* 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.
Stage #1: With sulfuric acid; nitric acid; sodium nitrite In water at 2 - 10℃; for 1 h; Stage #2: With copper(II) sulfate; sodium bromide In water at 6℃; for 8.5 h;
2-Amino-thiazol 0.25mol 150ml45percent sulfuric acid was dissolved in 500ml reaction flask and stirred to dissolve 2-aminothiazol-section and cooled to 2 , 50ml of concentrated nitric acid 65percent was added dropwise, maintaining the internal temperature should not exceed 10 . Then 50ml solution of sodium nitrite was slowly dropped 5mol / l, the addition was completed, stirring was continued for 1h, controlling the temperature below 7 . The reaction was continued with a dropping funnel, the red-brown diazonium salt solution was added dropwise 200ml solution containing 74g of sodium bromide and 40g copper sulfate carried bromination, maintained at 6 , dropping time of about 1.5h, after the addition was complete 7H, N2 so excluded; after cooling the solution was added 20percent NaOH and the solution was adjusted pH of 6 to 7, then washed with water steam distillation to collect the aqueous solution containing the 2-bromothiazole, dried over MgSO4 solution by distillation, vacuum distillation collect bp71 ~ 73 / 2.4kPa fraction, 2-bromothiazole 35.2g, a yield of 85.8percent, showing that the reaction temperature is maintained at the present application 0 ~ 10 , the reaction rate is faster, while also reducing side reactions, the reaction yield has been greatly improved.
2.5 g
Stage #1: for 0.166667 h; Stage #2: With sodium nitrite In water at 0℃; for 1 h; Stage #3: With copper(II) sulfate; sodium bromide In water at 0 - 20℃; for 22 h;
To a cool solution of thiazol-2-amine (5.0 g, 50 mmol) in 85percent H3P04 was added conc. nitricacid and stirred the reaction mixture for iO mins followed by addition of aq.NaNO2 (4. i4 g,60 mmol), continued stirring for i h at 0°C.Then added aq.Cu504 (6.36 g, 40 mmol) & NaBr(i4.49 g,i45 mmol).The reaction mass was further stirred at 0°C for 6 h then at ft for i6 h.The reaction mass was basified with KOH & Na2CO3 up to pH-9 and extracted with DCM.The organic layers were separated and concentrated to afford 2.5 g of title compound . ‘HNMR (300 MHz, DMSO-d6): 7.62-7.6i (d, J = 3.0 Hz, iH), 7.3 i-7.30 (d, J = 3.3 Hz, iH)
Reference：
[1] Synthesis, 2012, vol. 44, # 7, p. 1026 - 1029
[2] Patent: CN105348216, 2016, A, . Location in patent: Paragraph 0048; 0049
[3] Recueil des Travaux Chimiques des Pays-Bas, 1934, vol. 53, p. 77,78
[4] Recueil des Travaux Chimiques des Pays-Bas, 1962, vol. 81, p. 554 - 564
[5] Patent: WO2016/55947, 2016, A1, . Location in patent: Page/Page column 142
[6] Journal of Organic Chemistry, 2017, vol. 82, # 11, p. 5947 - 5951
4
[ 288-47-1 ]
[ 3034-53-5 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1957, vol. 27, p. 726,728; engl. Ausg. S. 799, 801
[2] Journal of Organometallic Chemistry, 2000, vol. 601, # 2, p. 233 - 236
5
[ 288-47-1 ]
[ 3034-53-5 ]
[ 4175-78-4 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1986, vol. 22, # 6, p. 663 - 666[2] Khimiya Geterotsiklicheskikh Soedinenii, 1986, vol. 22, # 6, p. 837 - 840
6
[ 3034-53-5 ]
[ 13816-02-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 15, p. 5303 - 5315
7
[ 3034-53-5 ]
[ 68-12-2 ]
[ 10200-59-6 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78 - -70℃; for 0.333333 h; Stage #2: at -65 - 20℃; for 3 h; Stage #3: With hydrogenchloride In diethyl ether; hexane; water at 0℃;
A sol. of 2-bromothiazole (10.00 g, 60.96 mmol) in Et2O (43 mL) was added dropwise over 1 h to a cooled sol. (-78 0C) of BuLi (1.6M in hexane, 46 mL, 73.5 mmol). The resulting mixture was stirred at -70 0C for 20 min, then DMF (7.50 mL, 97.5 mmol) was added over 1 h, while the temperature was kept below -65 0C. The reaction mixture was allowed to reach -40 0C during 1 h, then stirred at that temperature for one additional hour. The reaction mixture was allowed to warm to 0 0C, quenched with aq. 4M HCl, and the two layers were separated. The org. layer was washed with aq. 4M HCl, then discarded. The combined aq. layers were neutralized with K2CO3, and extracted with Et2O (3x). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed in vacuo to give a brown oil as the title compound (6.88 g, 99percent) that was not further purified.
87%
With tert.-butyl lithium In tetrahydrofuran; pentane
a. 2-Formylthiazole To a cooled solution (-95° C.) of t-butyllithium (1.7M in pentane, 17.9 mL, 30.5 mmol, 2.0 eq) in tetrahydrofuran (150 mL) under nitrogen was added 2-bromothiazole (2.50 g, 15.3 mmol). The resulting suspension was stirred below -80° C. for 45 min The lithiated thiazole solution was transferred via cannula to a solution of dimethylformamide (1.42 mL) in tetrahydrofuran (100 mL) at -90° C. The reaction was allowed to warm to room temperature over 2 h and quenched by the addition of water (100 mL). The aqueous phase was extracted with ethyl acetate (3*75 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered and reduced to a crude oil in 87percent yield. TLC analysis (Rf 0.50, 40percent ethyl acetate in hexane). No further characterization was undertaken; the crude title compound was taken on to the sodium borohydride reduction.
51%
Stage #1: With n-butyllithium In diethyl ether; cyclohexane at -78 - 70℃; for 1.5 h; Inert atmosphere Stage #2: at -40℃; for 2 h;
To a reaction flask were added a solution of n-butyl lithium in cyclohexane (60 mL,150 mmol, 2.5 mol/L) and anhydrous ethyl ether (100 mL). The mixture was stirred at -78 ocunder nitrogen protection, then 2-bromothiazole (20 g, 122 mmol) was added dropwise slowlyinto the mixture for 1 h. The mixture was heated to 70 oc and stirred for 30 min, then DMF(14.26 g, 195 mmol) was added for 1 h. The mixture was cooled to -40 oc and stirred for 1 h.The reaction mixture was warmed to 0 oc and to the reaction mixture was added HCl (4 M) (100mL), and the resulting mixture was partitioned. The aqueous layer was adjusted with saturatedaqueous potassium carbonte to pH about 7 to 8. The mixture was extracted with ethyl ether (100mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the titlecompound as brownish red oil (7 .0 g, 51 percent ).MS (ESI, pos. ion) m/z: 114.1 [M+Ht.
Reference：
[1] Patent: WO2006/92268, 2006, A1, . Location in patent: Page/Page column 22
[2] Journal of Organic Chemistry, 1995, vol. 60, # 15, p. 4749 - 4754
[3] Patent: US5512575, 1996, A,
[4] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2007, vol. 62, # 12, p. 1525 - 1529
[5] Patent: WO2018/108125, 2018, A1, . Location in patent: Paragraph 00539
[6] Organic Letters, 2012, vol. 14, # 23, p. 6104 - 6107
[7] Patent: WO2014/66795, 2014, A1, . Location in patent: Paragraph 0174 - 0175
[8] Patent: WO2014/143799, 2014, A2, . Location in patent: Page/Page column 386; 387
[9] Patent: US2014/275528, 2014, A1, . Location in patent: Paragraph 0304; 0305
[10] Russian Journal of General Chemistry, 2015, vol. 85, # 8, p. 1855 - 1861[11] Zh. Obshch. Khim., 2015, vol. 85, # 8, p. 1298 - 1304,7
8
[ 3034-53-5 ]
[ 10200-59-6 ]
Reference：
[1] Patent: US5475113, 1995, A,
9
[ 3034-53-5 ]
[ 10200-59-6 ]
Yield
Reaction Conditions
Operation in experiment
93.9%
With n-butyllithium In hexane; N,N-dimethyl-formamide
(a) To a solution of n-butyllithium (3.14 g, 49 mmol, 2M in hexane) in 80 ml of ether under argon at -78° C. was added dropwise a solution of 2-bromothiazole (7.8 g, 47.55 mmol) in 1 h. The mixture was stirred at -78° C. for 1 h, and then a solution of DMF (3.48 g, 47.55 mmol) in ether was added. The mixture was stirred for 1 h at -78° C., then at -15° C. for 18 h. The reaction mixture was then extracted with 4N HCl (4*20 ml), the aqueous layers were combined, cooled in an ice-bath, and neutralized with sodium bicarbonate. The aqueous layer was extracted with ether (4*35 ml), the organic layer was dried over sodium sulfate and concentrated in vacuo to afford 4.95 g (93.9percent) of 2-thiazolylcarboxaldehyde.
Reference：
[1] Patent: US5569655, 1996, A,
[2] Patent: US5569655, 1996, A,
10
[ 3034-53-5 ]
[ 4394-85-8 ]
[ 10200-59-6 ]
Reference：
[1] Synthesis, 1987, # 11, p. 998 - 1001
[2] Journal of Materials Chemistry, 1998, vol. 8, # 4, p. 833 - 835
11
[ 3034-53-5 ]
[ 74-89-5 ]
[ 6142-06-9 ]
Yield
Reaction Conditions
Operation in experiment
67%
at 120℃; for 2 h;
Synthesis of Exemplary Compound 14: N-Methyl-N-(2-(methyl(thiazol-2-yl)amino)-2-oxoethyl)-3-phenylpropiolamide; a) Synthesis of N-methylthiazol-2-amine; 900 μl (10 mmol) of 2-bromothiazole were heated together with a 33percent strength ethanolic methylamine soln. (70 ml) in an autoclave (to approx. 120° C.) until a pressure of 10 bar had developed. The mixture was stirred for 2 h under these conditions. The reaction mixture was then evaporated under a vacuum and the residue was redissolved in a 3percent strength aq. HCl soln. and washed with ether, after which the pH was adjusted to 12 with a 20percent strength aq. NaOH soln. The solution was saturated with NaCl and extracted with chloroform. The organic phase was dried over MgSO4, filtered and evaporated under a vacuum, 761 mg (6.7 mmol, 67percent) of N-methylthiazol-2-amine being obtained.
Reference：
[1] Proceedings - Indian Academy of Sciences, Section A, 1953, # 37, p. 758,763
[2] Helvetica Chimica Acta, 1954, vol. 37, p. 2057,2064
13
[ 3034-53-5 ]
[ 124-41-4 ]
[ 14542-13-3 ]
Reference：
[1] Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques, 1969, vol. 269, p. 1560 - 1561
14
[ 3034-53-5 ]
[ 141-52-6 ]
[ 15679-19-3 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1986, p. 1589 - 1592
[2] Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques, 1969, vol. 269, p. 1560 - 1561
15
[ 3034-53-5 ]
[ 1452-16-0 ]
Yield
Reaction Conditions
Operation in experiment
99%
With 1-methyl-1H-imidazole In toluene at 160℃; for 16 h;
In an autoclave, 1 equiv. of aryl halide or heteroaryl halide, 2 equiv. of 1-alkylimidazole, 0.1 equiv. of CuI, 0.2 equiv. of dried K4[Fe(CN)6] (potassium hexacyanoferrate(II)), tetradecane as an internal standard for the GC analysis and a suitable amount of toluene were combined under argon and heated to 160 C. (The K4[Fe(CN)6] was dried by heating powdered K4[Fe(CN)6]x3H2O in a vacuum of 1 mbar to 80 C. for at least 24 hours.) After 16 hours, the reaction mixture was cooled to room temperature. Conversion and yield were determinable by means of gas chromatography. An isolation of the product took place according to the customary workup (distillation, crystallization or chromatography).
Reference：
[1] Chemistry - A European Journal, 2007, vol. 13, # 21, p. 6249 - 6254
[2] Patent: WO2011/79114, 2011, A1, . Location in patent: Page/Page column 105; 106
17
[ 3034-53-5 ]
[ 544-92-3 ]
[ 1452-16-0 ]
Reference：
[1] Journal of the Chemical Society [Section] C: Organic, 1967, p. 515 - 518
18
[ 3034-53-5 ]
[ 141-78-6 ]
[ 24295-03-2 ]
Yield
Reaction Conditions
Operation in experiment
95.2%
Stage #1: at -78℃; for 3 h; Stage #2: for 3 h;
0.15mol containing a solution of 2-bromothiazole added dropwise to a solution containing 0.18mol butyllithium was added dropwise for about 2h, after the addition was completed, stirring was continued for 1h, maintained at low temperature (-78 deg.] C) reaction carried out under . 0.3mol ethyl acetate and then added to the solution dropwise addition was completed, stirring was continued for 3h, the reaction is complete, the organic phase extracted was allowed to stand, washed with distilled water, dried over anhydrous Na2SO4 was added, and then distilled under reduced pressure collecting bp89 ~ 91 / 1.6kPa fraction, 2-acetyl thiazole 18.16g. The yield was 95.2percent.
