* 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 sodium nitrite In 1,2-dichloro-ethane at 110℃; for 60 h; Sealed tube
It was added in a closed reaction vessel 0.3mmol 2-amino-6-chlorobenzothiazole, 0.6mmol sodium nitrite, 3mL1,2- dichloroethane,the reaction mixture was stirred at 110 reaction conditions 60 hours.After the reaction was stopped, cooled to room temperature, the reactionmixture was added 10mL diluted with dichloromethane, filtration and stripped ofsolvent under reduced pressure, the residue was purified by columnchromatography, eluent V (petroleum ether) / V (ethyl ester) = 6/1, to give6-chlorobenzothiazole, yield 89percent.
59%
Stage #1: With phosphoric acid; sodium nitrite In water at -10℃; for 2 h; Stage #2: With hypophosphorous acid In water at -5 - 20℃;
General procedure: Thiazoles (1b-f, j) were prepared from 2-aminothiazoles according to the reported procedure with slight modifications. 24 To a mechanically-stirred solution of 2-amino-6-chlorobenzothiazole (4 g, 21.7 mmol, 1.0 equiv) in 84percent aq phosphoric acid (80 mL) was added a solution of sodium nitrite (9.0 g, 13 mmol, 6.0 equiv) in water (28 mL) dropwise below the surface at -10 °C. After stirring at -10 °C for another 2 h, a 50percent aq solution of hypophosphorous acid (60 mL) was added dropwise to the resulting thick syrup mixture at -5 °C. The reaction mixture was warmed to room temperature, stirred overnight, and then diluted with water (300 mL). Na2CO3 was added portionwise to adjust to pH=8 and extracted with DCM. The organic phase was dried over Na2SO4, concentrated under vacuum, and purified over column chromatography (petroleum ether/EtOAc=100:1) to give 6-chlorobenzothiazole as white solid (2.2 g, 59percent yield).
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 4, p. 623 - 630
[2] Patent: CN105367442, 2016, A, . Location in patent: Paragraph 0018
[3] Chemical and Pharmaceutical Bulletin, 1997, vol. 45, # 9, p. 1547 - 1549
[4] Tetrahedron, 2013, vol. 69, # 22, p. 4436 - 4444
[5] Synthetic Communications, 1980, vol. 10, # 3, p. 167 - 174
[6] Journal of Heterocyclic Chemistry, 2000, vol. 37, # 6, p. 1655 - 1658
[7] Chemical Communications, 2012, vol. 48, # 42, p. 5181 - 5183
[8] Organic Letters, 2013, vol. 15, # 17, p. 4600 - 4603
[9] Tetrahedron, 2014, vol. 70, # 2, p. 245 - 250
[10] Organic and Biomolecular Chemistry, 2017, vol. 15, # 7, p. 1606 - 1611
2
[ 95-24-9 ]
[ 3622-23-9 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1939, vol. 9, p. 409,411[2] Chem. Zentralbl., 1940, vol. 111, # I, p. 545
[3] Journal of the Indian Chemical Society, 1933, vol. 10, p. 563,568
[4] Farmaco, Edizione Scientifica, 1977, vol. 32, p. 348 - 354
[5] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 14, p. 4022 - 4025
[6] Chemistry and Biodiversity, 2011, vol. 8, # 2, p. 253 - 265
[7] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3044 - 3049
3
[ 95-24-9 ]
[ 3507-17-3 ]
Yield
Reaction Conditions
Operation in experiment
69%
With tert.-butylnitrite; copper(I) bromide In acetonitrile at 60℃; for 1 h;
General procedure: To a stirred suspension of CuBr (1.57 g, 10.9 mmol) in MeCN (25 ml) was added tBuONO (1.63 ml, 13.7 mmol) and the mixture was stirred at 60 °C for 10 min. Then 2-amino-6-methylbenzothiazole (14b) (1.50 g, 9.13 mmol) was added to the mixture, and the reaction mixture was stirred at 60 °C for 1 h. After cooled to room temperature, the mixture was poured into 1 N HCl. The resulting precipitate was dissolved into EtOAc, washed with 1 N HCl, brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (7:1, v/v) as eluent to give the title compound (703 mg, 34percent) as a brown oil.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 3, p. 1201 - 1212
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 18, p. 5919 - 5923
4
[ 95-24-9 ]
[ 7787-70-4 ]
[ 3507-17-3 ]
Yield
Reaction Conditions
Operation in experiment
69%
With tert.-butylnitrite In hexane; ethyl acetate; acetonitrile
(Step 1) Synthesis of 2-bromo-6-chlorobenzothiazole Copper (I) bromide (1.40 g, 9.76 mmol) was suspended in acetonitrile (25 ml). To the resulting suspension was added tert-butyl nitrite (1.45 ml, 12.2 mmol) and the mixture was stirred at 60OEC for 15 minutes. To the reaction mixture was added 2-amino-6-chlorobenzothiazole (1.50 g, 8.12 mmol), followed by stirring at 60OEC for 30 minutes. After cooling, the reaction mixture was diluted with ethyl acetate. The ethyl acetate solution was washed with 1N HCl and saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (7:1, v/v) eluate fractions, 2-bromo-6-chlorobenzothiazole (1.39 g, 69percent) was obtained as a yellow solid. 1H-NMR (CDCl3) δ: 7.42-7.46 (m, 1H), 7.76-7.90 (m, 2H).
