* 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.
Reference：
[1] Organic Letters, 2004, vol. 6, # 19, p. 3337 - 3340
[2] Journal of Organic Chemistry, 2017, vol. 82, # 1, p. 76 - 85
[3] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 6, p. 515 - 518
[4] Patent: WO2005/811, 2005, A1, . Location in patent: Page/Page column 58; 123
2
[ 626-60-8 ]
[ 40138-16-7 ]
[ 176690-44-1 ]
Reference：
[1] European Journal of Organic Chemistry, 2012, # 31, p. 6248 - 6259,12
[2] European Journal of Organic Chemistry, 2012, # 31, p. 6248 - 6259
3
[ 1003-09-4 ]
[ 40138-16-7 ]
[ 99902-07-5 ]
Yield
Reaction Conditions
Operation in experiment
92%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene at 80℃; for 5 h; Inert atmosphere
In a 100-ml three-neck flask, 3.0 g (20 mmol) of compound a-1, 4.24 g (26 mmol) of compound a-2, 10.6 g(100.0 mmol) of sodium carbonate, 30 ml of toluene, 10 ml of ethanol, and 20 ml of water were placed, and in a nitrogen atmosphere, under stirring at room temperature, 693 mg of tetrakis (triphenylphosphine) palladium ( 0 ) was added thereto. The resulting mixture was heated to 80°C, and stirring was performed for 5 hours. After completion of the reaction, the organic layer was extracted with toluene and dried over anhydrous sodium sulfate, followed by purification by silica gel column chromatography (developing solvent:toluene/heptane mixture) to give 3.46 g (yield 92percent) of intermediate a-3 (white oil) .
Reference：
[1] Patent: WO2011/132623, 2011, A1, . Location in patent: Page/Page column 28-29
[2] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 6, p. 515 - 518
[3] Tetrahedron, 2008, vol. 64, # 38, p. 9033 - 9043
[4] Journal of Organic Chemistry, 2002, vol. 67, # 17, p. 6264 - 6267
4
[ 96-43-5 ]
[ 40138-16-7 ]
[ 99902-07-5 ]
Reference：
[1] European Journal of Organic Chemistry, 2012, # 31, p. 6248 - 6259,12
[2] European Journal of Organic Chemistry, 2012, # 31, p. 6248 - 6259
5
[ 188290-36-0 ]
[ 40138-16-7 ]
[ 99902-07-5 ]
Reference：
[1] Journal of Organic Chemistry, 2003, vol. 68, # 2, p. 578 - 580
6
[ 83813-73-4 ]
[ 40138-16-7 ]
[ 28272-96-0 ]
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 9, p. 3404 - 3410
7
[ 40138-16-7 ]
[ 26260-02-6 ]
Yield
Reaction Conditions
Operation in experiment
83%
With perfluoroisopropyl iodide; copper; hydroquinone In N,N-dimethyl-formamide at 20℃; for 24 h;
General procedure: (4-Nitrophenyl)boronic acid (0.067 g, 0.4 mmol), copper powder (0.0052 g, 0.08 mmol,), (CF3)2CFI (0.178 g, 0.6 mmol), and DMF (2 mL) were placed in a closed tube with a rubber stopper. The mixture was reacted at room temperature equipped with an air balloon for 24 h. The resulting suspension was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated to dryness. The crude product was purified by flash column chromatography on silica gel using petroleum ether/ethyl acetate = 20: 1 (v/v) as eluent to give 0.086 g of 2j as a light yellow solid (0.35 mmol, 87percent).