Reference：
[1] Patent: CN105348216, 2016, A, . Location in patent: Paragraph 0050; 0051
[2] Journal of the Chemical Society [Section] C: Organic, 1969, p. 2270 - 2273
[3] Journal of Organic Chemistry, 1991, vol. 56, # 18, p. 5294 - 5301
19
[ 3034-53-5 ]
[ 4175-78-4 ]
Reference：
[1] Synthesis, 2012, vol. 44, # 7, p. 1026 - 1029
[2] Journal of Organic Chemistry, 2017, vol. 82, # 11, p. 5947 - 5951
[3] Journal of Organic Chemistry, 2006, vol. 71, # 10, p. 3754 - 3761
[4] Helvetica Chimica Acta, 1954, vol. 37, p. 2057,2064
[5] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 4, p. 845 - 849
20
[ 288-47-1 ]
[ 3034-53-5 ]
[ 4175-78-4 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1986, vol. 22, # 6, p. 663 - 666[2] Khimiya Geterotsiklicheskikh Soedinenii, 1986, vol. 22, # 6, p. 837 - 840
21
[ 3034-53-5 ]
[ 7732-18-5 ]
[ 14190-59-1 ]
Reference：
[1] Patent: US5935966, 1999, A,
22
[ 3034-53-5 ]
[ 124-38-9 ]
[ 14190-59-1 ]
Reference：
[1] Patent: US2012/94971, 2012, A1, . Location in patent: Page/Page column 40
[2] European Journal of Inorganic Chemistry, 2011, # 4, p. 539 - 548
23
[ 3034-53-5 ]
[ 14190-59-1 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1954, vol. 73, p. 325,329
24
[ 3034-53-5 ]
[ 105-36-2 ]
[ 3292-77-1 ]
Reference：
[1] Journal of the American Chemical Society, 1994, vol. 116, # 8, p. 3324 - 3336
25
[ 3034-53-5 ]
[ 540-37-4 ]
[ 193017-26-4 ]
Reference：
[1] Synthesis, 2001, # 1, p. 128 - 134
26
[ 3034-53-5 ]
[ 540-38-5 ]
[ 81015-49-8 ]
Reference：
[1] Synthesis, 2001, # 1, p. 128 - 134
27
[ 3034-53-5 ]
[ 589-87-7 ]
[ 27149-27-5 ]
Yield
Reaction Conditions
Operation in experiment
18.3 g
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran for 1 h; Cooling with ice; Inert atmosphere Stage #2: With zinc(II) chloride-TMEDA In tetrahydrofuran at 20℃; for 1 h; Cooling with ice; Inert atmosphere Stage #3: With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran for 1.5 h; Reflux; Inert atmosphere
A flask which in 2-bromothiazole (16.4 g) and 50 ml of THF solution were put was cooled in an iced bath, and then 55 ml of a THF solution of 2 M isopropylmagnesium chloride was added dropwise there to under in a in nitrogen atmosphere while stirring the solution. After dropewise addition the rection mixture was stirred for 1 hour, and then a zinc chloride-tetramethylethylenediamine complex (30.3 g) was added. the resuting mixture was stirring for 1 hour at room temperature, and then 1-bromo-4-iodobenzene (28.3 g) and Pd(PPh3)4 (3.5 g) were added and then heated and stirred for 1.5 hours at reflux temperature. After cooling the reaction solution to room temperature, to remove the metal ions of the catalyst, a solution prepared by dissolving the compound ethylenediamine Inc. acid, use the sodium salt dihydrate equivalent to approximately 2-fold molar with respect to the objective to the appropriate amount of water (after and it stirred to fall abbreviated) EDTA · 4Na in an aqueous solution. Then, after removing also separated by adding toluene, and the solvent was distilled off under reduced pressure to the solution, and purified by silica gel column chromatography (eluent: toluene / ethyl acetate = 50/1 (volume ratio)) to give 2-(4-bromophenyl)thiazole (18.3g).
Reference：
[1] Patent: KR2015/138163, 2015, A, . Location in patent: Paragraph 0333; 0334
28
[ 3034-53-5 ]
[ 623-49-4 ]
[ 41731-83-3 ]
Reference：
[1] Journal of Organic Chemistry, 2011, vol. 76, # 16, p. 6972 - 6978
29
[ 3034-53-5 ]
[ 63-74-1 ]
[ 72-14-0 ]
Reference：
[1] Patent: CH229082, 1938, ,
30
[ 3034-53-5 ]
[ 758-96-3 ]
[ 43039-98-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 1991, vol. 34, # 7, p. 2176 - 2186
31
[ 3034-53-5 ]
[ 5685-05-2 ]
Yield
Reaction Conditions
Operation in experiment
18%
Stage #1: With thiourea In methanol for 2 h; Heating / reflux Stage #2: With sodium hydroxide In water for 0.25 h; Stage #3: With acetic acid In water
A mixture of 2-bromothiazole (4.6 g, 28 mmol) and thiourea (6.4 g, 84 mmol) in 250mL of methanol was heated under reflux for 2 h. The solution was evaporated and the residue stirred with 0.5N NaOH solution for 15 min. The solution was then acidified (pH 4) using acetic acid and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (Na2SO4) and evaporated. After evaporation of the solvent, the product (0.6 g, 18 percent yield) was precipitated from ethylacetate and petrol ether. 1H nmr (DMSO-D6): δ 13.2 (s, 1H, SH); 7.3 (d, 1H, CH=); 7.0 (d, 1H, CH=); ms: (+ACPI) m/z 118 (M+H)+.
Reference：
[1] Phosphorus and Sulfur and the Related Elements, 1980, vol. 8, p. 205 - 208
[2] Patent: EP1598354, 2005, A1, . Location in patent: Page/Page column 87
32
[ 3034-53-5 ]
[ 75-77-4 ]
[ 79265-30-8 ]
Yield
Reaction Conditions
Operation in experiment
76%
With n-butyllithium In diethyl ether; hexane at -78℃; for 2.83333 h;
{0203] 2-(TriraethyisiJyl)t at)le (18). A 500-mL, four-necked, round- bottomed flask, containing a magnetic stirring bar, was equipped with two 1 0- raL, pressure-equalizing dropping funnels and a low-temperature thermometer. The anh apparatus was filled with argon and kept under a slightly positive pressure during the entire reaction. The flask was charged with 80 mL of freshly distilled Et jO and 42 mL (67 mmol) of a 1.6 M solution of -BuLi in hexane. One of the two dropping funnels was charged with 5.5 mL (10 g, 6 mmol) of 2- bromoihiazoe in 20 ml, of EfcO and the other with 7.7 ml (6.6 g, 61 mmol) of chorotrimethylsilane in 20 mL of EtjO. The reaction flask was cooled to -78 in an acetone bath. While ihe solution in the flask was stirred, 2~bromot azole was added dropwise over a period of I h. After 20 mm of additional stirring, ehiorotrimethylsilane was added dropwise over 30 min and the stirring was continued for a period of i h at -78 "C. The resulting mixture was then allowed to wa m up to room temperature. A satd aq aHCO? was added and the mixture was transferred into a i L separatory funnel. The organic layer was recovered and the aqueous layer was extracted with two 200-raL portions of E0. The combined organic layer was dried (NajSO ), filtered, and concentrated under diminished pressure with the external bath iemperature not exceeding 40 °C. The residue was distilled from a 1 -mL flask at diminished pressure in a Classen apparatus. The distillation was carried out under diminished pressure at 45 'r'C after a forerun at 25 °C consisting mainly of bromobutane was collected. The pure product. 18 was isolated as a colorless oil: yield 7,3 g (76percent); SH NMR (CDC ) 0.39 (, I2H), 7.50 (111 d? J FontWeight="Bold" FontSize="10" 3.0 Hz) and 8.09 (111 d, J === 2.9 Hz); FontWeight="Bold" FontSize="10" NMR. (C£X) O 1.03, 127.3, 145.6 and 174,2.
76%
With n-butyllithium In diethyl ether; hexane at -78℃; for 2.83 h;
A 500-mL, four-necked, round-bottomed flask, containing a magnetic stirring bar, was equipped with two 1 00-mL, pressure- equalizing dropping funnels and a low-temperature thermometer. The anh apparatus was filled with argon and kept under a slightly positive pressure during the entire reaction. The flask was charged with 80 mL of freshly distilled Et20 and 42 mL (67 mmol) of a 1.6 M solution of n-BuLi in hexane. One of the two dropping funnels was charged with 5.5 mL (10 g, 61 mmol) of 2-bromothiazole in 20 mL of Et20 and the other with 7.7 mL (6.6 g, 61 mmol) of chlorotrimethylsilane in 20 mL of Et20. The reaction flask was cooled to —78 °C in an acetone bath. While the solution in the flask was stirred, 2-bromothiazole was added dropwise over a period of 1 h. After 20 mm of additional stirring, chiorotrimethylsilane was added dropwise over 30 mill and the stirring was continued for a period of 1 h at —78 °C. The resulting mixture was then allowed to warm up to room temperature. A satd aq NaHCO3 was added and the mixture was transferred into a 1 L separatory funnel. The organic layer was recovered and the aqueous layer was extracted with two 200-mL portions of Et20. The combined organic layer was dried (Na2SO4), filtered, and concentrated under diminished pressure with the external bath temperature not exceeding 40 °C. The residue was distilled from a 100-mL flask at diminished pressure in a Claisen apparatus. The distillation was carried out under diminished pressure at 45 °C after a forerun at 25°C consisting mainly of bromobutane was collected. The pure product 3 was isolated as a colorless oil: yield 7.3 g (76percent); ‘H NMR (CDC13) ö 0.39 (s, 12H), 7.50 (1H, d, J= 3.0 Hz) and 8.09 (1H, d, J= 2.9 Hz); ‘3C NMR (CDC13) ö 1.03,127.3, 145.6 and 174.2.
Reference：
[1] Tetrahedron, 2009, vol. 65, # 29-30, p. 5739 - 5746
[2] Patent: WO2014/145109, 2014, A1, . Location in patent: Paragraph 0203
[3] Patent: WO2014/152718, 2014, A1, . Location in patent: Paragraph 0196
[4] Journal of the Chemical Society, Chemical Communications, 1981, # 13, p. 655 - 656
[5] Journal of Organic Chemistry, 1988, vol. 53, # 8, p. 1748 - 1761
[6] Phosphorus and Sulfur and the Related Elements, 1985, vol. 24, p. 1 - 38
[7] Heterocycles, 1988, vol. 27, # 5, p. 1191 - 1196
[8] Patent: EP409418, 1991, A1,
[9] Patent: US5512575, 1996, A,
Stage #1: With n-butyllithium In hexane at -78℃; for 1 h; Inert atmosphere Stage #2: Inert atmosphere
Under argon a solution of n-BuLi in hexanes (6.14 mmol, 2.5 M) was dropped into a stirred solution of 2-bromothiazole (3.07 mmol) in dry ether at 0° C. After 1 h the mixture was cooled to −78° C. and a solution of tributyltin chloride (3.07 mmol) in dry ether was slowly added and the mixture was stirred overnight. The mixture was then added to water (50 ml). The aqueous layer was extracted with ether (3×30 ml). The combined organic layers were dried with magnesium sulfate, and the solvent was removed in vacuo to give the title product L-01b as a pale brown oil in quantitative yield which was used for synthesis of compound L-01a without further purification.
97%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 1.25 h; Inert atmosphere Stage #2: at -78℃; for 0.5 h; Inert atmosphere
2-bromothiazole under a nitrogen atmosphere (4.0g, 24.38mmol) was dissolved in diethyl ether 80mL, and cooled to -78 . There, n-butyllithium 1.6M in hexane (15.5mL, 24.78mmol) was dropped over a period of 15 minutes, followed by stirring for 1 hour at -78 . In addition the tributyltinchloride (8.70g, 26.73mmol), and stirred for 30 minutes at -78 , was then stirred for a further 2 hours at room temperature. The reaction was quenched with water, the reaction product was extracted 4 times with ethyl acetate 50 mL. The organic phase was washed with saturated brine, dried over MgSO4, the solvent was removed under reduced pressure and filtered, Compound 5 (brown liquid, 8.85 g, yield: 97percent) was obtained. Compound 5 was used in the subsequent reaction without further purification.
