* 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.
Stage #1: at 75℃; for 0.5 h; Stage #2: for 4 h; Reflux
General procedure: 5.1.1 5-(4-Morpholinophenyl)-1,3,4-thiadiazol-2-amine (59) A mixture of 4-morpholinobenzoic acid (5.18 g, 25 mmol) and N-aminothiourea (2.28 g, 25 mmol) in POCl3 (7 ml) was stirred vigorously at 75 °C for 0.5 h. After addition of H2O (30 ml), the reaction mixture was heated under reflux for 4 h and basified to pH 8 by 50percent NaOH solution. The mixture was filtered and the filter cake was recrystallized from ethanol to yield 3.90 g of compound 59 as a yellow crystal. Yield: 59percent; The synthetic procedures of compounds 60–81 were the same as that described above. 5.1.1.8 5-(3-Chlorophenyl)-1,3,4-thiadiazol-2-amine (67) Yield: 75percent, mp: 212-214 °C (EtOH). ESI-MS m/z: 212.1 [M+H]+; 1H NMR (CDCl3) δ 7.49-7.50 (m, 2H), 7.54 (s, 2H), 7.70-7.71 (m, 1H), 7.80 (s, 1H).
Reference：
[1] Journal of Chemical Research, 2011, vol. 35, # 12, p. 703 - 706
[2] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 21, p. 5766 - 5775
[3] Journal of Chemical Research, 2012, vol. 36, # 4, p. 218 - 221
[4] Pharmazie, 2018, vol. 73, # 3, p. 123 - 127
[5] Bioorganic Chemistry, 2018, vol. 81, p. 88 - 92
Reference：
[1] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 1, p. 413 - 421
4
[ 535-80-8 ]
[ 635-21-2 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1884, vol. 222, p. 95
[2] Justus Liebigs Annalen der Chemie, 1865, vol. 135, p. 108
[3] Chemische Berichte, 1873, vol. 6, p. 175
5
[ 535-80-8 ]
[ 1673-47-8 ]
Yield
Reaction Conditions
Operation in experiment
53%
With dmap; hydrazine hydrate In methanol; ethanol; dichloromethane
3-Chlorobenzhydrazide A mixture of 3-chlorobenzoic acid (0.5 g, 3.19 mmol), 1,3-diccyclohexylcarbodiimide (0.72 g, 3.51 mmol), 4-dimethylaminopyridine (0.04 g, 0.32 mmol) in ethanol was stirred at ambient temperature for 1.5 hour. The white solid was filtered off and the filtrate diluted with dichloromethane (100 mL). The organic solution was washed with 1N sodium hydrogen sulfate (100 mL), saturated sodium bicarbonate (100 mL), water (100 mL) and brine (100 mL). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude residue was dissolved in ethanol (15 mL) and treated with hydrazine monohydrate (0.46 mL, 9.58 mmol). The resulting clear solution was stirred overnight at ambient temperature. The reaction mixture was then concentrated to dryness in vacuo. Silica gel chromatography of the residue, using 3percent methanol in dichloromethane, afforded 0.29 g (53percent) of 3-chlorobenzhydrazide as a white solid.
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 396 - 406
[2] Patent: US2003/55085, 2003, A1,
[3] Journal of Chemical Research, 2010, vol. 34, # 12, p. 680 - 683
[4] Journal of Chemical Research, 2011, vol. 35, # 4, p. 234 - 237
[5] Monatshefte fur Chemie, 2010, vol. 141, # 4, p. 479 - 484
[6] Journal of Chemical Research, 2011, vol. 35, # 6, p. 364 - 367
[7] Arzneimittel-Forschung/Drug Research, 2011, vol. 61, # 8, p. 452 - 457
[8] Letters in Drug Design and Discovery, 2012, vol. 9, # 3, p. 276 - 281
[9] Journal of Chemical Research, 2012, vol. 36, # 7, p. 383 - 386
[10] Medicinal Chemistry, 2012, vol. 8, # 6, p. 1190 - 1197,8
[11] Medicinal Chemistry, 2012, vol. 8, # 6, p. 1190 - 1197
[12] Australian Journal of Chemistry, 2012, vol. 65, # 10, p. 1413 - 1419,7
[13] Australian Journal of Chemistry, 2012, vol. 65, # 10, p. 1413 - 1419
[14] Chemical Biology and Drug Design, 2013, vol. 82, # 5, p. 546 - 556
[15] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 1, p. 192 - 194
[16] Archives of Pharmacal Research, 2014, vol. 37, # 7, p. 852 - 861
[17] Synthetic Communications, 2014, vol. 44, # 18, p. 2724 - 2737
[18] Marine Drugs, 2014, vol. 12, # 4, p. 1839 - 1858
[19] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 15, p. 3052 - 3056
[20] Phosphorus, Sulfur and Silicon and the Related Elements, 2015, vol. 190, # 7, p. 1045 - 1055
[21] Chemical Communications, 2015, vol. 51, # 76, p. 14365 - 14368
[22] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 6014 - 6024
[23] Asian Journal of Chemistry, 2016, vol. 28, # 3, p. 639 - 643
[24] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2015, vol. 70, # 8, p. 609 - 616
[25] Journal of Molecular Structure, 2016, vol. 1117, p. 8 - 16
[26] Molecules, 2016, vol. 21, # 5,
[27] Journal of the Brazilian Chemical Society, 2016, vol. 27, # 11, p. 1998 - 2010
[28] Journal of the Chemical Society of Pakistan, 2016, vol. 38, # 5, p. 864 - 881
[29] Chemical Biology and Drug Design, 2017, vol. 89, # 1, p. 47 - 60
[30] Chinese Journal of Chemistry, 2016, vol. 34, # 12, p. 1236 - 1244
[31] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2016, vol. 55B, # 2, p. 207 - 212
[32] Arkivoc, 2016, vol. 2017, # 2, p. 87 - 106
[33] ChemMedChem, 2017, vol. 12, # 12, p. 972 - 985
[34] Chemical Biology and Drug Design, 2017, vol. 90, # 2, p. 236 - 243
[35] Biomedicine and Pharmacotherapy, 2017, vol. 94, p. 499 - 513
[36] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 20, p. 5652 - 5661
[37] Archiv der Pharmazie, 2017, vol. 350, # 11,
[38] Journal of the Chilean Chemical Society, 2017, vol. 62, # 1, p. 3370 - 3375
[39] Russian Journal of Bioorganic Chemistry, 2017, vol. 43, # 3, p. 328 - 339[40] Bioorg. Khim., 2017, vol. 43, # 3, p. 328 - 339,12
[41] RSC Advances, 2018, vol. 8, # 12, p. 6306 - 6314
[42] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 10, p. 1797 - 1803
6
[ 535-80-8 ]
[ 74-88-4 ]
[ 7499-08-3 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, # 10, p. 1265 - 1272
[2] Journal of Organic Chemistry, 2003, vol. 68, # 5, p. 2030 - 2033
7
[ 201230-82-2 ]
[ 625-99-0 ]
[ 7094-34-0 ]
[ 2050-67-1 ]
[ 108-90-7 ]
[ 535-80-8 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1996, vol. 133, # 1, p. 75 - 82
[2] Journal of Organometallic Chemistry, 1990, vol. 384, p. 193 - 197
8
[ 535-80-8 ]
[ 625-99-0 ]
Yield
Reaction Conditions
Operation in experiment
84%
With N-iodo-succinimide; [4,4’-bis(1,1-dimethylethyl)-2,2’-bipyridine-N1,N1‘]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(lll) hexafluorophosphate; iodine; caesium carbonate In 1,2-dichloro-ethane at 50℃; for 24 h; Inert atmosphere; Irradiation; Sealed tube
General procedure: To a 15 mL test tube with septum Cs2CO3 (0.6 mmol, 195 mg), aromaticcarboxylic acid (1) (0.3 mmol), [Ir(dF(CF3)ppy)2dtbbpy]PF6 (D) (6 μmmol, 6.7 mg), NIS (1.5mmol, 337.5 mg) and I2 (60 μmol, 20 molpercent) were added. The tube was evacuated and backfilledwith argon for three times, and then 3 mL of dry DCE was added through a syringer under argon.The tube was sealed with Parafilm Mr® and placed in an oil bath with a contact thermometer, andthe reaction was carried out at 50 °C under irradiation with 6 × 5 W blue LEDs (λmax = 455 nm).After 24 h or 36 h, the resulting mixture was filtered through a 2 cm thick pad of silica, and thesilica was washed with DCM) (50 mL). The filtrate was collected and the solvent was removed invacuo. The crude residue was purified by silica gel flash column chromatography to provide thetarget product (2). (Note: The reaction was very sensitive to moisture, and the yields sharplydecreased to less than 5percent when 0.01 equivalent of H2O was added to the reaction system).
