* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With (iPrPNP)CoCH2SiMe3 In neat (no solvent) at 60℃; for 24 h;
EXAMPLE 9 - Borylation of Aromatic Five-Membered Heterocycle According to the reaction scheme illustrated in Figure 2(a), a scintillation vial (with a magnetic stir bar) was charged with cobalt complex (0.01 mmol) selected from 1-4, 2 methylfuran (1 mmol) and pinacolborane (1 mmol). The reaction was monitored by the analysis of an aliquot of the mixture by GC-FID. The mixture was allowed to stir to completion at room temperature and was quenched by exposure to air. The resulting solid was solubilized in CDC13, 1 ] 3 passed through a plug of silica gel in a Pasteur pipette and then analyzed by H and C NMR spectroscopy without further purification. If desired, the foregoing reaction can also be administered in 2 ml of tetrahydrofuran (THF). Figure 2(a) provides conversion percentages for cobalt complexes 1-4 with values in parenthesis as isolated yields. Further, Figure 2(b) details additional borylation products achieved with Co complexes 2 and 3 according to the foregoing reaction parameters.
Reference：
[1] Organic Letters, 2012, vol. 14, # 16, p. 4266 - 4269
[2] Patent: WO2015/89119, 2015, A1, . Location in patent: Page/Page column 34
[3] Chemistry - An Asian Journal, 2010, vol. 5, # 7, p. 1657 - 1666
[4] Tetrahedron, 2008, vol. 64, # 26, p. 6103 - 6114
[5] Organometallics, 2015, vol. 34, # 19, p. 4732 - 4740
[6] Organic Syntheses, 2005, vol. 82, p. 126 - 133
3
[ 765-58-2 ]
[ 476004-80-5 ]
Yield
Reaction Conditions
Operation in experiment
85%
With magnesium In tetrahydrofuran at 25℃; for 3 h; Inert atmosphere
General procedure: To a solution containing 4-IboxBpin (0.651 g,2.0 mmol) and anhydrous THF (8 mL) under Ar, Mg turnings (0.048 g,2.0 mmol) were added. The corresponding halide reagent (2.0 mmol) wasthen introduced dropwise over 5 min with constant stirring at 25 C. Thereaction was complete after 3 h, as evidenced by the disappearance of4-IboxBpin (d +21.6) via 11B NMR. 1 M HCl (3 mL) was then added to thereaction flask and left to stir for 5 min. The reaction mixture was thentransferred to a separatory funnel and extracted with diethyl ether(3 15 mL). The combined organic layers were dried over anhydrous MgSO4,filtered, and dried in vacuo, (25 C, 1 Torr) to afford the correspondingpinacolboronate.
Reference：
[1] Organic Letters, 2012, vol. 14, # 16, p. 4266 - 4269
[2] Journal of the American Chemical Society, 2015, vol. 137, # 38, p. 12211 - 12214
[3] Bulletin of the Chemical Society of Japan, 2017, vol. 90, # 3, p. 332 - 342
[4] Tetrahedron Letters, 2002, vol. 43, # 32, p. 5649 - 5651
[5] Advanced Synthesis and Catalysis, 2003, vol. 345, # 9-10, p. 1103 - 1106
[6] Organic Syntheses, 2005, vol. 82, p. 126 - 133
[7] Chemical Communications, 2017, vol. 53, # 77, p. 10640 - 10643
6
[ 76-09-5 ]
[ 476004-80-5 ]
Yield
Reaction Conditions
Operation in experiment
108 mg
at 20℃; for 1.5 h; Inert atmosphere
General procedure: In a glovebox filled with nitrogen, [Ir(OMe)(cod)]2 (33.1 mg, 0.050 mmol, 0.10 equiv), ICy·HCl(26.2 mg, 0.10 mmol, 0.20 equiv), NaOt-Bu (19.2 mg, 0.20 mmol, 0.40 equiv) andmethylcyclohexane (1.0 mL) were added to a 10 mL-sample vial with a Teflon-sealed screwcap, andstirred for 5 min at room temperature. A heteroarene (0.50 mmol, 1.0 equiv) and 1g (113.1 mg, 2.0equiv) were added, and then the cap was screwed on seal the vial. The vial was stirred at 110 °C for4 h. The reaction mixture was cooled to room temperature. Pinacol (236 mg, 2.0 mmol) in THF (2.0mL) was added and the reaction mixture was stirred under N2 at room temperature for 1.5 h. Thecrude mixture was filtered through a pad of Celite and eluted with EtOAc. The filtrate wasconcentrated in vacuo and sampled for analysis by 1HNMR spectroscopy using 1,2-dichloroethaneas an internal standard. The residue was purified by flash column chromatography over silica geleluting with hexane/EtOAc. Product-containing fractions were concentrated in vacuo to give a pureborylated product.
