136.98 mmol, 3.00 eq) in HCI (12 M, 20 mL) was added dropwise at 0 C. The reaction mixture ws stirred at 25 C for 1 h TLC (DCM/MeOH = 10: 1) indicated the starting material was consumed completely and a new spot formed. The reaction mixture was filtered and the filter cake was dried under reduced pressure to afford (4-iodophenyl)hydrazine (9.50 g, HC1 salt, crude) as a purplish red solid. ' NMR (400 MHz, DMSO-aV) d ppm: 10 39 (br, 3H), 8.50 (br, GH), 7.59 (d, ,/= 8 8 Hz, 2H), 6.86 (d, J= 8.8 Hz, 2H).
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃;
IV-2A (2.19 g, 10 mmol) was added to a mixture of IV-2 (1.58 g, 10 mmol) and HATU (4.56 g, 12 mmol) in 20 mL of DCM. The reaction mixture was stirred at rt overnight. Then water (15 mL) was added and extracted with DCM. The organic layer was separated, dried and concentrated. The residue was purified by column (PE/EA=10/1) to afford IV-3 (1.2 g, yield 33.4%).
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 20h;Inert atmosphere;
General procedure: To a stirred solution of 40 (3.0 g, 5.85 mmol) in DMF (50 mL) were added triethylamine (2.4 mL, 17.3 mmol), CuI (113 mg, 0.593 mmol) and PdCl2(PPh3)2 (207 mg, 0.295 mmol) at room temperature under nitrogen. To the mixture was dropwise added phenylacetylene (1.9 mL, 17.3 mmol) at room temperature. The mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with EtOAc, THF and water. The organic extract was washed with water, dried over MgSO4, filtrated and then concentrated. The residue was purified with column chromatographyon NH silica gel (EtOAc). The resulting solid was washed with EtOAc/Et2O and filtrated to afford the title compound 41a as a light brown solid (2.61 g, 5.36 mmol, 91.7%).
With C35H20F34NO3(1-)*Pd(2+)*Cl(1-); N-ethyl-N,N-diisopropylamine; In neat (no solvent); at 130℃; for 0.2h;Microwave irradiation;
General procedure: A mixture of the aryl halide (1.0 mmol), alcohol (5.0 equiv), Mo(CO)6 (0.5 equiv), DIPEA (1.5 equiv) and palladacycle 1 (1 mol % Pd) was heated in a pressure tube at 130 C under microwave irradiation. The reaction was monitored by TLC. When the reaction has completed, the reaction mixture was cooled to room temperature and the alcohol was removed. The crude mixture was subjected to F-SPE to remove palladacycle 1 (see general procedure for the recycling of palladacycle 1) and the solution of crude product was concentrated, diluted with EtOAc (20 mL) and washed successively with 2 M HCl (210 mL) and water (10 mL). The organic layer was driedover anhydrous MgSO4, filtered and concentrated to give pure 6.
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In water; isopropyl alcohol; for 2h;Sealed tube; Inert atmosphere; Reflux;
Set the reflux reaction device, put the stirrer into the reaction flask, Add 4-propylphenylboronic acid, 4-iodoaniline, catalyst Pd (Pph3) 2Cl2, sodium carbonate; Sealing reaction system, The air in the sealing system is replaced with nitrogen; Immediately add isopropanol and water, stir and slowly heat to reflux, Ensure that the system is under nitrogen protection. After 2 hours, the degree of reaction was measured with TLC.
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water;Inert atmosphere; Reflux;
General procedure: To 0.329 g (1.5 mmol) 4-iodoaniline, 1.8 mmol ArB(OH)2, 0.318 g (3 mmol) Na2CO3 and 75 mg (0.075 mmol) PdCl2(PPh3)2, 15 mL of a blended solution of dioxane and water (v/v = 3/1) was added under N2 atmosphere. Then the reaction was heated to reflux and monitored by TLC. Upon cooling, the reaction mixture was dilute with sat. NH4Cl solution, then extracted with EA (3×20 mL), and the organic layer was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4 and purified by flash chromatography to afford different 4-aminobiphenyl derivatives. According to the reductive amination procedure, the 4-aminobiphenyl derivative was further treated with salicylaldehyde and to afford the corresponding compound 5&6.
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water;Inert atmosphere; Reflux;
General procedure: To 0.329 g (1.5 mmol) 4-iodoaniline, 1.8 mmol ArB(OH)2, 0.318 g (3 mmol) Na2CO3 and 75 mg (0.075 mmol) PdCl2(PPh3)2, 15 mL of a blended solution of dioxane and water (v/v = 3/1) was added under N2 atmosphere. Then the reaction was heated to reflux and monitored by TLC. Upon cooling, the reaction mixture was dilute with sat. NH4Cl solution, then extracted with EA (3×20 mL), and the organic layer was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4 and purified by flash chromatography to afford different 4-aminobiphenyl derivatives. According to the reductive amination procedure, the 4-aminobiphenyl derivative was further treated with salicylaldehyde and to afford the corresponding compound 5&6.
