Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 680596-79-6 | MDL No. : | MFCD04115656 |
Formula : | C14H23BO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JCHWHOHZZYWUMP-UHFFFAOYSA-N |
M.W : | 266.14 | Pubchem ID : | 3697076 |
Synonyms : |
|
Num. heavy atoms : | 19 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.86 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 73.86 |
TPSA : | 36.92 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.7 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 1.73 |
Log Po/w (WLOGP) : | 2.47 |
Log Po/w (MLOGP) : | 1.16 |
Log Po/w (SILICOS-IT) : | 1.65 |
Consensus Log Po/w : | 1.4 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.51 |
Solubility : | 0.815 mg/ml ; 0.00306 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.12 |
Solubility : | 2.01 mg/ml ; 0.00756 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.92 |
Solubility : | 0.32 mg/ml ; 0.0012 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 4.38 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 110℃; for 10 h; Inert atmosphere | 1,4-dioxaspiro [4.5] sunene-7-ene-8-trifluoromethanesulfonate (500 mg, 1.73 mmol)1,4-dioxane (8 mL)Potassium acetate (260 mg, 2.64 mmol) was added sequentially to the solution,Which aliphatic alcohol (530mg, 2.08mmol) with boronic acid,Pd (dppf) Cl2 (130 mg, 0.17 mmol), nitrogen,110 ° C for 10 hours, filtered,Concentrated column chromatography (petroleum ether / ethyl acetate (v / v) = 2/1) gave 540 mg of a yellow oil in 99percent yield. |
95% | With potassium acetate In 1,4-dioxane at 80℃; Inert atmosphere | Synthesis of 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)-1,3,2-dioxaborolane A solution of 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethane-sulfonate (1.0 equiv.) in dioxane (0.5 M) was purged with nitrogen for 30 min. Then 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.0 equiv.), KOAc (3.0 equiv.), Pd(dppf)Cl2-DCM (0.2 equiv.) were added and the solution was stirred in a sealed bomb at 80° C. The reaction was filtered over a pad of celite, then to the filtrate was added ethyl acetate, and washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column (ethyl acetate:hexanes=1:1) to give 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (95percent). LC/MS (m/z): MH+=267.1, Rt=0.95. |
81% | With potassium acetate In 1,4-dioxane at 80℃; for 16 h; | To a stirred solution of 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (2.20 g, 7.64 mmol) in dioxane (38 mL) was added bis(pinacolato)diboron (2.33 g, 9.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (1:1) (0.187 g, 0.23 mmol), 1,1'-bis(diphenylphosphino)ferrocene (0.127 g, 0.23 mmol), and potassium acetate (2.25 g, 22.92 mmol). The mixture was degassed by purging the reaction flask with vacuum/then N2 back-fill (3.x.). Under N2, the reaction was then heated to 80° C. and stirred overnight (approx. 16 hrs). The reaction was cooled to rt and diluted with H2O. The mixture was extracted with EtOAc (3.x.). The combined organic layers were washed with brine, dried over MgSO4, filtered, then purified by silica gel chromatography to give the title compound of step B (1.65 g, 6.20 mmol, 81percent) as a clear oil, that upon sitting in the fridge overnight changed to a white solid. MS (ESI): 267 [M+H]+. |
66% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; sodium bromide In 1,4-dioxane | A mixture of crude Preparation 14A (600 g,2.08mol ,1eq), B2Pin2 (687.1 g, 2.71 mol, 1.3eq), KOAc (613 g, 6.24 mol, 3eq) , NaBr (86 g 0.833mol,0.4 eq) and Pd(dppf)Cl2 (76 g, 0.1 mol, 0.05eq) in dioxane (6.5 L) was heated to reflux overnight. Once the reaction was complete, the mixture was concentrated and purified by FCC (2percent ^10percent ^20percent EtOAc/PE) to give Preparation 14B (369g, 66percent). Preparation 14B: LC-MS: 267.1 (M+1)+, 1H NMR (400 MHz, CDCl3) δ ^6.46 (s, 1H), 3.98 (s, 4H), 2.37-2.35 (m, 4H), 1.74-1.60 (t, 2H), 1.24 (s, 12H). |
59% | With bis-triphenylphosphine-palladium(II) chloride; potassium phenolate; triphenylphosphine In toluene at 20 - 50℃; for 28 h; Inert atmosphere | In a round–bottom flask 1.1 mmol (1.1 equiv.) of bis(pinacolato)diboron was dissolved in 50 mL of toluene and PdCl2(PPh3)2 (0.03 equiv), triphenylphosphine (0.06 equiv) and potassium phenolate (1.5 equiv) were added. The reaction mixture was flushed with N2 gas and 1 mmol (1 equiv.) of triflate 25 was added. The mixture was stirred at 50 C under a nitrogen atmosphere. After 4 hours the heat source was removed and the reaction was stirred for 24 hours at room temperature. The reaction mixture was partitioned between H2O/EtOAc and the organic layer was washed with brine and dried over MgSO4. Column chromatography was performed using a gradient of 0-10percent EtOAc in DCM as eluent. Yield = 59percent. 1H NMR (400 MHz, CDCl3) δ: 6.47 (s, 1H), 3.98 (s, 4H), 2.39–2.36 (m, 4H), 1.73 (t, J = 6.4 Hz, 2H), 1.25 (s, 12H). 13C NMR (100 MHz, CDCl3) δ: 139.7, 108.0, 83.4, 64.5, 37.2, 31.2, 25.9, 25.0. |
49% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 80℃; | [00385] Into a 3-L 4-necked round-bottom flask was placed 1,4-dioxaspiro[4.5]dec-7-en-8- yl trifluoromethanesulfonate (80 g, 277.55 mmol, 1.00 equiv), B2Pin2 (85 g, 334.65 mmol, 1.21 equiv), Pd(dppf)C12 (20 g, 27.33 mmol, 0.10 equiv), KOAc (82 g, 835.54 mmol, 3.01 equiv) and 1,4-dioxane (800 mL). The resulting solution was stirred overnight at 80°C using an oil bath then cooled to room temperature and concentrated under vacuum. The residue was extracted with 1 L of ethyl acetate and the organic layer washed with 3x 1 L of brine and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel column using ethyl acetate / petroleum ether (gradient: 5percent to 10percent ethyl acetate) to afford 36 g (49percent) of 2-[1,4-dioxaspiro[4.5]dec-7-en-8-yl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane as a yellow solid. ‘H-NMR (300 MHz, CDC13): 6.46-6.47 (m, 1H), 3.98(s, 4H), 2.39-2.35(m, 4H), 1.73(t, J=4.8Hz, 2H), 1.26(s, 12H) ppm. |
369 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; sodium bromide In 1,4-dioxaneReflux | A mixture of crude Preparation 40A (600 g,2.O8mol ,leq), B2Pin2 (687.1 g, 2.71mol, 1.3eq), KOAc (613 g, 6.24 mol, 3eq) , NaBr (86 g 0.833mo1,0.4 eq) and Pd(dppf)C12(76 g, 0.1 mol, 0.OSeq) in dioxane (6.5 L) was heated to reflux overnight. Once thereaction was complete, the mixture was concentrated and purified by FCC (2percent - 10percent-20percent EtOAc/PE) to give Preparation 40B (369g, 66percent).Preparation 40B: LC-MS: 267.1 (M+1)+, ‘H NMR (400 MHz, CDC13) ö 6.46 (s, 1H),3.98 (s, 4H), 2.37-2.35 (m, 4H), 1.74-1.60 (t, 2H), 1.24 (s, 12H). |
369 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; sodium bromide In 1,4-dioxaneReflux | [00165] A mixture of crude Preparation A (600 g,2.08mol ,leq), Β2ΡΠ12 (687.1 g, 2.71 mol, 1.3eq), KOAc (613 g, 6.24 mol, 3eq) , NaBr (86 g 0.833mol,0.4 eq) and Pd(dppf)Cb (76 g, 0.1 mol, 0.05eq) in dioxane (6.5 L) was heated to reflux overnight. Once the reaction was complete, the mixture was concentrated and purified by FCC (2percent - 10percent - 20percent EtOAc/PE) to give Preparation B (369g, 66percent). (0233) Preparation B: LC-MS: 267.1 (M+l)+, XH NMR (400 MHz, CDCb) δ 6.46 (s, 1H), 3.98 (s, 4H), 2.37-2.35 (m, 4H), 1.74-1.60 (t, 2H), 1.24 (s, 12H). |
369 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; sodium bromide In 1,4-dioxaneReflux | [00179] A mixture of intermediate 2A (600 g,2.08mol ,leq), B2Pin2 (687.1 g, 2.71 mol, 1.3eq), KOAc (613 g, 6.24 mol, 3eq) , NaBr (86 g 0.833mol,0.4 eq) and Pd(dppf)C12 (76 g, 0.1 mol, 0.05eq) in dioxane (6.5 L) was heated to reflux overnight. Once the reaction was complete, the mixture was concentrated and purified by via silica gel column chromatography to give Intermediate 2B (369 g, 66percent yield). LC-MS Anal. Calc'd for C14H23BO4 266.17, found [M+H] 267.1. 1H NMR (400 MHz, CDCI3) δ 6.46 (s, 1H), 3.98 (s, 4H), 2.37-2.35 (m, 4H), 1.74-1.60 (t, 2H), 1.24 (s, 12H). |
369 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; sodium bromide In 1,4-dioxaneReflux | A mixture of crude Preparation 4A (600 g,2.O8mol ,leq), B2Pin2 (687.1 g, 2.71 mol, 1.3eq), KOAc (613 g, 6.24 mol, 3eq) , NaBr (86 g 0.833mo1,0.4 eq) and Pd(dppf)C12 (76 g, 0.1 mol, 0.OSeq) in dioxane (6.5 L) was heated to reflux overnight. Once the reaction was complete, the mixture was concentrated and purified by FCC (2percent -10percent -20percent EtOAc/PE) to give Preparation 4B (369g, 66percent).Preparation 4B: LC-MS: 267.1 (M+1)+, ‘HNMR(400 MHz, CDC13) ö 6.46 (s, 1H), 3.98 (s, 4H), 2.37-2.35 (m, 4H), 1.74-1.60 (t, 2H), 1.24 (s, 12H). |
369 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; sodium bromide In 1,4-dioxaneReflux | j00169j A mixture of crude Preparation 1A(600 g,2.O8mol ,leq), B2Pin2 (687.1 g, 2.71 mol, 1.3eq), KOAc (613 g, 6.24 mol, 3eq) , NaBr (86 g 0.833mo1,0.4 eq) and Pd(dppf)C12 (76 g,0.1 mol, 0.OSeq) in dioxane (6.5 L) was heated to reflux overnight. Once the reaction was complete, the mixture was concentrated and purified by FCC (2percent -10percent -20percent EtOAc/PE) to give Preparation lB (369g, 66percent).Preparation 1B: LC-MS: 267.1 (M+1)+, ‘HNMR(400 MHz, CDC13) ö 6.46 (s, 1H), 3.98 (s, 4H), 2.37-2.35 (m, 4H), 1.74-1.60 (t, 2H), 1.24 (s, 12H). |
369 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; sodium bromide In 1,4-dioxaneReflux | A mixture of crude Preparation IA (60() g, 2O8moi ,leq), B2Pin2 (687.1g. 271 mol, 1.3eq), KOAc (613 g, 6.24 mol, 3eq) , NaBr (86g. 0.833mo1,0.4 eq) and Pd(dppf)C12(76 g, 0.1 mol, 0OSeq) in dioxane (6.5 L) was heated to reflux overnight, Once the reaction was complete, the mixture was concentrated and purified by FCC (2percent 10percent 20percent EtOAc/PE) to give Preparation lB (369g, 66percent).Preparation 1B: LC--MS: 267. 1 (M--1)--. ‘HNMR (400 MHz, CDG3) ö 6.46 (s, 1H), 3.98 (s, 4H), 2.37—2.35 (in, 4H), 1.74—I. 60 (L, 2H), 1.24 (s, 12H). |
3.6 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; sodium bromide In 1,4-dioxaneReflux | Compound 4.1 (6.0 g), dipinacol boronate(6.87 g, 27.1 mmol), potassium acetate (6.13 g,62.4 mmol), sodium bromide (8.6 g, 8.33 mmol) and Pd(dppf)Cl2 (0.76 g, 1.0 mmol) in 1,4-dioxane(65 mL) The mixture was stirred at reflux overnight.Then the reaction system was cooled to room temperature and the solvent was removed under reduced pressure.The residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 50/1 to 10/1) to give Compound 4.2 (3.6 g, two-step yield: 70percent) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl acetamide; water; at 80℃; for 24.0h; | Intermediate 37: Methyl 3-[4-[2-[5-f(4-fluorophenv0aminol-l,3,4-oxadiazol-2-yl1-lH- benzoimidazol-5-yllcvclohexylloxypropanoate; ) Benzyl N- [4-(l ,4-dioxaspiro [4.51 dec-7-en-8-vDphenyll carbamate; Tetrakistriphenylphosphine palladium (565 mg, 0.49 mmol) was added to a solution of 2- (l,4-dioxaspiro[4.5]dec-8-en-8-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.3 g, 4.88 mmol) and benzyl N-(4-bromophenyl)carbamate (1.50 g, 4.88 mmol) in degassed DME (20 mL) and degassed 2M aqueous potassium carbonate solution (6.25 mL) and stirred under a nitrogen atmosphere at 80 0C for 24 h. The reaction mixture was cooled to ambient temperature and EtOAc (50 mL) was added before washing with water (2 x 20 mL) and brine (20 mL), dried (MgSO4) and concentrated in vacuo to leave a residue. The crude residue was purified by column chromatography, using a gradient of 20-70% EtOAc in isohexane as eluent, to give the title compound as a cream coloured solid (1.30 g, 72 %). 1H NMR delta 1.87-1.97 (2H, m), 2.42-2.5 (2H, m), 2.6-2.73 (2H, m), 4.03 (4H, s), 5.2 (2H, s), 5.9-5.99 (IH, m), 6.65 (IH, s), 7.5-7.7 (9H, m); MS m/e MH+ 266. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 110℃; for 10.0h;Inert atmosphere; | 1,4-dioxaspiro [4.5] sunene-7-ene-8-trifluoromethanesulfonate (500 mg, 1.73 mmol)1,4-dioxane (8 mL)Potassium acetate (260 mg, 2.64 mmol) was added sequentially to the solution,Which aliphatic alcohol (530mg, 2.08mmol) with boronic acid,Pd (dppf) Cl2 (130 mg, 0.17 mmol), nitrogen,110 C for 10 hours, filtered,Concentrated column chromatography (petroleum ether / ethyl acetate (v / v) = 2/1) gave 540 mg of a yellow oil in 99% yield. |
95% | With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃;Inert atmosphere; | Synthesis of 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)-1,3,2-dioxaborolane A solution of 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethane-sulfonate (1.0 equiv.) in dioxane (0.5 M) was purged with nitrogen for 30 min. Then 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.0 equiv.), KOAc (3.0 equiv.), Pd(dppf)Cl2-DCM (0.2 equiv.) were added and the solution was stirred in a sealed bomb at 80 C. The reaction was filtered over a pad of celite, then to the filtrate was added ethyl acetate, and washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column (ethyl acetate:hexanes=1:1) to give 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (95%). LC/MS (m/z): MH+=267.1, Rt=0.95. |
81% | With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 80℃; for 16.0h; | To a stirred solution of 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (2.20 g, 7.64 mmol) in dioxane (38 mL) was added bis(pinacolato)diboron (2.33 g, 9.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (1:1) (0.187 g, 0.23 mmol), 1,1'-bis(diphenylphosphino)ferrocene (0.127 g, 0.23 mmol), and potassium acetate (2.25 g, 22.92 mmol). The mixture was degassed by purging the reaction flask with vacuum/then N2 back-fill (3×). Under N2, the reaction was then heated to 80 C. and stirred overnight (approx. 16 hrs). The reaction was cooled to rt and diluted with H2O. The mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, then purified by silica gel chromatography to give the title compound of step B (1.65 g, 6.20 mmol, 81%) as a clear oil, that upon sitting in the fridge overnight changed to a white solid. MS (ESI): 267 [M+H]+. |
73% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃;Inert atmosphere; | Under nitrogen protectionTo the 1,4-dioxaspiro[4.5]indole-7-en-8-yl trifluoromethanesulfonate (350.1 g,1214.3mmol),Drying of pinacol borate (310.0 g, 1220.8 mmol) and KOAc (300.2 g, 3058.9 mmol)Pd(dppf)Cl2 (36.0 g, 4 mmol) was added to the 1,4-dioxane (4 L) solution.The reaction mixture was warmed to 90 C and stirred overnight. TLC shows that the starting material is completely reacted,The reaction mixture was cooled to room temperature, poured slowly into water and extracted three times with EA.The organic layer was combined, washed with saturated brine and dried over anhydrous Na?The crude product obtained by concentration is subjected to column chromatography.(PE/EA=30/1~10/1) was isolated and purified to give the title compound (235.3 g, yield: 73%).It is a pale yellow oil. |
66% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; sodium bromide; In 1,4-dioxane; | A mixture of crude Preparation 14A (600 g,2.08mol ,1eq), B2Pin2 (687.1 g, 2.71 mol, 1.3eq), KOAc (613 g, 6.24 mol, 3eq) , NaBr (86 g 0.833mol,0.4 eq) and Pd(dppf)Cl2 (76 g, 0.1 mol, 0.05eq) in dioxane (6.5 L) was heated to reflux overnight. Once the reaction was complete, the mixture was concentrated and purified by FCC (2% ^10% ^20% EtOAc/PE) to give Preparation 14B (369g, 66%). Preparation 14B: LC-MS: 267.1 (M+1)+, 1H NMR (400 MHz, CDCl3) delta ^6.46 (s, 1H), 3.98 (s, 4H), 2.37-2.35 (m, 4H), 1.74-1.60 (t, 2H), 1.24 (s, 12H). |
59% | With bis-triphenylphosphine-palladium(II) chloride; potassium phenolate; triphenylphosphine; In toluene; at 20 - 50℃; for 28.0h;Inert atmosphere; | In a round-bottom flask 1.1 mmol (1.1 equiv.) of bis(pinacolato)diboron was dissolved in 50 mL of toluene and PdCl2(PPh3)2 (0.03 equiv), triphenylphosphine (0.06 equiv) and potassium phenolate (1.5 equiv) were added. The reaction mixture was flushed with N2 gas and 1 mmol (1 equiv.) of triflate 25 was added. The mixture was stirred at 50 C under a nitrogen atmosphere. After 4 hours the heat source was removed and the reaction was stirred for 24 hours at room temperature. The reaction mixture was partitioned between H2O/EtOAc and the organic layer was washed with brine and dried over MgSO4. Column chromatography was performed using a gradient of 0-10% EtOAc in DCM as eluent. Yield = 59%. 1H NMR (400 MHz, CDCl3) delta: 6.47 (s, 1H), 3.98 (s, 4H), 2.39-2.36 (m, 4H), 1.73 (t, J = 6.4 Hz, 2H), 1.25 (s, 12H). 13C NMR (100 MHz, CDCl3) delta: 139.7, 108.0, 83.4, 64.5, 37.2, 31.2, 25.9, 25.0. |
55% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; sodium bromide; In 1,4-dioxane;Reflux; | Step 2:Compound 1.1 (8.0 g, 27.8 mmol),Bispinol borate (9.17g, 36.1mmol),Potassium acetate (8.18g, 83.3mmol),Sodium bromide (1.14 g, 11.1 mmol)A mixture of Pd(dppf)Cl2 (1.0 g, 1.4 mmol) in 1,4-dioxane (100 mL) was stirred under reflux overnight.The reaction system was then cooled to room temperature and the solvent was removed under reduced pressure.The residue was purified by flash column chromatography ( petroleum ether / ethyl acetate = 8/1)Compound 1.2 (4.7 g, yield: 55%) was obtained as a yellow oil. |
49% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; | [00385] Into a 3-L 4-necked round-bottom flask was placed 1,4-dioxaspiro[4.5]dec-7-en-8- yl trifluoromethanesulfonate (80 g, 277.55 mmol, 1.00 equiv), B2Pin2 (85 g, 334.65 mmol, 1.21 equiv), Pd(dppf)C12 (20 g, 27.33 mmol, 0.10 equiv), KOAc (82 g, 835.54 mmol, 3.01 equiv) and 1,4-dioxane (800 mL). The resulting solution was stirred overnight at 80C using an oil bath then cooled to room temperature and concentrated under vacuum. The residue was extracted with 1 L of ethyl acetate and the organic layer washed with 3x 1 L of brine and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel column using ethyl acetate / petroleum ether (gradient: 5% to 10% ethyl acetate) to afford 36 g (49%) of 2-[1,4-dioxaspiro[4.5]dec-7-en-8-yl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane as a yellow solid. ?H-NMR (300 MHz, CDC13): 6.46-6.47 (m, 1H), 3.98(s, 4H), 2.39-2.35(m, 4H), 1.73(t, J=4.8Hz, 2H), 1.26(s, 12H) ppm. |
With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; triphenylphosphine; In 1,4-dioxane;Heating / reflux; | Intermediate 29.1 (3.58 g), bis(pinacolato)diboron (3.48 g), bis(triphenylphosphine)palladium(II)dichloride (262 mg), triphenylphosphine (195 mg) and K2CO3 (2.57 g) were dissolved in anhydrous dioxane (75 ml) under argon and refluxed overnight. After cooling down, a NaCl solution was added and the mixture was extracted with Hept. The org. layers were dried (Na2SO4) and evaporated off. The compound was used in the next step without purification or characterisation. | |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80℃;Inert atmosphere; | (0563) To a stirred solution of 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (1.19 g, 4.13 mmol) in dry dioxane (15 mL), bis(pinacolato)diboron (Alfa Aesar) (1.048 g, 4.13 mmol) was added followed by potassium acetate (Acros) (0.810 g, 8.26 mmol) and PdCl2(dppf).CH2Cl2 adduct (Alfa Aesar) (0.101 g, 0.124 mmol). The reaction mixture was flushed with nitrogen and stirred at 80 C. overnight. The resulting mixture was cooled to room temperature and filtered through Celite, washing with TBME. The organic filtrate was concentrated under reduced pressure and partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-30% EtOAc in iso-hexane afforded the title compound. | |
369 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; sodium bromide; In 1,4-dioxane;Reflux; | A mixture of crude Preparation 40A (600 g,2.O8mol ,leq), B2Pin2 (687.1 g, 2.71mol, 1.3eq), KOAc (613 g, 6.24 mol, 3eq) , NaBr (86 g 0.833mo1,0.4 eq) and Pd(dppf)C12(76 g, 0.1 mol, 0.OSeq) in dioxane (6.5 L) was heated to reflux overnight. Once thereaction was complete, the mixture was concentrated and purified by FCC (2% - 10%-20% EtOAc/PE) to give Preparation 40B (369g, 66%).Preparation 40B: LC-MS: 267.1 (M+1)+, ?H NMR (400 MHz, CDC13) oe 6.46 (s, 1H),3.98 (s, 4H), 2.37-2.35 (m, 4H), 1.74-1.60 (t, 2H), 1.24 (s, 12H). |
369 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; sodium bromide; In 1,4-dioxane;Reflux; | [00165] A mixture of crude Preparation A (600 g,2.08mol ,leq), Beta2RhoPi12 (687.1 g, 2.71 mol, 1.3eq), KOAc (613 g, 6.24 mol, 3eq) , NaBr (86 g 0.833mol,0.4 eq) and Pd(dppf)Cb (76 g, 0.1 mol, 0.05eq) in dioxane (6.5 L) was heated to reflux overnight. Once the reaction was complete, the mixture was concentrated and purified by FCC (2% - 10% - 20% EtOAc/PE) to give Preparation B (369g, 66%). (0233) Preparation B: LC-MS: 267.1 (M+l)+, XH NMR (400 MHz, CDCb) delta 6.46 (s, 1H), 3.98 (s, 4H), 2.37-2.35 (m, 4H), 1.74-1.60 (t, 2H), 1.24 (s, 12H). |
369 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; sodium bromide; In 1,4-dioxane;Reflux; | [00179] A mixture of intermediate 2A (600 g,2.08mol ,leq), B2Pin2 (687.1 g, 2.71 mol, 1.3eq), KOAc (613 g, 6.24 mol, 3eq) , NaBr (86 g 0.833mol,0.4 eq) and Pd(dppf)C12 (76 g, 0.1 mol, 0.05eq) in dioxane (6.5 L) was heated to reflux overnight. Once the reaction was complete, the mixture was concentrated and purified by via silica gel column chromatography to give Intermediate 2B (369 g, 66% yield). LC-MS Anal. Calc'd for C14H23BO4 266.17, found [M+H] 267.1. 1H NMR (400 MHz, CDCI3) delta 6.46 (s, 1H), 3.98 (s, 4H), 2.37-2.35 (m, 4H), 1.74-1.60 (t, 2H), 1.24 (s, 12H). |
369 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; sodium bromide; In 1,4-dioxane;Reflux; | A mixture of crude Preparation 4A (600 g,2.O8mol ,leq), B2Pin2 (687.1 g, 2.71 mol, 1.3eq), KOAc (613 g, 6.24 mol, 3eq) , NaBr (86 g 0.833mo1,0.4 eq) and Pd(dppf)C12 (76 g, 0.1 mol, 0.OSeq) in dioxane (6.5 L) was heated to reflux overnight. Once the reaction was complete, the mixture was concentrated and purified by FCC (2% -10% -20% EtOAc/PE) to give Preparation 4B (369g, 66%).Preparation 4B: LC-MS: 267.1 (M+1)+, ?HNMR(400 MHz, CDC13) oe 6.46 (s, 1H), 3.98 (s, 4H), 2.37-2.35 (m, 4H), 1.74-1.60 (t, 2H), 1.24 (s, 12H). |
369 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; sodium bromide; In 1,4-dioxane;Reflux; | j00169j A mixture of crude Preparation 1A(600 g,2.O8mol ,leq), B2Pin2 (687.1 g, 2.71 mol, 1.3eq), KOAc (613 g, 6.24 mol, 3eq) , NaBr (86 g 0.833mo1,0.4 eq) and Pd(dppf)C12 (76 g,0.1 mol, 0.OSeq) in dioxane (6.5 L) was heated to reflux overnight. Once the reaction was complete, the mixture was concentrated and purified by FCC (2% -10% -20% EtOAc/PE) to give Preparation lB (369g, 66%).Preparation 1B: LC-MS: 267.1 (M+1)+, ?HNMR(400 MHz, CDC13) oe 6.46 (s, 1H), 3.98 (s, 4H), 2.37-2.35 (m, 4H), 1.74-1.60 (t, 2H), 1.24 (s, 12H). |
369 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; sodium bromide; In 1,4-dioxane;Reflux; | A mixture of crude Preparation IA (60() g, 2O8moi ,leq), B2Pin2 (687.1g. 271 mol, 1.3eq), KOAc (613 g, 6.24 mol, 3eq) , NaBr (86g. 0.833mo1,0.4 eq) and Pd(dppf)C12(76 g, 0.1 mol, 0OSeq) in dioxane (6.5 L) was heated to reflux overnight, Once the reaction was complete, the mixture was concentrated and purified by FCC (2% 10% 20% EtOAc/PE) to give Preparation lB (369g, 66%).Preparation 1B: LC--MS: 267. 1 (M--1)--. ?HNMR (400 MHz, CDG3) oe 6.46 (s, 1H), 3.98 (s, 4H), 2.37-2.35 (in, 4H), 1.74-I. 60 (L, 2H), 1.24 (s, 12H). |
3.6 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; sodium bromide; In 1,4-dioxane;Reflux; | Compound 4.1 (6.0 g), dipinacol boronate(6.87 g, 27.1 mmol), potassium acetate (6.13 g,62.4 mmol), sodium bromide (8.6 g, 8.33 mmol) and Pd(dppf)Cl2 (0.76 g, 1.0 mmol) in 1,4-dioxane(65 mL) The mixture was stirred at reflux overnight.Then the reaction system was cooled to room temperature and the solvent was removed under reduced pressure.The residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 50/1 to 10/1) to give Compound 4.2 (3.6 g, two-step yield: 70%) as a yellow solid. |
369 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; sodium bromide; In 1,4-dioxane;Reflux; | A mixture of crude Intermediate 1A (600 g,2.08mol , leq), B2Pin2(687.1 g, 2.71 mol, 1.3eq), KOAc (613 g, 6.24 mol, 3eq) , NaBr (86 g 0.833mol,0.4 eq) and Pd(dppf)Ch (76 g, 0.1 mol, 0.05eq) in dioxane (6.5 L) was heated to reflux overnight. Once the reaction was complete, the mixture was concentrated and purified by FCC (2% - 10% ^20% EtOAc/PE) to give Intermediate IB (369g, 66%). LC-MS : 267.1 (M+l) +, MR (400 MHz, CDCb) 56.46 (s, IH) , 3.98 (s, 4H) , 2.37-2.35 (m, 4H) , 1.74-1.60 (t, 2H), 1.24 (s, 12H). |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃;Inert atmosphere; | To a solution of 13.9 g (52.1 mmol) of 4,4,5,5-tetramethyl-2-(tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 ,3,2-dioxaborolane in 60 mL of dioxane was added 2.83 g (3.5 mmol) of Pd(dppf)CI2.CH2Cl2, 10.2 g (104.2 mmol) of KOAc, and 10.0 g (34.7 mmol) of 1-1 at room temperature under Ar atmosphere. The mixture was stirred at 100 0 C overnight. The reaction mixture was cooled to room temperature and diluted with 50 mL of ethyl acetate. The mixture was filtered through Celite; the filter cake was washed with 30 mL of ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 25% ethyl acetate in petroleum ether to afford compound 1- 2. LC-MS: m/e = 267 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 80℃; for 16.0h; | To a stirred solution of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaspiro[4.5]dec-7-ene (1.09 g, 4.13 mmol) in dioxane (17 mL) was added 5-chloro-2-nitroanisole (0.64 g, 3.44 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.12 g, 0.17 mmol) and 1.0 M Na2CO3 in H2O (10.32 mL, 10.32 mmol). The mixture was degassed by purging the reaction flask with vacuum/then N2 back-fill (5×). Under N2 the reaction was then heated to 80 C. and stirred overnight (approximately 16 h). The reaction was cooled to rt and diluted with EtOAc, then filtered through Celite, washing with EtOAc. The filtrate was concentrated under vacuum. The residue was taken up in EtOAc and H2O. The H2O layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, then concentrated and purified by silica gel chromatography to give the title compound of step C (911 mg, 3.13 mmol, 91%) as an amber oil. MS (ESI): 292 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cesium fluoride;tetrakis(triphenylphosphine) palladium(0); In methanol; 1,2-dimethoxyethane; at 130℃; for 0.25h;microwave;Product distribution / selectivity; | Intermediate 9 8-(2,5-dimethyl-4-nitrophenyl)-l,4-dixoaspiror4.51dec-7-ene [0090] A mixture of 4,4,4,4-tetramethyl-2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)- 1,3,2-dixoaborolane (200 mg, 0.86 mmol), l-bromo-2,5-dimethyl-4-nitrobenzene (228 <n="36"/>mg, 0.86 mmol), tetrakis(triphenylphosphine)palladium(0) (98 mg, 0.09 mmol), and cesium fluoride (392 mg, 2.58 mmol) in a mixture of 1,2-dimethoxyethane (2 mL) and methanol (1 mL) was degassed for 5 min, and then heated at 1300C in a microwave reactor for 15 min. The reaction was concentrated in vacuo, and purified by silica chromatography (EtOAC/hexanes: 3/7) to afford 8-(2,5-dimethyl-4-nitrophenyl)-l,4- dixoaspiro[4.5]dec-7-ene; ESMS m/z 290.2 (M + H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cesium fluoride;tetrakis(triphenylphosphine) palladium(0); In methanol; 1,2-dimethoxyethane; at 130℃; for 0.25h;microwave; | Intermediate 11 2-fluoro-5-methyl-4-(l,4-dioxaspiror4.51dec-7-en-8-vl)anirine [0092] A mixture of 4,4,4,4-tetramethyl-2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)- 1,3,2-dioxaborolane (532.0 mg, 2.0 mmol), <strong>[418762-26-2]4-bromo-2-fluoro-5-methylaniline</strong> (406.0 mg, 2.0 mmol), tetrakis(triphenylphosphine)palladium(0) (231.1 mg, 0.2 mmol), cesium fluoride (912.0 mg, 6.0 mmol), 1,2-dimethoxyethane (4 mL) and methanol (2 <n="37"/>niL) was degassed for 5 min and then heated at 130C in a microwave reactor for 15 min. The reaction was concentrated in vacuo, and purified by silica chromatography (EtOAC / Hexanes: 3/7) to afford 2-fluoro-5-methyl-4-(l,4-dioxaspiro[4.5]dec-7-en- 8-yl)aniline; ESMS m/z 264.1 (M + H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 110℃; for 3.5h;Inert atmosphere; | Synthesis of 3-nitro-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine A solution of DME (0.2 M) and 2M aq. sodium carbonate (1.7 equiv.) was purged with nitrogen for 20 min. Then 4-chloro-3-nitropyridine (1.6 equiv.), <strong>[680596-79-6]4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane</strong> (1.0 equiv.), Pd(dppf)Cl2-DCM (0.05 equiv.) were added and stirred in a sealed bomb at 110 C. The reaction was stirred at that temperature for 3.5 hours. The reaction was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated. The residue was purified by column (ethyl acetate:hexanes=1:1 with 10% methanol) to give 3-nitro-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine (83%). LC/MS (m/z): MH+=263.2, Rt=0.71. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene (prepared as described in PCT Int. Appl. WO2006064189, 0.292 g, 1.10 mmol), 2-iodo-3-hydroxypyridine (Aldrich, 0.177 g, 0.801 mmol), and tetrakis (triphenylphosphino)palladium(0) (Aldrich, 0.048 g, 0.042 mmol) were dissolved in 1,4-dioxane (9 mL), treated with 2M aqueous Na2CO3 (2.0 mL, 4.0 mmol), bubbled with argon for a few minutes, and heated to 100 C. under reflux condenser for 24 h. After cooling to ambient temperature, the reaction was diluted with water (30 mL), extracted thrice with dichloromethane, aqueous layer acidified to ca. pH 7, extracted twice more with dichloromethane, and the combined organic layers washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give an orange oil. This was purified by thin layer chromatography on silica gel (EtOAc) to give the title compound as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) delta 8.16 (dd, J=4.5, 1.3 Hz, 1H), 7.22 (dd, J=8.1, 1.3 Hz, 0H), 7.07 (dd, J=8.2, 4.7 Hz, 1H), 5.95-6.09 (m, 2H), 4.03 (s, 4H), 2.73 (dddd, J=6.4, 4.4, 2.2, 2.0 Hz, 2H), 2.49 (d, J=2.8 Hz, 2H), 1.96 (t, J=6.6 Hz, 2H). ESI-MS (m/z): Calcd. For C13H15NO3: 233. found: 234 (M+H). | ||
