* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With C35H34N3OP2PdS(1+)*NO3(1-); sodium t-butanolate In 1,4-dioxane at 100℃; for 6 h;
General procedure: In a typical run, an oven-dried 10 ml round bottom flask was charged with a known mole percent of catalyst, NaOtBu (1.3 mmol), amine (1.2 mmol) and aryl halide (1 mmol) with the appropriate solvent(s) (4 ml). The flask was placed in a preheated oil bath at required temp. After the specified time the flask was removed from the oil bath, water (20 ml) was added, and extraction with ether (4×10 ml) was done. The combined organic layers were washed with water (3×10 ml), dried over anhydrous Na2SO4, and filtered. Solvent was removed under vacuum. The residue was dissolved in acetonitrile and analyzed by GC–MS.
With potassium carbonate In dimethyl sulfoxide at 120℃; for 12 h; Inert atmosphere
General procedure: To a mixture of 0.05 g catalyst and aryl halide (1.0 mmol)in 9.0 cm3 DMSO, Het-NH (1.2 mmol) and K2CO3(2.0 mmol) was added and the mixture was vigorouslystirred at 120 C for the appropriate time under a drynitrogen atmosphere. After completion (as monitored byTLC), the catalyst was filtered, and the filtrate wasextracted with ethyl acetate (3 9 20 cm3) and the combinedorganic layers were dried with anhydrous MgSO4,filtered, and evaporated under reduced pressure. The residuewas purified by column chromatography. The purity ofthe compounds was checked by 1H NMR and yields arebased on aryl bromide. All the products are known and thespectroscopic data (FT-IR and NMR) and melting pointswere consistent with those reported in the literature [36–41].
93%
With copper(l) chloride; sodium hydroxide; 3-(diphenylphosphino)propionic acid In dimethyl sulfoxide at 120℃; for 14 h; Inert atmosphere; Sealed tube
General procedure: NH-containing heterocycle (1.4 mmol) and DMF (2.0 mL) were added to a mixture of CuCl (15.0 molpercent) and ligand 1 (20.0 molpercent) in DMF (2.0 mL), aryl iodide (1.0 mmol), NaOH (2.0 mmol). The mixture was vigorously stirred at 120 °C for 14 h under a dry nitrogen atmosphere. After completion of the reaction (as monitored by TLC), H2O was added and the organic layer was extracted with EtOAc, washed with brine and dried over MgSO4. The solution was filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography. The purity of the compounds was checked by 1H NMR and yields are based on aryl iodide. All the products are known and the spectroscopic data (FT‑IR and NMR) and melting points were consistent with those reported in the literature.
90 %Chromat.
With C16H12ClN3OPdS; potassium hydroxide In dimethyl sulfoxide at 110℃; for 10 h;
General procedure: Arylhalide (1.0 mM), nitrogen-containing heterocycle (1.2 mM), KOH (2 mM), and the catalyst (0.75 Mpercent) were stirred in dimethyl sulfoxide (DMSO) (4 mL) at 110 °C for 10 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate(70 : 30) as eluent to afford the desired product. The products have been characterized by 1H NMR spectroscopy.
Reference：
[1] Journal of Organic Chemistry, 2009, vol. 74, # 5, p. 2200 - 2202
[2] Monatshefte fuer Chemie, 2015, vol. 146, # 8, p. 1329 - 1334
[3] Journal of Chemical Research, 2014, vol. 38, # 2, p. 128 - 129
[4] Journal of Coordination Chemistry, 2015, vol. 68, # 19, p. 3537 - 3550
4
[ 683-60-3 ]
[ 15164-44-0 ]
[ 18962-05-5 ]
Yield
Reaction Conditions
Operation in experiment
76%
With hemicucurbituril supported [Bmim]Cl In toluene for 8 h; Reflux
General procedure: A mixture of aryl halide (1 mmol) and sodium alkoxide(3.0 mmol) was refluxed in the presence of 200 mg ofHmCucSILP catalyst in toluene (5 mL) for an appropriatetime as indicated in Table 2. After completion of thereaction, the reaction mixture was filtered and solvent wasevaporated in vacuo to give the crude product, which waspurified by column chromatography over silica gel usinghexane/EtOAc as the eluent.
With C35H34N3OP2PdS(1+)*NO3(1-); sodium t-butanolate In 1,4-dioxane at 100℃; for 6 h;
General procedure: In a typical run, an oven-dried 10 ml round bottom flask was charged with a known mole percent of catalyst, NaOtBu (1.3 mmol), amine (1.2 mmol) and aryl halide (1 mmol) with the appropriate solvent(s) (4 ml). The flask was placed in a preheated oil bath at required temp. After the specified time the flask was removed from the oil bath, water (20 ml) was added, and extraction with ether (4×10 ml) was done. The combined organic layers were washed with water (3×10 ml), dried over anhydrous Na2SO4, and filtered. Solvent was removed under vacuum. The residue was dissolved in acetonitrile and analyzed by GC–MS.