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 18, p. 4794 - 4795
[2] Journal of Organic Chemistry, 1993, vol. 58, # 18, p. 4794 - 4795
10
[ 535-80-8 ]
[ 25118-59-6 ]
Reference：
[1] Journal of the Indian Chemical Society, 1980, vol. 57, # 6, p. 640 - 642
11
[ 535-80-8 ]
[ 2516-95-2 ]
Reference：
[1] Patent: CN106496036, 2017, A, . Location in patent: Paragraph 0025
12
[ 535-80-8 ]
[ 2516-95-2 ]
[ 4771-47-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1884, vol. 222, p. 95
[2] Recueil des Travaux Chimiques des Pays-Bas, 1901, vol. 20, p. 215,225
[3] Recueil des Travaux Chimiques des Pays-Bas, 1900, vol. 19, p. 199
[4] Justus Liebigs Annalen der Chemie, 1884, vol. 222, p. 95
[5] Recueil des Travaux Chimiques des Pays-Bas, 1901, vol. 20, p. 215,225
13
[ 7697-37-2 ]
[ 535-80-8 ]
[ 2516-95-2 ]
[ 4771-47-5 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1900, vol. 19, p. 55
[2] Justus Liebigs Annalen der Chemie, 1884, vol. 222, p. 95
[3] Recueil des Travaux Chimiques des Pays-Bas, 1901, vol. 20, p. 215,225
14
[ 535-80-8 ]
[ 34841-35-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 1, p. 1 - 6
15
[ 75-00-3 ]
[ 535-80-8 ]
[ 1128-76-3 ]
Yield
Reaction Conditions
Operation in experiment
87%
With 1,1'-(hexane-1,6-diyl)bis(1,8-diazabicyclo[5.4.0]undec-7-enium) dichlorine In ethanol; water at 70℃; for 2 h; Green chemistry
General procedure: Carboxylic acids (1.00 mmol), primary chloroalkanes(1.20mmol) and IL-1 (0.30mmol) were added respectivelyinto a two necked flask equipped with 6mL 50percentaqueous ethanol solution under stirring, then raised the systemtemperature to 70°C for a needed time in water bath.The progress of the reaction was monitored using thin layer chromatography (TLC). When the reaction was over, thereactor was cooled down to room temperature. The mixturewas diluted with water (10mL) and extracted with ethylacetate (3 × 5mL), the extract was dried over anhydrousNa2SO4,filtered, and concentrated in a rotary evaporatorto collect target product. Meanwhile, the reborn catalystcould be applied in the next cycle was after removing thesolvent and dried at 80°C under vacuum for 6h. All theesterification products were further purified by column
With sodium cyanide In N,N-dimethyl-formamide at 50℃; for 1 h; Molecular sieve
General procedure: Aldehyde 1 (1.0 mmol; 1.0 equiv.) and 4 Å molecular sieves (300 mg) were added to a mixture of DMF (3.0 mL) and an appropriate alcohol (or a thiol) (3.0 mL). To the above solution was added sodium cyanide (1.5 mmol; 1.5 equiv). The reaction mixture was stirred in an open flask at 50 C and monitored by TLC. After the complete consumption of 1, the mixture was poured into water (25 mL) and extracted with diethyl ether (5 × 10 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude mixture was further purified by column chromatography on silica gel using ethyl acetate/hexane as the eluent to furnish the desired ester compound 3. The aqueous layer was acidified with HCl, extracted with ether, and concentrated to yield the corresponding carboxylic acid 6, which was sufficiently pure needing no further purification.
Reference：
[1] Bulletin of the Korean Chemical Society, 2015, vol. 36, # 8, p. 2055 - 2061
17
[ 64-17-5 ]
[ 535-80-8 ]
[ 1128-76-3 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 100℃; for 24 h;
General procedure: A mixture of acid (0.2 mmol), alcohol (0.6 mmol) and GO (50 wtpercent, calculated with the mass of acid) in ethyl alcohol or DCE (1 mL) was placed in a test tube equipped with a magnetic stirring bar. The mixture was stirred at 100 °C for 24 h. After the reaction was finished, filtered the GO, solvent was removed, and the residue was separated by column chromatography to give the pure sample.
Reference：
[1] Synthesis, 2003, # 16, p. 2479 - 2482
[2] Organic Process Research and Development, 2017, vol. 21, # 7, p. 947 - 955
[3] Synlett, 2017, vol. 28, # 8, p. 981 - 985
[4] Canadian Journal of Chemistry, 1983, vol. 61, p. 230 - 234
[5] Journal fuer Praktische Chemie (Leipzig), 1901, vol. <2>64, p. 332
[6] Justus Liebigs Annalen der Chemie, 1857, vol. 102, p. 264
[7] Phosphorus, Sulfur and Silicon and the Related Elements, 2006, vol. 181, # 9, p. 2079 - 2087
[8] Canadian Journal of Chemistry, 1983, vol. 61, p. 230 - 234
[9] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 6, p. 808 - 816
[10] Journal of Organic Chemistry, 2004, vol. 69, # 19, p. 6449 - 6454
[11] Patent: WO2004/5282, 2004, A1, . Location in patent: Page 41
[12] Journal of Chemical Research, 2010, vol. 34, # 12, p. 680 - 683
[13] Journal of Chemical Research, 2011, vol. 35, # 4, p. 234 - 237
[14] Journal of Chemical Research, 2011, vol. 35, # 6, p. 364 - 367
[15] Journal of Chemical Research, 2012, vol. 36, # 7, p. 383 - 386
[16] Tetrahedron, 2014, vol. 70, # 12, p. 2190 - 2194
[17] Archives of Pharmacal Research, 2014, vol. 37, # 7, p. 852 - 861
[18] Marine Drugs, 2014, vol. 12, # 4, p. 1839 - 1858
[19] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 15, p. 3052 - 3056
[20] Phosphorus, Sulfur and Silicon and the Related Elements, 2015, vol. 190, # 7, p. 1045 - 1055
[21] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 6014 - 6024
[22] Asian Journal of Chemistry, 2015, vol. 27, # 10, p. 3605 - 3608
[23] Asian Journal of Chemistry, 2016, vol. 28, # 3, p. 639 - 643
[24] Chemistry - A European Journal, 2016, vol. 22, # 1, p. 211 - 221
[25] Journal of the Brazilian Chemical Society, 2016, vol. 27, # 11, p. 1998 - 2010
[26] Tetrahedron Letters, 2017, vol. 58, # 6, p. 574 - 577
[27] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2016, vol. 55B, # 2, p. 207 - 212
[28] European Journal of Medicinal Chemistry, 2017, vol. 130, p. 15 - 25
[29] ChemMedChem, 2017, vol. 12, # 12, p. 972 - 985
[30] Chemical Biology and Drug Design, 2017, vol. 90, # 2, p. 236 - 243
[31] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 20, p. 5652 - 5661
[32] Archiv der Pharmazie, 2017, vol. 350, # 11,
[33] Journal of the Chilean Chemical Society, 2017, vol. 62, # 1, p. 3370 - 3375
[34] Russian Journal of Bioorganic Chemistry, 2017, vol. 43, # 3, p. 328 - 339[35] Bioorg. Khim., 2017, vol. 43, # 3, p. 328 - 339,12
[36] RSC Advances, 2018, vol. 8, # 12, p. 6306 - 6314
18
[ 141-78-6 ]
[ 535-80-8 ]
[ 1128-76-3 ]
Reference：
[1] Synthesis, 2003, # 16, p. 2479 - 2482
19
[ 535-80-8 ]
[ 1128-76-3 ]
Reference：
[1] Synthesis, 2003, # 16, p. 2479 - 2482
[2] Justus Liebigs Annalen der Chemie, 1857, vol. 102, p. 264
20
[ 64-17-5 ]
[ 7664-93-9 ]
[ 535-80-8 ]
[ 1128-76-3 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1857, vol. 102, p. 264
21
[ 535-80-8 ]
[ 34662-36-7 ]
Yield
Reaction Conditions
Operation in experiment
2.65 g
at 0 - 20℃; for 1 h;
Concentrated sulfuric acid (12 mL) was added to concentrated nitric acid (1.6 mL) under ice cooling, and the mixture was stirred at 0 ° C. for 5 min.3-Chlorobenzoic acid (3 g) was added over 5 minutes, the temperature was raised to room temperature and stirred for 1 hour.The reaction solution was added dropwise to ice-cooled water, and the precipitated solid was collected by filtration and washed with water to give 3-chloro-5-nitrobenzoic acid (Compound 0004-1, 2.65 g) as a white solid.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 16, p. 4557 - 4561
[2] Patent: JP6052673, 2016, B2, . Location in patent: Paragraph 0081
Reference：
[1] Justus Liebigs Annalen der Chemie, 1884, vol. 222, p. 95
[2] Recueil des Travaux Chimiques des Pays-Bas, 1901, vol. 20, p. 215,225
[3] Recueil des Travaux Chimiques des Pays-Bas, 1900, vol. 19, p. 199
[4] Justus Liebigs Annalen der Chemie, 1884, vol. 222, p. 95
[5] Recueil des Travaux Chimiques des Pays-Bas, 1901, vol. 20, p. 215,225
