* 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 n-butyllithium; lithium diisopropyl amide In tetrahydrofuran; hexane at 0 - 20℃; for 0.666667 h;
A 300 mL four-necked flask was purged with argon,Distilled diisopropylamine (14.5 mL) was added and cooled to 0 ° C.1.6 M n-butyllithium,A hexane solution (40 mL) was added dropwise, the temperature was raised to room temperature,A small amount of tetrahydrofuran (THF) was added and diluted to prepare a THF solution of lithium diisopropylamide (LDA). The four-necked flask was purged with argon, and DS-0106 (4.80 g) was dissolved in THF (50 mL). After stirring at 0 ° C. for 10 minutes, the LDA solution was added dropwise and the mixture was stirred at 0 ° C. for 30 minutes. After the reaction, it was extracted with a water / ethyl acetate system. The organic layer was collected, dried over anhydrous magnesium sulfate, the solvent was removed, and ColumnPurified by Lomography to obtain 4.3 g of a light brown solid compound represented by DS-0105 in the above formula (5) (yield 90.9percent).
Reference：
[1] Angewandte Chemie - International Edition, 2012, vol. 51, # 24, p. 5971 - 5975
[2] Patent: JP2018/118935, 2018, A, . Location in patent: Paragraph 0075; 0076
[3] Synlett, 2007, # 19, p. 2975 - 2978
[4] Synthesis, 2008, # 19, p. 3099 - 3107
[5] Tetrahedron, 2010, vol. 66, # 40, p. 8051 - 8059
[6] Chemical Communications, 2017, vol. 53, # 31, p. 4339 - 4341
2
[ 4175-77-3 ]
[ 98-80-6 ]
[ 141305-40-0 ]
Yield
Reaction Conditions
Operation in experiment
84%
With potassium phosphate; palladium diacetate; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane In tetrahydrofuran at 60℃; for 18 h; Inert atmosphere
[00287] Under N2 atmosphere Pd(OAc)2 (0.084 g, 0.38 mmol) was combined with xantphos (0.220 g, 0.38 mmol) in 25 mL THF. After stirring for 5 min., the resulting solution was transferred to a round bottom flask containing 2,4 dibromothiazole (3.64 g, 15 mmol), phenylboronic acid (1.96 g, 16 mmol) and Κ3ΡO4 (9.55 g, 45 mmol). The resulting reaction mixture was heated at 60 °C for 18 h and then cooled to room temperature and filtered and washed with dichloromethane. Removal of the solvents under vacuum afforded the crude product which was purified by silica gel column chromatography using hexanes: ethyl acetate to afford 4- bromo-2-phenylthiazole as a white solid (3 g, 84percent). 1HNMR (400 MHz, CDC13): δ 7.95 (dd, J = 3.4 Hz, 8.2 Hz, 2H), 7.47-7.46 (m, 3H), 7.23 (s, 1H). LRMS (ESI) calcd. for C9H6BrNS [M+H]+: 241.12. Found: 241.00.
66%
With potassium phosphate; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane In tetrahydrofuran at 60℃; for 18 h; Inert atmosphere
Frame-dried 200 mL four-necked flask was purged with nitrogen and Xantphos (Xantphos, 220 mg, 0.38 mmol),Tris (dibenzylideneacetone) dipalladium (0) (Pd 2 (dba) 3,840 mg, 0.38 mmol) and dry tetrahydrofuran (dry THF, 75 mL) were added and stirred for 5 minutes, Thereby preparing a THF solution.Another flame-dried 200 mL four-necked flask was purged with nitrogen, 2,4-dibromothiazole (Compound 101 in the following formula (A), 3.6 g, 15 mmol),Phenylboronic acid (1.9 g, 16 mmol),Triopotassium phosphate (9.6 g, 45 mmol),The above THF solution was added, And the mixture was heated under reflux at 60 ° C. for 18 hours.After returning to room temperature,Celite filtration was carried out using dichloromethane. Removal of the solvent and purification by column chromatography gave the compound of the following formula (A), And 2.4 g of a white solid compound represented by "102" (yield: 66percent).