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 32, p. 9918 - 9929
7
[ 536-74-3 ]
[ 15164-44-0 ]
[ 57341-98-7 ]
Yield
Reaction Conditions
Operation in experiment
99%
With copper(l) iodide; C31H26N4PPdS(1+)*Cl(1-); sodium hydroxide In ethanol; toluene at 110℃; for 14 h;
General procedure: To slurry of aryl halide (1 mmol), cuprous iodide (10 molpercent) andpalladium catalyst (a known molpercent) in an appropriate solvent(4 mL), phenylacetylene (1.2 mmol) and NaOH (1.7 mmol) wasadded and heated at required temp. After completion of the reaction(monitored by TLC), the flask was removed from the oil bathand water (20 mL) added, followed by extraction with ether(4 10 mL). The combined organic layers were washed with water(3 10 mL), dried over anhydrous Na2SO4, and filtered. Solventwas removed under vacuum. The residue was dissolved in hexaneand analyzed by GC–MS using Elite-5 columns, which are fused silicacapillary columns coated with 5percent diphenyl and 95percent dimethylpolysiloxane.
96%
With C20H29Cl2N5O2Pd; potassium carbonate In ethanol at 80℃; for 2 h;
General procedure: A vial was charged with an aryl halide (0.1 mmol), an aryl or alkylacetylene(0.11 mmol), K2CO3 (0.15 mmol), palladium catalyst (0.05 mol percent), and EtOH(2 mL). The mixture was refluxed with stirring for 2 h. After this time, themixture was cooled and CH2Cl2–n-hexane (1:2, 2 mL) and H2O (2 mL) wereadded. The organic layer was separated, filtered through a small amount ofsilica gel and analyzed by GC–MS. The solvent was removed and the residueweighed and analyzed by 1H NMR.
96%
With copper(l) iodide; C26H24N6NiS4; triethylamine In N,N-dimethyl-formamide at 80℃; for 2 h; Inert atmosphere
General procedure: In an oven-dried round bottom flask under an atmosphere of N2, a mixture of aryl halide (1 mmol), phenylacetylene (1.5 mmol), 1 (60.75 ppm or 0.05 molpercent), copper(I) iodide (5 mmol), and Et3N (3.0 mmol) in DMF (5 mL) was taken. The reaction mixture was stirred 80 °C for 2 h. At the end of the mentioned time, the reaction mixture was diluted with EtOAc (20 mL), washed with water (3 x 10 mL). The combinedorganic layer was dried over anhydrous Na2SO4, filtered and stripped off the solvent under reduced pressure. The residue was subjected to column chromatography on silica gel using ethyl acetate and n-hexane mixtures to afford the desired product in high purity. The products were characterized by 1H and 13C NMR analysis.
92.3%
With potassium phosphate; palladium In 2-methoxy-ethanol; water at 80℃; for 0.5 h;
Iodobenzene 2.04 g (0.01 mol), phenylacetylene 1.53 g (0.015 mol), potassium phosphate 4.22 g (0.02 mol) were added to a round bottom flask of 50mL capacity purged with nitrogen, equipped with stirrer, thermometer, reflux condenser, then methyl cellosolve / water (1: 1) 20 mL was weighed and added. Then, alkali aqueous solution 10.02g containing palladium nanoparticle catalysts from synthesized in Production Example 1 (Pd amount relative iodobenzene is 0.01 molpercent) was added and heated in an oil bath and heated to reflux for 8 hours at 80 . After completion of the reaction, adding toluene 15mL and water 10 mL, the organic layer was separated. The organic layer was concentrated with an evaporator, and the resulting concentrated residue purified by silica gel column chromatography to obtain the target compound
85%
With [PdCl2((C6H5)2PCH2P(C6H5)2CHC(O)C6H4NO2)]; potassium carbonate In N,N-dimethyl-formamide at 130℃; for 4 h;
General procedure: A mixture of an aryl halide (1 mmol), phenylacetylene(1.3 mmol), catalyst (0.001 mol percent), K2CO3 (2.5 mmol), and DMF(2 ml) was heated to 130 C. The mixture was then cooled to roomtemperature and the solvent was removed under reduced pressure.The combined organic extracts were washed with brine and driedover CaCl2 or MgSO4. The solvent was evaporated and liquid residueswere purified by silica gel column chromatography (n-hexane:EtOAc, 80:20) and solid residues were purified byrecrystallization from EtOH and H2O. Products were identified bycomparison of their 1H and 13C NMR spectral data those reportedin the literature.
78%
With bis(cyclohexylisocyanide)palladium(II) chloride; potassium carbonate; benzoic acid hydrazide In ethanol at 80℃; for 2 h;
General procedure: A solution of comple 1 in ethanol with a required concentrationwas added with stirring to a mixture of iodoarene2a–2g (0.3 mmol), phenylacetylene (3, 0.5 mmol),potassium carbonate (0.7 mmol), and ethanol (2 mL). The mixture was heated for 2 h on an oil bath at a bathtemperature of 80°C. After cooling to room temperature,the mixture was diluted with 10 mL of waterand extracted with hexane–methylene chloride (5 : 1,2 × 5 mL), and the combined extracts were dried overanhydrous sodium sulfate and analyzed by GC/MS.The solvent was evaporated, and the product wasisolated by silica gel column chromatography usingn-hexane as eluent.The properties of the isolated compounds were inagreement with the data given in [23–27].