Reference：
[1] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 654 - 661
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃; for 8h;Inert atmosphere;
General procedure: Step 1 (0874) A solution of 2-bromo-5-fluorothiophene (LXXXV) (3 g, 16.57 mmol, 1.0 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (6.31 g, 24.86 mmol, 1.50 eq), Pd(dppf)Cl2 (1.21 g, 1.66 mmol, 0.10 eq) and KOAc (4.07 g, 41.43 mmol, 2.5 eq) in dioxane (100 mL) was de-gassed and then heated to 90 C. for 8 h under N2. TLC (EtOAc) showed the starting material was consumed completely. The reaction mixture was poured into H2O (10 mL). The mixture was extracted with EtOAc (3×50 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous MgSO4, concentrated in vacuum to give 2-(5-fluorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (LXXXVI), which was used directly for next step without further purification.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In N,N-dimethyl-formamide; at 90 - 100℃;
General procedure: After the bromine compound (1 equivalent) was dissolved in DMF,Bis (pinacolato) diboron (1.1 eq.), Pd (dppf) Cl2 (0.03 mmol)After addition of KOAc (3 eq) And stirred at 90 to 100 C. When the reaction was complete, DMF was removed by distillation and extracted with CH2Cl2 and water.The organic layer was dried over MgSO4 and concentrated. The resulting compound was purified by silicagel column and recrystallized to give product Sub2.
With (iPrPNP)CoCH2SiMe3; In neat (no solvent); at 60℃; for 24h;
EXAMPLE 9 - Borylation of Aromatic Five-Membered Heterocycle According to the reaction scheme illustrated in Figure 2(a), a scintillation vial (with a magnetic stir bar) was charged with cobalt complex (0.01 mmol) selected from 1-4, 2 methylfuran (1 mmol) and pinacolborane (1 mmol). The reaction was monitored by the analysis of an aliquot of the mixture by GC-FID. The mixture was allowed to stir to completion at room temperature and was quenched by exposure to air. The resulting solid was solubilized in CDC13, 1 ] 3 passed through a plug of silica gel in a Pasteur pipette and then analyzed by H and C NMR spectroscopy without further purification. If desired, the foregoing reaction can also be administered in 2 ml of tetrahydrofuran (THF). Figure 2(a) provides conversion percentages for cobalt complexes 1-4 with values in parenthesis as isolated yields. Further, Figure 2(b) details additional borylation products achieved with Co complexes 2 and 3 according to the foregoing reaction parameters.
With sodium hydrogencarbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 80℃; for 18h;Inert atmosphere;
Ethyl 5-amino-2-methylsulfanyl-4-(5-methylthiophen-2-yl)thienor2.3-d1pyrimidine-6-car- boxylate; A solution of 310 mg (3.69 mmol) of sodium hydrogencarbonate in 5 ml of water was added to a solution of 935 mg (3.08 mmol) of ethyl (theta-chloro-delta-cyano^-methylsulfanylpyrimidin^- ylsulfanyl)acetate and 758 mg (3.39 mmol) of pinacolyl 5-methylthiophene-2-boronate in 10 ml of DMF, and the mixture was heated to 8O0C under nitrogen. 108 mg (0.15 mmol) of bis(triphenylphosphine)palladium dichloride were added, and the mixture was stirred at 800C for 18 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was filtered with suction. The residue was washed with water, dried in vacuum and chromatographed on a silica-gel column with petroleum ether/tert-butyl methyl ether as eluent, giving ethyl 5-amino-2-methylsulfanyl-4-(5-methylthiophen-2-yl)- thieno[2,3-d]pyrimidine-6-carboxylate as yellow crystals; HPLC-MS: [M+H] 366.