0.71 g
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene for 6 h; Inert atmosphere; Reflux
A flask containing 238 mg of tetrakis(triphenylphosphine)palladium, 0.55 g of phenylboronic acid, and 1.00 g of 2,4-dibromothiazole was purged with nitrogen and then charged with 30 ml of toluene, 6.1 ml of ethanol, and 9.1 ml of a 2 M aqueous solution of sodium carbonate, and the mixture was stirred under reflux for 6 hours. After cooling to room temperature, 50 ml of water was added to the reaction mixture and two extractions were conducted with 50 ml of ethyl acetate. After being washed with 30 ml of saturated brine, the organic layer was dried over magnesium sulfate. After filtering the magnesium sulfate, the organic layer was concentrated and the residue was purified by column chromatography (Wakogel C-200; hexane:ethyl acetate=14:1) to give 0.71 g of 2-phenyl-4-bromothiazole.
Reference：
[1] Patent: WO2015/191630, 2015, A1, . Location in patent: Paragraph 00287
[2] Journal of Organic Chemistry, 2010, vol. 75, # 5, p. 1733 - 1739
[3] Patent: JP2018/140974, 2018, A, . Location in patent: Paragraph 0067; 0068
[4] Patent: EP2455371, 2012, A1, . Location in patent: Page/Page column 22
[5] Patent: US2013/296271, 2013, A1, . Location in patent: Paragraph 0175
3
[ 105361-77-1 ]
[ 141305-40-0 ]
Yield
Reaction Conditions
Operation in experiment
88%
With sodium tetrahydroborate; N,N,N,N,-tetramethylethylenediamine; palladium diacetate; triphenylphosphine In tetrahydrofuran at 25℃; for 16 h; Inert atmosphere
General procedure: Pd(OAc)2-PPh3, Pd2(dba)3-tbpf, Pd2(dba)3-DavePhos Pd2(dba)3-P(t-Bu)3 Pd2(dba)3-XantPhos and Pd(OAc)2-XPhos. Anhydrous THF (13.2 mL) was degassed by bubbling argon for few minutes, then Pd(OAc)2 (7.2 mg, 0.033 mmol, 5 molpercent) and PPh3 (17.7 mg, 1.132 mmol, 20 molpercent) were added and the resulting mixture stirred at room temperature for 30 min. The halogenated heterocycle (0.66 mmol), 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 or heated at 65 °C under argon for the proper time. The residue was taken up in brine and extracted with ethyl acetate. The organic phase was separated, dried, the solvent was evaporated and the residue was purified by flash chromatography (mixtures of petroleum ether and ethyl acetate) to give pure hydrodehalogenated heterocycles
Reference：
[1] Journal of Molecular Catalysis A: Chemical, 2014, vol. 393, p. 191 - 209
4
[ 591-51-5 ]
[ 4175-77-3 ]
[ 141305-40-0 ]
Reference：
[1] Journal of Organic Chemistry, 2002, vol. 67, # 16, p. 5789 - 5795
[2] Synthesis, 2011, # 2, p. 199 - 206
With N-Bromosuccinimide; In chloroform; for 16h;Reflux;
Compound 102 (2.38 g, 9.90 mmol) and N-bromosuccinimide (2.64 g, 14.9 mmol) were dissolved in chloroform (100 mL) in a 300 mL brown eggplant type flask and heated under reflux for 16 hours.An aqueous sodium thiosulfate solution was added and the mixture was extracted with chloroform.The organic layer was recovered,After drying with anhydrous magnesium sulfate,The solvent was removed and the residue was purified by column chromatography,In the above formula (A)3.00 g of a light brown acicular solid compound represented by "103" was obtained (yield 94%).
58.6%
With N-Bromosuccinimide; In chloroform; for 16h;Reflux;
DS-0105 (2.52 g) and NBS (2.32 g) were dissolved in chloroform (100 mL) in a 300 mL eggplant-shaped flask and heated under reflux for 16 hours. Sodium Thiosulfate WaterThe solution was added and the mixture was extracted with chloroform. The organic layer was collected, dried over anhydrous magnesium sulfate, and the solvent was removed, followed by purification by column chromatography to obtain a compound represented by the following formula (6) in DS-01031.8 g of a light brown acicular solid compound was obtained (yield: 58.6%).
With n-butyllithium; lithium diisopropyl amide; In tetrahydrofuran; hexane; at 0 - 20℃; for 0.666667h;
A 300 mL four-necked flask was purged with argon,Distilled diisopropylamine (14.5 mL) was added and cooled to 0 C.1.6 M n-butyllithium,A hexane solution (40 mL) was added dropwise, the temperature was raised to room temperature,A small amount of tetrahydrofuran (THF) was added and diluted to prepare a THF solution of lithium diisopropylamide (LDA). The four-necked flask was purged with argon, and DS-0106 (4.80 g) was dissolved in THF (50 mL). After stirring at 0 C. for 10 minutes, the LDA solution was added dropwise and the mixture was stirred at 0 C. for 30 minutes. After the reaction, it was extracted with a water / ethyl acetate system. The organic layer was collected, dried over anhydrous magnesium sulfate, the solvent was removed, and ColumnPurified by Lomography to obtain 4.3 g of a light brown solid compound represented by DS-0105 in the above formula (5) (yield 90.9%).