Reference：
[1] Patent: EP1346982, 2003, A1,
5
[ 333-20-0 ]
[ 106-47-8 ]
[ 95-24-9 ]
Yield
Reaction Conditions
Operation in experiment
93%
Stage #1: With nano-BF3/SiO2 In acetonitrile for 0.5 h; Cooling with ice Stage #2: With bromine In acetonitrile at 0 - 20℃; for 5 h;
General procedure: A solution of substituted aniline (2 mmol) in acetonitrile (15 ml) was added to a solution of KSCN (8 mmol) in acetonitrile (15 ml). Then, 0.06 g (30 mol percent BF3) of nano-BF3/SiO2 was added to the mixture, then was placed in a freezing mixture of ice and salt and mechanically stirred for 30 min. Then, bromine (4 mmol, 0.2 ml) in acetonitrile (3 ml) as solvent was added from a dropping funnel at such a rate that the temperature never rose beyond 0°C. After all the bromine was added at 60 min, the solution was stirred for 4 h at room temperature. The progress of the reaction was monitored by TLC. Then, the mixture was poured into water with stirring and the mixture was heated to 70°C on a steam bath and filtered hot to remove the catalyst and the recovered catalyst was washed with acetone and reused in the reaction. The filtrate was neutralized with 10 percent NaOH solution and the precipitate was collected on a filter, dried and recrystallized from ethanol (10 ml) to afford the corresponding products. All of the 2-aminobenzothiazole products were identified by physical and spectroscopic data as reported below, compared and contrasted with authentic samples.#10;Spectral data for selected products#10;6-Bromo-1,3-benzothiazol-2-amine (2e) Yellow solid; Yield = 93 percent; m.p. =202–204°C; (m.p. = 203°C), FT-IR (KBr)/t(cm-1): 3315, 3012, 2835,1580, 1476, 1261, 920, 742, 512. 1H NMR (400 MHz, CDCl3)/d ppm: 5.44 (s, 2H, NH2) 7.4–7.5 (d, 2H, Ar–H), 7.71 (s, 1H, Ar–H); 13C NMR/(100 MHz, DMSO-d6)/d ppm: 119, 120.9, 125.15, 126.07, 133.1, 152.15, 167.75.#10;
85%
Stage #1: at 15 - 20℃; for 2 h; Stage #2: at 15 - 20℃;
6.38 g (0.05 mol) of p-chloroaniline was placed in a 100 ml round bottom flask, dissolved in 50 ml of glacial acetic acid, and then 5.40 g (0.055 mol) of potassium thiocyanate was added.Stir at 15-20 ° C for 2 h until the solid disappears completelyThen, 1 ml of bromine acetic acid solution was added dropwise at 15-20 ° C.When the temperature is controlled, the temperature is not more than 20 ° C, and the addition is completed in about 1 h.Normal temperature reaction for 2-4 hours, TLC tracking reaction,After the raw material amine is completely reacted, dissolved in hot water, filtered after a little cold.A white filter droplet is added to add 5 ml of concentrated ammonia water to adjust the pH to neutral or weakly alkaline. During this period, a large amount of white solid precipitates, and after standing, it is filtered, the filter cake is washed with water, and dried under vacuum.7.86 g of a white to slightly yellow powdery solid product are obtained.Melting point: 199-200 ° C, yield 85percent.
72%
Stage #1: at 20℃; Cooling with ice Stage #2: With ammonium hydroxide In water
General procedure: A mixture of 0.1 mol of 4-substituted aniline and 0.1 mol of Potassium thiocyanate (KCNS) in 100 ml glacial acetic acid (AcOH) was cooled in an ice bath and stirred for 10-20 min, and then 0.1 mol bromine in glacial acetic acid was added dropwise at such a rate to keep the temperature below 10 °C throughout the addition. The reaction mixture was stirred at room temperature for 2-4 h, the hydrobromide (HBr) salt thus separated out was filtered, washed with acetic acid, dried, dissolved in hot water and basified to pH 11.0 with ammonia solution (NH4OH) and the resulting precipitate was filtered, washed with water and dried to get the desired product 3a-k. The progress of the reaction was monitored by Thin Layer Chromatography using toluene: acetone (8:2) solvent system.
68.5%
Stage #1: at -10 - 20℃; for 12.5 h; Stage #2: With ammonium hydroxide In waterHeating
General procedure: An appropriately p-substituted aniline (0.1 mol) and potassiumthiocyanate (KCNS, 9.718 g, 0.1 mol) were dissolvedin 100 mL of glacial acetic acid (AcOH), cooled inice–salt mixture and stirred mechanically, while a solutionof bromine (15.980 g, 0.1 mol) in AcOH (20 mL)was slowly added drop by drop (Palkar et al. 2010).External cooling was applied throughout the process to keepthe temperature below 10 °C and the stirring was continuedfor 30 min. After all of the bromine had been added, thesolution was stirred for 2 h below room temperature and atroom temperature for 10 h. It was then allowed to standovernight during which the precipitate of imino-benzo[d]thiazole hydrobromide salt thus separated out was filtered,washed with acetic acid, dried, dissolved in hot water andbasified to pH 11.0 with ammonia solution (NH4OH) andthe resulting precipitate was filtered, washed with water anddried to get the desired products 2-amino-6-substitutedbenzo[d]thiazole (1a–d). The progress of the reaction wasmonitored by TLC using acetone (20percent) in toluene solvent.
57.58%
at 10 - 20℃; for 3 h;
To a solution of 4-chloroaniline (3.0g, 23.52mmol, l .Oeq) in acetic acid (90mL) were added Potassium thiocyanate (2.28g, 23.52mmol, l .Oeq). The reaction mixture was cooled at 10°C and bromine solution (3.76g, 23.52mmol, l .Oeq) was added dropwise. Reaction mixture was further stirred at room temperature for 3h. After completion of reaction, reaction mixture was filtered and washed with acetic acid. Filtered solid was heated in water and then neutralized with aqueous ammonia to obtain solid which was filtered and dried well to obtain pure 118.1. (2.5g, 57.58percent). MS(ES): m/z 185.64 [M+H]+
42%
at 25 - 35℃; for 20 h;
General procedure: A solution of bromine (0.26mL, 10.0mmol) in acetic acid (5.0mL)was added over about 30 min to a mixture of aromatic amine(10.0 mmol) and potassium thiocyanate (1.07 g, 11.0 mmol) in aceticacid (20 mL), the temperature being kept between 25 and 35 °C. The slurry was then stirred for 20 h at room temperature. The precipitate was filtered, washed with a little acetic acid, slurried in water, made neutral with aqueous ammonia, and filtered again. The residue was boiled for 20 min with excess of hydrochloric acid (15percent v:v) and the hot mixture was filtered from impurities. The filtrate, cooled to 10 °C,was made alkaline with aqueous ammonia and the precipitate was filtered,washed, and dried. The crude product was recrystallized from ethanol–water to afford I–IV, respectively.
