* 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 N,N,N-trimethylbenzenemethanaminium dichloroiodate; calcium carbonate In methanol; dichloromethaneHeating / reflux
A solution of methyl 4-aminobenzoate (5.0 g; 0.033 mol.), benzyltrimethylammonium dichloroiodate (22.1 g; 0.056 mol.) and calcium carbonate (5.0 g; 0.050 mol.) in a mixture of dichloromethane (200 ml) and methanol (100 ml_) were stirred and heated under reflux overnight. The solution was cooled, washed with saturated sodium bisulphate, dried and evaporated to afford the desired product (9.6 g; quant.) which was used directly EPO <DP n="32"/>without further purification. 1 H NMR (400 MHz, DMSOd6) δ ppm 3.75 (s, 3 H) 6.09 (s, 2 H) 6.75 (d, J=8.59 Hz, 1 H) 7.66 (dd, J=8.59, 2.02 Hz, 1 H) 8.11 (d, J=2.02 Hz, 1 H).
100%
With N,N,N-trimethylbenzenemethanaminium dichloroiodate; calcium carbonate In methanol; dichloromethaneHeating / reflux
A solution of methyl 4-aminobenzoate (5.0 g; 0.033 mol.), benzyltrimethylammonium dichloroiodate (22.1 g; 0.056 mol.) and calcium carbonate (5.0 g; 0.050 mol.) in a mixture of dichloromethane(200 ml) and methanol (100 ml.) were stirred and heated under reflux overnight. The solution was cooled, washed with saturated sodium bisulphate, dried and evaporated to afford the desired product (9.6 g; quant.) which was used directly without further purification. 1 H NMR (400 MHz, DMSOd6) δ ppm 3.75 (s, 3 H) 6.09 (s, 2 H) 6.75 (d, J=8.59 Hz, 1 H)7.66 (dd, J=8.59, 2.02 Hz, 1 H) 8.1 1 (d, J=2.02 Hz, 1 H).
93%
With pyridine iodine monochloride In methanol for 2 h; Reflux; Inert atmosphere
To a stirred solution of methyl 4-aminobenzoate 18 (1.0 g, 6.62 mmol, 1.0 eq.) in methanol (60 mL) was added pyridinium iodochloride(1.60 g, 6.62 mmol, 1.0 eq.). The reaction mixture was refluxed for 2h under nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated in vacuo. The reaction was diluted with ethyl acetate and washed with brine. The organic layer was dried over MgSO4 and was concentrated in vacuo. The crude was purified by chromatography on silica gel column (cyclohexane/EtOAc, gradient 100:0 to 70:30) and concentrated under reduced pressure to afford the compound 19, as a pale yellow solid (93percent yield); mp 90°C; 1H NMR (CDCl3, 500 MHz) δ 8.33 (d, 4J = 1.9 Hz, 1H), 7.81 (dd, 3J = 8.5 Hz, 4J = 2.0 Hz, 1H), 6.70 (d, 3J = 8.5 Hz, 1H), 4.53 (br s, 2H), 3.85 (s, 3H); 13C NMR (CDCl3, 126 MHz) δ 166.0 (CO), 150.9 (Cq), 141.2 (CH), 131.4 (CH), 121.4 (CH), 113.3 (Cq), 82.3 (Cq), 52.0 (CH3); IR (neat, cm-1) ν 3472, 3365, 2997, 2948, 2844, 1684, 1627, 1249, 764. Spectral and analytical data matched with literature.[2]
90%
With N-iodo-succinimide; [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold(I) In dichloromethane; toluene at 20℃; for 14 h;
General procedure: To a stirred solution of the substrate (1 mmol) in CH2Cl2 or (CH2Cl)2 (0.1 M) were added Ph3PAuNTf2 (0.025 mmol, 19 mg; complex Ph3PAuNTf2 toluene, 2:1) followed by N-iodosuccinimide (1.1 mmol, 248 mg). The resulting solution was stirred at r.t. or under reflux until complete conversion of the starting material. After removal of the solvent under reduced pressure, the crude material was purified by flash column chromatography using different gradients of hexanes and EtOAc to obtain the pure desired products.
73%
With Iodine monochloride In acetic acid at 20 - 30℃; for 1 h;
10,4 g (68,8 [MMOL) 4-AMINOBENZOESaeUREMETHYLESTER] wurden in 100 ml Essigsaeure geloest und mit 11,17 g (68,8 [MMOL)] [LODMONOCHLORID] in 100 ml Essigsaeure versetzt. Dabei stieg die Reaktionstemperatur [AUF 30°C] an. Nach einer Stunde bei Raumtemperatur wurde auf [10percent] ige Natriumhydrogencarbonat-Loesung gegossen, mit Dichlormethan extrahiert, die organische Phase getrocknet und eingeengt. Man erhielt 14 g (73 percent) des gewuenschten Produktes.
Reference：
[1] Patent: WO2007/38331, 2007, A2, . Location in patent: Page/Page column 30-31
[2] Patent: WO2007/103759, 2007, A2, . Location in patent: Page/Page column 48
[3] European Journal of Medicinal Chemistry, 2019, p. 234 - 248
[4] European Journal of Organic Chemistry, 2001, # 24, p. 4607 - 4613
[5] Synlett, 2014, vol. 25, # 3, p. 399 - 402
[6] Tetrahedron Letters, 2002, vol. 43, # 5, p. 787 - 790
[7] Advanced Synthesis and Catalysis, 2007, vol. 349, # 7, p. 1159 - 1172
[8] RSC Advances, 2014, vol. 4, # 36, p. 18930 - 18932
[9] Tetrahedron, 1990, vol. 46, # 13/14, p. 4587 - 4594
[10] Tetrahedron Letters, 1986, vol. 27, # 11, p. 1293 - 1296
[11] Journal of Organic Chemistry, 2003, vol. 68, # 5, p. 1843 - 1851
[12] Patent: WO2003/104188, 2003, A1, . Location in patent: Page 27, 28
[13] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 9, p. 2722 - 2725
[14] Tetrahedron Letters, 1997, vol. 38, # 14, p. 2439 - 2442
[15] Chemical Communications, 2017, vol. 53, # 24, p. 3481 - 3484
[16] Journal of Labelled Compounds and Radiopharmaceuticals, 1996, vol. 38, # 3, p. 227 - 237
[17] Organic Letters, 2005, vol. 7, # 10, p. 2043 - 2046
[18] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 21, p. 5646 - 5649
[19] Journal of Organic Chemistry, 2002, vol. 67, # 18, p. 6395 - 6405
[20] Patent: WO2008/73865, 2008, A2, . Location in patent: Page/Page column 62
[21] Patent: US2002/19527, 2002, A1,
[22] Patent: WO2007/138033, 2007, A1, . Location in patent: Page/Page column 33-34
With copper(II) choride dihydrate; lithium chloride hydrate In ethanol for 48 h; Reflux
General procedure: A round-bottomed flask (25 mL) was charged with substrate (2 mmol), CuCl2·2H2O (6 mmol), LiCl·H2O (2 mmol) and EtOH (4 mL). The resulting reaction mixture was stirred at reflux. After the completion of the reaction monitored by TLC, EtOH was removed under reduced pressure. Then ammonium hydroxide (4 mL, 25percent) and water (10 mL) were added and the aqueous phase was extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with brine (8 mL×3) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude mixture was purified by chromatography on silica gel to obtain the desired products.