24
[ 7697-37-2 ]
[ 535-80-8 ]
[ 2516-95-2 ]
[ 4771-47-5 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1900, vol. 19, p. 55
[2] Justus Liebigs Annalen der Chemie, 1884, vol. 222, p. 95
[3] Recueil des Travaux Chimiques des Pays-Bas, 1901, vol. 20, p. 215,225
25
[ 95-94-3 ]
[ 124-38-9 ]
[ 13799-90-1 ]
[ 65-85-0 ]
[ 74-11-3 ]
[ 535-80-8 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 2000, vol. 65, # 6, p. 862 - 880
26
[ 535-80-8 ]
[ 13421-00-6 ]
Reference：
[1] Angewandte Chemie - International Edition, 2008, vol. 47, # 28, p. 5215 - 5219
27
[ 535-80-8 ]
[ 123278-03-5 ]
Reference：
[1] Journal of Organic Chemistry, 2003, vol. 68, # 5, p. 2030 - 2033
[2] Patent: TW2016/5834, 2016, A, . Location in patent: Paragraph 0335; 0336; 0337
28
[ 535-80-8 ]
[ 25487-66-5 ]
Reference：
[1] Journal of the American Chemical Society, 2012, vol. 134, # 28, p. 11667 - 11673
29
[ 535-80-8 ]
[ 56961-26-3 ]
Reference：
[1] Journal of Organic Chemistry, 2003, vol. 68, # 5, p. 2030 - 2033
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, # 10, p. 1265 - 1272
[3] Bulletin de la Societe Chimique de France, 1996, vol. 133, # 2, p. 133 - 141
[4] Tetrahedron Letters, 1995, vol. 36, # 6, p. 881 - 884
30
[ 6638-79-5 ]
[ 535-80-8 ]
[ 145959-21-3 ]
Yield
Reaction Conditions
Operation in experiment
61%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 3 h;
General procedure: To a solution of 3-cyanobenzoic acid 8a (3.0 g, 19.7 mmol) in DMF was added N,O-dimethylhydroxylamine hydrochloride (2.0 g, 20.7 mmol), Et3N (2.88 mL, d = 0.73, 20.7 mmol) and EDC*HCl (4.0 g, 20.7 mmol). After the mixture was stirred for 3 h at room temperature, the solvent was removed in vacuo and the residue was dissolved in EtOAc, washed with 10percent citric acid, 10percent NaHCO3 and saturated NaCl, and dried over Na2SO4. Then, the solvent was removed to give a colorless oil of compound 9a (3.0 g, 79percent).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 14, p. 4279 - 4289
[2] Patent: WO2017/214505, 2017, A1, . Location in patent: Paragraph 000678; 000679
31
[ 1117-97-1 ]
[ 535-80-8 ]
[ 145959-21-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 18, p. 5567 - 5571
With sulfuric acid; ozone; acetic acid;cerium(III) acetate; at 16℃; for 1.25h;
Example 6: 3-Chlorobenzoic Acid In a 100 ml jacketed vessel, 200 ml of acetic acid, 0.08 g of cerium(III) acetate, 4.9 g of sulfuric acid and 12.65 g of <strong>[108-41-8]3-chlorotoluene</strong> were initially charged. The mixture was cooled to 16 C. and 5.15 g of ozone were introduced within a period of 75 minutes. After completion of ozonolysis, the ozone present in the solvent was blown out using nitrogen. Analysis of the reaction mixture by means of HPLC or GC gave the following results: <strong>[108-41-8]3-chlorotoluene</strong>: >0.1%; 3-chlorobenzoic acid: 98%
86.5%
With copper(l) iodide; oxygen; nitric acid; at 160℃; under 11251.1 - 18751.9 Torr; for 4.7h;Autoclave;
General procedure: 2-Chloro-4-(methylsulfonyl)toluene (0.100 mol, 20.50 g), CuI (0.001 mol, 0.19 g) and 25 wt% HNO3 (12.60 g) were added in sequence to a 100 mL high pressure reaction kettle equipped with stirrer and a temperature measuring device. Oxygen gas filled the kettle until the pressure was 1.5 MPa. The reaction solution was heated to 160 C slowly (approximately 0.7 h). The autoclave pressure was raised to 2.5 MPa. The reaction was continued for 4 h with stirring at keeping 160 C (thermostated). At the conclusion of the reaction the pressure declined to 0.8 MPa and was stable (9 mol%NO2 and 5 mol% NO, gaseous species concentration determined by the concentration of NO2- and NO3- after passing the gas through NaOH solution). Thin layer chromatography (TLC) was used to determine reaction conversions in some instances. After the reaction was finished, a 25 wt% NaOH solution (0.200 mol NaOH) was added into the reaction solution and stirring was continued. After reduced pressure filtering, 36 wt% hydrochloric acid was used to adjust the pH of the filtrate to pH 2. The resulting precipitate was collected by filtration. This precipitate was added to MeOH (110 mL) containing 3.00 g of activated carbon. The mixture was heated gently to reflux temperature (60 C). The precipitate dissolved completely. Stirring was continued for 1 h. The mixture was filtered, and allowed to cool at 10 C. After 8 h at -5 C the reaction was filtered. The solid precipitate was dried at 80 C for 5 h to give 19.70 g (0.084 mol) of the product as white crystals. The yield was 84.2% and the product purity was 99.7%.
77%
With pyridine; dipotassium peroxodisulfate; oxygen; In acetonitrile; at 80℃; under 760.051 Torr; for 16h;Green chemistry;
General procedure: Ethylbenzene (3a) (0.0531 g, 0.5 mmol), K2S2O8 (0.2703 g, 1.0 mmol), pyridine (0.0158 g, 0.2 mmol) and CH3CN (1.0 mL) were added to an oven-dried pressure vessel with a magnetic stir bar. Then the pressure vessel was filled with dioxygen and the reaction mixture was stirred at 80 C for 16 hours (oil bath). After the completion of the reaction, the solvent was evaporated and the reaction mixture was purified with column chromatography (eluenet: ethyl acetate/PE = 1/10) to give acetophenone (4a) (0.0535 g yield 89%).
With tert.-butylhydroperoxide; 1-butyl-3-methylimidazolium Tetrafluoroborate; In water; at 150℃; for 1h;Microwave irradiation; Cooling;Conversion of starting material;
With the preliminary success in the oxidation of the methylene benzylic units, we then turned to a more challenging oxidation of methyl substituted aromatics.Oxidation of toluene to benzoic acid was first used as the model study. With six equivalents of 70% aqueous TBHP (2 folds in excess), toluene was converted in 9.1% to benzoic acid under microwave irradiation at 160 C. for 1 hr (Run 1, Table 2). It is well documented that solvents with high dielectric constants would enhance the microwave heating effect. When the oxidation reactions were carried out in tert-butanol, nitrobenzene or acetonitrile (Runs 2, 3, 4) as the co-solvents, the percentage conversions were increased to 20-27%. We also explored the uses of other TBHP formulations such as TBHP in isooctane and toluenel18,19. Oxidation can still take place but the results are inferior to the use of aqueous TBHP
With tert.-butylhydroperoxide; 5,10,15,20-tetrakis(2,3,4,5,6-pentafluorophenyl)porphyrin cobalt(II); sodium sulfate; In water; at 20℃; for 16h;Sealed tube;
In a 100 mL agate ball mill jar, 1.27 g (10 mmol) of <strong>[108-41-8]3-chlorotoluene</strong>, 0.0010 g (0.0010 mmol) of 5,10,15, 20-tetra(2,3,4,5,6-pentafluorophenyl)porphyrin Cobalt (II), 6.44 g (50 mmol) of a 70% t-butyl hydroperoxide solution and 6.85 g of anhydrous sodium sulfate were mixed uniformly, and the ball mill tank was sealed. At room temperature, the ball milling reaction was performed at a speed of 800 rpm for 16.0 h, and the ball milling was stopped every 1.0 h to release the gas in the ball milling tank. After completion of the reaction, the obtained reaction mixture was dissolved in 30 mL of absolute ethanol and stirred at room temperature for 30.0 min. Filter, wash the obtained filter cake with 2 × 10 mL of absolute ethanol, combine the ethanol solutions, and make the resulting ethanol solution to 100 mL. 20 mL of the obtained solution was removed, desolvated under reduced pressure, and the obtained reaction mixture was separated by column chromatography (V cyclohexane: V ethyl acetate = 4: 1 to 1: 4). The conversion rate of <strong>[108-41-8]3-chlorotoluene</strong> was 32%, and the selectivity of 3-chlorobenzoic acid was 99%. No other significant oxidation products were detected.