74.4%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 20℃;
1.1.23 Synthesis of compound 1.1.23 Step 1. Synthesis of 4-(phenylethynyl)benzaldehyde [1.1.23a] 1.1.23a To a degassed solution of ethynylbenzene (0.3 ml_, 2.73 mmol), 4-iodobenzaldehyde (761 mg, 3.28 mmol), and Et3N (0.757 mL, 5.46 mmol) in THF (Volume: 21.6 ml_), Pd(PPh3)2CI2 (96 mg, 0.137 mmol) and Cul (36.4 mg, 0.191 mmol) were added. After stirring at room temperature overnight, the reaction mixture was concentrated on to silica gel and purified by silica gel column chromatography (EtOAc/heptane, 0-50percent). Fractions containing product were collected. Pale yellow crystals crashed out, which were washed with pentane and heptane to afford 4-(phenylethynyl)benzaldehyde [1.1.23a] (419 mg, 74.4 percent yield). 1H NMR (400 MHz, CDCI3) δ ppm 7.30 - 7.44 (m, 3 H) 7.45 - 7.59 (m, 2 H) 7.62 - 7.73 (m, 2 H) 7.76 - 7.98 (m, 2 H) 10.02 (s, 1 H)
80 %Chromat.
With copper(l) iodide; C18H14N2Pd; sodium hydroxide In ethanol; toluene at 25℃; for 5 h;
General procedure: To slurry of aryl halide (1 mmol), cuprous iodide (10 molpercent) and palladium catalyst (a known molpercent) in 1:1 ethanol–toluene (4 mL), phenylacetylene (1.2 mmol) and NaOH (1.7 mmol) were added and heated at 25 °C. After completion of the reaction (monitored by TLC), the flask was removed from the oil bath and water (20 mL) added, followed by extraction with ether (4 × 10 mL). The combined organic layers were washed with water (3 × 10 mL), dried over anhydrous Na2SO4, and filtered. Solvent was removed under vacuum. The residue was dissolved in hexane and analyzed by GC–MS.#10;
Reference：
[1] Inorganica Chimica Acta, 2015, vol. 425, p. 67 - 75
[2] Tetrahedron Letters, 2014, vol. 55, # 13, p. 2101 - 2103
[3] Tetrahedron Letters, 2016, vol. 57, # 44, p. 4893 - 4897
[4] Journal of Chemical Sciences, 2015, vol. 127, # 3, p. 425 - 431
[5] Patent: JP6084874, 2017, B2, . Location in patent: Paragraph 0102; 0106
[6] Organic and Biomolecular Chemistry, 2018, vol. 16, # 15, p. 2748 - 2752
[7] European Journal of Organic Chemistry, 2008, # 31, p. 5244 - 5253
[8] Green Chemistry, 2015, vol. 17, # 2, p. 1071 - 1076
[9] Dalton Transactions, 2017, vol. 46, # 38, p. 13065 - 13076
[10] Tetrahedron Letters, 2013, vol. 54, # 35, p. 4656 - 4660
[11] Applied Organometallic Chemistry, 2018, vol. 32, # 12,
[12] Russian Journal of General Chemistry, 2017, vol. 87, # 8, p. 1663 - 1666[13] Zh. Obshch. Khim., 2017, vol. 87, # 8, p. 1247 - 1251,5
[14] Patent: WO2014/160649, 2014, A1, . Location in patent: Page/Page column 88-89
[15] RSC Advances, 2017, vol. 7, # 34, p. 21036 - 21044
[16] ACS Catalysis, 2016, vol. 6, # 6, p. 3771 - 3783
[17] Chemistry - An Asian Journal, 2017, vol. 12, # 17, p. 2221 - 2230
[18] European Journal of Inorganic Chemistry, 2011, # 21, p. 3174 - 3182
[19] Transition Metal Chemistry, 2010, vol. 35, # 3, p. 305 - 313
[20] Journal of Organometallic Chemistry, 2013, vol. 736, p. 1 - 8
[21] Journal of Organic Chemistry, 2015, vol. 80, # 13, p. 6922 - 6929
[22] Organic Letters, 2018, vol. 20, # 18, p. 5573 - 5577
8
[ 15164-44-0 ]
[ 637-44-5 ]
[ 57341-98-7 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2009, vol. 351, # 17, p. 2827 - 2832
[2] RSC Advances, 2016, vol. 6, # 75, p. 71117 - 71121
9
[ 15164-44-0 ]
[ 35674-27-2 ]
Reference：
[1] Journal of the Chemical Society, 1927, p. 25
10
[ 2065-66-9 ]
[ 15164-44-0 ]
[ 2351-50-0 ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h; Inert atmosphere Stage #2: at 20 - 55℃; for 5.5 h; Inert atmosphere
Under N2, 16 g (40 mmol) of methyltriphenylphosphine iodide was added to 200 mL of THF and stirred.Cool to -78 ° C, add 20 mL (48 mmol) of t-butyl lithium, react for 30 min,Continue to add 9.3g (40mmol) of p-iodobenzaldehyde, stir for 30min, and then naturally warm to room temperature.After heating to 55 ° C, the reaction was carried out for 5 h, 20 mL of a saturated ammonium chloride solution was added, and THF was distilled off.Extracted with ethyl acetate, dried, filtered, concentrated and purified by column chromatographyObtained iodine styrene, yield 77percent
Reference：
[1] Patent: CN108586460, 2018, A, . Location in patent: Paragraph 0006; 0012; 0013
11
[ 90965-06-3 ]
[ 15164-44-0 ]
[ 766-99-4 ]
Reference：
[1] Synlett, 2011, # 19, p. 2799 - 2802
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 18, p. 5644 - 5647
12
[ 925430-09-7 ]
[ 201230-82-2 ]
[ 15164-44-0 ]
[ 20034-50-8 ]
Yield
Reaction Conditions
Operation in experiment
10.6 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.
