* 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 tert.-butylnitrite; copper dichloride In acetonitrile at 65℃; for 2 h;
To a round bottomed flask was added 2-amino-6-fluorobenzothiazole (1.0017 g, 5.96 mmol, Sigma-Aldrich Chemical Company, Inc.), copper (II) chloride (1.201 g, 8.93 mmol, Sigma-Aldrich Chemical Company, Inc.), and tert-butyl nitrite (1.063 ml, 8.93 mmol, Acros Organics) in ACN and was heated to 65° C. for 2 hours. The reaction mixture was diluted with 1N HCl and extracted with EtOAc. The organic extract was washed with water, satd NaCl, dried over MgSO4, filtered and concentrated in vacuo to give the title compound (0.9249 g, 4.93 mmol, 83percent yield). 1H NMR (400 MHz, DMSO-d6) δ ppm s 7.45 (td, J=9.10, 2.74 Hz, 1H) 7.97-8.07 (m, 2H)
64%
With copper(II) choride dihydrate; isopentyl nitrite In acetonitrile at 65℃; for 3 h;
Intermediates 2: a) 2-Chloro-6-fluoro-benzothiazole (2a); 0.5 g (2.97 mmol) of 6-fluoro-benzothiazol-2-ylamine is placed in the presence of isoamyl nitrite (0.52 g, 4.46 mmol) and CuCI2.2H20 (0.61 g, 0.57 mmol) in 10 mL of acetonitrile. The reaction medium is heated to 65°C for 3h and then reduced to dryness; the residue is taken up by water and extracted using ethyl acetate. The organic phases are dried and then evaporated, and the residue obtained is purified by flash chromatography on silica (CH2CI2-AcOEt, gradient 100-0 to 97-3 over 30 min). 0.36 g of solid is obtained (yield 64percent). TLC silica gel 60 F 254 Merck, CH2CI2- MeOH:95-5, Rf=0.84.
64%
With copper(II) choride dihydrate; isopentyl nitrite In acetonitrile at 65℃; for 3 h;
a) 2-Chloro-6-fluoro-benzothiazole (2a) 0.5 g (2.97 mmol) of 6-fluoro-benzothiazol-2-ylamine is placed in the presence of isoamyl nitrite (0.52 g, 4.46 mmol) and CuCl2.2H2O (0.61 g, 0.57 mmol) in 10 mL of acetonitrile. The reaction medium is heated to 65° C. for 3 h and then reduced to dryness; the residue is taken up by water and extracted using ethyl acetate. The organic phases are dried and then evaporated, and the residue obtained is purified by flash chromatography on silica (CH2Cl2-AcOEt, gradient 100-0 to 97-3 over 30 min). 0.36 g of solid is obtained (yield 64percent). TLC silica gel 60 F 254 Merck, CH2Cl2-MeOH:95-5, Rf=0.84.
Reference：
[1] Patent: US2013/225552, 2013, A1, . Location in patent: Paragraph 0976
[2] Patent: WO2012/69503, 2012, A1, . Location in patent: Page/Page column 18-19
[3] Patent: US2013/172326, 2013, A1, . Location in patent: Paragraph 0081; 0082
[4] Journal of the Indian Chemical Society, 1933, vol. 10, p. 465,469
[5] Farmaco, Edizione Scientifica, 1977, vol. 32, p. 348 - 354
[6] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 14, p. 4022 - 4025
[7] Chemistry and Biodiversity, 2011, vol. 8, # 2, p. 253 - 265
[8] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3044 - 3049
[9] Organic Letters, 2017, vol. 19, # 21, p. 5836 - 5839
2
[ 333-20-0 ]
[ 371-40-4 ]
[ 348-40-3 ]
Yield
Reaction Conditions
Operation in experiment
84%
at 5 - 6℃; for 2 h;
General procedure: Arylamine (0.1 mol) and potassiumthiocyanate (0.4 mol) were dissolved in glacial aceticacid (40 mL) and cooled. Bromine (0.04 mol) mixed withglacial acetic acid (24 mL) was added from droppingfunnel at such a rate that temperature does not rise beyond5–6°C. After all bromine had been added, the solutionwas stirred with glass rod for an additional 2 h at lowtemperature. The mixture was allowed to stand overnight,during which period orange-yellow precipitates get settledat the bottom. Water was added and slurry formed washeated at 850°C on steam bath for 20 min and fi ltered hot.The fi ltrate was cooled and neutralised with ammoniasolution to pH 6. Yellow precipitates obtained werecollected, washed with water and recrystallized frombenzene to get crystals of 1,3-benzothiazol-2-amine andits derivatives 1-3 [21, 22].