General procedure: A mixture of acid (0.2 mmol), alcohol (0.6 mmol) and GO (50 wt%, calculated with the mass of acid) in ethyl alcohol or DCE (1 mL) was placed in a test tube equipped with a magnetic stirring bar. The mixture was stirred at 100 C for 24 h. After the reaction was finished, filtered the GO, solvent was removed, and the residue was separated by column chromatography to give the pure sample.
With sulfuric acid;
3-Chloro-benzoic acid ethyl ester is prepared from 3-chloro-benzoic acid using a standard protocol with [ETHANOL/H2SO4] according to L. -F. Tietze & T. Eicher, Reactions and Syntheses in the Organic Chemistry Laboratory; University Science Books, Mill Valley, CA, 1989). Title compound: single peak at tR= 7.29 min (System 1).
With thionyl chloride; at 20℃;Reflux;
General procedure: At firstseveral different acyl hydrazines Bwere synthesized. To do this, we have started with corresponding carboxylicacid A in solvent EtOH (2 mL/mmol), 4 equivalents ofthionyl chloride (SOCl2) was added dropwise at room temperature andrefluxed with stirring for 5-12 h (monitored by TLC). SOCl2 and EtOHwas evaporated. Water was added to the crude mixture, extracted withdichloromethane (DCM) and dried with anhydrous Na2SO4.Solvent DCM was evaporated and the residue was dried at high vacuum whichprovided the ethyl ester of the corresponding carboxylic acid A.The ester was added dropwise to hydrazinehydrate (NH2NH2,H2O) (5mmol/1mmol of ethylcarboxylate) and heated at 80 C for 5-20 hours (monitored by TLC) and allowedto stand for 12 hours. If solid appeared it was filtered and the residue wasdissolved in DCM and dried with anhydrous Na2SO4, DCM wasthen evaporated and the solid was dried at high vacuum. If solid was notobserved then the reaction mixture was extracted several occasions by DCM, andthe combined organic layer was dried with anhydrous Na2SO4. DCM was evaporated and residue was dried at high vacuum that leads usdifferent acyl hydrazine Bcorresponding to the starting carboxylic acid A.
With hydrogenchloride; In water;Reflux;
To a solution of 3-chlorobenzoic acid (1 g, 6.39 mmol) in ethanol (10 mL) was added cHCl (5 drops) and the mixture heated at reflux overnight. The solvents were evaporated to give the target compound as a white solid. This compound was then dissolved in ethanol (10 mL) and hydrazine hydrate (6.21 mL, 128 mmol) was added and the mixture heated at reflux overnight. Solvents were evaporated and the product was purified by flash chromatography using a gradient mixture of ethyl acetate and hexanes to give the desire compound as a yellow solid (890 mg, 81% over 2 steps). 1H NMR (CDCl3), ae 7.41 (t, J = 7 Hz, 1H), 7.49 (d, J = 7 Hz, 1H), 7.73 (m, 1H), 7.86 (m, J = 4 Hz, 1H); MS m/z = 171.5, 173.5 (M + H)+.
With sulfuric acid; at 70 - 80℃; for 12h;Reflux;
General procedure: To a solution of the R-substituted aromatic acid (10 mmol) in 20 ml ethanol was added 5 ml concentrated sulfuric acid. The mixture was refluxed at 70-80 C for 12 h. The reaction was concentrated and alkalized with saturated Na2CO3 solution to pH 6-7. The mixture was poured into 100 ml of ice-cold water and extracted with CH2Cl2 (3 50 ml). The organic layer was combined, washed with water, saturated NaHCO3 solution and brine, dried over anhydrous Mg2SO4 and concentrated to give a corresponding ester.
With sulfuric acid;Reflux;
General procedure: The aryl/aralkyl organic acids (5.0 g, 1a-k), the absolute ethanol (20 mL), and conc.H2SO4 (1.5 mL) were taken in 250 mL round bottom flask fitted with reflux condenser. Thereaction mixture was refluxed for 3-4 h. TLC was used to check the completion of reactionby using a solvent system, n-hexane, and EtOAc. On completion, reaction contents were transferred to a separating funnel containing distilled H2O (20 mL). Sodium carbonate(Na2CO3) solution was added to neutralize the acidic pH. Diethyl ether was added to theseparating funnel followed by shaking and the contents were left to set up two layers. Thelower aqueous layer was discarded and the upper organic ether layer containing requiredester was taken into the distillation flask. The organic layer, diethyl ether was distilled offand the corresponding esters (2a-k) were collected from the flask to follow the furtherreaction.17-19
With sulfuric acid; In water; for 6h;Reflux;
General procedure: Hydrazides (30-58) were synthesized by one pot conventionalmethod24 Benzoic acid or its derivative (10 mmol) was dissolvedin ethanol (20 mL). Sulfuric acid (3 N, 2 mL) was added and thereaction contents were refluxed for six hours. The reaction wasmonitored with TLC. After the completion of the reaction, the reactionmixture was neutralized by adding solid NaHCO3, and filteredto remove excess of NaHCO3. In the neutralized reaction mixture which contains ethyl ester, hydrazine monohydrate (1.5 mL,3 mmol) was added and refluxed for 3-6 h to complete the reaction.Ethanol and unreacted hydrazine were removed by distillationupto 1/3 volume. The reaction contents were cooled, filteredand recrystallized from methanol to obtain the desired hydrazidecrystals (see Supporting information).
With sulfuric acid;Reflux;
General procedure: To a stirred solution of different benzoic acids (6.42 mmol) in ethanol (3 mL) was added H2SO4 (0.1mL) and heated to reflux for 6-10 h. The reaction mixture was diluted with ethyl acetate followed by water. The organic layer was washed with saturated NaHCO3 followed by water and brine solution. The organic layer was dried over sodium sulphate, filtered and evaporated to obtain the respective ethyl benzoate derivatives.
With sulfuric acid; for 10h;Reflux;
General procedure: A mixture of benzoic acid (6.42 mmol), catalytic quantity of conc. H2SO4 in ethanol was heated to reflux for 10 h. The reaction mixture was diluted with ethyl acetate followed by water. The organic layer was washed with saturated NaHCO3 followed by water and brine solution. The organic layer was dried over sodium sulphate, filtered and evaporated to obtain respective ethyl benzoates.
With sulfuric acid; for 8h;Reflux;
General procedure: To a solution of substituted benzoic acid (1-15)(0.246 mol) in dry ethanol (2.5 mol), concentrated sulphuricacid (0.5 mL) was added. The reaction mixture was refluxedfor 8 h. Excess of ethanol was distilled off and the contentwas allowed to cool. The residue was poured into separatingfunnel containing 60 mL of water. Carbon-tetrachloride(5-10 mL) was added to obtain sharp separation of aqueousand ester layer. Ester layer was washed with sodiumhydrogen carbonate solution. The esters (16-30) were collected and recrystallized from ethanol. Details of thesecompounds are available in Supplementary Information.
With thionyl chloride; for 2h;Reflux;
General procedure: To a stirred solution of carboxylic acid (1.0 eq.) in ethanol (2 M) was added thionyl chloride (2.0 eq.) dropwise at room temperature, and then refluxed for 2 hours. After it was cooled to room temperature, the reaction mixture was concentrated under reduced pressure to give crude product, which was chromatographed on silica gel column using 1:30 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product esters in 80% - 95% yields. Esters (1.0 eq.) were added dropwise to a stirred solution of acetonitrile (2.0 eq.) and NaH (3.0 eq.) in THF (2 M) at room temperature, and then refluxed for 1h . After it was cooled to room temperature, Water was added dropwise to the reaction mixture under ice bath until no gas bubbles generated, and employing dilute hydrochloric acid neutralization to neutral, extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo to give crude product which was chromatographed on silica gel column using 1:4 to 1:2 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product beta-ketonitriles, white or light yellow solid compounds in 50% - 85% yields. Finally, stirred in concentrated sulfuric acid (3 M) at room temperature for 5 to 10 hours. The reaction mixture was neutralized to neutral by ammonia water, extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo to give crude product which was chromatographed on silica gel column using 1:1 to 2:1 (v/v) EtOAc-petroleum ether solution as eluent to afford isolated product beta-ketoamides 1a-p, white solid compounds in 45% - 85% yields.