Reference：
[1] Angewandte Chemie - International Edition, 2011, vol. 50, # 33, p. 7670 - 7673
25
[ 619-45-4 ]
[ 106896-49-5 ]
Yield
Reaction Conditions
Operation in experiment
93%
With N-Bromosuccinimide In chloroform at 0℃; for 3 h;
Preparation 166: 4-Amino-3-bromo-benzoic acid methyl ester; [1367] 4-Amino-benzoic acid methyl ester (17g, O.lmol) was dissolved in chloroform(25OmL). N-bromosuccinimide (2Og, O.lmol) was added at O0C, and at the same temperature the mixture was stirred for 3 h. The solvent was distilled off, and ethyl acetate (10OmL) was added to the residue. The mixture was washed with aqueous sodium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and purified from hexane to give the title compound (24.3g, Yield 93percent).[1368] NMR: 1H-NMR(CDCl3) δ 8.11(1H, d), 7.79-7.77(1H, m), 6.72(1H, d), 4.51(2H, br s), 3.85(3H, s)
1.4 g
at 0℃;
To a stirred solution of compound I (1.51 g) in acetic acid Br2 (1.59 g) was added at 0 °C. A large quantity of white solid was obtained. TCL result showed that no starting material remained. The solid was purified by column chromatography on silica gel (DCM:CH3OH = 20:1) to afford a white solid compound II (1.4g). The subsequent reaction followed the procedure outlined in Section 4.2.1.Total yield 0.7percent, brownish yellow, 1H NMR (400 MHz, DMSO-d6): δ 7.034 (s, 3H), 7.731 (dd, J1 = 11.4 Hz, J2 = 1.60 Hz, 1H), 7.955 (d, J = 1.60 Hz, 1H), 8.647 (d, J = 8.80 Hz, 1H), 9.556 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 179.38, 178.73, 159.26, 138.54, 128.52, 124.86, 123.93, 121.62, 116.51; HRMS (ESI) found: 345.9439, [C9H8N5S2BrO + H]+ calcd: 345.9432.
Reference：
[1] Journal of Organic Chemistry, 2014, vol. 79, # 21, p. 10410 - 10416
[2] Patent: WO2010/93191, 2010, A2, . Location in patent: Paragraph 1365-1368
[3] Organic Letters, 2015, vol. 17, # 12, p. 2886 - 2889
[4] European Journal of Medicinal Chemistry, 2011, vol. 46, # 7, p. 2930 - 2936
[5] Synthesis (Germany), 2013, vol. 45, # 11, p. 1497 - 1504
[6] Journal of the American Chemical Society, 2016, vol. 138, # 40, p. 13147 - 13150
[7] Chinese Journal of Chemistry, 2018, vol. 36, # 9, p. 815 - 818
26
[ 619-45-4 ]
[ 318276-74-3 ]
Reference：
[1] Journal of Organic Chemistry, 2002, vol. 67, # 18, p. 6395 - 6405
27
[ 619-45-4 ]
[ 162046-66-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 15, p. 4646 - 4661
28
[ 619-45-4 ]
[ 219763-85-6 ]
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 6, p. 2232 - 2235
29
[ 619-45-4 ]
[ 6296-89-5 ]
Reference：
[1] Angewandte Chemie - International Edition, 2013, vol. 52, # 47, p. 12426 - 12429[2] Angew. Chem., 2013, vol. 125, # 47, p. 12652 - 12656,4
30
[ 887144-94-7 ]
[ 619-45-4 ]
[ 167760-75-0 ]
Yield
Reaction Conditions
Operation in experiment
67%
With tris[2-phenylpyridinato-C2,N]iridium(III) In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Irradiation
Under nitrogen or argon, 0.4 mmol, 0.2mmol,Ir (ppy) 3 (2mg) and DMF1 ml was added to the reaction flask, followed by blue LEDlights (7W) at room temperature irradiation straight trivalent iodine reagent completeconversion of the reaction. Add 10 ml of saturated Na 2CO 3Aqueous solution, andextracted three times with ethyl acetate, washed with a saturated brine, dried overanhydrous Na 2SO 4The organic layer was dried. Column chromatography (eluent: petroleum ether 60-90: ethyl acetate = 15: 1-8: 1) to give the product in 67 percent.
With copper(II) choride dihydrate; lithium chloride hydrate; In ethanol; for 48h;Reflux;
General procedure: A round-bottomed flask (25 mL) was charged with substrate (2 mmol), CuCl2·2H2O (6 mmol), LiCl·H2O (2 mmol) and EtOH (4 mL). The resulting reaction mixture was stirred at reflux. After the completion of the reaction monitored by TLC, EtOH was removed under reduced pressure. Then ammonium hydroxide (4 mL, 25%) and water (10 mL) were added and the aqueous phase was extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with brine (8 mL×3) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude mixture was purified by chromatography on silica gel to obtain the desired products.
With 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 85.0℃; for 18h;
Step 1 4-(5-Bromoiotamiotadazo[l,2-a]pyraziotan-8-ylamiotano) benzoic acid methyl ester[00266] A mixture of 5,8-dibromoimidazo[l,2-a]pyrazme (2g, 7 3mmol), 4-amino benzoic acid methyl ester (0 93g, 6 2mmol), NaO'Bu (0 98g, 10 2mmol), Pd2(dba)3 (133mg, 0 14mmol), Xantphos (168mg, 0 29mmol) and toluene is degassed with nitrogen, then heated at 850C for 18 hours The toluene is removed in vacuo, then MeOH is added to the crude residue The solid is collected by filtration and dried in the vacuum oven The solid is identified as the desired title ester The filtrate is chromatographed with petrol EtOAc (70 30 followed by 50 50) and the fractions containing the desired product, combined, evaporated and triturated with MeOH The resultant solid is collected by filtration and is also identified as the desired ester
EXAMPLE 3A 7-(tert-Butoxycarbonylamino)heptanoic acid (0.96 g, 3.91 mmol) and methyl 4-aminobenzoate (0.65 g, 4.30 mmol) were processed as in example 1C to provide the title compound. MS (APCI+) m/e 379 (M+H)+.