With potassium phosphate;bis(dibenzylideneacetone)-palladium(0); XPhos; In water; butan-1-ol; at 100℃; for 20h;
Example 10Preparation of 3-benzyl-1,3,4-trimethyl-6-[1-[2-(5-methylthiophen-2-yl)pyridin-3-yl]meth-(4-ylidene]piperazine-2,5-dione134.5 mg of 4,4,5,5-tetramethyl-2-(5-methylthiophen-2-yl)-[1,3,2]dioxaborolane, 140.1 mg of K3PO4, 230 mg of 3-benzyl-6-[1-(2-iodopyridin-3-yl)meth-(Z)-ylidene]-1,3,4-trimethylpiperazine-2,5-dione (preparation see Ex. 3b), 57.2 mg of 2-dicyclohexyl-phosphino-2,4,6-triisopropyl-1,1-biphenyl and 28.8 mg (0.05 mmol) of bis(dibenzylideneacetone)palladium in 10 ml of n-butanol and 50 mul of water were stirred at 100 C. for 20 hours. After addition of about 20 ml of water, the reaction mixture was extracted 2× with in each case 30 ml of EA, the combined organic phases were dried and the solvent was removed under reduced pressure. The residue gave, after chromatography on silica gel (cyclohexane/EA), 110 mg of the title compound.HPLC-MS [m/z]: 431.9 [M+H]+
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃; for 0.75h;Inert atmosphere;
Example No. 81; Preparation of Compound No. 81[0378] To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH- pyrido[4,3-b]indole (100 mg, 0.281 mmol), 5-methylthiophene-2-boronic acid pinacol ester (0.13 ml, 0.562 mmol) and K2C03 (116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90 C for 45 min. The reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(5- methylthiophen-2-yl)phenyl)-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole as a TFA salt. 1H NMR (TFA salt, CD3OD) d (ppm): 7.8 (d, IH), 7.6 (t, IH), 7.5 (t, IH), 7.26-7.37 (m, 2H), 7.0 (d, IH), 6.8 (d, IH), 6.43-6.57 (m, 2H), 4.7 (m, IH), 4.4 (m, IH), 3.65 (m, IH), 3.42 (m, IH), 3.3 (m, 4H), 2.8 (m, IH), 2.4 (s, 3H), 2.27 (s, 3H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃; for 0.75h;
Example No. 81: Preparation of Compound No. 81[0369] To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH- pyrido[4,3-b]indole (100 mg, 0.281 mmol), 5-methylthiophene-2-boronic acid pinacol ester (0.13 ml, 0.562 mmol) and K2C03 (116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh )4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90 C for 45 min. The reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(5-methylthiophen-2- yl)phenyl)-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole as a TFA salt. 1H NMR (TFA salt, CD3OD) delta (ppm): 7.8 (d, IH), 7.6 (t, IH), 7.5 (t, IH), 7.26-7.37 (m, 2H), 7.0 (d, IH), 6.8 (d, IH), 6.43-6.57 (m, 2H), 4.7 (m, IH), 4.4 (m, IH), 3.65 (m, IH), 3.42 (m, IH), 3.3 (m, 4H), 2.8 (m, IH), 2.4 (s, 3H), 2.27 (s, 3H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 0.75h;Inert atmosphere; Reflux;
Example No. 79; Preparation of Compound No. 79[0376] To a solution of [5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH- pyrido[4,3-b]indole (100 mg, 0.25 mmol) in DME (2 mL) were added water (1 mL) and K2C03 (110 mg, 0.77 mmol) and purged the solution with N2. Pd(PPh3)4 (20 mg, 0.017 mmol) and 5-methylthiophene-2-boronic acid pinacol ester (0.15 mL, 0.628 mmol) were added to the reaction mixture which was refluxed under N2 for 45 min. The reaction mixture was cooled to RT and diluted with EtOAc. The aqueous layer was extracted with EtOAc (3x6 mL) and the combined organic layer dried over sodium sulfate. The solvent was removed under reduced pressure to afford crude material, which was purified by reverse phase HPLC. 1H NMR (TFA salt, CD3OD) d (ppm): 7.78 (d, 1H), 7.62 (d, 1H), 7.37 (s, 1H), 7.0 (d, 1H), 6.91 (d, 1H), 6.42 (d, 1H), 6.22 (d, 1H), 4.73 (m, 1H), 4.40 (m, 1H), 3.63 (m, 1H), 3.41 (m, 1H), 3.11 (s, 3H), 2.85 (m, 2H), 2.91 (s, 3H), 2.32 (s, 3H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water;Inert atmosphere;