Reference：
[1] Synlett, 2012, vol. 23, # 15, p. 2219 - 2222
[2] Research on Chemical Intermediates, 2016, vol. 42, # 12, p. 7855 - 7868
[3] Journal of Organic Chemistry, 2017, vol. 82, # 18, p. 9312 - 9320
[4] Patent: CN108623537, 2018, A, . Location in patent: Paragraph 0104; 0105
[5] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2010, vol. 49, # 6, p. 818 - 825
[6] Phosphorus, Sulfur and Silicon and the Related Elements, 2008, vol. 183, # 5, p. 1124 - 1133
[7] Journal of the Indian Chemical Society, 2008, vol. 85, # 3, p. 333 - 335
[8] European Journal of Medicinal Chemistry, 2008, vol. 43, # 5, p. 1114 - 1122
[9] Archiv der Pharmazie, 2015, vol. 348, # 4, p. 254 - 265
[10] European Journal of Medicinal Chemistry, 2012, vol. 53, p. 41 - 51
[11] Medicinal Chemistry Research, 2017, vol. 26, # 9, p. 1969 - 1987
[12] Patent: WO2018/71794, 2018, A1, . Location in patent: Paragraph 00630; 00631
[13] Journal of Molecular Liquids, 2013, vol. 188, p. 173 - 177
[14] Polish Journal of Chemistry, 1996, vol. 70, # 10, p. 1250 - 1256
[15] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3443 - 3446
[16] Archiv der Pharmazie, 2010, vol. 343, # 6, p. 353 - 359
[17] Journal of Enzyme Inhibition and Medicinal Chemistry, 2011, vol. 26, # 3, p. 332 - 340
[18] Patent: WO2011/151361, 2011, A1, . Location in patent: Page/Page column 43-44
[19] Asian Journal of Chemistry, 2011, vol. 23, # 9, p. 3969 - 3974
[20] Journal of the Korean Chemical Society, 2012, vol. 56, # 2, p. 251 - 256
[21] Asian Journal of Chemistry, 2011, vol. 23, # 11, p. 5133 - 5136
[22] Asian Journal of Chemistry, 2010, vol. 22, # 7, p. 5487 - 5492
[23] Heteroatom Chemistry, 2012, vol. 23, # 4, p. 399 - 410
[24] Medicinal Chemistry Research, 2012, vol. 21, # 9, p. 2661 - 2670
[25] Organic Letters, 2012, vol. 14, # 20, p. 5334 - 5337,4
[26] Journal of Enzyme Inhibition and Medicinal Chemistry, 2013, vol. 28, # 1, p. 1 - 10
[27] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 1 - 13
[28] European Journal of Medicinal Chemistry, 2014, vol. 71, p. 24 - 30
[29] Archiv der Pharmazie, 2013, vol. 346, # 11, p. 819 - 831
[30] Journal of Heterocyclic Chemistry, 2014, vol. 51, # 2, p. 459 - 465
[31] Combinatorial Chemistry and High Throughput Screening, 2013, vol. 16, # 3, p. 244 - 247
[32] Medicinal Chemistry, 2013, vol. 9, # 4, p. 596 - 607
[33] Journal of Heterocyclic Chemistry, 2014, vol. 51, # 6, p. 1641 - 1658
[34] Research on Chemical Intermediates, 2015, vol. 41, # 8, p. 5599 - 5609
[35] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5561 - 5565
[36] Synthetic Communications, 2016, vol. 46, # 2, p. 169 - 178
[37] Bioorganic Chemistry, 2016, vol. 67, p. 130 - 138
[38] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 2, p. 1327 - 1341
[39] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 6, p. 3282 - 3293
[40] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 16, p. 2568
[41] Archiv der Pharmazie, 2018, vol. 351, # 12,
6
[ 3696-23-9 ]
[ 95-24-9 ]
Yield
Reaction Conditions
Operation in experiment
43.1%
With bromine In chloroform; water at 50 - 70℃; for 9 h;
The chlorothiourea (8.50 g, 45.70 mmol) was added to a 250 mL eggplant-shaped flask and dissolved in 50.00 mL of chloroform.Reflow under a 50 ° C oil bath for 20 minutes,After the reaction solution is placed in an ice water bath,Slowly add bromine (2.58 mL, 50.27 mmol),After stirring for 5 minutes, transfer back to the oil bath.Raise the temperature to 70 ° C and continue to reflux.The progress of the reaction was monitored by thin layer chromatography and the reaction was complete after 9 h.After cooling to room temperature, a solid precipitated and was filtered under reduced pressure.Slowly add ammonia water to the filtrate.Adjust the pH to neutral and a white precipitate will form.After stirring for 5 minutes, the mixture was filtered under reduced pressure, and the solid was washed twice,Vacuum drying to constant weight,Obtained white solid 3.62g,The yield was 43.10percent.
Reference：
[1] Patent: CN108358869, 2018, A, . Location in patent: Paragraph 0035; 0036
[2] Journal of the Chemical Society, 1927, p. 1190
[3] Journal of the Indian Chemical Society, 1931, vol. 8, p. 147,163
[4] Journal fuer Praktische Chemie (Leipzig), 1974, vol. 316, p. 154 - 158
[5] Journal of the Chemical Society [Section] C: Organic, 1969, p. 268 - 272
[6] Journal of the Indian Chemical Society, 1989, vol. 66, p. 39 - 41
[7] Farmaco, Edizione Scientifica, 1982, vol. 37, # 3, p. 205 - 212
[8] Patent: US4563533, 1986, A,
[9] Acta Poloniae Pharmaceutica - Drug Research, 2009, vol. 66, # 4, p. 387 - 392
[10] Research on Chemical Intermediates, 2010, vol. 36, # 8, p. 985 - 993
[11] Asian Journal of Chemistry, 2012, vol. 24, # 6, p. 2747 - 2752
[12] Research on Chemical Intermediates, 2013, vol. 39, # 6, p. 2555 - 2564
[13] Medicinal Chemistry Research, 2013, vol. 22, # 9, p. 4211 - 4222
[14] Medicinal Chemistry Research, 2013, vol. 22, # 9, p. 4316 - 4321
[15] Research on Chemical Intermediates, 2015, vol. 41, # 9, p. 6141 - 6148
[16] Chemical Biology and Drug Design, 2016, p. 354 - 362
[17] Journal of Medicinal Chemistry, 2016, vol. 59, # 21, p. 9814 - 9824
[18] Russian Journal of General Chemistry, 2017, vol. 87, # 12, p. 3006 - 3016
[19] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 11, p. 2507 - 2515
7
[ 106-47-8 ]
[ 95-24-9 ]
Yield
Reaction Conditions
Operation in experiment
67%
Stage #1: at 10℃; Stage #2: at 10 - 20℃; for 4 h;
General procedure: A mixture of aniline (0.05mol) and NH4SCN (19.03g, 0.25mol) in glacial acetic acid (100mL) was cooled to 10°C in an ice bath and stirred for 10–20min. Then bromine (2.82mL, 0.055mol) in glacial acetic acid was added drop wise at such a rate to keep the temperature below 10°C. The mixture was stirred at room temperature for 4h and then poured into hot water (500mL), and basified to pH 11.0 with ammonia solution (NH4OH). The resulting precipitate was filtered, washed with water and dried to get a light yellow to brown solid. The crude product was purified by chromatography on silica gel using MeOH/CH2Cl2 to afford compounds 2a–2k in good yields.