β-(2-N-Acetylamino-5-carboxyphenyl)ethanol[ No CAS ]
[ 183430-69-5 ]
Yield
Reaction Conditions
Operation in experiment
9.5 g (29.3%)
With tert-butylhypochlorite; triethylamine; In hexane; dichloromethane; water; ethyl acetate;
EXAMPLE 33 STR37 beta-(2-N-Acetylamino-5-carboxyphenyl)ethanol. To a mixture of methyl 4-aminobenzoate (Aldrich, 15.1 g, 0.1 mol) in methylene chloride (400 mL) at -70 C. was added a solution of t-butyl hypochlorite (12.0 g, 0.011 mol in 50 mL methylene chloride) over a period of 10 min. The mixture was stirred at -70 C. for further 10 min and <strong>[4455-13-4]ethyl methylthioacetate</strong> (13.42 g, 0.1 mol in 50 mL methylene chloride) was added to it over a period of 10 min. The mixture was further stirred for 1 h at the same temperature and subsequently, triethylamine (11.2 g, 0.11 mol in 40 mL methylene chloride) was added to it over a period of 10 min. The cooling bath was removed and the mixture was brought to room temperature. Water (120 mL) was added, the organic layer separated, dried over sodium sulphate, filtered, and concentrated to give a brown viscous oil. The oil was taken in ether (200 mL) and triethylamine (40 mL) and cooled to 0-5 C. in an ice bath. Acetyl chloride (8.6 g, 0.11 mol) in ether (50 mL) was added dropwise over a period of 15 min. The reaction mixture was stirred for 1 h. Water (200 mL) was added, the organic layer separated, washed with water, dried over sodium sulphate, filtered, and concentrated to give a syrup. This syrup was purified by passing through a column of silica gel using ethyl acetate:hexane (1:2) as eluent. The appropriate fractions were pooled, combined, and concentrated. The residue of the desired product was recrystallized from ethyl acetate-hexane to give 9.5 g (29.3%) of ethyl alpha-(2-acetylamino-5-methoxycarbonylphenyl)-alpha-methylthio acetate as a white solid, mp 95-96 C. Analysis: Calculated for C15 H19 NO5 S: C, 55.37; H, 5.88; N, 4.31 Found: C, 55.43; H, 5.91; N, 4.28
methyl 4-(N-[2-(tert-butyldimethylsilyloxy)ethyl]-amino)-benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;
(a) methyl 4-(N-[2-(tert.-butyldimethylsilyloxy)ethyl]-amino)benzoate To a solution of 1-(tert.-butyldimethylsilyloxy)-2-iodoethane (45.10 gm, 160 mmol) in DMF (50 mL) was added methyl 4-aminobenzoate (4.54 gm, 30 mmol) and diisopropylethylamine (6 mL, 34 mmol). This solution was heated at 95° for approximately 21 hours. The solvent was removed by concentration, in vacuo, and the residue obtained was partitioned between CH2 Cl2 (150 mL) and water (150 mL). The layers were separated and the aqueous phase extracted with CH2 Cl2 (150 mL). The combined organic extracts were washed with 10percent Na2 S2 O3 (120 mL), dried over Na2 SO4 and concentrated, in vacuo, to give an orange oil which was purified by flash chromatography. Elution with hexane:EtOAc (9:1) provided the product as a colorless oil (3.85 gm, 41percent yield). The following analyses indicated that the product was methyl 4-(N-[2-(tert.-butyldimethylsilyloxy)ethyl]amino)benzoate: NMR(CDCL3) delta=7.86(2H, d, J=8.8 Hz), 6.57(2H, d, J=8.8 Hz), 4.48(1H, broad), 3.85(3H, s), 3.82(2H, t, J=5.2 Hz), 3.27(2H, q, J=5.2 Hz), 0.90(9H, s), 0.06(6H, s)
41%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;
(a) methyl 4-(N-[2-(tert.-butyldimethylsilyloxy)ethyl]-amino) benzoate To a solution of 1-(tert.-butyldimethylsilyloxy)-2-iodoethane (45.10 gm, 160 mmol) in DMF (50 mL) was added methyl 4-aminobenzoate (4.54 gm, 30 mmol) and diisopropylethylamine (6 mL, 34 mmol). This solution was heated at 95° for approximately 21 hours. The solvent was removed by concentration, in vacuo, and the residue obtained was partitioned between CH2 Cl2 (150 mL) and water (150 mL). The layers were separated and the aqueous phase extracted with CH2 Cl2 (150 mL). The combined organic extracts were washed with 10percent Na2 S2 O3 (120 mL), dried over Na2 SO4 and concentrated, in vacuo, to give an orange oil which was purified by flash chromatography. Elution with hexane: EtOAc (9:1) provided the product as a colorless oil (3.85 gm, 41percent yield). The following analyses indicated that the product was methyl 4-(N-[2-(tert.-butyldimethylsilyloxy)ethyl]amino)benzoate: NMR(CDCL3) delta=7.86(2H, d, J=8.8 Hz), 6.57(2H, d, J=8.8 Hz), 4.48(1H, broad), 3.85(3H, s), 3.82(2H, t, J=5.2 Hz), 3.27(2H, q, J=5.2 Hz), 0.90(9H, s), 0.06(6H, s)
Synthesis of 4-amino-3,5-dichlorobenzoic acid (used in synthesis of Compound 6) 4-Amino-3,5-dichlorobenzoic acid was prepared from 4-aminobenzoic acid in a similar manner to that described for the synthesis of methyl 4-amino-3,5-dichlorobenzoate from methyl 4-aminobenzoate. 4-Amino-3,5-dichlorobenzoic acid was obtained as a colourless solid (mpt 290 recrystallized from ethanol). Nuclear magnetic resonance spectrum (N.M.R.) was as follows: 1H (p.p.m. from TMs in (CD3)2SO, integral, number of peaks): 7.50, 3H, broad signal; 7.80, 2H s.
Example 131; To a stirred solution of <strong>[58530-53-3]2,4-dibromopyridinium hydrochloride</strong> (535 mg, 1.96 mmol) in 2,2,2-trifluoroethanol (5 mL) in a sealed tube, was added 4-aminobenzoic acid methyl ester (296 mg, 1.96 mmol, 1.0 eq). The resulting reaction was heated to 110 C. and allowed to stir at this temperature for 15 h. The reaction mixture was then was cooled to room temperature , concentrated in vacuo and the resulting residue was diluted with 10% aqueous NH3 (150 mL) and DCM (150 mL) and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with DCM (150 mL) and the combined organic phases were dried over MgSO4 and concentrated in vacuo to provide a give a white solid residue which was purified using column chromatography (AcOEt:Hexane 0% to 50%) to provide compound 61 (308 mg, 51%) as a white solid. Note: The 2-isomer (72 mg, 12%) was also obtained as a less polar compound.