With bis(((1Z,3Z)-3-((1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)imino)-1,3-diphenylprop-1-en-1-yl)oxy)palladium; potassium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 3.5h;Catalytic behavior;
General procedure: A mixture of aryl halide (1mmol), olefin (1mmol), K2CO3 (1mmol), and the Pd-Schiff base complex (2.1mg, 0.2mol %) in DMF-H2O (1:1) was stirred at 80C for 3-4h. The reaction progress was monitored periodically by TLC. After completion of the reaction, it was cooled to room temperature and the product was extracted with ethyl acetate (3×10mL) from aqueous phase. The combined organic fractions were dried over Na2SO4, the solvent removed under reduced pressure to afford a crude product. The residue was purified by short column chromatography on silica gel eluted with petroleum ether/ethyl acetate afforded the desired coupled products up to 98% yield. The products were confirmed by 1H and 13C NMR.General procedure for the Suzuki-Miyaura reaction: A mixture of aryl halide (1mmol), arylboronic acid (1mmol), K2CO3 (1mmol), and the Pd- Schiff base complex (2.1mg, 0.2mol %) in DMF-H2O (1:1) was stirred at 80C for 3-5h. The progress of reaction was monitored by TLC until the complete consumption of the aryl halide. After the reaction, the mixture was cooled down to room temperature and repeatedly extracted with ethyl acetate. The combined organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel to give the corresponding coupling products in up to 95% isolated yield. The products were confirmed by 1H and 13C NMR.
With dipyridinium dichromate; In dichloromethane; for 15h;
b. 4-IODOBENZALDEHYDE 11.49 g (49.1 mmol) of 2- (4-IODOPHENYL)- ethanol are dissolved in 375 ml of dichloromethane, and 37 g (98.2 mmol) of pyridinium dichromate are then added portionwise. The reaction medium is stirred for 15 hours, filtered through silica and eluted with dichloromethane. A yellow solid is obtained (10.4 g ; yield = 91%).
86%
With [ReOCl3(PPh3)2]; bis(4-chlorophenyl)sulfoxide; In toluene; for 17h;Reflux;
General procedure: To a solution of ReOCl3(PPh3)2 (0.083 g, 0.1 mmol) in toluene (3 mL) was added the bis(4-chlorophenyl) sulfoxide (0.271 g, 1 mmol) and the alcohol (1.0 mmol). The reaction mixture was heated at reflux temperature in air (the reaction times are indicated in Tables 1-4) and the progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was evaporated and purified by silica gel column chromatography with n-hexane to afford carbonyl compounds and bis(4-chlorophenyl) sulfide, which are all known compounds and their 1H NMR and 13C NMR data are consistent with those of the commercial products.
85%
With C48H36Cu2N4O8S2; dihydrogen peroxide; In acetonitrile; at 80℃; under 760.051 Torr; for 2h;
General procedure: To a solution of benzyl alcohol derivative (Eq. (4)) (5 mmol), in 10 mL acetonitrile catalyst [Cu2(L)2(NO3)2] (0.002 mmol), and 50% H2O2 (5 mL) was added and the mixture was refluxed at 80 C for 2 h. The mixture was then poured into water and the product was extracted with dichloromethane and dried over Na2SO4. The solvent was removed and the product was purified by column chromatography. The product was characterized by IR and 1H NMR spectra.
85%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; In n-heptane; at 80℃; under 760.051 Torr; for 24h;
General procedure: A mixture of catalyst PS-PEG-TD2-Cu(OAc)2 (100 mg, 0.05mmol Cu), BnOH (1a, 27.0 mg, 0.25 mmol), and TEMPO (7.8 mg,0.05 mmol) in heptane (2.0 mL) was stirred at 80 C for 24 hunder air (1 atm). The mixture was then cooled and filtered, andthe resulting solid material was washed with Et2O (3 × 2 mL).The organic phases were combined, concentrated to a volume of2 mL, and the internal standard was added to determine the GCyield. The crude product was purified by column chromatography[silica gel, hexane-Et2O (99:1)]. In the formation of somebenzaldehydes, low isolated yields were observed because ofinstability of the benzaldehydes on silica gel
82%
With C35H28Cl2N5PRu; potassium tert-butylate; In toluene; at 50℃; for 6h;
General procedure: using the complex 1 as catalyst in presence of a base following a general procedure. In a round-bottom flask, 1 mmol of substrate, 0.005mmol of catalyst (3.6mg) and 0.010 mmol of tBuOK (1.1mg) were mixed in 10mL toluene. The reaction mixture was heated at 50C in aerobic condition with continuous stirring for 6h and then the solvent was evaporated with a rotary evaporator under reduced pressure. The crude product, thus obtained, was purified on preparative silica gel GF-254 TLC plate using ethyl acetate: hexane (1:10) solvent mixture as eluent. The oxidized products were characterized by NMR spectroscopy (See Figs. S4-S32).
