* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Organic Chemistry, 1959, vol. 24, p. 1261,1266
2
[ 99-90-1 ]
[ 411235-57-9 ]
[ 6921-45-5 ]
Yield
Reaction Conditions
Operation in experiment
95%
With potassium phosphate tribasic heptahydrate; C45H53ClFeNO2PPd In water; toluene at 100℃; for 8 h; Inert atmosphere
General procedure: Potassium phosphate (0.75 mmol) and IIe (1 mol percent) was added to the solution of aryl halides (0.25 mmol) and cyclopropylboronic acid (0.5 mmol) in toluene (2.0 mL) and water (100 μL). The mixture was heated to 100 °C for a proper time under nitrogen atmosphere and cooled to room temperature. Water (10 mL) was added and the mixture was extracted with EtOAc (3.x.15 mL), evaporated and purified by chromatography on silica gel.
1.0 g
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In water; dimethyl sulfoxide at 100℃; for 48 h;
To a solution of 1-(4-bromophenyl)ethanone (3.Og, 0.0150 mmol) in mixture of DMSO: water (3:1, 30 mL) was added tripotassium phosphate (9.5 g, 0.045 mmol), 1,1 ‘-bi s(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (0.200 g,0.245 mmol) and cyclopropylboronic acid (1.9 g, 0.022 mmol). The reactionmixture was heated at 100 °C for 48 h. The reaction mass was quenched with water and extracted with EtOAc. The organic layer were washed with water and brine, dried over Na2504 and concentrated. The obtained solid was purified by column chromatography on silica gel to afford 1.0 g of the title product. ‘H NIVIR (300 IVIFIz, DMSO d6): 7.86-7.83 (d, J = 7.8 Hz, 2H), 7.13.7.10 (d, J = 7.8 Hz, 2H), 2.57 (s,3H), 1.94 (m, 1H), 1.07-1.05 (q, J= 7.2 Hz, 2H),0.79-0.77 (d, J= 4.8 Hz, 2H).
Reference：
[1] Tetrahedron, 2012, vol. 68, # 3, p. 900 - 905
[2] Synthetic Communications, 2006, vol. 36, # 1, p. 121 - 128
[3] Patent: WO2015/59618, 2015, A1, . Location in patent: Page/Page column 42
[4] Journal of the American Chemical Society, 2016, vol. 138, # 20, p. 6598 - 6609
[5] Patent: WO2016/201168, 2016, A1, . Location in patent: Paragraph 0662
Stage #2: With potassium phosphate In MeTHF; water; toluene at 100℃; for 3 h; Inert atmosphere
Example 3: Use of cyclopropyldioxazaborocane in the Suzuki coupling reaction; The boronic acid coupling products were obtained under the conditions recorded in the table below, by applying procedures 3a) and 3b).+ catalyst + ligand + K3PO4 solvent SIMes : 1 ,3-bis(2,4,6-trimethylphenyl)imidazolin-2-ylideneThe Suzuki coupling process has many advantages. The first is that the conditions are extremely simple to implement using catalysts which are readily available and usable (u n l i ke the rare model s issu ing from the l iteratu re relating to cyclopropylboronic acid) [19, 11]. The particularly short reaction times are also an element that simplifies the implementation of the process. Finally, it has been possible to carry out Suzuki couplings both with brominated derivatives and with chlorinated derivatives.Example 3a): Coupling with brominated derivatives: Procedure:Cyclopropyldioxazaborocane (1.5 eq.) is dissolved in a solution of 1 N HCI/NaClsat (1 ml/mmol of dioxazaborocane); boronic acid is then extracted with MeTHF (1.5 ml/mmol of dioxazaborocane). It is added to a solution containing aryl bromide (1 eq .), PdCI2dppf (0.5 eq.), PPh3 (0.1 eq.) and K3PO4 (2 eq .) in toluene (1.5 ml/mmol), anhydrous. The mixture is then heated at 1000C for 3 hours, under argon. After cooling, the organic phase is washed with water and then dried over MgSO4 and evaporated. The residue is then purified by flash chromatography (eluant: pure DCM). The fractions containing the product are then combined and evaporated.4-cyclopropylacetophenone:Yellowish liquid (41 1 mg, 2.57 mmol, 99percent). 1H NMR (CDCI3, 300 MHz), δ = 7.87 (d, 3JHH = 8.5 Hz, 2H, H5), 7.14 (d, 3JHH = 8.5 Hz, 2H, H4), 2.58 (s, 3H, H8), 1 .96 (tt, 3JHH = 8.4 Hz, 3JHH = 5.0 Hz, 1 H, H1), 1 .08 (ddd, 3JHH = 8.4 Hz, 3JHH = 5.0 Hz, 2Jgem = 6.6 Hz, 2H, H2), 0.80 (td, 3JHH = 4.8 Hz, 2Jgem = 6.7 Hz, 1 H, H2). 13C NMR (CDCI3, 75.5 MHz), δ = 197.7 (C7), 150.4 (C6), 134.6 (C3), 128.5 (C5), 125.5 (C4), 26.5 (Ce), 15.8 (CO, 10.4 (C2). Rf = 0.30 (DCM/EP 70 :30).