Reference：
[1] Journal of Fluorine Chemistry, 2016, vol. 189, p. 59 - 67
8
[ 380151-85-9 ]
[ 40138-16-7 ]
Reference：
[1] Tetrahedron Letters, 2005, vol. 46, # 46, p. 7899 - 7903
[2] Chemical Science, 2015, vol. 6, # 6, p. 3329 - 3333
9
[ 1229227-01-3 ]
[ 68-12-2 ]
[ 40138-16-7 ]
Yield
Reaction Conditions
Operation in experiment
93.0 g
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -80 - 20℃; Inert atmosphere Stage #2: With hydrogenchloride In tetrahydrofuran; hexane; water at 20℃;
Under nitrogen protection, the above-obtained o-bromobenzeneboronic acid trimer was added to anhydrous tetrahydrofuran (600 ml)After the addition, transfer to a 2 L three-necked flask and add dimethylformamide (87.7 g, 1.2 mol). Then cool the system to -70 ° C to -80 ° C, 520 ml (1.3 moles) of 2.5 M n-butyllithium hexane solution was slowly added dropwise, and the temperatureThe maximum temperature does not exceed -70 ° C, the addition is maintained at the temperature to continue stirring for 1-3 hours, then naturally rose to room temperatureMix 3-5 hours. TLC detection reaction is completed, the system cooled to 0 , adding 15percent hydrochloric acid aqueous solution quenching reaction, adjust the PHTo 1-2 to continue mixing at room temperature for 3-5 hours to ensure complete hydrolysis of the trimer. Distillation of the reaction solution, the organic solvent after distillation, solidAfter filtration, toluene was recrystallized to give 93.0 g of light gray solid o-aldehyde phenylboronic acid, HPLC: 99.0percentRate of 62percent.
Reference：
[1] Arkiv foer Kemi, 1957, vol. 10, p. 507,509
19
[ 40138-16-7 ]
[ 124-40-3 ]
[ 85107-53-5 ]
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 20, p. 6492 - 6495
20
[ 3034-53-5 ]
[ 40138-16-7 ]
[ 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
21
[ 3034-53-5 ]
[ 40138-16-7 ]
[ 223575-69-7 ]
Reference：
[1] Patent: US2009/29993, 2009, A1,
22
[ 4595-59-9 ]
[ 40138-16-7 ]
[ 640769-71-7 ]
Yield
Reaction Conditions
Operation in experiment
220 mg
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In water; acetonitrile at 150℃; for 0.0833333 h; Sealed tube; Microwave irradiation
The microwave vials (20 ml) were charged with 2-formylphenylboronic acid (290 mg, 2.0 mmol), 5-bromo-pyrimidine (316 mg,2.0 mmol) and 8 ml of acetonitrile. To the mixture was added 4 ml of an aqueous solution of sodium carbonate (1 M), followed by the addition of 100 mg of dichlorobis (triphenylYlphosphine) -palladium (II). The reaction vessel was sealed and heated at 150 & lt; 0 & gt; C for 5 minutes with microwave irradiation. After cooling the reaction mixtureExtracted with ethyl acetate. The organic layer was evaporated to provide a crude material which was purified by ISCO to give 220 mg of 2-pyrimidin-5-yl-benzaldehyde.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 18, p. 8607 - 8618
[2] Patent: US2008/153852, 2008, A1, . Location in patent: Page/Page column 27
[3] Patent: CN104045626, 2017, B, . Location in patent: Paragraph 0318
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In acetonitrile; at 60℃; for 72h;
To Pd (PPh3) 4 (0.085g, 0. 07mmol) in acetonitrile (6mL), under nitrogen, was added water (2mL) followed by 2-formylphenylboronic acid (0. 55g, 3. 68mmol), 3-bromopyridine (0.36 mL, 3.68mmol) and potassium carbonate (2.69g, 22. 07mmol). After stirring for 3 days at 60C, the reaction mixture was purified by flash chromatography on silica, eluting with ethyl ACETATE/ISOHEXANE (10: 90 to 30: 70), to give the title compound as an oil. MS: [M+H] = 184.
4'-(2-methoxyethoxy)-1,1'-biphenyl-2-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53.1%
With caesium fluoride;tetrakis(triphenylphosphine) palladium(0); In Dimethyl ether; at 65 - 80℃; for 20h;
The <strong>[39255-23-7]1-bromo-4-(2-methoxyethoxy)benzene</strong> obtained in the preceding step (2.30 g; 10.0 mmol), 2-formylphenylboronic acid (1.4 eq.; 14 mmol; 2.10 g) and caesium fluoride (3.0 eq. ; 30.0 mmol; 4.56 g) are dissolved in 38 ml of DME, and tetrakis(triphenylphosphine)palladium (0.3 mmol; 0.347 g) is then added and the reaction medium is heated at 65C for 16 hours, and then at 80C for 4 hours. The mixture is allowed to cool to room temperature and 15 ml of ethyl ether are then added; the reaction medium is washed twice with 45 ml of water, and then dried over sodium sulfate and evaporated to dryness. The crude product is purified by flash chromatography on silica (eluting with heptane 0-100 % DCM) to give 1.36 g of the expected product in the form of an oil. TLC (1/1 heptane/EtOAc): Rf = 0.54 Yld = 53.1 % ¹H NMR (300 MHz, chloroform-D) No. ppm: 3.5 (s, 3 H) ; 3.8 (m, 2 H) ; 4.2 (m, 2 H) ; 7.0 (m, 2 H) ; 7.3 (m, 2 H) ; 7.5 (m, 2 H) ; 7.6 (m, J = 7.5; 1.5 Hz, 1 H) ; 8.0 (dd, J = 7.5; 1.2 Hz, 1 H) ; 10.0 (d, J = 0.8 Hz, 1 H).
