* 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 hydrazine hydrate In ethanol at 80℃; for 5 h;
To a solution of 2-chlorobenzo[d]thiazole (0.169 g, 1 mmol) inethanol, N2H4H2O (80percent, 5 mmol) was dropwise added withrefluxing at 80 °C for 5 h. When cooled to room temperature, themixture was filtered, washed and recrystallized with ethanol. Thewhite solid thus obtained and dried under vacuum to get compound7 (0.154 g) in 93percent yield. 1H NMR (DMSO-d6, 600 MHz):δ(ppm): 9.01 (s, 1H), 7.68 (d, J 7.8 Hz, 1H), 7.32 (d, J 8.0 Hz, 1H),7.20 (t, J 7.6 Hz, 1H), 6.98 (t, J 7.5 Hz, 1H), 5.03 (s, 2H). 13C NMR(DMSO-d6, 151 MHz): δ (ppm): 174.4, 153.9, 130.9, 125.8, 121.4,120.7, 118.3 (Fig. S5).
Reference：
[1] Journal of Heterocyclic Chemistry, 1988, vol. 25, p. 543 - 547
[2] Dyes and Pigments, 2017, vol. 146, p. 344 - 351
[3] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 22, p. 294
[4] Journal of the American Chemical Society, 1951, vol. 73, p. 4007,4009
[5] Pubbl. Ist. Chim. ind. Univ. Bologna, 1943, # 5, p. 3
[6] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1071 - 1074
[7] Patent: US2018/22716, 2018, A1, . Location in patent: Paragraph 0282
[8] Patent: US2073600, 1934, ,
2
[ 615-20-3 ]
[ 615-21-4 ]
[ 1141-88-4 ]
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1999, vol. 38, # 6, p. 639 - 640
3
[ 95-16-9 ]
[ 615-20-3 ]
Yield
Reaction Conditions
Operation in experiment
88%
With tetrachloromethane; sodium t-butanolate In N,N-dimethyl-formamide at 20℃; for 3 h;
Benzothiazole (1 mmol, 135.9 mg),Carbon tetrachloride (1.1 mmol, 169.2 mg) was placed in a 10 mL round bottom flask.Add 5 mL of N,N-dimethylformamideSodium tert-butoxide (4.0 mmol, 384.4 mg),Stir at room temperature for 3 hours,TLC monitored the endpoint of the reaction.The mixture was poured into water and extracted with dichloromethane. The organic phase was collected and dried. The dichloromethane was removed by rotary evaporation to give the crude product.The crude product was subjected to silica gel column chromatography with petroleum ether and ethyl acetate as eluent (volume ratio = 30:1).2-Chlorobenzothiazole (brown oily liquid, 149.2 mg, yield 88percent) was obtained.
Reference：
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 6, p. 886 - 890
[2] Patent: CN107501023, 2017, A, . Location in patent: Paragraph 0063; 0064
[3] Organic Letters, 2009, vol. 11, # 2, p. 421 - 423
[4] Journal of Organic Chemistry, 2009, vol. 74, # 21, p. 8309 - 8313
[5] Chemische Berichte, 1880, vol. 13, p. 16
[6] Journal of Organometallic Chemistry, 1999, vol. 588, # 2, p. 155 - 159
[7] Journal of Organometallic Chemistry, 2000, vol. 601, # 2, p. 233 - 236
4
[ 149-30-4 ]
[ 615-20-3 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: at 20 - 25℃; for 0.25 h; Inert atmosphere Stage #2: at 20 - 25℃; for 3 h; Inert atmosphere
General procedure: A mixture of the 2-mercaptobenzo[d]thiazole (>1 g, 1 equiv) and sul-furyl chloride (10 equiv) was stirred at 20–25 °C for 15 min. Next, H 2 O(2 equiv) was added and the mixture was stirred at 20–25 °C for anadditional 3 h. A sample was taken, quenched with MeCN/H 2 O (2:1)and analyzed by HPLC. After completion of the reaction, the mixturewas diluted with MeCN (5 volumes) and slowly quenched with H 2 O(20 volumes). The product precipitated from the aqueous solution.The solid was collected and washed with H 2 O. Drying under vacuumafforded the pure product. In the case of the liquid product 2-chloro-benzo[d]thiazole (13), the reaction mixture was extracted withEtOAc. The organic layer was then dried and concentrated to affordthe product as an oil.2-Chlorobenzo[d]thiazole (13)Yield: 3.30 g, 19.5 mmol (90percent); yellow oil.1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.45–7.62 (m, 2 H), 7.96 (dd, J =8.07, 0.73 Hz, 1 H), 8.09 (dd, J = 7.89, 0.92 Hz, 1 H).13 C NMR (101 MHz, DMSO-d 6 ): δ = 122.81, 122.86, 126.49, 127.47,136.19, 150.91, 153.23. HRMS (ESI): m/z [M + H] + calcd for C 7 H 5 ClNS: 169.9831; found:169.9844.
36.1 g
With hydrogenchloride; dihydrogen peroxide In water at 38℃; for 4 h;
In a 500 ml reaction flask, 36.4 g of 2-mercaptobenzothiazole and 80 g of water were cast, 29.7 g of 30percent hydrochloric acid was added, the temperature was raised to 38 ° C,48.5g mass fraction of 20percent hydrogen peroxide was added dropwise, after the end of incubation was incubated dropwise to detect the bodyWhen the content of 2-mercaptobenzothiazole in the system is less than 0.2percent, hydrogen peroxide (about 4h)After the reaction was settled stratification,The upper oily liquid is 2 - chlorobenzothiazole crude,Finally, anhydrous 2 - chlorobenzothiazole dry crude product obtained2-Chlorobenzothiazole fine 36.1g.
Reference：
[1] Synthesis (Germany), 2018, vol. 50, # 10, p. 2027 - 2032
[2] Bulletin of the Chemical Society of Japan, 1992, vol. 65, # 11, p. 3163 - 3173
[3] , 1965, vol. 1, p. 1702 - 1704[4] Zhurnal Organicheskoi Khimii, 1965, vol. 1, p. 1679 - 1682
[5] Synthetic Communications, 2007, vol. 37, # 12, p. 2039 - 2050
[6] Patent: CN107129484, 2017, A, . Location in patent: Paragraph 0019; 0014; 0015; 0016; 0017; 0018
5
[ 136-95-8 ]
[ 615-20-3 ]
Reference：
[1] Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, # 9, p. 1561 - 1562
[2] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 14, p. 5275 - 5284
[3] Chemistry - A European Journal, 2018, vol. 24, # 55, p. 14622 - 14626
[4] Organic Process Research and Development, 2017, vol. 21, # 1, p. 44 - 51
[5] Organic and Biomolecular Chemistry, 2013, vol. 11, # 7, p. 1103 - 1108
[6] Zhurnal Obshchei Khimii, 1937, vol. 7, p. 2813,2815[7] Chem. Zentralbl., 1938, vol. 109, # II, p. 3084
[8] Journal of the Chemical Society, 1930, p. 2190,2209
[9] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 14, p. 4022 - 4025
[10] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3044 - 3049
6
[ 615-21-4 ]
[ 615-20-3 ]
Yield
Reaction Conditions
Operation in experiment
43%
at 50℃; for 2 h;
SOCl2 (8.4 mL, 13.8 g, 116 mmol) was heated to 50°C,and then treated with 2-hydrazinobenzothiazole, 14 (2.50 g,15.1 mmol), portionwise over 45 min. The reaction mixturewas heated at 50°C for 2 h, allowed to cool to room temperature,and was filtered. The filtrate was concentrated underreduced pressure, to provide 2-chlorobenzothiazole, 15 (1.10g, 43percent yield), which was used in the following step withoutfurther purification.
2.64 g
at 50℃; for 2 h;
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.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 14, p. 4022 - 4025
[2] Letters in Organic Chemistry, 2018, vol. 15, # 5, p. 455 - 461
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3044 - 3049
Reference：
[1] Pharmaceutical Bulletin, 1953, vol. 1, p. 319,321
[2] Zhurnal Obshchei Khimii, 1937, vol. 7, p. 2813,2815[3] Chem. Zentralbl., 1938, vol. 109, # II, p. 3084
[4] Patent: US1757930, 1927, ,
[5] Patent: US1923957, 1929, ,
[6] Patent: US2043948, 1933, ,
[7] Journal of Organic Chemistry, 1937, vol. 2, p. 148,153
[8] Journal of the American Chemical Society, 1946, vol. 68, p. 1666
[9] Patent: US2469697, 1946, ,
[10] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 17, p. 611
[11] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 17, p. 611
9
[ 515-84-4 ]
[ 126507-54-8 ]
[ 615-20-3 ]
[ 32137-76-1 ]
Reference：
[1] Journal of Organometallic Chemistry, 1999, vol. 588, # 2, p. 155 - 159
10
[ 125602-94-0 ]
[ 615-20-3 ]
Reference：
[1] Patent: US4929618, 1990, A,
11
[ 103-72-0 ]
[ 615-20-3 ]
Reference：
[1] Journal of the Chemical Society, 1925, vol. 127, p. 1488
[2] Chemische Berichte, 1879, vol. 12, p. 1128[3] Chemische Berichte, 1880, vol. 13, p. 10
12
[ 1986-08-9 ]
[ 615-20-3 ]
Reference：
[1] Journal of the Indian Chemical Society, 1982, vol. 59, # 8, p. 1004 - 1005
13
[ 62-53-3 ]
[ 615-20-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3044 - 3049
14
[ 934-34-9 ]
[ 615-20-3 ]
Reference：
[1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 17, p. 611
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 17, p. 611
15
[ 120-78-5 ]
[ 615-20-3 ]
Reference：
[1] Patent: US2043948, 1933, ,
[2] Kogyo Kagaku Zasshi, 1943, vol. 46, p. 679[3] Chem.Abstr., 1949, p. 2022
16
[ 149-30-4 ]
[ 615-20-3 ]
[ 4074-77-5 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1937, vol. 7, p. 2813,2815[2] Chem. Zentralbl., 1938, vol. 109, # II, p. 3084
17
[ 136-95-8 ]
[ 67-66-3 ]
[ 95-16-9 ]
[ 615-20-3 ]
[ 34263-66-6 ]
[ 2602-85-9 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1980, # 12, p. 4935 - 4953
[2] Journal of Chemical Research, Miniprint, 1980, # 12, p. 4935 - 4953
18
[ 75-15-0 ]
[ 62-53-3 ]
[ 615-20-3 ]
Reference：
[1] Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques, 1976, vol. 283, p. 319 - 321
19
[ 76-02-8 ]
[ 126507-54-8 ]
[ 41268-26-2 ]
[ 615-20-3 ]
[ 4271-09-4 ]
Reference：
[1] Journal of Organometallic Chemistry, 1999, vol. 588, # 2, p. 155 - 159
20
[ 95-16-9 ]
[ 10026-13-8 ]
[ 615-20-3 ]
Reference：
[1] Chemische Berichte, 1880, vol. 13, p. 16
21
[ 10026-13-8 ]
[ 103-72-0 ]
[ 615-20-3 ]
[ 622-44-6 ]
Reference：
[1] Chemische Berichte, 1879, vol. 12, p. 1128[2] Chemische Berichte, 1880, vol. 13, p. 10
22
[ 615-20-3 ]
[ 2406-90-8 ]
Reference：
[1] Antimicrobial agents and chemotherapy, 2002, vol. 46, # 8, p. 2588 - 2594
[2] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 14, p. 3328 - 3332
[3] Chemical Communications, 2013, vol. 49, # 77, p. 8644 - 8646
23
[ 615-20-3 ]
[ 80945-86-4 ]
Reference：
[1] Bollettino Scientifico della Facolta di Chimica Industriale di Bologna, 1943, vol. 4, # 1, p. 67[2] Gazzetta Chimica Italiana, 1948, vol. 78, p. 462,468
24
[ 615-20-3 ]
[ 62266-82-4 ]
Reference：
[1] Bollettino Scientifico della Facolta di Chimica Industriale di Bologna, 1944, vol. 5, p. 11,14, 16, 18
25
[ 615-20-3 ]
[ 2407-11-6 ]
Yield
Reaction Conditions
Operation in experiment
87%
Stage #1: With sulfuric acid In water at 10 - 17℃; for 1.5 h; Stage #2: With potassium nitrate In water at 12 - 40℃;
Step l1.088 g (6.42 mmol) of 2-chlorobenzothiazole and 8.56 ml of sulfuric acid were placed in a 50 niL flask, followed by keeping the mixture at 10-17°C for 1.5 hrs. After observing that the color of the reaction mixture was white, the reaction mixture was cooled to 12°C, 714 mg (7.062 mmol) of potassium nitrate was added thtereto, and the resulting mixture was stirred with maintaining the reaction temperature less than 18 °C for 1 hr. The resulting solution was heated to 25 °C , stirred for 1.5 hrs, and slowly heated to 40 "C . After confirming the completion of the reaction by TLC, the resulting mixture was cooled to room temperature and poured into ice water, and the resulting solid was filtered, washed with water (until pH is 7), and dried under a vacuum condition to obtain 2-chloro-6-nitrobenzothiazole (yield: 87percent).
82%
at 0 - 20℃; for 18.5 h;
2-Chloro-1,3-benzothiazole (16, 10.0 g, 58.95 mmol) was addedportion wise to concentrated H2SO4(60 mL) in a cooled roundbottomed flask (ice bath). Potassium nitrate (6.56 g,64.85 mmol)was added portion wise, and the resulting reaction mixture was stirred at 0 °C (ice bath) for 30 min, and then atroom temperature for 18 h. The solution was poured onto iceand the formed precipitate collected by filtration. The collectedsolid was rinsed with ice cold water until acid free, and thendried under reduced pressure. The crude product was furtherpurified by recrystallisation from MeCN (≈100 mL) or EtOH(≈425 mL)to yield 6as fine off-white needles. Yield fromEtOH (10.37 g, 48.34 mmol, 82percent), from MeCN (9.21 g, 42.89mmol, 73percent). Mp 193–194 °C (EtOH); 1H NMR (500 MHz,CDCl3) δ8.75 (d, J= 2.3 Hz, 1H, CH-7), 8.38 (dd, J= 9.0, 2.3Hz, 1H, CH-5), 8.07 (d, J= 9.0 Hz, 1H, CH-4); 13C NMR (125MHz, CDCl3) δ158.9 (C-2), 154.9 (C-6), 145.6 (C-7a), 136.6(C-3a), 123.5 (CH-4), 122.4 (CH-5), 117.8 (CH-7).