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 24.0h;Inert atmosphere; | Example 1 : N-( l-(4-( 3-hvdroxypyridin-2-yl)cvclohexyl)azetidin-3-yl)-2-( ( 6- ftrifluoromethyl) uinazolin-4-yl)amino)acetamideStep A: 2-(l,4-Dioxa-spiro[4.5]dec-7-en-8-yl)-pyridin-3-ol; 8-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-l,4-dioxa-spiro[4.5]dec-7-ene(prepared as described in PCT Int. Appl. WO2006064189, 0.292 g, 1.10 mmol), 2-iodo-3- hydroxypyridine (Aldrich, 0.177 g, 0.801 mmol), and tetrakis (triphenylphosphino)palladium(O) (Aldrich, 0.048 g, 0.042 mmol) were dissolved in 1,4-dioxane (9 mL), treated with 2M aqueous Na2C03 (2.0 mL, 4.0 mmol), bubbled with argon for a few minutes, and heated to 100 C under reflux condenser for 24 h. After cooling to ambient temperature, the reaction was diluted with water (30 mL), extracted thrice with dichloromethane, aqueous layer acidified to ca. pH 7, extracted twice more with dichloromethane, and the combined organic layers washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to give an orange oil. This was purified by thin layer chromatography on silica gel (EtOAc) to give the title compound as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) delta 8.16 (dd, J=4.5, 1.3 Hz, 1 H), 7.22 (dd, J=8.1, 1.3 Hz, 0 H), 7.07 (dd, J=8.2, 4.7 Hz, 1 H), 5.95 - 6.09 (m, 2 H), 4.03 (s, 4 H), 2.73 (dddd, J=6.4, 4.4, 2.2, 2.0 Hz, 2 H), 2.49 (d, J=2.8 Hz, 2 H), 1.96 (t, J=6.6 Hz, 2 H). ESI-MS (m/z): Calcd. For Ci3Hi5N03: 233; found: 234 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / 1,4-dioxane; water / 24 h / 100 °C / Inert atmosphere 2: palladium 10% on activated carbon; hydrogen / methanol / 2 h / 20 °C / 2585.81 Torr 3: hydrogenchloride / acetone / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 24h;Inert atmosphere; | General procedure: N-(Azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide TFA salt: 3-Amino-azetidine-1-carboxylic acid tert-butyl ester (1.2 g, 6.97 mmol) and (3-trifluoromethyl-benzoylamino)-acetic acid (1.57 g, 6.36 mmol) were treated with EDCI (1.57 g, 6.36 mmol), HOBT (1.22 g, 6.36 mmol) in DCM (10 mL) at room temperature for 4 hours. The reaction solution was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give yellow oil, which was then purified by silica gel column on a CombiFlash system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford 3-[2-(3-trifluoro-methyl-benzoylamino)-acetylamino]-azetidine-1-carboxylic acid tert-butyl ester as white solid, 2.23 g, 80% yield. 1H NMR (400 MHz, CDCl3) d 8.10 (s, 1H), 8.02 (d, J = 6.6 Hz, 1H), 7.80 (d, J = 6.8 Hz, 1H), 7.56 (t, J = 6.5 Hz, 1H), 4.61 (m, 1H), 4.25 (t, J = 7.2 Hz, 2H), 4.18 (d, J = 5.5 Hz, 2H), 3.82 (t, J = 7.5 Hz, 2H), 1.41 (s, 9H). 3-[2-(3-Trifluoromethyl-benzoylamino)-acetylamino]-azetidine-1-carboxylic acid tert-butyl ester (2.10 g, 5.24 mmol) was dissolved in 1:1 TFA and DCM mixed solution (10 mL) at room temperature. The reaction was stirred for another 2 hours. The solvent was removed and the residue was dried to give N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide as a TFA salt containing extra TFA (colorless oil), ~ 2.5 g, 100% yield. 1H NMR (400 MHz, CDCl3) d 8.10 (s, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.78 (d, J = 6.2 Hz, 1H), 7.55 (m, 2H), 4.78 (m, 1H), 4.15 (d, J = 3.2 Hz, 2H), 3.95 (t, J = 7.0 Hz, 2H), 3.52 (t, J = 7.0 Hz, 2H).8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene (PCT Int. Appl. WO2006064189, 0.292 g, 1.10 mmol), 5-bromobenzo[d][1,3]dioxole (Aldrich, 161 mg, 0.801 mmol), and tetrakis (triphenylphosphino)palladium(0) (Aldrich, 0.048 g, 0.042 mmol) were dissolved in 1,4-dioxane (9 mL), treated with 2M aqueous Na2CO3 (2.0 mL, 4.0 mmol), bubbled with argon for a few minutes, and heated to 100oC under reflux condenser for 24 h. After cooling to ambient temperature, the reaction was diluted with water (30 mL), extracted thrice with dichloromethane, aqueous layer acidified to ca. pH 7, extracted twice more with dichloromethane, and the combined organic layers washed with brine, dried over Na2SO4, filtered, and the filtrate concentrated in vacuo to give an orange oil. This was purified by thin layer chromatography on silica gel (EtOAc) to give 5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzo[d][1,3]dioxole as a yellow solid (110 mg, 53%). 5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzo[d][1,3]dioxole (110 mg, 0.42 mmol) in MeOH (5 mL) was placed in a hydrogenation Par Shaker under 40 psi at room temperature using 5% Pd/C (~ 50 mg) as catalyst for 2 hour. The resulting solution was filtered through a pad of Celite , concentrated and purified by silica gel column on a CombiFlash system to afford 5-(1,4-dioxaspiro[4.5]decan-8-yl)benzo[d][1,3]dioxole as white solid, 91 mg, 82% yield. 5-(1,4-dioxaspiro[4.5]decan-8-yl)benzo[d][1,3]dioxole (91 mg, 0.35 mmol) was treated with 1N HCl ( ~ 2 mL) in acetone (4 mL) at room temperature for 4 hours. The reaction was neutralized with saturate NaHCO3 solution and the solvent was removed. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give yellow solid, which was then purified by silica gel column on a CombiFlash system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford 4-(benzo[d][1,3]dioxol-5-yl)cyclohexanone as white solid, 75 mg, 98% yield.4-(benzo[d][1,3]dioxol-5-yl)cyclohexanone (75 mg, 0.35 mmol) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide TFA salt (151 mg, 0.50 mmol) in DCM (2 mL) was treated with TEA (0.1 mL, 0.75 mmol) for 10 min followed by NaBH(OAc)3 (Aldrich, 225 mg, 1.05 mmol) for another 4 hours at room temperature. The reaction was quenched with saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted 3 times with chloroform and IPA "cocktail" (~ 3:1, v/v). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford two title compounds as white solids: 8a, less polar isomer (cis), 67 mg, 38% yield; 9a, more polar isomer (trans), 45 mg, 26% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 24h;Inert atmosphere; | General procedure: N-(Azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide TFA salt: 3-Amino-azetidine-1-carboxylic acid tert-butyl ester (1.2 g, 6.97 mmol) and (3-trifluoromethyl-benzoylamino)-acetic acid (1.57 g, 6.36 mmol) were treated with EDCI (1.57 g, 6.36 mmol), HOBT (1.22 g, 6.36 mmol) in DCM (10 mL) at room temperature for 4 hours. The reaction solution was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give yellow oil, which was then purified by silica gel column on a CombiFlash system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford 3-[2-(3-trifluoro-methyl-benzoylamino)-acetylamino]-azetidine-1-carboxylic acid tert-butyl ester as white solid, 2.23 g, 80% yield. 1H NMR (400 MHz, CDCl3) d 8.10 (s, 1H), 8.02 (d, J = 6.6 Hz, 1H), 7.80 (d, J = 6.8 Hz, 1H), 7.56 (t, J = 6.5 Hz, 1H), 4.61 (m, 1H), 4.25 (t, J = 7.2 Hz, 2H), 4.18 (d, J = 5.5 Hz, 2H), 3.82 (t, J = 7.5 Hz, 2H), 1.41 (s, 9H). 3-[2-(3-Trifluoromethyl-benzoylamino)-acetylamino]-azetidine-1-carboxylic acid tert-butyl ester (2.10 g, 5.24 mmol) was dissolved in 1:1 TFA and DCM mixed solution (10 mL) at room temperature. The reaction was stirred for another 2 hours. The solvent was removed and the residue was dried to give N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide as a TFA salt containing extra TFA (colorless oil), ~ 2.5 g, 100% yield. 1H NMR (400 MHz, CDCl3) d 8.10 (s, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.78 (d, J = 6.2 Hz, 1H), 7.55 (m, 2H), 4.78 (m, 1H), 4.15 (d, J = 3.2 Hz, 2H), 3.95 (t, J = 7.0 Hz, 2H), 3.52 (t, J = 7.0 Hz, 2H).8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene (PCT Int. Appl. WO2006064189, 0.292 g, 1.10 mmol), 5-bromobenzo[d][1,3]dioxole (Aldrich, 161 mg, 0.801 mmol), and tetrakis (triphenylphosphino)palladium(0) (Aldrich, 0.048 g, 0.042 mmol) were dissolved in 1,4-dioxane (9 mL), treated with 2M aqueous Na2CO3 (2.0 mL, 4.0 mmol), bubbled with argon for a few minutes, and heated to 100oC under reflux condenser for 24 h. After cooling to ambient temperature, the reaction was diluted with water (30 mL), extracted thrice with dichloromethane, aqueous layer acidified to ca. pH 7, extracted twice more with dichloromethane, and the combined organic layers washed with brine, dried over Na2SO4, filtered, and the filtrate concentrated in vacuo to give an orange oil. This was purified by thin layer chromatography on silica gel (EtOAc) to give 5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzo[d][1,3]dioxole as a yellow solid (110 mg, 53%). 5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)benzo[d][1,3]dioxole (110 mg, 0.42 mmol) in MeOH (5 mL) was placed in a hydrogenation Par Shaker under 40 psi at room temperature using 5% Pd/C (~ 50 mg) as catalyst for 2 hour. The resulting solution was filtered through a pad of Celite , concentrated and purified by silica gel column on a CombiFlash system to afford 5-(1,4-dioxaspiro[4.5]decan-8-yl)benzo[d][1,3]dioxole as white solid, 91 mg, 82% yield. 5-(1,4-dioxaspiro[4.5]decan-8-yl)benzo[d][1,3]dioxole (91 mg, 0.35 mmol) was treated with 1N HCl ( ~ 2 mL) in acetone (4 mL) at room temperature for 4 hours. The reaction was neutralized with saturate NaHCO3 solution and the solvent was removed. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give yellow solid, which was then purified by silica gel column on a CombiFlash system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford 4-(benzo[d][1,3]dioxol-5-yl)cyclohexanone as white solid, 75 mg, 98% yield.4-(benzo[d][1,3]dioxol-5-yl)cyclohexanone (75 mg, 0.35 mmol) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide TFA salt (151 mg, 0.50 mmol) in DCM (2 mL) was treated with TEA (0.1 mL, 0.75 mmol) for 10 min followed by NaBH(OAc)3 (Aldrich, 225 mg, 1.05 mmol) for another 4 hours at room temperature. The reaction was quenched with saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted 3 times with chloroform and IPA "cocktail" (~ 3:1, v/v). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford two title compounds as white solids: 8a, less polar isomer (cis), 67 mg, 38% yield; 9a, more polar isomer (trans), 45 mg, 26% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In 1,4-dioxane; water at 100℃; for 24h; Inert atmosphere; | 38.A Example 38: N-fl-ffls.,4s)-4-ftetrahv(iro-2H-pyran-4-yl)cvclohexyl)azeti(iin-3-yl)-2-ff6- ftrifluoromethyl) uinazolin-4-yl)amino)acetamide-( 3, 6-dihydro-2H-pyran-4-yl)-l, 4-dioxaspiro[ 4.5] dec- 7-ene; 8-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-l,4-dioxa-spiro[4.5]dec-7-ene(prepared as described in PCT Int. Appl. WO2006064189, 1.57 g, 5.90 mmol), commercially available 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (5.23 mmol), and tetrakis (triphenylphosphino)palladium(O) (302 mg, 0.262 mmol) were dissolved in 1,4-dioxane (20 mL), treated with 2M aqueous Na2C03 (14 mL, 28 mmol), bubbled with argon for a few minutes, and heated to 100 °C under reflux condenser for 24 h. After cooling to ambient temperature, the reaction was diluted with water (30 mL), extracted thrice with dichloromethane, aqueous layer acidified to ca. pH 7, extracted twice more with dichloromethane, and the combined organic layers washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to give an orange oil. This was purified by flash chromatography (silica gel, EtOAc) to give the title compound as a colorless crystalline solid.1H NMR (CHLOROFORM-d) δ: 5.75 (br. s., 1H), 5.68 - 5.73 (m, 1H), 4.26 (br. s., 2H), 4.01 (s, 3H), 3.79 - 3.90 (m, 2H), 2.38 - 2.50 (m, 3H), 2.25 - 2.34 (m, 2H), 1.86 (t, J = 6.6 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; at 80℃; for 16.0h;Inert atmosphere; | 4-Bromo-2,5-difluoronitrobenzene (19.82 g, 83.28 mmol) was dissolved in 1,4-dioxane (410 mL) and then 8-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1,4-dioxaspiro[4.5]dec-7-ene (26 g, 99.88 mmol) was added thereto. After dichlorobis(triphenylphosphine) palladium(2) (2.9 g, 4.16 mmol) was added, 1.0M sodium carbonate (250 mL, 249.85 mmol) was added thereto. The mixture was made vacuous by using a vacuum pump and purged with nitrogen. Under nitrogen gas, the mixture was refluxed at 80 C for 16 hours. The reaction was terminated by adding water, filtered with celite, and washed with ethyl acetate, water and saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography using 4:1 mixture solution of hexane and ethyl acetate to obtain the title compound (21.1 g, 85% yield).