* 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.
Reference:
[1] Journal of Organic Chemistry, 2014, vol. 79, # 9, p. 4196 - 4200
3
[ 22121-86-4 ]
[ 61272-76-2 ]
[ 348-36-7 ]
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4
[ 371-40-4 ]
[ 61272-76-2 ]
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[14] Synthesis (Germany), 2016, vol. 48, # 6, p. 855 - 864
[15] Journal of Organic Chemistry, 2016, vol. 81, # 22, p. 10987 - 10999
[16] Patent: WO2017/12647, 2017, A1, . Location in patent: Paragraph 0259
[17] Patent: US28939, 1976, E1,
5
[ 61272-76-2 ]
[ 61272-77-3 ]
Reference:
[1] Patent: US28939, 1976, E1,
6
[ 61272-76-2 ]
[ 16626-02-1 ]
Reference:
[1] Journal of Organic Chemistry, 2001, vol. 66, # 13, p. 4525 - 4542
[2] Tetrahedron Letters, 1999, vol. 40, # 4, p. 657 - 660
7
[ 75-15-0 ]
[ 61272-76-2 ]
[ 80087-71-4 ]
Yield
Reaction Conditions
Operation in experiment
72%
With sodiumsulfide nonahydrate In N,N-dimethyl-formamide at 110℃; for 12 h; Sealed tube; Inert atmosphere
General procedure: A sealed tube (50 mL) was charged with 2-haloaniline 1a (2mmol), CS2 (10 mmol), Na2S (4mmol) and DMF (2 mL) at room temperature under an argon gas atmosphere and the tube was flushed with argon for three times and sealed. Then the mixture was stirred electromagnetically at 110 °C for 12 hours. The reaction process was monitored by TLC on silica gel. After the reaction was completed, the reaction mixture was cooled to room temperature, 2 mL HCl (3 mol/L) was added and stirred for 30 minutes. Then the reaction mixture solution was extracted by dichloromethane (3*20 mL). Subsequently, the combined organic solution were dried by anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel colum chromatography (eluent: petroleum ether / ethyl acetate) give the corresponding pure product 2a.
43.8%
With sodium sulphide nonahydrate In N,N-dimethyl-formamide at 110℃; for 12 h; Inert atmosphere
To the reaction tube was added 0.50 mmol (0 • 1185 g) of 4-fluoro-2-iodoaniline, 0 · 25mmol (0 0600g) of the nine Water sodium sulfide, 2 mL of N, N-dimethylformamide and 1.50 mmol (0.1142 g) of carbon disulfide were added under an inert gas atmosphere and the reaction was stirred at 110 ° C for 12 hours, After the reaction was complete, the reaction solution was cooled to room temperature, and 3 mL of 4N hydrochloric acid was added for 15 min. The reaction solution was extracted three times with methylene chloride. The organic phases were combined and dried over anhydrous magnesium sulfate for 2 hours. And finally the crude dichloromethane solvent was distilled off under reduced pressure to give the crude product. The crude product was subjected to column chromatography (200-300 mesh silica gel) eluting with a petroleum ether and ethyl acetate (8: 1-2: 1) to give a white powder having a purity of more than 99percent Thiobenzothiazole 40.6 mg, the isolated yield was 43.8percent.
With iron(III) trifluoride; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In N,N-dimethyl-formamide at 110℃; for 3 h; Inert atmosphere; Sealed tube
General procedure: A 25 mL reaction tube was charged with 2-haloaniline 1 (0.6 mmol), potassium o-ethyldithiocarbonate 2 (1.8 mmol), FeF3 (0.06 mmol), 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl (0.03 mmol) and DMF (4 mL). The reaction vessel was flushed with argon for three times and sealed. Then the mixture was stirred electromagnetically in an oil bath at 110 for 3 - 21 hours. The reaction process was monitored by TLC on silica gel. After the reaction was completed, the reaction mixture was cooled to room temperature, then 4 mL HCl (3mol/L) was added and stirred for 30 minutes. Then the reaction mixture solution was extracted by ethyl acetate (3*20 mL). Subsequently, the combined organic solution were dried by anhydrous sodium sulfate and the target product was purified by silica gel colum chromatography (eluent: petroleum ether / ethylacetate) to give the corresponding pure product 3.