92%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 1 h; Stage #2: at -78 - 20℃;
Compound 2 is commercially available from Chemical Communications (Cambridge, United Kingdom), 49 (73), 8036-8038; 2013.To a dried reaction flask, 2-bromothiazole (10 g, 61.0 mmol) was added to diethyl etherwas dissolved in diethyl ether (100 mL) To this solution was added n-butyllithium (2.5 M in hexane,29 mL,67.1 mmol) was slowly added dropwise at -78 C.The reaction solution was reacted at -78 ° C for 1 hour,Tributyltin chloride (18.2 mL, 67.1 mmol) was slowly added dropwise at -78 C,The temperature of the reaction solution was gradually raised to room temperature.The reaction was terminated by adding water to the solution,The mixture was extracted with diethyl ether, and the organic layers were combined and dried using magnesium sulfate.After drying, the filter and filtrate were concentrated to give 21 g (92percent yield) of the compound 2 [2- (tributylstannyl) thiazole as a brown oil (scheme 2).
90%
Stage #1: With n-butyllithium In diethyl ether; hexane at -70℃; for 0.5 h; Stage #2: at -70 - 20℃; for 5 h;
2-Tributylstannylthiazole; [Show Image] To a mixture of 2-bromothiazole (4.6 mL, 50 mmol) and anhydrous ether (50 mL), there was added an n-BuLi hexane solution (22 mL, 55 mmol) dropwise at -70°C under nitrogen atmosphere, and the mixture was stirred for 30 minutes. A solution of n-Bu3SnCl (14 mL, 50 mmol) in ether (20 mL) was then added at -70°C, and after stirring for 4 hours, the mixture was raised to room temperature and stirred for another hour. After adding water (50 mL), the organic layer was extracted three times with ether (50 mL), and the solvent was distilled away. It was then purified by silica gel chromatography (hexane: ethyl acetate = 20: 1) to yield the title compound (17 g, 90percent). 1H-NMR (Bruker (ARX-300), 300 MHz, CDCl3) δ (ppm): 8.17 (1H, d, J = 3.05 Hz), 7.54 (1H, d, J = 3.05 Hz), 1.65-1.55 (6H, m), 1.38-1.19(12H, m), 0.89 (9H, t, J = 7.25 Hz).
90%
Stage #1: With n-butyllithium In diethyl ether; hexane at -70℃; for 0.5 h; Inert atmosphere Stage #2: at -70 - 20℃; for 5 h; Inert atmosphere
To a mixture of 2-bromothiazole (4.6 mL, 50mmol) and anhydrous ether (50 mL), there was added an n-BuLi hexane solution(22 mL, 55 mmol) dropwise at −70° C. under nitrogen atmosphere, and the mixturewas stirred for 30 minutes. A solution of n-Bu3SnCl (14 mL, 50 mmol) in ether (20 mL) was then added at −70°C., and after stirring for 4 hours, the mixture was raised to room temperatureand stirred for another hour. After adding water (50 mL), the organic layer wasextracted three times with ether (50 mL), and the solvent was distilled away.It was then purified by silica gel chromatography (hexane:ethyl acetate=20:1)to yield the title compound (17g, 90percent).
Reference：
[1] Patent: US8575355, 2013, B2, . Location in patent: Paragraph 0032
[2] Patent: JP2016/56276, 2016, A, . Location in patent: Paragraph 0129; 0130
[3] Patent: KR2017/26286, 2017, A, . Location in patent: Paragraph 0112-0115
[4] Patent: EP1982982, 2008, A1, . Location in patent: Page/Page column 76
[5] Patent: KR101511396, 2015, B1, . Location in patent: Paragraph 1061-1064
[6] Patent: US5521173, 1996, A,
[7] Patent: EP1375486, 2004, A1, . Location in patent: Page 114; 116
[8] Patent: WO2016/168619, 2016, A1, . Location in patent: Paragraph 00305
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Yield
Reaction Conditions
Operation in experiment
74%
With sodium carbonate In ethanol; water; toluene
(1) A mixture of 2-bromothiazole (0.9 ml, 10 mmols), 4-formylphenylboronic acid (1.65 g, 11 mmols), sodium carbonate (2.65 g, 25 mmols), toluene (150 ml), ethanol (30 ml) and water (30 ml) was stirred in an argon atmosphere at room temperature for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.58 mg, 0.5 mmols) was added thereto and heated under reflux for 15 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, then dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography, and then recrystallized from ethyl acetate/hexane to give 4-(2-thiazolyl)benzaldehyde (1.4 g, 74 percent).m.p. 91.5-92.5°C Elemental Analysis for C10H7NOS: Calcd.: C, 63.47; H, 3.73; N, 7.40 Found: C, 63.67; H, 3.60; N, 7.316 1H-NMR (CDCl3) δ: 7.46(1H,d,J=3.2Hz), 7.95-7.99(3H,m),
35%
With sodium hydrogencarbonate In 1,2-dimethoxyethane; water
REFERENCE EXAMPLE 72 4-(2-Thiazolyl)benzaldehyde A mixture of NaHCO3 (3.83 g, 45.6 mmol) and 4-formylphenylboronic acid (2.69 g, 18.0 mmol) in water (60 mL) was added to a solution of 2-bromothiazole (2.50 g, 15.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (500 mg, 0.43 mmol) in DME (60 mL). The reaction mixture was heated to reflux for 18 h, cooled to room temperature, diluted with ethyl acetate, washed with sat. aq. NaHCO3 and brine, dried with Na2SO4, and concentrated in vacuo. Two consecutive recrystallizations from hexanes/ethyl acetate yielded 998 mg (35percent) of the title compound. MS 190 (M+H)+.
985 mg
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene at 20℃; Inert atmosphere; Reflux
(1) 4-(thiazol-2-yl)benzaldehyde 2-Bromothiazole (0.538 ml, 6.06 mmol), 4-formylphenylboronic acid (1.0 g, 6.67 mmol), and Na2CO3 (1.61 g) were suspended in the mixed solution of toluene (25 ml), ethanol (5 ml), and H2O (5 ml). The mixture was stirred at room temperature for 15 minutes under an argon gas atmosphere. After reducing the pressure inside of the reaction container by using a vacuum line, the mixture was degassed by introducing Ar gas and this procedure was repeated twice. After that, tetrakis(triphenylphosphine)palladium (0.701 g, 0.606 mmol) was added, and the mixture was stirred for 15 hours by heating under reflux. The end point of the reaction was confirmed on TLC (EtOAc:n-hexane=1:4), and the mixture was cooled to room temperature. H2O (50 ml) and EtOAc (50 ml) were added and the mixture was stirred for 15 minutes. Black insoluble matter was removed by filtration with Celite and the filtrate was separated by the step of extraction/separation. The organic layer was washed with saturated brine (50 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified on silica gel column chromatography (EtOAc:hexane=1:3) to obtain the title compound (985 mg) as an opaque white solid.
Reference：
[1] Journal of Medicinal Chemistry, 1998, vol. 41, # 18, p. 3387 - 3401
[2] Patent: US5849911, 1998, A,
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Reference：
[1] Patent: US6251911, 2001, B1,
38
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[ 223575-69-7 ]
Yield
Reaction Conditions
Operation in experiment
38%
With sodium carbonate In water; acetonitrile at 160℃; for 0.0833333 h; Microwave irradiation
6.21. Synthesis of (S)-2-Amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(2-thiazol-2-yl-phenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid To a 40 ml microwave reactor, was added 1.04 g of 2-formyl phenylboronic acid (6.9 mmoles), 1.14 g of 2-bromo thiazole (6.9 mmoles), 240 mg of palladium bistriphenyl-phosphine dichloride (Pd(PPh3)2Cl2, 0.34 mmoles). Then, 13.8 ml of 1M Na2CO3 (13.8 mmoles) and 10 ml of CH3CN were added to the mixture. The reactor was sealed, and the reaction was run under microwave at 160° C. for 5 minutes. LCMS shows completion of the reaction with desired product. The reaction mixture was then poured into a separation funnel. Then 200 ml of methylene chloride and 100 ml of water were added for extraction. The methylene chloride layer was dried over MgSO4. Removal of solvent gave a crude product, which was purified by silica gel column chromatography eluding with hexanes/ethyl acetate mixture (5/1 to 2/1) to give pure 2-thiazol-2-yl-benzaldehyde (0.5 g, yield: 38percent).
38%
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In acetonitrile at 160℃; for 0.0833333 h; Sealed tube; Microwave irradiation
To a 40 ml microwave reactor was added 1.04 g of 2-formylphenylboronic acid (6.9 mmol) of 1.14 g of 2-bromothiazole(6.9 mmol), 240 mg of bistriphenyl-phosphine palladium dichloride (Pd (PPh3) 2Cl2, 0.34 mmol). then,To the mixture was added 13.8 ml of 1 M Na2CO3 (13.8 mmol) and 10 ml of CH3CN. Sealed reactor,The reaction was run under microwave at 160 ° C for 5 minutes.LCMS shows the desired reaction of the desired product. The reaction mixture was then poured into a separation funnel. Add 200 ml of dichloromethaneAlkane and 100 ml of water for extraction. The dichloromethane layer was dried over MgSO4. The solvent was removed to give the crude product, which was passed through siliconThe column chromatography was eluted with a hexane / ethyl acetate mixture (5/1 to 2/1)To give pure 2-thiazol-2-yl-benzaldehyde (0.5 g, yield: 38percent).
Reference：
[1] Patent: US2008/153852, 2008, A1, . Location in patent: Page/Page column 20
[2] Patent: CN104045626, 2017, B, . Location in patent: Paragraph 0240
[3] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 18, p. 8607 - 8618
[4] Patent: EP1392687, 2017, B1, . Location in patent: Paragraph 0133-0136
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Reference：
[1] Synthesis, 2001, # 1, p. 128 - 134
40
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Reference：
[1] Patent: US2009/29993, 2009, A1,
41
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Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 38, p. 12605 - 12614
42
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Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 20, p. 5523 - 5527
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 13, p. 5800 - 5816
With hydrogen bromide; bromine; In water; at 20 - 100℃; for 4h;
Bromine (28mL) was added in aqueous hydrobromic acid (100mL, 20%) carefully, followed with 2-bromothiazole (20g) at room temperature. The resulting solution is warmed to reflux. After 4hr, the solution is cooled to room temperature, extracted with dichloromethane, washed with saturated sodium bicarbonate solution and dried. The solvent was removed to give yellow oil. The condensation product can be used for the next step without further purification. A mixture of fuming HNO3 (13mL) and Trifluoroacetic anhydride (40mL) was cooled to -20oC. The temperature of the system was keeped at -20oC about 2hr. Then 2,5-dibromothiazole (14g) was added dropwise for 1h and stirred at this temperature until complete. The solvent was removed and water was dropped in the residue slowly. The mixture was extracted with EtOAc, dried, concentrated and washed with petroleum ether to afford the crude yellow solid product. 3,5-dichloropyridine-4-thiol (2.3g) was dissolved in anhydrous methanol (50mL), followed with Sodium methoxide (690mg). The reaction mixture was stirred at 40oC for 2hr and then 2,5-dibromo-4-nitrothiazole (3.34g) was added. After 2.5hr at this temperature, solvent was removed. The residue was poured into water (50mL), extracted with EtOAc, dried. The yellow solid can be obtained via disturbing in petroleum ether without further purification. 1HNMR (CDCl3, 300 MHz) d (ppm): 8.73 (s, 2H); 13CNMR (CDCl3, 300 MHz) d (ppm): 171.5, 148.9, 137.1, 131.8, 126.6, 114.5. HRMS for C8H2BrCl2N3O2S2+H calcd. 385.8222 found 385.8221.
With hydrogenchloride; In tetrahydrofuran; hexane; water;
16a 4-(Thiazol-2-yl)-benzaldehyde Under argon, 9.2 g (379 mmol) of magnesium are placed in 84 ml of THF and heated to 60 C. A solution of 82.6 g (357 mmol) of 4-bromobenzaldehyde dimethyl acetal (for preparation see J. Org. Chem. 56, 4280 (1991)) in 677 ml of THF is added dropwise thereto within a period of 30 min and the mixture is stirred at boiling temperature for a further 40 min. The Grignard solution is cooled, decanted into a dropping funnel and added dropwise within a period of 30 min to a reddish suspension of 31.7 ml (338 mmol) of 2-bromothiazole (Fluka, Buchs, Switzerland) and 5.39 g (9.95 mmol) of DPPP in 1.68 litres of THF. The mixture is stirred at room temperature for 12 hours; a further 5.39 g of DPPP are added and the mixture is stirred for a further 7 hours. 840 ml of water are added and the mixture is stirred for 10 min; the THF is evaporated off using a rotary evaporator and the residue is stirred for 1.5 hours in 1.0 litre of ether and 340 ml of 2N HCl. The aqueous phase is separated off and extracted 2* with ethyl acetate. The organic phases are washed 2* with 0.5N HCl, water, sat. NaHCO3 solution, water and brine, dried (Na2 SO4) and concentrated by evaporation. Chromatography (SiO2; hexane/ethyl acetate 4:1) and digestion in hexane yield the title compound: TLC: Rf =0.21 (hexane/ethyl acetate 3:1); m.p: 91-92 C.; Anal. (C10 H7 NOS) calc. C 63.47, H 3.73, N 7.40, S 16.94: found C 63.14, H 3.79, N 7.27, S 17.08; 1 H-NMR (CDCl3) delta 10.05 (s, HCO), 8.15 (d, J=8, 2H), 7.95 (m, 3H), 7.45 (d, J=3, 1H).