Reference：
[1] Chemistry of Heterocyclic Compounds, 2009, vol. 45, # 11, p. 1343 - 1353
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 1759 - 1775
[3] European Journal of Medicinal Chemistry, 2010, vol. 45, # 9, p. 4293 - 4299
[4] Archiv der Pharmazie, 2010, vol. 343, # 11-12, p. 692 - 699
8
[ 1147550-11-5 ]
[ 106-47-8 ]
[ 95-24-9 ]
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 19, p. 12129 - 12142
[2] European Journal of Organic Chemistry, 2011, # 31, p. 6206 - 6217
[3] Heterocyclic Communications, 2002, vol. 8, # 3, p. 275 - 280
[4] Medicinal Chemistry Research, 2011, vol. 20, # 7, p. 1033 - 1041
[5] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 14, p. 4022 - 4025
[6] Chemische Berichte, 1934, vol. 67, p. 944,947
[7] Journal of Enzyme Inhibition and Medicinal Chemistry, 2011, vol. 26, # 4, p. 527 - 534
[8] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3044 - 3049
[9] Archiv der Pharmazie, 2016, p. 651 - 661
[10] European Journal of Medicinal Chemistry, 2018, vol. 148, p. 477 - 486
[11] International Journal of Pharmacy and Pharmaceutical Sciences, 2018, vol. 10, # 10, p. 57 - 61
9
[ 1367199-79-8 ]
[ 95-24-9 ]
Reference：
[1] Archiv der Pharmazie, 2009, vol. 342, # 8, p. 462 - 468
[2] Medicinal Chemistry Research, 2013, vol. 22, # 1, p. 195 - 210
[3] Medicinal Chemistry Research, 2013, vol. 22, # 9, p. 4211 - 4222
[4] Journal of Chemical Research, 2014, vol. 38, # 10, p. 611 - 616
10
[ 106-47-8 ]
[ 95-24-9 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1981, vol. 18, # 4, p. 759 - 761
11
[ 106-47-8 ]
[ 95-24-9 ]
Reference：
[1] Chinese Journal of Chemistry, 2016, vol. 34, # 11, p. 1081 - 1085
12
[ 106-47-8 ]
[ 95-24-9 ]
Reference：
[1] Journal of the Chemical Society [Section] C: Organic, 1969, p. 268 - 272
[2] Research on Chemical Intermediates, 2010, vol. 36, # 8, p. 985 - 993
[3] Letters in Drug Design and Discovery, 2011, vol. 8, # 9, p. 717 - 724
[4] Letters in Drug Design and Discovery, 2011, vol. 8, # 8, p. 717 - 724
[5] Asian Journal of Chemistry, 2012, vol. 24, # 6, p. 2747 - 2752
[6] Medicinal Chemistry Research, 2013, vol. 22, # 1, p. 195 - 210
[7] Research on Chemical Intermediates, 2013, vol. 39, # 6, p. 2555 - 2564
[8] Medicinal Chemistry Research, 2013, vol. 22, # 9, p. 4211 - 4222
[9] Journal of Chemical Research, 2014, vol. 38, # 10, p. 611 - 616
[10] Chemical Biology and Drug Design, 2016, p. 354 - 362
[11] Journal of Medicinal Chemistry, 2016, vol. 59, # 21, p. 9814 - 9824
[12] Russian Journal of General Chemistry, 2017, vol. 87, # 12, p. 3006 - 3016
[13] Patent: CN108358869, 2018, A,
[14] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 11, p. 2507 - 2515
Reference：
[1] Die Pharmazie, 1967, vol. 22, # 6, p. 229 - 233
[2] Patent: US2212175, 1939, ,
15
[ 1280582-67-3 ]
[ 95-24-9 ]
Reference：
[1] Letters in Drug Design and Discovery, 2011, vol. 8, # 9, p. 717 - 724
[2] Letters in Drug Design and Discovery, 2011, vol. 8, # 8, p. 717 - 724
With copper dichloride; isopentyl nitrite; In acetonitrile; at 20℃;Reflux;
In a 100 ml three-necked flask,2.69 g of 2-amino-6-chlorobenzothiazole (0.02 mol, 97%, 1 eq) was dissolved in 20 ml of acetonitrile while adding 2.68 g (0.03 mol, 1 eq) of anhydrous copper chloride.54 g (0.03 mol, 98%, 1.5 eq) of isoamyl nitrite was added dropwise by magnetic stirring at room temperature.After the addition is completed, the temperature is raised to reflux, and the reaction is carried out for 2 to 3 hours.The system is a dark green solution with insoluble materials.After the completion of the reaction, acetonitrile was removed under reduced pressure to give a residue of 20 mL of ethyl acetate.Washed with saturated aqueous sodium chloride, and the layers were dried.Concentrated to give an orange solid.Recrystallization and column chromatography gave 2.71 g of an orange solid 2,6'-dichlorobenzothiazole product.GC: 97%, isolated yield 66%
With sodium bromide In isopropanol at 20℃; Electrolysis; Green chemistry;
43.1%
With bromine In chloroform; lithium hydroxide monohydrate at 50 - 70℃; for 9h;
1.2 Preparation of 6-chloro-2-aminobenzothiazole
The chlorothiourea (8.50 g, 45.70 mmol) was added to a 250 mL eggplant-shaped flask and dissolved in 50.00 mL of chloroform.Reflow under a 50 ° C oil bath for 20 minutes,After the reaction solution is placed in an ice water bath,Slowly add bromine (2.58 mL, 50.27 mmol),After stirring for 5 minutes, transfer back to the oil bath.Raise the temperature to 70 ° C and continue to reflux.The progress of the reaction was monitored by thin layer chromatography and the reaction was complete after 9 h.After cooling to room temperature, a solid precipitated and was filtered under reduced pressure.Slowly add ammonia water to the filtrate.Adjust the pH to neutral and a white precipitate will form.After stirring for 5 minutes, the mixture was filtered under reduced pressure, and the solid was washed twice,Vacuum drying to constant weight,Obtained white solid 3.62g,The yield was 43.10%.