95.5%
With copper(l) chloride In N,N-dimethyl-formamide at 110℃; for 6 h; Inert atmosphere; Sealed tube
General procedure: A 25 mL Wattecs reaction tube was charged with 2-haloaniline 1 (0.6 mmol), potassium O-ethyl dithiocarbonate 2 (1.8 mmol),CuCl (0.06 mmol), and DMF (2 mL). The reaction vessel was flushed with argon three times and sealed. Then the mixture was stirred electromagnetically in an oil bath at 110°C for 6 h.The reaction process was monitored by TLC on silica gel. After the reaction was completed, the reaction mixture was cooled to room temperature, and then HCl (3 mL, 3 mol/L) was added and stirred for another 30 min. The reaction mixture solution was extracted by ethyl acetate (3 × 20 mL). Subsequently, the combined organic solutions were dried by anhydrous sodium sulfate and the target product was purified by chromatography on a silica gel column (eluent: petroleum ether/ethyl acetate) togive the corresponding pure product 3. Complete characterization characterizationof the products (all known) is found in the Supplemental Materials (Figures S1–S13).
Reference:
[1] Synthetic Communications, 2015, vol. 45, # 20, p. 2378 - 2385
[2] Phosphorus, Sulfur and Silicon and the Related Elements, 2016, vol. 191, # 5, p. 699 - 701
[2-(4-fluoro-2-iodo-phenylimino)-cyclopentyl]-acetic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With toluene-4-sulfonic acid; In benzene; for 24h;Heating / reflux;
A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of ethyl 2-(2- oxocyclopentyl)acetate and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24h After this time, the benzene was removed under distillation. Then, 60ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg of Pd(OAc)2 were added successively. The solution was heated to 115C for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluting with 100% toluene, to provide the title compound.1H NMR (acetone-d6) delta 9.76 (br s, 1H), 7.34 (dd, 1H), 7.03 (d, 1H), 6.78 (td, 1H), 4.14 (q, 2H), 3.57 (m, 1H), 2.85-2.55 (m, 5H), 2.15 (m, 1H), 1.22 (t, 3H).
Step 1: (+/-)-('7-Fluoro-l12,3,4-tetrahvdrocyclopenta[b]indol-3-yl)acetic acid ethyl ester.A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of ethyl 2-(2- oxocyclopentyl)acetate and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24h. After this time, the benzene was removed under distillation. Then, 60ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg OfPd(OAc)2 were added successively. The solution was heated to 115C for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluting with 100% toluene, to provide the title compound.1H NMR (acetone-d6) delta 9.76 (br s, IH), 7.34 (dd, IH), 7.03 (d, IH), 6.78 (td, IH), 4.14 (q, 2H), 3.57 (m, IH), 2.85-2.55 (m, 5H), 2.15 (m, IH), 1.22 (t, 3H).
A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of ethyl 2-(2- oxocyclopentyl)acetate and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24h. After this time, the benzene was removed under distillation. Then, 60ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg Of Pd(OAc)2 were added successively. The solution was heated to 1150C for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluting with 100% toluene, to provide the title compound. 1H NMR (acetone-d6) delta 9.76 (br s, IH), 7.34 (dd, IH), 7.03 (d, IH), 6.78 (td, IH), 4.14 (q, 2H), 3.57 (m, IH), 2.85-2.55 (m, 5H), 2.15 (m, IH), 1.22 (t, 3H).
Step 1: (+/-)-(7-Fluoro-l,2,3,4-tetrahvdrocvclopentarb]indol-3-yl)acetic acid ethyl ester. A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of ethyl 2-(2- oxocyclopentyl)acetate and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24h. After this time, the benzene was removed under distillation. Then, 60ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg OfPd(OAc)2 were added successively. The solution was heated to 115C for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluting with 100% toluene, to provide the title compound.1H NMR (acetone-d6) delta 9.76 (br s, IH), 7.34 (dd, IH), 7.03 (d, IH), 6.78 (td, IH), 4.14 (q, 2H), 3.57 (m, IH), 2.85-2.55 (m, 5H), 2.15 (m, IH), 1.22 (t, 3H).
A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of <strong>[20826-94-2]ethyl 2-(2-oxocyclopentyl)acetate</strong> and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24 h. After this time, the benzene was removed under distillation. Then, 60 ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg of Pd(OAc)2 were added successively. The solution was heated to 115 C. for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluting with 100% toluene, to provide the title compound. 1H NMR (acetone-d6) delta 9.76 (br s, 1H), 7.34 (dd, 1H), 7.03 (d, 1H), 6.78 (td, 1H), 4.14 (q, 2), 3.57 (m, 1H), 2.85-2.55 (m, 5H), 2.15 (m, 1H), 1.22 (t, 3H).
Step 1: (+/-)-(7-Fluoro-l,2,3,4-tetrahvdrocvclopentarb1indol-3-yl)acetic acid ethyl ester.A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of ethyl 2-(2- oxocyclopentyl)acetate and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24h. After this time, the benzene was removed under distillation. Then, 60ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg OfPd(OAc)2 were added successively. The solution was heated to 1150C for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluting with 100% toluene, to provide the title compound. 1H NMR (acetone-d6) delta 9.76 (br s, IH), 7.34 (dd, IH), 7.03 (d, IH), 6.78 (td, IH), 4.14(q, 2H), 3.57 (m, IH), 2.85-2.55 (m, 5H), 2.15 (m, IH), 1.22 (t, 3H).