80%
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.
77.3%
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.
Reference：
[1] Organic Letters, 2017, vol. 19, # 21, p. 5836 - 5839
[2] Molecular Crystals and Liquid Crystals, 2013, vol. 575, # 1, p. 64 - 76
[3] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 24, p. 8599 - 8607
[4] Russian Journal of Applied Chemistry, 2015, vol. 88, # 12, p. 2065 - 2073[5] Zh. Prikl. Khim. (S.-Peterburg, Russ. Fed.),
[6] European Journal of Medicinal Chemistry, 2008, vol. 43, # 5, p. 1114 - 1122
[7] Archiv der Pharmazie, 2015, vol. 348, # 4, p. 254 - 265
[8] European Journal of Medicinal Chemistry, 2012, vol. 53, p. 41 - 51
[9] Medicinal Chemistry Research, 2017, vol. 26, # 9, p. 1969 - 1987
[10] Journal of Organic Chemistry, 2017, vol. 82, # 18, p. 9312 - 9320
[11] Journal of Pharmaceutical Sciences, 1994, vol. 83, # 10, p. 1425 - 1432
[12] Journal of Medicinal Chemistry, 1999, vol. 42, # 15, p. 2828 - 2843
[13] Journal of the Indian Chemical Society, 2008, vol. 85, # 3, p. 333 - 335
[14] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3443 - 3446
[15] Archiv der Pharmazie, 2010, vol. 343, # 6, p. 353 - 359
[16] Patent: WO2011/151361, 2011, A1, . Location in patent: Page/Page column 53-54
[17] Asian Journal of Chemistry, 2011, vol. 23, # 9, p. 3969 - 3974
[18] Asian Journal of Chemistry, 2010, vol. 22, # 7, p. 5487 - 5492
[19] Heteroatom Chemistry, 2012, vol. 23, # 4, p. 399 - 410
[20] Organic Letters, 2012, vol. 14, # 20, p. 5334 - 5337,4
[21] Journal of Enzyme Inhibition and Medicinal Chemistry, 2013, vol. 28, # 1, p. 1 - 10
[22] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 1 - 13
[23] European Journal of Medicinal Chemistry, 2014, vol. 71, p. 24 - 30
[24] Archiv der Pharmazie, 2013, vol. 346, # 11, p. 819 - 831
[25] Journal of Heterocyclic Chemistry, 2014, vol. 51, # 2, p. 459 - 465
[26] Chemical Biology and Drug Design, 2014, vol. 84, # 1, p. 123 - 129
[27] Medicinal Chemistry, 2013, vol. 9, # 4, p. 596 - 607
[28] Journal of Heterocyclic Chemistry, 2014, vol. 51, # 6, p. 1641 - 1658
[29] Research on Chemical Intermediates, 2015, vol. 41, # 8, p. 5599 - 5609
[30] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5561 - 5565
[31] Research on Chemical Intermediates, 2016, vol. 42, # 12, p. 8329 - 8344
[32] Archiv der Pharmazie, 2018, vol. 351, # 12,
3
[ 1147550-11-5 ]
[ 371-40-4 ]
[ 348-40-3 ]
Yield
Reaction Conditions
Operation in experiment
78%
With bromine In dichloromethane at 20℃; for 16 h;
General procedure: To a mixture of aniline (1) (2.0 g, 0.021 mol) and ammonium thiocyanate (6.5 g, 0.086 mol), bromine (2.2 mL, 0.043 mol) in dichloromethane (20 mL) and stirred for 16 h at ambient temperature. Later than water was added to the reaction mixture and the product was extracted in dichloromethane (3 × 30 mL). The solvent was evaporated under vacuum to afford the as crude, which was further purified by column chromatography using EtOAc:Hexane (4:6) to give compounds 2a-d.