Preparation 5 A solution of 4'-(trifluoromethyl)-1,1'-biphenyl-2-carboxylic acid (4.0 g) and HOBT.H2O (2.03 g) and WSC.HCl (3.2 g) in N,N-dimethylformamide (30 ml) was stirred at ambient temperature for an hour. Methyl 4-aminobenzoate (3.20 g) was added to the above mixture and the reaction mixture was stirred at ambient temperature for 20 hours. The resultant mixture was poured into a mixture of ethyl acetate and water. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give methyl 4-([4'-(trifluoromethyl)-1,1'-biphenyl-2-yl]carbonyl}amino)benzoate (3.16 g) 1H-NMR (DMSO-d6): delta3.82 (3H, s), 7.52-7.74 (13H, m), 7.90 (2H, d, J=8.65 Hz), 10.73 (1H, s).
methyl 4-(((2E)-3-(1H-indazol-3-yl)prop-2-enoyl)amino)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A solution of acryloyl chloride (2.38 g, 26.3 MMOL) in CH2Cl2 (50 mL) was treated with methyl 4-amino benzoate (3.98 g, 26.3 MMOL) and triethylamine (3.67 mL, 26.3 MMOL) and stirred at ambient temperature for 1 hour. The solvent was evaporated and the residue was dissolved in DMF (60 mL). To this solution was added <strong>[290368-00-2]N-Boc-3-iodoindazole</strong> (5.16 G, 15 MMOL), triethylamine (6.3 mL, 45 MMOL), Pd (OAc) 2 (101 mg, 0.45 MMOL), and tri-o- tolylphosphine (411 mg, 1.35 MMOL) and the mixture was heated at 100 C for 18 hours. The reaction mixture was cooled and partitioned between EtOAc (200 mL) and H20 (200 mL). The organic layer was washed with 0.1 N HCI (150 mL) and brine (150 mL), dried (MGS04), filtered, and concentrated to give a brown oil. Purification by chromatography on silica gel eluting with 50: 50 EtOAc: Hexane gave methyl 4-(((2E)-3-(LH-INDAZOL-3-YL) prop-2- enoyl) amino) benzoate as tan solids (2.33 g). 1H NMR (DMSO-d6) 8 13. 58 (s, 1H), 10. 58 (s, 1H), 8. 09 (d, 1H, J=7. 9 Hz), 7.90 (m, 5H), 7.62 (d, 1H, J=8. 4 Hz), 7.45 (t, 1H, J=7.1 Hz), 7.3 (m, 2H), 3.83 (s, 3H). MS m/z 322 (M+1).
With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 150℃; for 1.0h;Microwave irradiation;
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; triethylamine; In chloroform; at 70℃; for 16h;
Example 1 tert-Butyl-1-((4-((2-aminophenyl)carbamoyl)phenyl)carbamoyl)cyclohexyl carbamate To 1-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (516 mg, 2.12 mmol) in chloroform (10 mL), was added EEDQ (629 mg, 2.54 mmol), 4-amino-benzoic acid methyl ester (320 mg, 2.12 mmol) and TEA (0.4 mL, 3.18 mmol) and stirred at 70 C. for 16 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed twice with 10% aq. citric acid, twice 1 N NaOH, water and brine, and dried over magnesium sulfate, filtered and concentrated to give the ester, which was used for the next step without purification.
With toluene-4-sulfonic acid; In toluene; for 12h;Reflux;
A mixture of 4-aminobenzoic acid methyl ester (10.8 g, 71.4 mmol), <strong>[22062-53-9]5-fluoro-2-methylbenzaldehyde</strong> (10.0 g, 72.4 mmol) and p-toluenesulfonic acid (271.8 mg, 1.4 mmol) in toluene (150 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[(5-fluoro-2-methyl-benzylidene)-amino]-benzoic acid methyl (16.0 g, 82.6%) as a light yellow solid. MS (ESI+) [(M+H)+] 272.0.
82.6%
With toluene-4-sulfonic acid; In toluene; for 12h;Reflux;
Example 1 2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid 4-[(5-Fluoro-2-methyl-benzylidene)-amino]-benzoic acid methylA mixture of 4-aminobenzoic acid methyl ester (10.8 g, 71.4 mmol), 5-fluoro-2- methylbenzaldehyde (10.0 g, 72.4 mmol) and p-toluenesulfonic acid (271.8 mg, 1.4 mmol) in toluene (150 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4- [(5-fluoro-2-methyl-benzylidene)-amino] -benzoic acid methyl (16.0 g, 82.6%) as a light yellow solid. MS (ESI+) [(M+H)+] 272.0.
82.6%
With toluene-4-sulfonic acid; In toluene; for 12h;Reflux;
The mixture solution of 4-aminobenzoic acid methyl ester (10.8 g, 71.4 mmol), <strong>[22062-53-9]5-fluoro-2-methylbenzaldehyde</strong> (10.0 g, 72.4 mmol) and p-toluenesulfonic acid (271.8 mg, 1.4 mmol) in toluene (150 mL) was heated to reflux for 12 h. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[(5-fluoro-2-methyl-benzylidene)-amino]-benzoic acid methyl (16.0 g, 82.6%) as a light yellow solid: MS (ESI) M+1=272.0.