64%
at 0℃; for 1 h;
2-chlorobenzothiazole (8.0 g, 47.16 mmol) placed in a 100 mL ofthree-necked flask was added by concentrated H2SO4 (40mL) carefully under 0 0C. At 0 0C KNO3 (5.0 g,49.52 mmol) was added portionwise and kept stirring for 1 hour. The mixture wasthen poured into ice-water (100 mL). The precipitate was collected, washed withNaHCO3 solution, dissolved into 200 mL of DCM, dried over Na2SO4and triturated by EtOH (80 mL) to get the desired product as light yellowsolid. (6.5 g, 64percent yield)LC-MS (ESI):no mass observed, tR = 3.90 min.1H NMR (400 MHz, CDCl3)δ 8.75 (s, 1H), 8.38 (d, J = 9.0 Hz, 1H), 8.07 (d, J = 8.9 Hz,1H).13C NMR (101 MHz, CDCl3)δ 158.77, 154.75, 145.43, 136.47, 123.33, 122.24, 117.69.
58%
at 0 - 5℃; for 3.33333 h;
To a solution of 2-chlorobenzothiazole (1.20g, 7.07 mmol) in concentrated H2SO4 (6 mL) was addedHNO3 (69percent solution, 0.6 mL) dropwise at 0 °C for 20 min.The mixture was stirred at 5 °C for 3 h, poured in ice-water.The precipitate was collected and washed 5percent sodiumbicarbonate and water, dried in vacuo.
49%
at 0 - 20℃; for 1.5 h;
(A) Synthesis of 2-chloro-6-nitrobenzothiazole (2) Compound 1 (25.1 g, 147 mmol) was added dropwise to concentrated sulfuric acid (135 mL) under ice cooling, then potassium nitrate (16.4 g, 162 mmol) was added to the mixture. The mixture was stirred under ice cooling as it was for 30 minutes, and then stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, and the precipitates were separated by filtration and washed with water. The precipitates were recrystallized from ethanol to obtain Compound 2 as white acicular crystals (15.6 g, 49percent yield). 1H-NMR (300 MHz, CDCl3) δ 8.07 (d, 1H, J=8.9 Hz), 8.39 (dd, 1H, J=2.2, 8.9 Hz) 8.75 (d, 1H, J=2.2 Hz). MS (EI+) 214, M+.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 14, p. 3328 - 3332
[2] Advanced Synthesis and Catalysis, 2017, vol. 359, # 11, p. 1837 - 1843
[3] Patent: WO2008/153325, 2008, A1, . Location in patent: Page/Page column 36
[4] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 2019 - 2025
[5] Farmaco, 1994, vol. 49, # 3, p. 153 - 166
[6] Journal of the American Chemical Society, 2010, vol. 132, # 39, p. 13586 - 13587
[7] Chemical Communications, 2013, vol. 49, # 77, p. 8644 - 8646
[8] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 24, p. 7661 - 7670
[9] Bulletin of the Korean Chemical Society, 2013, vol. 34, # 2, p. 495 - 499
[10] Patent: US2007/155806, 2007, A1, . Location in patent: Page/Page column 5
[11] Chemistry - An Asian Journal, 2011, vol. 6, # 7, p. 1800 - 1810
[12] Chemische Berichte, 1880, vol. 13, p. 10
[13] Antimicrobial agents and chemotherapy, 2002, vol. 46, # 8, p. 2588 - 2594
[14] Patent: US5475014, 1995, A,
[15] Patent: EP1308439, 2003, A1,
[16] Mutation Research - Genetic Toxicology and Environmental Mutagenesis, 2008, vol. 650, # 2, p. 104 - 114
[17] Chemical Science, 2017, vol. 8, # 2, p. 1511 - 1524
26
[ 615-20-3 ]
[ 3622-38-6 ]
[ 2407-11-6 ]
Yield
Reaction Conditions
Operation in experiment
72%
With sulfuric acid; nitric acid In water at 0 - 5℃; for 3.33333 h;
To a solution of 2-CHLOROBENZOTHIAZOLE (12.0 g, 70.7 MMOL) in concentrated H2SO4 (60 mL) was added HN03 (69percent solution, 6 mL) dropwise at 0°C for 20 min. The mixture was stirred at 5°C for 3h, poured into ice-water (150 mL). The precipitate was collected and washed with 5percent sodium bicarbonate and water, dried in VACUO.APOS;H NMR analysis showed the mixture contained 78percent 6-nitro-2-chlorobenzothiazole and 8percent 5-nitro-2- chlorobenzothiazole. Recrystallization from ethanol gave 6-nitro-2-chlorobenzothiazole as white crystalline solid (11 g, 72percent). 3.5 g of the solid was dissolved in refluxing ethanol-acetic acid (150: 15 mL), Iron powder was added in one portion.. The mixture was refluxed for 1.5h, filtered. The filtrate was concentrated in vacuo to half volume and neutralized with 10percent NaOH to pH 7.5, extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and evaporated to give a residue, which was RECRYSTALLIZED from ethanol. Light purple crystals (2.5 g, 83percent) were obtained. Mp 160-164°C ; TLC single spot at Rf 0.27 (30percent EtOAc/hexane) ;APOS;HNMR (270 MHz, DMSO-d6) 5 7.58 (1H, d, J = 9.0 Hz, 4-H), 7.03 (1H, d, J = 2.0 Hz, 7-H), 6.77 (1 H, dd, J = 9.0, 2. 0 Hz, 5-H), 5.55 (2H, s, NH2). The mother liquor from the RECRYSTALLIZATION of nitration product was evaporated and subjected to iron powder reduction as described above. The crude product was purified with flash chromatography (ethyl acetate-DCM gradient elution) to give 2-CHLORO- benzothiazol-5-yl-amine as yellow solid. Mp 146-149°C ; TLC single spot at Rf 0.52 (10percent EtOAc/DCM) ;APOS;HNMR (270 MHZ, DMSO-d6) 8 7.63 (1 H, d, J = 8. 6 HZ, 7-H), 7.05 (1 H, d, J = 2.3 Hz, 4-H), 6.78 (1 H, dd, J = 8.6, 2.3 Hz, 6-H), 5.40 (2H, s, NH2).
With sulfuric acid; nitric acid In water at 0 - 5℃; for 3.33333 h;
To a solution of 2-CHLOROBENZOTHIAZOLE (12.0 g, 70.7 MMOL) in concentrated H2SO4 (60 mL) was added HN03 (69percent solution, 6 mL) dropwise at 0°C for 20 min. The mixture was stirred at 5°C for 3h, poured into ice-water (150 mL). The precipitate was collected and washed with 5percent sodium bicarbonate and water, dried in VACUO.APOS;H NMR analysis showed the mixture contained 78percent 6-nitro-2-chlorobenzothiazole and 8percent 5-nitro-2- chlorobenzothiazole. Recrystallization from ethanol gave 6-nitro-2-chlorobenzothiazole as white crystalline solid (11 g, 72percent). 3.5 g of the solid was dissolved in refluxing ethanol-acetic acid (150: 15 mL), Iron powder was added in one portion.. The mixture was refluxed for 1.5h, filtered. The filtrate was concentrated in vacuo to half volume and neutralized with 10percent NaOH to pH 7.5, extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and evaporated to give a residue, which was RECRYSTALLIZED from ethanol. Light purple crystals (2.5 g, 83percent) were obtained. Mp 160-164°C ; TLC single spot at Rf 0.27 (30percent EtOAc/hexane) ;APOS;HNMR (270 MHz, DMSO-d6) 5 7.58 (1H, d, J = 9.0 Hz, 4-H), 7.03 (1H, d, J = 2.0 Hz, 7-H), 6.77 (1 H, dd, J = 9.0, 2. 0 Hz, 5-H), 5.55 (2H, s, NH2). The mother liquor from the RECRYSTALLIZATION of nitration product was evaporated and subjected to iron powder reduction as described above. The crude product was purified with flash chromatography (ethyl acetate-DCM gradient elution) to give 2-CHLORO- benzothiazol-5-yl-amine as yellow solid. Mp 146-149°C ; TLC single spot at Rf 0.52 (10percent EtOAc/DCM) ;APOS;HNMR (270 MHZ, DMSO-d6) 8 7.63 (1 H, d, J = 8. 6 HZ, 7-H), 7.05 (1 H, d, J = 2.3 Hz, 4-H), 6.78 (1 H, dd, J = 8.6, 2.3 Hz, 6-H), 5.40 (2H, s, NH2).
With chlorine; trichlorophosphate; In chlorobenzene; at 80 - 100℃;
With a cooler and a hydrogen chloride tail gas absorption device,Can be stirred and equipped with a chlorine gas introduction tubeIn a 2000 ml reaction flask,600 g of benzothiazole, 500 g of chlorobenzene and 10 g of phosphorus oxychloride catalyst were introduced, and the temperature was raised to 80 C.Start to pass chlorine gas at (3 ~ 5) g / min, the reaction is maintained at (80 ~ 100) C. Insulation reaction until the HPLC detection of the benzothiazole content in the system is less than 0.5%, the chlorine is stopped, the amount of chlorine is about 300 grams . After the reaction, the nitrogen gas is purged of excess chlorine, which is a 2-chlorobenzothiazole chlorobenzene solution.After distillation under reduced pressure, chlorobenzene and a small amount of raw materials are removed for the next batch.The remaining material was subjected to a high vacuum of 0.099 mPa, and distilled to 165 C to obtain 2-chlorobenzothiazole, 725 g, content 99%.The yield was 95.3%.
88%
With tetrachloromethane; sodium t-butanolate; In N,N-dimethyl-formamide; at 20℃; for 3h;
Benzothiazole (1 mmol, 135.9 mg),Carbon tetrachloride (1.1 mmol, 169.2 mg) was placed in a 10 mL round bottom flask.Add 5 mL of N,N-dimethylformamideSodium tert-butoxide (4.0 mmol, 384.4 mg),Stir at room temperature for 3 hours,TLC monitored the endpoint of the reaction.The mixture was poured into water and extracted with dichloromethane. The organic phase was collected and dried. The dichloromethane was removed by rotary evaporation to give the crude product.The crude product was subjected to silica gel column chromatography with petroleum ether and ethyl acetate as eluent (volume ratio = 30:1).2-Chlorobenzothiazole (brown oily liquid, 149.2 mg, yield 88%) was obtained.
With polyethylene glycol; copper dichloride; isopentyl nitrite In acetonitrile at 65℃; for 3h;
95%
With pyrylium tetrafluoroborate; magnesium chloride In acetonitrile for 16h; Heating; Sealed tube;
General procedure for the chlorination of amino heteroaromatic compounds
General procedure: Unless otherwise specified, an 18 ml screw-capped tube under normal atmosphere is charged with pyrylium tetrafluoroborate 1 (1.5 equiv.) and MgCl2 (2.0 equiv.). The starting material (1.0 equiv.) is then added and directly followed by CH3CN (0.1 M). The resulting mixture is then stirred 5 minutes at 25 °C and then 16 hours at 120 °C. The reaction is allowed to cool to 25 °C. The crude mixture is partitioned between water and EtOAc. The aqueous layer is extracted with EtOAc (3 × 10 ml). The combined organic layers are dried over Na2SO4, concentrated to dryness and purified on silica gel to afford the desired product.
94%
With hydrogenchloride; copper; sodium nitrite In water at -5 - 55℃;
90%
With N-chloro-succinimide; sodium nitrite In N,N-dimethyl-formamide at 20℃; for 6h;
74%
Stage #1: 2-amino-benzthiazole With tert.-butylnitrite In acetonitrile at 20℃; Flow reactor;
Stage #2: With copper dichloride In ethylene glycol; acetonitrile at 82℃; Flow reactor;
70%
With hydrogenchloride; sodium nitrite In water at -5 - 45℃;
With hydrogenchloride; water; sodium nitrite
Multi-step reaction with 2 steps
1: 85 percent / NH2NH2*H2O; NH2NH2*H2SO4 / ethane-1,2-diol / 2 h / 120 °C
2: 93 percent / SOCl2 / 2 h / 50 °C
Multi-step reaction with 2 steps
1: hydrazine hydrochloride; hydrazine hydrate / ethylene glycol / 2 h / 140 °C
2: thionyl chloride / 2 h / 50 °C
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium tetrahydroborate; N,N,N,N,-tetramethylethylenediamine; In tetrahydrofuran; at 25℃; for 21h;Inert atmosphere;
General procedure: PdCl2(dppf), PdCl2(tbpf) and (A.caPhos)PdCl2. A mixture of the halogenated heterocycle (0.66 mmol) in anhydrous THF (13.2 mL) was degassed by bubbling argon for few minutes. Then, PdCl2(dppf) (27.0 mg, 0.033 mmol, 5.0 mol%), TMEDA (0.130 g, 1.12 mmol, 1.7 equiv) and finally NaBH4 (42.4 mg, 1.12 mmol, 1.7 equiv) were introduced in sequence. The mixture was stirred at room temperature under argon for the proper time and then worked up as described above.
Step l1.088 g (6.42 mmol) of <strong>[615-20-3]2-chlorobenzothiazole</strong> and 8.56 ml of sulfuric acid were placed in a 50 niL flask, followed by keeping the mixture at 10-17C for 1.5 hrs. After observing that the color of the reaction mixture was white, the reaction mixture was cooled to 12C, 714 mg (7.062 mmol) of potassium nitrate was added thtereto, and the resulting mixture was stirred with maintaining the reaction temperature less than 18 C for 1 hr. The resulting solution was heated to 25 C , stirred for 1.5 hrs, and slowly heated to 40 "C . After confirming the completion of the reaction by TLC, the resulting mixture was cooled to room temperature and poured into ice water, and the resulting solid was filtered, washed with water (until pH is 7), and dried under a vacuum condition to obtain 2-chloro-6-nitrobenzothiazole (yield: 87%).