43.1%
With bromine In chloroform at 70℃; for 9h;
With chloroform Reduktion des entstandenen Hydrodibromids mit schwefliger Saeure;
With lead(II) dihydrogen orthophosphate; H2<Pb(H2PO4)2(HPO4)2>; buffer solution In methanol for 1.5h; Heating;
With bromine In chloroform
With bromine
With bromine In chloroform
With sulfuryl dichloride In chlorobenzene
3 EXAMPLE 3
EXAMPLE 3 101.6 Parts of 4-chlorophenylthiourea (91.7% strength, moist) and 35 parts of barium oxide were introduced with stirring into 400 parts of chlorobenzene. At a temperature of 52°-55° C., a mixture of 116.9 parts of sulfuryl chloride and 70.0 parts of chlorobenzene was added dropwise within about 3 hours. Stirring was continued for about 5 hours at this temperature until the development of gas had ceased. The cyclization being complete, the crude product was worked up as described in Example 2. Yield: 82 parts of 2-amino-6-chlorobenzothiazole=88.8% of th.
With bromine In chloroform
Stage #1: 1-(4-chlorophenyl)thiourea With bromine In chloroform at 5℃; Reflux;
Stage #2: With ammonia In lithium hydroxide monohydrate
With bromine In chloroform
Stage #1: 1-(4-chlorophenyl)thiourea With bromine In chloroform at 5℃; for 4h;
Stage #2: With ammonia In lithium hydroxide monohydrate
Multi-step reaction with 2 steps
1: bromine / chloroform / 4 h
2: ammonia / ethanol
With bromine In chloroform
With chloroform; bromine
With bromine Reflux;
With bromine; glacial acetic acid; lithium bromide at 40℃;
With bromine; glacial acetic acid at 0 - 15℃; for 2h;
Synthesis of 2-aminobenzothiazole derivatives (8a-8d)
General procedure: One of compounds 6a-6d (10 mmol) and ammonium thiocyanate (0.91 g, 12 mmol) were dissolved in glacial acetic acid and the reaction mixture was stirred for 4 h. Bromine (0.6 mL, 11 mmol) in glacial acetic acid (8 mL) was added dropwise to the reaction mixture and it was stirred at 15°C for 2 h. Then, the solid was filtered off and dissolved in hot water. The filtrate was quenched with saturated aqueous sodium bicarbonate. The solid residue of the corresponding product 8a-8d was filtered off.
With sodium nitrite; In 1,2-dichloro-ethane; at 110℃; for 60h;Sealed tube;
It was added in a closed reaction vessel 0.3mmol 2-amino-6-chlorobenzothiazole, 0.6mmol sodium nitrite, 3mL1,2- dichloroethane,the reaction mixture was stirred at 110 reaction conditions 60 hours.After the reaction was stopped, cooled to room temperature, the reactionmixture was added 10mL diluted with dichloromethane, filtration and stripped ofsolvent under reduced pressure, the residue was purified by columnchromatography, eluent V (petroleum ether) / V (ethyl ester) = 6/1, to give6-chlorobenzothiazole, yield 89%.
88%
With isopentyl nitrite; In tetrahydrofuran; at 120℃; under 5250.53 Torr; for 0.333333h;
General procedure: A solution of the selected heterocyclic starting material (1.00 mmol) in THF (10 mL) and a solutionof isopentyl nitrite (141 mg, 1.20 mmol) in THF (10 mL) were both pumped at a flow rate of 0.25 mLmin1 with a Vapourtech ?Easy MedChem V3? system, meeting at a PTFE T-piece and the outputflowing through a 10.0 mL coil reactor maintained at 120 C, giving a residence time of 20 min.The pressure of the system was maintained at 7 bar with a back-pressure regulator. For compoundswhere an isolated yield was reported: the output mixture was concentrated under reduced pressureto give an oil (or powder). The oil (or powder) was purified using column chromatography withvarious mixtures of ethyl acetate and hexane as the eluent, or by recrystallisation using methanol, togive isolated compounds that showed no impurities by NMR spectroscopy. For compounds where aconversion was reported (due to volatility of products), the output mixture was carefully concentratedunder a reduced pressure of 100 mbar for 10 min and the conversion was calculated by integration ofproduct peaks to a quantified internal standard (nitrobenzene).
59%
General procedure: Thiazoles (1b-f, j) were prepared from 2-aminothiazoles according to the reported procedure with slight modifications. 24 To a mechanically-stirred solution of 2-amino-6-chlorobenzothiazole (4 g, 21.7 mmol, 1.0 equiv) in 84% aq phosphoric acid (80 mL) was added a solution of sodium nitrite (9.0 g, 13 mmol, 6.0 equiv) in water (28 mL) dropwise below the surface at -10 C. After stirring at -10 C for another 2 h, a 50% aq solution of hypophosphorous acid (60 mL) was added dropwise to the resulting thick syrup mixture at -5 C. The reaction mixture was warmed to room temperature, stirred overnight, and then diluted with water (300 mL). Na2CO3 was added portionwise to adjust to pH=8 and extracted with DCM. The organic phase was dried over Na2SO4, concentrated under vacuum, and purified over column chromatography (petroleum ether/EtOAc=100:1) to give 6-chlorobenzothiazole as white solid (2.2 g, 59% yield).
With isopentyl nitrite; In tetrahydrofuran; for 0.5h;Reflux;
General procedure: A 50 mLSchlenk tube was charged with 2-aminobenzothiazole derivative (6.5 mmol) and 10mL of THF, and then isoamyl nitrite (14.3 mmol) was added slowly into thesolution. The resultant mixture was refluxed for 30 minutes, and poured intoice-water, and the resultant aqueous mixture was extracted with ethyl acetate(3×30 mL). The organic extracts were combined and washed with brine, dried overMgSO4, filtered, concentrated in vacuum andpurified by column chromatography, giving the desired benzothiazoles in similaryields with the reported procedure.