With C7H10N2*Pd(2+)*2Cl(1-); potassium carbonate; In methanol; water; for 0.166667h;Reflux; Schlenk technique;
General procedure: A 20mL Schlenk tube with a magnetic stir bar was charged with aryl halide (2mmol), arylboronic acid (2.4mmol), K2CO3 (5mmol), 10mL of solvent [H2O, H2O-MeOH (1:1), H2O-EtOH (1:1), H2O-EG (1:1)] and an aliquot of 0.01M solution of palladium complexes PdCl2(L)2 or Pd[(L)4]Cl2 in MeOH (0.001-0.2mol%) under air atmosphere. The reaction mixture was placed in a preheated oil bath: at 100C for MeOH-H2O, at 110C for EtOH-H2O, at 140C for H2O and at 160C for EG-H2O; and stirred under reflux for the given time. After this time, the mixture was cooled, acidified by 5M HCl (in the case of acids) and diluted with 10mL of H2O and 10mL of Et2O (or EtOAc). The organic phase was separated, and the aqueous layer was extracted with Et2O EtOAc) (2×10mL). The combined organic layers were washed with H2O (10mL), brine (10mL), and dried over Na2SO4. The pure products were obtained by a simple filtration of ether solution through silica gel pad and evaporation of a solvent.
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 48h;
11.7 mmol of iodoaniline,46.8 mmol of potassium carbonate, 35.1 mmol of 1-bromo-2-butyl octane and 25 mL of dimethylformamide were mixed to obtain a reaction solution. The reaction solution was heated to 110 C and reacted for two days. After the completion of the reaction, the reaction mixture was concentrated and extracted with water and methylene chloride. The resulting extract was concentrated and purified by column chromatography (hexane: hexane) to give a clear compound of formula (S13 ) (Yield 8.7%).
(R)-2-(2-hydroxy-3-((4-iodophenyl)amino)propyl)isoindolin-1,3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.9%
In ethanol; water; at 100℃; for 12h;
To a round bottom flask was added S-2- (oxiran-2-ylmethyl) isoindoline-1, 3-dione (2.0 g, 9.84 mmol), 4-iodoaniline (2.2 g, 10.0 mmol),Ethanol (90 mL) and water (10 mL) and heated to 100 C for 12 hours.The product precipitated out of solution.The precipitate was suction filtered, the filter cake was washed with ether and dried in vacuo. The mother liquors were combined and the solvent was distilled off under reduced pressure. To the residue, S-2- (oxiran-2-ylmethyl)Isoindoline-1, 3-dione(1.0 g, 4.92 mmol),Ethanol (90 mL) and water (10 mL),The resulting mixture was heated to 100 C for 12 hours. After filtration, the filter cake was washed with ether and dried in vacuo. The combined and dried filter cake was the title compound as a white solid (3.6 g,84.9%).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In 1-methyl-pyrrolidin-2-one; at 250℃; for 0.2h;Flow reactor;
General procedure: Selective N-monomethlyation reactions were performed in a Vapourtec E-series continuous flow system equipped with a high temperature tube reactor (10 mL, stainless steel, 0.03'' i.d., Fig. 2 ) and a membrane back pressure regulator (Zaiput). Stock solutions of aniline (20 mmol, 1.0 equiv, 2 M), DMC (5.05 mL, 60 mmol, 3.0 equiv, 6 M), and DBU (4.47 mL, 30 mmol, 1.5 equiv, 3 M) were prepared in oven-dried 10 mL volumetric flasks using NMP as the solvent. The solutions were transferred to screw-thread vials with septum caps and reagents were pumped directly from the vials. After the high temperature coiled tube reactor was heated to 250 C, peristaltic pumps (Vapourtec V-3) were used to pump the reactant solutions into the system (0.277 mL/min each for a 12 min residence time). The solutions were mixed with a cross-mixer (0.4? i.d.), passed though the high temperature coiled tube reactor. Upon exiting the reactor, the reaction stream was passed through a short segment of stainless steel tubing to enable the reaction to cool and then exited the system by passage through the back pressure regulator (Note: PFA fittings should not be used at the exit of the reactor as they will deform due to the high temperature of the reaction stream and cause leaks in the system. Stainless steel connectors and tubing (12'') were used in our system.). After the flow system was equilibrated for 18 min, the product stream was collected for 5 min (2.77 mmol of aniline). The crude mixture was dissolved in ethyl acetate and washed with brine. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 25 g Ultra-sil, 3-15% ethyl acetate in hexanes) to afford the desired product.