82%
With sulfuric acid; potassium nitrate; at 0 - 20℃; for 18.5h;
2-Chloro-1,3-benzothiazole (16, 10.0 g, 58.95 mmol) was addedportion wise to concentrated H2SO4(60 mL) in a cooled roundbottomed flask (ice bath). Potassium nitrate (6.56 g,64.85 mmol)was added portion wise, and the resulting reaction mixture was stirred at 0 C (ice bath) for 30 min, and then atroom temperature for 18 h. The solution was poured onto iceand the formed precipitate collected by filtration. The collectedsolid was rinsed with ice cold water until acid free, and thendried under reduced pressure. The crude product was furtherpurified by recrystallisation from MeCN (?100 mL) or EtOH(?425 mL)to yield 6as fine off-white needles. Yield fromEtOH (10.37 g, 48.34 mmol, 82%), from MeCN (9.21 g, 42.89mmol, 73%). Mp 193-194 C (EtOH); 1H NMR (500 MHz,CDCl3) delta8.75 (d, J= 2.3 Hz, 1H, CH-7), 8.38 (dd, J= 9.0, 2.3Hz, 1H, CH-5), 8.07 (d, J= 9.0 Hz, 1H, CH-4); 13C NMR (125MHz, CDCl3) delta158.9 (C-2), 154.9 (C-6), 145.6 (C-7a), 136.6(C-3a), 123.5 (CH-4), 122.4 (CH-5), 117.8 (CH-7).
64%
With sulfuric acid; potassium nitrate; at 0℃; for 1h;
<strong>[615-20-3]2-chlorobenzothiazole</strong> (8.0 g, 47.16 mmol) placed in a 100 mL ofthree-necked flask was added by concentrated H2SO4 (40mL) carefully under 0 0C. At 0 0C KNO3 (5.0 g,49.52 mmol) was added portionwise and kept stirring for 1 hour. The mixture wasthen poured into ice-water (100 mL). The precipitate was collected, washed withNaHCO3 solution, dissolved into 200 mL of DCM, dried over Na2SO4and triturated by EtOH (80 mL) to get the desired product as light yellowsolid. (6.5 g, 64% yield)LC-MS (ESI):no mass observed, tR = 3.90 min.1H NMR (400 MHz, CDCl3)delta 8.75 (s, 1H), 8.38 (d, J = 9.0 Hz, 1H), 8.07 (d, J = 8.9 Hz,1H).13C NMR (101 MHz, CDCl3)delta 158.77, 154.75, 145.43, 136.47, 123.33, 122.24, 117.69.
64%
With sulfuric acid; potassium nitrate; at 0℃; for 1h;
<strong>[615-20-3]2-chlorobenzothiazole</strong> (8.0 g, 47.16 mmol) placed in a 100 mL of three-necked flask was added by concentrated H2SO4 (40 mL) carefully under 0 C. At 0 C. KNO3 (5.0 g, 49.52 mmol) was added portionwise and kept stirring for 1 hour. The mixture was then poured into ice-water (100 mL). The precipitate was collected, washed with NaHCO3 solution, dissolved into 200 mL of DCM, dried over Na2SO4 and triturated by EtOH (80 mL) to get the desired product as light yellow solid. (6.5 g, 64% yield) LC-MS (ESI): no mass observed, tR=3.90 min. 1H NMR (400 MHz, CDCl3) delta 8.75 (s, 1H), 8.38 (d, J=9.0 Hz, 1H), 8.07 (d, J=8.9 Hz, 1H). 13C NMR (101 MHz, CDCl3) delta 158.77, 154.75, 145.43, 136.47, 123.33, 122.24, 117.69.
58%
With sulfuric acid; nitric acid; at 0 - 5℃; for 3.33333h;
To a solution of <strong>[615-20-3]2-chlorobenzothiazole</strong> (1.20g, 7.07 mmol) in concentrated H2SO4 (6 mL) was addedHNO3 (69% solution, 0.6 mL) dropwise at 0 C for 20 min.The mixture was stirred at 5 C for 3 h, poured in ice-water.The precipitate was collected and washed 5% sodiumbicarbonate and water, dried in vacuo.
49%
With sulfuric acid; potassium nitrate; at 0 - 20℃; for 1.5h;
(A) Synthesis of 2-chloro-6-nitrobenzothiazole (2) Compound 1 (25.1 g, 147 mmol) was added dropwise to concentrated sulfuric acid (135 mL) under ice cooling, then potassium nitrate (16.4 g, 162 mmol) was added to the mixture. The mixture was stirred under ice cooling as it was for 30 minutes, and then stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, and the precipitates were separated by filtration and washed with water. The precipitates were recrystallized from ethanol to obtain Compound 2 as white acicular crystals (15.6 g, 49% yield). 1H-NMR (300 MHz, CDCl3) delta 8.07 (d, 1H, J=8.9 Hz), 8.39 (dd, 1H, J=2.2, 8.9 Hz) 8.75 (d, 1H, J=2.2 Hz). MS (EI+) 214, M+.
With nitric acid; In sulfuric acid;
Preparation Example 9 2-Chloro-6-nitrobenzothiazole STR33 300 g of <strong>[615-20-3]2-chlorobenzothiazole</strong> was dissolved in 1500 ml of concentrated sulfuric acid and then 134 ml of concenrated nitric acid was added dropwise to the solution at 0 to 10 C. After stirring for 1 h, the reaction mixture was poured into ice/water. The precipitates thus obtained were recovered by filtration, washed with water and then with acetone, and dried to give 380 g of the titled compound. 1 H-NMR (CDCl3)delta: 8.07 (1H, d), 8.39 (1H, dd), 8.76 (1H, d)
With conc. nitric acid; sulfuric acid; In water;
(1) Conc. sulfuric acid (50 mL) was added to <strong>[615-20-3]2-chlorobenzothiazole</strong> (10 g) under ice-cooling, and conc. nitric acid (5 mL) was added dropwise under ice-cooling. The mixture was stirred under ice-cooling for 1 hr, and iced water (600 mL) was added to the reaction mixture. The precipitated solid was collected by filtration, which was then recrystallized from acetone to give 2-chloro-6-nitrobenzothiazole (6.36 g) as a pale-yellow powder.
With hydrazine hydrate; In ethanol; at 80℃; for 5h;
To a solution of 2-chlorobenzo[d]thiazole (0.169 g, 1 mmol) inethanol, N2H4H2O (80%, 5 mmol) was dropwise added withrefluxing at 80 C for 5 h. When cooled to room temperature, themixture was filtered, washed and recrystallized with ethanol. Thewhite solid thus obtained and dried under vacuum to get compound7 (0.154 g) in 93% yield. 1H NMR (DMSO-d6, 600 MHz):delta(ppm): 9.01 (s, 1H), 7.68 (d, J 7.8 Hz, 1H), 7.32 (d, J 8.0 Hz, 1H),7.20 (t, J 7.6 Hz, 1H), 6.98 (t, J 7.5 Hz, 1H), 5.03 (s, 2H). 13C NMR(DMSO-d6, 151 MHz): delta (ppm): 174.4, 153.9, 130.9, 125.8, 121.4,120.7, 118.3 (Fig. S5).
With hydrazine hydrate; at 100℃;
General procedure: A mixture of 2-chloro-5-methyl-benzimidazole (10.2 g, 61.2 mmol) and hydrazine monohydrate (59 mL, 1.22 mol) was stirred at 100 C overnight. After being cooled to ambient temperature, to the reaction mixture was added to water (60 mL). After stirring under ice cooling, the resulting precipitates were collected by filtration. The precipitates were washed with water 3 times, and then dried in vacuo to give 2-hydrazino-5-methyl-benzimidazole (8.4 g, 84.6%).
With 1H-imidazole; sodium chloride; In water; for 6h;Reflux; Green chemistry;
General procedure: In a 50-mL, round-bottom flask, 0.87 g (0.01 mol) of morpholine, 0.68 g(0.01 mol) of imidazole, 0.274 g (0.001 mol) of tributylbenzyl ammonium choride,and 1.69 g (0.01 mol) <strong>[615-20-3]2-chlorobenzothiazole</strong> were added to 20mL of 5% NaCl (aqueous)solution. The reaction mixture was refluxed for 6 h. The progress of the reactionwas monitored by thin-layer chromatography (TLC). After completion of the reaction,the aqueous layer was washed with ethyl acetate (310 mL). The combinedorganic layer was dried over anhydrous Na2SO4 and concentrated at reduced pressure.Products were purified either by crystallizing or by flash chromatography. Whitecrystalline solid
80%
In water; at 20℃; for 4h;Green chemistry;
General procedure: The reaction was carried out in a 25 mL round bottom flask equipped with magnetic stir bar charged with <strong>[615-20-3]2-chlorobenzothiazole</strong> (1 mmol), aminating agent (2.0 equiv), and water (2 mL). The resulting reaction mixture was stirred at room temperature for 30 min to 5 h (varies with nature of the amine). The reaction progress was monitored by TLC. After the reaction, it was worked up with ethyl acetate. Crude product was purified by column chromatography (for piperazine derivatives column is not required). The identity and purity of the product was confirmed by 1H NMR, 13C NMR, and ESI-MS.
70%
With 1-C10H7Ni(P(C6H5)3)2Br; potassium tert-butylate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride; In toluene; at 23℃; for 24h;Inert atmosphere;
An oven-dried 25-mL three-necked flask was charged with KOtBu (4 mmol), Ni(PPh3)2(1-naphthyl)Cl (C-1) (0.05 mmol) and IPr*HCl (0.05 mmol). Then the aryl or heteroaryl halide (1 mmol) if solid and amine if solid (3 mmol) were added. The flask was evacuated and backfilled with nitrogen, with the operation being repeated twice. The halide and amine if liquid, dried toluene (5 ml) were added via syringe at this time. The reaction mixture was stirred at room temperature for 24 h, and filtered through a silica-gel pad that was washed with ethyl acetate. The combined organic phases were evaporated under reduced pressure and the residue purified by silica-gel column chromatography to give the desired product.
With 1-C10H7Ni(P(C6H5)3)2Br; potassium tert-butylate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride; In toluene; at 23℃; for 24h;Inert atmosphere;
An oven-dried 25-mL three-necked flask was charged with KOtBu (4 mmol), Ni(PPh3)2(1-naphthyl)Cl (C-1) (0.05 mmol) and IPr*HCl (0.05 mmol). Then the aryl or heteroaryl halide (1 mmol) if solid and amine if solid (3 mmol) were added. The flask was evacuated and backfilled with nitrogen, with the operation being repeated twice. The halide and amine if liquid, dried toluene (5 ml) were added via syringe at this time. The reaction mixture was stirred at room temperature for 24 h, and filtered through a silica-gel pad that was washed with ethyl acetate. The combined organic phases were evaporated under reduced pressure and the residue purified by silica-gel column chromatography to give the desired product.
84%
With 1H-imidazole; sodium chloride; In water; for 6h;Reflux; Green chemistry;
In a 50-mL, round-bottom flask, 0.87 g (0.01 mol) of morpholine, 0.68 g(0.01 mol) of imidazole, 0.274 g (0.001 mol) of tributylbenzyl ammonium choride,and 1.69 g (0.01 mol) <strong>[615-20-3]2-chlorobenzothiazole</strong> were added to 20mL of 5% NaCl (aqueous)solution. The reaction mixture was refluxed for 6 h. The progress of the reactionwas monitored by thin-layer chromatography (TLC). After completion of the reaction,the aqueous layer was washed with ethyl acetate (310 mL). The combinedorganic layer was dried over anhydrous Na2SO4 and concentrated at reduced pressure.Products were purified either by crystallizing or by flash chromatography. Whitecrystalline solid
66%
With C45H39BrNiOP2; lithium tert-butoxide; phenylboronic acid; In toluene; at 110℃; for 16h;Inert atmosphere; Glovebox; Sealed tube;
General procedure: In a nitrogen atmosphere glove box C1 (5 mol%, 0.05 mmol),phenylboronic acid (5 mol%, 0.015 mmol), LiOt-Bu (1.5 mmol),(hetero)aryl chloride (1 mmol), amine/azole (1.1 mmol), anddry, degassed toluene (10 mL) were added to an oven-dried 4dram vial containing a magnetic stir bar. The vial was sealedwith a screw cap featuring a PTFE/silicone septum and removedfrom the glove box. The reaction mixture was magneticallystirred in a temperature-controlled aluminum heating block setto 110 C for 16 h (unoptimized). The reaction mixture was thencooled to r.t., taken up in EtOAc (ca. 30 mL) and washed withbrine (3 × 50 mL). The organic layer was separated, dried overNa2SO4, filtered, and concentrated with the aid of a rotary evaporatorto afford the crude product, which was purified via chromatographicmethods (see the Supporting Information for completedetails).
In water; at 20℃; for 3.3h;Green chemistry;
General procedure: The reaction was carried out in a 25 mL round bottom flask equipped with magnetic stir bar charged with <strong>[615-20-3]2-chlorobenzothiazole</strong> (1 mmol), aminating agent (2.0 equiv), and water (2 mL). The resulting reaction mixture was stirred at room temperature for 30 min to 5 h (varies with nature of the amine). The reaction progress was monitored by TLC. After the reaction, it was worked up with ethyl acetate. Crude product was purified by column chromatography (for piperazine derivatives column is not required). The identity and purity of the product was confirmed by 1H NMR, 13C NMR, and ESI-MS.
With sodium hydrogencarbonate; In methanol; water; for 12h;Heating / reflux;
Step l0.50 g (5.90 mmol) of piperazine was dissolved in 10 ml of 80% methanol/water in a dried round flask provided with nitrogen gas, 1.0 g (11.9 mmol) of sodium hydrogen carbonate and 0.50 g (3.0 mmol, leq) of <strong>[615-20-3]2-chlorobenzothiazole</strong> was slowly added thereto, and the mixture was refluxed with stirring and heating for 12 hrs. After adding water thereto, the reaction mixture was extracted with ethyl acetate, and the formed organic layer was dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting residue was subjected to silica <n="28"/>gel column chromatography (dichloromethane:methanol=9:l) to obtain 0.61 g of 2-(piperazin-l-yl)benzothiazole (yield: 94%).
With triethylamine; In tetrahydrofuran; at 60 - 70℃; for 2h;Inert atmosphere;
General procedure: To a solution of 2-chlorobenzoxazole (2 g, 13.13 mmol) in THF was added 2-methylaminoethanol (1.47 g, 19.54 mmol) and triethylamine (1.98 g, 19.54 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 60-70C for 2 h and then quenched by addition of water. The mixture was extracted with EtOAc. The extract was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexane/EtOAc = 1/1) to afford the title compound 3 (2.24 g, 89 %) as a white solid.: Rf = 0.20 (n-hexane/EtOAc = 1 : 1); 1H NMR (400 MHz, CDCl3) delta 7.26 (d, 1H, J = 7.6 Hz) 7.18 (d, 1H, J = 7.6 Hz), 7.09 (t, 1H, J = 7.6 Hz), 6.95 (t, 1H, J = 7.6 Hz) 4.12 (s, 1H), 3.85 (t, 2H, J = 5.2 Hz), 3.62 (2H, t, J = 5.2 Hz), 3.18 (s, 3H); 13C NMR (100 MHz, CDCl3) delta 163.0, 148.7, 142.7, 123.9, 120.4, 115.7, 108.7, 60.7, 53.2, 36.6.