Example No. 79: Preparation of Compound No. 79[0367] To a solution of [5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro- 1H- pyrido[4,3-b]indole (100 mg, 0.25 mmol) in DME (2 mL) were added water (1 mL) and K2CO3 (110 mg, 0.77 mmol) and purged the solution with N2. Pd(PPh3)4 (20 mg, 0.017 mmol) and 5- methylthiophene-2-boronic acid pinacol ester (0.15 mL, 0.628 mmol) were added to the reaction mixture which was refluxed under N2 for 45 min. The reaction mixture was cooled to RT and diluted with EtOAc. The aqueous layer was extracted with EtOAc (3x6 mL) and the combined organic layer dried over sodium sulfate. The solvent was removed under reduced pressure to afford crude material, which was purified by reverse phase HPLC. 1H NMR (TFA salt, CD3OD) delta (ppm): 7.78 (d, IH), 7.62 (d, IH), 7.37 (s, IH), 7.0 (d, IH), 6.91 (d, IH), 6.42 (d, IH), 6.22 (d, n . m, H , . m, H , . m, H , . s, H w n s, 3H), 2.32 (s, 3H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃; for 0.75h;Inert atmosphere;
Example No. 64; Preparation of Compound No. 64[0361] To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH- pyrido[4,3-b]indole (100 mg, 0.281 mmol), 5-methylthiophene-2-boronic acid pinacol ester (175 mg, 0.784 mmol) and K2C03 (162 mg, 1.1 mmol) in DME-water (2:1) was added Pd(PPh3)4 (22 mg, 0.019 mmol). The reaction mixture was stirred at 90 C for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(5-methylthiophen-2- yl)phenyl)-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 7.7 (d, 1H), 7.6 (m, 2H), 7.37 (s, 1H), 7.23 (m, 2H), 7.19 (d, 1H), 7.03 (d, 1H), 6.8 (s, 1H), 4.6 (m, 2H), 3.7 (m, 2H), 3.3 (m, 1H), 3.1-3.2 (m, 4H), 2.5 (s, 3H), 2.42 (s, 3H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃; for 0.75h;
Example No. 64: Preparation of Compound No. 64[0352] To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH- pyrido[4,3-b]indole (100 mg, 0.281 mmol), 5-methylthiophene-2-boronic acid pinacol ester (175 mg, 0.784 mmol) and K2C03 (162 mg, 1.1 mmol) in DME-water (2: 1) was added Pd(PPh3)4 (22 mg, 0.019 mmol). The reaction mixture was stirred at 90 C for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(5-methylthiophen-2-yl)phenyl)-2,3,4,5-tetrahydro-lH- n miD pynaoL^ -Djinaoie. H NMR (TFA salt, CD3OD) 0 (ppm): 7.7 (d, IH), / .o ^m, znj, / .;> / ^s,IH), 7.23 (m, 2H), 7.19 (d, IH), 7.03 (d, IH), 6.8 (s, IH), 4.6 (m, 2H), 3.7 (m, 2H), 3.3 (m, IH),3.1-3.2 (m, 4H), 2.5 (s, 3H), 2.42 (s, 3H).
(Z)-2-(2-(5-methylthiophen-2-yl)vinyl)isoindoline-1,3-dione[ No CAS ]
[ 1374010-83-9 ]
Yield
Reaction Conditions
Operation in experiment
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; toluene; at 50℃; for 24h;Inert atmosphere;
General procedure: To a solution of Pd(PPh3)4 (0.017 mmol, 19.3 mg), (E)-N-(2-iodovinyl)phthalimide (0.334 mmol, 100 mg), and 0.337 mmol of boronic acid (for the synthesis of compounds 2a-e and 2h-j) or boronic acid pinacol ester (for compounds 2f,g) in toluene (3.3 mL, 0.1 M) an aqueous K2CO3 (1 mmol, 0.5 mL, 2 M) and ethanol (5 mmol, 230 mg, 0.29 mL) were added. The reaction mixture was stirred at 50 C under an argon atmosphere for 24 h. The organic layer was concentrated and the crude product was preloaded onto silica. Products were purified by silica gel chromatography, eluting with EtOAc in n-hexane-0-50%.
Example 24; Stepl; The product of Example 22 (1.5g) and triethylamine (0.7 mL) were dissolved in methylene chloride (40 mL) and the mixture cooled in an ice bath. Triflic anhydride (0.4 mL) dissolved in methylene chloride (10 mL) was added in a 5 minutes period. After 5 minutes, the reaction mixture was passed through a silica gel plug and the product eluted using methylene chloride. The collected compound (1.5g) was dissolved in ethanol (50 mL) and toluene (50 mL). Then K2C03 (2.8g) dissolved in water (50 mL) and 5-methylthiophene-2-boronic acid pinacol ester (0.53 mL) were added. The mixture was bubbled with nitrogen for 5 minutes and then PdCI2 2PPh3 (0.14g) was added. The mixture was refluxed for 5 h and then extracted with ethyl acetate (150 mL). After evaporation of the solvents, the residue was purified by column chromatography using 6:1 hexanes ethyl acetate mixture as the eluent. NMR analysis indicated the structure of the product (0.7g) to be consistent with 3-(4-butoxyphenyl)-3-(4- methoxyphenyl)-5,7-difluoro-11 -(5-methythiophen-2-yl)-13, 3-dimethyl- indeno[2',3':3,4]naphtho[1 ,2-b]pyran.