With thionyl chloride; for 2h;Reflux;
General procedure: To a solution of substituted benzoic acid 3a-h (0.07 mol) inabsolute ethyl alcohol (100 mL) was slowly added thionyl chloride (15 mL). The mixture was heated to reflux for 2 h, and then cooledto room temperature. The solvent was removed and the solid residuewas dissolved in ethyl acetate (100 mL), and washed withsaturated NaHCO3 solution (100 mL 2). The organic layer wasdried and concentrated to give the intermediates 4a-h as paleyellow oily matter in 94.4e99.4% yield. They were used in the nextstep without additional purification.To a solution of NaH (5.6 g, 0.14 mol, 60%) in anhydrous THF(250 mL) was added 4a-h (0.07 mol) under the mechanical agitation.After heating to 60 C, N-Vinylpyrrolidone (0.07 mol) wasadded by dropwise and the mixture was heated to 72 C for 3 h.Then the reaction mixture was cooled to room temperature, thenpoured into ice water (500 mL), extracted with ethyl acetate(100 3 mL), and washed with saturated NH4Cl solution (300 mL)and brine (300 mL). The organic layer was dried and concentratedto give the intermediates 5a-h as brown oily matter in 82.3e94.2%yield, which was used in the next step without additionalpurification.A solution of 5a-h (0.06 mol) in THF (15 mL) was added to the5 N HCl (60 mL) under reflux. After the reaction mixture wasrefluxed for 3e5 h, then the reaction mixture was cooled to roomtemperature and concentrated in vacuo to remove the solvent THF.The pH was adjusted to 11 with saturated NaOH solution, thenextracted with ethyl acetate (100 mL 3), and washed with brine(150 mL 2). The organic layer was dried and concentrated to givethe intermediates 6a-h as brown oily matter in 82.8e87.2% yield,which was used in the next step without additional purification.To a solution of 6a-h (0.05 mol) in methanol (80 mL) was addedacetic acid two drops, and then NaBH4 (3.8 g, 0.1mol) was addedslowly under the condition of ice salt bath. After reaction at roomtemperature for 3 h, the solvent was removed and the residue wasdissolved in water. The pH was adjusted to 1 with 6 N HCl, washedwith methyl tertiary butyl ether (50 mL 3), and then the pH wasadjusted to 12 with NaOH solution. The mixturewas extracted withdichloromethane (100 mL 3), and washed with brine(150 mL 2). The organic layer was dried and concentrated to givethe brown oil, which was dissolved in acetone to form oxalic acidsalt. Intermediates 7a-h were obtained as white solid in42.3e55.6% yield.
With sulfuric acid;Reflux;
General procedure: We added dense H2SO4 (0.098g, 1mmol) to a solution of substituted benzoic acid (5mmol) in dry ethyl alcohol (10mL). The mixture was heated under reflux until completion (as monitored via TLC), and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (50mL) and washed with 0.1M Na2CO3, brine, dried and concentrated, respectively. The crude products (intermediate 3) were used directly for the next step.
With sulfuric acid;Reflux;
General procedure: The different organic acid (0.02 mol; 1a-o) was taken in 200 mL roundbottom flask. 20 mL absolute ethanol (99%) was added to the flask andstirred for ten minutes to homogenize the reaction contents. Later on, 2.5 mLconcentrated sulphuric acid, an activator, was added and reaction contents wererefluxed for 3-4 hours. Thin layer chromatography was the technique used tomonitor the completion of reaction by using 1:4 ratio of n-hexane and ethylacetate as mobile phase. After maximum completion, reaction mixture wastreated with 10% aqueous Na2CO3 (pH 9-10) to neutralize the reaction mixtureand to remove unreacted free acid. To get the pure esters, solvent extraction ofneutralized reaction mixture was performed by 50 mL of CHCl3 in a separatingfunnel for 3-4 times. After that CHCl3 layer was separated from the lowerdensity aqueous layer and was distilled by using rotary evaporator to acquireethyl esters.
With sulfuric acid;Reflux;
General procedure: Aryl/aralkyl carboxylic acids (Ia-n) (0.032 mol)were homogenized in ethanol (99%, 30 mL) in a 250mL round bottom flask. Concentrated sulfuric acid(2.5 mL) was added in the mixture and set to reflux for3-5 h. TLC was developed for monitoring reactioncompletion. At maximum completion, the 10% aqueoussodium carbonate solution was poured to neutralizethe mixture up to pH of 9-10 after addition of 150mL distilled water. This step converted untreatedorganic acid and sulfuric acid into salts washed awayby aqueous layer. The esters were filtered or extractedby solvent extraction technique using 50 mL chloroformor diethyl ether from a separating funnel. Chloroform wasdistilled off to collect esters (IIa-n) [18, 19].
With sulfuric acid;Reflux;
General procedure: (Un)Substituted benzoic acid (IVa-n) (0.02 mol) was refluxed with 60 mL EtOH for 4-5 h in the presence of conc. H2SO4 (1.25 mL) in around-bottom flask (250 mL). TLC plates were used to monitor the reaction. Excess distilled water (150 mL) was added after reaction completion and pH was adjusted to 8-10 by 20% aq. Na2CO3 solution. The product was collected through sequential extraction with CHCl3 (20 mL × 3). Chloroform was distilled off to collect the product. In some cases, the product was collected through filtration. Esters (Va-n) were used in further synthesis [18, 19].
With sulfuric acid; at 80℃; for 7h;
General procedure: Taking 6a as an example, a mixture of benzoic acid (2.5 g,20.0 mmol), 4 mL sulfuric acid, and 50 mL ethanol was heated under reflux for 7 h (hour, h). After finishing the reaction, it was poured into water and extracted by ethylacetate, dried with anhydrous Na2SO4, and then the solventof the organic phase was evaporated under vacuum to give colorless liquid 4a. Then excess 80% N2H4·H2O and 15 mLof ethanol were added into the flask containing 4a, which was heated under reflux about 5 h. After the reaction was completed, it should be cooled into room temperature overnight and the white solid 5a was given after being filtered, washed with ethanol and dried in open air. Finally, 5a (1.4 g,8.0 mmol) was then subjected to substitution reaction with KOH (0.9 g, 15.6 mmol) and CS2(1.2 g, 15.0 mmol) togenerate intermediate 6a. At the same time, 6b-6m was synthesized by the methods described in the literature (Shi et al.2015; Du et al. 2013).
General procedure: 5.1.3. General procedure C. To the carboxylic acid substrate (0.42 mmol, 1.2 equiv) in DMF (1.5 mL) was added CDI (0.50 mmol, 1.1equiv) and DBU (0.67 mmol, 1.9 equiv). The reaction was stirred for 30 min at 23 C. Next, 2-amino-4-(2-pyridyl)thiazole 20 (0.35 mmol, 1.0 equiv) was added and the reaction mixture was stirred for 16 h at 23 C. A small amount of silica gel was added to the reaction mixture, which was concentrated in vacuo under reduced pressure. The crude product impregnated on the silica gel was purified by silica gel flash chromatography (0-10% MeOH-CH2Cl2) to afford the title compound.
The 2,2,6,6-tetramethylpiperidine (39.7g, 281.03mmol), was dissolved in 100mL of anhydrous tetrahydrofuran at -78C nitrogen was slowly added dropwise n-butyllithium (18.0g, 281.03mmol ), - 78 stirred for 1 hour. A solution of 3-chloro-benzoic acid 85a (20.0g, 127.7mmol) in 150mL of tetrahydrofuran was slowly added dropwise to the reaction mixture, -78 stirred for 4 hours. A solution of iodine (129.7g,510.96mmol) in 250mL of tetrahydrofuran was slowly added dropwise to the reaction mixture, -78 stirred for 3 hours. The reaction mixture was quenched with water, acidified with 4M aqueous hydrochloric acid, extracted with ethyl acetate, washed with sodium thiosulfate, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product of 3-chloro -2 - iodobenzoate 85b (30g, white solid).1
With potassium carbonate; In ethanol; water; at 70℃; for 12h;Green chemistry;
General procedure: NHC-PdMNPs nanomagnetic catalyst (0.15 molpercent Pd),aryl halide (1.0 mmol), phenylboronic acid (1.1 mmol) andpotassium carbonate (2.2 mmol) were placed in a roundbottomedflask. To the mixture, EtOH:H2O (1:1, 5 mL) wasadded and stirred at 70 °C for various times. The progressof the reaction was monitored by TLC. After reaction completion,the mixture was cooled to room temperature andthe NHC-PdMNPs nanomagnetic catalyst was separatedby using an external magnet. To the filtrate, ethyl acetate(10 mL) and water (10 mL) were added. Ethyl acetate layerwas separated from the water layer using a separatory funneland dried with sodium sulphate. The dried ethyl acetatewas concentrated in vacuo and the product was purifiedby column chromatography using n-hexane and ethylacetate as eluents to afford the corresponding products ingood to excellent yields. All the coupling products wereknown molecules and were confirmed by comparing the melting point, 1H NMR and mass spectroscopic data withthe authentic samples.
To a mixture of 6-Chloro-4,5-diaminopyrimidine (0.70 g, 4.84 mmol) and 3-chlorobenzoic acid (0.76 g, 4.84 mmol) in the flask was added phosphoryl chloride (40.0 mL), and the resulting mixture was stirred for 16 h at 100 C. The reaction mixture was evaporated to remove excess phosphoryl chloride, and the residue was added to water (20 mL). The precipitate was filtered and purified by flash chromatography (0 to 5% Methanol/DCM) to afford the title compound (1.28 g, 31%) as a yellow solid. LC/MS: R.=1.59 min, ES+ 265.0 (FA standard).