Reference：
[1] Heterocyclic Communications, 2002, vol. 8, # 3, p. 275 - 280
[2] Asian Journal of Chemistry, 2015, vol. 27, # 12, p. 4575 - 4578
[3] European Journal of Organic Chemistry, 2011, # 31, p. 6206 - 6217
[4] Journal of Organic Chemistry, 2018, vol. 83, # 19, p. 12129 - 12142
[5] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 1, p. 131 - 136
[6] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 14, p. 4022 - 4025
[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] European Journal of Medicinal Chemistry, 2018, vol. 148, p. 477 - 486
4
[ 371-40-4 ]
[ 348-40-3 ]
Yield
Reaction Conditions
Operation in experiment
75%
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] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 1759 - 1775
[2] European Journal of Medicinal Chemistry, 2010, vol. 45, # 9, p. 4293 - 4299
[3] Archiv der Pharmazie, 2010, vol. 343, # 11-12, p. 692 - 699
5
[ 371-40-4 ]
[ 348-40-3 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1981, vol. 18, # 4, p. 759 - 761
6
[ 459-05-2 ]
[ 348-40-3 ]
Reference：
[1] Biological and Pharmaceutical Bulletin, 2002, vol. 25, # 3, p. 335 - 341
[2] Journal of the Indian Chemical Society, 1931, vol. 8, p. 147,163
[3] Patent: US2033949, 1933, ,
[4] Journal of the Chemical Society [Section] C: Organic, 1969, p. 268 - 272
[5] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 16, p. 5678 - 5682
[6] Acta Poloniae Pharmaceutica - Drug Research, 2009, vol. 66, # 4, p. 387 - 392
[7] Medicinal Chemistry Research, 2013, vol. 22, # 9, p. 4211 - 4222
[8] Chemical Biology and Drug Design, 2016, p. 354 - 362
[9] Journal of Medicinal Chemistry, 2016, vol. 59, # 21, p. 9814 - 9824
[10] Patent: US2061186, 1933, ,
7
[ 371-40-4 ]
[ 348-40-3 ]
Reference：
[1] Journal of the Indian Chemical Society, 1931, vol. 8, p. 147,163
[2] Journal of the Chemical Society [Section] C: Organic, 1969, p. 268 - 272
[3] Medicinal Chemistry Research, 2013, vol. 22, # 1, p. 195 - 210
[4] Medicinal Chemistry Research, 2013, vol. 22, # 9, p. 4211 - 4222
[5] Journal of Chemical Research, 2014, vol. 38, # 10, p. 611 - 616
[6] Chemical Biology and Drug Design, 2016, p. 354 - 362
[7] Journal of Medicinal Chemistry, 2016, vol. 59, # 21, p. 9814 - 9824
8
[ 2146-07-8 ]
[ 348-40-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 16, p. 5678 - 5682
[2] Biological and Pharmaceutical Bulletin, 2002, vol. 25, # 3, p. 335 - 341
[3] Medicinal Chemistry Research, 2013, vol. 22, # 9, p. 4211 - 4222
9
[ 540-72-7 ]
[ 371-40-4 ]
[ 348-40-3 ]
Reference：
[1] Die Pharmazie, 1967, vol. 22, # 6, p. 229 - 233
10
[ 1544-68-9 ]
[ 348-40-3 ]
Reference：
[1] Journal of the Indian Chemical Society, 1931, vol. 8, p. 147,163
11
[ 1111-67-7 ]
[ 371-40-4 ]
[ 348-40-3 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1988, vol. 27, # 1-12, p. 189 - 190
12
[ 348-40-3 ]
[ 63754-96-1 ]
Reference：
[1] Farmaco, Edizione Scientifica, 1977, vol. 32, p. 348 - 354
13
[ 348-40-3 ]
[ 78364-55-3 ]
Yield
Reaction Conditions
Operation in experiment
89%
With hydrogenchloride; hydrazine hydrate In water at 5℃; for 5 h; Reflux
6-Fluoro-2-hydrazinobenzothiazole (2). Hydrochloric acid (10 mL) was added dropwise to hydrazine hydrate 99percent (10 g, 0.2 mol) at 5-10 °C, followed by addition of a solution of 2-amino-6-fluorobenzothiazole (1) (3.364 g, 0.02 mol) in ethylene glycol (40 mL). The mixture was heated at reflux temperature for 5 h. On cooling, the precipitated solid was collected by filtration, washed with water, dried and crystallized from ethanol. Yield 89percent, m.p. 194-196 °C [1].