With potassium phosphate; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tetrahydrofuran; at 60℃; for 18h;Inert atmosphere;
[00287] Under N2 atmosphere Pd(OAc)2 (0.084 g, 0.38 mmol) was combined with xantphos (0.220 g, 0.38 mmol) in 25 mL THF. After stirring for 5 min., the resulting solution was transferred to a round bottom flask containing 2,4 dibromothiazole (3.64 g, 15 mmol), phenylboronic acid (1.96 g, 16 mmol) and Kappa3RhoO4 (9.55 g, 45 mmol). The resulting reaction mixture was heated at 60 C for 18 h and then cooled to room temperature and filtered and washed with dichloromethane. Removal of the solvents under vacuum afforded the crude product which was purified by silica gel column chromatography using hexanes: ethyl acetate to afford 4- bromo-2-phenylthiazole as a white solid (3 g, 84%). 1HNMR (400 MHz, CDC13): delta 7.95 (dd, J = 3.4 Hz, 8.2 Hz, 2H), 7.47-7.46 (m, 3H), 7.23 (s, 1H). LRMS (ESI) calcd. for C9H6BrNS [M+H]+: 241.12. Found: 241.00.
83%
With potassium phosphate; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tetrahydrofuran; at 60℃;Inert atmosphere; Schlenk technique;
According to the literature procedure,23 Pd(OAc)2(49.8 mg, 2.5 mol%) and Xantphos (129 mg, 2.5mol%) weredissolved in THF (10 mL) under an N2 atmosphere. After stirringfor 5min at room temperature, this solution was transferredto a two-neck round-bottom flask equipped with an N2balloon and a rubber cap containing 2,4-dibromothiazole(2.16 g, 8.88mmol), phenylboronic acid (1.16 g, 9.5mmol),K3PO4 (5.66 g, 26.6mmol), and THF (20 mL). The mixture washeated at 60 C overnight. The resulting suspension was dilutedwith H2O and was extracted with EtOAc three times. The combinedorganic layer was dried over Na2SO4 and concentratedin vacuo. The crude material was subjected to silica gel chromatography(eluent: hexane/EtOAc = 10/1) to give 4-bromo-2-phenylthiazole as white solid in 83% yield (1.76 g, 7.33mmol). NMR data were identical with those reported in theliterature.23 1HNMR (400 MHz, CDCl3) delta 7.22 (s, 1H), 7.427.47(m, 3H), 7.919.97(m, 2H).
66%
With potassium phosphate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tetrahydrofuran; at 60℃; for 18h;Inert atmosphere;
Frame-dried 200 mL four-necked flask was purged with nitrogen and Xantphos (Xantphos, 220 mg, 0.38 mmol),Tris (dibenzylideneacetone) dipalladium (0) (Pd 2 (dba) 3,840 mg, 0.38 mmol) and dry tetrahydrofuran (dry THF, 75 mL) were added and stirred for 5 minutes, Thereby preparing a THF solution.Another flame-dried 200 mL four-necked flask was purged with nitrogen, 2,4-dibromothiazole (Compound 101 in the following formula (A), 3.6 g, 15 mmol),Phenylboronic acid (1.9 g, 16 mmol),Triopotassium phosphate (9.6 g, 45 mmol),The above THF solution was added, And the mixture was heated under reflux at 60 C. for 18 hours.After returning to room temperature,Celite filtration was carried out using dichloromethane. Removal of the solvent and purification by column chromatography gave the compound of the following formula (A), And 2.4 g of a white solid compound represented by "102" (yield: 66%).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 6h;Inert atmosphere; Reflux;
(7) In the general formula (I), R1 = 2-phenyl-4-thiazolyl, R2 = H, and R3-R4 = thiophene (Synthesis of compound No. 76 in Table 1)Stage A: 4-Bromo-2-phenylthiazole A flask containing 238 mg of tetrakis(triphenylphosphine)palladium, 0.55 g of phenyl boronic acid and 1.00 g of 2,4-dibromothiazole was subjected to nitrogen substitution. To this flask, 30 ml of toluene, 6.1 ml of ethanol, and 9.1 ml of a 2 M sodium carbonate aqueous solution were added, and the obtained mixture was then stirred under reflux for 6 hours. Thereafter, the reaction solution was cooled to a room temperature, and 50 ml of water was then added thereto, followed by extraction with 50 ml of ethyl acetate twice. The organic layer was washed with 30 ml of a saturated brine, and it was then dried over magnesium sulfate. The magnesium sulfate was filtrated, and the organic layer was then concentrated. The residue was then purified by column chromatography (Wako Gel C-200; hexane : ethyl acetate = 14 : 1), so as to obtain 0.71 g of 2-phenyl-4-bromothiazole.