A. 8-CHLORO-11-(1-ETHOXYCARBONYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINE N-OXIDE STR510 8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (5 g, 13.06 mmol) was dissolved in CH2 Cl2 at -10 C. 3-Chlorobenzoic acid(4.9 g, 15,67 mmol) was then added and the reaction mixture stirred for 95 minutes. The reaction mixture was taken up in CH2 Cl2 and extracted with sodium bisulfite, 10% NaOH. The crude reaction product was purified on silica gel eluding first with 1% and then with 2% MeOH in CH2 Cl2 to give the title compound (2.7 g, MH+ 399).
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h;
EXAMPLE 9; Preparation of 1,3-oxazole intermediate-2-(3-chlorophenyl)-1,3-oxazole-4-carboxylic acid; i) Methyl 2-[(3chlorobenzoyl)amino]-3-hydroxypropanoate; N-methylmorpholine (7.0 ml, 63.8 mmol) and EDCI (4.97 g, 31.9 mmol) were added to a mixture of 3-chlorobenzoic acid (5.0 g, 31.9 mmol), serine methyl ester hydrochloride (6.1 g, 31.9 mmol) and HOBt (4.31 g, 31.9 mmol) in DMF (100 ml) at 0 C. The mixture was allowed to warm to RT and stirred for 18 h. The mixture was diluted with ethyl acetate (300 ml) and then washed with water (3×250 ml) followed by brine. The organic extract was dried over Na2SO4 (anhydrous) and then concentrated in vacuo to give the title compound (7.2 g, 93%, pale yellow solid). 1H NMR (CDCl3) delta (ppm): 7.78 (s, 1 H), 7.66 (d, 1 H), 7.45, (dd, 1 H), 7.34 (t, 1 H), 7.25 (br, d, 1H), 4.82 (m, 1 H), 4.08 (m, 2 H), 3.79 (s, 3 H), 3.19 (br, t, 1H).
3-[5-(3-chlorophenyl)-[1,2,4]oxadiazoi-3-yl]piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
To a stirred solution of 3-chloro-benzoic acid (0.32 g, 2 mmol) in dry DMF (5 ml)NMM (22 ml, 2 mmol) and isobutyl chloroformate (0.26 ml, 2 mmol) were added at 0 0C and the reaction mixture was stirred at 0 0C for half an hour. Then a solution of l-(tert- butoxycarbonyl)-N-hydroxy~piperidine-2-carboxamidine (Intermediate C; 0.5 g, 2 mmol) in dry DMF was added, and the reaction mixture was stirred for 1 hour, during this time the temperature reached 25 C. Then TBAF (0.1 g, 0.4 mmol) was added to the solution, and the mixture was stirred at 100 0C for 5 hours. The solution was concentrated in vacuo and the residue was partitioned between water (20 ml) and dichloromethane (20 ml). The aqueous EPO <DP n="39"/>phase was extracted with dichloromethane (20 ml), the combined organic layers were dried and concentrated. The crude product was purified by column chromatography on silica gel (Kieselgel 60, eluent: chloroformmethanol = 98:2) to yield 0.35 g (49%) of the title compound as an oil. MS:m/e=364 (M+H)+.
To a solution of 3.26 g (20.0 mmol) of <strong>[78607-32-6]2,5-dichloro-pyridin-3-ylamine</strong> in acetonitrile (50 mL) is added 3.50 g (20.0 mmol) of 3-chlorobenzoic acid. The mixture is stirred overnight at room temperature during which time a precipitate forms. The formed solid is collected by filtration, washed with cold diethyl ether and dried to give 5.43 g (90percent) of 2,5-dichloro-N-(3-chloro-phenyl)-nicotinamide as a white solid.
General procedure: 5.1.1 5-(4-Morpholinophenyl)-1,3,4-thiadiazol-2-amine (59) A mixture of 4-morpholinobenzoic acid (5.18 g, 25 mmol) and N-aminothiourea (2.28 g, 25 mmol) in POCl3 (7 ml) was stirred vigorously at 75 C for 0.5 h. After addition of H2O (30 ml), the reaction mixture was heated under reflux for 4 h and basified to pH 8 by 50% NaOH solution. The mixture was filtered and the filter cake was recrystallized from ethanol to yield 3.90 g of compound 59 as a yellow crystal. Yield: 59%; The synthetic procedures of compounds 60-81 were the same as that described above. 5.1.1.8 5-(3-Chlorophenyl)-1,3,4-thiadiazol-2-amine (67) Yield: 75%, mp: 212-214 C (EtOH). ESI-MS m/z: 212.1 [M+H]+; 1H NMR (CDCl3) delta 7.49-7.50 (m, 2H), 7.54 (s, 2H), 7.70-7.71 (m, 1H), 7.80 (s, 1H).
General procedure: The synthetic approach to 5-substituted-1,3,4-thiadiazol-2-amine derivatives wasadapted from the literature (Foronmadi et al. 1999). Briefly, a mixture of carboxylicacid derivatives (50 mmol), POCl3 (13 ml) and N-aminothiourea (50 mmol) wasreacted for 0.5 h at 75 C. After cooling down to 0 C, water was added. The reactionmixture was refluxed for 4 h. After reaction, the mixture was basified to pH 8 by thedropwise addition of 50% NaOH solution. The precipitate was filtered and recystallizedfrom ethanol to get the title compounds.
General procedure: A mixture ofcorresponding acid, 1 (2.00 mmol), and POCl3 (0.80 ml) wasstirred for 20 min at room temperature. Then, thiosemicarbazide(2.0 mmol, 0.182 g) was added, and theresulting suspension was refluxed for 1 h. After cooling theflask in an ice bath, 2.4 ml of distilled water was addedcarefully, and refluxwas continued for 1 h. The mixturewasthen cooled to the room temperature, saturated aqueoussolution of NaOH was added until pH 8.5 was reached, andthe suspensionwas stirred for 1 h at the room temperature.The formed precipitate of the corresponding 2-amino-1,3,4-thiadiazole derivative (2aeo) was then filtrated, driedover CaCl2, and recrystallized from hot 50% aqueous EtOH.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;
General procedure: To a solution of 3-cyanobenzoic acid 8a (3.0 g, 19.7 mmol) in DMF was added N,O-dimethylhydroxylamine hydrochloride (2.0 g, 20.7 mmol), Et3N (2.88 mL, d = 0.73, 20.7 mmol) and EDC·HCl (4.0 g, 20.7 mmol). After the mixture was stirred for 3 h at room temperature, the solvent was removed in vacuo and the residue was dissolved in EtOAc, washed with 10% citric acid, 10% NaHCO3 and saturated NaCl, and dried over Na2SO4. Then, the solvent was removed to give a colorless oil of compound 9a (3.0 g, 79%).
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 25℃; for 16h;
To a solution of 3-chlorobenzoic acid 81A (1.56 g, 10 mmol), N,O- dimethylhydroxylamine hydrochloride (1.2 g, 12.8 mmol), and EDCI (2.5 g, 12.8 mmol) in dichloromethane (40 mL) was dropped triethylamine (3 g, 30 mmol) at 0oC. The mixture was stirred at 25oC for 16 hours and diluted with dichloromethane (50 mL). The organic layer was washed with water (30 mL x 2) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to leave a crude Compound 81C. LC-MS (ESI) m/z: 200 [M+H]+;1H-NMR (CDCl3, 400 MHz): delta (ppm) 3.36 (s, 3H), 3.55 (s, 3H), 7.34 (t, J = 8.0 Hz, 1H), 7.42-7.44 (m, 1H), 7.55-7.57 (m, 1H), 7.66 (s, 1H).
General procedure: Equimolar quantities of compound 2 (1 mmol) and a substituted carboxylic acid were dissolved in phosphoryl chloride (5 mL) and heated at 80C for 3-6 h, the progress of reaction being monitored by TLC. The reaction mixture was then heated under reduced pressure to allow excess phosphoryl chloride to distill off, and the residue was subjected to flash chromatography on silica gel using 15-25% acetone in petroleum ether as eluent to give the target compounds 3a-m (Table 1).
With sulfuric acid; nitric acid; at 0 - 20℃; for 1h;
Concentrated sulfuric acid (12 mL) was added to concentrated nitric acid (1.6 mL) under ice cooling, and the mixture was stirred at 0 C. for 5 min.3-Chlorobenzoic acid (3 g) was added over 5 minutes, the temperature was raised to room temperature and stirred for 1 hour.The reaction solution was added dropwise to ice-cooled water, and the precipitated solid was collected by filtration and washed with water to give 3-chloro-5-nitrobenzoic acid (Compound 0004-1, 2.65 g) as a white solid.