Reference：
[1] Journal of Heterocyclic Chemistry, 2014, vol. 51, # 2, p. 459 - 465
[2] Chinese Chemical Letters, 2015, vol. 26, # 12, p. 1522 - 1528
[3] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 14, p. 4022 - 4025
[4] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1981, vol. <B> 20, # 4, p. 314 - 316
[5] European Journal of Medicinal Chemistry, 2010, vol. 45, # 9, p. 4293 - 4299
[6] Archiv der Pharmazie, 2010, vol. 343, # 11-12, p. 692 - 699
[7] Journal of Enzyme Inhibition and Medicinal Chemistry, 2011, vol. 26, # 4, p. 527 - 534
[8] Journal of the Indian Chemical Society, 2008, vol. 85, # 3, p. 333 - 335
[9] Chemistry and Biodiversity, 2011, vol. 8, # 2, p. 253 - 265
[10] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3044 - 3049
[11] Journal of Medicinal Chemistry, 2013, vol. 56, # 13, p. 5514 - 5540
[12] Chinese Chemical Letters, 2016, vol. 27, # 3, p. 380 - 386
[13] Chemical Biology and Drug Design, 2016, p. 354 - 362
[14] Research on Chemical Intermediates, 2016, vol. 42, # 12, p. 8329 - 8344
14
[ 348-40-3 ]
[ 152937-04-7 ]
Yield
Reaction Conditions
Operation in experiment
40%
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
15
[ 348-40-3 ]
[ 7787-70-4 ]
[ 152937-04-7 ]
Yield
Reaction Conditions
Operation in experiment
40%
With tert.-butylnitrite In hexane; ethyl acetate; acetonitrile
(Step 1) Synthesis of 2-bromo-6-fluorobenzothiazole Copper (I) bromide (619 mg, 4.32 mmol) was suspended in acetonitrile (10 ml). To the resulting suspension was added tert-butyl nitrite (640 ael, 5.38 mmol), followed by stirring at 60OEC for 5 minutes. To the reaction mixture was added 2-amino-6-fluorobenzothiazole (605 mg, 3.60 mmol). The resulting mixture was stirred at 60OEC for 10 minutes. After cooling to the room temperature, the reaction mixture was diluted with ethyl acetate. The ethyl acetate solution was washed with 1N HCl, 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 (5:1, v/v) eluate fractions, 2-bromo-6-fluorobenzothiazole (330 mg, 40percent) was obtained as a brown solid. 1H-NMR (CDCl3) δ: 7.19-7.24 (m, 1H), 7.49-7.52 (m, 1H), 7.92-7.96 (m, 1H). MS (ESI) m/z 273.8 (M++1+MeCN).
With tert.-butylnitrite; copper dichloride; In acetonitrile; at 65℃; for 2h;
To a round bottomed flask was added 2-amino-6-fluorobenzothiazole (1.0017 g, 5.96 mmol, Sigma-Aldrich Chemical Company, Inc.), copper (II) chloride (1.201 g, 8.93 mmol, Sigma-Aldrich Chemical Company, Inc.), and tert-butyl nitrite (1.063 ml, 8.93 mmol, Acros Organics) in ACN and was heated to 65 C. for 2 hours. The reaction mixture was diluted with 1N HCl and extracted with EtOAc. The organic extract was washed with water, satd NaCl, dried over MgSO4, filtered and concentrated in vacuo to give the title compound (0.9249 g, 4.93 mmol, 83% yield). 1H NMR (400 MHz, DMSO-d6) delta ppm s 7.45 (td, J=9.10, 2.74 Hz, 1H) 7.97-8.07 (m, 2H)
64%
With copper(II) choride dihydrate; isopentyl nitrite; In acetonitrile; at 65℃; for 3h;
Intermediates 2: a) 2-Chloro-6-fluoro-benzothiazole (2a); 0.5 g (2.97 mmol) of 6-fluoro-benzothiazol-2-ylamine is placed in the presence of isoamyl nitrite (0.52 g, 4.46 mmol) and CuCI2.2H20 (0.61 g, 0.57 mmol) in 10 mL of acetonitrile. The reaction medium is heated to 65C for 3h and then reduced to dryness; the residue is taken up by water and extracted using ethyl acetate. The organic phases are dried and then evaporated, and the residue obtained is purified by flash chromatography on silica (CH2CI2-AcOEt, gradient 100-0 to 97-3 over 30 min). 0.36 g of solid is obtained (yield 64%). TLC silica gel 60 F 254 Merck, CH2CI2- MeOH:95-5, Rf=0.84.
64%
With copper(II) choride dihydrate; isopentyl nitrite; In acetonitrile; at 65℃; for 3h;
a) 2-Chloro-6-fluoro-benzothiazole (2a) 0.5 g (2.97 mmol) of 6-fluoro-benzothiazol-2-ylamine is placed in the presence of isoamyl nitrite (0.52 g, 4.46 mmol) and CuCl2.2H2O (0.61 g, 0.57 mmol) in 10 mL of acetonitrile. The reaction medium is heated to 65 C. for 3 h and then reduced to dryness; the residue is taken up by water and extracted using ethyl acetate. The organic phases are dried and then evaporated, and the residue obtained is purified by flash chromatography on silica (CH2Cl2-AcOEt, gradient 100-0 to 97-3 over 30 min). 0.36 g of solid is obtained (yield 64%). TLC silica gel 60 F 254 Merck, CH2Cl2-MeOH:95-5, Rf=0.84.