With potassium carbonate; In dimethyl sulfoxide; at 150℃; for 4h;
2-amino-6-chlorobenzothiazole (3.68 g, 20 mmol) and <strong>[20098-48-0]1,2,3-trichloro-5-nitrobenzene</strong> (4.53 g, 20 mmol) were dissolved in anhydrous DMSO (10 mL). Solid K2CO3 (3.04 g, 22 mmol) was added and the reaction mixture heated to 150 C. for 4 hours. Let cool, then poured into 200 mL deionized water. A fine yellow solid precipitated which was collected by filtration after attempts to dissolve the product in ethyl acetate failed. The yellow solid was suspended in 100 mL of ethyl acetate and heated to reflux. After cooling to room temperature, filtration, rinsing with ethyl acetate followed by hexanes, and drying under vacuum provided the nitro compound 200 as a yellow powder. (1.06 g) 1H NMR (d6-DMSO) delta 8.37 (s, 2H); 7.76 (bs, 1H); 7.30 (dd, 1H); 7.23 (bs, 1H). MS (M-H) 372
With tert.-butylnitrite; In hexane; ethyl acetate; acetonitrile;
(Step 1) Synthesis of 2-bromo-6-chlorobenzothiazole Copper (I) bromide (1.40 g, 9.76 mmol) was suspended in acetonitrile (25 ml). To the resulting suspension was added tert-butyl nitrite (1.45 ml, 12.2 mmol) and the mixture was stirred at 60ØC for 15 minutes. To the reaction mixture was added 2-amino-6-chlorobenzothiazole (1.50 g, 8.12 mmol), followed by stirring at 60ØC for 30 minutes. After cooling, the reaction mixture was diluted with ethyl acetate. The ethyl acetate solution was washed with 1N HCl and saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (7:1, v/v) eluate fractions, 2-bromo-6-chlorobenzothiazole (1.39 g, 69%) was obtained as a yellow solid. 1H-NMR (CDCl3) delta: 7.42-7.46 (m, 1H), 7.76-7.90 (m, 2H).
With tert.-butylnitrite; copper(I) bromide; In acetonitrile; at 60.0℃; for 1.0h;
General procedure: To a stirred suspension of CuBr (1.57 g, 10.9 mmol) in MeCN (25 ml) was added tBuONO (1.63 ml, 13.7 mmol) and the mixture was stirred at 60 C for 10 min. Then 2-amino-6-methylbenzothiazole (14b) (1.50 g, 9.13 mmol) was added to the mixture, and the reaction mixture was stirred at 60 C for 1 h. After cooled to room temperature, the mixture was poured into 1 N HCl. The resulting precipitate was dissolved into EtOAc, washed with 1 N HCl, brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (7:1, v/v) as eluent to give the title compound (703 mg, 34%) as a brown oil.
With triethylamine In dichloromethane at 20℃; for 1h;
KY01041
3,4-Dimethoxybenzoylyl chloride (100 mg, 0.55 mmol) and triethylamine (83.0 µl, 6 mmol) were dissolved in methylene chloride (500 µl), 2-amino-6-chlorobenzothiazole (105 mg, 0.57 mmol) was added thereto, and the mixture was stirred for 1 hour at room temperature. After completion of the reaction, the reaction solution was diluted in methylene chloride and washed with a saturated saline solution. The solution was dried over magnesium sulfate and the solvent was evaporated. Ethanol was added to the residue, which was heated to 70°C, dissolved and recrystallized by cooling the temperature to room temperature, thereby obtaining 130 mg of 2-(3,4-dimethoxybenzamide)-6-chlorobenzothiazole in a yield of 68%. 1H NMR (CDCl3) : δ10.15 (s, 1H), 7.83 (d, J= 1.8 Hz, 1H), 7.63-7.45 (m, 3H), 7.36 (dd, J= 1.8, 8.7 Hz, 1H), 6.91 (d, J= 8.2 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H)MS(ESI) Found: 349 [M+H]+
With C39H34CuN3P2S; potassium hydroxide In toluene at 100℃; for 12h; regioselective reaction;
4. Typical procedure for N-alkylation of aromatic amines with alcohols
General procedure: In a 25 mL round bottomed flask were placed 0.1 mol % of copper(I) catalyst, 1 mmol of alcohol, 1 mmol of amine, 0.2 mmol of KOH and 2 mL of toluene. The reaction flask was heated at 100 °C for 12 h in an oil bath. Upon completion (as monitored by TLC), the reaction mixture was cooled at ambient temperature, H2O (3 mL) was added and the organic layer was extracted with CH2Cl2 (3 10 mL). The combined organic layers were dried with magnesium sulphate and concentrated. The crude product was purified by column chromatography (ethyl acetate/hexane). Reported isolated yields are an average of two runs
82%
With sodium hydroxide In toluene at 120℃; for 15h;
With C39H34CuN3P2S; potassium hydroxide In toluene at 100℃; for 12h; regioselective reaction;
4. Typical procedure for N-alkylation of aromatic amines with alcohols
General procedure: In a 25 mL round bottomed flask were placed 0.1 mol % of copper(I) catalyst, 1 mmol of alcohol, 1 mmol of amine, 0.2 mmol of KOH and 2 mL of toluene. The reaction flask was heated at 100 °C for 12 h in an oil bath. Upon completion (as monitored by TLC), the reaction mixture was cooled at ambient temperature, H2O (3 mL) was added and the organic layer was extracted with CH2Cl2 (3 10 mL). The combined organic layers were dried with magnesium sulphate and concentrated. The crude product was purified by column chromatography (ethyl acetate/hexane). Reported isolated yields are an average of two runs
90%
With sodium hydroxide In toluene at 120℃; for 15h;
5-((6-chlorobenzo[d]thiazol-2-ylamino)-(4-hydroxyphenyl)-methyl)-quinolin-6-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With sodium chloride In water at 90℃; for 0.15h; Microwave irradiation;
4.2. General procedure for the synthesis of 1-[(6-halo or 4-methylbenzo[d]thiazol-2-ylamino)-phenyl-methyl]-naphthalen-2-ol 4a-k and 5-[(6-halo or 4-methyl-benzo[d]thiazol-2-ylamino)-phenylmethyl]-quinolin-6-ol derivatives 4l-p
General procedure: To a suspension of 2-naphthol or 6-hydroxyquinoline (1 mmol), arylaldehyde (1 mmol) and 2-amino-6-halo or 4-methyl-benzo[d]thiazole (1 mmol), 10 mL of 10% w/v sodium chloride in water was added. The reaction mixture was stirred for 2 min in order to prevent aggregation of solid substances and then heated with microwave irradiation using domestic microwave oven [5 cycles of 2 min each, with cooling periods of 20 s, at 320 W and additional 5mL of water] for 10 min, the reaction time is shown in Table 2. The progress and completion of reaction were monitored by TLC. Th reaction vessel was then cooled to room temperature; the precipitate obtained was filtered and washed with cold water. The crude products were purified by recrystallization from acetone or methyl tert-butyl ether in 85-93% yields.