In diethyl ether; dibutyl ether; at -78℃;Inert atmosphere;
General procedure: 4-Fluorophenylboronic acid neopentylglycol ester (187 mg, 0.9 mmol) was dissolved in dry Et2O (8 mL) and the solution cooled to -78 C. PhLi (1.8 M in n-Bu2O, 0.5 mL, 0.9 mmol) was then added slowly to the solution and the mixture was stirred at -78 C. The reaction was quenched after 30 min at -78 C with 5 mL 1 M aq HCl, and the biphasic mixture was stirred for 15 min at rt. The organic layer was then collected and the aqueous layer extracted with Et2O. All organic layers were combined, dried over Na2SO4 and concentrated in vacuo to obtain a yellow-orange viscous oil.
5-methyl-2,3-bisthiophene-5-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
General procedure: To 4-bromothiophene-2-carbaldehdyde (1, 0.704 mmol) 5% mol Pd(PPh3)4 was added in 1,4-dioxane under argon atmosphere. The reaction mixture was stirred at room temperature for 30 min. Arylboronicesters/acids (0.774 mmol), and potassium phosphate (1.409 mmol) were added along with water (1.5 mL) under an argon atmosphere. The solution was stirred at 90 C for 12 h and then cooled to room temperature. The organic layer was extracted using ethyl acetate, decanted and dried over magnesium sulphate. Then the solvent was removed under reduced pressure. The crude residue obtained was purified by column chromatography using n-hexane and ethyl acetate in 1:1 ratio to obtain the desired products, which were characterized by spectroscopic techniques.
2-(4-iodobutoxy)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane[ No CAS ]
[ 476004-80-5 ]
Yield
Reaction Conditions
Operation in experiment
85%
With magnesium; In tetrahydrofuran; at 25℃; for 3h;Inert atmosphere;
General procedure: To a solution containing 4-IboxBpin (0.651 g,2.0 mmol) and anhydrous THF (8 mL) under Ar, Mg turnings (0.048 g,2.0 mmol) were added. The corresponding halide reagent (2.0 mmol) wasthen introduced dropwise over 5 min with constant stirring at 25 C. Thereaction was complete after 3 h, as evidenced by the disappearance of4-IboxBpin (d +21.6) via 11B NMR. 1 M HCl (3 mL) was then added to thereaction flask and left to stir for 5 min. The reaction mixture was thentransferred to a separatory funnel and extracted with diethyl ether(3 15 mL). The combined organic layers were dried over anhydrous MgSO4,filtered, and dried in vacuo, (25 C, 1 Torr) to afford the correspondingpinacolboronate.
5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4, 3-b]indole[ No CAS ]
[ 476004-80-5 ]
[ 1393914-72-1 ]
Yield
Reaction Conditions
Operation in experiment
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 0.75h;
Example 162 Preparation of Compound No. 190 (1379) To a degassed solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 5-methylthiophene-2-boronic acid pinacol ester (100 mg, 0.575 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-DME (4 mL) and water (2 mL) was added Pd(PPh3)4 (17 mg, 0.0147 mmol). The reaction mixture was heated at 90 C. for 45 min. The reaction mixture was concentrated under reduced pressure and the residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(5-methylthiophen-2-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR, (CD3OD, TFA salt) delta (ppm): 7.3 (s, 1H), 7.0 (m, 2H), 6.71 (d, 1H), 6.58 (d, 1H), 4.72 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.51 (m, 1H), 3.12 (s, 3H), 3.03 (m, 4H), 2.8 (m, 2H), 2.4 (s, 3H), 2.2-2.3 (m, 5H).
N-((5'-methyl-[2,2'-bithiophen]-5-yl)sulfonyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
General procedure: To a 1,4-dioxane (3 mL) solution of 5-bromothiophene-2-sulfonylacetamide (3, 0.704 mmol) 5 mol%Pd(PPh3)4 was added and the resulting mixture stirred for 30 min at room temperature under a nitrogen atmosphere. Next, arylboronic acids and arylboronic esters (0.774 mmol), and potassium phosphate (1.409 mmol) were added along with water (1.5 mL) under a nitrogen atmosphere. The solution was stirred at 95 C for 30 h and later cooled to 20 C. Later on H2O was added and the reaction mixture was extracted with ethyl acetate to obtain an organic layer that was filtered and dried by the addition of MgSO4. The solvent was removed under reduced pressure. The residue was purified by column chromatography using ethyl acetate and n-hexane (1:1) to obtain the desired products which were characterized by spectroscopic techniques.