Multi-step reaction with 2 steps
1: bromine / chloroform / 4 h
2: ammonia / ethanol
With bromine Reflux;
With bromine; acetic acid; lithium bromide at 40℃;
With sulfuryl dichloride; bromine; chlorobenzene
With bromine In chloroform
With bromine at 0 - 5℃;
With bromine In dichloromethane at 5℃;
General procedure: Substituted phenylthiourea (0.1 mol) was taken in CHCl3 and stirred with a mechanical stirrer and bromine (0.1 mol) was added drop by drop for a period of an hour with continuous stirring. The temperature was maintained <5°C. After bromine addition, the stirring was maintained for 4-5 hours. The product obtained was dried, followed by SO2 water treatment and filtered. The filtrate obtained was treated with aq. NH3 in neutral conditions. The obtained precipitate was filtered, dried, and recrystallized from absolute alcohol.
With hydrogenchloride; hydrazine hydrate; In water; at 5℃; for 5h;Reflux;
6-Fluoro-2-hydrazinobenzothiazole (2). Hydrochloric acid (10 mL) was added dropwise to hydrazine hydrate 99% (10 g, 0.2 mol) at 5-10 C, followed by addition of a solution of 2-amino-6-fluorobenzothiazole (1) (3.364 g, 0.02 mol) in ethylene glycol (40 mL). The mixture was heated at reflux temperature for 5 h. On cooling, the precipitated solid was collected by filtration, washed with water, dried and crystallized from ethanol. Yield 89%, m.p. 194-196 C [1].
With hydrazine hydrochloride; hydrazine hydrate; In ethylene glycol; at 140℃; for 2h;
General procedure: The substituted aniline (1eq.) and ammonium thiocyanate (2eq.) in 150mL glacial acetic acid were cooled in an ice bath and stirred mechanically. To the sulution, bromine (2eq.) in 25ml glacial acetic acid was added dropwise at such arate to keep the temperature below 10oC throughout the addition. Stirring was continued for additional 30 min after the bromine addition. The precipitate was collected and recrystallization from ethanol to give 2-aminobenzthiazoles. Then, the substituted 2-aminobenzthiazoles (1eq) in ethylene glycol were added hydrazine hydrate (2eq.) and hydrazine dihydrochloride (2eq). The mixture was heated at 140 oC for 2h. After cooling, the precipitate was filtered to give used directly for next step without further purification. Then, the hydrazino compound was added to thionyl chloride (1eq.) for 2h at 50 oC. After evaporated under reduced pressure, the residue was taken up in ethyl acetate and washed with 1 M NaHCO3 and brine each for twice. The organic layer was dried and evaporated to give the crude final product. The crude product was purified by silica gel column chromatography using PE-EA as an eluent.
With hydrogenchloride; hydrazine hydrate; In water; ethylene glycol; at 5℃; for 5h;Reflux;
Hydrochloric acid (10 mL) was added dropwise to hydrazine hydrate 99% (10 g, 0.2 mol) at 5-10 C, followed by addition of a solution of 2-amino-6-fluorobenzothiazole (1) (3.364 g, 0.02 mol) in ethylene glycol (40 mL). The mixture was heated at reflux temperature for 5 h. On cooling, the precipitated solid was collected by filtration, washed with water, dried and crystallized from ethanol. Yield 89%, m.p. 194-196 C [1].