With hydrogenchloride; toluene-4-sulfonic acid;palladium diacetate; In ethyl acetate; N,N-dimethyl-formamide; benzene;
Step 1 (+-)-(7-Fluoro-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid ethyl ester A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of <strong>[20826-94-2]ethyl 2-(2-oxocyclopentyl)acetate</strong> and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24 h. After this time, the benzene was removed under distillation. Then, 60 ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg of Pd(OAc)2 were added successively. The solution was heated to 115 C. for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluding with 100% toluene to provide 5.36 g of the title compound as a yellow solid. 1H NMR (acetone-d6) delta9.76 (br s, 1H), 7.34 (dd, 1H), 7.03 (d, 1H), 6.78 (td, 1H), 4.14 (q, 2H), 3.57 (m, 1H), 2.85-2.55 (m, 5H), 2.15 (m, 1H), 1.22 (t, 3H).
With toluene-4-sulfonic acid;palladium diacetate; In ethyl acetate; N,N-dimethyl-formamide; benzene;
Step 1: (+-)-(7-Fluoro-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid ethyl ester A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of <strong>[20826-94-2]ethyl 2-(2-oxocyclopentyl)acetate</strong> and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24 h. After this time, the benzene was removed under distillation. Then, 60 ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg of Pd(OAc)2 were added successively. The solution was heated to 115 C. for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCI and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluding with 100% toluene, to provide the title compound. 1H NMR (acetone-d6) delta 9.76 (br s, 1H), 7.34 (dd, 1H), 7.03 (d, 1H), 6.78 (td, 1H), 4.14 (q, 2H), 3.57 (m, 1H), 2.85-2.55 (m, 5H), 2.15 (m, 1H), 1.22 (t, 3H).
Step 1 (+/-) 2-(7-fluoro-1,2,3-trihydrocyclopenta[2,3-b]indol-3-yl)acetic acid The ethyl ester of the title compound was prepared from 10.00 g of 4-fluoro-2-iodophenylamine and 6.57 g of ethyl 2-(2-oxocyclopentyl)acetate according to example 1, step 2, to yield 5.36 g of a yellow solid. 1H NMR (acetone-d6) delta9.76 (1H, br s), 7.34 (1H, dd), 7.03 (1H, d), 6.78 (1H, td), 4.14 (2H, q), 3.57 (1H, m), 2.85-2.55 (5H, m), 2.15 (1H, m), 1.22 (3H, t).
Fifteen grams of cuprous cyanide and 14 g. of dry pyridine are heated to a homogeneous melt. After adding 25.0 g. of 4-fluoro-2-iodoaniline, the mixture is heated at about 160-170 C. for two hours. To the cooled mixture, concentrated sodium cyanide solution is added. The solid material is filtered off and extracted with benzene. The benzene extracts are concentrated and fractionally distilled to give 2-cyano-4-fluoroaniline.
25.A
A solution of thiocarbamoyl-acetic acid tert-butyl ester (0.2 g, 1.05 mmol), 4-fluoro-2-iodo-phenylamine (0.230 g, 1.05 mmol), Pd2 dba3 (0.096 g, 0.105 mmol), and dppf (0.117 g, 0.210 mmol) in DMF (10 mL) was heated at 60° C. for 12 h. The mixture was diluted with EtOAc (20 mL) and washed with stad. aq. NaHCO3 (3×20 mL). The organic layer was dried over MgSO4 and concentrated. Purification of the residue (SiO2; 20% EtOAc in hexanes) provided the desired product (0.216 g, 78%).
Stage #1: 4-phthalimidobutanal; 4-fluoro-2-iodoaniline With 1,4-diaza-bicyclo[2.2.2]octane In N,N-dimethyl-formamide for 0.333333h;
Stage #2: With palladium diacetate In N,N-dimethyl-formamide at 85℃;
With potassium <i>tert</i>-butylate; copper(I) bromide In tetrahydrofuran at 60℃; for 4h; Schlenk technique;
General procedure for synthesis of 2-aminobenzothiazoles derivatives (3a-i)
General procedure: A mixture of 2-iodoanilines (1.0 mmol), THF (3 mL), and t-BuOK (3 mmol) was stirred in a 10-mL sealed Schlenk tube for 5 min, and then dimethylthiocarbamoyl chloride (1.2 mmol) and CuBr (10 mol %) were added. The reaction mixture was heated at 60 °C until completion as indicated by TLC. Then the mixture was cooled down to room temperature and quenched with sat. NH4Cl solution (5 mL). The aqueous phase was extracted with EtOAc (3 x10 mL). The combined organic phases were dried (Na2SO4), and the solvent was removed under reduced pressure. The obtained crude product was purified by flash column chromatography.