With di-tert-butyl peroxide; copper(II) bis(trifluoromethanesulfonate); In 1,2-dichloro-ethane; at 130℃; for 12.0h;Sealed tube;
General procedure: A 50 mL sealed tube (with a Teflon high pressure valve) equipped with a magnetic stir bar was charged with Cu(OTf)2 (0.05 mmol), followed by carboxylic acid (0.5 mmol), formamide (2.0 mmol), tert-butyl peroxide (DTBP, 1 mmol), and DCE (1 mL). After the reaction mixture was stirred at 130 C for 12 h, it was allowed to cool to ambient temperature. The reaction mixture was diluted with ethyl acetate, and then filtered through a small pad of Celite. The filtrate was washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL, twice). The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel preparative TLC to give the corresponding product.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
General procedure: The vacuum dried intermediate 3 (0.002 mol) was then reacted with mono- and di-substituted benzoic acids (0.003 mol) separately in presence of anhydrous potassium carbonate (0.003 mol) in DMF (10 mL). The reaction mixture was stirred at room temperature for about 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water and allowed stir for 10 min. The solid obtained was filtered and washed successively with distilled water and recrystallized from ethanol to obtain4(a?n).
With oxygen; sodium t-butanolate; 1,3-bis[(2,6-diisopropyl)phenyl]imidazolinium chloride; In dichloromethane; at 20℃; for 30h;Molecular sieve;
General procedure: Under Oxygen atmosphere, aryl alcohol (2.00 mmol), precatalyst(SIMesHCl or SIPrHCl, 0.06 mmol), NaOtBu (960.5 mg,10.00 mmol), and 1 g 3 A molecular sieve were added todichloromethane (20 mL). This solutionwas allowed to stir for 30 h.After filtrating through a pad of Celite, the cake was added tohydrochloric acid (2N, 50 mL) and extracted with ethyl acetate(50 mL3). The organic layer was dried over Na2SO4 and concentratedunder reduced pressure. The products did not need furtherpurification.
67%
With Iron(III) nitrate nonahydrate; iodine; oxygen; dimethyl sulfoxide; at 130℃; under 750.075 Torr; for 12h;Sealed tube; Green chemistry;
General procedure: To a 20-mL tube equipped with a magnetic stirring bar was added acetophenone 1a (120 mg, 1 mmol), 2 mL of DMSO, iodine (25 mg, 0.1 mmol) and Fe(NO3)3·9H2O (40 mg, 0.1 mmol). Then the tube was sealed after being charged with oxygen to replace the air in it. The tube was placed into a preheated oil bath (130C), and the reaction solution was stirred for 12h. Then the reaction was quenched with water, and the pH of the aqueous phase was adjusted to 11 with 0.1 mol/L NaOH. After being washed with ethyl acetate (3 x 3 mL), the pH of the aqueous phase was adjusted to 2 with 0.1mol/L HCl and extracted with ether (3 x 6 mL). The combined ether phase was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to obtain the crude product. The crude product was purified by column chromatography on silica gel using ethyl acetate/petroleum ether as eluent to afford 2a as a white solid (104 mg, 85% yield). 1H NMR(600 MHz, DMSO-d6) delta 12.88 (s, 1H), 7.95 (d, J = 7.9 Hz, 2H), 7.62-7.59 (m, 1H), 7.50-7.48 (m, 2H); 13C NMR (125MHz, DMSO-d6) delta 167.3, 132.7, 130.8, 129.2, 128.5.
67%
With Iron(III) nitrate nonahydrate; iodine; oxygen; In dimethyl sulfoxide; at 130℃; for 12h;Sealed tube;
In assembling the magnetic force of the solder 25 ml glass tube by adding 1 mmol of 1 - (chlorophenyl between) ethanol (formula (1 - 9)), 0.1 mmol of I2, 0.1 Mmol of Fe (NO3)3· 9 H2O, 2 ml of DMSO, oxygen is used for replacement in the glass tube after the air sealing glass tube, will then be sealed glass tube is put into the pre-heating to 130 C the pot of the oil bath, and opening of the magnetic stirrer, reaction 12 h after, is taken out of the sealed glass tube, to be its cooling to room temperature, the reaction solution is added in the quenching reaction, then the concentration of 0.1 mol/L of sodium hydroxide solution to adjust the pH to 11 the left and right, for washing three times with ethyl acetate, the aqueous phase is in a concentration of 0.1 mol/L hydrochloric acid solution to pH value to 2 the left and right, then the extraction three times with ethyl ether, the merging of the three times of the ether extract, reducing pressure and ethyl ether, then column chromatography, using ethyl acetate/petroleum ether volume ratio 1:25 of the mixed solution is the eluant, collecting the eluant containing the compound, evaporate the solvent to obtain the product between chlorobenzoic acid, separation in the yield of 67%.
With sodium cyanide; In N,N-dimethyl-formamide; at 50℃; for 1h;Molecular sieve;
General procedure: Aldehyde 1 (1.0 mmol; 1.0 equiv.) and 4 A molecular sieves (300 mg) were added to a mixture of DMF (3.0 mL) and an appropriate alcohol (or a thiol) (3.0 mL). To the above solution was added sodium cyanide (1.5 mmol; 1.5 equiv). The reaction mixture was stirred in an open flask at 50 C and monitored by TLC. After the complete consumption of 1, the mixture was poured into water (25 mL) and extracted with diethyl ether (5 × 10 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude mixture was further purified by column chromatography on silica gel using ethyl acetate/hexane as the eluent to furnish the desired ester compound 3. The aqueous layer was acidified with HCl, extracted with ether, and concentrated to yield the corresponding carboxylic acid 6, which was sufficiently pure needing no further purification.
General procedure: To a solution of 2-Methylbenzoic acid (1.36 g, 10 mmol) in DCM (50 mL), Et3N (1.12 g, 11 mmol) and TBTU (3.60 g,11 mmol) were added in turn. After 20 min, compound b (n =4, 1.17 g, 5 mmol) and Et3N (0.50 g, 5 mmol) were added. The reaction solution was stirred at room temperature for 8 h.Then, the solvent was evaporated with the residue being takenup in EtOAc (50 mL). the EtOAc solution was washed with saturated citric acid (3 × 20 mL), NaHCO3 (3 × 20 mL), and brine (3 × 20 mL), dried over MgSO4, and evaporated under vacuum. The desired compound c (1.50 g, 76 percent yield) was derived by crystallization in EtOAc/petroleum ether (1/4) as white powder. ESI-MS: m/z: 397.8 [M+H]+.
To a solution of 2-Methylbenzoic acid (1.36 g, 10 mmol) in DCM (50 mL), Et3N (1.12 g, 11 mmol) and TBTU (3.60 g,11 mmol) were added in turn. After 20 min, compound b (n =4, 1.17 g, 5 mmol) and Et3N (0.50 g, 5 mmol) were added. The reaction solution was stirred at room temperature for 8 h.Then, the solvent was evaporated with the residue being takenup in EtOAc (50 mL). the EtOAc solution was washed with saturated citric acid (3 × 20 mL), NaHCO3 (3 × 20 mL), and brine (3 × 20 mL), dried over MgSO4, and evaporated under vacuum. The desired compound c (1.50 g, 76 % yield) was derived by crystallization in EtOAc/petroleum ether (1/4) as white powder. ESI-MS: m/z: 397.8 [M+H]+.
8-chloro-3-(3-chlorophenyl)-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With trichlorophosphate; In ethanol; at 140℃; for 0.25h;Microwave irradiation;
A CEM-designed 10-mL pressure-rated vial was charged with POCl3(2 mL), <strong>[89570-82-1]3-chloro-2-hydrazinyl-5-(trifluoromethyl)pyridine</strong> (211 mg,1mmol), 4-methoxylbenzoic acid or analogous acid (1mmol). The mixture was irradiated in a CEM Discover Focused Synthesiser (150 W, 140C, 200 psi, 15min). The mixture was cooled to room temperature by passing compressed air through the microwave cavity for 2 min. It was poured into cold ice (40 mL) and the formed precipitate filtered. The crude solid was recrystallised from EtOH to give the title compound 2a and others. All the other compounds were synthesised according to the same procedure.
With water; potassium carbonate; In acetonitrile; at 100℃; under 3750.38 Torr; for 0.0161111h;
General procedure: A 25 mM solution of iodobenzene (5a) and K2CO3 (2 equiv) in H2O/CH3CN (2:1) was pumped at a flow rate of 1.0 mL/min(contact time: 58 s) through a Phoenix flow reactor systemequipped with two cartridges of 4 (total 500 mg; 0.084 mmolPd). Flow hydroxycarbonylation with CO gas introduced from agas module (10 mL/min) was conducted at 100 C and a systempressure of 5 bar. The resulting solution was collected for 50min (50 mL) and the solvent was removed by evaporation. 2 Naq HCl (10 mL) was added and the resulting solid was collectedby filtration, washed with H2O (3 × 10 mL), and dried undervacuum to give benzoic acid (9a) as a white solid without anyfurther purification.Yield: 125 mg (82%); mp 122 C; 1H NMR(400 MHz, DMSO-d6): delta = 12.96 (br s, 1 H, COOH), 7.93 (d, J = 7.2Hz, 2 H, PhH-2 and PhH-6), 7.62 (t, J = 7.2 Hz, 1 H, PhH-4), 7.49 (t, J =7.2 Hz, 2 H, PhH-3 and PhH-5); 13C NMR (101 MHz, DMSO-d6): delta = 167.32 (COOH), 132.87 (Ph), 130.76 (Ph), 129.26 (Ph),128.57 (Ph); ESI-TOF-MS (neg.): m/z = 121 [M - H]-.