With caesium carbonate;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; at 80℃; for 12h;
Example 262A 2-Phenylthiazole A solution of 2-bromothiazole (1.0 g, 6.1 mmol, Aldrich) in dioxane (25 mL) was treated with phenylboronic acid (0.82 g, 6.4 mmol), Pd(PtBu3)2 (0.16 g, 0.3 mmol, Strem) and Cs2CO3 (3.97 g, 12.2 mmol). The mixture was stirred at 80 C. for 12 hours. The reaction mixture was cooled to ambient temperature, concentrated under reduced pressure, and purified by column chromatography (SiO2, 1:1 hexanes/ethyl acetate) to give provide the title compound (0.69 g, 4.3 mmol, 70%). 1H NMR (CDCl3, 300 MHz) 67.33 (m, 1H), 7.41-7.48 (m, 3H), 7.87 (d, 1H, J=3.4 Hz), 7.95-8.00 (m, 2H); MS (DCl/NH3) m/z 162 (M+H+).
2-Bromothiazole 1 (2 equiv), 5-amino-2-R-phenol 2 (1 equiv) and 37percent HCl solution (2 equiv) in 10percent aqueous EtOH solution was stirred at 900C for 24h. The reaction mixture was diluted with ethyl acetate and washed with 5percent aqueous K2CO3 solution and brine. The organic phase was dried over Na2SO4, concentrated and the crude product was purified by flash chromatography on silica gel.; Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol, 2- bromothiazole (0.25 mL, 2.78 mmol), <strong>[6358-06-1]5-amino-2-chlorophenol</strong> (200 mg, 1.39 mmol) and 37percent HCl solution (0.24 mL, 2.78 mmol) in 10percent aqueous EtOH solution (5 mL) was stirred at 900C for 24h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 69 percent yield (217 mg).1H NMR (400 MHz, CD3OD) .pound. 7.34 (d, J= 2.5 Hz, IH), 7.21 (d, J= 3.7 Hz, IH), 7.18 (d, J= 8.6 Hz, IH), 6.88 (dd, J= 8.6, 2.5 Hz, IH), 6.76 (d, J= 3.7 Hz, IH); 13C NMR (125 MHz5CD3OD) .pound. 167.1, 155.0, 142.8, 139.8, 131.4, 114.7, 111.4, 109.7, 107.3.
With hydrogenchloride; In ethanol; water; at 80 - 90℃;Product distribution / selectivity;
The preparation of the analogues 4a-h involved the reaction between 2-bromotbiazole 1 with the corresponding 5-amino-2-R-phenol 2, followed by reaction with 4-bromo-2-methyl-2- butene in presence Of Cs2CO3 as a base (Scheme 1; see Table 1 for antiviral activities (EC50) and cytotoxicities (IC50) of these compounds, as determined using human MT-2 cells infected with IHB strain of HIV-I). EPO <DP n="25"/>Scheme 1. General synthesis for analogues 4a-h.
2-Bromothiazole 1 (2 equiv), 5-amino-2-R-phenol 2 (1 equiv) and 37% HCl solution (2 equiv) in 10% aqueous EtOH solution was stirred at 900C for 24h. The reaction mixture was diluted with ethyl acetate and washed with 5% aqueous K2CO3 solution and brine. The organic phase was dried over Na2SO4, concentrated and the crude product was purified by flash chromatography on silica gel.; Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol, 2- bromothiazole (0.94 mL, 10.4 mmol), <strong>[67608-58-6]4-amino-2-hydroxybenzonitrile</strong> (696 mg, 5.2 mmol) and 37% HCl solution (0.88 mL, 10.4 mmol) in 10% aqueous EtOH solution (20 mL) was stirred at 9O0C for 24h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 1/1) in 26 % yield (293 mg).1H NMR (500 MHz, CD3OD) £7.60 (d, J= 1.8 Hz, IH), 7.39 (d, J= 8.6 Hz, IH), 7.31 (d, J= 3.7 Hz, IH), 6.93 (dd, J= 8.6, 1.9 Hz, IH), 6.91 (d, J= 3.7 Hz, IH); 13C NMR (125 MHz,CD3OD) £ 165.4, 163.3, 148.5, 140.3, 135.1, 119.1, 111.2, 110.4, 104.5, 92.7.
With hydrogenchloride; In ethanol; water; at 80 - 90℃;Product distribution / selectivity;
The preparation of the analogues 4a-h involved the reaction between 2-bromotbiazole 1 with the corresponding 5-amino-2-R-phenol 2, followed by reaction with 4-bromo-2-methyl-2- butene in presence Of Cs2CO3 as a base (Scheme 1; see Table 1 for antiviral activities (EC50) and cytotoxicities (IC50) of these compounds, as determined using human MT-2 cells infected with IHB strain of HIV-I). EPO <DP n="25"/>Scheme 1. General synthesis for analogues 4a-h.
With 1-methyl-1H-imidazole;copper(l) iodide; In toluene; at 160℃; for 16h;Product distribution / selectivity;
In an autoclave, 1 equiv. of aryl halide or heteroaryl halide, 2 equiv. of 1-alkylimidazole, 0.1 equiv. of CuI, 0.2 equiv. of dried K4[Fe(CN)6] (potassium hexacyanoferrate(II)), tetradecane as an internal standard for the GC analysis and a suitable amount of toluene were combined under argon and heated to 160 C. (The K4[Fe(CN)6] was dried by heating powdered K4[Fe(CN)6]x3H2O in a vacuum of 1 mbar to 80 C. for at least 24 hours.) After 16 hours, the reaction mixture was cooled to room temperature. Conversion and yield were determinable by means of gas chromatography. An isolation of the product took place according to the customary workup (distillation, crystallization or chromatography).
63.58%
With copper(l) iodide; at 140℃; for 5h;Inert atmosphere;Catalytic behavior;
In the reaction vessel, 0.02 mol of K4[Fe(CN)6], a designed amount of CuI, and 50 mL of N-methylimidazole were sequentially added, and the temperature was raised to the designed temperature, and 0.1 mol of the injection pump was slowly added while stirring. 2-Bromothiazole, after the addition was completed, stirring was continued, and the reaction temperature was kept constant under nitrogen protection.After the reaction is completed, the temperature is lowered to room temperature, 50 mL of H 2 O is added, and then the organic solvent layer is extracted with a selected organic solvent (3×100 mL), the temperature is lowered to 0 C., concentrated hydrochloric acid is added until pH=2 to 3, and then the aqueous layer of hydrochloric acid is used. Extraction by organic solvent extraction (3 x 50 mL), combining all organic solvent layers, and then steaming to give 2-cyanothiazole. The target product is detected by nuclear magnetic resonance, and the hydrogen spectrum carbon spectrum of the target product is as follows:
5-thiazol-2-yl-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With johnphos; sodium t-butanolate;palladium diacetate; In 1,4-dioxane; at 80℃;
A mixture of 2-bromothiazole (200mg,1.22mmol), palladium acetate (15 mg, 0.06 mmol), sodium ferf-butoxide ( 217 mg, 2.26 mmol), (S1 S) 2,5-diaza- bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (280mg, 1.4 mmol) and 2-Di-t- butylphosphino)-biphenyl (37 mg, 0.118mmol) was stirred in dioxane (10ml) at 800C for overnight. The reaction was cooled, diluted with ethyl acetate (40 ml) and H2O (50ml).The organic layer was separated, dried (NaaSCu), filtered and solvent evaporated. The residue was purified by chromatography eluting with 5% MeOH/DCM yielding product as a white solid. (180 mg, 52% yield)
52%
With johnphos; sodium t-butanolate;palladium diacetate; In 1,4-dioxane; at 80℃;
A mixture of 27bromothiazole (200mg,1.22mmol),; palladium 5cetate,.(15. retag, . :0.06 mmol), sodium tert-butoxide ( 217 mg, 2.26 mmol), (S, S) 2,5-diaza- bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (280mg, 1.4 mmol) and 2-Di-t- butylphosphino)-biphenyl (37 mg, 0.118mmol) was stirred in dioxane (10ml) at 80 C for overnight. The reaction was cooled, diluted with ethyl acetate (40 ml) and H2O (50ml).The organic layer was separated, dried (Na2SO4), filtered and solvent evaporated. The residue was purified by chromatography eluting with 5% MeOH/DCM yielding product as a white solid. (180 mg, 52% yield)
With 1-methyl-1H-imidazole;copper(l) iodide; In 1-methyl-pyrrolidin-2-one; at 140℃; for 16h;sealed tube;
2-Bromothiazole (13.0 g, 1.0 eq), 1-methyl-imidazole (2.0 eq), Cul (0.05 eq) and K4[Fe(CN)6] (0.1 eq) were combined in 80 mL of dry NMP and heated in a sealed tube at 140 C for 16h. This mixture was extracted with EtOAc and solvent was removed from the organic fraction to give thiazole-2-carbonitrile (compound2-Im-2).
Synthesis of 3-methyl-1-thiazol-2-ylpiperazine 30.06 g (300.0 mmol) of 2-methylpiperazine were combined with 4.51 ml (50.0 mmol) of 2-bromothiazole. This mixture was fused and refluxed 5 min. The reaction mixture was cooled and taken up in 10% strength hydrochloric acid and washed with EA. The aqueous phase was set to pH>12 with a 10% strength aq. NaOH solution and then extracted with EA. The organic phase was dried over MgSO4 and conc. in vacuo. There were obtained 8.26 g (45.1 mmol, 90%) of 3-methyl-1-thiazol-2-ylpiperazine.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; toluene; at 115℃; for 24h;Inert atmosphere;
The (4-formylphenyl)boronic acid 118 (0.30 g, 2.0 mmol), 2-bromo-l,3-thiazole 119a (0.33 g, 2.0 mmol), Pd(PPh3)4(0.12 g, 0.1 mmol), aqueous solution of potassium carbonate (0.4 M, 5 mL), ethanol (5 mL) and toluene (2mL) were added to a 50 mL flask under nitrogen. The reaction mixture was stirred at 115 C for 24 hours and then cooled to room temperature. After removing the solvent, the crude residue was purified by column chromatography on silica gel using EA/hexane (1/5) as eluent. The product 120a was obtained as a white solid at a yield of 95%.
74%
With sodium carbonate;tetrakis(triphenylphosphine)palladium (0); In ethanol; water; toluene;
(1) A mixture of 2-bromothiazole (0.9 ml, 10 mmols), 4-formylphenylboronic acid (1.65 g, 11 mmols), sodium carbonate (2.65 g, 25 mmols), toluene (150 ml), ethanol (30 ml) and water (30 ml) was stirred in an argon atmosphere at room temperature for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.58 mg, 0.5 mmols) was added thereto and heated under reflux for 15 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, then dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography, and then recrystallized from ethyl acetate/hexane to give 4-(2-thiazolyl)benzaldehyde (1.4 g, 74 %).m.p. 91.5-92.5C Elemental Analysis for C10H7NOS: Calcd.: C, 63.47; H, 3.73; N, 7.40 Found: C, 63.67; H, 3.60; N, 7.316 1H-NMR (CDCl3) delta: 7.46(1H,d,J=3.2Hz), 7.95-7.99(3H,m),
998 mg (35%)
With sodium hydrogencarbonate;tetrakis(triphenylphosphine)palladium (0); In 1,2-dimethoxyethane; water;
REFERENCE EXAMPLE 72 4-(2-Thiazolyl)benzaldehyde A mixture of NaHCO3 (3.83 g, 45.6 mmol) and 4-formylphenylboronic acid (2.69 g, 18.0 mmol) in water (60 mL) was added to a solution of 2-bromothiazole (2.50 g, 15.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (500 mg, 0.43 mmol) in DME (60 mL). The reaction mixture was heated to reflux for 18 h, cooled to room temperature, diluted with ethyl acetate, washed with sat. aq. NaHCO3 and brine, dried with Na2SO4, and concentrated in vacuo. Two consecutive recrystallizations from hexanes/ethyl acetate yielded 998 mg (35%) of the title compound. MS 190 (M+H)+.