82.6%
With toluene-4-sulfonic acid; In toluene; for 12h;Reflux;
Example 2 2'-(5-Fluoro-2-methylphenyl)-N-(methylsulfonyl)-2',3'-dihydro-l'H- spiro[cyclopropane- 1 ,4 ' - quinoline] -6 ' -carboxamideThe mixture solution of 4-aminobenzoic acid methyl ester (10.8 g, 71.4 mmol), 5-fluoro-2- methylbenzaldehyde (10.0 g, 72.4 mmol) and /?-toluenesulfonic acid (271.8 mg, 1.4 mmol) in toluene (150 mL) was heated to reflux for 12 h. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[(5-fluoro-2-methyl-benzylidene)-amino]-benzoic acid methyl (16.0 g, 82.6%) as a light yellow solid: MS(ESI) M+l = 272.0.To a stirred solution 4-[(5-fluoro-2-methyl-benzylidene)-amino]-benzoic acid methyl (2.7 g, 10.0 mmol) in acetonitrile (16.0 mL) were added methylene-cyclopropane (2.8 mL, 40.0 mol) and scandium(III) trifluoromethanesulfonate (Sc(OTf)3) (980.0 mg, 2.0 mmol). The resulting mixture solution was stirred at 80 C for 16 h in sealed tube. The mixture solution was diluted with ethyl acetate (300 mL) and washed with water (100 mL x 2) and brine (100 mL x 2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10 - 50% ethyl acetate in petroleum ether) to afford 2-(5-fluoro-2-methyl-phenyl)- spiro(cyclopropane-l,4'- ,2',3',4'-tetrahydroquinoline)-6-carboxylic acid methyl ester (1.2 g, 37%) as a light yellow solid: MS(ESI) M+l = 326.2.To a stirred solution of 2-(5-fluoro-2-methyl-phenyl)-spiro(cyclopropane-l,4'- ,2',3',4'- tetrahydroquinoline)-6-carboxylic acid methyl ester (800.0 mg, 2.5 mmol) intetrahydrofuran (10.0 mL) and methanol (10.0 mL) was added 3 N sodium hydroxide (2.0 mL). The reaction mixture was stirred at 80C for 6 h, and then diluted with water (10.0 mL), extracted with diethyl ether (20.0 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with ethyl acetate (40 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed in vacuo and afforded 2-(5-fluoro-2-methyl-phenyl)- spiro(cyclopropane-l,4'- ,2',3',4'-tetrahydroquinoline)-6-carboxylic acid (650 mg, 85%) as a light yellow powder: MS(ESI) M+l = 312.3. To a suspension of 60% sodium hydride (128 mg, 3.2 mmol) in N, N-dimethylformamide (1.5 mL) was added methanesulfonamide (314 mg, 3.3 mmol) at room temperature. The resulting mixture was stirred at 25C for 1 h to afford Solution A2. A solution of 2-(5- fluoro-2-methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid (102.0 mg, 0.33 mmol) and Iota,Gamma-carbonyldiimidazole (136 mg, 0.84 mmol) in N, N-dimethylformamide (2.0 mL) was stirred at 70C for 1 h and cooled to room temperature to afford Solution B2. Solution B2 was added to Solution A2 and the resulting mixture was stirred at 25C for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm x 100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2'-(5-fluoro-2-methylphenyl)-N-(methylsulfonyl)-2',3'- dihydro-1 'H-spiro [cyclopropane- l,4'-quinoline]-6'-carboxamide (38.4 mg, 30%) as a white solid: MS(ESI) M+l = 389.2.
With iron(III) chloride; 9-bora-bicyclo[3.3.1]nonane; In 2-methyltetrahydrofuran; at 10℃;Inert atmosphere;
Representative procedure for the synthesis of methyl 2-(4-methoxycyclohexylamino) benzoate (3a): To a stirred solution of 194.6 mg (1.2 mmol) of FeCl3 and 2 mL of anhydrous THF at 0 C under nitrogen atmosphere were added 151.2 mg (1.0 mmol) of methyl 2-aminobenzoate (1) and 141.0 mg (1.1 mmol) of <strong>[13482-23-0]4-methoxycyclohexanone</strong> (2a). 6.0 mL of 0.5 M 9-BBN in THF (3.0 mmol) was then added slowly to maintain internal temperature below 5 C. The reaction mixture was further stirred at 0 C for 2 h. After completion of the reaction (monitored by HPLC), 290 muL (3.0 mmol) of diethanolamine was added to the reaction mixture at 0 C and stirred for 30 min to remove 9-BBN by forming an insoluble solid. After filtering out the precipitate, the crude mixture of 3a was purified by column chromatography over silica gel using pure hexanes to 10% ethyl acetate in hexanes as eluent to give 247 mg of 3a (0.94 mmol) as light yellow oil after drying. The corresponding trans-3a and cis-3a were further purified on silica gel.
General procedure: Preparation of the arenediazonium chloride To an ice-cooled degassed solution of aniline (5.00 mmol) in 3 N hydrochloric acid (5 mL) and water (5 mL) was dropwise added a degassed solution of sodium nitrite (5.00 mmol, 0.35 g) in water (2.5 mL) over a period of 10 min. After stirring for 20 more minutes at 0 C, the clear solution was used for the aryl-aryl coupling reactions (5 mmol/12.5 mL = 0.4 M). Biaryl synthesis A 5 mL aliquot of the 0.4 M arenediazonium chloride solution (2.00 mmol) was added dropwise by a syringe pump to a vigorously stirred solution of <strong>[60-19-5]tyramine hydrochloride</strong> (6.00 mmol, 1.04 g) in water (6 mL), acetonitrile (4 mL), and titanium(III)-chloride (4.00 mmol, 4.00 mL, ca. 1 M solution in 3 N hydrochloric acid) under nitrogen atmosphere over 10-15 min. After the addition was complete, the mixture was left to stir for 10 more minutes and a solution of sodium hydroxide (2 g) and sodium sulfite (2 g) in water (20 mL) was added. After extraction with diethylether (3 × 75 mL), the combined organic phases were washed with satd. aqueous sodium chloride and dried over sodium sulfate. The solvent was removed under reduced pressure. Prior to purification by HPLC, the crude product was dissolved in dichloromethane (10 mL) and TFA (1.5 equiv) was added. After concentration in vacuo, the trifluoroacetate salt was submitted to preparative HPLC (gradient: CH3CN/(H2O + 0.1% TFA) = 10:90?95:5 over 8 min, flow: 20 mL/min). Additional analytic data obtained from the characterization of the compounds can be found in the Supplementary data.
With ytterbium(III) triflate; In acetonitrile; at 85℃; for 18h;sealed tube;
To a stirred solution of 4-amino-benzoic acid methyl ester (11.3 g, 78.4 mmol) and <strong>[188813-02-7]3-bromo-5-fluoro-benzaldehyde</strong> (15.9 g, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85 C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(3-bromo-5-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (12.3 g, 40.0%) as a light yellow solid: MS (ESI) M+1=394.0.