With hydrogenchloride; hydrazine hydrate; In water; ethylene glycol; at 5℃;Reflux;
Concentrated hydrochloric acid (0.067 mol) was added dropwise with stirring tohydrazine hydrate (0.12 mol) at 5-6 C followed by ethylene glycol (30 mL);thereafter, 6-uorobenzo[d]thiazol-2-amine (1) (20 mmol) was added in portionsand the resultant mixture was reuxed for 2-3 h and cooled at room temperature.The reaction progress was monitored by TLC using toluene:ethylacetate (75:25) asmobile phase. The reaction mixture was ltered and the resulting precipitates werewashed with distilled water. The resulting crude was recrystallized from ethanol. IR(KBr) mmax: 3010 (=C-H str), 1645 (C=C str), 1398 (C=N str). The 1HNMR(DMSO-d6) spectrum of this product showed signals: d 7.2-7.4 (3H, m, Ar C-H), at4.0 (1H, br, NH) and 4.75 (2H, br, NH2) ppm. The peaks in its 13CNMR (DMSO-d6)d: 106.1, 112.4, 115.5, 129.7, 145.5, 157.5, 171.2 ppm.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20℃;
Example 112A N-(6-fluoro-1,3-benzothiazol-2-yl)-2,2,3,3-tetramethylcyclopropanecarboxamide A mixture of 6-fluoro-benzothiazol-2-ylamine (1 equiv), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (1 equiv), 1-hydroxybenzotniazole, triethylamine (1.1 equiv), and 2,2,3,3-tetramethylcyclopropanecarboxylic acid (0.8 equiv) in 3:1 THF/Et3N (1 M) and were stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with 1 M aqueous NaHCO3, dried (Na2SO4), filtered, and concentrated. Puried by silica gel chromatography afforded the title compound. MS (ESI+) m/z 293 (M+H)+.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20℃;
N-(6-fluoro-1.3-benzothiazol-2-yl)-2.2.3.3-tetramethylcyclopropanecarboxamide A mixture of 6-fluoro-benzothiazol-2-ylamine (1 equiv), N-(3-dimethylaminopropyl)-N- ethylcarbodiimide hydrochloride (1 equiv), 1-hydroxybenzotriazole, triethylamine (1.1 equiv), and 2,2,3,3-tetramethylcyclopropanecarboxylic acid (0.8 equiv) in 3:1 THF/Et3N (1 M) and were stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with 1 M aqueous NaHCO3, dried (Na2SO4), filtered, and concentrated. Puried by silica gel chromatography afforded the title compound. MS (ESI+) m/z 293 (M+H)+
With tert.-butylnitrite; In hexane; ethyl acetate; acetonitrile;
(Step 1) Synthesis of 2-bromo-6-fluorobenzothiazole Copper (I) bromide (619 mg, 4.32 mmol) was suspended in acetonitrile (10 ml). To the resulting suspension was added tert-butyl nitrite (640 ael, 5.38 mmol), followed by stirring at 60ØC for 5 minutes. To the reaction mixture was added 2-amino-6-fluorobenzothiazole (605 mg, 3.60 mmol). The resulting mixture was stirred at 60ØC for 10 minutes. After cooling to the room temperature, the reaction mixture was diluted with ethyl acetate. The ethyl acetate solution was washed with 1N HCl, 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 (5:1, v/v) eluate fractions, 2-bromo-6-fluorobenzothiazole (330 mg, 40%) was obtained as a brown solid. 1H-NMR (CDCl3) delta: 7.19-7.24 (m, 1H), 7.49-7.52 (m, 1H), 7.92-7.96 (m, 1H). MS (ESI) m/z 273.8 (M++1+MeCN).
With sodium nitrite; In water; hydrogen bromide;
EXAMPLE 28 [(2-(6-Fluorobenzothiazolyl))carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester STR36 Slurry 2-amino-6-fluorobenzothiazole (0.255 mol) in water (325 mL), heat to reflux and add 48% hydrobromic acid (130 mL). Maintain at reflux for 20 minutes, cool to 0 C. and add a solution of sodium nitrite (17.56 g, 0.255 mol) water (90 mL), maintaining a temperature of 0 C. Stir at 0 C. for 15 minutes and add by dropwise addition (while keeping cold) to a rapidly stirring mixture of copper (I) bromide (42.03 g, 0.293 mol) in 48% hydrobromic acid (86 mL) and water (225 mL). Stir at room temperature for 20 minutes. Allow to stand overnight, extract into methylene chloride and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give 2-bromo-6-fluorobenzothiazole.
General procedure: A mixture of 2-aminopyridine-5-carboxylic acid (2) or substituted 2-aminobenzothiazole (3.0 mmol) in MeOH-DCM (2:3, 15.0 mL) and aldehyde (3.0 mmol) containing 5 mol% of Sc(OTf)3 was stirred for 1 h at room temperature, followed by the addition of 3 mmol of the phenyl isocyanide, and the mixture was stirred for another 12 h at rt. Then 1 mL of hexane was added and the resulting yellowish solid was filtered, washed three times with hexane-ethyl acetate mixture (5:1, 20 mL) and triturated with ethyl acetate-hexane. The crude product was used in the next step without further purification.