985 mg
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 20℃;Inert atmosphere; Reflux;
(1) 4-(thiazol-2-yl)benzaldehyde 2-Bromothiazole (0.538 ml, 6.06 mmol), 4-formylphenylboronic acid (1.0 g, 6.67 mmol), and Na2CO3 (1.61 g) were suspended in the mixed solution of toluene (25 ml), ethanol (5 ml), and H2O (5 ml). The mixture was stirred at room temperature for 15 minutes under an argon gas atmosphere. After reducing the pressure inside of the reaction container by using a vacuum line, the mixture was degassed by introducing Ar gas and this procedure was repeated twice. After that, tetrakis(triphenylphosphine)palladium (0.701 g, 0.606 mmol) was added, and the mixture was stirred for 15 hours by heating under reflux. The end point of the reaction was confirmed on TLC (EtOAc:n-hexane=1:4), and the mixture was cooled to room temperature. H2O (50 ml) and EtOAc (50 ml) were added and the mixture was stirred for 15 minutes. Black insoluble matter was removed by filtration with Celite and the filtrate was separated by the step of extraction/separation. The organic layer was washed with saturated brine (50 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified on silica gel column chromatography (EtOAc:hexane=1:3) to obtain the title compound (985 mg) as an opaque white solid.
ETHYL 2-[N-(1'-AMINOCITRACONAMIDO)]-4-(2'-THIAZOLYL)PYRIMIDINE-5-CARBOXYLATE[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With n-butyllithium; carbon dioxide;
Example 105 ETHYL 2-[N-(1'-AMINOCITRACONAMIDO)]-4-(2'-THIAZOLYL)PYRIMIDINE-5-CARBOXYLATE 2-Bromothiazole (8.25 g, 0.05 moles) in anhydrous ether (60 mL) is added dropwise to a solution of nBuLi (34 mL, 1.5M solution, 0.051 mmol) in anhydrous ether (60 mL) cooled to -78° C. and stirred for 30 minutes. Carbon dioxide is bubbled into the solution and after saturation is achieved, the reaction mixture is poured over dry-ice. H2 O (10 mL) is added and the mixture basified to pH=9 with NaOH (1N). The aqueous layer is acidified with concentrated HCl to pH <3 then extracted into ether, dried (MgSO4) and concentrated to provide the thiazole-2-carboxylic acid in 57percent yield (3.2 g); 1 H NMR (MeOD) delta 8.00 (d, 1H); 7.94 (d, 1H).
With n-butyllithium; potassium carbonate;tetrakis(triphenylphosphine)palladium (0); In tetrahydrofuran; deoxygenated toluene; ethanol; hexane; dichloromethane; ethyl acetate; acetone;
Example 37 2-Phenyl-5-thiazole sulfonamide 2-Bromothiazole (1.2 mmol, 0.11 mL) and phenylboric acid (1.2 mmol, 0.146 g) were added to a solution of potassium carbonate (2M, 1.2 mL) and ethanol (0.6 mL) in deoxygenated toluene (12 mL). The resulting mixture was degassed for 30 minutes, then tetrakistriphenylphosphine palladium (0.036 mmol, 0.042 g) was added and the solution heated at reflux for 48 hours. The solids were removed by filtration and the solution extracted with toluene (5x), dried (MgSO4), filtered and concentrated. The residue was subjected to flash chromatography (hexane followed with 5% ethyl acetate/hexane and then 10% ethyl acetate/hexane) to afford 0.13 g (69%) of <strong>[1826-11-5]<strong>[1826-11-5]2-phenylthiazol</strong>e</strong>. n-BuLi (0.86 mmol, 0.54 mL, 1.6M) was added dropwise to a -78 C. solution of <strong>[1826-11-5]<strong>[1826-11-5]2-phenylthiazol</strong>e</strong> (0.13 g, 0.82 mmol) in dry THF (8 mL). The solution was stirred for 1 h at -78 C., then SO2 gas was bubbled over the surface of the solution for 10 min. The solution was warmed to rt, then the solvent was removed and the residue taken up in CH2 Cl2 (8 mL) and NCS (0.11 g, 0.86 mmol) was added. After stirring at rt for 2 hour, the solution was filtered and the filtrate concentrated. The residue was dissolved in acetone (1 mL) and NH4 OH (1.6 mL) was added. After 10 min, the acetone was removed in vacuo and the aqueous extracted with EtOAc, dried (MgSO4) and concentrated. The residue was purified by flash chromatography using 30% EtOAc/hexane to give 0.093 g (47%) of 2 -phenyl-5-thiazole sulfonamide. m.p. 209-210 C. 1 H NMR (CD3)2 CO:
Under argon a solution of n-BuLi in hexanes (6.14 mmol, 2.5 M) was dropped into a stirred solution of 2-bromothiazole (3.07 mmol) in dry ether at 0 C. After 1 h the mixture was cooled to -78 C. and a solution of tributyltin chloride (3.07 mmol) in dry ether was slowly added and the mixture was stirred overnight. The mixture was then added to water (50 ml). The aqueous layer was extracted with ether (3×30 ml). The combined organic layers were dried with magnesium sulfate, and the solvent was removed in vacuo to give the title product L-01b as a pale brown oil in quantitative yield which was used for synthesis of compound L-01a without further purification.
97%
2-bromothiazole under a nitrogen atmosphere (4.0g, 24.38mmol) was dissolved in diethyl ether 80mL, and cooled to -78 . There, n-butyllithium 1.6M in hexane (15.5mL, 24.78mmol) was dropped over a period of 15 minutes, followed by stirring for 1 hour at -78 . In addition the tributyltinchloride (8.70g, 26.73mmol), and stirred for 30 minutes at -78 , was then stirred for a further 2 hours at room temperature. The reaction was quenched with water, the reaction product was extracted 4 times with ethyl acetate 50 mL. The organic phase was washed with saturated brine, dried over MgSO4, the solvent was removed under reduced pressure and filtered, Compound 5 (brown liquid, 8.85 g, yield: 97%) was obtained. Compound 5 was used in the subsequent reaction without further purification.
92%
Compound 2 is commercially available from Chemical Communications (Cambridge, United Kingdom), 49 (73), 8036-8038; 2013.To a dried reaction flask, 2-bromothiazole (10 g, 61.0 mmol) was added to diethyl etherwas dissolved in diethyl ether (100 mL) To this solution was added n-butyllithium (2.5 M in hexane,29 mL,67.1 mmol) was slowly added dropwise at -78 C.The reaction solution was reacted at -78 C for 1 hour,Tributyltin chloride (18.2 mL, 67.1 mmol) was slowly added dropwise at -78 C,The temperature of the reaction solution was gradually raised to room temperature.The reaction was terminated by adding water to the solution,The mixture was extracted with diethyl ether, and the organic layers were combined and dried using magnesium sulfate.After drying, the filter and filtrate were concentrated to give 21 g (92% yield) of the compound 2 [2- (tributylstannyl) thiazole as a brown oil (scheme 2).
90%
2-Tributylstannylthiazole; [Show Image] To a mixture of 2-bromothiazole (4.6 mL, 50 mmol) and anhydrous ether (50 mL), there was added an n-BuLi hexane solution (22 mL, 55 mmol) dropwise at -70C under nitrogen atmosphere, and the mixture was stirred for 30 minutes. A solution of n-Bu3SnCl (14 mL, 50 mmol) in ether (20 mL) was then added at -70C, and after stirring for 4 hours, the mixture was raised to room temperature and stirred for another hour. After adding water (50 mL), the organic layer was extracted three times with ether (50 mL), and the solvent was distilled away. It was then purified by silica gel chromatography (hexane: ethyl acetate = 20: 1) to yield the title compound (17 g, 90%). 1H-NMR (Bruker (ARX-300), 300 MHz, CDCl3) delta (ppm): 8.17 (1H, d, J = 3.05 Hz), 7.54 (1H, d, J = 3.05 Hz), 1.65-1.55 (6H, m), 1.38-1.19(12H, m), 0.89 (9H, t, J = 7.25 Hz).
90%
To a mixture of 2-bromothiazole (4.6 mL, 50mmol) and anhydrous ether (50 mL), there was added an n-BuLi hexane solution(22 mL, 55 mmol) dropwise at -70 C. under nitrogen atmosphere, and the mixturewas stirred for 30 minutes. A solution of n-Bu3SnCl (14 mL, 50 mmol) in ether (20 mL) was then added at -70C., and after stirring for 4 hours, the mixture was raised to room temperatureand stirred for another hour. After adding water (50 mL), the organic layer wasextracted three times with ether (50 mL), and the solvent was distilled away.It was then purified by silica gel chromatography (hexane:ethyl acetate=20:1)to yield the title compound (17g, 90%).
With n-butyllithium; In tetrahydrofuran; water;
Reference Example 48 2-(Tributylstannyl)thiazole To a solution of 10.0 g of 2-bromothiazole under nitrogen in 50 ml of tetrahydrofuran while cooling in a dry ice-acetone bath is added dropwise 36.6 ml of a 1.6M solution of butyl lithium via syringe. Stirring is continued for 1 hour. To the reaction mixture is added dropwise 29.8 g of tributyltin chloride in 20 ml of tetrahydrofuran. Stirred 1 additional hour. The reaction mixture is quenched with 20 ml of water and 50 ml additional water is added. After stirring for 20 minutes the reaction mixture is extracted with chloroform (3*60 ml). The organic layer is dried (Na2 SO4) and evaporated in vacuo to give 11.7 g of the desired product.
1.59 M n-butyllithium (13.0 ml, 20.7 mmol) in n-hexane was added dropwise to ether (24 ml). This solution was cooled to -78 C , and a solution of 2-bromothiazole (compound 128)(1.70 ml, 18.9 mmol) in ether (6 ml) was added dropwise to the solution. The reaction mixture was stirred at -78 C for 20 minutes, and a solution of tri n-butyl tin chloride (5.20 ml, 19.2 mmol) in ether (6 ml) was added dropwise to the mixture. The reaction mixture was stirred for 1 hour and warmed up to 0 C. 10 % Sodium hydrogen carbonate solution (24 ml) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with ether (24 ml). The combined organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure (50 C, 4 mmHg) to give yellow oil (7.15 g). This crude yellow oil (1.65 g) was purified by distillation (170 C, 0.4 mmHg) to give compound 129 as a colorless oil (1.28 g).
To a stirring solution of 2-bromothiazole 33 (5 g, 30.48 mmol) in diethyl ether (50 mL) under inert atmosphere was added -butyl lithium (12.2 mL, 33.53 mmol, 2.5 M solution in hexane) dropwise for 15 min at -70 C and stirred for 30 min. To this a solution of tributyltin chloride (10 mL, 30.48 mmol) in diethyl ether (15 mL) was added dropwise for 10 min at -70 C and stirred at the same temperature for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with diethylether (3 x 50 mL), washed with saturated potassium fluoride solution (50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford crude compound 34 (11 g) as brown color syrup. The crude was carried forward for next step without further purification. TLC: 30% EtOAc/ hexanes (R/. 0.2); 1H NMR (CDC13, 400 MHz): delta 8.17 (d, J= 3.0 Hz, 1H), 7.54 (d, J= 3.0 Hz, 1H), 1.58-1.50 (m, 6H), 1.34-1.27 (m, 6H), 1.16-1.10 (m, 6H), 0.89-0.83 (m, 9H) (NMR shows excess of tin reagent as impurity in the aliphatic region).
1,3-bis(diphenylphosphino)-propanenickel-(II) chloride[ No CAS ]
[ 24856-58-4 ]
[ 198904-53-9 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In tetrahydrofuran; diethyl ether; hexane; water;
Step 57.1 Under argon, 9.2 g (379 mmol) of magnesium are placed in 84 ml of THF and heated to 60 C. A solution of 82.6 g (357 mmol) of 4-bromo-benzaldehyde dimethyl acetal (for preparation see J. Org. Chem. 56, 4280 (1991)) in 677 ml of THF is then added dropwise thereto in the course of 30 min and the mixture is stirred at boiling temperature for a further 40 min. The Grignard solution is cooled, decanted into a dropping funnel and added dropwise in the course of 30 min to a reddish suspension of 31.7 ml (338 mmol) of 2-bromo-thiazole and 5.39 g (9.95 mmol) of 1,3-bis(diphenylphosphino)propane-nickel(II) chloride (Aldrich; Milwaukee/USA) in 1.68 liters of THF. The reaction mixture is stirred at RT for 12 hours; a further 5.39 g of 1,3bis(diphenylphosphino)-propane-nickel(II) chloride are added and stirring is continued for a further 7 hours. 840 ml of water are added, stirring is carried out for 10 min, the THF is evaporated off in a rotary evaporator and the residue is stirred in 1.0 liter of diethyl ether and 340 ml of 2N HCl for 1.5 hours. The aqueous phase is separated off and extracted twice with ethyl acetate. The organic phases are washed twice with 0.5N HCl, water, sat. NaHCO3 solution, water and brine, dried (Na2SO4) and concentrated by evaporation. Chromatography (SiO2; hexane/ethyl acetate=4:1) and digestion in hexane yield 4-(thiazol-2-yl)-benzaldehyde; TLC: Rf=0.21 (hexane/ethyl acetate=3:1); m.p. 91-92 C.