40%
ytterbium(III) triflate; In acetonitrile; at 85℃; for 18h;Sealed tube;
Example 4N-[2-(3-fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carbonyl] -methanesulf onamide To a stirred solution of 4-amino-benzoic acid methyl ester (11.3 g, 78.4 mmol) and 3- bromo-5-fluoro-benzaldehyde (15.9 g, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85 C for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL x 2) and brine (100 mL x 2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10 - 50% ethyl acetate in petroleum ether) to afford 2-(3-bromo-5-fluoro- phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (12.3 g, 40.0%) as a light yellow solid: MS(ESI) M+l = 394.0. 2-(3-bromo-5-fluoro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (3.9 g, 10.0 mmol), morpholine (9.0 mL, 95.0 mmol), copper(I) iodide (1.1 g, 6.0 mmol), N, N-dimethylglycine hydrochloride (1.1 g, 8.0 mmol), and potassium carbonate (4.1 g, 30.0 mmol) in dimethyl sulfoxide (20 mL) was stirred at 120C for 16 h. Then the reaction mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate (200 mL x 2), washed with saturated aqueous ammonium chloride solution (50 mL x 3) and brine (50 mL x 2), dried over anhydrous sodium sulfate and then concentrated in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30 - 50% ethyl acetate in petroleum ether) to afford 2- (3-fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid methyl ester (3.2 g, 80%) as a white solid: MS(ESI) M+l = 399.0. To a stirred mixture solution of 2-(3-fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl- l,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (398.0 mg, 1.0 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (1.5 mL). The reaction mixture was stirred at 70C for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2 x 100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl- l,2,3,4-tetrahydro-quinoline-6-carboxylic acid (345.6 mg, 90%) as a light white solid which was used for next step without further purification: MS(ESI) M+l = 385.1. To a suspension of 60% sodium hydride (128 mg, 3.2 mmol) in N, N-dimethylformamide (1.5 mL) was added methanesulfonamide (314 mg, 3.3 mmol) at room temperature. The resulting mixture was stirred at 25C for 1 h to afford Solution A4. A solution of 2-(3- fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid (126.7 mg, 0.33 mmol) and Iota,Gamma-carbonyldiimidazole (136 mg, 0.84 mmol) in N, N- dimethylformamide (2.0 mL) was stirred at 70C for 1 h and cooled to room temperature to afford Solution B4. Solution B4 was added to Solution A4 and the resulting mixture was stirred at 25C for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm x 100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[2-(3-fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl- 1, 2,3, 4-tetrahydro-quinoline-6-carbonyl] -methanesulfonamide (45.6 mg, 30%) as a white solid: MS(ESI) M+l = 462.1.
2-(2-ethyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With ytterbium(III) triflate; In acetonitrile; at 85℃; for 16h;sealed tube;
To a stirred solution of 4-amino-benzoic acid methyl ester (1 g, 6 mmol) and <strong>[22927-13-5]2-ethyl-benzaldehyde</strong> (1.2 g, 8.9 mmol) in acetonitrile (40 mL) were added isobutene (1.7 mL, 24 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (0.55 g, 0.9 mmol). The resulting mixture was stirred at 85 C. for 16 h in sealed tube. The mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL×2) and brine (50 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(2-ethyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1 g, 49%) as a light yellow solid: MS (ESI) M+1=337.0.
49%
ytterbium(III) triflate; In acetonitrile; at 85℃; for 16h;Sealed tube;
Example 48Cyclopropanesulfonic acid [2-(2-ethyl-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro- quinoline-6-carbonyl] -amideTo a stirred solution of 4-amino-benzoic acid methyl ester (1 g, 6 mmol) and 2-ethyl- benzaldehyde (1.2 g, 8.9 mmol) in acetonitrile (40 mL) were added isobutene (1.7 mL, 24 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (0.55 g, 0.9 mmol). The resulting mixture was stirred at 85C for 16 h in sealed tube. The mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL x 2) and brine (50 mL x 2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10 - 50% ethyl acetate in petroleum ether) to afford 2-(2-ethyl-phenyl)-4,4-dimethyl- 1,2,3, 4-tetrahydro- quinoline-6-carboxylic acid methyl ester (1 g, 49%) as a light yellow solid: MS(ESI) M+1 = 337.0.To a stirred mixture solution of 2-(2-ethyl-phenyl)-4,4-dimethyl- 1,2,3, 4-tetrahydro- quinoline-6-carboxylic acid methyl ester (0.6 g, 1.78 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL) was added 30% sodium hydroxide in water (10 mL). The reaction mixture was stirred at 60C for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2 x 100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(2- ethyl-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.5 g, 90%) as a light white solid which was used for next step without further purification: MS(ESI) M+l = 310.1.To a suspension of 60% sodium hydride (381 mg, 9.52 mmol) in N,N-dimethylformamide (4 mL) was added cyclopropanesulfonic acid amide (1.15 g, 9.52 mmol) at room temperature. The resulting mixture was stirred at 25C for 1 h to afford Solution A48. A solution of 2-(2-ethyl-5-morpholin-4-yl-phenyl)-4,4-dimethyl- 1,2,3, 4-tetrahydro-quinoline- 6-carboxylic acid (420 mg, 1.36 mmol) and Iota,Gamma-carbonyldiimidazole (441 mg, 2.72 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70C for 1 h and cooled to room temperature to afford Solution B48. Solution B48 was added to Solution A48 and the resulting mixture was stirred at 25C for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm x 100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [2-(2-ethyl-phenyl)- 4,4-dimethyl-l, 2,3, 4-tetrahydro-quinoline-6-carbonyl] -amide (100 mg, 17%) as a white solid: MS(ESI) M+l = 413.1.
With 18-crown-6 ether; potassium carbonate; In 1,2-dichloro-benzene; for 48h;Reflux;
2-3: Synthesis of methyl4-(bis(9,9-dimethyl-9H-fluorene-2-yl)amino)benzoate: The obtained <strong>[144981-85-1]9,9-dimethyl-2-iodofluorene</strong> (5.00 g, 15.6 mmol), methyl-4-aminobenzate (1.00 g, 6.62 mol), acopper-tin alloy (0.12 g, 0.66 mmol), 18-crown-6 (0.180 g, 0.68 mmol) and potassium carbonate (4.1 g, 29.6 mmol) weredissolved in 1,2-dichlorobenzene, and then refluxed and stirred for 2 days to prepare a mixed solution. After the reactionof the mixed solution was finished, the mixed solution was extracted with dichloromethane and water several times toform an organic layer. The organic layer was dried by magnesium sulfate (MgSO4) and then filtered, a solvent wasremoved from the filtered organic layer under reduced pressure, and a reaction product was separated by silica columnchromatography (dichloromethane:hexane = 2:1). The yield ofthe reaction product was 59percent. 1H NMR(300 MHz, CDCl3) delta(TMS, ppm): 1.43(12H, s, -CH3), 3.89(3H, s, -CH3), 7.31(4H, m, Ar-H)), 7.45(2H, m, Ar-H),7.66(6H, m, Ar-H), 7.73(4H, d, Ar-H), 7.85(2H, d, Ar-H)
With tris[2-phenylpyridinato-C2,N]iridium(III); In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; Irradiation;
Under nitrogen or argon, 0.4 mmol, 0.2mmol,Ir (ppy) 3 (2mg) and DMF1 ml was added to the reaction flask, followed by blue LEDlights (7W) at room temperature irradiation straight trivalent iodine reagent completeconversion of the reaction. Add 10 ml of saturated Na 2CO 3Aqueous solution, andextracted three times with ethyl acetate, washed with a saturated brine, dried overanhydrous Na 2SO 4The organic layer was dried. Column chromatography (eluent: petroleum ether 60-90: ethyl acetate = 15: 1-8: 1) to give the product in 67 %.