80%
With C36H27CuN8O2; dihydrogen peroxide; In acetonitrile; at 70℃; for 4h;
General procedure: A mixture of the aromatic alcohol (0.5 mmol), catalyst 4a (0.002 mmol) and 30% H2O2 (5 equiv.) was added to a roundbottom flask containing 10 mL of acetonitrile. The total mixture was stirred at 70 C for 4 h. The reaction was monitored by TLC. After completion of the reaction, the solvent was removed, theorganic phase was separated and dried over Na2SO4, and the product was purified by column chromatography (hexane/ethyl acetate).Yields were determined by weighing the isolated products, which were characterized by 1H NMR and IR spectroscopy (Table 5).
73%
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide; In dichloromethane; acetonitrile; at 20℃; for 2h;4 A molecular sieves;
A solution of 4-iodobenzyl alcohol (9g, 38. 29mmol) in dichloromethane (90mL) and acetonitrile (lOmL) was treated sequentially with 4 A molecular sieves powder (9g), tetra-n-propyl ammoniumperruthenate (0.13g) and N-methyl morpholine-N-oxide (9g, 76. 6mmol). After stirring at ambient temperature for 2h, the reaction mixture was diluted with hexane and subjected to flash column chromatography over silica gel (230-400mesh) using 6-10% ethyl acetate in hexane as the eluent to afford the title compound (2. 5g pure and 4g-95% pure, 73%). 'H NMR (300 MHz, CDCl3) : b 9.96 (s, 1H), 7.92 (d, 2H, J= 8. 5Hz), 7.59 (d, 2H, J= 8. 5Hz).
73%
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide; In dichloromethane; acetonitrile; at 20℃; for 2h;Molecular sieve;
4-Iodo-benzaldehyde; A solution of 4-iodobenzyl alcohol (9g, 38. 29mmol) in dichloromethane (90mL) and acetonitrile (lOmL) was treated sequentially with 4 A molecular sieves powder (9g), tetra-ra-propyl ammoniumperruthenate (0.13g) and N-methyl morpholine-N-oxide (9g, 76.6mmol). After stirring at ambient temperature for 2h, the reaction mixture was diluted with hexane and subjected to flash column chromatography over silica gel (230-400mesh) using 6-10% ethyl acetate in hexane as the eluent to afford the title compound (2. 5g pure and 4g-95% pure, 73%). 'H NMR (300 MHz, CDC13) : 8 9.96 (s, 1H), 7.92 (d, 2H, J= 8. 5Hz), 7.59 (d, 2H, J = 8. 5Hz).
88%Chromat.
With C49H43IrN2P2; potassium carbonate; In acetone; for 8h;
General procedure: In a typical run, an oven-dried round bottom flask was charged with a known mole percent of catalyst, K2CO3 (1.7mmol), primary or secondary alcohol (1.0mmol) in acetone medium (8mL). The mixture was stirred at 40C. After the specified time the reaction mixture was extracted with ether (4×10mL). The combined organic layer was washed with water (3×10mL), and dried over anhydrous Na2SO4. Solvent was removed under vacuum. The residue was dissolved in hexane and analyzed by GC-MS.
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; water-d2; cyclomaltooctaose; at 60℃; for 0.5h;Green chemistry;
General procedure: To a clean and dry small vial, a solution of substrate 1 (15.0 mumol, 1.0 equivalent) was added using an aqueous cyclodextrin solution (1.0 mL) of the specified concentration in D2O. DBDMH 3 (4.3 mg, 15.0 mumol, 1.0 equivalent) was added to the reaction mixture and sonicated to make sure that the reagents were well suspended. The reaction mixture was heated at 60 C with occasional shaking to maintain the homogeneity of the solution. After the desired period of time, the 1H NMR spectrum of the reaction mixture was recorded to determine the percent conversion.
87%Chromat.
With potassium carbonate; In toluene; at 110℃; for 12h;
General procedure: Benzyl alcohol (108mg, 1.0mmol), AuSBA-15 (6wt%, 20mg) and K2CO3 (829mg, 6.0mmol) was dissoveled in toluene (6.0mL), the reaction mixture was stirred for 12hat 110C. It was monitored by TLC. After the reaction was completed, the solvent was removed under reduced pressure and purified of the crude product by column chromatography on silica-gel afforded the title compound.
Example 105,6-Dicyano-2-(4-iodophenyl)-1-propylbenzimidazole (6c). A 25 mL round-bottom flask was charged with 3 (340 mg, 2.15 mmol), NMP (10 mL), 4-iodobenzaldehyde, (499 mg, 2.15 mmol), and a magnetic stirring bar. The flask was fitted with a Hickman still, placed in an oil bath heated to 120 C., and stirred for 1 h. Then FeCl3.6H2O (29 mg, 0.11 mmol) was added to the reaction vessel and oxygen was bubbled through the mixture as it was heated and stirred for an additional 24 h. The reaction mixture was then removed from heat and added to ethyl acetate. The ethyl acetate solution was washed three times with water, then washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue (603 mg, 1.63 mmol) was suspended in CH3CN and heated to 80 C. Then DBU (243 muL, 1.63 mumol) was added and the mixture was stirred for 2 min, and iodopropane (159 muL, 1.63 mmol) was added. After 20 min, the mixture was treated with a second round of DBU and iodopropane, and after an additional 20 min, a third round of reagents was added. After a final 20 min of heating, the mixture was transferred to ethyl acetate and washed three times with water, followed by brine. After drying the organic layer over Na2SO4, the mixture was filtered, concentrated to dryness, and chromatographed (silica, CHCl3, 5% ethyl acetate), giving a white solid (440 mg, 50%): mp 208-209 C.; 1H NMR (CDCl3) delta 0.91 (t, J=7.6 Hz, 3H), 1.80-1.91 (m, 2H) 4.26 (t, J=7.6 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.87 (s, 1H), 7.95 (d, J=8.0 Hz, 2H), 8.22 (s, 1H); 13C NMR (CDCl3) delta 11.4, 23.6, 47.4, 98.4, 109.0, 109.3, 116.55, 116.62, 116.9, 126.7, 128.2, 130.9, 137.8, 138.7, 145.3, 158.4; Anal. Calcd for C18H13IN4: C, 52.45; H, 3.18; N, 13.59; Found: C, 52.40; H, 3.06; N, 13.40.