General procedure: A mixture of 2-aminopyridine-5-carboxylic acid (2) or substituted 2-aminobenzothiazole (3.0 mmol) in MeOH-DCM (2:3, 15.0 mL) and aldehyde (3.0 mmol) containing 5 mol% of Sc(OTf)3 was stirred for 1 h at room temperature, followed by the addition of 3 mmol of the phenyl isocyanide, and the mixture was stirred for another 12 h at rt. Then 1 mL of hexane was added and the resulting yellowish solid was filtered, washed three times with hexane-ethyl acetate mixture (5:1, 20 mL) and triturated with ethyl acetate-hexane. The crude product was used in the next step without further purification.
Stage #1: 2-amino-6-fluoro-1,3-benzothiazole; 6-methoxyquinoline-3-carbaldehyde With scandium tris(trifluoromethanesulfonate) In methanol; dichloromethane at 20℃; for 1h;
Stage #2: 4-fluorophenyl isocyanide In methanol; dichloromethane at 20℃; for 12h;
4.2.1. General experimental procedure A for the synthesis of compounds 4a-4c, 9a-9e, 14a-d and 15a-e
General procedure: A mixture of 2-aminopyridine-5-carboxylic acid (2) or substituted 2-aminobenzothiazole (3.0 mmol) in MeOH-DCM (2:3, 15.0 mL) and aldehyde (3.0 mmol) containing 5 mol% of Sc(OTf)3 was stirred for 1 h at room temperature, followed by the addition of 3 mmol of the phenyl isocyanide, and the mixture was stirred for another 12 h at rt. Then 1 mL of hexane was added and the resulting yellowish solid was filtered, washed three times with hexane-ethyl acetate mixture (5:1, 20 mL) and triturated with ethyl acetate-hexane. The crude product was used in the next step without further purification.
With n-butyllithium In tetrahydrofuran; hexane at 20℃;
1.) Synthesis of the urea derivatives
General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.
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.
Stage #1: 2-amino-6-fluoro-1,3-benzothiazole With benzotriazol-1-ol In N,N-dimethyl-formamide at 0℃; for 0.166667h;
Stage #2: 2-(phenylamino)nicotinic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 8h;
d. General method for the synthesis of substituted benzothiazole 2-anilinonicotinamide (7a-g)
General procedure: To a stirred solution of substituted 2-(phenylamino)nicotinic acid (500 mg) in dry DMF (10 mL) hydroxyl benzotriazole HOBt (1.2 mmol) were added at 0 °C. After 10 min EDCI (1.2 mmol) was added and finally substituted benzo[d]thiazol-2-amine (0.74 mmol) were added. Then the resulting mixture was stirred at room temperature for 8 h and then the reaction mixture was quenched with saturated solution of NaHCO3 and extracted with ethyl acetate from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting products were purified by column chromatography employing EtOAc/Hexane as an eluent.
Stage #1: 2-amino-6-fluoro-1,3-benzothiazole With benzotriazol-1-ol In N,N-dimethyl-formamide at 0℃; for 0.166667h;
Stage #2: 2-((4-methoxyphenyl)amino)nicotinic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 8h;
d. General method for the synthesis of substituted benzothiazole 2-anilinonicotinamide (7a-g)
General procedure: To a stirred solution of substituted 2-(phenylamino)nicotinic acid (500 mg) in dry DMF (10 mL) hydroxyl benzotriazole HOBt (1.2 mmol) were added at 0 °C. After 10 min EDCI (1.2 mmol) was added and finally substituted benzo[d]thiazol-2-amine (0.74 mmol) were added. Then the resulting mixture was stirred at room temperature for 8 h and then the reaction mixture was quenched with saturated solution of NaHCO3 and extracted with ethyl acetate from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting products were purified by column chromatography employing EtOAc/Hexane as an eluent.
5-bromo-N-(6-fluorobenzo[d]thiazol-2-yl)-6-methoxypicolinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
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 0 - 20℃; for 16h;
General procedure: To a solution of compound 2 (150 mg, 0.001 mol) in dichloromethane (4 mL), cooled to 0 C, was added compound 3 (255 mg, 0.0011 mol), O-(7-azabenzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium hexafluorophosphate (HATU) (570 mg, 0.0015 mol), N,Ndiisopropylethylamine (DIPEA) (0.358 mL, 0.0020 mol) and the mixture was stirred for 16 h at ambient temperature. Water was added and extracted with ethyl acetate, dried and purified by column chromatography using a gradient of hexane-EtOAc (8:2-5:5) to give compound 4.