2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diazabenzo[f]azulene[ No CAS ]
[ 476004-80-5 ]
4-(1-methylpiperidin-4-yloxy)-2-(5-methylthiophen-2-yl)-9,10-dihydro-4H-3,10a-diazabenzo[f]azulene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; cesium fluoride; In 1,4-dioxane; at 100℃;Inert atmosphere;
To a solution of 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,55 10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 2A)(50 mg, 0.12 mmoles) in 1,4-dioxane (2.5 mL) in a screwcappedvial under argon are added 4-methylthiophene-2-boronicacid pinacol ester ( 40 mg, 0.18 mmole), PdC12 (dppf)2(6.7 mg, 12 f.tmole), CsF (36 mg, 0.24 mmoles). The reaction60 mixture is heated at 100 C. overnight. As the reaction is notcompleted, CsF (18 mg, 0.12 mmole) and PdC12 (dppf)2 (6.7mg, 12 f.tmole) are added and the reaction mixture is heated at100 C. overnight. Water is added, pH is made alkaline by adding concentrated ammonia solution and the aqueousphase is extracted three times with CH2Cl2 . The organicphase is dried over magnesium sulphate, filtered and thesolvent is removed under reduced pressure. The residue is concentrated ammonia solution and the aqueousphase is extracted three times with CH2Cl2 . The organicphase is dried over magnesium sulphate, filtered and thesolvent is removed under reduced pressure. The residue is NH40H) as eluent with a gradient from (98:2:0.2) to (96.5:3.5:0.35) followed by a purification on a preparative TLCover silica gel eluting with (9:1:0.1) to give 4-(1-methylpiperidin-4-y loxy )-2-( 5 -methylthiophen-2-y 1)-9, 1 O-dihydro-4H -3,1 Oa-diaza-benzo[ f]azulene.1HNMR: 7.38-7.20 (m, 5H), 7.09-7.05 (m, lH), 7.04-6.99(m, lH), 6.74 (s, lH), 5.66 (s, lH), 4.57-4.45 (m, lH), 4.32-4.18 (m, lH), 4.10-3.95 (m, lH), 3.62-3.48 (m, lH), 2.98-2.85 (m, lH), 2.75-2.58 (m, 2H), 2.30-2.20 (m, 6H), 2.20-1.95 (m, 3H), 1.95-1.55 (m, 3H).
5-(5-methylthiophen-2-yl)-4-nitropyridin-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61.8%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;
[0694] A solution of 4,4,5,5-Tetramethyl-2-(5-methylthiophen-2-yl)-l,3,2- dioxaborolane (XCIIX) (2.23 g, 9.95 mmol, 1.2 eq), 5-bromo-4-nitropyridin-3-amine (XCIII) (1.80 g, 8.26 mmol, 1.0 eq), Na2C03 (3.08 g, 29.01 mmol, 3.5 eq) and Pd(dppf)Cl2 (307.47 mg, 414.50 mutauetaomicron, 0.05 eq) in dioxane (40 mL) and H2O (8 mL) was de-gassed and then heated to 80C overnight under N2. TLC (PE:EtOAc=l : 1) showed the starting material was consumed completely. The reaction mixture was poured into H2O (300 mL). The mixture was extracted with EtOAc (3 x 250 mL). The organic phase was washed with saturated brine (300 mL), dried over anhydrous NaSO/t, concentrated in vacuum to give a residue. The crude product was purified by silica gel chromatography (PE:EtOAc=10: 1) to give 5-(5-methylthiophen-2-yl)-4-nitropyridin-3-amine (XCIV) (1.20 g, 5.10 mmol, 61.8% yield) as brown solid. ESIMS found C10H9N3O2S mlz 236.1 (M+H).
1.20 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;
Step 2 (0879) A solution of 4,4,5,5-Tetramethyl-2-(5-methylthiophen-2-yl)-1,3,2-dioxaborolane (XC) (2.23 g, 9.95 mmol, 1.2 eq), 5-bromo-4-nitropyridin-3-amine (XCI) (1.80 g, 8.26 mmol, 1.0 eq), Na2CO3 (3.08 g, 29.01 mmol, 3.5 eq) and Pd(dppf)Cl2 (307.47 mg, 414.50 mumol, 0.05 eq) in dioxane (40 mL) and H2O (8 mL) was de-gassed and then heated to 80 C. overnight under N2. TLC (PE:EtOAc=1:1) showed the starting material was consumed completely. The reaction mixture was poured into H2O (300 mL). The mixture was extracted with EtOAc (3×250 mL). The organic phase was washed with saturated brine (300 mL), dried over anhydrous NaSO4, concentrated in vacuum to give a residue. The crude product was purified by silica gel chromatography (PE: EtOAc=10:1) to give 5-(5-methylthiophen-2-yl)-4-nitropyridin-3-amine (XCII) (1.20 g, 5.10 mmol, 61.8% yield) as brown solid. ESIMS found C10H9N3O2S m/z 236.1 (M+H).