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; acetonitrile; at 150℃; for 0.08333330000000001h;Microwave irradiation;
6.34. Synthesis of (S)-2-Amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(2-pyrimidin-5-yl-phenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid A microwave vial (20 ml) was charged with 2-formylphenylboronic acid (290 mg, 2.0 mmol), 5-bromo-pyrimidine (316 mg, 2.0 mmol) and 8 ml of acetonitrile. To this mixture was added 4 ml of aqueous sodium carbonate (1M), followed by 100 mg of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150 C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was extracted with ethylacetate. The organic layer was evaporated to provide a crude material, which was purified by ISCO to give 220 mg of 2-pyrimidin-5-yl-benzaldehyde.
220 mg
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In water; acetonitrile; at 150℃; for 0.08333330000000001h;Sealed tube; Microwave irradiation;
The microwave vials (20 ml) were charged with 2-formylphenylboronic acid (290 mg, 2.0 mmol), 5-bromo-pyrimidine (316 mg,2.0 mmol) and 8 ml of acetonitrile. To the mixture was added 4 ml of an aqueous solution of sodium carbonate (1 M), followed by the addition of 100 mg of dichlorobis (triphenylYlphosphine) -palladium (II). The reaction vessel was sealed and heated at 150 & lt; 0 & gt; C for 5 minutes with microwave irradiation. After cooling the reaction mixtureExtracted with ethyl acetate. The organic layer was evaporated to provide a crude material which was purified by ISCO to give 220 mg of 2-pyrimidin-5-yl-benzaldehyde.
6.66. Synthesis of (S)-2-Amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(2-pyrimidin-5-yl-phenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid A microwave vial (20 ml) was charged with 2-formylphenylboronic acid (290 mg, 2.0 mmol), 5-bromo-pyrimidine (316 mg, 2.0 mmol) and 8 ml of acetonitrile. To this mixture was added 4 ml of aqueous sodium carbonate (1M), followed by 100 mg of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150 C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was extracted with ethylacetate. The organic layer was evaporated to provide a crude material, which was purified by ISCO to give 220 mg of 2-pyrimidin-5-yl-benzaldehyde.
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 150℃; for 0.166667h;microwave irradiation;
<Sterho 4>; 4-Bromo-2-methylisoindolin-l-one (60 mg, 0.26 mmol) obtained in Step3, 2-formylphenylboronic acid (48 mg, 0.32 mmol), tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol) and cesium carbonate (259 mg, 0.80 mmol) were dissolved in a 1 mi ethanol-2 mi toluene mixture and placed in a vessel. The vessel was sealed using aseptum, and heated for 10 min at 150C in a microwave reactor and cooled to room temperature. The reaction mixture was filtered through a cellite column while washing with ethyl acetate, and the solvent was evaporated under a reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 5-methyldibenzoindol-4(5H)-one (62 mg (99%)).1H NMR (300 MHz, CDCl3) delta 8.62-8.51 (m, 2H), 8.12-8.08 (m, IH), 7.90-7.80 (m, 2H), 7.65-7.54 (m, 2H), 7.10 (s, IH), 3.52 (s, 3H).
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; N,N-dimethyl-formamide; at 110℃; for 2h;Microwave irradiation; Inert atmosphere;
General procedure: Method B: In a20 mL microwave Biotage tube, a 1M Na2CO3 aqueous solution(5 mL) purged with argon were introduced into a mixture purged with argon of <strong>[71759-89-2]4-iodo-1H-imidazole</strong> (1a) (0.194 g, 1.0 mmol), a boronicacid 2 (1.6 mmol) and Pd(PPh3)4 (0.80 g, 0.05 mmol) in DMF (15 mL). The mixture washeated under microwaveirradiation. When the reaction was complete, the mixture was cooled toroom temperature and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel to provide compounds 3j and 3p-3u in yields ranging from 30 to 95%. Time and temperaturereactions were collected in Table 1.