General procedure: To a solution of 3a (1 g) in ethanol was added Pd/C (5%, 0.1 g) and the mixture was stirred for 24 hrs at room temperature in a hydrogen atmosphere under atmospheric pressure. Insoluble matters were removed using Celite, and the filtrate was concentrated in vacuo to give the desired product 4a (0.76 g) as a yellow solid. To a solution of carboxylic acid (1 equiv) in CH2Cl2 (15 mL) at 0 C was added DMAP (1 equiv) and EDCI (1 equiv). The reaction mixture was stirred at 0 C for 45 minutes. At this time 4a (1 equiv) was added and the mixture was warmed to room temperature and stirred overnight. The resulting mixture was concentrated in vacuo, partitioned between 1.0 M HCl (20 ml) and ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2 × 15 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatograph using a mixture of petroleum ether/ethyl acetate (20 : 5, v/v) as eluent to afford the product as a white solid. To a solution of the obtained solid (1 equiv) in 2:3:1 THF/MeOH/H2O (18 ml) was added LiOH·H2O (1.5 equiv). After stirring at room temperature for 4 h, the volatiles were removed under reduced pressure. The residue was acidified with 1N hydrochloric acid solution, and then filtered and the filter cake was washed with 5 mL of water, dried in vacuum to afford a white powder. Recrystallization from 75% EtOH gave the desired compounds 2-17 as white solid.
With di-tert-butyl peroxide; copper(I) bromide; In ethyl acetate; at 120℃;
General procedure: Benzoic acid (1.0 mml), tetramethylthiuram disulfide (TMTD) (1.1 mmol), CuBr (10% mmol), DTBP (di-tert-butyl peroxide, 2.0 equiv) were added in dried seal tube equipped with a septum and magnetic stirrer bar, EtOAc (ethyl acetate, 2 mL) was then added. The mixture was stirred at 120 oC and checked by TLC until the starting material was finished (about 10-12 h). The reaction was cooled down to room temperature, quenched with sat. NH4Cl solution (5 mL) and then extracted with ethyl acetate (10 mml). The crude solution was dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by flash column chromatography to afford the desired product.
With di-tert-butyl peroxide; copper(I) bromide; In ethyl acetate; at 120℃;
General procedure: Benzoic acid (1.0 mml), tetramethylthiuram disulfide (TMTD) (1.1 mmol), CuBr (10% mmol), DTBP (di-tert-butyl peroxide, 2.0 equiv) were added in dried seal tube equipped with a septum and magnetic stirrer bar, EtOAc (ethyl acetate, 2 mL) was then added. The mixture was stirred at 120 oC and checked by TLC until the starting material was finished (about 10-12 h). The reaction was cooled down to room temperature, quenched with sat. NH4Cl solution (5 mL) and then extracted with ethyl acetate (10 mml). The crude solution was dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by flash column chromatography to afford the desired product.
With 1,1'-(hexane-1,6-diyl)bis(1,8-diazabicyclo[5.4.0]undec-7-enium) dichlorine; In ethanol; water; at 70℃; for 2h;Green chemistry;
General procedure: Carboxylic acids (1.00 mmol), primary chloroalkanes(1.20mmol) and IL-1 (0.30mmol) were added respectivelyinto a two necked flask equipped with 6mL 50%aqueous ethanol solution under stirring, then raised the systemtemperature to 70C for a needed time in water bath.The progress of the reaction was monitored using thin layer chromatography (TLC). When the reaction was over, thereactor was cooled down to room temperature. The mixturewas diluted with water (10mL) and extracted with ethylacetate (3 × 5mL), the extract was dried over anhydrousNa2SO4,filtered, and concentrated in a rotary evaporatorto collect target product. Meanwhile, the reborn catalystcould be applied in the next cycle was after removing thesolvent and dried at 80C under vacuum for 6h. All theesterification products were further purified by column
With boron trifluoride diethyl etherate; In toluene; at 20.0℃; for 0.5h;
Carboxylic acid (0.2 g, 1.64 mmol), tert-butoxypyridine (0.33 g, 2.21 mmol) and boron trifluoride diethyl etherate (0.31 g, 2.21 mmol) in dry PhCH3 (2 mL) were added to a 20-ml vial. The reaction mixture was then allowed to stir at room temperature for 30 min before quenching with anhydrous NaHCO3. The reaction mixture was diluted with ethyl acetate (30 mL), then washed with water (20 mL), followed by brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and carefully concentrated under reduced pressure. The resulting residue was then purified by flash column chromatography on silica gel with 0:4 to 1:4 dichloromethane/hexane as eluent to yield the desired product 5a as a colorless oil.
3-chloro-N-(3-cyano-4-fluorophenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 16h;
General procedure: To the solution of carboxylic acid (1 eq.) in DCM were added HATU (1.05 eq.), amine (1.1 eq.) and DIPEA (2 eq.). The mixture was stirred for 16 h at room temperature. Afterwards, the solution was washed with water and brine. The resulting organic layer was dried over MgSO4, and the solvent was removed by evaporation. The crude material was purified by flash chromatography (CH2Cl2:MeOH).
tert-butyl (1-(4-(3-chlorobenzamido)phenyl)cyclobutyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In tetrahydrofuran; ethyl acetate; at 20℃; for 3.0h;
To a stirred solution of 3-chlorobenzoic acid (2.1 g, 14 mmol) in THF (100 mL) was added <strong>[1259224-00-4]tert-butyl (1-(4-aminophenyl)cyclobutyl)carbamate</strong> (3.0 g, 11 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (15 g, 22.87 mmol) (50% in the EtOAc), and pyridine (2.77 mL, 34 mmol). The reaction mixture was stirred at RT for 3 h, then concentrated under reduced pressure. The residue was dissolved in DCM (100 mL), washed with water (100 mL), and the organic layer was concentrated under reduced pressure to afford tert-butyl (1-(4-(3-chlorobenzamido)phenyl)cyclobutyl)carbamate.
General procedure: Complex 1 was prepared by the reaction of an aqueous solution of copper(II) acetate monohydrate (1mmol, 0.20g) with N-methylnicotinamide (2mmol, 0.27g) followed by addition of 4-fluorobenzoic acid (2mmol, 0.28g). The reaction mixture was stirred until a blue product was precipitated (3days). The fine blue microcrystals were filtered off, washed with a small portion of water and dried at ambient temperature. The mother liquor obtained from filtration were left to crystallize. The blue crystals suitable for X-ray structure determination were separated after several days. Yield: 0.41g (65%).
According to the procedure reported by Yu and co-workers [3], palladium acetate (22 mg, 0.10mmol), iodobenzene diacetate (644 mg, 2.0 mmol), iodine (507 mg, 2.0 mmol), and tetrabutylammonium iodine (739 mmol, 2.0 mmol) were added to a solution of 3-chlorobenzoic acid (313 mg, 2.0 mmol) in 1,2-dichloroethane (20 mL). The mixture was heated at 100 C with stirring for 2 h and then allowed to cool to room temperature. Iodobenzene diacetate (644 mg, 2.0 mmol) and iodine (507 mg, 2.0 mmol) were added to the mixture. After stirring at 100 C for 4 h, the resulting mixture was diluted with10% sodium carbonate. The aqueous layer was separated, washed with Et2O, and then acidified with 10% HCl. The resulting mixture was extracted with EtOAc and the organic layer was dried over Na2SO4; filtered; and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/EtOAc = 4/1) to give crude 5-chloro-2-iodobenzoic acid (223 mg) as a colorless solid, which was suspended in thionyl chloride (2 mL). After stirring under reflux conditions for 2 h, the resulting mixture was concentrated under reduced pressure. The remaining thionyl chloride was removed by azeotropic distillation with benzene. The residue was dissolved in anhydrous CH2Cl2 (3 mL). To the mixture were added isopropylamine (56 mg, 0.95 mmol) and triethylamine (240 mg,2.37 mmol) at 0 C under a nitrogen atmosphere. After stirring at room temperature for 13 h, the resulting solution was diluted with EtOAc. The mixture was washed with 10% HCl, saturated aqueous NaHCO3, water, and brine; dried overNa2SO4; filtered; and concentrated under reduced pressure. The residue was purified by recrystallization from hexaneand CHCl3 to give 19 (138 mg, 21% in 3 steps) as colorless needles.
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