3-(5-methylthiophen-2-yl)-2-nitroaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61.79%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;
A solution of 3-bromo-2-nitroaniline (LXVIII) (1.80 g, 8.29 mmol, 1 eq), 4,4,5,5 -tetramethyl-2-(5 -methylthiophen-2-yl)- 1,3 ,2-dioxaborolane (CXI) (2.23 g, 9.95 mmol,1.2 eq) , Na2CO3 (3.08 g, 29.01 mmol, 3.5 eq) and Pd(PPh3)4 (307.47 mg, 414.50 jimol, 0.05 eq) in dioxane (30 mL) and water (6 mL) was de-gassed and then heated to 80C overnight under N2. TLC (PE: EtOAc= 1:1) showed the starting material was consumed completely. The reaction mixture was poured into H20 (300 mL). The mixture was extracted with EtOAc (3 x 250 mL). The organic phase was washed with saturated brine (300 mL), dried over anhydrous Na2504, concentrated in vacuum to give a residue. The cmde product was purified by silica gel chromatography (PE: EtOAc= 10:1) to give 3 -(5 -methylthiophen-2-yl)-2-nitroaniline (CXII) (1.20 g, 5.12 mmol, 61.79% yield) as a brown solid. ESIMS found for C,,H,0N2025 mlz 345.1 (M+H).
61.79%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere;
Step 1 (0893) A solution of 3-bromo-2-nitroaniline (LXVI) (1.80 g, 8.29 mmol, 1 eq), <strong>[476004-80-5]4,4,5,5-tetramethyl-2-(5-methylthiophen-2-yl)-1,3,2-dioxaborolane</strong> (CIV) (2.23 g, 9.95 mmol, 1.2 eq), Na2CO3 (3.08 g, 29.01 mmol, 3.5 eq) and Pd(dppf)Cl2 (307.47 mg, 414.50 mumol, 0.05 eq) in dioxane (30 mL) and water (6 mL) was de-gassed and then heated to 80 C. overnight under N2. TLC (PE:EtOAc=1:1) showed the starting material was consumed completely. The reaction mixture was poured into H2O (300 mL). The mixture was extracted with EtOAc (3×250 mL). The organic phase was washed with saturated brine (300 mL), dried over anhydrous Na2SO4, concentrated in vacuum to give a residue. The crude product was purified by silica gel chromatography (PE:EtOAc=10:1) to give 3-(5-methylthiophen-2-yl)-2-nitroaniline (CV) (1.20 g, 5.12 mmol, 61.79% yield) as a brown solid. ESIMS found for C11H10N2O2S m/z 345.1 (M+H).
N-(6-(5-methylthiophen-2-yl)benzo[d]thiazol-2-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
General procedure: The preparation of products 3a-3h was carried out under a nitrogen atmosphere. Compound 2 (synthesized by literature reported method [19]) (2.183 mmol) and 5 mol % Pd(PPh3)4 in 1,4-dioxane (20 mL) was mixed and stirred for 30 min. After 30 min K3PO4 (4.366 mmol), aryl boronic pinacol esters/aryl boronic acids (2.401 mmol), and H2O (1.5 mL) was added under inert atmospheric conditions. The mixture was stirred for 30 h at 95 C and cooled down to room temperature. Ethyl acetate was used for work up and the organic layer was separated and dried under vacuum. For purification purposes, column chromatography was done. The desired product was obtained by using ethyl acetate and n-hexane (20% and 80% respectively) as eluents. The desired products were characterized by various spectroscopic techniques [34].