tert-butyl 2-iodoazetidine-1-carboxylate[ No CAS ]
[ 5518-52-5 ]
[ 15164-44-0 ]
[ 74-95-3 ]
3-(4-formyl-phenyl)-azetidine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With chloro-trimethyl-silane; zinc; In N,N-dimethyl-formamide;
Preparation 80 tert-butyl 3-(4-formylphenyl)-1-azetidinecarboxylate Zinc dust (253 mg) was stirred under nitrogen overnight. To this was added DMF (5 ml) and dibromomethane (55 mg) dissolved in DMF (1 ml) and the mixture warmed to ~70 C. The reaction mixture was cooled to room temperature and chlorotrimethylsilane (32 mg) in DMF (1 ml) added and stirred at room temperature for 15 minutes. To this was added 2-iodo-N-Boc-azetidine (Billotte, S., Synlett, 1998, 379-380) (1.04 g) in DMF (5 ml). The reaction mixture warmed to 40 C. and the mixture sonicated for 30 minutes during which time the zinc powder dissolved to leave a hazy solution. To the solution of zincate was added 4-iodobenzaldehyde (Preparation 43) (851 mg in 5 ml DMF), <strong>[5518-52-5]tri-2-furylphosphine</strong> (35 mg in 1 ml DMF) and Pd(dbq)2 (42 ml in 1 ml DMF). The resulting mixture was heated at 60-70 C. for 4 hours, cooled to room temperature and partitioned between ammonium chloride solution and diethyl ether, and the aqueous layer was extracted with diethyl ether (3*). The combined organic extracts were dried (Na2SO4), evaporated in vacuo and purified over silica (pentane:ethyl acetate; 4:1) to afford the title compound as a mobile oil, 626 mg. m/z: 262 (MH+)
(4-Iodophenyl)methanol (2). To a solution of compound (1) (50 g, 0.21 mol, 1.0 equiv) in methanol (500 mL) was added with NaBH4 (20.5 g, 0.5 mol, 2.5 equiv) slowly under 1OC for 1 h and stirred for 2 h. The reaction mixture was concentrated under reduced pressure, quenched with water (300 mL), and extracted with EtOAc (300 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dried in vacuo overnight to provide the title compound (2) (49 g, 97%).
86%
With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; tris[3,5-bis(trifluoromethyl)phenyl]-borane; In 1,4-dioxane; at 25℃; for 12h;Glovebox;
General procedure: In a glovebox, aldehydes (0.25 mmol) and the Hantzsch ester 1 (95 mg, 0.38 mmol) were added to asolution of tris[3,5-bis(trifluoromethy)phenyl]borane (9) (8.1 mg, 12.5 mumol) in 1 mL of anhydrous1,4-dioxane. The reaction mixture was stirred at 25 or 100 C for 12 h. An internal standard (biphenylor mesitylene) was added to the reaction mixture and filtrated through a cotton plug. The resultingsolution was analyzed with gas chromatography.
(Z)-4-(2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 35Preparation of Compound 110: (E)-Ethyl 3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate hydrochlorideStep 1: (E)-4-(2-(2-Chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1,1-indazol-5-yl)but-1-en-1-yl)benzaldehyde A round-bottom flask equipped with a magnetic stir bar, a reflux condenser, internal thermometer, and a N2 inlet was charged with 5-(but-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (50.0 g, 197 mmol; Intermediate 3), bis(pinacolato)diboron (50.4 g, 199 mmol), and anhydrous 2-methyltetrahydrofuran (393 mL) followed by Pt(PPh3)4 (1.83 g, 1.5 mmol). This mixture was degassed with three vacuum/N2 cycles, heated at 83 C. (internal temperature; oil bath at 95 C.) for 5 h under N2, and then allowed to cool to room temperature. 2-Methyltetrahydrofuran (393 mL), cesium carbonate (128.1 g, 393 mmol), and water (11.8 mL, 1.5% v/v) were added, and the reaction was cooled to 4 C. 4-Iodobenzaldehyde (45.6 g, 197 mmol) and PdCl2(PPh3)2 (6.90 g, 9.8 mmol) were added, and the reaction was degassed with three vacuum/N2 cycles. The mixture was allowed to warm to room temperature and stirred overnight. Aqueous KOH solution (4M, 275 mL, 1100 mmol) and <strong>[101335-11-9]2-chloro-4-fluoroiodobenzene</strong> (70.6 g, 275 mmol) were added. The reaction was degassed with 3 vacuum/N2 cycles, heated at 75 C. (internal temperature; oil bath at 90 C.) for 7 h under N2, and then allowed to cool to room temperature. The layers were separated, and the organic layer was washed with brine (800 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-20% ethyl acetate in hexanes) to give the title compound (82.6 g, 7:1 mixture of regioisomers) as a pale yellow foam. Data for major isomer; (E)-4-(2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)benzaldehyde: 1H NMR (300 MHz, DMSO-d6): delta 9.82 (s, 1H), 8.15 (s, 1H), 7.78-7.71 (m, 2H), 7.61 (d, 2H), 7.43-7.27 (m, 3H), 7.15 (m, 3H), 5.86 (dd, 1H), 3.93-3.85 (m, 1H), 3.79-3.68 (m, 1H), 2.44-2.36 (m, 3H), 2.10-1.96 (m, 2H), 1.81-1.67 (m, 1H), 1.63-1.53 (m, 2H), 0.92 (t, 3H); LCMS: 405 [(M-THP+H)+H]+.