Synthesis of (R)-3-methyl-1-thiazol-2-ylpiperazine (R)-3-methyl-1-thiazol-2-ylpiperazine was obtained by reaction of 2-methylpiperazine with 2-bromothiazole under the conditions described above Precursor BBB14.
With potassium carbonate; In dimethyl sulfoxide; at 140℃; for 5h;
N-Boc-4-hydroxy-aniline (3.9 g, 0.019 mol) was combined with 2-bromothiazole (2.4 mL, 0.027 mol) in DMSO (20 mL) at room temperature. K2CO3 (3.9 g, 0.028 mol) was added and with rapid stirring, the reaction mixture was heated at about 140 C. for 5 hours. After cooling to room temperature, the reaction mixture was poured into water (300 mL), extracted with ethyl acetate (2×) and the combined organics were dried over MgSO4. Decolorizing charcoal was added, stirred for 30 minutes and filtered through a plug of celite and silica (1:1) to obtain an amber filtrate. The solvent was removed by rotary evaporation and the residue was purified by flash column chromatography (ethyl acetate:hexanes; 5% -50% ethyl acetate gradient) to give the title compound (1.4 g, 4.8 mmol, 25%) MS (ESI APCI) m/z 293.0 (M+H+); 1H NMR (300 MHz, DMSO-d6) delta 9.49 (s, 1 H) 7.53 (d, J=9.0 Hz, 2 H) 7.21-7.28 (m, 2 H) 7.16-7.19 (m, 2 H) 1.48 (s, 9 H).
With potassium carbonate; In dimethyl sulfoxide; at 160℃; for 4h;
A mixture of <strong>[18113-03-6]2-chloro-4-methoxy-phenol</strong> (7.93 g, 0.05 mol), 2-bromothiazole (9.0 g, 0.055 mol) and potassium carbonate (7.6 g, 0.055 mol) in dimethyl sulfoxide was heated at 160 C. under nitrogen for 4 hours. The solution was cooled and treated with water, and the aqueous phase was extracted with dichloromethane. The organic layer was washed with brine, dried and concentrated to give 30 g of the crude material, which was purified on a silica gel (ethyl acetate/hexane 5-35%) to afford 10.62 g of the product as a light yellow oil (88% yield), 1H NMR (300 MHz, CDCl3) delta ppm 3.81 (s, 3 H) 6.80 (d, J=4.04 Hz, 1 H) 6.85 (dd, J=9.19, 2.94 Hz, 1 H) 7.01 (d, J=2.94 Hz, 1 H) 7.19 (d, J=3.68 Hz, 1 H) 7.27 (d, J=8.82 Hz, 1 H). MS (ESI), m/z 241.9 (M+H)+.
81%
With potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 4h;Product distribution / selectivity;
To a suspension of <strong>[18113-03-6]2-chloro-4-methoxyphenol</strong> (10 g, 63 mmol) and K2CO3 (9.7 g, 69.4 mmol) in N,N-dimethyl formamide (120 mL) was added 2-bromothiazole (11.4 g, 69.4 mmol). The suspension was heated at 150 C. for 4 hours, cooled to ambient temperature, and poured into water (1000 mL). The mixture was extracted with ether (2×300 mL) and the combined ether layers were dried (MgSO4), filtered and concentrated. The resulting black oil was purified by flash chromatography on silica gel eluting with a solvent gradient from 10% to 25% ethyl acetate in hexanes to provide 12.3 g of the title compound (81%) as a light yellow liquid. 1H NMR (300 MHz, DMSO-d6) delta ppm 3.81 (s, 3 H) 7.01 (dd, J=9.01, 3.13 Hz, 1 H) 7.18-7.21 (m, 1 H) 7,23 (t, J=3.13 Hz, 2 H) 7.47 (d, J=9.19 Hz, 1 H); MS (ESI) m/z 241.9(M+H)+.
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; acetonitrile; at 160℃; for 0.0833333h;Microwave irradiation;
6.21. Synthesis of (S)-2-Amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(2-thiazol-2-yl-phenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid To a 40 ml microwave reactor, was added 1.04 g of 2-formyl phenylboronic acid (6.9 mmoles), 1.14 g of 2-bromo thiazole (6.9 mmoles), 240 mg of palladium bistriphenyl-phosphine dichloride (Pd(PPh3)2Cl2, 0.34 mmoles). Then, 13.8 ml of 1M Na2CO3 (13.8 mmoles) and 10 ml of CH3CN were added to the mixture. The reactor was sealed, and the reaction was run under microwave at 160 C. for 5 minutes. LCMS shows completion of the reaction with desired product. The reaction mixture was then poured into a separation funnel. Then 200 ml of methylene chloride and 100 ml of water were added for extraction. The methylene chloride layer was dried over MgSO4. Removal of solvent gave a crude product, which was purified by silica gel column chromatography eluding with hexanes/ethyl acetate mixture (5/1 to 2/1) to give pure 2-thiazol-2-yl-benzaldehyde (0.5 g, yield: 38%).
38%
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In acetonitrile; at 160℃; for 0.0833333h;Sealed tube; Microwave irradiation;
To a 40 ml microwave reactor was added 1.04 g of 2-formylphenylboronic acid (6.9 mmol) of 1.14 g of 2-bromothiazole(6.9 mmol), 240 mg of bistriphenyl-phosphine palladium dichloride (Pd (PPh3) 2Cl2, 0.34 mmol). then,To the mixture was added 13.8 ml of 1 M Na2CO3 (13.8 mmol) and 10 ml of CH3CN. Sealed reactor,The reaction was run under microwave at 160 C for 5 minutes.LCMS shows the desired reaction of the desired product. The reaction mixture was then poured into a separation funnel. Add 200 ml of dichloromethaneAlkane and 100 ml of water for extraction. The dichloromethane layer was dried over MgSO4. The solvent was removed to give the crude product, which was passed through siliconThe column chromatography was eluted with a hexane / ethyl acetate mixture (5/1 to 2/1)To give pure 2-thiazol-2-yl-benzaldehyde (0.5 g, yield: 38%).
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,2-dimethoxyethane; water; for 6h;Reflux;
Example 4 1-phenyl-8-[[2-(2-thiazolyl)phenyl]methyl]-1,3,8-triazaspiro[4.5]decan-4-one (Compound 24) Step A: To a mixture of 2-bromothiazole (826 mg, 4.99 mmol) and tetrakis(triphenylphosphine) palladium (0) (175 mg, 0.151 mmol) in 1,2-dimethoxyethane (20 mL) was added 2-formylbenzeneboronic acid (0.9017 g, 6.01 mmol) and 1 N aqueous NaHCO3 (8 mL). The resultant mixture was heated at reflux for 6 hrs. The reaction mixture was diluted with water and extracted with EtOAc (2 X 50 mL). The organic solution was dried over Na2SO4, filtered and concentrated. The crude product was purified by gradient flash chromatography (10% to 25% EtOAc in hexane) to yield 2-(2-thiazolyl)benzaldehyde as a white solid. MS (loop pos) MH+ = 190.1 1 H NMR (300 MHz, CDCl3) 7.50 (m, 1 H), 7.55-7.60 (m, 1 H), 7.65-7.70 (m, 1 H), 7.75-7.80 (m, 1 H), 7.95-7.97 (m, 1 H), 8.00-8.05 (m, 1 H), 10.5 (s, 1 H)
palladium bistriphenyl-phosphine dichloride[ No CAS ]
[ 40138-16-7 ]
[ 223575-69-7 ]
Yield
Reaction Conditions
Operation in experiment
With sodium carbonate; In dichloromethane; water; acetonitrile;
6.54. Synthesis of (S)-2-Amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(2-thiazol-2-yl-phenyl)-ethoxyl-pyrimidin-4-yl}-phenyl)-propionic acid To a 40 ml microwave reactor, was added 1.04 g of 2-formyl phenylboronic acid (6.9 mmoles), 1.14 g of 2-bromo thiazole (6.9 mmoles), 240 mg of palladium bistriphenyl-phosphine dichloride (Pd(PPh3)2Cl2, 0.34 mmoles). Then, 13.8 ml of 1M Na2CO3 (13.8 mmoles) and 10 ml of CH3CN were added to the mixture. The reactor was sealed, and the reaction was run under microwave at 160 C. for 5 minutes. LCMS shows completion of the reaction with desired product. The reaction mixture was then poured into a separation funnel. Then 200 ml of methylene chloride and 100 ml of water were added for extraction. The methylene chloride layer was dried over MgSO4. Removal of solvent gave a crude product, which was purified by silica gel column chromatography eluding with hexanes/ethyl acetate mixture (5/1 to 2/1) to give pure 2-thiazol-2-yl-benzaldehyde (0.5 g, yield: 38%).
2-bromo-1 ,3-thiazole (commercially available from Aldrich, 0.165 ml, 1.829 mmol) was dissolved in degassed 1 ,2-Dimethoxyethane (DME) (5 ml). Pd(Ph3)4 (106 mg, 0.091 mmol) was added. The reaction mixture was stirred at room temperature for 15min. [2,4- bis(methyloxy)-5-pyrimidinyl]boronic acid (commercially available from Aldrich, 707 mg, 3.84 mmol) and 5ml_ of degassed 1 M aqueous solution of NaHCO3 were added to the reaction mixture under N2 atmosphere. After 2h30min stirring at 900C, the reaction mixture was diluted with water and extracted with DCM. The collected organic phases were evaporated. The residue was purified by flash chromatography eluting with cyclohexane/EtOAc 5:1. 294 mg of the title compound were isolated as a yellow solid. MS (ES) (mlz): 224.06 [M+H]+.
Synthesis of Exemplary Compound 14: N-Methyl-N-(2-(methyl(thiazol-2-yl)amino)-2-oxoethyl)-3-phenylpropiolamide; a) Synthesis of N-methylthiazol-2-amine; 900 mul (10 mmol) of 2-bromothiazole were heated together with a 33% strength ethanolic methylamine soln. (70 ml) in an autoclave (to approx. 120 C.) until a pressure of 10 bar had developed. The mixture was stirred for 2 h under these conditions. The reaction mixture was then evaporated under a vacuum and the residue was redissolved in a 3% strength aq. HCl soln. and washed with ether, after which the pH was adjusted to 12 with a 20% strength aq. NaOH soln. The solution was saturated with NaCl and extracted with chloroform. The organic phase was dried over MgSO4, filtered and evaporated under a vacuum, 761 mg (6.7 mmol, 67%) of N-methylthiazol-2-amine being obtained.
With sodium hydride; potassium iodide; In N,N-dimethyl-formamide; at 0 - 140℃; for 23h;Inert atmosphere;
Example 2: Preparation of 2-(1 -methyl-5-trifluoromethyl-1 H-pyrazol-3-yloxy)-thiazole- 5-sulfonic acid (2-methoxy-pyridin-4-ylmethyl)-amide (Table I, example I-4) Example 2.1 : Preparation of 2-(1-methyl-5-trifluoromethyl-1 H-pyrazol-3-yloxy)-thiazole 1-Methyl-5-trifluoromethyl-1 H-pyrazol-3-ol (5.1 g) in dry DMF (50 ml) under nitrogen was treated at 00C with sodium hydride (0.82 g). After the initial effervescence ceased 2-bromothiazol (5 g) and Kl (4.4 g) were added. The mixture was stirred for 23 h at1400C, the solvent was removed by rotary evaporation and the residue was purified by flash column chromatography on silica gel (cyclohexan/ethyl acetate) to yield the title compound as yellow oil (4.94 g). 1H-NMR (CDCI3): d= 3.98 (s, 3H), 6.6 (s, 1 H), 6.9 (s, 1 H), 7.3 ppm (s,1 H)
To a stirred solution of 2-bromothiazole (0.90 g, 5.5 mmol) in anhydrous diethyl ether (10 mL), cooled to-70 C was added a solution of n-butyllithium (2.0 ML of 2.5 M solution in hexane, 5.0 mmol) under nitrogen by syringe and stirring was continued for 30 minutes AT-70 C. A solution of N- benzyloxycarbonyl pyrrolidine-3-carbaldehyde (1.17 g, 5.0 mmol) in anhydrous tetrahydrofuran (2 ML) was added by syringe AT-70 C, the mixture was stirred at - 70 C for 1 hour, and then it was allowed to warm to 0 C. The mixture was quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NH4CL solution, brine, dried over anhydrous NA2SO4 and concentrated under vacuum. Purification by flash chromatography over silica gel (hexane/ethyl acetate, 3: 2 to 1: 2) gave the title compound as pale yellow oil (Yield: 0.66 g, 42 %). H NMR (400 MHZ, CDCL3) 8 7.71 (m, 1H), 7.38-7. 24 (m, 6H), 5.10 (m, 2H), 4. 98-4. 87 (m, 1H), 4.07-3. 90 (m, 1H), 3.64-3. 28 (m, 4H), 2.72 (m, 1H), 1.98-1. 77 (m, 2H).