2-[((6-fluorobenzothiazol-2-yl)amino)methyl]-5-nitro-1H-benzimidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With triethylamine In N,N-dimethyl-formamide Reflux;
5.1.1. Preparation of 2-(arylamino)methyl-5-(un)substituted-1Hbenzimidazoles3a-m, 1-((un)substituted-1H-benzimidazol-2-yl)methyl-3-methyl-1H-pyrazol-5(4H)-ones 3n,o and 2-((2-(4-fluorophenyl)piperazin-1-yl)methyl)-5-nitro-1H-benzimidazole(3p)
General procedure: A mixture of 2-chloromethyl-1H-benzimidazole derivative 2a,b(0.002 mol), the appropriate arylamine, ethyl 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylate, 2-methyl-1H-pyrazol-5(4H)-one or 1-(4-fluorophenyl)piperazine (0.002 mol)and triethylamine (0.3 mL) in DMF (10 mL) was refluxed for 6e12 h.The mixture was poured onto ice and the precipitate formed wasfiltered, dried and crystallized from ethanol/water (2:1).
3-(7-fluoro-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
91%
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.
6-fluoro-N-(isochroman-1-yl)benzo[d]thiazol-2-amine[ No CAS ]
2-(6-fluorobenzo[d]thiazol-2-yl)-3,4-dihydroisoquinolin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%; 23%
With acetic acid; at 80℃; for 4h;
General procedure: Mixture of <strong>[22901-09-3]2-<strong>[22901-09-3](2-bromoethyl)benzaldehyde</strong></strong> 1 (0.1g, 0.0047 mmol) and 4-methoxybenzo[d]thiazol-2-amine 2b (0.102 g, 0.0056 mmol) in 3.0 mL of acetic acid was stirred at 80 oC for 4 h, after cooling to room temperature, the reaction mixture was poured into saturated aqueous NaHCO3, and the resulting mixture was extracted with EtOAc three times. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford pure isochroman 3b (0.107g, 73%) and isoquinolinone 10b (0.029g, 20%).
2-chloro-2-fluoro-N-(6-fluorobenzo[d]thiazol-2-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; at 0 - 20℃; for 3.0h;
General procedure: To a stirred solution of 5-amino-1-naphthol (126 mg, 0.792 mmol) and <strong>[70395-35-6]sodium chlorofluoroacetate</strong> (159 mg,1.18 mmol) in dichloromethane (8 mL) was added T3P (50 wt%solution in AcOEt, 701 μL, 1.18 mmol) and N,N-diisopropylethylamine(DIPEA) (273 μL, 1.57 mmol) at 0C. Afterstirred at ambient temperature for 1 h, the reaction mixturewas diluted with water and extracted thrice with CHCl3. Thecombined organic layers were washed with brine, dried overNa2SO4, filtered and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (hexane/AcOEt = 3 : 1) to afford the title compound (37.2 mg, 18% yield) as a pale purple solid.
Stage #1: 2-amino-6-fluoro-1,3-benzothiazole With sulfuric acid In propionic acid at -5 - 0℃; for 0.5h;
Stage #2: With nitrosyl sulphuric acid In lithium hydroxide monohydrate; propionic acid for 3h;
Stage #3: 3-[(2-hydroxyethyl)(phenyl)amino]propanenitrile With hydrogenchloride In lithium hydroxide monohydrate; propionic acid at 0 - 15℃; for 5h;
2
The preparation method of the fluorine-containing alkali-resistant azo disperse dyes includes the following steps: adding 8 mL of 98% concentrated sulfuric acid solution and 20 mL of propionic acid solution in sequence to a 100 mL beaker, and slowly adding 3.43 g (0.02 g (0.02 g) of propionic acid in a stirring state mol) 2-amino-6-fluorobenzothiazole, and then placed in a salt ice bath (-5-0 ° C) to disperse for 30 min, slowly add 6.35 g of 40% nitrosyl sulfuric acid solution dropwise, keep warm, stir and react for 3 h, After the reaction is complete, a certain amount of urea is added to eliminate excess nitrous acid in the reaction system, and the preparation of the diazonium salt is completed, and is ready for use;Add 96 mL of deionized water, 0.02 mol of N-(2-cyanoethyl)-N-hydroxyethylaniline and 4 mL of hydrochloric acid solution to a 500-mL three-necked flask in turn, and stir well until N-(2-cyanoethyl)-N-hydroxyl Ethylaniline is completely dissolved, keeping the reaction temperature at 0-5°C, slowly adding the above prepared diazonium salt solution to the reaction system, stirring for 30min, heating up to 10-15°C, and adjusting the pH of the reaction system with sodium carbonate The reaction time is about 4-5 hours, and the reaction is carried out for 5 hours; suction filtration, washing with water, and drying are carried out to obtain the crude product; and the target product is obtained by repeated recrystallization and purification with ethanol.
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