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 16.0h;Inert atmosphere;
Stock solution of 5 mol% Pd catalyst in dioxane was prepared as follows. A flask was charged with Pd(OAc)2 (0.025 mmol, 5.6 mg) and Xantphos (0.03 mmol, 17 mg); dry dioxane (5 mL) was added and the resulting solution was stirred for 15 min under an argon atmosphere. Next, a 50 mL round bottomed flask was charged with 2,5-dichloro-5-fluoropyridine (0.5 mmol, 83 mg), an aniline 2 (0.6 mmol) and t- BuONa (0.7 mmol, 67 mg). Freshly prepared stock solution of Pd catalyst was added and the resulting solution was stirred for 2 min under an argon atmosphere. The round bottomed flask was kept in 110 C preheated oil bath and reaction mixture was refluxed for 16 h, then allowed to cool down to room temperature and filtered through Celite. Celite cake was washed with 100 mL dichloromethane, combined organic phases were evaporated to dryness under reduced pressure and the residue separated with an automated chromatography system using Silica Flash Cartridges applying a heptane-ethyl acetate gradient (from 100% heptane to 100% ethylacetate in 35 minutes, 35 mL/min). The general procedure B was followed using Pd(OAc)2 (0.1 mmol, 22 mg), xantphos (0.120 mmol, 0.069 g), 2,5-dichloro-5- fluoropyridine (2.0 mmol, 0.332 g), methyl 4-aminobenzoate (2.0 mmol, 0.302 g) and Cs2C03 (10.0 mmol, 3.26 g). white solid; yield 66% (0.367 g); mp 159-160 C; H NMR (400 MHz, CDCI3): 5 3.89 (s, 3H), 6.78 (dd, J = 8.2 Hz, 2.8 Hz, 1 H), 6.83 (brs, 1 H), 7.27 (dd, J = 8.2 Hz, 9.9 Hz, 1 H), 7.71 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.8 Hz, 2H).
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 2h;
Step 1:A solution of DIPEA (1.2 mL, 7.0 mmol), Al5a (Aldrich, 530 mg, 3.5 mmol) and Ala (300 mg,2.3 mmol) in DMF (14 mL) is treated with HATU (1 .3 g, 3.5 mmol). The mixture is stirred for 2 hand then is diluted with water and EtOAc. The organic layer is separated and washed with water(2 x). The organic layer is passed through a phase separator and the filtrate evaporated todryness. The product is purified by Combif lash to give A15b.
3-[(4-methoxycarbonylphenyl)aminomethyl]benzothiophene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
Synthesis of methyl 4-aminobenzoate esters 5a-d and 11a-b The synthesis of 3-[(4-methoxycarbonylphenyl)aminomethyl]benzothiophene 5a will be used as an example for the synthesis of secondary amines 5a-d and 11 a-b. Benzothiophene-3- carbaldehyde 3a (406 mg, 2.5 mmol, 1 equiv) was dissolved in ethanol (15 mL) and to this solution were added glacial acetic acid (751 mg, 12.5 mmol, 5 equiv) and methyl 4- aminobenzoate (454 mg, 3 mmol, 1 .2 equiv). This reaction mixture was stirred for one hour at refluxing conditions after which it was cooled to 0C. Sodium cyanoborohydride (471 mg, 7.5 mmol, 3 equiv) was added and the reaction mixture was allowed to warm to room temperature. After one hour the mixture was poured in to brine (15 mL) and three times extracted with EtOAc (15 mL). The combined organic fraction was thereafter three times washed with brine (15 mL), dried (MgS04), filtered and evaporated under vacuum. Purification through recrystallization from ethanol yielded 3-[(4- methoxycarbonylphenyl)aminomethyl]-benzothiophene 5a (520 mg, 1 .75 mmol, 70%) as a white powder. For secondary amine 5b a solvent mixture of ethanol/CH2CI2(1 /1 ) was used as solvent for the reaction. 5a: 3-[(4-methoxycarbonylphenyl)aminomethyl]benzothiophene 70% as white powder; recrystallization from EtOH; m.p. 127C;1H-NMR (300 MHz, CDCI3): delta = 3.84 (s, 3H); 4.48 (s(broad), 1 H); 4.58 (d, J = 5.0 Hz, 2H); 6.62 (d, J = 8.8 Hz, 2H); 7.32 (s, 1 H); 7.35-7.43, 7.73-7.81 and 7.86-7.90 (3 m, 2H, 1 H and 3H);13C-NMR (75 MHz, CDCI3): delta = 42.2, 51 .7,1 1 1 .8, 1 19.0, 121 .7, 123.2, 124.1 , 124.4, 124.8, 131 .7, 132.8, 137.8, 141 .0, 151 .7 and 167.4; IR (cm"1): v = 3379 (N H); 1685 (C=0); MS (70 eV): m/z (%) = 296 (100) [M"- H]; HRMS (ESI)Anal. Calcd. for Ci7H14N02S 296.0751 [M"- H], Found 296.0760.
methyl 4-(1-methyl-3-phenyl-1H-pyrazole-5-amido)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With 3-Methylpyridine; methanesulfonyl chloride; In acetonitrile; at 0 - 20℃; for 17h;
Step 1: Synthesis of methyl 4-(l-methyl-3-phenyl-lH-pyrazole-5-amido)benzoate 41.1 [00491] Methanesulfonyl chloride (0.05 ml, 0.69 mmol) was added to a mixture of methyl 4- aminobenzoate (75mg, 0.49 mmol), l-methyl-3 -phenyl- lH-pyrazole-5-carboxylic acid (100 mg, 0.49 mmol) and 3-picoline (0.14 ml, 1.48 mmol) in MeCN (dry, 5ml) at 0C. After addition, the reaction mixture was allowed to reach rt and stirred for 17h. The reaction mixture was diluted with DCM (50ml) and water (50ml). The aqueous layer was further extracted with DCM (2 x 30ml) and the combined layers dried over Na2S04. Evaporation of the solvent afforded a material which was triturated from DMSO:MeCN (1 :2) to afford 134mg (77%) of methyl 4-(l- methyl-3 -phenyl- lH-pyrazole-5-amido)benzoate 41.1 as a white solid.