42%
To a stirred solution of 2-bromothiazole (0.90 g, 5.5 mmol) in anhydrous diethyl ether (10 mL), cooled to-70 C was added a solution of n-butyllithium (2.0 mL of 2.5 M solution in hexane, 5.0 mmol) under nitrogen by syringe and stirring was continued for 30 minutes AT-70 C. A solution of N- benzyloxycarbonyl PYRROLIDINE-3-CARBALDEHYDE (1.17 g, 5.0 mmol) in anhydrous tetrahydrofuran (2 ML) was added by syringe AT-70 C, the mixture was stirred at - 70 C for 1 hour, and then it was allowed to warm to 0 C. The mixture was quenched with saturated aqueous NH4C1 solution and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NH4C1 solution, brine, dried over anhydrous NA2SO4 and concentrated under vacuum. Purification by flash chromatography over silica gel (hexane/ethyl acetate, 3: 2 to 1: 2) gave the title compound as pale yellow oil (Yield: 0.66 g, 42 %). H NMR (400 MHz, CDC13) 8 7.71 (m, 1H), 7. 38-7. 24 (m, 6H), 5.10 (m, 2H), 4.98-4. 87 (m, 1H), 4.07-3. 90 (m, 1H), 3.64-3. 28 (m, 4H), 2.72 (m, 1H), 1.98-1. 77 (m, 2H).
To an oven-dried round bottomed flask cooled at -78 C. under N2, was added anhydrous Et2O (15 mL) and nBuLi (1.6 M in hexanes, 2.5 mL, 4.0 mmol, 1 eq.) sequentially. An Et2O solution (3 mL) of 2-bromothiazole (0.66 g, 4.0 mmol) was added to the above solution at -78 C. dropwise. The resulting solution was stirred at -78 C. to -70 C. for 20 min. To the lightly pale yellow solution, was added <strong>[149793-69-1]3-fluoro-5-trifluoromethyl-benzonitrile</strong> in THF (2 mL) dropwise at -78 C. The resulting mixture was stirred at -78 to -70 C. for 2.5 h. Pretreated TMSCl (10:1 v/v TMSCl:Et3N, then centrifuge at r.t. for 15 min, 0.51 mL of the clear solution, 1.01 eq) was added to the stirred mixture dropwise at -78 C. The resulting mixture was stirred at -78 to -60 C. for 15 min, then room temperature for 30 min, during which period the solution changed from dark brown to light tan. The reaction mixture was cooled back to -78 C., benzyl magnesium chloride (2.0 M in THF, 2.0 mL) was added dropwise. The resulting mixture was stirred at -78 C. for 15 min, then gradually warmed up to room temperature for 1.5 h. The reaction mixture was quenched by adding sat'd NH4Cl and 1 N HCl, and stirred for 20 min. The resulting crude reaction mixture was extracted with EtOAc, washed with 1N NaOH, sat'd NaHCO3, H2O, brine, dried over MgSO4, filtered, and concentrated to dryness in vacuo. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc, came out 20% EtOAc) to give racemic 1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl-1-(thiazol-2-yl)ethanamine as light brownish viscous oil (0.35 g, yield: 24%). LC-MS ESI (10-90% MeOH in H2O with 0.1% TFA in a 4-min run), retention time=2.97 min 367.04 (M+H), 350.02 (M-NH3). 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 7.78 (d, J=3.18 Hz, 1H), 7.66 (s, 1H), 7.52-7.61 (m, 1H), 7.08-7.19 (m, 5H), 6.82 (dd, J=7.6, 2.0 Hz, 2H), 3.86 (d, J=13.2 Hz, 1H), 3.35 (d, J=13.2 Hz, 1H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100.0℃; for 2.5h;Microwave irradiation;
To a mixture of 2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- benzonitrile (100 mg, 0.405 mmol), 2-bromothiazole (0.11 mL, 1.221 mmol), and K2CO3 (168 mg, 1.214 mmol) in 1,4-dioxane (1.5 mL) and water (0.5 mL) was added Pd(Ph3P)4 (5 mg, 0.004 mmol). The vial was capped and the reaction mixture was heated in a Biotage Initiator microwave reactor to 100 0C for 30 min followed by an additional 2 h at 100 0C. Water (4 mL) and EtOAc (5 mL) were added to the reaction mixture. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 3 mL). The combined organic layers were washed with brine (3 x 1 mL) and concentrated under a stream of nitrogen at 50 0C onto Isolute. Purification via flash column chromatography (0-20% EtOAc/hexanes) afforded the title compound (2.4 mg, 2.9%). LC-MS m/z 205 (M+H)+, 0.87 min (ret time).
tetrakis(triphenylphosphine) palladium(0); In toluene; at 125℃; for 48h;Inert atmosphere; Sealed pressure vessel;
A solution of 2-bromothiazole (2.85 g, 17.4 mmol), 2-(tributylstannyl)thiazole (5.00 g, 13.4 mmol) and tetrakistriphenylphosphine palladium (0.77 g, 0.67 mmol) in toluene (120 mL) was degassed under vacuum for several minutes, backfilled with nitrogen and heated in a sealed pressure vessel at 125 C for 48 h. The crude reaction mixture was concentrated and the residue was purified by column chromatography (0 to 30% ethyl acetate/hexanes) to yield 2,2'- bithiazole (2.21 g, 12.5 mmol, 93 % yield) as a white solid.[00166] LC-MS retention time 1.17 min; m/z 168.8 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nm. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MS data was determined using a MICROMASS Platform for LC in electrospray mode. XH NMR (300 MHz, CDC13) delta ppm 7.90 (d, J=3.3 Hz, 2H), 7.45 (d, J=3.3 Hz, 2H).
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 85℃; for 24h;Inert atmosphere;
At nitrogen atmosphere <strong>[668493-36-5]4'-(diphenylamino)biphenyl-4-ylboronic acid</strong> (1.06 g, 2.90 mmol), 2-bromothiazole (0.40 mL, 4.44 mmol), and Pd(PPh3)4 (0.080 g, 0.070 mmol) were weighted into a round-botton flask. An aqueous solution of Na2CO3 (2 M, 7 mL), 15 mL of toluene and 5 mL of ethanol were then added and the resulting solution was heated at 85 C for 1 day. The solvent was removed under vacuum and the residue was dissolved in CH2Cl2, washed with brine and dried over MgSO4. The crude product was purified by column chromatography using CH2Cl2 as the eluent to give a yellow intermediate (0.83 g, 71%). 1H NMR (400 MHz, CDCl3): delta 8.00 (d, JHH=8.4 Hz, 2H), 7.86 (d, JHH=3.2 Hz, 1H), 7.63 (dd, JHH=8.4 Hz, 2H), 7.50 (d, JHH=8.4 Hz, 2H), 7.31 (d, JHH=3.6 Hz, 1H), 7.26 (t, 4H), 7.14 (m, 6H), 7.03 (t, 2H). This yellow intermediate (0.70 g, 1.73 mmol) was further dissolved in 20 mL of THF under nitrogen and the solution was cooled using acetone bath to -78 C, n-butyl lithium (1.6 M in hexane, 1.18 mL, 1.90 mmol) was added to the cold solution via syringe in 5 min. After the solution was stirred for 35 min, 0.26 mL of DMF (0.87 mmol) was added all at once. The resulting mixture was stirred for 90 min at -35 C and was allowed to warm to room temperature and stirred for 30 min. The solution was then quenched by aqueous NH4Cl, diluted with Et2O, and washed with brine for several times. The organic extract was dried over MgSO4 and purified by column chromatography using hexanes/ethyl acetate (2:3, v/v) as the eluent. The product was obtained as a yellow powder (0.50 g, 58%).
General procedure: Aryl or heteroaryl bromide (4 mmol) was charged in oven dried Radley's synthesis tube that was equipped with a stir bar under a stream of nitrogen. Anhydrous diethyl ether was added and the reaction mixture was cooled to -78 C. n-BuLi (1.6 M in hexanes, 2.5 mL, 4.00 mmol) was added dropwise and the reaction mixture was stirred at -78 C for 10 min. A solution of aryl or heteroaryl nitrile in THF (4 mmol) was added dropwise and the reaction mixture was stirred at -78 C for 2 h. TMSCl (0.550 mL, 4.00 mmol) was added to the reaction mixture at -78 C and the reaction mixture was allowed to warm up to 0 C. The reaction mixture was cooled to -78 C, benzylmagnesium chloride in either THF or ether (2 mmol) or benzyl zinc(II) bromide in ether (2 mmol), was added dropwise, stirred at -78 C for 2 h, and then stirred at rt for 12 h. The reaction mixture was worked up and purified as in general procedure 1.
2-(2-methyl-lH-indol-5-yl)thiazole[00319] To a slurry of zinc dust (1.21 g, 18.6 mmol) in tetrahydrofuran (5 mL) was added 1,2-dibromoethane (0.144 mL, 1.67 mmol). This slurry was heated to a rapid boil with a heat gun twice (to incite evolution of ethylene). To this resulting slurry was addedchlorotrimethylsilane (0.0950 mL, 0.743 mmol) followed by a solution of 2-bromothiazole (1.02 g, 6.19 mmol) in tetrahydrofuran (3 mL). The reaction was stirred for 15 minutes, after which a solution of Pd(Ph3P)4 (0.143 g, 0.124 mmol) and 5-bromo-2-methyl-lH-indole (1.30 g, 6.19 mmol) was added. The reaction was refluxed at 95 °C for 24 hours, after which the reaction was cooled to room temperature, filtered through a pad of celite, extracted with dichloromethane (3 x 50 mL), dried (sodium sulfate), filtered and concentrated to an orange residue. Purification of the reaction mixture by silica gel chromatography (Luknova 120g, 20 mL/min) using 10 to 50percent ethyl acetate in hexanes over 60 minutes afforded 2-(2-methyl-lH- indol-5-yl)thiazole (640 mg, 2.99 mmol, 48 percent yield) as a yellow foam. 1H NMR (400 MHz, CDCI3) 6 (ppm): 8.12 (s, 1H), 8.08 (br. s, 1H), 7.82 (d, 1H), 7.76 (dd, 1H), 7.31 (dd, 1H), 7.24 (d, 1H), 6.28 (s, 1H), 2.45 (s, 3H).
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; at 80℃; for 16h;Inert atmosphere;
2.0 g (8.97 mmol) of the pyridyl boric ester, 1.47 g (8.97 mmol) of the 2-bromothiazole, 197 mg (0.27 mmol) of bis(diphenylphosphino)ferrocenepalladium(II) chloride and 3.72 g (26.9 mmol) of potassium carbonate were stirred under argon in 40 ml of dimethoxyethane at 80 C. for 16 h.For workup, the mixture was concentrated and purified by means of column chromatography on silica gel (eluent: cyclohexane/ethyl acetate).Yield: 778 mg (48% of theory)HPLC-MS: logP(HCOOH): 1.48; mass (m/z): 180.9 (M+H)+;1H NMR (d6-DMSO): 7.95 (m, 1H), 8.04 (m, 1H), 8.24 (m, 1H), 8.69 (m, 1H), 9.04 (m, 1H) ppm.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; for 18h;Reflux; Inert atmosphere;
To a stirred solution of 2-bromothiazole (1 .0 g, 6.1 mmol) in dioxane/water (20 / 5 mL) was added <strong>[87199-14-2](2-(hydroxymethyl)phenyl)boronic acid</strong> (1.4 g, 9.1 mmol), sodium carbonate (1 .29 g, 12.2 mmol), and Pd(PPh3)4 under nitrogen. The mixture was heated at reflux for 18 h. Afetr cooling to rt, water (50 mL) was added and aqueous was extracted with DCM (3 x 50 mL). The combined organic layer was dried and evaporated. The residue was purified by column chromatography to yield (2-(thiazol-2-yl)phenyl)methanol (0.95 g, 5.1 mmol).
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere;
5-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (1.25 g, 5.7 mmol), 2-bromo-thiazole (923 mg, 5.7 mmol), Cs2C03 (7.4 g, 22.8 mmol), Pd(PPh3)4 (200 mg) were stirred in 1,4-dioxane (15 mL) and water (3 mL) at 100 C under N2 for 4 h. Then the solvent was concentrated under reduced-pressure. The residue was dissolved in water and the aqueous phase was extracted with EtOAc (30 mL x3). The organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated to dryness under reduced pressure. The crude was purified via silica gel column (DCM/MeOH, 20/1) to afford 350 mg (yield: 35%) of 5- thiazol-2-yl-pyridin-3-ylamine. MS: m/z 177.9 (M+H+).