General procedure: A mixture of the 2-mercaptobenzo[d]thiazole (>1 g, 1 equiv) and sul-furyl chloride (10 equiv) was stirred at 20-25 C for 15 min. Next, H 2 O(2 equiv) was added and the mixture was stirred at 20-25 C for anadditional 3 h. A sample was taken, quenched with MeCN/H 2 O (2:1)and analyzed by HPLC. After completion of the reaction, the mixturewas diluted with MeCN (5 volumes) and slowly quenched with H 2 O(20 volumes). The product precipitated from the aqueous solution.The solid was collected and washed with H 2 O. Drying under vacuumafforded the pure product. In the case of the liquid product 2-chloro-benzo[d]thiazole (13), the reaction mixture was extracted withEtOAc. The organic layer was then dried and concentrated to affordthe product as an oil.2-Chlorobenzo[d]thiazole (13)Yield: 3.30 g, 19.5 mmol (90%); yellow oil.1 H NMR (400 MHz, DMSO-d 6 ): delta = 7.45-7.62 (m, 2 H), 7.96 (dd, J =8.07, 0.73 Hz, 1 H), 8.09 (dd, J = 7.89, 0.92 Hz, 1 H).13 C NMR (101 MHz, DMSO-d 6 ): delta = 122.81, 122.86, 126.49, 127.47,136.19, 150.91, 153.23. HRMS (ESI): m/z [M + H] + calcd for C 7 H 5 ClNS: 169.9831; found:169.9844.
36.1 g
With hydrogenchloride; dihydrogen peroxide; In water; at 38℃; for 4h;
In a 500 ml reaction flask, 36.4 g of 2-mercaptobenzothiazole and 80 g of water were cast, 29.7 g of 30% hydrochloric acid was added, the temperature was raised to 38 C,48.5g mass fraction of 20% hydrogen peroxide was added dropwise, after the end of incubation was incubated dropwise to detect the bodyWhen the content of 2-mercaptobenzothiazole in the system is less than 0.2%, hydrogen peroxide (about 4h)After the reaction was settled stratification,The upper oily liquid is 2 - chlorobenzothiazole crude,Finally, anhydrous 2 - chlorobenzothiazole dry crude product obtained2-Chlorobenzothiazole fine 36.1g.
4-benzothiazol-2-yl-piperazine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With potassium phosphate; (1,3,5-triaza-7-phosphaadamantan-1-ium-1-yl)butane-1-sulfonate; copper(II) acetate monohydrate In water at 30℃; for 22h; Schlenk technique; Inert atmosphere;
88%
In water at 20℃; for 120h;
tert-Butyl 4-(benzo[d]thiazol-2-yl)piperazine-1-carboxylate (100).
2-Chlorobenzo[d]thiazole (170mg, 1.00mmol) and tert-butyl piperazine-1-carboxylate (373mg, 2.00mmol) were suspended in water (2mL) and stirred for 5dat rt. The precipitate was dissolved in EtOAc, the aqueous phase was extracted 3-times with EtOAc (50mL) and dried over MgSO4. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography on silica (cylcohexane/EtOAc 20:1 → EtOAc) to afford 282mg (0.88mmol, 88%) of 100 as a colorless solid. TLC: RF=0.81 (SiO2, cyclohexane/EtOAc, 1:1); 1H NMR (500MHz, CDCl3, 300K): δ=7.61 (d, 3J=7.9Hz, 1H), 7.56 (d, 3J=8.0Hz, 1H), 7.30 (dt, 3J=7.7, 1.3Hz, 1H), 7.09 (dt, 3J=7.7, 1.2Hz, 1H), 3.64-3.54 (m, 8H), 1.49 (s, 9H) ppm; 13C NMR (126MHz, CDCl3, 300K): δ=168.8, 154.7, 152.7, 130.8, 126.2, 121.8, 120.9, 119.4, 80.6, 48.3, 43.4, 28.5ppm; MS (ESI pos.): m/z (%)=342.18 (65) ([M+Na]+, calcd. 342.13), 320.24 (36) ([M+H]+, calcd. 320.15), 264.19 (100) ([M-Boc+EtOH]+, calcd. 264.12), 220.08 (61) ([M-Boc+H]+, calcd. 220.09).
77%
With 5 wt% ruthenium/carbon; lithium tert-butoxide at 80℃; for 8h;
72 % Chromat.
With tris(dibenzylideneacetone)dipalladium (0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 85℃; for 16h;
Stage #1: 2-chlorobenzo[d][1,3]thiazole; 1-t-Butoxycarbonylpiperazine With macroporous polymer-supported carbonate In dimethyl sulfoxide at 100℃;
Stage #2: With macroporous polymer-supported isocyanate In dichloromethane at 60℃;
With sodium carbonate In N,N-dimethyl-formamide at 100℃;
General Procedure of Amine Synthesis (GP4)
General procedure: GP4-1: A mixture of substituted2-chlorobenzothiazole (1.0eq), N-Bocpiperazine (1.05 eq) and Na2CO3 (1.2 eq) inDMF (10 volume) was heated up at 100 0C for hours, the process ofwhich was monitored by TLC. The mixture was diluted by EA and added by water.After extraction by EA (2 times), the collected organic layers were washed by10% citric acid, and then brine, dried over Na2SO4 andconcentrated to give crude product, which could be used directly withoutfurther purification.GP4-2: N-Bocprotected amine in DCM (5 volume) was added by TFA (2.5 volume). The mixturewas stirred at rt for four hours and monitored by TLC. After consumption ofstarting material, volatile solvent was removed under reduced pressure and theresidue was neutralized by saturated Na2CO3 solution toobtain the slurry, which was extracted by 10% methanol in DCM (3 times). Theorganic layers were collected, dried and concentrated to give the desired freeamine, for direct use for next step.GP4-3: Free amine (1.0 eq) suspendedin DCM (10 volume) was added by aldehyde (1.1 eq) under N2atmosphere. The mixture was stirred at rt 15 min. Then trimethylsilylazide (TMSN3, 1.1 eq) was added, and stirring was kept foranother 15 min, followed by addition of isonitrile (1.0 eq). The mixture wasstirred at for 12 h. After removal of solvent, the residue was purified bypreparative TLC (DCM/MeOH as eluent) to give the product, which could bere-purified by trituration with ether.
With N-ethyl-N,N-diisopropylamine In water; acetonitrile at 0℃; for 2h; Inert atmosphere; Reflux;
13.1 Step 1: Preparation of tert-butyl 4-(benzo[d]thiazole-2-yl)piperazine-1-carboxylate
2.0 g of tert-butyl piperazine-1-carboxylate was dissolved in AN/distilled water (100/50 ml) in a flask with stirring in nitrogen atmosphere, to which 2.1 ml of DIPEA was added at 0° C. 0.9 g of 2-chlorobenzo[d]thiazole was added thereto, followed by heat-reflux for at least 2 hours. Upon completion of the reaction, distilled water was slowly added thereto, followed by extraction using EA. The extracted organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated to give the target compound. (0309) 1H NMR (400 MHz, CDCl3): δ 7.61 (1H, d), 7.60 (1H, d), 7.29 (1H, m), 7.09 (1H, m), 3.77 (4H, m), 2.62 (4H, m), 1.52 (9H, s).
With N-ethyl-N,N-diisopropylamine In water; acetonitrile at 0℃; for 2h; Inert atmosphere; Reflux;
13.1 Preparation of tert-butyl 4-(benzo[d]thiazol-2-yl)piperazine-1-carboxylate
Under a nitrogen atmosphere, 2.0 g of tert-butyl piperazine-1-carboxylate was added to AN/distilled water (100/50 mL) in a flask and stirred to dissolve, and then 2.1 mL of DIPEA was added dropwise at 0□. Thereafter, 0.9 g of 2-chlorobenzo[d]thiazole was added dropwise thereto, and the mixture was heated under reflux for 2 hours or longer. Upon completion of the reaction, distilled water was slowly added dropwise, extracted with EA, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated to give the title compound. (0203) 1H NMR (400MHz, CDCl3) : δ 7.61(1H, d), 7.60(1H, d), 7.29(1H, m), 7.09(1H, m), 3.77(4H, m), 2.62(4H, m), 1.52(9H, s).
With sodium carbonate In N,N-dimethyl-formamide at 100℃;
4.VII tert-butyl 4-(benzothiazol-2-yl)piperazine-1-carboxylate
GP4-1: A mixture of substituted 2-chlorobenzothiazole (1.0 eq), N-Boc piperazine (1.05 eq) and Na2CO3 (1.2 eq) in DMF (10 volume) was heated up at 100° C. for hours, the process of which was monitored by TLC. The mixture was diluted by EA and added by water. After extraction by EA (2 times), the collected organic layers were washed by 10% citric acid, and then brine, dried over Na2SO4 and concentrated to give crude product, which could be used directly without further purification.; tert-butyl 4-(benzothiazol-2-yl)piperazine-1-carboxylate The title compound was prepared according to GP4-1 as off-white solid (11.4 g, 61% yield), which was used without further purification. LC MS (ESI): [M+1]+=320.21, tR=4.24 min.
(R)-(-)-2-(benzo[d]thiazol-2-ylamino)-2-phenylethanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With N-ethyl-N,N-diisopropylamine; 1,2-dichloro-benzene; In toluene; at 195℃; for 24h;Dean-Stark;
A 250 mL round-bottomed flask containing a stirrer bar was chargedwith (R)-2-phenylglycinol [(R)-2; 10.00 g, 72.80 mmol, 1.05 equiv), odichlorobenzene(34.5 mL, 2.0 M), i-Pr2NEt (31.0 mL, 173.6 mmol, 2.5equiv), and <strong>[615-20-3]2-chlorobenzothiazole</strong> (1; 8.60 mL, 69.43 mmol, 1.0equiv). The resulting yellow suspension was stirred vigorously andheated to reflux at 195 C (DrySyn temperature), at which point thesuspended solid had dissolved to leave a yellow solution. After 24 h atreflux,24 the orange reaction mixture was allowed to cool to r.t. Oncecooled, the mixture was diluted with distilled H2O (100 mL) and toluene(75 mL) with vigorous stirring. A precipitate formed over the next15 min and stirring was maintained for a further 1 h. The reactionmixture was filtered through a 1.0 L sintered glass filter funnel (porosity3) under vacuum to leave the solid precipitate. The solid waswashed with toluene (2 × 100 mL) and dried on the sinter under vacuumfor 30 min until a free-flowing powder was obtained. The crudeproduct (typically 22-24 g) was transferred to a 500 mL round-bottomedflask containing a stirrer bar, followed by toluene (100 mL). A10 mL Dean-Stark trap filled with toluene and a reflux condenserwere fitted to the flask, and the suspension heated to reflux (180 CDrySyn temperature). Once at reflux, further 10 mL portions of toluenewere added down the condenser, waiting ~5 min between portions,until a clear solution was obtained (4-6 portions were typicallyneeded). The reflux was maintained until no further H2O was observedcondensing into the trap (typically 30 min were sufficient).The flask was removed from the heating block and allowed to coolslowly to r.t., over which time a precipitate formed. Once cooled, theflask was further cooled to -10 C in a NaCl/ice/water bath for 30 min.The solid precipitate was recovered by vacuum filtration on a 1.0 Lsintered glass filter funnel (porosity 3), and washed with further portionsof toluene (2 × 100 mL). The solid was dried on the sinter undervacuum for 30 min, then transferred to a 250 mL round-bottomedflask and dried in vacuo to constant weight. This gave title compound(R)-3 as fluffy white crystals; yield: 14.81 g (54.78 mmol, 79%). A secondrecrystallisation from toluene at reflux may be required if a powderis obtained from the first attempt. Typical mass loss on secondrecrystallisation was 99% ee.1H NMR (500 MHz, MeOH-d4): delta = 3.80 [1 H, dd, J = 11.4, 7.4 Hz,C(1)HAHB], 3.85 [1 H, dd, J 11.4, 5.0 Hz, C(1)HAHB], 5.00 [1 H, dd, J = 7.4,5.0 Hz, C(2)H], 7.03 (1 H, td, J = 7.5, 1.1 Hz, ArH), 7.22 (1 H, td, J = 7.5,1.2 Hz, ArH), 7.26 (1 H, t, J = 7.4 Hz, p-PhH), 7.34 (2 H, t, J = 7.4 Hz, m-PhH), 7.38 (1 H, d, J = 8.1 Hz, ArH), 7.44 (2 H, d, J = 7.4 Hz, o-PhH), 7.55(1 H, d, J = 7.8 Hz, ArH).13C{1H} NMR (126 MHz, MeOH-d4): delta = 62.2, 66.9, 119.0, 121.7, 122.7,126.8, 128.1, 128.6, 129.5, 131.3, 141.1, 153.0, 169.0.Anal. Calcd for C15H14N2OS: C, 66.64; H, 5.22; N, 10.36. Found: C,66.57; H, 5.31; N, 10.33.1H and 13C NMR data were consistent with literature values.1
With triethylamine; at 180℃; for 0.0833333h;Irradiation;
A mixture of 2-chloro-benzothiazole (2.00 g, 12.0 mmol, 1.0 equiv), ethyl 4-amino-1-piperidine carboxylate (2.44 g, 14.0 mmol, 1.2 equiv) and triethylamine (1.79 g, 18.0 mmol, 1.5 equiv) was heated by microwave irradiation to 180 C. for 5 min. To the crude reaction mixture was added dichloromethane (10 mL) and the suspension quickly poured onto tert-butyl methylether (200 mL). The hydrochloric salts of remaining ethyl 4-amino-1-piperidine carboxylate and triethylamine precipitated out and were removed by filtration. The filtrate was evaporated to dryness and the residue purified with column chromatography on silica eluting with dichloromethane/methanol (95:5) to yield 2.7 g (75%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO): delta 1.19 (t, J=7.1 Hz, 3H), 1.31-1.44 (m, 2H), 1.96-2.01 (m, 2H), 2.98-3.06 (m, 2H), 3.88-3.98 (m, 3H), 4.04 (q, J=7.1 Hz, 2H), 7.01 (t, J=7.4 Hz, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 8.01 (d, J=7.3 Hz, 1H). MS (ISP): 306.0 [M+H]+.