N-(4-iodophenyl)-5-nitropyrimidin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
In acetonitrile;Inert atmosphere;
The first method of preparation:A dry 50 mL reaction jar was evacuated and passed through nitrogen three times. Then, 4-iodoaniline (219 mg, 1.0 mmol, 1.0 equiv) was added to the reaction flask, and 10.0 mL of dried acetonitrile was added to stir to 4-iodoaniline. Fully soluble,Then <strong>[10320-42-0]2-chloro-5-nitropyrimidine</strong> (0.1593 g, 1.0 mmol, 1.0 equiv) was added to the reaction flask.The entire mixture was reacted under nitrogen pressure for 4-5 hours.The reaction detects the progress of the reaction by TLC.The reaction can be stopped if it is detected that all the aniline is completely reacted.The experimental treatment is to drain the solution in the reaction;The solute in the reaction flask was dissolved with ethyl acetate.And transferred to a 100 mL round bottom flask,Add 2 mL (200-300 mesh) of silica gel to the round bottom flask for spin-drying (petroleum ether and acetic acid B)Ester) over silica gel in the column.Wait until the intermediate product is pale yellow crystalN-(4-iodophenyl)-5-nitropyrimidin-2-amine(302 mg, 88% yield).
2 mmol of trifluoroethylamine hydrochloride, 1 mL of water, 34 uL of acetic acid, and 1 mL of dichloromethane were placed in a reaction tube, and a rubber stopper was placed and fixed on a stirrer. Take 42 mg of sodium nitrite in a 1.5 mL sample tube.Add 1 mL of water to the sample tube.Shake the sample tube to dissolve sodium nitrite.Dissolving the dissolved sodium nitrite solution into the reaction tube with a syringe,Stir for half an hour at room temperature.Dissolve the iron porphyrin of formula 3 with 1 mL of dichloromethane (R1 = calixarene, R2 = R3 = CN, L = OAc) (catalytic amount, for theA molar amount of amine 9/1000), 0.24 mmol of 4-iodoaniline was taken in the sample tube. After half an hour, mix the sample in the sample tubeThe mixture was added dropwise to the reaction tube, and stirred while stirring for 12 hours. The reaction solution was cooled to room temperature, and some impurities were removed by filtration, and concentrated.After purification by column chromatography, the desired product is obtained. The column chromatography eluent is a mixed solvent of petroleum ether and acetone. 4-The structure of iodine-N-(2,2,2-trifluoroethyl)aniline is as follows:The compound was a pale yellow liquid with a yield of 63%
To a 1000mL round-bottomed flask equipped with a magnetic stir bar was added 4-iodoaniline (1, 40.0 g, 183 mmol, 1 equiv), (HCHO)n (7.67 g, 256 mmol, 1.4 equiv) and CH3ONa (13.8 g, 256 mmol, 1.4 equiv). The flask was evacuated and refilled with nitrogen three times and then 400 20 mL MeOH was injected slowly into the flask under ice bath. The reaction solution was stirred at r.t. for 5 h. After the reaction was cooled again in ice bath, NaBH4 (15.2 g, 402 mmol, 2.2 equiv) was added in three portions at the interval of 5 min. The reaction was refilled with nitrogen and stirred at 60 C for 16 h. Then the reaction mixture was filtered over celite. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel with PE/EA (6:1) as the eluent. The product 2 was obtained as a yellow liquid in 82% yield (35.0 g, 150mmol). 1H NMR (500 MHz, CDCl3) delta 7.47-7.37 (m, 2H), 6.43-6.33 (m, 2H), 3.68 (s, 1H), 2.78 (s, 3H). 13C NMR (126 MHz, CDCl3) delta 148.81, 137.73, 114.67, 77.79, 30.62. HRMS (ESI) Calcd. for C7H9IN: [M+H]+, 233.9780. Found: m/z 233.9773.
N-(4-iodophenyl)imidazo[1,2-a]pyrazine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With 1-methyl-1H-imidazole; 2-chloro-1-methyl-pyridinium iodide; In N,N-dimethyl-formamide; at 80℃; for 0.25h;Inert atmosphere; Microwave irradiation; Sealed tube; Green chemistry;
General procedure: Imidazo[1,2-a]pyrazine-2-carboxylic acid (5) (1.0 equiv.) Mukaiyama?s reagent and 2-chloro-1-methylpyridinium iodide (1.2 equiv.) were suspended in DMF (5.0 mL) under nitrogen atmosphere. Into the reaction mixture, aliphatic/aromatic amines (6a-l) (1.0 equiv.) and 1-methylimidazole (2.0 equiv.) were added. A homogeneous solution was formed after a gentle stirring. The reaction mixture was sealed in a microwave glass reactor and then irradiated by microwave oven at a constant temperature of 80 C with continuous stirring (1 min ramp, 15 min reaction time). After the reaction was completed, the solvent was removed through a rotary evaporator and the resulting residue was extracted by a biphasic system of 45 mL diethyl ether and 45 mL water. After the layer separation, the ether layer was dried by anhydrous sodium sulphate, followed by an evaporation of ether to get compounds 7a-l (Scheme-I).