5-((6-chlorobenzo[d]thiazol-2-ylamino)-(4-methoxyphenyl)-methyl)-quinolin-6-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With sodium chloride In water at 90℃; for 0.133333h; Microwave irradiation;
4.2. General procedure for the synthesis of 1-[(6-halo or 4-methylbenzo[d]thiazol-2-ylamino)-phenyl-methyl]-naphthalen-2-ol 4a-k and 5-[(6-halo or 4-methyl-benzo[d]thiazol-2-ylamino)-phenylmethyl]-quinolin-6-ol derivatives 4l-p
General procedure: To a suspension of 2-naphthol or 6-hydroxyquinoline (1 mmol), arylaldehyde (1 mmol) and 2-amino-6-halo or 4-methyl-benzo[d]thiazole (1 mmol), 10 mL of 10% w/v sodium chloride in water was added. The reaction mixture was stirred for 2 min in order to prevent aggregation of solid substances and then heated with microwave irradiation using domestic microwave oven [5 cycles of 2 min each, with cooling periods of 20 s, at 320 W and additional 5mL of water] for 10 min, the reaction time is shown in Table 2. The progress and completion of reaction were monitored by TLC. Th reaction vessel was then cooled to room temperature; the precipitate obtained was filtered and washed with cold water. The crude products were purified by recrystallization from acetone or methyl tert-butyl ether in 85-93% yields.
5-((6-chlorobenzo[d]thiazol-2-ylamino)-(4-nitrophenyl)-methyl)-quinolin-6-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With sodium chloride In water at 90℃; for 0.166667h; Microwave irradiation;
4.2. General procedure for the synthesis of 1-[(6-halo or 4-methylbenzo[d]thiazol-2-ylamino)-phenyl-methyl]-naphthalen-2-ol 4a-k and 5-[(6-halo or 4-methyl-benzo[d]thiazol-2-ylamino)-phenylmethyl]-quinolin-6-ol derivatives 4l-p
General procedure: To a suspension of 2-naphthol or 6-hydroxyquinoline (1 mmol), arylaldehyde (1 mmol) and 2-amino-6-halo or 4-methyl-benzo[d]thiazole (1 mmol), 10 mL of 10% w/v sodium chloride in water was added. The reaction mixture was stirred for 2 min in order to prevent aggregation of solid substances and then heated with microwave irradiation using domestic microwave oven [5 cycles of 2 min each, with cooling periods of 20 s, at 320 W and additional 5mL of water] for 10 min, the reaction time is shown in Table 2. The progress and completion of reaction were monitored by TLC. Th reaction vessel was then cooled to room temperature; the precipitate obtained was filtered and washed with cold water. The crude products were purified by recrystallization from acetone or methyl tert-butyl ether in 85-93% yields.
4-((6-chlorobenzo[d]thiazol-2-ylamino)-(6-hydroxyquinolin-5-yl)-methyl)-benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With sodium chloride In water at 90℃; for 0.133333h; Microwave irradiation;
4.2. General procedure for the synthesis of 1-[(6-halo or 4-methylbenzo[d]thiazol-2-ylamino)-phenyl-methyl]-naphthalen-2-ol 4a-k and 5-[(6-halo or 4-methyl-benzo[d]thiazol-2-ylamino)-phenylmethyl]-quinolin-6-ol derivatives 4l-p
General procedure: To a suspension of 2-naphthol or 6-hydroxyquinoline (1 mmol), arylaldehyde (1 mmol) and 2-amino-6-halo or 4-methyl-benzo[d]thiazole (1 mmol), 10 mL of 10% w/v sodium chloride in water was added. The reaction mixture was stirred for 2 min in order to prevent aggregation of solid substances and then heated with microwave irradiation using domestic microwave oven [5 cycles of 2 min each, with cooling periods of 20 s, at 320 W and additional 5mL of water] for 10 min, the reaction time is shown in Table 2. The progress and completion of reaction were monitored by TLC. Th reaction vessel was then cooled to room temperature; the precipitate obtained was filtered and washed with cold water. The crude products were purified by recrystallization from acetone or methyl tert-butyl ether in 85-93% yields.
Benzo[b]thiophene-3-carbaldehyde (1.0 equiv.) in toluene (5 mL) was slowly added with constant stirring to a 50 mL three-necked round bottomf lask containing substituted 2-aminobenzothiazole (1.0 equiv.) and anhydrous toluene (10 mL). The reaction mixture was refluxed for 10 h and then cooled down to room temperature. The solvent was removed under reduced pressure, and the crude product was purified by recrystallization using N,N-dimethylethanamine/acetone/petroleum etherto yield pure imines 1a-1f.
4-((6-chlorobenzo[d]thiazol-2-ylamino)(4-methoxyphenyl)methyl)-3-hydroxy-9H-xanthen-9-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With iron(III) chloride In N,N-dimethyl-formamide at 120℃; for 2h;
Typical experimental procedure
General procedure: 3-hydroxyxanthone (1 mmol), benzaldehyde (1mmol) and 2-aminobenzothiazole (1 mmol) were taken in a 10 mL RB flask. Tothis 0.3 mL DMF is added followed by 0.2 eq of FeCl3. The resulting mixture isheated at 120 C until the reaction is completed as indicated by TLC (~2 h).The reaction mixture is then cooled to r.t., quenched with water, extracted withEtOAc and purified by column chromatography.
3-(7-chloro-2-(4-nitrophenyl)benzo[d]imidazo[2,1-b]thiazol-3-yl)-4-hydroxy-2H-chromen-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With PEG-600; In ethanol; for 1.5h;Reflux;
General procedure: A round bottom flask was charged with 2-Amino-6-methylbenzothiazole (1, 1.0 mmol), Phenylglyoxal monohydrate (2, 1.0 mmol) and 4-hydroxycoumarin (3, 1.0 mmol) in 2.7 ml ethanol and 0.3 ml PEG-600. The mixture was stirred at refluxing temperature for 60-90 min. After completion of the reaction (confirmed by TLC), the reaction mixture was cooled to room temperature. The crystalline solid was collected and washed with a little cold ethanol to give the analytically pure compound (4a) in 95% yield. Compounds 4a-4z were also synthesized by adopting this procedure.
In dichloromethane at 20 - 70℃; for 5h; Alkaline conditions;
General Procedure for Target Compounds 1-29.