2-(6'-oxo-1'-phenyl-1',6'-dihydro-[2,3'-bipyridin]-5'-yl)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8 g
With palladium diacetate; caesium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 110 - 120℃;
240 ml of dimethyl formamide 10.0 gm of 5'-bromo- -phenyl-[2,3'-bipyridin]- 6'-(l'H)-one, 9.165 gm of 2-formyl phenyl boronic acid and 19.9 gm of cesium carbonate were charged in to a RBF. To the resulting reaction mixture Palladium (II) Acetate (0.171 gm) and triphenyl phosphine (0.8 gm) were added, reaction mixture was heated to 110 to 120C. After completion of reaction, the reaction mixture was filtered and the filtrate was cooled to precipitate the solid. The solid was dried under vacuum at below 70C for 12 hrs to give 8.0 gm of title compound.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 16h;Inert atmosphere;
To a single-necked flask was added <strong>[87941-55-7]4-bromo-1-trityl-1H-imidazole</strong> (1.5 g, 3.9 mmol)Sodium carbonate (1.2 g, 11.7 mmol),2-formylbenzeneboronic acid (864 mg, 5.8 mmol) and DMF (10 ml)Water (2 ml), the reaction system was filled with nitrogen,Tetrakis (triphenylphosphine) palladium (242 mg, 0.195 mmol) was added under nitrogen,90 C for 16 h, add water,Ethyl acetate, the combined organic layers were dried over anhydrous sodium sulfate, the solvent was concentrated,Purification by column chromatography on silica gel afforded compound 8 (930 mg, yield 58%).
2-(1-trityl-1H-imidazol-5-yl)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 4h;Inert atmosphere;
2-formylphenylboronic acid (15.0 g, 0.1 mol), <strong>[87941-55-7]4-bromo-1-trityl-1H-imidazole</strong> (38.8 g,0.1 mol) and K2CO3(27.6 g, 0.2 mol) 500mL single-necked flask, add 200mL dioxane and 20mL water dissolved.System setafter the change of nitrogen was added Pd (dppf) CI2(1.5 g, 2.3 mmol).The reaction mixture was stirred at 90 & lt; 0 & gt; C under nitrogen for 4 h.TLCafter completion of the detection reaction, the reaction solution was poured into 500mL water, EA (200mLx3), the combined organic phase with saturated NaCl, dried over anhydrous Na2SO4 dried sufficiently, spin dry by column chromatography (PE / EA = 20/1 )To give 31 g of the title compound as ayellow solid in 75% yield.
With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate; In dimethyl sulfoxide; at 90℃; for 6h;Inert atmosphere;
General procedure: 2-bromobenzaldehyde (1 mmol), 2-formylphenylboronic acid (1.2 mmol), Pd(PPh3)2Cl2 (10 mol%) and K3PO4 (1.5 mmol) was taken in a two neck round bottomed flask. 5 mL DMSO was added to it and the reaction mixture was degassed properly with N2. Next the reaction was allowed to stir at 90 oC for 6 h. After the completion of the reaction, the reaction mixture was cooled to room temperature and to it were added CuCl (5 mol %) and TBHP (3 equivalent). It was stirred for another 1 h at rt. Then it was diluted with water and extracted with ethyl acetate several times. The organic parts were collected together and concentrated under vacuum after drying over Na2SO4. Products were purified by column chromatography using 60-120 mesh silica gel and 5:1 pet ether : ethyl acetate as the eluent.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 20℃;Inert atmosphere;
Add 32.4g (100mmol) 4,6-dibromodibenzothiophene and 112.8g (300mmol) 2-formylbenzeneboronic acid to a freshly dried 3000mL two-necked bottle, add 62.1g (450mmol) under nitrogen protection Anhydrous potassium carbonate, 6.9 g (6 mmol) of tetratriphenylphosphine palladium, and 225 mL of water and 1500 mL of 1,4-dioxane. After the reaction, the temperature was lowered to room temperature, and the solvent of the reaction system was distilled off under reduced pressure. The crude product was dissolved in 500 mL of dichloromethane and washed with a large amount of water. The organic phase was dried over anhydrous sodium sulfate and concentrated. Dichloromethane: petroleum ether = 1: 1 was used as the eluent for column chromatography to obtain 30 g of off-white solid with a yield of 80%.
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