With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 12.0h;Inert atmosphere;
General procedure: A mixture of 2-phenylacetic acid (2.72 g, 20.0 mmol), methyl 4-aminobenzoate(3.02 g, 20.0 mmol), triethylamine (6.07 g, 60 mmol), and HATU (7.60 g, 20.0 mmol)in dimethylformamide (40.0 mL) was flushed with argon, and stirred at r.t. for 12hours. The reaction mixture was extracted with ice water (200.0 mL) and ethyl acetate(50.0 mL x 3). The combined organic extracts were washed with 2M HCl(aq) (50.0mL), NaHCO3(sat) (50.0 mL), dried with Na2SO4, filtered, and evaporated. The crudeproduct was purified with flash column chromatography on silica gel, and using 20%Ethyl acetate/Hexanes to afford 46 [methyl 4-(2-phenylacetamido)benzoate] (5.027 g,18.7 mmol, 93%) as a white solid.
With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 12.0h;Inert atmosphere;
General procedure: A mixture of 2-phenylacetic acid (2.72 g, 20.0 mmol), methyl 4-aminobenzoate(3.02 g, 20.0 mmol), triethylamine (6.07 g, 60 mmol), and HATU (7.60 g, 20.0 mmol)in dimethylformamide (40.0 mL) was flushed with argon, and stirred at r.t. for 12hours. The reaction mixture was extracted with ice water (200.0 mL) and ethyl acetate(50.0 mL x 3). The combined organic extracts were washed with 2M HCl(aq) (50.0mL), NaHCO3(sat) (50.0 mL), dried with Na2SO4, filtered, and evaporated. The crudeproduct was purified with flash column chromatography on silica gel, and using 20%Ethyl acetate/Hexanes to afford 46 [methyl 4-(2-phenylacetamido)benzoate] (5.027 g,18.7 mmol, 93%) as a white solid.
methyl 4-((5-nitropyrimidin-2-yl)amino)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
In acetonitrile;Inert atmosphere;
The first step: a vacuum 50mL reaction bottle is vacuumed three times,After adding methyl 4-aminobenzoate (151 mg, 1.0 mmol, 1.0 equiv) to the reaction flask, 10.0 mL of dried acetonitrile was added and stirred until the methyl 4-aminobenzoate was completely dissolved.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,2 mL (200-300 mesh) of silica gel was added to a round bottom flask for spin-drying (petroleum ether and ethyl acetate) over silica gel.Wait until the intermediate product is pale yellow crystals of methyl 4-((5-nitropyrimidin-2-yl)amino)benzoate(246 mg, 90% yield).
With sodium azide; methanesulfonic acid; trifluoroacetic acid; In hexane; at 40℃; for 4h;Sealed tube;
General procedure: A 20 ml vial equipped with a magnetic stirring bar was charged with secondary alcohols (0.3 mmol, 1 equiv.), NaN3 (0.75 mmol, 2.5 equiv.), n-hexane (1.0 ml, 0.3 M) and TFA (5.4 mmol, 18 equiv.) or a mixture of TFA (3.6 mmol,12 equiv.) and MeSO3H (1.8 mmol, 6 equiv.). The vial was sealed and stirred under air at 40 C for 4 h. On completion, the reaction mixture was quenched by 2 M NaOH (5 m), extracted by ethyl acetate (5 × 2 m) and the combined organic phase was washed with brine and dried over Na2SO4. Then the mixture was concentrated and purified by flash chromatography on a short silica gel column.
78%
With sodium azide; methanesulfonic acid; trifluoroacetic acid; In hexane; at 40℃; for 10h;
Take a reaction tube, add 50 mg of sodium azide, 54 mg of <strong>[84851-56-9]1-(4-methoxycarbonylphenyl)ethanol</strong>, and 300 uL of trifluoroacetic acid.150 uL of methanesulfonic acid and 1.0 mL of n-hexane were stirred at 40 C for 10 hours.After the reaction was completed, 10 mL of a sodium hydroxide solution was added to quench the reaction, and the mixture was extracted three times with ethyl acetate.Column chromatography gave 32.3 mg of p-methoxycarbonylaniline in a yield of 78%.
methyl 4-(1H-naphtho[1,8-de][1,3,2]diazaborinin-2(3H)-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24.5 mg
With tert.-butylnitrite; sodium acetate; tetra-(n-butyl)ammonium iodide; dibenzoyl peroxide; In acetonitrile; at 80℃;Schlenk technique; Inert atmosphere;
General procedure: In air, Bpin-B(dan) (0.1 mmol, 1.0 eq.), aryl amide (0.2 mmol, 2.0 eq.), TBAI (0.01 eq.),NaOAc (0.15 eq.), and BPO (0.01 eq.) were sequentially weighed and added to a screw-cappedSchenk tube containing a magnetic stir bar. The vessel was evacuated and refilled with nitrogen forthree times. t-BuONO (0.2 eq.) and MeCN (0.6 mL) were added in turn under N2 atmosphere usingsyringes through a septum which was temporarily used to replace the screw cap. The reaction mixturewas then vigorously stirred at 80 C for the indicated time. The resulting mixture was filtered through a pad of Celite, and the filter cake was washed with ethyl acetate (3 mL x 2). The combined filtratewas evaporated under vacuum to dryness and the residue was purified by column chromatography toyield the desired product.
methyl 4-((5-bromo-3-fluoro-2-nitrophenyl)amino)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With potassium tert-butylate; In 1,4-dioxane; at 90℃; for 18h;Inert atmosphere;
General procedure: A 20 mL Biotage microwave vial loaded with <strong>[147808-42-2]5-bromo-1,3-difluoro-2-nitrobenzene</strong> (1.19 g, 5.0 mmol), benzo[d][1,3]dioxol-5-amine (0.686 g, 5.0 mmol), DMF (10 mL) and triethylamine (1.394 mL, 10.0 mmol), was capped, purged with argon, then heated to 90 C. for 18 h in an oil bath. The reaction was cooled, poured into a solution of H2O and the precipitated product was filtered, washed with H2O and hexanes, affording N-(5-bromo-3-fluoro-2-nitrophenyl)benzo[d][1,3]dioxol-5-amine 3-A as a red solid (1.6 g, 4.51 mmol, 90% yield). 1H NMR (DMSO) delta: 8.77 (s, 1H), 7.08 (dd, J=10.5, 2.0 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 6.83 (t, J=1.8 Hz, 1H), 6.74 (dd, J=8.2, 2.1 Hz, 1H), 6.07 (s, 2H).
Chemistry
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Material Science
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110K+ Compounds
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