General procedure: Compound H2N-X (0.01 mol) or NH2-Y-NH2 (0.005 mol) wascompletely dissolved in CH2Cl2. Triethylamine (Et3N) or pyridine (3 mL) was added to the mixture (Scheme 1). Understirring, the acyl chloride (1a, 2a, or 3a) was slowly added to the mixture at room temperature. Afterwards, the reactionmixture was stirred for another 5 h at 20-70C. After the reaction was completed, the mixture was washed with HCl (10%) andNaOH (10%) in turn. The solvent was removed under reduced pressure. The progress of the reactions was monitored by TLC.The crude products of compounds 7, 8, and 25-27 were recrystallized with dimethyl sulfoxide (DMSO) and water (15:1), andthe rest were recrystallized from anhydrous ethanol.
N-(6-chloro-1,3-benzothiazol-2-yl)-5-methylbicyclo[3.3.1]nonane-1-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 5-Methyl-bicyclo<3.2.1>nonan-carbonsaeure-(5) 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 1,2-dichloro-ethane at 20℃; for 0.166667h;
Stage #2: 6-chloro-2-aminobenzothiazole In 1,2-dichloro-ethane at 45℃;
General procedure
General procedure: Carboxylic acid 3 (0.2 mmol, 1 equiv.) and HATU (0.2 mmol, 1 equiv.) were dissolved in 1 mL DCE in a one dram vial charged with a stir bar. DIPEA (0.1 mL, 0.6 mmol, 3 equiv.) was added and the resulting solution was stirred at RT for 10 minutes. Amine 2 (0.2 mmol, 1 equiv.) was added to the mixture. The reaction solution was heated to 45 °C and stirred overnight. Upon completion the reaction mixture was condensed and loaded onto a 60g C-18 cartridge and purified over a gradient of 5-95% ACN/H2O. The fractions containing product were identified by LC-MS and condensed under vacuum to give the final product 4. The final product was characterized by NMR.
N-(6-chlorobenzo[d]thiazol-2-yl)-1-phenyl-1-(pyridin-2-yl)methanimine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With acetic acid In ethanol for 6h; Reflux;
2.2.1. Preparation of N'-(phenyl(pyridin-2-yl)methylene) isonicotinohydrazide (L1H)
General procedure: A colorless solution of 2-benzoylpyridine (0.730 g, 3.985 mmol) in EtOH (15mL) was added to an ethanol solution of isonicotinohy- drazide (0.547g, 3.985 mmol) in (20 mL) with some drops of glacial acetic acid. The mixture was refluxed for 6 h, the formed solution was filtered and left aside to cool slowly, then the dark creamy ppt. was separated and recrystallized from hot ethanol and dried under vacuum.
N-(6-chloro-benzothiazol-2-yl)-4-(4-chloro-phenyl)-4-oxo-butyramide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57.8%
Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 1h; Inert atmosphere;
Stage #2: 6-chloro-2-aminobenzothiazole In tetrahydrofuran at 20℃; Inert atmosphere;
4.2.2. General synthesis of final compound (2a-x)
General procedure: Different substituted benzothiazolamines were synthesized usingknown method [16]. The weighed amounts of reactants (1a-h) (1 mol)were dissolved in dry tetrahydrofuran and a pinch of HOBt (10 mg) wasadded to the reaction mixture. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide(EDC) (1.2 mol) was weighed and quickly added to reactionmass under nitrogen atmosphere after half an hour. The reaction masswas kept on stirring for another half hour and one equivalent of otherreactant (substituted benzothiazolamine) was added to it. Reactionprogress was monitored using TLC. The reaction mass was diluted withwater when the reactants were consumed and extraction was carried outusing ethyl acetate. Corresponding desired products (2a-x) were obtainedfrom organic layer. The organic layer was dried on anhydroussodium sulfate and concentrated to give the final product as solid.
4-(4-bromo-phenyl)-N’-(6-chloro-benzothiazol-2-yl)-4-oxo-butyramide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54.6%
General procedure: Different substituted benzothiazolamines were synthesized usingknown method [16]. The weighed amounts of reactants (1a-h) (1 mol)were dissolved in dry tetrahydrofuran and a pinch of HOBt (10 mg) wasadded to the reaction mixture. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide(EDC) (1.2 mol) was weighed and quickly added to reactionmass under nitrogen atmosphere after half an hour. The reaction masswas kept on stirring for another half hour and one equivalent of otherreactant (substituted benzothiazolamine) was added to it. Reactionprogress was monitored using TLC. The reaction mass was diluted withwater when the reactants were consumed and extraction was carried outusing ethyl acetate. Corresponding desired products (2a-x) were obtainedfrom organic layer. The organic layer was dried on anhydroussodium sulfate and concentrated to give the final product as solid.
N-(6-chloro-benzothiazol-2-yl)-4-(4-methoxy-phenyl)-4-oxobutyramide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61.2%
Stage #1: 4-(4-methoxy-phenyl)-4-oxo-butyric acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 1h; Inert atmosphere;
Stage #2: 6-chloro-2-aminobenzothiazole In tetrahydrofuran at 20℃; Inert atmosphere;
4.2.2. General synthesis of final compound (2a-x)
General procedure: Different substituted benzothiazolamines were synthesized usingknown method [16]. The weighed amounts of reactants (1a-h) (1 mol)were dissolved in dry tetrahydrofuran and a pinch of HOBt (10 mg) wasadded to the reaction mixture. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide(EDC) (1.2 mol) was weighed and quickly added to reactionmass under nitrogen atmosphere after half an hour. The reaction masswas kept on stirring for another half hour and one equivalent of otherreactant (substituted benzothiazolamine) was added to it. Reactionprogress was monitored using TLC. The reaction mass was diluted withwater when the reactants were consumed and extraction was carried outusing ethyl acetate. Corresponding desired products (2a-x) were obtainedfrom organic layer. The organic layer was dried on anhydroussodium sulfate and concentrated to give the final product as solid.
With isopentyl nitrite In acetonitrile at 60℃; for 3h;
19.2 Step 2: Preparation of 6-chlorobenzo[d]thiazole-2-carbonitrile
6-Chlorobenzo[d]thiazol-2-amine (5 g, 27 mmol)and cuprous cyanide (2.9 g, 32.5 mmol) was added to acetonitrile (60 mL),Then add isoamyl nitrite (4.8g, 41mmol),The reaction was carried out at 60°C for 3 hours.After the reaction was cooled to room temperature, it was filtered and the filter cake was washed with ethyl acetate.After concentration under reduced pressure, it was purified by column chromatography (petroleum ether:ethyl acetate=20:1-10:1)The product 6-chlorobenzo[d]thiazole-2-carbonitrile was obtained (1 g, yield: 19%).
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