Stage #2: With potassium phosphate In MeTHF; toluene at 100℃; for 48 h; Inert atmosphere
Example 3b): Coupling with chlorinated derivatives:; Procedure:Cyclopropyldioxazaborocane (1.5 eq.) is dissolved in a solution of 1 N HCI/NaClsat(1 ml/mmol of d ioxazaborocane), and the boron ic acid then formed is subsequently extracted with MeTHF (1.5 ml/mmol of dioxazaborocane). It is added to a solution of aryl chloride (1 eq.), Pd(OAc)2 (0.05 eq.), IMes (0.1 eq.) and K3PO4 (2 eq.) in toluene (same volume as MeTHF) containing several drops of water. The mixture is then heated at 1000C for 48 hours, under argon. After cooling, the organic phase is washed with water and then dried over MgSO4 and evaporated. The residue is then purified by flash chromatography (eluant: pure DCM). The fractions containing the product are then combined and evaporated.4-cyclopropylacetophenone:Yellowish liquid (72 mg, 0.45 mmol, 90percent). 1H NMR (CDCI3, 300 MHz), δ = 7.87 (d, 3JHH = 8.5 Hz, 2H, H5), 7.14 (d, 3JHH = 8.5 Hz, 2H, H4), 2.58 (s, 3H, H8), 1.96 (tt, 3JHH = 8.4 Hz, 3JHH = 5.0 Hz, 1 H, H1), 1.08 (ddd, 3JHH = 8.4 Hz, 3JHH = 5.0 Hz, 2Jgem = 6.6 Hz, 2H, H2), 0.80 (td, 3JHH = 4.8 Hz, 2Jgem = 6.7 Hz, 1 H, H2). 13C NMR (CDCI3, 75.5 MHz), δ = 197.7 (C7), 150.4 (C6), 134.6 (C3), 128.5 (C5), 125.5 (C4), 26.5 (C8), 15.8 (C?), 10.4 (C2). Rf = 0.30 (DCM/EP 70 :30).In this case, the coupling remains extremely effective in terms of isolated yield, but the reaction times are increased considerably. The cost of and ease of access to the chlorinated derivative nevertheless remain a major advantage and illustrate even more the flexibility of the method.
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 9, p. 3604 - 3607
7
[ 925430-09-7 ]
[ 109613-00-5 ]
[ 6921-45-5 ]
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 9, p. 3604 - 3607
8
[ 925430-09-7 ]
[ 13329-40-3 ]
[ 201230-82-2 ]
[ 6921-45-5 ]
Yield
Reaction Conditions
Operation in experiment
15.7 mg
With (η3-allyl)(N,N'-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene)chloropalladium(II); sodium carbonate; lithium chloride In N,N-dimethyl-formamide at 80℃; for 16 h; Inert atmosphere; Sealed tube
General procedure: Method A: A sealed tube equiped with a magnetic stirring bar was charged with the arylhalide (1) or (5) (1.0 equiv), sodium carbonate (2.0 equiv), anhydrous lithium chloride (2.0equiv) and (SIPr)Pd(allyl)Cl (0.05 equiv). Tricyclopropylbismuth (2a) (1.0 equiv), preparedas described above, was dissolved in anhydrous DMF (0.1 M) under argon and was addedinto the sealed tube. Carbon monoxide was bubbled in the reaction mixture for 45 seconds,then the tube was sealed and heated at 40 °C for 16 hours. The reaction mixture was cooledto room temperature, transferred in a separatory funnel containing 20 mL of an aq. sat.NaHCO3 solution and was extracted with EtOAc (3 x 20 mL). The combined organic layerswere washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated underreduced pressure. The residue was purified by flash column chromatography using theindicated solvent system to afford the desired aryl cyclopropyl ketone (3) or (6).Method B: Same as method A except that 1.5 equivalents of tricyclopropylbismuth 2ainstead of 1.0 equivalent and 0.1 equivalents of (SIPr)Pd(allyl)Cl instead of 0.05 equivalentswere used and that the reaction was heated at 80 C instead of 40 C.