To a solution of 58 (120 mg, 0.74 mmol) in dimethylformamide (DMF) (1 mL) was added NaH (40 mg, 1.6 mmol). The mixture was stirred for 0.5 h at room temperature and 2- bromo-l,3-thiazole (125 mg, 0.74 mmol) was added. The reaction mixture was stirred for 1 h at room temperature. The reaction temperature was raised to 90C and stirred overnight. The reaction was quenched with MeOH and solvent was removed in vacuo. The residue was treated with water and EtOAc. The organic layer was separated and aqueous was extracted with EtOAc. The combined organic phase was dried over a2S04, filtered, and concentrated to give crude product. The crude product was purified on ISCO columns. Fractions containing pure product were combined and evaporated to give 59 (67 mg, 37%) as a yellow solid.
To a solution of 4-bromo-3 -methyl-1H-pyrazole 1 (12.8 g, 80 mmol) indimethylformamide (DMF) (150 mL) was added NaH (7.7 g, 320 mmol). The mixture was stirred for 0.5 h at room temperature and 2-bromo-l,3-thiazole (13 g, 80 mmol) was added. The reaction mixture was stirred for 1 h at room temperature. The reaction temperature was raised to 90C and stirred for overnight. The reaction was quenched with MeOH and solvent was removed in vacuo. The residue was treated with water and EtOAc. The organic layer was separated and aqueous was extracted with EtOAc. The combined organic phase was dried over Na2S04, filtered, and concentrated to give crude product. The crude product was purified on ISCO columns. Fractions containing pure product were combined and evaporated to afford 2 (8.1 g, 42%) as a yellow solid.
To a solution of 4-bromo-3-trifluoromethyl-lH-pyrazole 33 (0.645 g, 3 mmol) in dimethylformamide (DMF) (50 niL) was added NaH (0.2 g, 9 mmol). The mixture was stirred for 0.5 h at room temperature and the 2-bromo-l ,3-thiazole (0.76 g, 4.5 mmol) was added. The reaction mixture was stirred for 1 h at room temperature. The reaction temperature was raised to 90C and stirred for overnight. The reaction was quenched with MeOH and solvent was removed in vacuo. The residue was treated with water and EtOAc. The organic layer was separated and aqueous was extracted with EtOAc. The combined organic phase was dried over Na2S04, filtered, and concentrated to give crude product. The crude product was purified on ISCO columns. Fractions containing pure product were combined and evaporated to give 34 as a brown oil (0.45 g, 50%).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 85℃; for 7h;Inert atmosphere;
2-fluoro-5-(thiazol-2-yl)benzonitrile (THZ INT-1) A solution of 2-bromothiazole (25 g, 153.4 mmol), <strong>[214210-21-6](3-cyano-4-fluorophenyl)boronic acid</strong> (25.3 g, 153.3 mmol), K2CO3 (63.6 g, 460 mmol) and 3:1 DME/H2O (205 mL) was purged with N2 for 1 h before the addition of Pd(PPh3)4 (9.2 g, 7.9 mmol). The mixture was further degassed with N2 for 5 min and then heated to 85 C. for 7 h under N2. Upon cooling, the reaction mixture was diluted with EA (250 mL), washed with water (200 mL) and brine (200 mL), and dried over MgSO4. The reaction mixture was filtered and concentrated to give beige solid. The crude product was purified by recrystallization from 20% EA/hexanes to afford 22 g (71%) of 2-fluoro-5-(thiazol-2-yl)benzonitrile THZ INT-1 as a pale yellow solid. LCMS-ESI (m/z) calculated for C10H5FN2S: 204.2. found 205.0 [M+H]+, tR=3.26 min. 1H NMR (400 MHz, CDCl3) delta 8.21-8.16 (m, 1H), 8.15-8.08 (m, 1H), 7.86-7.81 (m, 1H), 7.36-7.32 (m, 1H), 7.27-7.21 (m, 1H).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 85.0℃; for 11.0h;Inert atmosphere;
Compound 13-3 (0406) To a mixture of 13-2 (257 mg, 1.57 mmol), K2CO3 (653 mg, 4.7 mmol) and 2-bromothiazole (367 mg, 1.57 mmol) in the mixed solvent (Dioxane/H2O=2/1, 15 mL) was added Pd(PPh3)4 (182 mg, 0.157 mmol). After having been degassed and recharged with nitrogen, the mixture was refluxed at 85 C. for 11 h. TLC showed that the reaction was complete. Water (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (PE:Acetone=10:1) to afford 13-3 as a yellow oil (229 mg, yield 76%).
General procedure: To a solution of aryl bromide (0.5 mmol, 0.2 M) in Et2O at -78 C was added n-butyl lithium (1.6 M in hexane, 0.6 mmol, 0.375 mL). After stirring at this temperature for 30 min, a solution of 2-choloroquinzoline (0.5 mmol) in Et2O (2 mL) was added dropwise at -78 C. The resulting reaction mixture was stirred at -78 C for 1 h, then allowed to warm to r.t. LC-MS analysis showed that starting materials had disappeared. A solution of DDQ (3 equiv) in THF (3 mL) was added dropwise and the resulting solution was stirred at r.t. for 2 h. H2O (20 mL) was added and the mixture was extracted with EtOAc (3 × 20 mL).The organic layer was washed with aqueous ammonium chloride solution, followed by brine, and then dried over sodium sulfate and concentrated in vacuo. The crude mixture was purified by silica gel flash chromatography to give 5a-g.
A flask which in 2-bromothiazole (16.4 g) and 50 ml of THF solution were put was cooled in an iced bath, and then 55 ml of a THF solution of 2 M isopropylmagnesium chloride was added dropwise there to under in a in nitrogen atmosphere while stirring the solution. After dropewise addition the rection mixture was stirred for 1 hour, and then a zinc chloride-tetramethylethylenediamine complex (30.3 g) was added. the resuting mixture was stirring for 1 hour at room temperature, and then 1-bromo-4-iodobenzene (28.3 g) and Pd(PPh3)4 (3.5 g) were added and then heated and stirred for 1.5 hours at reflux temperature. After cooling the reaction solution to room temperature, to remove the metal ions of the catalyst, a solution prepared by dissolving the compound ethylenediamine Inc. acid, use the sodium salt dihydrate equivalent to approximately 2-fold molar with respect to the objective to the appropriate amount of water (after and it stirred to fall abbreviated) EDTA · 4Na in an aqueous solution. Then, after removing also separated by adding toluene, and the solvent was distilled off under reduced pressure to the solution, and purified by silica gel column chromatography (eluent: toluene / ethyl acetate = 50/1 (volume ratio)) to give 2-(4-bromophenyl)thiazole (18.3g).
With C17H36ClN6NiP2(1+)*Cl(1-); In tetrahydrofuran; for 6h;Inert atmosphere;
General procedure: Substrate (0.1 mmol) and catalyst (2 mol%, 2 mumol) were mixed in 3 cm3 THF, organomagnesium reagent(1.3 mmol) was added at room temperature. After 6 h at 60 C, 1.5 cm3 NaCl solution (15%) was added carefully, the organic layer was dried over MgSO4, evaporated and purified via silica column chromatography.
With C17H36ClN6NiP2(1+)*Cl(1-); lithium chloride; In tetrahydrofuran; at 60℃; for 6h;Inert atmosphere;
General procedure: Substrate (0.1 mmol) and catalyst (2 mol%, 2 mumol) were mixed in 3 cm3 THF, organozinc reagent (1.3 mmol), and LiCl (1.3 mmol) were added at room temperature. After 6 h at 60 C, the solution was allowed to reach room temperature. NaCl solution (15%, 1 cm3) was added carefully, the organic layer was dried over MgSO4, evaporated and purified via silica column chromatography.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In tetrahydrofuran;Reflux;
1,4-Dibromo-2-nitrobenzene (4.60 g, 0.016 mol) and phenylboronic acid (2.0 g, 0.016 mol) were refluxed in toluene (40 ml) with a catalytic amount of Pd(PPh3)4 (568 mg, 0.492 mmol). 4-Bromo-2-nitro-1-phenylbenzene (3.17 g, 0.011 mol) was formed and then refluxed in triethylphosphite to yield 2-bromocarbazole.2-Bromocarbazole (1.27 g, 5.162mmol) and iodobenzene (0.87 ml,7.741 mmol) were refluxed to yield 2-bromophenylcarbazole. After consecutive reactions with n-butyllithium and trimethylborate,boronic acid (0.622 g, 2.167 mmol) prepared would react with 2-bromothiazole (0.16 ml, 1.734 mmol). The ligand L3 was obtained as a white powder (60%). Spectral data: MS (MALDITOF):m/z 326.36 (M+). 1H NMR (CDCl3): delta (ppm) 8.17 (t, J=8.8 Hz,2H, Ar), 8.05 (s, 1H, Ar), 7.87-7.85 (m, 2H, Ar), 7.66-7.52 (m, 2H,Ar), 7.52-7.48 (m, 2H, Ar), 7.46-7.38 (m, 2H, Ar), 7.33-7.29 (m, 2H,Ar).
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; at 80℃;Inert atmosphere;
To a solution of 2-bromo-1,3-thiazole (4.0 g), <strong>[269409-99-6]ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate</strong> (7.94 g) and 2M aqueous cesium carbonate solution (30 mL) in 1,2-dimethoxyethane (150 mL) was added tetrakis(triphenylphosphine)palladium(0)(1.41 g), and the mixture was stirred overnight at 80 C. under argon atmosphere. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution (100 mL), and the mixture was extracted twice with ethyl acetate (150 mL). The obtained organic layer was washed with saturated brine (30 mL), and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (3.99 g). MS: [M+H]+ 234.0.
General procedure: Methyl iodide (for mono-methoxyindoles: 47muL, 0.78mmol, 2.9eq; for di-methoxyindoles: 40muL, 0.66mmol, 2.9eq) was added to the mixture of Mg (for mono-methoxyindoles: 13.6mg, 0.54mmol, 2.0eq; for di-methoxyindoles: 11.6mg, 0.46mmol, 2eq) in dry Et2O (1.0mL) under argon at room temperature. After all magnesium was dissolved, ether was distilled off and dry benzene (0.50mL) was added to the reaction mixture. A solution of methoxyindole (for mono-methoxyindoles: 40mg, 0.27mmol, 1.0eq; for di-methoxyindoles: 40mg, 0.23mmol, 1.0eq) in dry benzene (1.5mL) was added drop wise to the reaction mixture. The reaction mixture was stirred for an additional 10min, followed by addition of 2-bromothiazole (for mono-methoxyindoles: 57muL, 0.57mmol, 2.1eq; for di-methoxyindoles: 48muL, 0.48mmol, 2.9eq) q) and heating at reflux for 24h. The reaction mixture was quenched with cold water, neutralized with HCl (5%) and extracted with EtOAc. The combined extracts dried and concentrated to dryness. The residue was fractionated by FCC on silica gel (EtOAc-hexane, 3:7) to afford camalexin (1a), methoxycamalexins 1c-1, 1h and 1k.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; toluene; at 80℃; for 12h;Inert atmosphere;
A mixture of 4-nitrophenyl)boronic acid (23.00 g, 137.78 mmol, 1.00 eq.), 2-bromothiazole (25.54 g, 155.69 mmol, 14.03 mL, 1.13 eq.), Na2C03 (36.51 g, 344.45 mmol, 2.50 eq.) and Pd(dppf)Cl2.CH2Cl2 (6.75 g, 8.27 mmol, 0.06 eq.) in Tol. (250.00 mL)/H20 (100.00 mL)/dioxane (250.00 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 80C for 12 hrs under N2 atmosphere and LCMS showed the reaction was complete. The mixture was concentrated and the residue was purified by column chromatography (Petroleum ethenEthyl acetate=50: l to 5: 1) to give 2-(4-nitrophenyl)thiazole (14.00 g, 67.89 mmol, 56.00% yield) as a yellow solid. 1H NMR (400MHz, CHLOROFORM-d) delta = 8.35 - 8.29 (m, 2H), 8.21 - 8.12 (m, 2H), 7.99 (d, J = 3.2 Hz, 1H), 7.50 (d, J = 3.2 Hz, 1H).
With palladium diacetate; sodium carbonate; triphenylphosphine; In water; N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere;
To a solution of (4-hydroxyphenyl)boronic acid (1.18 g, 8.54 mmol), Na2C03 (1.94 g, 18.30 mmol) and PPh3 (234 mg, 915.00 umol) in DMF (20 mL) was added to a solution of 2-bromothiazole (1 g, 6.10 mmol) in H20 (7 mL) followed with Pd(OAc)2 (41 mg, 183.00 umol). The mixture was stirred at 100 C for 2lh under N2. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with water (20 mL x 2) and brine (20 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column ( petroleum : ethyl acetate = ( 1:0 to 2:1) to afford compound 19A (343.9 mg, yield 29.27%) as brown solid. 1H NMR (DMSO-d6, 400MHz) d 9.96 (s, 1H), 7.84 - 7.70 (m, 3H), 7.60 (d, J = 3.2 Hz, 1H), 6.83 (d, J = 8.4 Hz, 2H). MS (ESI) m/z (M+H)+ 178.1.
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