0.71 g
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; for 6h;Inert atmosphere; Reflux;
A flask containing 238 mg of tetrakis(triphenylphosphine)palladium, 0.55 g of phenylboronic acid, and 1.00 g of 2,4-dibromothiazole was purged with nitrogen and then charged with 30 ml of toluene, 6.1 ml of ethanol, and 9.1 ml of a 2 M aqueous solution of sodium carbonate, and the mixture was stirred under reflux for 6 hours. After cooling to room temperature, 50 ml of water was added to the reaction mixture and two extractions were conducted with 50 ml of ethyl acetate. After being washed with 30 ml of saturated brine, the organic layer was dried over magnesium sulfate. After filtering the magnesium sulfate, the organic layer was concentrated and the residue was purified by column chromatography (Wakogel C-200; hexane:ethyl acetate=14:1) to give 0.71 g of 2-phenyl-4-bromothiazole.
With (x)CHCl3*3C17H14O*2Pd; potassium acetate; tricyclohexylphosphine; In 1,4-dioxane; at 170℃; for 2.5h;Microwave irradiation;
In a microwave synthesis vial, DS-0105 (1.56 g), bispinacolatodiboron (1.65 g), tricyclohexylphosphine (0.28 g)Potassium acetate (0.96 g) was dissolved in 1,4-dioxane (19 mL). After degassing,A catalytic amount (4 mol%) of tris (dibenzylideneacetone) dipalladium (0) (Pd 2 (dba) 3) chloroform adduct was added and stirred at 170 C. for 150 min using microwaves. After completion of the reaction, water was added and the mixture was extracted with a water / ethyl acetate system. The organic layer was collected, dried over anhydrous magnesium sulfate, and the solvent was removed to obtain a compound (crude product) as a yellow oily substance represented by DS-0104 in the above-described formula (5)
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In tetrahydrofuran; for 4h;Inert atmosphere; Reflux;
Stage B: 2-[4-(2-Phenylthiazol-4-yl)-3-butynyl]isoindol-1,3-dione Under a nitrogen atmosphere, 15 ml of tetrahydrofuran, 1.50 g of the <strong>[141305-40-0]2-phenyl-4-bromothiazole</strong> obtained in the above described stage, and 3.8 ml of triethylamine were added to 221 mg of dichlorobis(triphenylphosphine)palladium, 60 mg of copper iodide, and 1.24 g of N-(3-butynyl)phthalimide. The obtained mixture was stirred under reflux for 4 hours. After completion of the stirring, the reaction solution was cooled to a room temperature, and a solid was then filtrated. The filtrate was concentrated, and the residue was then purified by column chromatography (Wako Gel C-200; toluene : ethyl acetate = 9 : 1), so as to obtain 1.24 g of a phthalimide compound.
1.24 g
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In tetrahydrofuran; for 4h;Inert atmosphere; Reflux;
To 221 mg of dichlorobis(triphenylphosphine)palladium, 60 mg of copper iodide, and 1.24 g of N-(3-butynyl)phthalimide were added 15 ml of tetrahydrofuran, 1.50 g of the <strong>[141305-40-0]2-phenyl-4-bromothiazole</strong> obtained in the foregoing stage, and 3.8 ml of triethylamine in a nitrogen atmosphere, and the mixture was stirred under reflux for 4 hours. After the stifling, the reaction mixture was cooled to room temperature and the solids were filtered. After concentrating the filtrate, the residue was purified by column chromatography (Wakogel C-200; toluene:ethyl acetate=9:1) to give 1.24 g of a phthalimide compound
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium tetrahydroborate; N,N,N,N,-tetramethylethylenediamine; In tetrahydrofuran; at 25℃; for 30h;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.