4-benzothiazol-2-yl-1,4-diaza-bicyclo[3.2.2]nonane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
With triethylamine In DMF (N,N-dimethyl-formamide) at 100℃; for 2h;
With triethylamine In chloroform; N,N-dimethyl-formamide
2 4-BENZOTHIAZOL-2-YL-1,4-DIAZA-BICYCLO[3.2.2]NONANE
EXAMPLE 2 4-BENZOTHIAZOL-2-YL-1,4-DIAZA-BICYCLO[3.2.2]NONANE 2-Chlorobenzothiazole (Aldrich, 109 μL, 0.841 mmol) was added to a solution of 1,4-diazabicyclo[3.2.2]nonane (57%, 169 mg, 0.765 mmol), Et3N (213 μL, 1.53 mmol) in DMF (2.5 mL). The reaction mixture was heated at 100° C. for 2 h. The mixture was allowed to cool to RT, diluted with EtOAc and H2O and the layers were partitioned. The aqueous layer was extracted with EtOAc (3*) and the combined organic extracts were washed successively with H2O and brine and then dried (Na2SO4), filtered and concentrated. The crude residue was purified by chromatography (Biotage, 12L) eluding with 5% MeOH in CHCl3 to afford 68 mg (34%) of the title compound as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 7.58 (d, 1H, J=7.9 Hz), 7.57 (d, 1H, J=7.9 Hz), 7.27 (t, 1H, J=8.3 Hz), 7.04 (td, 1H, J=7.9, 1.2 Hz), 4.31 (s, 1H), 3.92 (t, 2H, J=5.8 Hz), 3.19-2.98 (m, 6H), 2.25-2.16 (m, 2H), 1.84-1.77 (m, 2H); MS (Cl) m/z 260.2 (M+1). The hydrochloride salt was prepared by dissolving the title compound in iPrOH and adding 0.1 mL of 6 M hydrochloric acid. The 2-mercaptobenzoxazoles were prepared by two different methods and the general procedures are described in the literature, see: Sato, Y.; Yamada, M.; Yoshida, S.; Soneda, T.; Ishikawa, M.; Nizato, T.; Suzuki, K.; Konno, F. J. Med. Chem. 1998, 41, 3015-3021 and Van Allan, J. A.; Deacon, B. D. Organic Syntheses; Wiley: N.Y., 1963; Collect. Vol. IV, pp 569-70.
With sulfuric acid; nitric acid; In water; at 0 - 5℃; for 3.33333h;
To a solution of 2-CHLOROBENZOTHIAZOLE (12.0 g, 70.7 MMOL) in concentrated H2SO4 (60 mL) was added HN03 (69percent solution, 6 mL) dropwise at 0°C for 20 min. The mixture was stirred at 5°C for 3h, poured into ice-water (150 mL). The precipitate was collected and washed with 5percent sodium bicarbonate and water, dried in VACUO.APOS;H NMR analysis showed the mixture contained 78percent 6-nitro-2-chlorobenzothiazole and 8percent 5-nitro-2- chlorobenzothiazole. Recrystallization from ethanol gave 6-nitro-2-chlorobenzothiazole as white crystalline solid (11 g, 72percent). 3.5 g of the solid was dissolved in refluxing ethanol-acetic acid (150: 15 mL), Iron powder was added in one portion.. The mixture was refluxed for 1.5h, filtered. The filtrate was concentrated in vacuo to half volume and neutralized with 10percent NaOH to pH 7.5, extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and evaporated to give a residue, which was RECRYSTALLIZED from ethanol. Light purple crystals (2.5 g, 83percent) were obtained. Mp 160-164°C ; TLC single spot at Rf 0.27 (30percent EtOAc/hexane) ;APOS;HNMR (270 MHz, DMSO-d6) 5 7.58 (1H, d, J = 9.0 Hz, 4-H), 7.03 (1H, d, J = 2.0 Hz, 7-H), 6.77 (1 H, dd, J = 9.0, 2. 0 Hz, 5-H), 5.55 (2H, s, NH2). The mother liquor from the RECRYSTALLIZATION of nitration product was evaporated and subjected to iron powder reduction as described above. The crude product was purified with flash chromatography (ethyl acetate-DCM gradient elution) to give 2-CHLORO- benzothiazol-5-yl-amine as yellow solid. Mp 146-149°C ; TLC single spot at Rf 0.52 (10percent EtOAc/DCM) ;APOS;HNMR (270 MHZ, DMSO-d6) 8 7.63 (1 H, d, J = 8. 6 HZ, 7-H), 7.05 (1 H, d, J = 2.3 Hz, 4-H), 6.78 (1 H, dd, J = 8.6, 2.3 Hz, 6-H), 5.40 (2H, s, NH2).
With potassium carbonate;tetrabutylammomium bromide; In acetic acid butyl ester; water; at 90 - 100℃; for 5.5h;
Under a nitrogen gas stream, a mixed solution of 10.7 g (18.7 mmol) of Compound (II-1) (hydrochloride), 23.3 g (168.6 mmol) of potassium carbonate, 1.81 g (5.61 mmol) of tetrabutylammonium bromide, 9.52 g (56.3 mmol) of chlorobenzothiazole, 20 mL of butyl acetate and 7.5 mL of water was heated for 5.5 hours at the inside temperature of from 90 to 100oC. The production ratio of Compound (I-18) was 92.8% (HPLC area%, detection wavelength at 254 nm). When the temperature was allowed to cool down to 70oC, 20 mL of water and 20 mL of ethyl acetate were added to separate the reaction mixture into layers. After concentration of the oil layer thus obtained, the concentrate was crystallized from 40 mL of methanol. The crystals thus precipitated were collected by filtration. The resulting crystals were washed with 40 mL of methanol and dried, whereby 12.56 g (yield: 84%, purity: 98. 2%) of Compound (I-1) was obtained.
With potassium carbonate;tetrabutylammomium bromide; In acetic acid butyl ester; water; at 90 - 100℃; for 5h;
Under a nitrogen gas stream, a mixed solution of 10.0 g (18.2 mmol) of Compound (II-1) (containing a 1/2 molecule of methanol as a crystal solvent), 20.7 g (149.6 mmol) of potassium carbonate, 1.81 g (5.61 mmol) of tetrabutylammonium bromide, 9.52 g (56.3 mmol) of chlorobenzothiazole, 20 mL of butyl acetate and 7.5 mL of water was heated for 5 hours at the inside temperature of from 90 to 100oC. The production ratio of Compound (I-1) was 91.7% (HPLC area%, detection wavelength at 254 nm). When the temperature was allowed to cool down to 70oC, 20 mL of water and 20 mL of ethyl acetate were added to separate the reaction mixture into layers. After concentration of the oil layer thus obtained, the concentrate was crystallized from 40 mL of methanol. The crystals thus precipitated were filtered. The resulting crystals were washed with 40 mL of methanol and dried, whereby 11.77 g (yield: 81%, purity: 98.1%) of Compound (I- 1) was obtained.
78%
With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 4h;
To 10.0 g (18.2 mmol) of Compound (II-1) (containing a 1/2 molecule of methanol as a crystal solvent), 10.3 g (74.8 mmol) of potassium carbonate and 12.7 g (74.8 mmol) of chlorobenzothiazole was added 70 mL of DMSO. Under nitrogen bubbling, the resulting mixture was heated for 4 hours at the inside temperature of 80oC. The production ratio of Compound (I-1) was 73.4% (HPLC area%, detection wavelength at 254 nm). After completion of the reaction, the crystals thus precipitated were collected by filtration and washed with 70 mL of DMSO. The crystals were then dispersed in 500 mL of water, filtered and dried, whereby 11.41 g (yield: 78%, purity: 88.1%) of Compound (I-1) was obtained.
77%
With potassium carbonate;tetrabutylammomium bromide; In acetic acid butyl ester; at 100 - 110℃; for 5h;
Under a nitrogen gas stream, a mixed solution of 9.64 g (17.5 mmol) of Compound [(II-1)] (containing a 1/2 molecule of methanol as a crystal solvent), 7.53 g (54.6 mmol) of potassium carbonate, 0.70 g (2.17 mmol) of tetrabutylammonium bromide, 11.81 g (69.6 mmol) of chlorobenzothiazole, and 20 mL of butyl acetate was heated for 5 hours at the inside temperature of from 100 to 110oC. The production ratio of the compound (I-1) was 82.1% (HPLC area%, detection wavelength at 254 nm). When the inside temperature was allowed to cool down to 70oC, 20 mL of water and 20 mL of ethyl acetate were added to separate the reaction mixture into layers. After concentration of the oil layer thus obtained, the concentrate was crystallized from 40 mL of methanol. The crystals thus precipitated were filtered. The resulting crystals were washed with 40 mL of methanol and dried, whereby 10.76 g (yield: 77%, purity: 98. 0%) of Compound (I-1) was obtained. lambdamax=558 nm (DMF solution). m/Z (POSI) =802.
61%
With potassium carbonate;18-crown-6 ether; In acetic acid butyl ester; at 100 - 110℃; for 11h;
Under a nitrogen gas stream, a mixed solution of 9.64 g (17.5 mmol) of Compound (II-1) (containing a 1/2 molecule of methanol as a crystal solvent), 7.53 g (54.6 mmol) of potassium carbonate, 1.39 g (5.25 mmol) of 18-Crown-6, 11. 81 g (69.6 mmol) of chlorobenzothiazole and 20 mL of butyl acetate was heated at the inside temperature of from 100 to [110oC.] After 8 hours, 0.50 g (1.89 mmol) of 18- Crown-6 was added, and 1 hour after the addition, 2.01 [G] (14.5 mmol) of potassium carbonate was added. Two hours after the addition, the production ratio of Compound (I-18) was 77.6% (HPLC area%, detection wavelength at 254 nm). When the temperature was allowed to cool down to 70oC, 20 mL of water and 20 mL of ethyl acetate were added to separate the reaction mixture into layers. After concentration of the oil layer thus obtained, the concentrate was crystallized from 40 mL of methanol. The crystals thus precipitated were filtered. The resulting crystals were washed with 40 mL of methanol and dried, whereby 8.56 g (yield: 61%, purity: 97.9%) of Compound (I- 1) was obtained.
1-[4-(benzothiazol-2-yloxy)benzyl]piperidine-4-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With potassium carbonate; In acetonitrile; at 80℃;
To a stirring solution of 1-(4-hydroxy-benzyl)-piperidine-4-carboxylic acid ethyl ester (508 mg, 1.93 mmol) in CH3CN (15 mL), was added K2CO3 (564 mg, 4.1 mmol) and <strong>[615-20-3]2-chlorobenzothiazole</strong> (0.50 mL, 4.0 mmol). The suspension was heated to 80 C. and stirred overnight. The reaction mixture was allowed to cool to room temperature and then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified on SiO2 (12 g; 0-15% acetone/CH2Cl2) to give a clear and colorless tacky oil (717 mg, 94% yield). TLC (SiO2, 15% acetone/CH2Cl2): Rf=0.5. MS (ESI): mass calculated for C22H24N2O3S, 396.2; m/z found, 397.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 7.92 (d, J=8.0, 1H), 7.68 (d, J=8.0, 1H), 7.48-7.33 (m, 5H), 7.33 (t, J=7.1, 1H), 4.06 (q, J=7.1, 2H), 3.49 (s, 2H), 2.76 (d, J=11.5, 2H), 2.34-2.22 (m, 1H), 2.02 (t, J=11.6, 2H), 1.80 (d, J=10.2, 2H), 1.64-1.54 (m, 2H), 1.18 (t, J=7.1, 3H).
94%
With potassium carbonate; In acetonitrile; at 80℃;
C. 1-[4-(Benzothiazol-2-yloxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester. To a stirring solution of 1- (4-HYDROXY-BENZYL)-PIPERIDINE-4-CARBOXYLIC acid ethyl ester (508 mg, 1.93 MMOL) in CH3CN (15 mL), was added K2CO3 (564 mg, 4.1 MMOL) and 2-CHLOROBENZOTHIAZOLE (0.50 mL, 4. 0 MMOL). The suspension was heated to 80 C and stirred overnight. The reaction mixture was allowed to cool to room temperature and then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified ON SI02 (12 g; 0-15% ACETONE/CH2CI2) TO GIVE a clear and colorless tacky oil (717 MG, 94% yield). TLC (SI02, 15% ACETONE/CH2CI2) : Rf = 0. 5. MS (ESI) : MASS CALCULATED FOR C22H24N203S, 396.2 ; m/z found, 397.3 [M+H] +. 1H NMR (400 MHz, DMSO-D6) : 7.92 (d, J = 8.0, 1 H), 7.68 (d, J = 8.0, 1 H), 7.48-7. 33 (m, 5H), 7. 33 (t, J = 7.1, 1 H), 4.06 (q, J = 7.1, 2H), 3.49 (s, 2H), 2. 76 (d, J = 11.5, 2H), 2.34-2. 22 (m, 1 H), 2.02 (t, J = 11. 6,2H), 1.80 (d, J = 10.2, 2H), 1. 64-1. 54 (m, 2H), 1. 18 (t, J = 7. 1,3H)
(2S)-1-[2-(Benzothiazol-2-ylamino)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 167 (2S)-1-[2-(Benzothiazol-2-ylamino)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile This compound was prepared in analogy to example 166, steps A] to B] starting from 2-chlorobenzothiazole, 1,2-diaminoethane and IIA. It was isolated as its free amine, as a white foam. MS (ISP): 330.4 (MH+).
N-(5-hydroxypentyl)-N-methyl-2-benzothiazolamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium carbonate; In water; 4-methyl-2-pentanone;
a) A mixture of 5-(methylamino)pentanol (0.23 mol), 2-chlorobenzothiazole (0.3 mol), sodium carbonate (0.4 g) and potssium iodide (catalytic quantity) in methylisobutylketon (1000 ml) was stirred and refluxed overnight. The reaction mixture was cooled, washed with water, dried, filtered and the filtrate was evaporated. The residue was stirred in water, acidified with HCl, stirred, washed with diisopropylether, and the acidic layer was alkalized with NH4 OH. This mixture was extracted twice with CH2 Cl2. The separated organic layer was dried, filtered, and the solvent was evaporated, yielding 56 g of N-(5-hydroxypentyl)-N-methyl-2-benzothiazolamine (interm. 7).
48 Example 48
Analog 47: Preparation of 4-( Benzol i/|thiazol-2-ylthio)ani line. 2-Chlorobenzothiazole (2.00 g, 11.8 mmol), 4-aminothiophenol (1.70 g, 13.6 mmol), and potassium carbonate (3.24 g, 23.4 mmol) were stirred together in EtOH (15 mL) for 18 h. The reaction was then diluted with water and the precipitate was filtered, rinsed with water, and collected. Flash chromatographic purification (hexanes :EtO Ac gradient) afforded 47 as an off-white solid (2.71 g, 89% yield). 1 H- NMR (300 MHz, ifc-DMSO) d 7.85-7.91 (m, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.37-7.45 (m, 3H), 7.25-7.34 (m, 1H), 6.66-6.73 (m, 2H), 5.84 (s, 1H); MS (ESI) C13H11N2S2 [MH]+ m/z expected = 259.0, observed = 259.0; HPLC-l = >99%.
85%
Stage #1: 2-chlorobenzo[d][1,3]thiazole With (1,3,5-triaza-7-phosphaadamantan-1-ium-1-yl)butane-1-sulfonate; palladium diacetate In N,N-dimethyl-formamide for 0.0833333h; Schlenk technique; Inert atmosphere;
Stage #2: 4-aminotiophenol With tripotassium phosphate tribasic In N,N-dimethyl-formamide at 50℃; for 2h; Schlenk technique; Inert atmosphere;
50%
With potassium carbonate In ethanol for 18h;
4.3.1. 4-(Benzo[d]thiazol-2-ylthio)aniline (4)
General procedure: The solution of 2-chlorobenzothiazole SM3 (845 mg, 5.0 mmol), 4-aminothiophenol SM4 (620 mg, 5.0 mmol), and potassium carbonate (1.4 g, 10.0 mmol) in EtOH (10 mL) were stirred for 18 h. The reaction was then diluted with water and the precipitate was filtered, rinsed with water, and dried. The crude product was purified by column chromatography on silica gel (petroleum ether/ EtOAc, gradient) to afford 4 as an off-yellow powder (642 mg, 50% yield). 4.3.2. 2
With potassium carbonate In ethanol; hexane; ethyl acetate
12 1-[4-(2-Benzothiazolylthio)phenyl]-3-(4-chloro-3-trifluoromethylphenyl)thiourea
The necessary amine starting material was prepared as follows: 2-Chlorobenzothiazole (0.06 moles, 10.1 g), 4-aminothiophenol (0.06 moles, 7.5 g) and potassium carbonate (0.06 moles, 8.3 g) were stirred for 3 days at room temperature in 250 ml ethanol, filtered, and concentrated. Ethyl acetate was added and the solution washed with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with 40-60% ethyl acetate in hexane to yield 2-(4-aminophenylthio)benzothiazole 13.7 g, 88%. Mass spec (FD) 258. Calculated for C11 H10 N2 S2: C, 60.44; H, 3.90; N, 10.84. Found: C, 60.63; H, 3.98; N, 11.01.
With potassium carbonate In ethanol; hexane; ethyl acetate
12 1-[4-(2-Benzothiazolylthio)phenyl]-3-(4-chloro-3-trifluoromethylphenyl)thiourea
The necessary amine starting material was prepared as follows: 2-Chlorobenzothiazole (0.06 moles, 10.1 g), 4-aminothiophenol (0.06 moles, 7.5 g) and potassium carbonate (0.06 moles, 8.3 g) were stirred for 3 days at room temperature in 250 ml ethanol, filtered, and concentrated. Ethyl acetate was added and the solution washed with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with 40-60% ethyl acetate in hexane to yield 2-(4-aminophenylthio)benzothiazole 13.7 g, 88%. Mass spec (FD) 258. Calculated for C11 H10 N2 S2: C, 60.44; H, 3.90; N, 10.84. Found: C, 60.63; H, 3.98; N, 11.01.
2-(benzothiazol-2-ylthio)-2-phenylacetic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N,N-dimethyl-formamide;
EXAMPLE 48 18.2 g of 2-mercapto-2-phenylacetic acid methyl ester is added to a suspension of 2.4 g of NaH in 200 ml of DMF and the mixture is stirred until the evolution of gas has ceased. 17 g of 2-chlorobenzothiazole (or 21.5 g of <strong>[2516-40-7]2-<strong>[2516-40-7]bromobenzothiazole</strong></strong>) is then introduced. The mixture is stirred for 5 hours at 80° and is worked up in the customary manner to give 2-(benzothiazol-2-ylthio)-2-phenylacetic acid methyl ester, in the form of an oil.
With lithium chloride;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride; In tetrahydrofuran; 1,2-dimethoxyethane; at 20℃; for 1h;Product distribution / selectivity;
A vial was charged with Ih (7 mg, 2 mol %) and LiCl (67.0 mg, 1.6 mmol) as necessary followed by a stirbar under an inert atmosphere. The vial was then sealed with a septum and purged under an inert atmosphere after which DME (0.8 mL) was added and the suspension was stirred until 1 h had dissolved. After this time, the organohalide (0.5 mmol) and the organomagnesium (0.8 mL, 1.0 M in THF or ether, 0.8 mmol) were added (active catalyst is indicated by the reaction solution turning orange). The septum was replaced with a Teflon-lined screw cap under an inert atmosphere and the reaction stirred at RT or warmed to 60 or 70 C. until complete. After this time, the mixture was diluted with a suitable organic solvent (15 mL) and washed successively with 1 M Na3EDTA solution (prepared from EDTA and 3 equiv of NaOH), water and brine. After drying (anhydrous MgSO4) the solution was filtered, the solvent removed in vacuo, and the residue purified by flash chromatography. A summary of the substrate scope that was explored is presented in Table 8.
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 50h;
Example 76; meso-8-[4-(Benzothiazol-2-yloxy)-2-fluoro-benzyl]-3,8-diaza-bicyclo[3.2.1]octane-3-carboxylic acid amide Step A: 4-(Benzothiazol-2-yloxy)-2-fluoro-benzoic acid. A solution of <strong>[65145-13-3]2-fluoro-4-hydroxy-benzoic acid</strong> (4.0 g, 25.6 mmol) in DMF (250 mL) was added Cs2CO3 (9.2 g, 28.2 mmol) and the reaction mixture was stirred at 80 C. for 1 h prior to the addition of 2-chloro-benzothiazole (3.3 mL, 25.6 mmol). The reaction mixture was stirred at 100 C. for 50 h, then cooled to rt, and the solid was filtered. The filtrate was diluted with EtOAc (200 mL) and water (100 mL), neutralized with 1 M HCl and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×200 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated to afford the title compound as a colorless solid (4.7 g, 63%). MS (ESI): mass calcd. for C14H8FNO3S, 289.0; m/z found, 290.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.21 (t, J=8.5 Hz, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.11 Hz, 1H), 7.63-7.45 (m, 4H).
With copper(ll) sulfate pentahydrate; ethane-1,2-dithiol; potassium hydroxide; In water; dimethyl sulfoxide; at 110℃; for 20h;Inert atmosphere;
General procedure: A test tube equipped with a magnetic stir bar was charged with an aryl halide(aryl halide, 1 mmol),CuSO4.5H2O(12.5 mg, 0.05 mmol),KOH (280 mg, 5 mmol) orCs2CO3 (1.62 g, 5 mmol), DMSO (2 mL), and water (0.2 mL; water was not used in case of using Cs2CO3 as base).After flushing with argon, 1,2-ethanedithiol (0.18 mL, 2 mmol) was added.The mixture was heated in a preheated oil bath for 20 hours90 C or 110 C bath which is pre-heated with agitation.After cooling to ambient temperature, the reaction mixture was distributed in aqueous HCl (5%) and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography (EtOAc / n-Hexane) to give the aryl thiol (see Table 2 below).
2-Cyanobenzothiazole: A suspension of potassium cyanide (1.50 g, 23.0 mmol) in dimethylsulfoxide (DMSO, 100 mL) was prepared in a 1-L 3-necked flask fitted with a reflux condenser, a heating mantle and an internal temperature probe. The 2-chlorobenzothiazole (2.6 g, 2.0 mL, 15.3 mmol) was added to the reaction flask via pipet and the reaction was heated at 80 C. (internal temperature). The reaction was monitored periodically by TLC (9:1 heptane-ethyl acetate). After 5 hours the reaction appeared to be about 50% complete. After 17 hours the reaction was judged complete by TLC analysis. The reaction mixture was allowed to cool to room temperature and was then extracted with ether (5×100 mL). The extracts were dried over sodium sulfate and concentrated to give a yellow-orange solid. The crude solid was purified on silica gel (100 g) using 9:1 heptane-ethyl acetate. Fractions containing product were pooled and concentrated to give 1.4 g (57%) of the desired product as a yellow-orange solid. The structure was confirmed by 1H NMR analysis in DMSO-d6
With sodium carbonate;trans-bis(triphenylphosphine)palladium dichloride; In toluene; for 3h;Reflux;
In toluene (100 mL), dissolved were 2-chlorobenzo[d]thiazole (10.0 g, 59.0 mmol), 4-chlorophenylboronic acid (11.1 g, 70.7 mmol), and trans-dichlorobis(triphenylphosphine)palladium (II) (Pd(PPh3)2Cl2 (4.2 g, 5.9 mmol). To the solution, added was 2M sodium carbonate solution (87 mL), and the resultant mixture was stirred under reflux for 3 hours.After the reaction was completed, the reaction mixture was cooled to room temperature, and extracted with ethyl acetate (300 mL). The extract was dried under reduced pressure and recrystallized from dichloromethane (100 mL) and hexane (100 mL) to obtain 2-(4-chlorophenyl)benzo[d]thiazole (13.0 g, 53.1 mmol, yield: 90%).
81%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; for 4h;Reflux;
2-chlorobenzo[d]thiazole (50 g, 295.9 mmol) and (4-chlorophenyl)boronic acid (50.8 g, 325.5 mmol) were dispersed in tetrahydrofuran (500 ml), aqueous solution of 2M potassium carbonate (aq. K2CO3) (444 ml, 887.7 mmol) was added and tetrakis(triphenylphosphine)palladium [Pd(PPh3)4] (10.3 g, 3 mol%) was added.After stirring, the mixture was refluxed for 4 hours. The temperature was lowered to room temperature and the resulting solid was filtered.The filtered solid was recrystallized with tetrahydrofuran and ethyl acetate, filtered and dried to give Compound B-1 (58.7 g, Yield 81%)
61%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; for 12h;Reflux; Inert atmosphere;
2-chlorobenzo [d] thiazole (30.0 g, 177.5 mmol) and (4-chlorophenyl) boron in a nitrogen atmosphere((4-chlorophenyl) boronic acid) (27.7 g, 177.5 mmol) was added to 300 ml of tetrahydrofuran and stirred andIt was refluxed. After dissolving potassium carbonate (73.6 g, 532.6 mmol) in 100 ml of water, stirred sufficiently and thenRakistriphenyl-phosphinopalladium (6.2 g, 3 mol%) was added. After reaction for 12 hours, lower the temperature to room temperatureAfter separating the base layer and the water layer, the organic layer was distilled under reduced pressure. The distillate was extracted with chloroform and water and the organic layer wasDried over sodium. The organic layer was dried and recrystallized with ethyl acetate to prepare C-3 (26.5 g, 61%).
With potassium carbonate;palladium diacetate; triphenylphosphine; In 1,2-dimethoxyethane; water; at 100℃; for 22h;Inert atmosphere;
(4a) t-Butyl 2-(1,3-benzothiazol-2-yl)-1H-pyrrole-1-carboxylate Commercially available 1-(t-butoxycarbonyl)pyrrole-2-boronic acid (417 mg, 1.98 mmol) was dissolved in 1,2-dimethoxyethane (20 mL), and 2-chloro-1,3-benzothiazole (0.25 mL, 2.02 mmol), palladium (II) acetate (23.0 mg, 0.102 mmol), triphenylphosphine (105 mg, 0.400 mmol) and an aqueous potassium carbonate solution (3M, 1.3 mL, 0.433 mmol) were added, followed by stirring at 100C for 22 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) and ethyl acetate (20 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-20%) to afford the desired compound (490 mg, yield 82%) as a pale yellow oil. 1H-NMR (CDCl3, 400 MHz): delta 1.38 (9H, s), 6.30 (1H, t, J=3.1 Hz), 6.72 (1H, dd, J=2.0, 3.1 Hz), 7.39 (1H, ddd, J=1.2, 7.0, 8.0 Hz), 7.46 (1H, dd, J=2.0, 3.1 Hz), 7.49 (1H, ddd, J=1.2, 7.0, 8.0 Hz), 7.89 (1H, brd, J=8.0 Hz), 8.05 (1H, dt, J=1.2, 8.0 Hz).
1-(tert-Butoxycarbonyl)piperidin-3-ylmethanol (300 mg, 1.39 mmol) was dissolved in N,N-dimethylformamide (5 mL). While this solution was chilled in an ice bath, 60% sodium hydride in oil (83.6 mg, 2.09 mmol) was added. The reaction mixture was stirred for 10 min while ice-chilled and for another 10 min at room temperature. 2-chlorobenzothiazole (0.344 mL, 2.78 mmol) and sodium iodide (208 mg, 1.39 mmol) were then added and the mixture was stirred at room temperature for 5 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract was washed with brine. The washed product was then dried over magnesium sulfate and the solvent was evaporated. Purification of the resulting residue by silica gel column chromatography (hexane : ethyl acetate = 20:1 -> 5:1) gave 460 mg (95%) of the desired compound as a colorless powder. 1H NMR (400 MHz, DMSO-d6) delta 1.25-1.45 (11H, m), 1.56-1.67 (1H, m), 1.75-1.85 (1H, m), 1.93-2.06 (1H, m), 2.59-3.11 (2H, m), 3.53-4.07 (2H, m), 4.38-4.48 (2H, m), 7.28 (1H, td, J = 7.9, 1.2 Hz), 7.40 (1H, td, J = 7.9, 1.2 Hz), 7.66 (1H, d, J = 7.3 Hz), 7.88 (1H, dd, J = 7.9, 1.2 Hz).