General procedure: A suspension of sodium diethyl oxalacetate (3) (1 equiv), methylamine(2) (1 equiv), and aldehyde (1) (1 equiv) in ethanol was heated atreflux till completion (TLC).After cooling, the mixture was added on ice-water and then acidified with HCluntil pH 4. The precipitate was filtered, washed with water and petroleum etherin order to remove traces of aldehyde. After drying under reduced pressure the2,3-dioxopyrrolidines 4a-c wereobtained with sufficient purity as white solids
General procedure: A mixture of <strong>[6310-09-4]2-acetyl-5-chlorothiophene</strong> (0.01 mol) and substituted benzaldehyde (0.01 mol) wasdissolved in methanol (20 mL). A catalytic amount of NaOH was added to the solution dropwise withvigorous stirring. The reaction mixture was stirred for about 3-4 h at room temperature. The resultantcrude products were filtered, wash successively with distilled water and recrystallized from ethanol to get the corresponding chalcone. Crystals suitable for X-ray diffraction studies were obtained by the slowevaporation technique using a suitable solvent.
General procedure: To <strong>[2879-20-1]1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one</strong>(A) (1 mmol) alcohol solution (5 mL) was added substituted benzaldehyde(1 mmol). After dissolution, 50% NaOH (0.5 mL) was added. After confirming the completion of the reaction by thin layer chromatography, the sediment was filtered, washed with ethanol and dried to obtain chalcone
4-iodobenzaldehyde (1.15 g, 4.96 mmol)And (1,3-dioxolan-2-ylmethyl) triphenylphosphonium bromide (4.26 g, 9.91 mmol)Was suspended in tetrahydrofuran (50.0 mL)Sodium hydride (475 mg, 19.8 mmol) and 18-crown-6 (10.0 mg) were added,And the mixture was stirred at room temperature for 2 hours.Further sodium hydride (475 mg, 19.8 mmol) was added,And the mixture was stirred at room temperature for 12 hours.Distilled water was added,After stopping the reaction,And extracted with diethyl ether (50 mL × 3).After distilling off the organic layer under reduced pressure,Was dissolved in tetrahydrofuran (50.0 mL)A 10% hydrochloric acid aqueous solution (20.0 mL) was added and the mixture was stirred at room temperature for 6 hours.The mixture was extracted with dichloromethane (100 mL × 2) and 1 mol / L sodium hydroxide aqueous solution,And washed with saturated brine.After dehydration with anhydrous magnesium sulfate,The solvent was distilled off under reduced pressure,The residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/4 (volume ratio)) as an elution solvent to obtain Compound 5 in a yield of 1.28 g (100%).
78.7%
With 18-crown-6 ether; sodium hydride; In tetrahydrofuran; at 20℃; for 2h;Inert atmosphere;
General procedure: To a stirred solution of 4-bromobenzaldehyde (2000mg, 10.81mmol), 18-crown-6 (25mg) and (1,3-dioxolan-2-ylmethyl)-triphenylphosphoniumbromide (7000mg, 16.3mmol) in THF (90mL) under N2, NaH (1038mg, 86.5mmol) was added in one portion. After 2-h stirring at room temperature, the reaction mixture was quenched with water and extracted with EtOAc. After evaporation of EtOAc, the residue was dissolved in the mixture of THF (90mL) and 20% hydrochloric acid, and stirred for 2h at room temperature. After the mixture was turned basic with 2N NaOHaq and aqueous saturated solution of NaHCO3, the organic solvent was evaporated, and the mixture extracted with EtOAc. The combined EtOAc extracts were washed with brine and dried over Na2SO4.The solvent was removed, and the residue was purified by silica gel chromatography (EtOAc/hexane=17/83) to give 2 (1568mg, 68.8%).
With (eta3-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℃; under 760.051 Torr; for 16h;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.
tert-butyl (3-((4-formylphenyl)ethynyl)phenyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; triphenylphosphine; In tetrahydrofuran; at 75℃; for 16h;Inert atmosphere;
In a 500 m10f round bottom flask 4-iodobenzaldehyde(30.2 g,130 mmol),bis(triphenylphosphine)palladium(II)chloride(4.56 g,6.50 mmol),copper()iodide(2.476 g,13.00mmol)and triphenylphosphine(3.41 g,13.00 mmol)were dissolved in THF(200 mL)and triethylamine(181 mL,1300 mmol)fo11owed by addition of<strong>[185619-66-3]tert-butyl (3-ethynylphenyl)carbamate</strong>(28.2 g,130 mmol).The mixture was stirred at 75 C under nitrogen atmosphere for 16 h. after completion of the reaction,thevolatile solvents were completely removed. The crude material was purified by silica gel columnchromatography(eluted with PE/CH2Ciz=1:3)to obtain tert-butyl (3-((4-formylphenyl)ethynyl)phenyl)carbamate(35.5 g,111 mmol,85% yield)as an off-white solid. LCMS(Method f,Table 7)R1=2.08 min; MS m/z = 322 [M+H+].
Step D: 95 (1.00g, 4.58mmol, 1.00eq) was dissolved in 10mL tetrahydrofuran and cooled to -78C. LDA (2M,2.75mL, 1.20eq) was added dropwise, and the mixture was maintained below -70C for 30 minutes, then a solution of4-iodobenzaldehyde (1.06g, 4.58mmol, 1.00eq) in 5mL tetrahydrofuran was added dropwise at -70C and the reactionsolution was stirred at this temperature for 1 hour. The reaction solution was slowly quenched with 10mL saturatedaqueous ammonium chloride solution, then diluted with 10mL water, partitioned, and the aqueous phase was extractedthree times with 30mL ethyl acetate each time. The organic phase was combined, washed with 20mL saturated brine,dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by silica gelcolumn chromatography (EA/PE=20%-100%) to give the product 96 as a yellow solid. MS (ESI,M+1): 450.9.
With manganese; 4,4'-Dimethoxy-2,2'-bipyridin; tetra-(n-butyl)ammonium iodide; nickel dibromide; In 1-methyl-pyrrolidin-2-one; at 80℃; for 24.0h;Inert atmosphere; Sealed tube;
Under a nitrogen atmosphere, nickel bromide (4.4 mg, 0.02 mmol),4,4'-dimethyl-2,2'-bipyridine (3.68 mg, 0.02 mmol),Tetrabutylammonium iodide (14.77 mg, 0.04 mmol) manganese powder (43.95 mg, 0.8 mmol),Add solvent NMP (0.5 mL) and stir well. Weigh 4-iodobenzaldehyde (46.40mg, 0.2mmol) in NMP (0.5mL),After dissolution, add (2-bromo-1-fluoroethyl) benzene (60.92 mg, 0.3 mmol) and mix well.The solution was transferred to a sealed tube. After sealing, the reaction was stirred in an oil bath at 80 C for 24 hours.Cool the reaction to room temperature, ether (5mL)Add an equal volume of saturated ammonium chloride solution to the diluted reaction solution.Filter through a diatomaceous sand core funnel, rinse with a small amount of ether, and collect the filtrate.The filtrate was extracted three times with diethyl ether, and the organic phases were combined (add internal standard dodecane,GC-MS determined crude yield). Dry over anhydrous sodium sulfate, filter, and remove the solvent by distillation under reduced pressure.After the residue was separated by silica gel column chromatography, the product was weighed, and the calculated yield was 46%.
With tetrakis(triphenylphosphine) palladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl acetamide; at 25℃; for 8h;Inert atmosphere; Schlenk technique;
General procedure: The reaction substrates oxothioglycolic acid (1.5 equivalents, 0.75 mmol), halides (1.0 equivalent, 0.5 mmol), Pd (PPh3) 4 (5mol%, 28.9mg) and Xantphos (6mol%, 17.4mg) placed in a transparent Schlenk tube (Beijing Xinweier Glass Instrument Co., Ltd., F891410 reaction tube, capacity 10mL, grinding mouth 14/20) equipped with a magnetic stirrer (if the oxothioglycolic acid or halide is liquid, then It needs to be added in a subsequent step through a micro syringe under an argon atmosphere). The tube was evacuated and filled with argon (three times). Under an argon atmosphere, anhydrous N, N-dimethylacetamide (5.0 mL) was passed through a syringe. The reaction mixture was stirred at 25 C. (for aryl iodide substrate) or 100 C. (for aryl bromide substrate) for 8 hours (using an IKA magnetic stirrer, RCT basic type, stirring speed 500 rpm). The mixture was quenched with a saturated sodium chloride solution and extracted with ethyl acetate (3 × 20 mL). The organic layers were combined and concentrated in vacuo (Buchi, Switzerland, BUCHI rotary evaporator R-3). The product was separated by silica gel flash column chromatography (Beijing Xinweier Glass Instrument Co., Ltd., C383040C with sand plate storage ball chromatography column, 35/20,effective length: 500mm) to obtain the product (petroleum ether / ethyl acetate = 100: 1 ~ 2: 1).
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In tetrahydrofuran; at 45℃; for 8h;
Compound 4b 1 g (3.73 mmol) CuI in dissolved tetrahydrofuran / triethylamine (1: 1) solution0.0251g (0.135mmol) and Pd (PPh3) 2Cl2 0.094g (0.135mmol)After adding the compound 0.86 g (3.74 mmol) of 4-Iodobenzaldehyde was added and stirred for 8 hours while maintaining the temperature at 45 C. Chromatography after stirring(n-hexane: dichloromethane = 4: 1 (v / v)) separated and purified to give a dark green solid productof (4-Ethynyl-N, N-diphenylaniline) -benzaldehyde (5b) 0.99 g (yield: 58%) was obtained
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