[321] NMR: 1H-NMR(CDCl3) 7.81~7.77(1H, m), 7.24~7.00(1H, m), 6.11(1H, m), 4.03(4H, s), 2.64~2.61(2H, m), 2.52~2.51(2H, m), 1.92(2H, t) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; at 110℃; for 1.5h;Inert atmosphere; Microwave irradiation; | Intermediate 15A. 8-(3-(trifluoromethoxy)phenyl)-l,4-dioxaspiro[4.5]dec-7-ene[00192] To a solution of 4,4,5,5-tetramethyl-2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)- 1,3,2-dioxaborolane (150 mg, 0.560 mmol) in dioxane (2.5 mL) was added l-iodo-3- (trifluoromethoxy)benzene (195 mg, 0.680 mmol), bis(triphenylphosphine)palladium (II) chloride (20 mg, 0.028 mmol) and a solution of sodium carbonate (179 mg, 1.69 mmol) in water (1.127 mL). The reaction mixture was degassed, refilled with Ar three times, subject to microwave irradiation at 110 C for 90 min. The reaction mixture was diluted with H20 and the aqueous phase extracted with DCM twice. The combined organic portions were dried over MgS04, filtered, concentrated under reduced pressure and purified by flash chromatography (EtOAc/Hexanes 0-50% over 20 min, column 4g, flow rate 40 mL/min) to give Intermediate 15A (119 mg, 0.400 mmol, 70.0% yield) as a clear oil. XH NMR (400 MHz, CHLOROFORM-d) delta ppm1.93 (2 H, t, J=6.4 Hz), 2.48 (2 H, d, J=3.8 Hz), 2.59 - 2.71 (2 H, m), 4.02 (4 H, s), 5.96 - 6.1 1 (1 H, m), 7.03 - 7.1 1 (1 H, m), 7.22 (1 H, s), 7.27 - 7.36 (2 H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; acetonitrile; at 90℃; for 72.0h; | Example B l : 4-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)cyclohexanone To a solution of 2-[(4-iodopyrazol-l-yl)methoxy]ethyl-trimethyl-silane (1.000 g, 3.08 mmol; see Bioorg. Med. Chem. Lett. 2004, 14, 3063) in acetonitrile (23 mL) was added 2-(l,4- dioxaspiro[4.5]dec-8-en-8-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane; 1.30 equiv.; 4.009 mmol), sodium carbonate (493 mg, 1.50 equiv., 4.62 mmol), tetrakistriphenylphosphinepalladium(O) (184 mg, 0.050 equiv., 0.1542 mmol) and deoxygenated water (13 mL). The mixture was heated to 90 C and stirred for 3 days. The mixture was diluted with water, extracted 3X with EtOAc, then the combined organic extracts were dried (MgSC^) and concentrated in vacuo. Purification by CombiFlash (40 g; 100:0 to 70:30 heptane: EtOAc) provided 2-[[4-(l ,4-dioxaspiro[4.5]dec-8-en-8-yl)pyrazol- 1 -yl]methoxy]ethyl-trimethyl-silane (881 mg, 2.62 mmol, 85%). This material was diluted with methanol (20 mL), then 10% palladium on carbon (228 mg) was added and the mixture was stirred under an atmosphere of hydrogen at 65 C overnight. After cooling to rt, the mixture was filtered through Celite, concentrated in vacuo and used directly. This material was diluted with glacial acetic acid (10 mL) and water (3 mL) and heated to 65 C overnight. The mixture was diluted with sat. NaHC03(aq) and washed with 10% MeOH in CH2CI2 (3X). The combined organic extracts were dried (MgSC^) and concentrated in vacuo. Purification by CombiFlash (40 g; 100:0 to 0:100 heptane :EtO Ac) provided the title compound (620 mg, 2.10 mmol, 68%>). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100.0℃; for 16.0h; | A mixture of <strong>[1676-57-9]5-bromo-2-methylpyrimidin-4-ol</strong> (100 mg, 0.53 mmol), 4,4,5, 5-tetramethyl- 2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-l,3,2-dioxaborolane (155 mg, 0.59 mmol), K2C03 (146 mg, 1.06 mmol), Pd(PPh3)4 (31 mg, 0.026 mmol) in Dioxane (4 mL) and water (1 mL) was stirred at 100 C for 16 hours .Then the reaction mixture was allowed to cool to ambient temperature and diluted with EA (10 mL) which was washed with water (10 mL), dried and concentrated. The resulting residue was purified by column (PE : EA = 8 : 1) to afford the product (35 mg, 27 %) as a white solid: LC/MS m/z = 249.1 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 80℃;Inert atmosphere; | Argon gas was bubbled through a mixture of XXXIV-1 (2.0 g, 7.52 mmol) and XXXIV-2 (2.92 g, 7.52 mmol) in 30 mL of DME/H2O (v/v=3/1). The Na2CO3 (2.39 g, 22.56 mmol) and Pd(dppf)Cl2 (275 mg, 0.38 mmol) was added. The mixture was heated to 80 C. and stirred overnight. After cooled, the mixture was filtered through Celite and the filtrate was washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash column chromatography over silica gel (PE:EA=2/1) to afford XXXIV-3 (2.3 g, yield 77%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate tribasic trihydrate; In 1,2-dimethoxyethane; water; at 75℃; | [00386] Into a 2-L 4-necked round-bottom flask was placed 2-[1,4-dioxaspiro[4.5]dec-7- en-8-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (44 g, 165.33 mmol, 1.00 equiv) and 3- iodo- 1- (oxan-2-yl)- 1H-pyrazole-4-carbaldehyde (45.5 g, 148.64 mmol, 0.90 equiv). This was followed by the addition of Pd(dppf)C12 (12 g, 16.40 mmol, 0.10 equiv). To this was added K3P04 (105 g, 494.66 mmol, 2.99 equiv), ethylene glycol dimethyl ether (500 mL) and water (50 mL). The resulting mixture was stuffed overnight at 75C in an oil bath then cooled to room temperature and concentrated under vacuum. The residue was extracted with 500 mL of ethyl acetate and the organic layer washed with 3 x 500 mL of brine and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel column using ethyl acetate / petroleum ether (gradient: 20% to 30% EA) as eluent to afford 35.5 g (67%) of (R/S) 3-[1,4-dioxaspiro[4.5]dec-7-en-8-yl]-1-(oxan-2-yl)- 1H-pyrazole-4-carbaldehyde as a light yellow solid. ?H-NMR (300 MHz,CDC13): 9.91(s, 1H), 8.26(s, 1H), 6.29-6.26(m, 1H), 5.38-5.34 (m, 1H), 4.09-4.01(m, 5H),3.74-3.63(m, 1H), 2.79-2.74(m, 2H), 2.50-2.49(d, J=3.6Hz, 2H), 2.12-1.89(m, 5H), 1.72-1.60(m, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 80℃; for 10.0h;Inert atmosphere; Microwave irradiation; | General procedure: In a 20 mL microwave tube 0.75 mmol (1 equiv.) of the boron ester 26 was dissolved in 10 mL of dioxane and 5 mol% of Pd(PPh3)4 was added along with 0.75 mmol (1 equiv.) of the corresponding arylbromide. Next, 8 equivalents of 2 M Na2CO3 in H2O solution was added and the reaction mixture was flushed with N2 gas and capped. The reaction mixture was heated in the microwave for 10 hours at 80 C. Upon completion, the reaction mixture was partitioned between DCM/H2O and the organic layer was dried over MgSO4. Column chromatography was performed with DCM as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 80℃; for 10.0h;Inert atmosphere; Microwave irradiation; | General procedure: In a 20 mL microwave tube 0.75 mmol (1 equiv.) of the boron ester 26 was dissolved in 10 mL of dioxane and 5 mol% of Pd(PPh3)4 was added along with 0.75 mmol (1 equiv.) of the corresponding arylbromide. Next, 8 equivalents of 2 M Na2CO3 in H2O solution was added and the reaction mixture was flushed with N2 gas and capped. The reaction mixture was heated in the microwave for 10 hours at 80 C. Upon completion, the reaction mixture was partitioned between DCM/H2O and the organic layer was dried over MgSO4. Column chromatography was performed with DCM as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 80℃; for 10.0h;Inert atmosphere; Microwave irradiation; | General procedure: In a 20 mL microwave tube 0.75 mmol (1 equiv.) of the boron ester 26 was dissolved in 10 mL of dioxane and 5 mol% of Pd(PPh3)4 was added along with 0.75 mmol (1 equiv.) of the corresponding arylbromide. Next, 8 equivalents of 2 M Na2CO3 in H2O solution was added and the reaction mixture was flushed with N2 gas and capped. The reaction mixture was heated in the microwave for 10 hours at 80 C. Upon completion, the reaction mixture was partitioned between DCM/H2O and the organic layer was dried over MgSO4. Column chromatography was performed with DCM as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 80℃; for 10.0h;Inert atmosphere; Microwave irradiation; | General procedure: In a 20 mL microwave tube 0.75 mmol (1 equiv.) of the boron ester 26 was dissolved in 10 mL of dioxane and 5 mol% of Pd(PPh3)4 was added along with 0.75 mmol (1 equiv.) of the corresponding arylbromide. Next, 8 equivalents of 2 M Na2CO3 in H2O solution was added and the reaction mixture was flushed with N2 gas and capped. The reaction mixture was heated in the microwave for 10 hours at 80 C. Upon completion, the reaction mixture was partitioned between DCM/H2O and the organic layer was dried over MgSO4. Column chromatography was performed with DCM as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 80℃; for 10h;Inert atmosphere; Microwave irradiation; | General procedure: In a 20 mL microwave tube 0.75 mmol (1 equiv.) of the boron ester 26 was dissolved in 10 mL of dioxane and 5 mol% of Pd(PPh3)4 was added along with 0.75 mmol (1 equiv.) of the corresponding arylbromide. Next, 8 equivalents of 2 M Na2CO3 in H2O solution was added and the reaction mixture was flushed with N2 gas and capped. The reaction mixture was heated in the microwave for 10 hours at 80 C. Upon completion, the reaction mixture was partitioned between DCM/H2O and the organic layer was dried over MgSO4. Column chromatography was performed with DCM as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 2.0h; | Step 3. Methyl 4-(3-amino-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrazin-2-yl)-2-fluorobenzoate To a solution of methyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate (10 g, 30.7 mmol) in DME (77 mL) was added <strong>[680596-79-6]4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane</strong> (9.79 g, 36.8 mmol), PdCl2(dppf).CH2Cl2 adduct (1.252 g, 1.533 mmol), H2O (25.6 mL) and then last sodium carbonate (9.75 g, 92 mmol). The reaction was heat at 100 C. in oil bath for 2 h. Cooled down. The reaction mixture was extracted by EtOAc 3 times, the organic was washed with water and brine, dried and concentrated. The crude material was recrystallized in DCM and heptane (1:1) to give product methyl 4-(3-amino-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrazin-2-yl)-2-fluorobenzoate in 75% yield. LCMS (m/z): 382.2 (MH+), 0.82 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 2.0h; | Step 5. Tert-butyl 4-(3-amino-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrazin-2-yl)-2-fluorobenzoate To tert-butyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate (5.17 g, 46.2 mmol) in DME (115 mL) were added <strong>[680596-79-6]4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane</strong> (15.36 g, 57.7 mmol), PdCl2(dppf).CH2Cl2 adduct (1.885 g, 2.309 mmol), and then 2 M aqueous solution sodium carbonate (19.57 g, 185 mmol). The reaction mixture was heated at 100 C. overnight. LCMS indicated the reaction was completed. The reaction was cooled down. To the mixture was added 1000 mL of EtOAc and 300 mL of water. The resulting mixture was stirred for 30 min, and the organic layer was separated. The aqueous layer was extracted with EtOAc (3*200 mL). The organic layers were combined, washed with water three times and brine, dried over sodium sulfate, filtered off, and concentrated in vacuo. The crude product was triturated by ether to provide tert-butyl 4-(3-amino-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrazin-2-yl)-2-fluorobenzoate (19.5 g, 45.6 mmol, 99%) as a light yellow solid. LCMS (m/z): 428.1 (MH+), 1.02 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; at 120℃; for 0.25h;Microwave irradiation; | Step 1. 5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrazin-2-amine To 5-bromopyrazin-2-amine (225 mg, 1.293 mmol) was added <strong>[680596-79-6]4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane</strong> (482 mg, 1.810 mmol), PdCl2(dppf)-CH2Cl2 adduct (84 mg, 0.103 mmol), DME (3.5 mL) and then last sodium carbonate 2M (1.616 mL, 3.23 mmol). The reaction was microwaved at 120 C. for 15 min. To the reaction was added 80 mL of DCM, washed with water (1*), dried sodium sulfate, filtered and concentrated to residue. The crude was purified by silica gel chromatography using 12 gram column (solid load) eluting with 10-90% ethyl acetate and heptane. The desired fractions were concentrated to constant mass to give 173 mg of the desired product as free base used as is (56% yield). LCMS (m/z): 234.2 (MH+), 0.43 min; 1H NMR (400 MHz, DMSO-d6) delta ppm 8.01 (d, J=1.2 Hz, 1H), 7.80 (d, J=1.2 Hz, 1H), 6.33 (s, 2H), 6.27 (t, J=3.9 Hz, 1H), 3.89 (s, 4H), 2.52 (d, J=1.6 Hz, 2H), 2.33 (br. s., 2H), 1.76 (t, J=6.7 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water;Reflux; | A mixture of Preparation 40B (368g, 1.38 mol, 1.3eq), 4-Chloro-6- fluoroquinoline (195 g, 1.07 mol, leq), K2C03 (445 g, 3.22 mol,3eq) and Pd(PPh3)4(25 g, 22 mmol, 0.O2eq) in dioxane-water (3L, 4:1) was heated to reflux overnight. The solution was then concentrated and extracted with EtOAc. Purification by FCC (38% EtOAc/petrolium ether) gave Preparation 40C (236 g, 77%). Preparation 40C: LC-MS: 286.1 (M+1)+, ?H NMR (400 MHz, CDC13) oe 8.80-8.29 (d, 1H), 8.11-8.07 (q, 1H), 7.63-7.61 (q, 1H), 7.47-7.46 (q, 1H), 7.26-7.22(m,1H),5.75-5.74 (m, 1H), 4.08-4.05 (m, 4H), 2.63-2.59 (m, 2H),2.59-2.53(m,2H), 2.0-1 .97(m,2H). |
77% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water;Reflux; | [00166] A mixture of Preparation B (368g, 1.38 mol, 1.3eq), 4-Chloro-6- fluoroquinoline (195 g, 1.07 mol, leq), K2CO3 (445 g, 3.22 mol,3eq) and Pd(PPh3)4 (25 g, 22 mmol, 0.02eq) in dioxane-water (3L, 4: 1) was heated to reflux overnight. The solution was then concentrated and extracted with EtOAc. Purification by FCC (38% EtOAc/petrolium ether) gave Preparation C (236 g, 77%). (0236) Preparation C: LC-MS: 286.1 (M+l)+, XH NMR (400 MHz, CDCh) delta 8.80-8.29 (d, 1H), 8.11-8.07 (q, 1H), 7.63-7.61 (q, 1H), 7.47-7.46 (q, 1H), 7.26-7.22(m,lH), 5.75-5.74 (m, 1H), 4.08-4.05 (m, 4H), 2.63-2.59 (m, 2H),2.59-2.53(m,2H), 2.0-1.97(m,2H). |
77% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water;Reflux; | [00180] A mixture of Intermediate 2B (368 g, 1.38 mol, 1.3eq), 4-Chloro-6- fluoroquinoline (195 g, 1.07 mol, leq), K2C03 (445 g, 3.22 mol,3eq) and Pd(PPh3)4 (25 g, 22 mmol, 0.02eq) in dioxane-water (3L, 4: 1) was heated to reflux overnight. The solution was concentrated and extracted with EtOAc. The crude residue was purified via silica gel column chromatography to give Intermediate 2C (236 g, 77% yield). LC-MS Anal. Calc'd for (0260) Ci7Hi6FN02 285.12, found [M+H] 286.1. 1H NMR (400 MHz, CDC13) delta 8.80-8.29 (d, 1H), 8.11-8.07 (q, 1H), 7.63-7.61 (q, 1H), 7.47-7.46 (q, 1H), 7.26-7.22(m,lH), 5.75-5.74 (m, 1H), 4.08-4.05 (m, 4H), 2.63-2.59 (m, 2H),2.59-2.53(m,2H), 2.0-1.97(m,2H). |
77% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water;Reflux; | A mixture of Preparation 4B (368g, 1.38 mol, 1.3eq), 4-Chloro-6- fluoroquinoline (195 g, 1.07 mol, leq), K2C03 (445 g, 3.22 mol,3eq) and Pd(PPh3)4 (25 g, 22 mmol, 0.O2eq) in dioxane-water (3L, 4:1) was heated to reflux overnight. The solution was then concentrated and extracted with EtOAc. Purification by FCC (38% EtOAc/petrolium ether) gave Preparation 4C (236 g, 77%).Preparation 4C: LC-MS: 286.1 (M+1)+, ?H NIVll (400 IVEHz, CDC13) oe 8.80-8.29 (d, 1H), 8.11-8.07 (q, 1H), 7.63-7.61 (q, 1H), 7.47-7.46 (q, 1H), 7.26-7.22(m,1H), 5.75-5.74 (m, 1H), 4.08-4.05 (m, 4H), 2.63-2.59 (m,2H),2.59-2.53(m,2H), 2.0-1 .97(m,2H). |
77% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water;Reflux; | A mixture of Preparation 14B (368g, 1.38 mol, 1.3eq), 4-Chloro-6- fluoroquinoline (195 g, 1.07 mol, 1eq), K2CO3 (445 g, 3.22 mol,3eq) and Pd(PPh3)4 (25 g, 22 mmol, 0.02eq) in dioxane-water (3L, 4:1) was heated to reflux overnight. The solution was then concentrated and extracted with EtOAc. Purification by FCC (38% EtOAc/petrolium ether) gave Preparation 14C (236 g, 77%). Preparation 14C: LC-MS: 286.1 (M+1)+, 1H NMR (400 MHz, CDCl3) ^delta ^8.80-8.29 (d, 1H), 8.11-8.07 (q, 1H), 7.63-7.61 (q, 1H), 7.47-7.46 (q, 1H), 7.26-7.22(m,1H), 5.75-5.74 (m, 1H), 4.08-4.05 (m, 4H), 2.63-2.59 (m, 2H),2.59-2.53(m,2H), 2.0-1.97(m,2H). |
77% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water;Reflux; | A mixture of Preparation TB (368g. 13 mol. i.3eq), 4-chloro-6-fluoroquinoline (195 g, 107mol, leq), K2C03 (445 g, 3.22 mol, 3eq) and Pd(PPh3)4 (25 g, 22 rnmol, 0.O2eq) in dioxane-water(3L, 4:1) was heated to refiux overnight. The solution was then concentrated and extracted withEtOAc. Purification by FCC (38% EtOAc/peiroliurn ether) gave Preparation if (236 g, 77%). Preparation 1C: LC-MS: 286.1 (M+1)+, ?HNMR(400 MHz, CDC13) oe 8.80- 8.29 (d, 1H), 8.11-8.07 (q, 1H), 7.63-7.61 (q, 1H), 7.47-7.46 (q, IH), 7.26-7.22(in,IH), 5.75-5.74 ,in, 1H), 4.08-4.05 (m. 4H), 2.63-2.59 (rn, 2H).2.59-2.53(m,2H), 2.0-i.97(rn,2H). |
77% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water;Reflux; | A mixture of Intermediate IB (368g, 1.38 mol, 1.3eq), 4-Chloro-6-fluoroquinoline (195 g, 1.07 mol, leq), K2CO3 (445 g, 3.22 mol,3eq) and Pd(PPh3)4(25 g, 22 mmol, 0.02eq) in dioxane-water (3L, 4: 1) was heated to reflux overnight. The solution was then concentrated and extracted with EtOAc. Purification by FCC (38% EtOAc/petrolium ether) gave Intermediate 1C (236 g, 77%). LC-MS: 286.1 (M+l)+, NMR (400 MHz, CDCb) delta 8.80-8.29 (d, IH), 8.11-8.07 (q, IH), 7.63-7.61 (q, IH), 7.47-7.46 (q, IH), 7.26- 7.22(m,lH), 5.75-5.74 (m, IH), 4.08-4.05 (m, 4H), 2.63-2.59 (m, 2H),2.59-2.53(m,2H), 2.0-1.97(m,2H). |
67% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; potassium bromide; In diethylene glycol dimethyl ether; water; at 90℃;Inert atmosphere; | Under nitrogen protection,To the presence of 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-ene-8-yl)-1,3,2-dioxaboron Alkane (235.3 g, 884.1 mmol), 4-chloro-6-fluoroquinoline (160.0 g, 881.1 mmol), KBr (52.0 g, 437.0 mmol) and K2CO3 (366.0 g, 2648.1 mmol) of DME/H2O (3L/ 0.6 L) of Pd(dppf)Cl2 (26.0 g, 35.5 mmol) was added to the solution, and the reaction mixture was warmed to 90 C and stirred overnight.After TLC showed that the starting material was completely reacted, water was added to the reaction mixture to quench it.It was extracted three times with EA, and the organic layer was combined and washed with brine.Dry with anhydrous Na2SO4,The crude product obtained by concentration is subjected to column chromatography.(PE/EA = 5/1 to 1/1), the title compound (170.0 g, yield: 67%) was obtained as a pale yellow oil. |
58% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water;Inert atmosphere; Reflux; | Step 3:Under nitrogen protection,Compound 1.2 (3.22 g, 12.1 mmol),4-chloro-6-fluoroquinoline (2.1 g, 13.8 mol),Potassium carbonate (3.85g, 27.3mmol)A mixture of water/1,4-dioxane (50 mL, 4:1) of Pd(PPh3) 4 (0.22 g, 0.19 mmol) was stirred at reflux overnight.The reaction was then concentrated and extracted with ethyl acetate (60 mL×3).The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated.The residue was flash chromatographed (petroleum ether / ethyl acetate = 3/1)Purification afforded compound 1.3 (2.0 g, yield: 58%) as pale yellow solid. |
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water;Reflux; | j00170j A mixture of Preparation lB (368g, 1.38 mol, 1.3eq), 4-Chloro-6- fluoroquinoline (195 g, 1.07 mol, leq), K2C03 (445 g, 3.22 mol,3eq) and Pd(PPh3)4 (25 g, 22 mmol, 0.O2eq) in dioxane-water (3L, 4:1) was heated to reflux overnight. The solution was then concentrated and extracted with EtOAc. Purification by FCC (38% EtOAc/petrolium ether) gave Preparation 1C (236 g, 77%).Preparation 1C: LC-MS: 286.1 (M+1)+, ?HNMR (400 MHz, CDC13) oe 8.80-8.29 (d, 1H), 8.11-8.07 (q, 1H), 7.63-7.61 (q, 1H), 7.47-7.46 (q, 1H), 7.26-7.22(m,1H), 5.75-5.74 (m,1H), 4.08-4.05 (m, 4H), 2.63-2.59 (m, 2H),2.59-2.53(m,2H), 2.0-1.97(m,2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 95℃; | To a solution of <strong>[3964-04-3]4-bromoquinoline</strong> (4.70 g, 22.67 mmol) in 1, 4-dioxane (150 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (6.00 g, 22.67 mmol), Pd (dppf) Cl2 (2.47 g, 3.40 mmol) and Cs2CO3 (11.00 g, 34.0 mmol) and the mixture was heated at 95 for overnight. Then evaporated the solvent under reduced pressure and the residue was purified by column chromatography (PE: EA = 4: 1) to give product as a clear oil (4.41 g in 73% yield). 1H NMR (DMSO-d6) deltaH 8.83 (d, J = 4.4 Hz, 1H), 8.01-8.05 (m, 2H), 7.74-7.78 (m, 1H), 7.59-7.64 (m, 1H), 7.31 (d, J = 4.4 Hz, 1H), 5.70-5.72 (m, 1H), 3.99 (s, 4H), 2.51-2.56 (m, 2H), 2.45-2.46 (m, 2H), and 1.91 (t, J = 6.4 Hz, 2H). |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine; In 1,3-dioxane; water; at 100℃; for 15h;Inert atmosphere; | To a 20 mL reaction vial containing 4,4,5,5-tetramethyl-2-(l,4- dioxaspiro[4.5]dec-7-en-8-yl)-l,3,2-dioxaborolane (See General Procedure K for reference to preparation)commercially available, CAS [680596-79-6]) (1.0 g, 3.8 mmol, 1.0 equiv.), <strong>[3964-04-3]4-bromoquinoline</strong> (0.86 g, 4.1 mmol, 1.1 equiv.), and Pd(dppf)Ci2 (0.154 g, 0.188 mmol, 0.05 equiv.) was added dioxane (12 mL), water (1.2 mL), and NEt3 (1.0 mL, 7.5 mmol, 2.0 equiv.). The flask was flushed with argon and placed in a pre-heated block at 100 C for 15 hours. The crude residue was diluted with EtOAc (100 mL), filtered through a pad of CELITE, and concentrated. The crude residue was purified by silica gel chromatography (0% to 50% EtOAc in hexanes) to afford Intermediate 30A (1.0 g, 99% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.5% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 16.0h;Inert atmosphere; | 5-bromo-2-iodo-pyrimidine (2.0g, 7.0mmol), 4,4,5,5- tetramethyl-2- (1,4-dioxa-spiro [4.5] dec-7-ene -8 - yl) 1,3,2-dioxaborolane (1.86g, 7.0mmol), potassium carbonate (1.93g, 14mmol) and tetrakis (triphenylphosphine) palladium (404mg, 0.35mmol) was dissolved in 1, 4- dioxane (20mL) and water (5mL) in a mixed solvent, nitrogen was heated to 80 , 16 hours.After completion of the reaction the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (PE: EA = 20: 1) to give the title compound (1.9 g of, yield 90.5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 50℃; for 2.5h;Inert atmosphere; | Step 1 : 8-(4-methoxy-3-methylphenyl)- 1 ,4-dioxaspiro [4.5] dec-7-ene [00412] A mixture of l,4-dioxa-spiro[4,5]dec-7-en-8-boronic acid pinacol ester (25.0 g, 93.9 mmol), 4-iodo-2-methylanisole (28.0 g, 113 mmol), l,l '-bis(diphenylphosphino)ferrocene dichlorlopalladium(II) (1.38 g, 1.89 mmol), dioxane (470 mL) and lM a2C03 (282 mL, 282 mmol) was degassed with vacuum/nitrogen cycles (3*), stirred at 50 C for 2.5 h, and then allowed to cool to rt. The mixture was diluted with ethyl acetate (500 mL) and washed with saturated NaHCCh (500 mL chi 2). The aqueous layers were back extracted with ethyl acetate (200 mL). The combined ethyl acetate extracts were dried ( a2S04), filtered, concentrated and purified by silica gel chromatography (0-5% ethyl acetate in hexanes) to give 8-(4-methoxy-3- methylphenyl)-l,4-dioxaspiro[4.5]dec-7-ene (19.9 g, 81%). NMR (400 MHz, DMSO-<&): delta 7.21-7.16 (m, 2H), 6.85 (d, 1H), 5.89-5.84 (m, 1H), 3.90 (s, 4H), 3.76 (s, 3H), 2.52-2.47 (m, 2H), 2.32 (br s, 2H), 2.13 (s, 3H), 1.77 (t, 2H); MS: 261.1 [M+H]+. |
81% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; at 50℃; for 2.5h;Inert atmosphere; | j00452j A mixture of 1,4-dioxa-spiro[4,5]dec-7-en-8-boronic acid pinacol ester (25.0 g, 93.9 mmol), 4-iodo-2-methylanisole (28.0 g, 113 mmol), 1,1?-bis(diphenylphosphino)ferrocene dichloropalladium(II) (1.38 g, 1.89 mmol), dioxane (470 mL) and 1MNa2CO3 (282 mL, 282 mmol) was degassed with 3 vacuum/N2 cycles, stirred at 50 C for 2.5 h, and then allowed to cool to a The mixture was diluted with ethyl acetate (500 mL) and washed with saturated NaHCO3 (500 mL x 2). The aqueous layers were back extracted with ethyl acetate (200 mL). The combined ethyl acetate extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography (0-5% ethyl acetate in hexanes) to give 8-(4-methoxy-3-methylphenyl)-1,4- dioxaspiro[4.5]dec-7-ene (19.9 g, 81%). ?H NMR (400 MHz, DMSO-d6): 7.21-7.16 (m, 2H), 6.85 (d, 1H), 5.89-5.84 (m, 1H), 3.90 (s, 4H), 3.76 (s, 3H), 2.52-2.47 (m, 2H), 2.32 (br s, 2H),2.13 (s, 3H), 1.77 (t, 2H); MS: 261.1 [M+H]. |
81% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; at 50℃; for 2.5h;Inert atmosphere; | A mixture of 1,4-dioxa-spiro[4,5]dec-7-en-8-boronic acid pinacol ester (25.0 g, 93.9 mmol), 4-iodo-2-methylanisole (28.0 g, 113 mmol), 1,1?-bis(diphenylphosphino)ferrocenedichlorlopalladium(II) (1.38 g, 1.89 mmol), dioxane (470 mL) and 1MNa2CO3 (282 mL, 282 mmol) was degassed with 3 vacuum/N2 cycles, stirred at 50 C for 2.5 h, and then allowed to cool to a The mixture was diluted with ethyl acetate (500 mL) and washed with saturated NaHCO3 (500 mL x 2). The aqueous layers were back extracted with ethyl acetate (200 mL). The combined ethyl acetate extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography (0-5% ethyl acetate in hexanes) to give 8-(4-methoxy-3-methylphenyl)-1,4- dioxaspiro[4.5]dec-7-ene (19.9 g, 81%). ?H NMR (400 MHz, DMSO-d6): 7.21-7.16 (m, 2H), 6.85 (d, 1H), 5.89-5.84 (m, 1H), 3.90 (s, 4H), 3.76 (s, 3H), 2.52-2.47 (m, 2H), 2.32 (br s, 2H),2.13 (s, 3H), 1.77 (t, 2H); MS: 261.1 [M+H]. |
81% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; at 50℃; for 2.5h;Inert atmosphere; | A mixture of 1,4-dioxa-spiro[4,5]dec-7-en-8-boronic acid pinacol ester (25.0 g, 93.9 mmol), 4-iodo-2-methylanisole (28.0 g, 113 mmol), Pd(dppf)Cl2(1.38 g, 1.89 mmol), dioxane (470 mL) and 1M Na2C03(282 mL, 282 mmol) was degassed with 3 vacuum/N2cycles, stirred at 50 C for 2.5 h, and then allowed to cool to rt. The mixture was diluted with EtOAc (500 mL) and washed with saturated NaHC03(2x500 mL). The aqueous layers were back extracted with EtOAc (200 mL). The combined EtOAc extracts were dried (Na2S04), filtered, concentrated and purified by silica gel chromatography (0-5% EtOAc in hexanes) to give 8-(4-methoxy-3-methylphenyl)-l,4-dioxaspiro[4.5]dec-7-ene (19.9 g, 81%).1H MR (400 MHz, DMSO-i): delta 7.21-7.16 (m, 2H), 6.85 (d, 1H), 5.89-5.84 (m, 1H), 3.90 (s, 4H), 3.76 (s, 3H), 2.52-2.47 (m, 2H), 2.32 (br s, 2H), 2.13 (s, 3H), 1.77 (t, 2H); MS: 261.1[M+H]+. |
81% | With sodium carbonate; In 1,4-dioxane; at 50℃; for 2.5h;Inert atmosphere; | A mixture of 1,4-dioxa-spiro[4,5]dec-7-en-8-boronic acid pinacol ester (25.0 g, 93.9 mmol), 4-iodo-2-methylanisole (28.0 g, 113 mmol), 1,1?-bis(diphenylphosphino)ferrocene dichlorlopalladium(II) (1.38 g, 1.89 mmol), dioxane (470 mL) and 1 MNa2CO3 (282 mL, 282 mmol) was degassed with 3 vacuum/N2 cycles, stirred at 50 C for 2.5 h, and then allowed to cool to a The mixture was diluted with EtOAc (500 mL) and washed with sat?d NaHCO3 (2x500 mL). The aqueous layers were back extracted with EtOAc (200 mL). The combined EtOAc extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography (0-5% EtOAc in hexanes) to give 8-(4-methoxy-3-methylphenyl)-1,4- dioxaspiro[4.5]dec-7-ene (19.9 g, 81%). ?H NMR (400 MHz, DMSO-d6): 7.21-7.16 (m, 2H), 6.85 (d, 1H), 5.89-5.84 (m, 1H), 3.90 (s, 4H), 3.76 (s, 3H), 2.52-2.47 (m, 2H), 2.32 (br s, 2H), 2.13 (s, 3H), 1.77 (t, 2H); LCMS: 261.1 [M+H]. |
81% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; at 50℃; for 2.5h;Inert atmosphere; | A mixture of 1,4-dioxa-spiro[4,5]dec-7-en-8-boronic acid pinacol ester (25.0 g, 93.9 mmol), 4-iodo-2-methylanisole (28.0 g, 113 mmol), Pd(dppf)Cl2 (1.38 g, 1.89 mmol), dioxane (470 mL) and 1 M Na2CO3 (282 mL, 282 mmol) was degassed with 3 vacuum/N2 cycles, stirred at 50 C. for 2.5 h, and then allowed to cool to rt. The mixture was diluted with EtOAc (500 mL) and washed with saturated NaHCO3 (2×500 mL). The aqueous layers were back extracted with EtOAc (200 mL). The combined EtOAc extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography (0-5% EtOAc in hexanes) to give 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]dec-7-ene (19.9 g, 81%). 1H NMR (400 MHz, DMSO-d6): delta 7.21-7.16 (m, 2H), 6.85 (d, 1H), 5.89-5.84 (m, 1H), 3.90 (s, 4H), 3.76 (s, 3H), 2.52-2.47 (m, 2H), 2.32 (br s, 2H), 2.13 (s, 3H), 1.77 (t, 2H); LCMS: 261.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 100℃; for 3.0h;Inert atmosphere; | Step 1: 8-(5-cyclopropoxy-2-methyl-4-nitrophenyl)-1,4-dioxaspiro [4.5] dec-7-ene 1,4-dioxaspiro [4.5] dec-7- ene -8-boronic acid pinacol ester (0.38g, 1.43mmol), 1-bromo-5-cyclopropoxy-2-methyl-4-nitrobenzene (0.35g, 1.29mmol), bis (triphenylphosphine) palladium dichloride (0.18g, 0.26mmol), sodium carbonate (0.27g, 2.55mmol), 1,4-dioxane (3.5mL) and water (1.4mL) were added to a 25ml reaction flask. The reaction mixture was heated up to 100 C under the protection of nitrogen and reacted for 3 hours. After completion of the reaction, water was added to dissolve, ethyl acetate was added to extract and the organic layer was washed with water, dried, concentrated and purified by column chromatography (ethyl acetate/petroleum ether = 1: 5) to obtain the title compound (white solid, 0.3g, 70%). (MS: [M+1] 332.1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.9% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 80℃; for 0.5h; | To a solution of 8-bromo-9-(4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (500 mg, 1.09 mmol), in dioxane/water (80/20; V/V, 25 ml), was added 1,4-dioxa-spiro[4,5]dec-7-en-8-boronic acid pinacoyl ester (412.93 mg, 1.52 mmol), Cs2CO3 (743.85 mg, 2.28 mmol), and Pd(dppf)Cl2 (53.22 mg, 65.16 mumol). The reaction mixture was heated at 80 C. for 30 minutes, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0% to 4%) to give a solid which was further purified on strong cation exchange (SCX) column to give 485 mg (85.9%) of 6-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-5-{4-[(S)-1-(3-fluoropropyl)pyrrolidin-3-yloxy]phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium phosphate; palladium diacetate; triphenylphosphine; In 1,4-dioxane; water; at 70 - 110℃; for 1.75h;Inert atmosphere; Sealed tube; | A solution of tripotassium phosphate (701 mg, 3.3 mmol) in water (1.4mL) was added to a nitrogen-degassed suspension of compound 1 (200 mg, 0.55 mmol),4,4,5,5-tetramethyl-2-(1 ,4-dioxaspiro[4. Sjdec-7-en-8-yl)- 1 ,3,2-dioxaborolane (161 mg, 0.61 mmol), triphenylphosphine (72.2 mg, 0.28 mmol), and Pd(OAc)2 (12.4 mg, 0.06 mmol) inpdioxane (13.5 mL). The reaction vessel was sealed with a screw cap and heated at 100 - 110C for 15 mm and then stirred at 70C for 1.5 h. The cooled mixture was concentrated and the residue was distributed between water and dichloromethane. The organic phase was dried (Na2SO4) and concentrated to a solid that was triturated in ethanol, collected, and dried to give 77 (205 mg, 88%). ?H NMR (400 MHz, chloroform-d): 3 9.16 (s, 1H), 8.37 (s, 1H), 8.25 (d, J= 2.4 Hz, 1H), 7.78 (dd, J= 8.7, 2.4 Hz, 1H), 7.44 (d, J 8.7 Hz, 1H), 6.16- 6.08 (m, 1H), 5.87 (s, 1H), 4.40 (q, J= 7.1 Hz, 2H), 4.04 (s, 4H), 2.81 -2.69 (m, 2H), 2.52 (t, J2.5 Hz, 2H), 1.97 (t, J= 6.5 Hz, 2H), 1.44 (t, J= 7.1 Hz, 3H). MS TOFES: m/z 423.0 (M+H)t |
88% | With potassium phosphate; palladium diacetate; triphenylphosphine; In 1,4-dioxane; water; at 70 - 110℃; for 1.75h;Sealed tube; | General procedure: (a) Suzuki couplings[1]General Procedure: A nitrogen-degassed solution of a potassium base in water was addedto a nitrogen-degassed suspension of substrate aryl bromide, alk-1-en-1-yl/cycloalk-1-en-1-yl boronic acid/pinacol ester, trialkyl-/triphenylphosphine, and palladium catalyst in anorganic solvent. The reaction vessel was sealed with a screw cap and heated for aspecified time, generally resulting in a clear orange solution. Workup was carried out byconcentrating the mixture to a residue that was diluted with water and extracted withdichloromethane. Further workup left a residue that was purified by trituration in anappropriate solvent or by silica gel chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere; | Under N2, a mixture of <strong>[4965-36-0]7-bromoquinoline</strong> (4.0 g, 19.3 mmoL) , 4, 4, 5, 5-tetramethyl-2-(1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (5.0 g, 18.8 mmol) , Pd (dppf) Cl2(2.7 g, 2.7 mmol) and Cs2CO3(9.0 g, 27.6 mmol) in dioxane/H2O (60 mL/15 mL) was heated to 90 for 16 hours. Then evaporated the solvent under reduced pressure and the residue was purified by column chromatography to give 8.0 g oil. [M+H]+=268.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 90℃; for 3.0h;Inert atmosphere; | To a solution of 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (20 g, 75.15 mmol) , 1-bromo-4-iodobenzene (32 g, 112.7 mmol) , Pd (dppf ) Cl2(5.5 g, 7.5 mmol) and Cs2CO3(36.6 g, 112.5 mmol) in dioxane (200 mL) , the mixture was stirred at 90 under N2for 3h. TLC (PE: EA=5: 1, Rf =0.5) showed the reaction was completed. Filtered and concentrated, H2O (100 ml) was was added and extracted with EA (50 ml×3) . The combined organic layer was dried over Na2SO4, filtered and concentrated to give crude product, which was purified by silica gel chromatography (PE: EA =20: 1-6: 1) to give product (18 g, 81%) as a red solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.7% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 80℃; for 20h; | To a solution of tert-butyl (4-iodophenyl) carbamate (7.2 g, 22.6 mmoL) in 1, 4-dioxane (100 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (6.0 g, 22.6 mmol) , Pd (dppf) Cl2(1.6 g, 2.2 mmol) and Cs2CO3(11.0 g, 33.9 mmol) and the mixture was heated at 80 for 20 hours. Then filter off the solid, the filtrate was evaporated under reduced pressure and the residue was purified by column chromatography (PE: EA=4: 1) to give product as yellow solid (2.9 g in 38.7%yield) . [M+H]+= 332.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 80℃; for 2h; | To a solution of 5-bromobenzo [b] thiophene (8.5 g, 40 mmoL) in 1, 4-dioxane (150 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (10.6 g, 40 mmol), Pd (dppf) Cl2 (4.4 g, 6 mmol) and Cs2CO3 (19.5 g, 60 mmol) and the mixture was heated at 80 for 2 hours. Then filter off the solid, the filtrate was evaporated under reduced pressure and the residue was purified by column chromatography (PE: EA=25: 1) to give product as yellow solid (6.6 g in 61% yield). 1HNMR (400 MHz, DMSO-d6) deltaH 7.92 (d, J= 8.8 Hz, 1H), 7.89 (s, 1H), 7.74 (d, J= 5.2 Hz, 1H), 7.46 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 7.43 (d, J = 5.6 Hz, 1H), 6.09 (t, J = 3.6 Hz 1H), 3.93 (s, 4H), 2.63 (t, J= 5.6 Hz, 2H), 2.40 (s, 2H), and 1.85 (t, J= 6.4 Hz, 2H). [M+H] += 273.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 70℃; for 5.0h; | To a solution of 1-bromo-4-fluoronaphthalene (2.25 g, 10 mmoL) in 1, 4-dioxane /H2O (80 mL/20mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (2.66 g, 10 mmol) , Pd (dppf) Cl2(731 mg, 1.0 mmol) and Cs2CO3(4.88 g, 1.5 mmol) and the mixture was heated at 70 for 5 hours. Then evaporated the solvent under reduced pressure and the residue was purified by column chromatography (PE: EA=5: 1) to give product as an oil (2.1 g in 74%yield) . [M+H]+=285 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.6% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 70℃; for 5.0h; | To a solution of 1, 2, 3-trifluoro-4-iodobenzene (3.3 g, 18.8 mmoL) in 1, 4-dioxane (100 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (5 g, 18.8 mmol) , Pd (dppf) Cl2(1.3 g, 1.88 mmol) and Cs2CO3(9.2 g, 28.2 mmol) and the mixture was heated at 70 for 5 hours. Then evaporated the solvent under reduced pressure and the residue was purified by column chromatography (PE: EA=5: 1) to give product as an oil (4.5 g in 88.6%yield) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.7% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 90℃; | To a solution of <strong>[458-50-4]1-bromo-2-fluoro-4-methoxybenzene</strong> (4.1 g, 20 mmoL) in 1, 4-dioxane (60 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (5.32 g, 20 mmol) , Pd (dppf) Cl2(731 mg, 1 mmol) and Cs2CO3(9.7 g, 30 mmol) and the mixture was heated at 90 overnight. The mixture was cooled to room temperature, diluted with water (100 mL) , extracted with ethyl acetate (75 mL×2) , washed with brine, dried over Na2SO4, filtered and filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (PE: EA=50: 1) to give product as an oil (4 g in 75.7percentyield) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 90℃; | To a solution of <strong>[50638-46-5]1-bromo-2-chloro-4-methoxybenzene</strong> (6.6 g, 30 mmoL) in 1, 4-dioxane (150 mL) was added with 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (8 g, 30 mmol) , Pd (dppf)2Cl2(2.2 g, 3 mmol) and Cs2CO3(14.7 g, 45 mmol) and the mixture was heated at 90 overnight. After evaporated the solvent under reduced pressure, the residue was added with water (80 mL) , extracted with ethyl acetate (80 mL) . The organic layer was dried, concentrated and purified by column chromatography (PE: EA=80: 1) to give product as a white solid (6.2 g in 74%yield) .1H NMR (CDCl3) deltaH7.12 (d, J = 12.0 Hz, 1H) , 6.90 (d, J = 1.2 Hz, 1H) , 6.75 (dd, J1=8.0 Hz, J2=4.0 Hz, 1H) , 5.56-5.54 (m, 1H) , 4.04-4.01 (m, 4H) , 3.79 (s, 3H) , 2.55-2.51 (m, 2H) , 2.45-2.42 (m, 2H) , 1.89 (t, J = 6.4 Hz, 2H) . [M+H]+=281.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.7% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 90℃; for 3h; | To a solution of <strong>[75676-72-1]2-chloro-4-iodo-1-methoxybenzene</strong> (2.68 g, 10 mmoL) in 1, 4-dioxane (100 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (2.66 g, 10 mmol) , Pd (dppf) Cl2(0.73 g, 1 mmol) and Cs2CO3(6.4 g, 20 mmol) and the mixture was heated at 90 for 3 hours. Then evaporated the solvent under reduced pressure and the residue was purified by column chromatography (PE: EA=5: 1) to give product as a yellow solid (1.7 g in 60.7%yield) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 70℃; for 5h; | To a solution of 1-bromo-2, 4, 5-trifluorobenzene (5 g, 24 mmol) in 1, 4-dioxane (150 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (7 g, 68 mmol) , Pd (dppf) Cl2(1.0 g, 1.3 mmol) and Cs2CO3(12.5 g, 26 mmol) and the mixture was heated at 70 for 5 hours. Then evaporated the solvent under reduced pressure and the residue was purified by column chromatography (PE: EA=5: 1) to give product as an oil (4.5 g in 69%yield) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.3% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 80℃; for 18.0h; | To a solution of 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (5.3 g, 20.0 mmoL) in 1, 4-dioxane (50 mL) was added 3-bromobenzo [b] thiophene (4.3 g, 20.0 mmol) , Pd (dppf) Cl2(1.5 g, 2.0 mmol) and Cs2CO3(9.7 g, 30.0 mmol) and the mixture was heated at 80 for 18 hours. Then filter off the solid, the filtrate was evaporated under reduced pressure and the residue was purified by column chromatography (PE: EA=5: 1) to give product as yellow solid (4.76 g in 87.3%yield) .1HNMR (400 MHz, DMSO-d6) deltaH8.04-7.94 (m, 1H) , 7.94 -7.87 (m, 1H) , 7.60 (s, 1H) , 7.42-7.34 (m, 2H) , 5.94 (t, J = 3.6 Hz, 1H) , 3.95 (s, 4H) , 2.62-2.59 (m, 2H) , 2.44 (b, 2H) , 1.86 (t, J = 6.4 Hz, 2H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere; | To a solution of 6-fluoroquinolin-4-yl trifluoromethanesulfonate (8.56 g, 28.9 mmol) in 1, 4-dioxane (60 mL) and H2O (20 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (7.7 g, 28.9 mmol), Pd (dppf) Cl2 (3.1 g, 4.3 mmol) and Cs2CO3 (18.8 g, 57.8 mmol) and the mixture was heated at 80 overnight under N2. Then evaporated the solvent under reduced pressure and the residue was purified by column chromatography (PE: EA=1: 0 4: 1) to give product as a brown solid (8.3 g, 85%). [M+H] +=286. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere; | To a solution of 8-fluoroquinolin-4-yl trifluoromethanesulfonate (16.1 g, 54 mmol) in 1, 4-dioxane (100 mL) and H2O (40 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (15 g, 58 mmol), Pd (dppf) Cl2 (6.2 g, 8.7 mmol) and Cs2CO3 (34 g, 116 mmol) and the mixture was heated at 80 overnight under N2. Then evaporated the solvent under reduced pressure and the residue was purified by column chromatography (PE: EA=1: 0 4: 1) to give product as a brown solid (14.2 g, 81%). [M+H] +=286. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.7% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 90℃; for 3.0h;Inert atmosphere; | To a solution of 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (20 g, 75 mmol), 1-fluoro-4-iodobenzene (20 g, 90 mmol), Pd (dppf) Cl2 (5.5 g, 7.5 mmol) and Cs2CO3 (36.6 g, 112.5 mmol) in dioxane (200 mL), the mixture was stirred at 90 under N2 for 3h. TLC (PE: EA=5: 1, Rf =0.5) showed the reaction was completed. Filtered and concentrated, H2O (100 ml) was was added and extracted with EA (50 ml3). The combined organic layer was dried over Na2SO4, filtered and concentrated to give crude product, which was purified by silica gel chromatography (PE: EA =20: 1-6: 1) to give compound 3 (15 g, 85.7%) as a red solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.7% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 90℃; for 3.0h;Inert atmosphere; | To a solution of 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (20 g, 75 mmol), 1-fluoro-2-iodobenzene (20 g, 90 mmol), Pd (dppf) Cl2 (5.5 g, 7.5 mmol) and CS2CO3 (36.6 g, 112.5 mmol) in dioxane (200 mL), the mixture was stirred at 90 under N2 for 3h. TLC (PE: EA=5: 1, Rf =0.5) showed the reaction was completed. Filtered and concentrated, H2O (100 ml) was added, extracted with EA (50 ml3). The combined organic layer was dried over Na2SO4, filtered and concentrated to give crude product, which was purified by silica gel chromatography (PE: EA =20: 1-6: 1) to give compound 3 (15 g, 85.7%) as a red solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.7% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 90℃; for 3.0h;Inert atmosphere; | To a solution of 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (20 g, 75 mmol), 1-fluoro-3-iodobenzene (20 g, 90 mmol), Pd (dppf) Cl2 (5.5 g, 7.5 mmol) and Cs2CO3 (36.6 g, 112.5 mmol) in dioxane (200 mL), the mixture was stirred at 90 under N2 for 3h. TLC (PE: EA=5: 1, Rf =0.5) showed the reaction was completed. Filtered and concentrated, H2O (100 ml) was added, extracted with EA (50 ml3). The combined organic layer was dried over Na2SO4, filtered and concentrated to give crude product, whichwas purified by silica gel chromatography (PE: EA =20: 1-6: 1) to give product (15 g, 85.7%) as a red solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 70℃; for 5h; | To a solution of 5-bromo-2- (trifluoromethyl) pyridine (15.3 g, 68 mmoL) in 1, 4-dioxane (200 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (18 g, 68 mmol), Pd (dppf) Cl2 (8.0 g, 6.8 mmol) and Cs2CO3 (22 g, 68 mmol) and the mixture was heated at 70 for 5 hours. Then evaporated the solvent under reduced pressure and the residue was purified by column chromatography (PE: EA=5: 1) to give product as an oil (12 g in 63% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 90℃;Inert atmosphere; | To a solution of 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (19.2 g, 72 mmol), 1-bromonaphthalene (15 g, 72 mmol), Pd (dppf) Cl2 (5.26 g, 7.2 mmol) and Cs2CO3 (35.0 g, 108 mmol) in 1, 4-dioxane (400 ml), the mixture was stirred at 90 under N2 for over night. TLC (PE: EA=5: 1, Rf =0.5) showed the reaction was completed. Filtered and concentrated, H2O (100 ml) was added and extracted with ethyl acetate (50 ml3). The combined organic layer was dried over Na2SO4, filtered and concentrated to give crude product, which was purified by silica gel chromatography (PE: EA =40: 1-10: 1) to give product (18.20 g, in 95% yield) as a yellow oil. 1H NMR (DMSO-d6) deltaH 7.91-7.95 (m, 2H), 7.82 (d, J = 8.4 Hz, 1H), 7.50-7.53 (m, 2H), 7.45 (t, J=7.6 Hz, 1H), 7.27 (d, J=6.8 Hz, 1H), 5.58-5.60 (m, 1H), 3.98 (s, 4H), 3.86 (s, 2H), 2.48 (s, 2H), 2.43-2.48 (m, 2H), 1.91 (t, J = 6.4 Hz, 2H). MS (ESI) m/e [M+1] +=267. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.32% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 90℃;Inert atmosphere; | To a solution of 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (19.2 g, 72 mmol), 2-bromonaphthalene (15 g, 72 mmol), Pd (dppf) Cl2 (5.26 g, 7.2 mmol) and Cs2CO3 (35.0 g, 108 mmol) in 1, 4-dioxane (400 mL), the mixture was stirred at 90 under N2 for over night. TLC (PE: EA=5: 1, Rf =0.5) showed the reaction was completed. Filtered and concentrated, H2O (100 ml) was added and extracted with ethyl acetate (50 mL3). The combined organic layer was dried over Na2SO4, filtered and concentrated to give crude product, which was purified by silica gel chromatography (PE: EA =40: 1-10: 1) to give product (13.66 g, in 71.32% yield) as a yellow oil. 1H NMR (DMSO-d6) deltaH 7.88-7.96 (m, 4H), 7.71 (d, J = 8.4 Hz, 1H), 7.51-7.55 (m, 2H), 6.72 (s, 1H), 3.99 (s, 4H), 2.73-2.74 (s, 2H), 2.48 (s, 2H), 1.92 (t, J=6.4Hz, 2H). MS (ESI) m/e [M+1] +=267. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 90℃; | To a solution of 1, 2-difluoro-4-iodobenzene (9 g, 38 mmoL) in 1, 4-dioxane (150 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (10 g, 38 mmol), Pd (dppf) Cl2 (1.4 g, 1.9 mmol) and Cs2CO3 (18.4 g, 56 mmol) and the mixture was heated at 90 overnight. Then evaporated the solvent under reduced pressure and the residue was purified by column chromatography (PE: EA=5: 1) to give product as an yellow solid (8g in 84% yield). 1H NMR (400 MHz, CDCl3) delta 7.22 -7.14 (m, 1H), 7.12 -7.02 (m, 2H), 6.05 -5.86 (m, 1H), 4.05 -3.96 (m, 4H), 2.67 -2.54 (m, 2H), 2.51 -2.36 (m, 2H), 1.91 (t, J= 6.5 Hz, 2H). [M+H] +=253.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 95℃; for 2h; | A mixture of <strong>[156150-67-3]2-chloro-1-fluoro-4-iodobenzene</strong> (7.0 g, 27.3 mmol), 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (7.2 g, 27.1 mmol), Pd (dppf) Cl2 (1.0 g, 1.36 mmol) and Cs2CO3 (14.0 g, 42.9 mmol) in 1, 4-dioxane (200 mL) was heated at 95 for 2 hours. The mixture was filtered and the filtrate was concentrated and the resulted residue was purified by column chromatography (PE: EA=50: 1 to 20: 1) to give product (3.8 g, crude) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 70℃; for 5.0h; | To a solution of 1-chloro-3-iodobenzene (7.14 g, 30 mmoL) in 1, 4-dioxane /H2O (80 mL/20mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (7.98 g, 30 mmol), Pd (dppf) Cl2 (2.19 g, 3.0 mmol) and Cs2CO3 (11.7 g, 36 mmol) and the mixture was heated at 70 for 5 hours. Then evaporated the solvent under reduced pressure and the residue was purified by column chromatography (PE: EA=5: 1) to give product as an oil (7.2 g in 96% yield). [M+H] +=251 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 90℃; | To a solution of 1-chloro-2-iodobenzene (13.4 g, 56 mmoL) in 1, 4-dioxane (200 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (15 g, 56 mmol), Pd (dppf) 2Cl2 (4.1 g, 5.6 mmol) and Cs2CO3 (27.6 g, 85 mmol) and the mixture was heated at 90 overnight. After evaporated the solvent under reduced pressure, the residue was added with water (100 mL), extracted with ethyl acetate (100 mL). The organic layer was dried, concentrated and purified by column chromatography (PE: EA=100: 1) to give product as an oil (10.3 g in 73% yield). 1H NMR (CDCl3) deltaH 7.35-7.33 (m, 1H), 7.21-7.16 (m, 3H), 5.59-5.57 (m, 1H), 4.05-4.01 (m, 4H), 2.57-2.54 (m, 2H), 2.46-2.45 (m, 2H), 1.91 (t, J =4.0 Hz, 2H). [M+H] +=251.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 90℃; | To a solution of 2, 4-difluoro-1-iodobenzene (9 g, 38 mmoL) in 1, 4-dioxane (150 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (10 g, 38 mmol), Pd (dppf) Cl2 (1.4 g, 1.9 mmol) and Cs2CO3 (18.4 g, 56 mmol) and the mixture was heated at 90 overnight. Then evaporated the solvent under reduced pressure and the residue was purified by column chromatography (PE: EA=5: 1) to give product as an yellow solid (7g in 74% yield). 1H NMR (400 MHz, CDCl3) delta 7.25 -7.14 (m, 1H), 6.87 -6.70 (m, 2H), 5.87 -5.70 (m, 1H), 4.02 (t, J = 1.5 Hz, 4H), 2.68 -2.55 (m, 2H), 2.50 -2.36 (m, 2H), 1.89 (t, J = 6.4 Hz, 2H). [M+H] +=253.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 80℃; | To a solution of <strong>[202982-67-0]1-chloro-2-fluoro-4-iodobenzene</strong> (5.72 g, 22.67 mmol) in 1, 4-dioxane (150 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (6.00 g, 22.67 mmol), Pd (dppf) Cl2 (2.47 g, 3.38 mmol) and Cs2CO3 (11.00 g, 33.83mmol) and the mixture was heated at 80 for overnight. Then evaporated the solvent under reduced pressure and the residue was purified by column chromatography (PE: EA = 20: 1) to give product as a clear oil (4.06 g in 67% yield). 1H NMR (DMSO-d6) deltaH 7.51 (t, J= 8.0 Hz, 1H), 7.46 (m, 1H), 7.28 (m, 1H), 7.12-7.20 (m, 1H), 3.91 (s, 4H), 2.51-2.56 (m, 2H), 2.34-2.40 (m, 2H), and 1.80 (t, J = 6.8 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.8% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 95℃; | To a solution of <strong>[101335-11-9]2-chloro-4-fluoro-1-iodobenzene</strong> (7.7 g, 30 mmoL) in 1, 4-dioxane (150 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (8 g, 30 mmol), Pd (dppf) Cl2 (2.2 g, 3 mmol) and Cs2CO3 (14.7 g, 45 mmol) and the mixture was heated at 95 overnight. The mixture was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (80 mL3), washed with brine, dried over Na2SO4, filtered and filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (PE: EA=100: 1) to give product as a solid (3.2 g in 39.8% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere; | To a solution of 4-chloro-2-fluoro-1-iodobenzene (11.5 g, 45 mmoL) in 1, 4-dioxane (100 mL) and H2O (10 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (7.98 g, 30 mmol), Pd (dppf) Cl2 (3.3 g, 4.5 mmol) and Cs2CO3 (19.6 g, 60 mmol) and the mixture was heated at 80 overnight under N2. Then evaporated the solvent under reduced pressure and the residue was purified by column chromatography (PE: EA=1: 0 50: 1) to give product as a brown solid (6.9 g, 85%). [M+H] +=269. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 70℃; for 5h; | To a solution of <strong>[38573-88-5]1-<strong>[38573-88-5]bromo-2,3-difluorobenzene</strong></strong> (5 g, 26 mmol) in 1, 4-dioxane (150 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (7 g, 68 mmol), Pd (dppf) Cl2 (1.9 g, 2.6 mmol) and Cs2CO3 (12.5 g, 26 mmol) and the mixture was heated at 70 for 5 hours. Then evaporated the solvent under reduced pressure and the residue was purified by column chromatography (PE: EA=5: 1) to give product as an oil (5 g in 76% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.8% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 80℃; for 2h; | To a solution of 6-bromobenzo [b] thiophene (5.3 g, 25 mmol) in 1, 4-dioxane (150 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (6.6 g, 25 mmol), Pd (dppf) Cl2 (2.2 g, 3.8 mmol) and Cs2CO3 (12 g, 38 mmol) and the mixture was heated at 80 for 2 hours. Then filtered off the solid, the filtrate was evaporated under reduced pressure and the residue was purified by column chromatography (PE: EA=5: 1) to give product as an oil (3.8 g in 55.8% yield). 1HNMR (400 MHz, DMSO-d6) deltaH 8.01 (s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 5.6 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 5.6 Hz, 2H), 6.11 (s, 1H), 3.93 (s, 4H), 2.63 (s, 2H), 2.40 (s, 2H), and 1.84 (t, J = 6.4 Hz, 2H). [M+H] += 273.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 70℃; for 5h; | To a solution of <strong>[5467-58-3]1-bromo-4-methoxynaphthalene</strong> (4.72 g, 20 mmoL) in 1, 4-dioxane /H2O (80 mL/20mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (5.32 g, 10 mmol), Pd (dppf) Cl2 (1462 mg, 2.0 mmol) and Cs2CO3 (9.75 g, 30 mmol) and the mixture was heated at 70 for 5 hours. Then evaporated the solvent under reduced pressure and the residue was purified by column chromatography (PE: EA=5: 1) to give product as an oil (4.1 g in 69% yield). [M+H] +=297. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 90℃; | To a solution of 1-bromo-3,5-difluorobenzene (5 g, 26 mmoL) in 1, 4-dioxane (50 mL) was added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (6.2 g, 26 mmol), Pd (dppf) Cl2 (1.9 g, 2.6 mmol) and Cs2CO3 (12.7 g, 39 mmol) and the mixture was heated at 90 overnight. Then evaporated the solvent under reduced pressure and the residue was purified by column chromatography (PE: EA=5: 1) to give product as an yellow solid (7g in 74% yield). [M+H] +=253.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.5 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water;Reflux; | <strong>[103966-66-1]2-methoxy-4-bromo-1-nitrobenzene</strong> (3.0 g),4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-ene-8-yl)-1,3,2-dioxaborolane(3.8 grams),Pd(dppf)Cl2 (950 mg) and sodium carbonate (3.5 g) were added in sequenceIn a mixed solvent of 1,4-dioxane and water, heated to reflux overnight.The solvent was concentrated under reduced pressure, and the residue was evaporated.After drying and concentration with anhydrous sodium sulfate, the obtained residue was subjected to flash chromatography on silica gel.(petroleum ether: ethyl acetate, 2:1, v/v), isolated and purified to obtain the desired product(yellow solid, 3.5 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere; | The compound <strong>[661463-17-8]4-bromo-6-fluoroquinoline</strong> 3a (5 g, 22.12 mmol),4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-ene-8-yl)-1,3,2-dioxaborolan (6.5 g, 24.3 mmol), potassium carbonate (6.1 g, 44.24 mmol),[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.9 g, 1.1 mmol), 1,4-dioxane (50 ml) and water ( 10 ml) was mixed at room temperature, then heated to 100 C under a nitrogen atmosphere and stirring was continued for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure.The residue was purified by silica gel column chromatography(petroleum ether/ethyl acetate = 3/1), To give the desired product 6-fluoro-4-(1,4-dioxaspiro[4.5]indole-7-en-8-yl)quinoline 3b (5.2g, pale yellow solid), yield: 82%. |
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 100℃;Inert atmosphere; | To a stirred solution of 3.92 g (17.4 mmol) of <strong>[661463-17-8]4-bromo-6-fluoroquinoline</strong> in 65 mL of 1 ,4- dioxane was added 7.2 g (52.2 mmol) of K2C03, 1 .0 g (0.87 mmol) of Pd(PPh3)4, and 6.0 g (22.6 mmol) of compound 1-2 at room temperature under Ar atmosphere. After addition of 13 mL of water, the reaction mixture was stirred at 100 C overnight under Ar atmosphere, and then cooled to room temperature. The mixture was concentrated under reduced pressure and the residue was diluted with 40 mL of ethyl acetate and filtered through Celite. The filter cake was washed with 30 mL of ethyl acetate, and the filtrate was concentrated to give a residue, which was purified by silica gel column chromatography eluting with 16% ethyl acetate in petroleum ether to afford compound 1-3. LC- MS: m/e = 286 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14.12% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere; | 1 5-Chloro-4-[1,4-dioxaspiro[4.5]dec-7-en-8-yl]-2-(oxan-2-yl)-2,3-dihydropyridazin-3-one To a solution of 4,5-dichloro-2-(oxan-2-yl)-2,3-dihydropyridazin-3-one(100 mg, 0.40 mmol, 1 equiv.) and 2-[1,4-dioxaspiro[4.5]dec-7-en-8-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(106.8 mg, 0.40 mmol, 1.00 equiv.) in 1,4-dioxane (5 mL)and H2O (1 mL) were added K2CO3 (111.0 mg, 0.80 mmol, 2 equiv.) and Pd(PPh3)4 (46.4 mg, 0.04 mmol, 0.10 equiv.). After stirring for overnight at 100 degrees celsius under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with PE/EtOAc (1:1) to afford 4-chloro-5-[1,4-dioxaspiro[4.5]dec-7-en-8-yl]-2-(oxan-2-yl)-2,3- dihydropyridazin-3-one(20 mg, 14.12%) as a yellow solid and 5-chloro-4-[1,4- dioxaspiro[4.5]dec-7-an-8-yl]-2-(oxan-2-yl)-2,3-dihydropyridazin-3-one (20 mg, 14.12%) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water; at 70℃; for 2.0h;Inert atmosphere; Sealed tube; | To a solution of tert-butyl 5-bromo-3-isopropyl-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (19.00 g, 56.0 mmol), <strong>[680596-79-6]4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane</strong> (16.40 g, 61.6 mmol) and 2 M aqueous potassium phosphate tribasic (84 mL, 168 mmol) in THF (300 mL) was added PdCl2(dppf)-CH2Cl2 adduct (1.372 g, 1.680 mmol). The bi-phasic mixture was degassed with nitrogen gas for 10 minutes and the sealed vial was stirred at 70 C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and water. The mixture was transferred to a separatory funnel and the layers were separated. The combined organics were washed with saturated sodium sulfate, filtered and concentrated to dryness. Further purification was done by silica gel chromatography, which afforded tert-butyl 3-isopropyl-5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (18.00 g, 45.0 mmol, 86% yield) as a light yellow solid. LCMS retention time 1.09 min [A1]. MS m/z: 399.5 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.7% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 100℃;Inert atmosphere; Sealed tube; | [00739] Step B: 3-bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4- c]pyridine (750 mg, 2.07 mmol) and <strong>[680596-79-6]4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane</strong> (605 mg, 2.27 mmol) were dissolved in dioxane (20 mL) and 2.0 M K2CO3 (3.1 mL, 6.2 mmol) and Pd(PPh3)4 were added and purged with argon for 5 minutes, tube sealed and warmed to 100 C overnight. The reaction mixture was partitioned between EtOAc and water, extracted with EtOAc, dried over sodium sulfate, filtered and concentrated. The residue was purified over silica gel (10-50% EtOAc in hexanes) to afford 5-chloro-3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (713 mg, 81.7% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water at 80℃; Inert atmosphere; | 279 Reference Example 4 [00515] Synthesis of 4-((4'-bromo-[l,l'-biphenyl]-4-yl)thio)-lH-l,2,3-triazole-5- carboxylic acid (4) General procedure: A mixture of (4-iodophenyl)(methyl)sulfane (Compound 4A) (500 mg, 2 mmol), 4-bromophenylboronic acid (400 mg, 2 mmol), Na2CCh (636 mg, 6 mmol), and Pd(PPh3)4 (115 mg, 0.1 mmol) in toluene/EtOH/H20 (20/10/4 mL) was stirred at 80 °C under nitrogen overnight The mixture was concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 4B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. - NMR (CDCb, 500 MHz): d (ppm) 2.52 (s, 3H), 7.32 (d, J= 8.5 Hz, 2H), 7.43 (d, J= 8.5 Hz, 2H), 7.48 (d, J= 8.5 Hz, 2H), 7.55 (d, J= 8.5 Hz, 2H). | |