With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 120℃; for 1h;Microwave irradiation;
A toluene solution of 6-amino-2N-Boc-1,2,3,4-tetrahydroisoquinoline (248 mg), 2-chlorobenzothiazole (186 mg), palladium acetate (22 mg), cesium carbonate (651 mg), and Xanphos (58 mg) was stirred at 120C for 1 hour under microwave irradiation. The reaction solution was purified by column chromatography to obtain the title compound (381 mg, quantitative yield). 1H NMR (400 MHz, CDCl3) : delta (ppm) = 7.77 (1H, d, J = 8.2 Hz), 7.69 (1H, d, J = 7.8 Hz), 7.40-7.29 (3H, m), 7.25-7.19 (2H, m), 4.69 (2H, s), 3.70 (2H, t, J = 5.3 Hz), 2.90 (2H, t, J = 5.7 Hz), 1.50 (9H, s).
Synthetic Example 24; Methyl (S)-2-(benzothiazol-2-yl)amino-4-acetylthio-butyrate; Step 1 : (S)-2-fBenzo[dlthiazol-2-ylamino)-4-hydroxybutanoic acid, and (RV3-rBenzordlthiazol-2-ylamino)dihvdrofuran-2r3HVone; To a mixture of <strong>[672-15-1]L-homoserine</strong> (6.0 g, 50.5 mmol) and K2CO3 (27.9 g, 0.2 mol) in DMSO (30 mL), was added 2-chlorobenzothiazole (17.1 g, 101 mmol). After stirring for 19 h at 900C, the reaction mixture was poured into saturated aqueous NaHCO3 (150 mL) and extracted with ethyl acetate (3 x 150 mL). The aqueous layer was acidified to pH 5 using 6N HCl and then NaCl solution was added and the product extracted into ethyl acetate/THF (1 :1) (3 x 200 mL). The combined organic extracts were dried over Na2SO4 and evaporated to give the two title compounds as brown oil (14.4 g, crude), which were used in the next step directly.(S)-2-(benzo[d]thiazol-2-ylamino)-4-hydroxybutanoic acid: 1H-NMR (CDCl3, ppm, 500 MHz): delta = 7.58 (d, J= 7.5 Hz, IH), 7.49 (d, J= 8.0 Hz5 IH), 7.36 (t, J= 7.0 Hz, IH), 7.19 (t, J= 7.0 Hz, IH), 4.35 (br s, IH), 3.93-3.98 (m, IH), 3.84- 3.89 (m, IH), 2.28 (br s, 2H). ESI-MS: 253.0(M++H). HPLC purity: 78.4 % (214 nm). <n="115"/>(R)-3-(berizo[d]thiazol-2-ylamino)dihydrofuran-2(3H)-one: 1H-NMR (CDCl3, ppm, 500 MHz): delta = 7.58 (dd, J= 7.5 and 3.5 Hz, 2H), 7.31 (t, J= 8.0 Hz, IH), 7.13 (t, J= 8.0 Hz, IH), 4.71-4.76 (m, IH), 4.54 (t, J= 8.5 Hz, IH), 4.34-4.39 (m, IH), 3.08-3.13 (m, IH), 2.27-2.36 (m, IH). ESI-MS: 235.1(MVH). HPLC purity: 7.4 % (214 nm).
Synthetic Example 24; Methyl (S)-2-(benzothiazol-2-yl)amino-4-acetylthio-butyrate; Step 1 : (S)-2-fBenzo[dlthiazol-2-ylamino)-4-hydroxybutanoic acid, and (RV3-rBenzordlthiazol-2-ylamino)dihvdrofuran-2r3HVone; To a mixture of <strong>[672-15-1]L-homoserine</strong> (6.0 g, 50.5 mmol) and K2CO3 (27.9 g, 0.2 mol) in DMSO (30 mL), was added 2-chlorobenzothiazole (17.1 g, 101 mmol). After stirring for 19 h at 900C, the reaction mixture was poured into saturated aqueous NaHCO3 (150 mL) and extracted with ethyl acetate (3 x 150 mL). The aqueous layer was acidified to pH 5 using 6N HCl and then NaCl solution was added and the product extracted into ethyl acetate/THF (1 :1) (3 x 200 mL). The combined organic extracts were dried over Na2SO4 and evaporated to give the two title compounds as brown oil (14.4 g, crude), which were used in the next step directly.(S)-2-(benzo[d]thiazol-2-ylamino)-4-hydroxybutanoic acid: 1H-NMR (CDCl3, ppm, 500 MHz): delta = 7.58 (d, J= 7.5 Hz, IH), 7.49 (d, J= 8.0 Hz5 IH), 7.36 (t, J= 7.0 Hz, IH), 7.19 (t, J= 7.0 Hz, IH), 4.35 (br s, IH), 3.93-3.98 (m, IH), 3.84- 3.89 (m, IH), 2.28 (br s, 2H). ESI-MS: 253.0(M++H). HPLC purity: 78.4 % (214 nm). <n="115"/>(R)-3-(berizo[d]thiazol-2-ylamino)dihydrofuran-2(3H)-one: 1H-NMR (CDCl3, ppm, 500 MHz): delta = 7.58 (dd, J= 7.5 and 3.5 Hz, 2H), 7.31 (t, J= 8.0 Hz, IH), 7.13 (t, J= 8.0 Hz, IH), 4.71-4.76 (m, IH), 4.54 (t, J= 8.5 Hz, IH), 4.34-4.39 (m, IH), 3.08-3.13 (m, IH), 2.27-2.36 (m, IH). ESI-MS: 235.1(MVH). HPLC purity: 7.4 % (214 nm).; Step 2: (SV2-fBenzothiazol-2-yl)amino-4-bromo-butyric acid; 45% HBr in acetic acid (30 mL) was added to a mixture of compounds (S)-2-(benzo[d]thiazol-2-ylamino)-4-hydroxybutanoic acid, and (R)-3- (benzo[d]thiazol-2-ylamino)dihydrofuran-2(3H)-one (7.0 g, crude) and the mixture was stirred for 2 h at 80 C. The mixture was evaporated to afford (S)-2-(benzothiazol-2-yl)amino-4-bromo-butyric acid as a brown oil (7.7 g, crude), which was used directly in the next step. 1H-NMR (DMSOd6, ppm, 500 MHz): delta = 8.03 (d, J= 7.5 Hz, IH), 7.66 (d, J= 8.0 Hz, IH), 7.59 (t, J= 8.0 Hz, IH), 7.44 (t, J= 7.5 Hz, IH), 4.66 (q, J= 7.5 Hz, IH), 4.25-4.30 (m, IH), 4.18-4.23 (m, IH), 2.52-2.56 (m, IH), 2.32-2.39 (m, IH). ESI-MS: 316.0 (M+-HH). HPLC purity: 53.4 % (214 nm).
With N-ethyl-N,N-diisopropylamine; 1,2-dichloro-benzene; In toluene; at 195℃; for 24h;Dean-Stark;
General procedure: A 250 mL round-bottomed flask containing a stirrer bar was chargedwith (R)-2-phenylglycinol [(R)-2; 10.00 g, 72.80 mmol, 1.05 equiv), odichlorobenzene(34.5 mL, 2.0 M), i-Pr2NEt (31.0 mL, 173.6 mmol, 2.5equiv), and <strong>[615-20-3]2-chlorobenzothiazole</strong> (1; 8.60 mL, 69.43 mmol, 1.0equiv). The resulting yellow suspension was stirred vigorously andheated to reflux at 195 C (DrySyn temperature), at which point thesuspended solid had dissolved to leave a yellow solution. After 24 h atreflux,24 the orange reaction mixture was allowed to cool to r.t. Oncecooled, the mixture was diluted with distilled H2O (100 mL) and toluene(75 mL) with vigorous stirring. A precipitate formed over the next15 min and stirring was maintained for a further 1 h. The reactionmixture was filtered through a 1.0 L sintered glass filter funnel (porosity3) under vacuum to leave the solid precipitate. The solid waswashed with toluene (2 × 100 mL) and dried on the sinter under vacuumfor 30 min until a free-flowing powder was obtained. The crudeproduct (typically 22-24 g) was transferred to a 500 mL round-bottomedflask containing a stirrer bar, followed by toluene (100 mL). A10 mL Dean-Stark trap filled with toluene and a reflux condenserwere fitted to the flask, and the suspension heated to reflux (180 CDrySyn temperature). Once at reflux, further 10 mL portions of toluenewere added down the condenser, waiting ~5 min between portions,until a clear solution was obtained (4-6 portions were typicallyneeded). The reflux was maintained until no further H2O was observedcondensing into the trap (typically 30 min were sufficient).The flask was removed from the heating block and allowed to coolslowly to r.t., over which time a precipitate formed. Once cooled, theflask was further cooled to -10 C in a NaCl/ice/water bath for 30 min.The solid precipitate was recovered by vacuum filtration on a 1.0 Lsintered glass filter funnel (porosity 3), and washed with further portionsof toluene (2 × 100 mL). The solid was dried on the sinter undervacuum for 30 min, then transferred to a 250 mL round-bottomedflask and dried in vacuo to constant weight. This gave title compound(R)-3 as fluffy white crystals; yield: 14.81 g (54.78 mmol, 79%). A secondrecrystallisation from toluene at reflux may be required if a powderis obtained from the first attempt. Typical mass loss on secondrecrystallisation was 99% ee.1H NMR (500 MHz, MeOH-d4): delta = 3.80 [1 H, dd, J = 11.4, 7.4 Hz,C(1)HAHB], 3.85 [1 H, dd, J 11.4, 5.0 Hz, C(1)HAHB], 5.00 [1 H, dd, J = 7.4,5.0 Hz, C(2)H], 7.03 (1 H, td, J = 7.5, 1.1 Hz, ArH), 7.22 (1 H, td, J = 7.5,1.2 Hz, ArH), 7.26 (1 H, t, J = 7.4 Hz, p-PhH), 7.34 (2 H, t, J = 7.4 Hz, m-PhH), 7.38 (1 H, d, J = 8.1 Hz, ArH), 7.44 (2 H, d, J = 7.4 Hz, o-PhH), 7.55(1 H, d, J = 7.8 Hz, ArH).13C{1H} NMR (126 MHz, MeOH-d4): delta = 62.2, 66.9, 119.0, 121.7, 122.7,126.8, 128.1, 128.6, 129.5, 131.3, 141.1, 153.0, 169.0.Anal. Calcd for C15H14N2OS: C, 66.64; H, 5.22; N, 10.36. Found: C,66.57; H, 5.31; N, 10.33.1H and 13C NMR data were consistent with literature values.1
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 2h;microwave;
A mixture of (l S,3S)-3-aminocyclobutanol hydrochloride (120 mg, 0.98 mmol, 1.0 eqv), 2-chloro-benzothiazole (purchased from ALDRICH) (169 mg, 1 mmol, 1.02 eqv ) and DIEA (286 mg, 2 mmol, 2.04 eqv) in NMP (2 mL) was heated to 180C for 2 hours in microwave. To the reaction mixture was added water, and the residue was extracted with EtOAc (30 mL). The combined organic layer was washed with brine and dried over Na2S04. The organic layers were concentrated and purified by column chromatography on silica gel to give (lS,3S)-3-(benzo[d]thiazol-2-ylamino)cyclobutanol (160 mg, 0.72 mmol, yield 73%). ESI-MS (M+l): 221 calc. for CnHi2N2OS 221.
With hydrogenchloride; In 1,4-dioxane; ethanol; at 120℃; for 1h;Microwave irradiation;
Preparation of intermediate 1A:N-(4-bromophenyl)benzothiazol-2-ylamine2-chlorobenzothiazole (1.24 mL, 10 mmol), 4-bromoaniline (1.72g, 10 mmol) were dissolved in ethanol, to which was added a solution of 4 N hydrochloric acid in 1 ,4-dioxane (1 mL, 4 mmol). Under microwave irradiation, the reaction proceeded at 120C for 1 h. The mixture was cooled to room temperature and filtered. The precipitate was washed with a small amount of ethanol and dried to give 2.13 g of 1A. Yield: 70.0%. MS (ESI, m/z): [M+H]+: 304.9; 1H-NMR (300 MHz, OMSO-d6): 10.62 (s, 1 H), 7.78-7.83 (m, 3H), 7.63 (d, 1H, J = 8.1 Hz), 7.51 -7.56 (m, 2H), 7.3 1 -7.36 (m, 1H), 7.15-7.20 (m, 1H).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water;
Starting material 2-(2,5-dimethylphenyl)-benzothiazole was prepared by the reaction of 1 - chlorobenzothiazole with <strong>[85199-06-0]2,5-dimethylphenylboronic acid</strong> using Suzuki-Miyaura coupling methods with Pd(PPh3)4 (5 mol%) as the catalyst and K2C03 (3 equiv) as the base in degassed THF and water (3: 1) mixture. NMR and 13C NMR data agreed with those previously reported for this compound (H. Hachiva, et al. Org. Lett. 2009, 11, 1737). H-BuLi (0.57 mL, 0.92 mmol) was added to a mixture solution of 2-(2,5-dimethylphenyl)benzothiazole (200 mg, 0.84 mmol) and TMEDA (0.25 mL, 1.67 mmol) in THF (50mL) at -78C. After stirring the mixture at -78C for 2 hrs, BMes2F (268 mg, 1.00 mmol) was added. After being stirred for 1 hr at -78C, the mixture was allowed to warm up to room temperature and stirred for another 16 hrs. After the removal of the solvent, the residue was washed with water and extracted with CH2C12. After the hydrophobic phase was dried over MgS04 and filtered, it was purified by column chromatography on silica gel to afford BN-3 as a white solid (285 mg, 70% yield). NMR (C6D6, 500 MHz): delta 8.17 (d, J=8.2 Hz, IH), 7.34 (s, IH), 7.16 (m, IH), 7.00 (d, J=7.7 Hz, IH), 6.92 (s, 4H), 6.86 (m, 2H), 6.75 (d, J=7.8 Hz IH), 3.29 (s, 2H), 2.31 (s, 12H), 2.28 (s, 6H), 1.94 (s, 3H). 13C NMR (CD2C12 ,125 MHz): delta 172.31, 149.66, 147.93, 144.67, 141.87, 134.44, 134.25, 133.45, 130.56, 129.88, 129.64, 128.08, 127.25, 126.86, 126.08, 122.00, 121.98, 77.51, 24.65, 20.50, 20.30. UB NMR (CD2C12, 160 MHz): delta 2.09; HR-EIMS (m/z): [MH+] calcd. for C33H34BNS, 488.25778; found 488.25654. Elemental analysis, calcd: C 81.30, H 7.03, N 2.87, S 6.58; found: C 81.29, H 7.13, N 2.87, S 6.57.
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 1h;
[001084] In an oven-dried 2-dram vial equipped with a stir bar, tert-butyl azetidin-3- ylcarbamate (20 mg, 0.116 mmol) and 2-chlorobenzothiazole (22 mg, 0.131 mmol) were massed and dissolved in DMF (2 mL) at ambient temperature. Sodium hydride (60% dispersion in mineral oil, 10 mg, 0.25 mmol) was added and the reaction was allowed to stir at ambient temperature for 1 hr and monitored by LCMS. Upon complete consumption of the starting material, the reaction was quenched with 0 (1 mL). The reaction mixture was diluted into DCM/H20 (20 mL, 1 : 1). The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 10 mL). The combined organic fractions were dried over MgS04, filtered, and concentrated under reduced pressure to afford tert-butyl (1- (benzo[d]thiazol-2-yl)azetidin-3-yl)carbamate (LCMS: RT = 0.549 min, m/z = 306 [M+H]+). The crude product was carried forward without further purification.
With dmap; N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 110℃; for 2h;
Tert-butyl(trans-3-aminocyclobutyl)carbamate (1.48 g, 7.95 mmol), 2-chlorobenzothiazole (1.6 ml, 12.93 mmol), 4-dimethylaminopyridine (0.051 g, 0.417 mmol), and diisopropylethylamine (3.0 ml, 17.25 mmol) were suspended in dry dimethylsulfoxide (5 mL) under nitrogen. The mixture was heated at 110 C. for 2 hours then cooled to room temperature. Then, the mixture was partitioned between 30% saturated ammonium chloride (300 mL) and ethyl acetate (300 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude product was triturated with 1:1 dichloromethane:hexane (50 mL total) at 40 C. The mixture was filtered through a sintered glass frit and the solids washed with additional 1:1 dichloromethane:hexane (10 mL) before drying under high vacuum to give tert-butyl(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl) carbamate (2.063 g, 6.46 mmol, 81% yield) as an off white solid
With triethylamine; at 80℃; for 0.5h;Flow reactor; Inert atmosphere;
[0381] A four-necked reactor equipped with a thermometer was charged with 2.0 g (10.3 mmol) of <strong>[20570-96-1]benzyl hydrazine dihydrochloride</strong> and 10 ml of tTriethylamine under a nitrogen stream to prepare a homogeneous solution. After the addition of 3.48 g (20.5 mmol) of 2-chlorobenzothiazole to the solution, the mixture was stirred at 80C for 30 minutes. After completion of the reaction, the reaction mixture was cooled to 20C, added to 100 ml of a saturated sodium hydrogen carbonate aqueous solution, and extracted with 200 ml of ethyl acetate. After drying the ethyl acetate layer over anhydrous sodium sulfate, sodium sulfate was filtered off. Ethyl acetate was evaporated from the filtrate under reduced pressure using a rotary evaporator to obtain a yellow solid. The yellow solid was purified by silica gel column chromatography (n-hexane:ethyl acetate=75:25 (volume ratio)) to obtain 1.76 g of an intermediate a as a white solid (yield: 66.9%). [0382] The structure of the target product was identified by 1H-NMR. [0383] 1H-NMR (400 MHz, CDCl3, TMS, delta ppm): 7.62 (dd, 1H, J=0.8 Hz, 7.7 Hz), 7.57 (d, 1H, J=8.1 Hz), 7.28-7.39 (m, 6H), 7.09 (ddd, 1H, 1=1.1 Hz, 7.5 Hz, 7.7 Hz), 5.00 (s, 2H), 4.07 (s, 2H).
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 7h;
A solution of 3-(4-piperidyl)propan-1 -ol (5 g, 35 mmol), 2-chlorobenzothiazole (6.5 g, 38.4 mmol, 1 .1 eq.) and DIPEA (7.6 mL, 43.6 mmol, 1.25 eq.) in dry DMF (50 mL) was stirred at 90 ^ for 7 hours. After the mixture was allowed to cool down, water (100 mL) was added and the mixture was extracted with ethyl acetate (4 X 200 mL). The combined organic phases were dried over MgS04 and concentrated under reduced pressure. The product was purified by successive precipitation with ethyl acetate and hexane to afford 3-[1 -(1 ,3-benzothiazol-2-yl)-4-piperidyl]propan-1 -ol (6.66 g, 69percent). ESI-MS m/z: 277 ([M+H]+) 100percent); RT = 3.12 min (Method 1 ).
General procedure: In a 50 mL round bottom flask, 0.86 gm (0.01 mol) of piperazine and 1.58 gm(0.01 mol) of <strong>[142-64-3]piperazine dihydrochloride</strong> were added in 20 mL of water and stirred forhalf hour. 0.68 gm (0.01 mol) of Imidazole, 0.274 gm (0.001 mol) of tributylbenzylammonium choride, 1.69 gm (0.01 mol) 2-chlorobenzothiazole and 2gm NaCl(aq) wereadded in the reaction mixture and refluxed for 10 hrs. The progress of reaction wasmonitored by TLC. After completion of the reaction, aqueous layer was washed withethyl acetate (3 x 10 ml). The combined organic layer was dried over anhydrous Na2SO4and concentrated at reduced pressure. Products were purified either by crystallizing or byflash chromatography.
(±)-2-(benzo[d]thiazol-2-ylamino)-2-phenylethanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With N-ethyl-N,N-diisopropylamine; 1,2-dichloro-benzene In toluene at 195℃; for 24h; Dean-Stark;
(R)-(-)-2-(Benzo[d]thiazol-2-ylamino)-2-phenylethanol [(R)-3]
General procedure: A 250 mL round-bottomed flask containing a stirrer bar was chargedwith (R)-2-phenylglycinol [(R)-2; 10.00 g, 72.80 mmol, 1.05 equiv), odichlorobenzene(34.5 mL, 2.0 M), i-Pr2NEt (31.0 mL, 173.6 mmol, 2.5equiv), and 2-chlorobenzothiazole (1; 8.60 mL, 69.43 mmol, 1.0equiv). The resulting yellow suspension was stirred vigorously andheated to reflux at 195 °C (DrySyn temperature), at which point thesuspended solid had dissolved to leave a yellow solution. After 24 h atreflux,24 the orange reaction mixture was allowed to cool to r.t. Oncecooled, the mixture was diluted with distilled H2O (100 mL) and toluene(75 mL) with vigorous stirring. A precipitate formed over the next15 min and stirring was maintained for a further 1 h. The reactionmixture was filtered through a 1.0 L sintered glass filter funnel (porosity3) under vacuum to leave the solid precipitate. The solid waswashed with toluene (2 × 100 mL) and dried on the sinter under vacuumfor 30 min until a free-flowing powder was obtained. The crudeproduct (typically 22-24 g) was transferred to a 500 mL round-bottomedflask containing a stirrer bar, followed by toluene (100 mL). A10 mL Dean-Stark trap filled with toluene and a reflux condenserwere fitted to the flask, and the suspension heated to reflux (180 °CDrySyn temperature). Once at reflux, further 10 mL portions of toluenewere added down the condenser, waiting ~5 min between portions,until a clear solution was obtained (4-6 portions were typicallyneeded). The reflux was maintained until no further H2O was observedcondensing into the trap (typically 30 min were sufficient).The flask was removed from the heating block and allowed to coolslowly to r.t., over which time a precipitate formed. Once cooled, theflask was further cooled to -10 °C in a NaCl/ice/water bath for 30 min.The solid precipitate was recovered by vacuum filtration on a 1.0 Lsintered glass filter funnel (porosity 3), and washed with further portionsof toluene (2 × 100 mL). The solid was dried on the sinter undervacuum for 30 min, then transferred to a 250 mL round-bottomedflask and dried in vacuo to constant weight. This gave title compound(R)-3 as fluffy white crystals; yield: 14.81 g (54.78 mmol, 79%). A secondrecrystallisation from toluene at reflux may be required if a powderis obtained from the first attempt. Typical mass loss on secondrecrystallisation was 99% ee.1H NMR (500 MHz, MeOH-d4): δ = 3.80 [1 H, dd, J = 11.4, 7.4 Hz,C(1)HAHB], 3.85 [1 H, dd, J 11.4, 5.0 Hz, C(1)HAHB], 5.00 [1 H, dd, J = 7.4,5.0 Hz, C(2)H], 7.03 (1 H, td, J = 7.5, 1.1 Hz, ArH), 7.22 (1 H, td, J = 7.5,1.2 Hz, ArH), 7.26 (1 H, t, J = 7.4 Hz, p-PhH), 7.34 (2 H, t, J = 7.4 Hz, m-PhH), 7.38 (1 H, d, J = 8.1 Hz, ArH), 7.44 (2 H, d, J = 7.4 Hz, o-PhH), 7.55(1 H, d, J = 7.8 Hz, ArH).13C{1H} NMR (126 MHz, MeOH-d4): δ = 62.2, 66.9, 119.0, 121.7, 122.7,126.8, 128.1, 128.6, 129.5, 131.3, 141.1, 153.0, 169.0.Anal. Calcd for C15H14N2OS: C, 66.64; H, 5.22; N, 10.36. Found: C,66.57; H, 5.31; N, 10.33.1H and 13C NMR data were consistent with literature values.1
77%
With N-ethyl-N,N-diisopropylamine In 1,2-dichloro-benzene at 195℃; for 24h;
With trifluorormethanesulfonic acid; Selectfluor; copper(I) bromide In acetonitrile at 50℃; for 5h;
14 Example 14
2-Chlorobenzothiazole (0.5 mmol, 84.8 mg),Tetrahydrofuran (10 mmol, 720 mg), CuBr (0.025 mmol, 3.6 mg),Selective fluoro reagent (1mmol 354.3mg) and trifluoromethanesulfonic acid (0.5mmol, 75mg) were added to 5mL single-mouthIn the bottle, acetonitrile (5.0 mL) was added as a solvent.The oil bath was heated to 50 ° C for 5 h. After the reaction,The reaction solution is washed with water,After ethyl acetate extraction, the organic layer and the aqueous layer were separated, and the organic layer was dried over anhydrous sodium sulfate.Concentration under reduced pressure gave a yellow oil.The yellow oil is separated by column chromatography.a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 as an eluent,Collect the eluate containing the target compound,Evaporate the solvent and dry to give 87.2mgLight yellow oil 2-(tetrahydrofuran-2-yl)benzothiazole,The yield is 85% and its chemical structure is:
59%
With benzophenone; sodium acetate In water; acetonitrile at 20℃; for 120h; Inert atmosphere; Schlenk technique; UV-irradiation;
15 %Spectr.
With 4-Benzoylpyridine at 20℃; for 24h; Irradiation; Inert atmosphere;
4-(benzo[d]thiazol-2-ylamino)-2-fluorophenol hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With toluene-4-sulfonic acid; In ethanol; at 80℃; for 4h;
2-Chlorobenzothiazole(169 mg, 1 mmol) and EtOH (5 ml), and <strong>[399-96-2]3-fluoro-4-hydroxyaniline</strong> (127 mg, 1 mmol) was dissolved in and p-TsOH*H2O (30.4 mg, 0.1 mmol) was added and the mixture was stirred for 4 hours at 80 C. After checking the completion of the reaction, then cooled at room temperature, then evaporated under reducedpressure to remove the solvent. The concentrated residue was extracted with ethyl acetate (5 ml) and water (3 x 3ml). The extractedorganic layer was filtered and then dried over anhydrous magnesium sulfate, the reduced pressure of the filtrate was evaporated,and purified by column chromatography, and diluted with an equal volume of HCl solution and dried. As a result, 4-(benzo[d]thiazol-2-ylamino)-2-fluorophenol was obtained (222 mg, 75% yield).
N-(2-methoxyethyl)-N-methylbenzo[d]thiazol-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With C45H39BrNiOP2; lithium tert-butoxide; phenylboronic acid; In toluene; at 110℃; for 16h;Inert atmosphere; Glovebox; Sealed tube;
General procedure: In a nitrogen atmosphere glove box C1 (5 mol%, 0.05 mmol),phenylboronic acid (5 mol%, 0.015 mmol), LiOt-Bu (1.5 mmol),(hetero)aryl chloride (1 mmol), amine/azole (1.1 mmol), anddry, degassed toluene (10 mL) were added to an oven-dried 4dram vial containing a magnetic stir bar. The vial was sealedwith a screw cap featuring a PTFE/silicone septum and removedfrom the glove box. The reaction mixture was magneticallystirred in a temperature-controlled aluminum heating block setto 110 C for 16 h (unoptimized). The reaction mixture was thencooled to r.t., taken up in EtOAc (ca. 30 mL) and washed withbrine (3 × 50 mL). The organic layer was separated, dried overNa2SO4, filtered, and concentrated with the aid of a rotary evaporatorto afford the crude product, which was purified via chromatographicmethods (see the Supporting Information for completedetails).
(E)-1-[4-(benzo[d]thiazol-2-yloxy)phenyl]-3-phenylprop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With potassium carbonate; In acetonitrile; at 85℃;
General procedure: Intermediates 1a (1.0 mmol) and 2-chlorobenzothiazole(1.1 mmol) were added to a round-bottomed flask withK2CO3(1.5 mmol) and 20 cm3 acetonitrile as a solvent andstirred at 85 °C for 3?5 h. After the reaction was complete,the system was filtered with alcohol as a flushing fluid. Asufficient amount of water was then added to the filtrate,and liquid was separated under constantly stirring, suctionfiltration, drying, and recrystallization from petroleum etherto obtain the title compound 2a. Compounds 2b?2q wereprepared in the same way.
8-(benzo[d]thiazol-2-yl)-1,3,8-triazaspiro [4.5]decane-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30.8%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 2h;
To a suspension of l ,3,8~triazaspiro[4.5]decane-2,4-dione (CAS 13625-39-3, 20 mg, 1 18 mhio, eq. 1) and DIPEA (45.8 mg, 61.9 m, 355 pmol, eq. 3) in AVV-dimethylformamide (0.5 ml) was added 2-chlorobenzo[d]thiazole (22.1 mg, 130 mtho, eq 1.1) The reaction mixture was stirred at 120 C for 2 hours. The reaction mixture was poured into a mixture of ethylacetate/tetrahydrofuran (1 : 1) and the organic layer was washed with water and brine, dried over NazSCri and concentrated in vacuo. The crude material was purified by flash column chromatography (silica gel, eluent: 0 to 5% of methanol in dichloromethane) to afford 8- (benzo[d]thi azol-2-yl)- 1 ,3 , 8-tri azaspiro[4.5]decane-2,4-di one (11 mg, 36.4 mtho, 30.8 %) as a white solid. MS (ISP): 303.1 {I M 1 1 | }.
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