3-(6-bromo-7-(difluoromethyl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide[ No CAS ]
[ 476004-80-5 ]
tert-butyl 3-[7-(difluoromethyl)-6-(5-methyl-2-thienyl)-3,4-dihydro-2H-quinolin-1-yl]-1-tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl tert-butyl ether; potassium carbonate; XPhos; In tetrahydrofuran; water; at 100℃; for 16h;Inert atmosphere;
To a vial was added tert-butyl 3 ..[6-bromo-7-(difluoromethyl)-3,4,4a,8a-tetrahydro-2H- quinolin- l-yl]-1 -tetrahydropyran-4-yl-6,7-dihydro-4H-pyrazolo [4,3 -cpyridine-5-earboxy1ate (intermediate R, 35.0 mg, 0.0617 mmol), 4,4,5,5 -tetramethyl-2-(5-methyl-2-thienyl)- 1,3,2- dioxaborolane (20.7 mg, 0.0925 mmol), K2C03 (39.3 mg, 0.185 mmol), 2-dicyclohexylphosphino-2?,4?,6?-lriisopropylbiphenyl (1.7 mg, 0.0037 mmol) and (2- dicyclohexylphosphino-2 ?,4 ?,6?-triisopropyl- 1,1 ?-biphenyl)[2-(2-arninoethyl)phenyl)Jpalladium(1I) chloride (1 .4 mg, 0.0018 mmol). THF (0.4 mL) and water (0.1 mL) were added and the mixture was sparged with an argon ballon before being heated to 100 C for 16 h under argon atmosphere. After cooling the reaction to room temperature,DCM (1 mL) was added and the reaction was filtered through celeit and concentrated in vacuo to give crude product that was purified by reverse phase preparative HPLC (acetonitrile 50-90% / 0.1 % formic acid in water) to give the title compound (25.1 mg, 70% yield) as a white solid. ?H NMR (400 MHz, DM80-cl6) S 7.11 (d, J 1.3 Hz, 1H), 6.99- 6,56 (m, 4H), 4.35 -4.23 (m, 1H), 4.06 (d, J= 1.9 Hz, 2H), 4.00-3.90 (in, 2H), 3.67-3.55(m, 4H), 3.49-3.41 (m, 2H), 2.88-2.81 (m, 2H), 2.79 (ddddd, J 5.1, 3.6, 3., 1.5, 1.0 Hz,LCMS M/Z (M+H) 585.
In tetrahydrofuran; at 20℃; for 1.5h;Inert atmosphere;
General procedure: In a glovebox filled with nitrogen, [Ir(OMe)(cod)]2 (33.1 mg, 0.050 mmol, 0.10 equiv), ICy·HCl(26.2 mg, 0.10 mmol, 0.20 equiv), NaOt-Bu (19.2 mg, 0.20 mmol, 0.40 equiv) andmethylcyclohexane (1.0 mL) were added to a 10 mL-sample vial with a Teflon-sealed screwcap, andstirred for 5 min at room temperature. A heteroarene (0.50 mmol, 1.0 equiv) and 1g (113.1 mg, 2.0equiv) were added, and then the cap was screwed on seal the vial. The vial was stirred at 110 C for4 h. The reaction mixture was cooled to room temperature. Pinacol (236 mg, 2.0 mmol) in THF (2.0mL) was added and the reaction mixture was stirred under N2 at room temperature for 1.5 h. Thecrude mixture was filtered through a pad of Celite and eluted with EtOAc. The filtrate wasconcentrated in vacuo and sampled for analysis by 1HNMR spectroscopy using 1,2-dichloroethaneas an internal standard. The residue was purified by flash column chromatography over silica geleluting with hexane/EtOAc. Product-containing fractions were concentrated in vacuo to give a pureborylated product.
5-fluoro-2-(5-methylthiophen-2-yl)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57.2%
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,4-dioxane; water; at 111℃; for 3h;Inert atmosphere;
2-Bromo-5-fluorobenzaldehyde (1 g, 4.93 mmol) was added to a stirred solution of 4,4,5,5-tetramethyl-2-(5-methylthiophen-2-yl)-l,3,2-dioxaborolane (1.987 g, 8.87 mmol) and sodium bicarbonate (0.828 g, 9.85 mmol) in 20 mL of l,4-Dioxane:water (4: 1). The reaction mass was degassed and flushed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.569 g, 0.493 mmol) was added to it and stirred at 111 C for 3 hours/ Reaction mixture was cooled, diluted with water and extracted with ethyl acetate (2 X 25 mL). The organic layer was washed with water (25 mL), brine (25 mL) and dried over sodium sulphate to obtain crude which was purified by column chromatography to provide 5-fluoro-2-(5-methylthiophen-2-yl)benzaldehyde. (0.650 g, 2.82 mmol, 57.2% yield). XH NMR (300 MHz, CDCI3) : delta 10.04 (d, J = 3.3 Hz, 1H), 7.66-7.57 (m, 3H), 7.05 (d, J = 3.3 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 2.51 (s, 3H); MS (m/z) : 221 (M+l).
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