Reference：
[1] Journal of the American Chemical Society, 2001, vol. 123, # 18, p. 4155 - 4160
10
[ 99-90-1 ]
[ 23719-81-5 ]
[ 6921-45-5 ]
Reference：
[1] Journal of the American Chemical Society, 2001, vol. 123, # 18, p. 4155 - 4160
11
[ 873-49-4 ]
[ 75-36-5 ]
[ 6921-45-5 ]
Reference：
[1] Molecular Crystals and Liquid Crystals Science and Technology, Section A: Molecular Crystals and Liquid Crystals, 1995, vol. 258, p. 229 - 238
[2] Journal of Organic Chemistry, 1959, vol. 24, p. 1261,1266
[3] Journal of the American Chemical Society, 1975, vol. 97, # 10, p. 2895 - 2898
[4] J. Gen. Chem. USSR (Engl. Transl.), 1963, vol. 33, p. 358 - 363[5] Zhurnal Obshchei Khimii, 1963, vol. 33, # 2, p. 365 - 371
[6] Journal of Medicinal Chemistry, 2009, vol. 52, # 14, p. 4329 - 4337
With potassium phosphate tribasic heptahydrate; C45H53ClFeNO2PPd; In water; toluene; at 100℃; for 8h;Inert atmosphere;
General procedure: Potassium phosphate (0.75 mmol) and IIe (1 mol %) was added to the solution of aryl halides (0.25 mmol) and <strong>[411235-57-9]cyclopropylboronic acid</strong> (0.5 mmol) in toluene (2.0 mL) and water (100 muL). The mixture was heated to 100 C for a proper time under nitrogen atmosphere and cooled to room temperature. Water (10 mL) was added and the mixture was extracted with EtOAc (3×15 mL), evaporated and purified by chromatography on silica gel.
1.0 g
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; dimethyl sulfoxide; at 100℃; for 48h;
To a solution of 1-(4-bromophenyl)ethanone (3.Og, 0.0150 mmol) in mixture of DMSO: water (3:1, 30 mL) was added tripotassium phosphate (9.5 g, 0.045 mmol), 1,1 ?-bi s(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (0.200 g,0.245 mmol) and <strong>[411235-57-9]cyclopropylboronic acid</strong> (1.9 g, 0.022 mmol). The reactionmixture was heated at 100 C for 48 h. The reaction mass was quenched with water and extracted with EtOAc. The organic layer were washed with water and brine, dried over Na2504 and concentrated. The obtained solid was purified by column chromatography on silica gel to afford 1.0 g of the title product. ?H NIVIR (300 IVIFIz, DMSO d6): 7.86-7.83 (d, J = 7.8 Hz, 2H), 7.13.7.10 (d, J = 7.8 Hz, 2H), 2.57 (s,3H), 1.94 (m, 1H), 1.07-1.05 (q, J= 7.2 Hz, 2H),0.79-0.77 (d, J= 4.8 Hz, 2H).
To a stirred solution of 1-(4-bromophenyl) ethan-1-one (2 g, 10 mmol) in toluene: EtOH: water (1: 1: 1, 20 mL) at room temperature under an argon atmosphere were added <strong>[411235-57-9]cyclopropylboronic acid</strong> (1.03 g, 12 mmol), potassium phosphate (4.4 g, 21 mmol) and purged under argon for 15 mm. Then Pd(PPh3)4 (580 mg, 0.5 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 100 C for 16 h. After consumption of starting material (monitored by TLC), the reaction mixture was filtered. The filtrate was concentrated in vacuo. The crude material was purified by column chromatography using 2-3% EtOAc: Hexane to afford 1-(4-cyclopropyiphenyl) ethan-1-one (1.5 g, crude) as colorless liquid. ?H NMR (DMSO-d6, 400 MHz): 7.83 (d, 2H), 7.20 (d, 2H), 2.57 (s, 3H), 2.04-1.97 (m, 1H), 1.10-0.98 (m, 2H), 0.81- 0.72 (m, 2H); LCMS: 91.2%; 160.8 (M+1); (column; Ascentis Express C-18 (50 x 3.0 mm,2.7 pm); RT 2.40 mm; mobile phase: 0.025% Aq TFA+5% ACN: ACN+5% 0.025% Aq TFA; T/B%: 0.01/5, 0.5/5, 3/100, 5/100; flow rate: 1.2 mL/min) (Gradient); TLC: 5% EtOAc/ Hexane (R1 0.4).
4,7-dichloro-3-(2-(4-cyclopropylphenyl)-2-oxoethyl)-3-hydroxyindolin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With diethylamine; In methanol; at 50℃; for 24h;
4,7-Dichloro-3-(2-(4-cyclopropylphenyl)-2-oxoethyl)-3-hydroxyindolin-2-one EXAMPLE 7): To <strong>[18711-13-2]4,7-dichloroindoline-2,3-dione</strong> (A) (300 mg, 1.39 mmol) in 15 niL of methanol were added l-(4-cyclopropylphenyl)ethanone (B) (0.9 g, 5.5 mmol) and 10 drops of diethylamine (2). The reaction was stirred at 50C for 24 hours. The solvent was removed and the residue was purified with flash chromatography (0-5% Methanol/CH2C12) to get an off white solid. 4,7-Dichloro-3-(2-(4-cyclopropylphenyl)-2-oxoethyl)-3-hydroxyindolin-2- one (EXAMPLE 7): off-white solid; 1H NMR (DMSO-d6, 400 MHz) delta 0.76 (m, 2H), 1.06 (m, 2H), 2.0(m, 1H), 3.65 (d, 1H, J=16 Hz), 4.35 (d, 1H, J=16Hz), 6.43(s, 1H), 6.89(d, 1H, J=8Hz), 7.19 (d, 2H, J=8Hz), 7.30 (d, 1H, J=8Hz), 7.79 (d, 2H, J=8Hz), 10.97 (s, 1H).
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