With sodium tetrahydroborate; N,N,N,N,-tetramethylethylenediamine; palladium diacetate; triphenylphosphine; In tetrahydrofuran; at 25℃; for 16h;Inert atmosphere;
General procedure: Pd(OAc)2-PPh3, Pd2(dba)3-tbpf, Pd2(dba)3-DavePhos Pd2(dba)3-P(t-Bu)3 Pd2(dba)3-XantPhos and Pd(OAc)2-XPhos. Anhydrous THF (13.2 mL) was degassed by bubbling argon for few minutes, then Pd(OAc)2 (7.2 mg, 0.033 mmol, 5 mol%) and PPh3 (17.7 mg, 1.132 mmol, 20 mol%) were added and the resulting mixture stirred at room temperature for 30 min. The halogenated heterocycle (0.66 mmol), 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 or heated at 65 C under argon for the proper time. The residue was taken up in brine and extracted with ethyl acetate. The organic phase was separated, dried, the solvent was evaporated and the residue was purified by flash chromatography (mixtures of petroleum ether and ethyl acetate) to give pure hydrodehalogenated heterocycles
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; for 2h;Inert atmosphere; Reflux;
[00288] To a mixture of <strong>[141305-40-0]4-bromo-2-phenylthiazole</strong> (3.0 g, 12.5 mmol), 3-bromophenylboronic acid (3.0 g, 15 mmol) and tetrakistriphenylphosphinepalladium(0) (1.44 g, 1.25 mmol) were in DME (40 mL) was added a 2M Na2CO3 solution (25 mL, 50 mmol). The resulting solution was heated at reflux in an atmosphere of N2 for 2 h. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrous Na2SO4. The solvent was evaporated in vacuum to obtain the crude product as a pale yellow solid. Column chromatography using hexanes/ethyl acetate solvent system afforded 4-(3- bromophenyl)-2-phenylthiazole as a colorless solid (3.4 g, 86%). 1HNMR (400 MHz, CDC13): delta 8.16 (d, J= 1.8 Hz, 1H), 8.03-8.01 (m, 2H), 7.90-7.87 (m, 1H), 7.48-7.44 (m, 5H), 7.31-7.38 (m, 1H). LRMS (ESI) calcd. for C15H10BrNS[M+H]+: 315.97. Found: 316.00.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 120℃; for 3h;
22.5 g of <strong>[141305-40-0]4-bromo-2-phenylthiazole</strong> (93.7 mmol), 19 g of (4-chloro-2-formylphenyl)boronic acid (103.1 mmol), 4.3 g of tetrakis(triphenylphosphine)palladium (3.7 mmol), 24.8 g of sodium carbonate (234 mmol), 400 mL of toluene, and 100 mL of ethanol were introduced into a reaction vessel, 100 mL of distilled water was added thereto, and the mixture was then stirred for 3 hours at 120. After completion of the reaction, the reaction product was washed with distilled water and extracted with ethyl acetate. The extracted organic layer was then dried with magnesium sulfate. The solvent was removed with a rotary evaporator, and the resulting product was purified by column chromatography to obtain 20.7 g of compound1-1(yield: 74%).
According to the literature procedure,24 a two-neckround-bottom flask equipped with an N2 balloon and a rubbercap was charged with <strong>[141305-40-0]4-bromo-2-phenylthiazole</strong> (717 mg, 3.0mmol) and Et2O (20 mL). To the solution was added n-BuLi(1.6 mol/L in hexane, 3.6mmol) dropwise at 78 C, and themixture was stirred at 50 C for 30min. Then the reactionmixture was cooled again to 78 C, followed by the slowaddition of tributyltin chloride (1.1 mL, 4.1mmol). After stirringfor 10min, the resulting solution was allowed to warm toroom temperature and stirred for an additional 1 h. The resultingsuspension was diluted with H2O and was extracted withEtOAc three times. The combined organic layer was dried overNa2SO4 and concentrated in vacuo. The crude material wassubjected to silica gel (containing ca. 10 wt% K2CO3) chromatography(eluent: hexane/EtOAc = 9/1) to give 2-phenyl-4-(tributylstannyl)thiazole as pale yellow oil in 74% yield (1.00 g,2.22mmol). NMR data were identical with those reported inthe literature.25 1HNMR (400 MHz, CDCl3) delta 0.721.73(m,27H), 7.32 (s, 1H), 7.387.46(m, 3H), 7.988.03(m, 2H).
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