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water at 80℃; Inert atmosphere; | 279 Synthesis of 4-((4'-bromo-[1,1'-biphenyl]-4-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (4) General procedure: A mixture of (4-iodophenyl)(methyl)sulfane (Compound 4A) (500 mg, 2 mmol), 4-bromophenylboronic acid (400 mg, 2 mmol), Na2CO3 (636 mg, 6 mmol), and Pd(PPh3)4 (115 mg, 0.1 mmol) in toluene/EtOH/H2O (20/10/4 mL) was stirred at 80 oC under nitrogen overnight. The mixture was concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 4B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.1H- NMR (CDCl3, 500 MHz): d (ppm) 2.52 (s, 3H), 7.32 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere; | General procedure: A mixture of (4-iodophenyl)(methyl)sulfane (Compound 4A) (500 mg, 2 mmol), 4-bromophenylboronic acid (400 mg, 2 mmol), Na2CCh (636 mg, 6 mmol), and Pd(PPh3)4 (115 mg, 0.1 mmol) in toluene/EtOH/H20 (20/10/4 mL) was stirred at 80 C under nitrogen overnight The mixture was concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 4B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. - NMR (CDCb, 500 MHz): d (ppm) 2.52 (s, 3H), 7.32 (d, J= 8.5 Hz, 2H), 7.43 (d, J= 8.5 Hz, 2H), 7.48 (d, J= 8.5 Hz, 2H), 7.55 (d, J= 8.5 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere; | General procedure: A mixture of (4-iodophenyl)(methyl)sulfane (Compound 4A) (500 mg, 2 mmol), 4-bromophenylboronic acid (400 mg, 2 mmol), Na2CCh (636 mg, 6 mmol), and Pd(PPh3)4 (115 mg, 0.1 mmol) in toluene/EtOH/H20 (20/10/4 mL) was stirred at 80 C under nitrogen overnight The mixture was concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 4B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. - NMR (CDCb, 500 MHz): d (ppm) 2.52 (s, 3H), 7.32 (d, J= 8.5 Hz, 2H), 7.43 (d, J= 8.5 Hz, 2H), 7.48 (d, J= 8.5 Hz, 2H), 7.55 (d, J= 8.5 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water;Reflux; Inert atmosphere; | General procedure: A mixture of 2,4-dibromothiazole (Compound 8A) (3.9 g, 16 mmol), 3,4- dichlorophenylboronic acid (3.05 g, 16 mol), Pd(dppf)C12 (0.7 g, 0.87 mmol), and cesium carbonate (15 g, 46 mmol) in DME (120 mL) and water (10 mL) was heated at reflux under nitrogen overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 2). The combined extracts were washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to yield Compound 8B. LC-MS (ESI) m/z: 308 [M+H]t |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 80℃;Inert atmosphere; | General procedure: A mixture of (4-iodophenyl)(methyl)sulfane (Compound 4A) (500 mg, 2 mmol), 4-bromophenylboronic acid (400 mg, 2 mmol), Na2CCh (636 mg, 6 mmol), and Pd(PPh3)4 (115 mg, 0.1 mmol) in toluene/EtOH/H20 (20/10/4 mL) was stirred at 80 C under nitrogen overnight The mixture was concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to afford Compound 4B. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. - NMR (CDCb, 500 MHz): d (ppm) 2.52 (s, 3H), 7.32 (d, J= 8.5 Hz, 2H), 7.43 (d, J= 8.5 Hz, 2H), 7.48 (d, J= 8.5 Hz, 2H), 7.55 (d, J= 8.5 Hz, 2H). | |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In water; toluene;Inert atmosphere; Reflux; | General procedure: A mixture of 2,4-dibromothiazole (Compound 8A) (3.9 g, 16 mmol), 3,4- dichlorophenylboronic acid (3.05 g, 16 mol), Pd(dppf)Cl2 (0.7 g, 0.87 mmol), and cesium carbonate (15 g, 46 mmol) in DME (120 mL) and water (10 mL) was heated at reflux under nitrogen overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 2). The combined extracts were washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to yield Compound 8B. LC-MS (ESI) m/z: 308 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water;Reflux; Inert atmosphere; | General procedure: A mixture of 2,4-dibromothiazole (Compound 8A) (3.9 g, 16 mmol), 3,4- dichlorophenylboronic acid (3.05 g, 16 mol), Pd(dppf)C12 (0.7 g, 0.87 mmol), and cesium carbonate (15 g, 46 mmol) in DME (120 mL) and water (10 mL) was heated at reflux under nitrogen overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 2). The combined extracts were washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to yield Compound 8B. LC-MS (ESI) m/z: 308 [M+H]t |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium hydrogencarbonate; In 1,2-dimethoxyethane; water; at 80℃; for 20.0h; | Formation of 8-(2-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene To a solution of 1-bromo-2-fluoro-benzene (0.98 g, 5.64 mmol) and <strong>[680596-79-6]2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane</strong> (1.50 g, 5.64 mmol) in DME (20 mL) was added NaHCO3 (9.4 mL of 1.2 M aq solution, 11.27 mmol), and PdCl2(dppf) (0.43 g, 0.52 mmol) under a nitrogen atmosphere. The mixture was heated at 80 C. for 20 hours. The reaction mixture was filtered through a pad of celite and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40 g ISCO column) eluting with heptanes/EtOAc (0% to 40% gradient) to afford 1.0 g (76%) of the desired product: 1H NMR (300 MHz, CDCl3) delta 7.34-7.16 (m, 2H), 7.14-6.90 (m, 2H), 5.87 (qd, J=2.2, 0.7 Hz, 1H), 4.05 (s, 4H), 2.66 (tdd, J=5.5, 2.6, 1.5 Hz, 2H), 2.55-2.43 (m, 2H), 1.99-1.86 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.46% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90℃; | The mixture of methyl 4-bromo-2-fluorobenzoate (2.33 g, 10 mmol), 4, 4, 5, 5- tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (2.93 g, 11 mmol), 1, 1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (731 mg, 1 mmol), K 2CO 3 (3.45 g, 25 mmol) in a solution of 1, 4-dioxane (100 mL) and water (5 mL) was heated to 90 C and stirred overnight. After cooled to room temperature, the reaction mixture was concentrated in vacuum and purified by chromatography column on silica (eluent: EA/PE = 1/5) to give the product (2.7 g, 92.46%) as a white solid. 1H NMR (400 MHz, CDCl 3) delta ppm: 7.87 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.16-6.11 (m, 1H), 4.03 (s, 4H), 3.92 (s, 3H), 2.64-2.62 (m, 2H), 2.50-2.48 (m, 2H), 1.93-1.82 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.8% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 95℃; for 2.5h;Inert atmosphere; | To a solution of methyl 2- ((1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4-bromobenzoate (3.3 g, 9.57 mmol) in 1, 4-dioxane (50 mL) were added 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (2.8 g, 10.53 mmol), 1N K 2CO 3 (20 mL, H 2O) and Pd (dppf) Cl 2 (700 mg, 0.96 mmol), the reaction was heated at 95C under N 2 for about 2.5 h. The reaction mixture was cooled to ambient temperature, concentrated and purified by chromatography on silica gel (eluent: DCM: MeOH = 40: 1) to afford the desired compound as a yellow solid (3.4 g, 87.8%). MS (ESI, m/e) [M+1] + 407.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 95℃;Inert atmosphere; | A mixture of 2- ((1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4-bromo-N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide (100 mg, 0.16 mmol), 4, 4, 5, 5-tetramethyl-2- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1, 3, 2-dioxaborolane (64 mg, 0.24 mmol), Pd (dppf) Cl 2 (12 mg, 0.016 mmol) and K 2CO 3 (44 mg, 0.32 mmol) in dioxane (5 mL) and H 2O (0.5 mL) was stirred at 95 C under N 2 overnight. It was cooled to r.t. and filtered off the inorganic salt. The filtrate was concentrated. The residue was purified by pre-TLC (MeOH/DCM = 1/10) to give the desired product as a yellow solid (76 mg, 68%). 1H NMR(400 MHz, DMSO-d 6) delta 12.24 (s, 1H), 11.70 (s, 1H), 8.56-8.59 (m, 2H), 8.03 (s, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.48-7.58 (m, 3H), 7.20 (d, J = 7.9 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.76 (s, 1H), 6.40 (s, 1H), 5.95 (s, 1H), 3.85 (s, 6H), 3.23-3.27 (m, 2H), 2.98 (s, 2H), 2.37 (s, 2H), 2.28 (s, 2H), 2.03-1.96 (m, 2H), 1.87 (s, 1H), 1.71 (t, J = 6.2 Hz, 2H), 1.60 (d, J = 12.4 Hz, 2H). MS (ESI, m/e) [M+1] + 690.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With bis(tri-t-butylphosphine)palladium(0); sodium hydrogencarbonate; In dichloromethane; N,N-dimethyl-formamide; at 50℃; for 12.0h;Inert atmosphere; Schlenk technique; Sealed tube; | Under a nitrogen atmosphere, a mono-substituted aromatic hydrocarbon substrate 1a (0.2 mmol), thioanthracene-S-oxide (0.24 mmol) was added to a 25 mL Schlenk tube, and DCM (1.0 mL) was added, followed by stirring at -40C.After slowly dropping Tf2O (0.24 mmol), it was stirred at -40C for 30 minutes, followed by stirring at room temperature for 1 hour.Then, under a nitrogen atmosphere, sodium bicarbonate (0.6 mmol), alkenyl borate substrate 6 g (0.3 mmol), bis(tri-tert-butylphosphine) palladium (0.01 mmol), DMF (1.0 mL) was added, and screwed tightly. Cap the bottle and stir at 50C for 12 hours.After the reaction was completed, a small amount of DCM was added to quench the reaction, the celite was filtered, and the solvent was removed under reduced pressure. The crude product was separated and purified by a preparation plate (hexane/EtOAc (50/1)) to obtain a white solid 5g (29.0mg), yield 63%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium methanolate; copper(l) chloride; In N,N-dimethyl acetamide; at 70℃; for 24.0h;Glovebox; Schlenk technique; Sealed tube; | In the glove box, add 1,4-dioxa-spiro[4,5]dec-7-ene-8-boronic acid pinacol ester (1mmol, 266.2mg) to a 50mL Schlenk bottle equipped with a stir bar. ,Potassium methoxide (2mmol, 2 equivalents, 140.2mg), CuCl (0.03mmol, 0.03 equivalents, 3.0mg), 5mL solvent N,N-dimethylacetamide.Take out the capped Schlenk bottle from the glove box, fully ventilate, fill the reaction system with carbon dioxide and seal it, and then stir the reaction mixture at 70C for 24 hours.After cooling to room temperature, add 1mol/L hydrochloric acid to acidify, and extract with ethyl acetate, and then wash with brine once.The organic phase was collected and concentrated in vacuo. The liquid mixture was dropped on a silica gel column and purified by column chromatography. The developing solvent was petroleum ether/ethyl acetate.The desired product 1,4-dioxa-spiro[4,5]dec-7-ene-8-carboxylic acid was obtained with a yield of 73%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; tricyclohexylphosphine In 1,4-dioxane; water Inert atmosphere; Reflux; | 110.2 Step 2: A mixture of 2-(1,4-dioxaspiro[4.5]dec-7- en-8-yl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (741 mg, 2.78 mmol), compound llOa (480 mg, 2.32 mmol), K2C03 (960 mg, 6.96 mmol), Pd2(dba)3 (106 mg, 0.116 mmol) and PCy3 (78 mg, 0.28 mmol) in 1,4-dioxane/H20 (40 mE/lO mE) was heated to reflux under N2 atmosphere overnight. The solution was then concentrated and extracted with EtOAc. The organic layer was concentrated and purified by FCC give compound llOb (540 mg, 75% yield) as a white solid. MS (ESI): mlz 312.5 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 98℃; for 2h; Inert atmosphere; | 13.3 step 3: 6-methyl-N-(5-methyl-1H-pyrazol-3-yl)-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl )Pyrimidine-4-amine (13d) Compound 1d (900.00mg, 4.0mmol) and 13c (1.39g, 5.2mmol) were dissolved in 1,4-dioxane (30mL),Then Pd(PPh3)4 (465mg, 402μmol) was added, and finally an aqueous solution (6.0mL) of Na2CO3 (853mg, 8.1mmol) was added. After the addition, it was heated to 98°C and stirred for 2h under the protection of nitrogen. After the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure, diluted with EA (300 mL), washed with water 3 times, then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure, and separated by Flash C18 column Purification (acetonitrile: 0.05% ammonium bicarbonate aqueous solution = 50:50) to obtain the target compound 13d, |
Tags: 680596-79-6 synthesis path| 680596-79-6 SDS| 680596-79-6 COA| 680596-79-6 purity| 680596-79-6 application| 680596-79-6 NMR| 680596-79-6 COA| 680596-79-6 structure
[ 1310384-24-7 ]
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enol
Similarity: 0.79
[ 141091-37-4 ]
2-(Cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Similarity: 0.77
[ 859217-67-7 ]
2-(4,4-Dimethyl-1-cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Similarity: 0.76
[ 1049004-32-1 ]
Ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate
Similarity: 0.76
[ 151075-20-6 ]
Methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate
Similarity: 0.76
[ 1310384-24-7 ]
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enol
Similarity: 0.79
[ 141091-37-4 ]
2-(Cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Similarity: 0.77
[ 859217-67-7 ]
2-(4,4-Dimethyl-1-cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Similarity: 0.76
[ 1049004-32-1 ]
Ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate
Similarity: 0.76
[ 151075-20-6 ]
Methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate
Similarity: 0.76
[ 1142363-56-1 ]
4,4,5,5-Tetramethyl-2-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl)-1,3,2-dioxaborolane
Similarity: 0.74
[ 287944-16-5 ]
3,6-Dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyran
Similarity: 0.70
[ 1356111-39-1 ]
1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)pyrrolidine
Similarity: 0.65
[ 862129-81-5 ]
2-(3,6-Dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Similarity: 0.60
[ 364794-82-1 ]
4-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)morpholine
Similarity: 0.56
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :