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CAS No. : | 1208-86-2 | MDL No. : | MFCD00228649 |
Formula : | C13H13NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OBHGSIGHEBGGFS-UHFFFAOYSA-N |
M.W : | 199.25 | Pubchem ID : | 14581 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.08 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 62.48 |
TPSA : | 21.26 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.28 cm/s |
Log Po/w (iLOGP) : | 2.46 |
Log Po/w (XLOGP3) : | 3.15 |
Log Po/w (WLOGP) : | 3.44 |
Log Po/w (MLOGP) : | 2.95 |
Log Po/w (SILICOS-IT) : | 2.74 |
Consensus Log Po/w : | 2.95 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.45 |
Solubility : | 0.0701 mg/ml ; 0.000352 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.27 |
Solubility : | 0.108 mg/ml ; 0.000541 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -5.1 |
Solubility : | 0.00159 mg/ml ; 0.00000798 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.65 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | 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 |
---|---|---|
76% | With dmap; copper(I) bromide dimethylsulfide complex; oxygen In dichloromethane at 20℃; for 17h; | |
With potassium permanganate; acetone at 5℃; | ||
With dmap; copper(I) bromide dimethylsulfide complex; oxygen In dichloromethane for 17h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With copper diacetate; palladium diacetate In N,N-dimethyl-formamide at 130℃; for 1h; Sealed tube; Microwave irradiation; | |
76% | With N,N-dimethyl-formamide for 0.025h; microwave irradiation; | |
72% | With palladium diacetate In acetic acid for 1.5h; Heating; |
31% | With palladium diacetate; acetic acid at 20 - 130℃; for 12h; Inert atmosphere; | 3-Methoxycarbazole (21b) General procedure: To a stirred solution of 2-methoxy-N-phenylaniline (20a) (200 mg, 1.00mmol) in acetic acid (5 mL) was added to a solution of Pd(OAc)2 (270 mg, 1.21 mmol) at rt, and then themixture was heated at 130 oC for 12 h. After cooling the reaction to an ambient temperature, the mixturewas quenched with water. The resulting mixture was extracted with EtOAc. The EtOAc phase waswashed with water and brine, dried with Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography. |
With air; potassium carbonate; Trimethylacetic acid at 110℃; for 14h; | ||
With oxygen; palladium diacetate; acetic acid In toluene at 90℃; for 20.5h; | ||
With oxygen; acetic acid In toluene Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With C31H26N4PPdS(1+)*Cl(1-); sodium t-butanolate In toluene at 95℃; for 15h; | 2.5.4. General procedure for C-N coupling reactions General procedure: In a typical run, an oven-dried 10 mL round bottom flask wascharged with a known mole percent of catalyst, NaOt-Bu(1.3 mmol), aryl amine (1.2 mmol) and aryl halide (1 mmol) withthe appropriate solvent(s) (4 mL). The flask was placed in a preheatedoil bath at required temp. After the specified time the flaskwas removed from the oil bath, water (20 mL) was added, and extraction with ether (4 10 mL) was done. The combined organiclayers were washed with water (3 10 mL), dried over anhydrousNa2SO4, and filtered. Solvent was removed under vacuum. The residuewas dissolved in hexane and analyzed by GC-MS using Elite-5columns, which are fused silica capillary columns coated with 5%diphenyl and 95% dimethyl polysiloxane. |
99% | With potassium <i>tert</i>-butylate at 20℃; for 12h; | |
95% | With C16H16N6PdS2; sodium t-butanolate; XPhos at 145℃; for 24h; |
90% | With copper(l) iodide; potassium carbonate; <i>L</i>-proline In dimethyl sulfoxide at 90℃; for 40h; | |
89% | With toluene-4-sulfonic acid at 165℃; for 0.583333h; Ionic liquid; Microwave irradiation; | 4.1 General procedure for the MW-assisted C-N cross coupling General procedure: In a new sealed pressure regulation 10-mL pressurized vial were placed aryl halide (1 mmol), p-toluenesulfonic acid (1 mmol, 0.172 g), [DBU][HOAc] (1.5 mL), N-nucleophile (2 mmol), and a Teflon-coated magnetic stir bar. The vessel was closed with a snap-on cap, stirred at room temperature for 5 min and then placed into the MW cavity. Microwave irradiation of 100 W at a set temperature of 165°C was used and the reaction mixture was held under these conditions for the specified time. After completion of the reaction (monitored through TLC), the mixture was cooled to room temperature and was poured to a vessel containing distilled water. This was extracted with ethyl acetate (3*10 mL) and the combined organic phase was washed with brine (2*10 mL), dried over Na2SO4, and was concentrated under rotary vacuum evaporator. The crude product was purified by column chromatography using a mixture of ethyl acetate/n-hexane as eluent. |
89% | With dicyclohexyl(2-methoxy-6-methylbiphenyl-2<SUP>,</SUP>-yl)phosphine; potassium <i>tert</i>-butylate; palladium diacetate In 1,4-dioxane at 160℃; for 0.166667h; Inert atmosphere; Microwave irradiation; | |
88% | With 0.068 mol% Ni(II) and 0.026 mol% Pd(II) complexed in pyridine grafted demetalated chlorophyll b co-polymer modified SiO2 shell on Fe3O4 core at 120℃; for 6.5h; | |
83% | With N'-phenyloxalyl bishydrazide; tetrabutylammomium bromide; copper(II) acetate monohydrate; 2,5-hexanedione; potassium hydroxide In water at 100℃; Inert atmosphere; Sealed tube; | |
83% | With palladium diacetate; potassium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 20 - 140℃; for 12h; | 4-Methoxy-N-phenylaniline (20b) General procedure: To a stirred solution of o-anisidine (18a) (1 g, 8.12 mmol) in drytoluene (10 mL) was added to a solution of bromobenzene (19a) (1.27 g, 8.12 mmol), Pd(OAc)2 (73 mg,0.32 mmol), rac-BINAP (202 mg, 0.32 mmol) and K2CO3 (1.57 g, 11.37 mmol) at rt, and then themixture was heated at 140 oC for 12 h. After cooling to an ambient temperature, the mixture wasquenched with water. The resulting mixture was extracted with EtOAc. The EtOAc phase was washedwith water and brine, dried with Na2SO4, and concentrated under reduced pressure. The residue waspurified by column chromatography. |
83% | With potassium carbonate In methanol; water Reflux; Green chemistry; | |
82% | With palladium/alumina; C9H16N2*BF4(1-)*H(1+); potassium <i>tert</i>-butylate In toluene at 110℃; for 4h; Inert atmosphere; | |
81% | With iron(III) chloride; caesium carbonate; copper(II) oxide; 1,1'-bi-2-naphthol In N,N-dimethyl-formamide at 110℃; for 24h; Inert atmosphere; | |
78% | With CuMoO4; caesium carbonate In dimethyl sulfoxide at 90℃; for 22h; Inert atmosphere; | |
75% | With copper(l) iodide; potassium carbonate; <i>L</i>-proline In dimethyl sulfoxide at 90℃; for 40h; Inert atmosphere; | |
75% | With Ni[3-(4-nitrophenyl)-1-picolyimidazolin-2-ylidene]2Cl2; potassium <i>tert</i>-butylate In tetrahydrofuran for 12h; Schlenk technique; Inert atmosphere; Reflux; | |
75% | With copper(l) iodide; C19H19N5O; potassium carbonate In water at 100℃; for 24h; Green chemistry; | |
74% | With Pd(tris[2-(diphenylphosphino)ethyl]phosphine tetrasulfide)(dibenzylideneacetone); caesium carbonate In isopropyl alcohol at 80℃; for 24h; | General experimental procedure for arylation of amines and phenols General procedure: To a stirred solution of aryl halide (1.2mmol) and [Pd(pp3S4)(dba)] (1mol %) in isopropanol (2.5ml) was added nitrogen/oxygen nucleophile (1mmol) followed by Cs2CO3 (2mol %) in the atmosphere of air. The mixture was heated to 80°C and the progress of the reaction was monitored by TLC. After completion, the solvent was evaporated through rotavapour and the crude mixture was washed with dichloromethane-H2O and the organic phase was separated and dried over Na2SO4. The dichloromethane was evaporated followed by flash column purification on silica gel of the crude to obtain the pure products. The products were characterized using 1H, 13C NMR spectroscopy and GC-MS spectroscopy. The characterization data were in good agreement with those described in the literature. |
72% | With sodium t-butanolate at 75℃; for 24h; | |
57.9% | With tris-(dibenzylideneacetone)dipalladium(0); potassium <i>tert</i>-butylate; tris[tert-butyl]phosphonium tetrafluoroborate In toluene at 20℃; Inert atmosphere; | |
51% | With bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; sodium t-butanolate; 1,3-diisopropyl-1H-imidazol-3-ium chloride In 1,2-dimethoxyethane at 80℃; for 12h; Inert atmosphere; | |
50% | With C14H14Cl2N3O4Ti; potassium carbonate In N,N-dimethyl-formamide at 22 - 34℃; for 8h; Irradiation; | 2.4 Typical procedure for C-N cross coupling reaction General procedure: The procedure for the C-N cross coupling reaction was the same for the different heterogeneous photocatalysts. In a typical procedure, to a stirred mixture of bromobenzene (1mmol, 0.093g), aniline derivatives (1mmol) and K2CO3 (1mmol, 0.138g) in DMF (4mL), M1L8 (10) (0.4mol%, 0.0016g) was added. The reaction mixture was located under sunlight irradiation at ambient temperature (a sunny day, in July, in Mashhad between 10 am to 5pm at the temperature ranges of 22-34 °C). The reaction was monitored by TLC. The reaction mixture colour changed from yellow to brown. After completion of the reaction, the catalyst was separated and the desired product was extracted by ethyl acetate (4mL). The obtained crude product was purified by thin layer chromatography using n-hexane/ethyl acetate (50:1). |
45% | With tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene for 23h; Reflux; Inert atmosphere; | |
42% | Stage #1: bromobenzene With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0) In toluene at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 4-methoxy-aniline With sodium t-butanolate In toluene at 90℃; for 22h; | |
With bis(2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)palladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; Et3CONa In benzene-d6 at 60℃; | ||
With potassium phosphate; XPhos In toluene for 20h; Heating; | ||
95 %Chromat. | With C18H14N2Pd; sodium t-butanolate In 1,4-dioxane at 90℃; for 24h; | 4.7 General procedure for C-N coupling reactions 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 dioxane (4 mL). The flask was placed in a preheated oil bath at 90 °C. 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 hexane and analyzed by GC-MS. |
51 %Chromat. | With potassium phosphate; copper(l) iodide; pyrrole-2-carboxyl acid In dimethyl sulfoxide at 110℃; for 24h; Inert atmosphere; Glovebox; Sealed tube; | |
43%Chromat. | With hydrazine hydrate; [Ru(1,2-bis(diphenylphosphino)benzene )(CO)2Cl2] at 130℃; for 24h; | |
100 %Spectr. | With [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1, 1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate; potassium carbonate; tert-butyl XPhos at 110℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With copper diacetate; potassium carbonate; benzoic acid In ethyl acetate at 20 - 80℃; | |
96% | With Fe3O4 magnetic nanoparticles-supported EDTA-copper(II) complex In water at 50℃; for 2h; Green chemistry; | |
95% | With potassium carbonate In water at 20℃; | General procedure for the preparation of arylated amines indicate solvent/ratio for chromatography: General procedure: In a typical example, phenylboronic acid 1 (1.22 g, 1 mmol) was charged in the flask containing K2CO3 (2 equiv) in water as solvent (2 mL). To this was added aniline 2 (0.93 g, 1 mmol) and Cu-Mn catalyst, and the reaction mixture was allowed to stir at room temperature. The completion of the reaction was monitored by TLC. After completion, the base was neutralized using 2 N HCl and the catalyst was filtered off, thorough washings of water were given, extracted with ethyl acetate, and the organic layer was separated and dried under reduced vacuum. The crude product obtained was purified on silica gel column chromatography (solvents, ratio?), to obtain white crystalline product diphenylamine 3a (1.60 g) with 95% yield. All reactions were similarly carried out. |
93% | With potassium carbonate In methanol; water at 20℃; for 8h; | Typical Procedure: N-Arylation of Aniline with PhenylboronicAcid General procedure: In a 50 mL round-bottomed flask, aniline (0.5 mmol), phenylboronicacid (1 mmol), K2CO3 (1.5 mmol), nanocatalyst (30 mol%with respect to aniline substrate) were added and stirred inMeOH-H2O (1:1) under air at r.t. for the required time, monitoringby TLC. After completion, the mixture was diluted with H2O,and the product was extracted with EtOAc (3×). The combined extracts were washed with brine (3×) and dried over Na2SO4.The product was purified by column chromatography (60-120mesh silica gel, eluting with EtOAc-hexane solvent). |
91% | With polystyrene-supported Cu(I) catalyst In methanol at 40℃; for 15h; Inert atmosphere; | |
90% | With copper-exchanged fluorapatite In methanol at 20℃; for 4h; | |
90% | With potassium hydroxide In dimethyl sulfoxide at 120℃; for 15h; Inert atmosphere; | |
90% | With pyridine; oxygen; copper(II) acetate monohydrate; triethylamine In dichloromethane at 40℃; for 2h; Flow reactor; Green chemistry; | A) catalytic Chan-Lam in flow: General procedure: A solution was prepared from the amine (0.781 mmol) in DCM (5.5 mL) and the boronic acid(1.25 mmol) and NEt3 (0.039 g, 54 μL, 0.391 mmol) were added. A second solution was prepared with Cu(OAc)2*H2O (0.195 mmol, 0.25 equiv), NEt3 (0.039 g, 54 μL, 0.391 mmol) and pyridine (0.062 g, 63 μL, 0.781 mmol) in DCM (5.5 mL). The two solutions were introduced to independent 5 mL sample loop as shown in (Scheme 1). The dispensing HPLC pumps were each set at 0.125 mL/min to achieve a residence time of 2 h. Two reverse “tubein-tube” reactors were used in series to achieve a combined reactor volume of 30 mL which were heated at 40 °C. The reaction mixture was then passed through an Omnifit column (r =0.33 cm, h = 10.00 cm) filled with QP-DMA followed by a back pressure regulator (175 psi).The crude reaction mixture was passed through a plug of silica to remove base line residue and the solvent evaporated under reduced pressure. The resultant crude material was then purified using flash chromatography. |
90% | With CoCuFe2O4; potassium hydroxide In ethanol at 60℃; for 5h; Green chemistry; | |
89% | With potassium carbonate In dimethyl sulfoxide at 140℃; for 15h; Inert atmosphere; | 2.3. General procedure for the amination of aromatic amines with arylboronic acids General procedure: In a 100 mL RB flask, polymer supported Cu(II) catalyst (50 mg,0.0098 mmol), arylboronic acid (1.5 mmol), aromatic amines(1.2 mmol), K2CO3 (1 mmol), and 10 ml DMSO stirred under nitrogen atmosphere, at 140 °C. The reaction mixtures were collected at different time intervals and identified by GCMS and quantified by GC. After the completion of the reaction, the catalyst was filtered off and washed with water followed by acetone and dried in oven. The filtrate was extracted with ethyl acetate(3 x 20 mL) and the combined organic layers were dried with anhydrous Na2SO4 by vacuum. The filtrate was concentrated by vacuum and the resulting residue was purified by column chromatography on silica gel to provide the desired product. |
89% | With copper(II)(1,1′-di(2-picolyl)-3,3′-methylenedibenzimidazolium) dihexafluorophosphate In methanol at 20℃; for 24h; | |
85% | With potassium hydroxide In methanol; water for 14h; Reflux; | |
83% | With (1,3-bis(2,6-diisopropyl-4-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenyl)-2,3-dihydro-1H-imidazole-2-yl)copper(I) chloride In dichloromethane at 20℃; for 24h; | 4.3.2. General procedure for complex 1-catalyzed the Chan-Evans-Lam coupling of arylboronic acid with amines General procedure: To a mixture of amines 3 (1 mmol), arylboronic acid 2 (1.2 mmol, 1.2 equiv.) and CH2Cl2 (3.0 mL) in a 20mL Schlenk reaction tube was added complex 1 (0.5 mol%). Then the reaction mixture was stirred at room temperature for 24 h. After completion, the mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 10 mL). Then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography (SiO2) to give the coupling product |
82% | With C21H16CuN2O2; potassium carbonate In water at 28℃; for 16h; | General procedure for the N-arylation of anilines with aryl boronic acids General procedure: A 50 mL round bottomed flask was charged with amine (0.5 mmol), arylboronicacid (0.75 mmol), K2CO3 (1.5 mmol, 207 mg), C-1 complex (20 mol %, 39.15 mg) in 3 mL of water at room temperature. The reaction mixture was stirred with a magnetic stirrer for appropriate time. The progress of the reaction was monitored by TLC. After the completion of the reaction, the mixture was diluted with 20 mL of water and extracted with diethylether (3*20 mL). The combined organic layer were washed with brine and dried over by anhydrous Na2SO4 and evaporated in a rotary evaporator under reduced pressure. The crude was purified by column chromatography on silica gel (hexane/ethyl acetate, 9:1) to afford the desired product. |
82% | With triethylamine In methanol at 20℃; for 5h; | 2.3 General procedure for the Chan-Lam C-N cross-coupling reaction General procedure: In a typical reaction, arylboronic acid (1 mmol), amino-compound (1 mmol), catalyst (5 wt%), Et3N (2 mmol) were mixed in methanol ( 5mL) in a 25mL round bottomed flask. The reaction mixture was subjected under continuous stirring at room temperature for 5 h. Reaction was monitored from time to time using TLC. After completion of the reaction, catalyst was separated with the aid of an external magnet and reaction mixture was taken in ethyl acetate. The organiclayer was washed using brine solution, dried over sodium sulfate. After evaporating the solvent, the crude product was puried by column chromatography using 230-400 silica mesh. The recovered catalyst was washed with methanol and ethyl acetate, dried in oven and kept in desiccator for further use. |
81% | With [Cu(4-(dimethylamino)pyridine)4I]I In methanol at 20℃; for 0.25h; | |
80% | With potassium carbonate In acetonitrile for 14h; Reflux; | General procedure for N-arylationof amines with arylboronic acid General procedure: Aniline (0.0931g, 1mmol) and phenylboronic acid (0.2438g, 2mmol) were dissolved in acetonitrile (10mL) in a50mL round bottomed flask and stirred for 20 minutes. The base K2CO3(0.2764g, 2mmol) and complex (C3) (8 mol%) were added to thereaction flask. The mixture washeated under reflux for specific time (9-12 hr). The progress of the reactionwas monitored by TLC at regular intervals. After completion, the reactionmixture was cooled to room temperature and the catalyst was removed byfiltration. The filtrate was treated with ethyl acetate (3x10mL). The combinedorganic layers were treated with saturated brine solution and dried overanhydrous sodium sulphate. The removal of solvent yields crude product, whichafter purification by column chromatographyover Silica gel G-60, afforded the desired product. The spectral data ofsynthesized product are given below. |
77% | With copper(II) acetate monohydrate; silica gel; potassium carbonate In neat (no solvent) for 1.5h; Milling; Green chemistry; | |
76% | With 2,6-dimethylpyridine; fac-tris(2-phenylpyridinato-N,C2')iridium(III); copper diacetate; n-tetradecanoic acid In toluene; acetonitrile at 35℃; for 20h; Irradiation; | |
72% | With potassium hexafluorophosphate; 1,1'-dimethylferrocene; copper(II) acetate dihydrate; sodium acetate; triethylamine In acetonitrile at 40℃; Inert atmosphere; | |
70% | With 2,6-dimethylpyridine; tetrabutylammonium perchlorate; copper diacetate; triethylamine In acetonitrile at 20℃; for 20h; Electrochemical reaction; chemoselective reaction; | |
38% | With potassium phosphate; 4,4'-dimethyl-2,2'-bipyridines; [Ni(DHASICy)CpCl] In N,N-dimethyl-formamide; toluene at 70℃; for 8h; | 3. Typical procedure for the [Ni(DHASICy)CpCl] catalyzed Chan-Lam coupling. General procedure: A flask was charged with [Ni(DHASICy)CpCl] (4.3 mg, 7.5 μmol), 4,4’-dimethyl-2,2’-bipyridyl (1.4 mg, 7.5 μmol), K3PO4 (159.2 mg, 0.75 mmol), phenylboronic acid (91.4 mg, 0.75 mmol), and a stir bar at r.t. (if an amine was solid, it was added to the flask at this point). Solvent (DMF:75 μL, toluene: 0.925 mL (1.425 mL in the case of solid amine)) was added to the resultant vessel at r.t. and stirred well. Amine (0.375 mmol) in toluene (0.3 mL) was added using a syringe, and an additional 0.2 mL of toluene was used to rinse the flask which had been charged with amine (skipped this process in the case of solid amine). The resultant flask was capped with a reflux condenser and the reaction solution was then heated at 70 for 8 h. The reaction was quenched with H2O (5 mL) at r.t., and the resultant mixture was extracted with EtOAc (10 mL ×3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (30 mL) to afford the cross-coupling product. |
With 2,6-dimethylpyridine; n-tetradecanoic acid In toluene at 20℃; | ||
38 %Spectr. | With C30H25N4O(1-)*3C2H3O2(1-)*2Cu(2+) In methanol at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium hydroxide; air In ethanol at 20℃; | |
55% | With potassium hydroxide; air In ethanol; water | |
With potassium hydroxide; air In ethanol; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With [Pd(2-aminobiphenyl)(PCyp2ArXyl2)](OMs); sodium tertiary butoxide In tetrahydrofuran at 80℃; for 19h; Inert atmosphere; Schlenk technique; | |
98% | With sodium tertiary butoxide In 1,4-dioxane at 100℃; for 0.166667h; | |
98% | With 4-(2-(dicyclohexylphosphanyl)phenyl)-1,2,3-triphenyl-1H-pyrrole; Palladium(0) bis(dibenzylideneacetone); sodium tertiary butoxide In 1,4-dioxane; water monomer at 20℃; for 0.5h; Inert atmosphere; Sealed tube; Reflux; | 3-1 Coupling reaction between aryl chloride and amine: Synthesis of aromatic amine compounds General procedure: Under an argon atmosphere, Pd (dba) 2 (2.9 mg, 0.005 mmol, 0.5 mol%), phosphine compound L1 (3.4 mg, 0.006 mmol, 0.6 mol%), 1,4-dioxane was added to the reaction vessel. (0.9 mL) was added and heated to reflux for 2 minutes. The solution was mixed with 4-chlorotoluene (127 mg, 1 mmol), benzylamine (126 mg, 1.2 mmol, 1.2 equiv), NaOtBu (144 mg, 1.5 mmol, 1.5 equiv), H 2 O (14.4 μL, 0.8 mmol). , 0.8 equiv), 1,4-dioxane (2.1 mL) was added to the reaction vessel sealed. After stirring for 10 minutes at room temperature, the mixture was stirred for 1 hour under reflux. The reaction solution was passed through a short column of sodium sulfate and silica gel and then concentrated. The residue was purified by column chromatography to obtain a coupling product with a yield of 99%. The yield of diarylate was less than 1%. |
98% | With 4-(2-(dicyclohexylphosphanyl)phenyl)-1,2,3-triphenyl-1H-pyrrole; water monomer; Palladium(0) bis(dibenzylideneacetone); sodium tertiary butoxide In 1,4-dioxane at 110℃; for 0.5h; Sealed tube; chemoselective reaction; | |
97% | With C16H34ClPPd; sodium tertiary butoxide In toluene at 80℃; Inert atmosphere; | |
97% | With dicyclohexyl(2′,4′,6′-tri-isopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphane; C47H63NO2PPd(2+)*CH3O3S(1-); sodium tertiary butoxide In 1,4-dioxane at 100℃; for 24h; | |
97% | With dicyclohexyl(2′,4′,6′-tri-isopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphane; [(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′- triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate methanesulfonate; sodium tertiary butoxide In 1,4-dioxane at 100℃; for 24h; Inert atmosphere; | 4 General Procedure for Catalyzed Arylation of Primary Amines General procedure: An oven-dried, resealable tube equipped with a magnetic stir bar and Teflon septum was charged with OMsBrettPhos precatalyst (0.01-0.5 mol %), BrettPhos (0.01-0.5 mol %) NaOt-Bu (115 mg, 1.20 mmol, 1.20 eq), aryl halide (1.00 mmol, 1.00 eq) and amine (1.20 mmol, 1.20 eq) if they are solids. The tube was evacuated and backfilled with argon. This process was repeated three times. Then the aryl halide and amine were added if they are liquid, followed by dioxane (1 mL). The reaction was heated at 100° C. and monitored by thin-layer chromatography or gas chromatography, observing the disappearance of aryl halide. After completion the reaction was cooled to room temperature, diluted with ethyl acetate, and filtered through a plug of Celite. The solvent was removed via rotary evaporation and the crude product was then purified by flash chromatography. See FIG. 14. |
97% | With PdCl2(N,N’-bis-(2,6-di(iso-propyl)phenyl)imidazolidin-2-ylidene)(SbPh3); potassium-t-butoxide In 1,4-dioxane at 110℃; for 4h; | |
96% | With sodium tertiary butoxide In 1,4-dioxane at 110℃; for 2h; | |
96% | With C49H68NO5PPdS; sodium tertiary butoxide In tetrahydrofuran; 1,4-dioxane at 110℃; for 24h; Sealed tube; Inert atmosphere; | |
96% | With dichloro(3-chloropyridinyl)(1,3-(diisopropylphenyl)-4,5-bis(dimethylamino)imidazol-2-ylidene)palladium(II); potassium-t-butoxide In 1,4-dioxane at 80℃; for 18h; Inert atmosphere; Schlenk technique; Sealed tube; | |
96% | With tris-(dibenzylideneacetone)dipalladium(0); C33H48N7P; sodium tertiary butoxide In toluene at 80℃; for 24h; Inert atmosphere; Schlenk technique; Glovebox; | |
95% | With 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene; Palladium(0) bis(dibenzylideneacetone); sodium tertiary butoxide In toluene at 70℃; for 15h; | |
95% | With sodium tertiary butoxide In toluene | 47 4-methoxy-diphenylamine (Table 6, Entry 1) Example 47 4-methoxy-diphenylamine (Table 6, Entry 1) According to the general procedure B, 4-chloroanisole (72 mg, 0.50 mmol) reacted with aniline (47 mg, 0.50 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (59 mg, 0.60 mmol) in toluene at 70° C. to give the title compound (96 mg, 95%): 1H-NMR (300 MHz, CDCl3): δ 7.26 (t, 2H, J=8.4 and 7.5 Hz), 7.12 (d, 2H, J=8.7 Hz), 6.86-6.97 (m, 5H), 5.55 (bs, 1H, -NH-), 3.84 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ GC/MS(EI): m/z 199 (M+). |
94% | With sodium tertiary butoxide In toluene at 110℃; | |
94% | With ϖ-allylpalladium (II) chloride dimer; biphenyl; dicyclohexyl(2′,4′,6′-tri-isopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphane; tetrabutylammonium bromide; potassium hydroxide In water monomer; ethyl acetate; toluene Inert atmosphere; | |
94% | With potassium-t-butoxide; C39H55Cl2N3Pd In tetrahydrofuran at 70℃; for 6h; Sealed tube; | |
93% | With BrettPhos Pd G4; potassium hydroxide In dodecane; water monomer; toluene at 100℃; Flow reactor; | |
92% | With dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II); Cs2CO3 In 1,2-dimethoxyethane at 80℃; for 24h; Inert atmosphere; | |
92% | With bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; N-[2-(di-1-adamantylphosphino)phenyl]morpholine; potassium hydroxide; sodium tertiary butoxide In water monomer at 110℃; for 36h; Inert atmosphere; chemoselective reaction; | |
92% | With [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride; Cs2CO3 In 1,2-dimethoxyethane at 80℃; for 24h; Inert atmosphere; Schlenk technique; | |
92% | With C36H27NOP2*CH3O3S(1-)*C12H10N(1-)*Pd(2+); lithium hexamethyldisilazane In 1,2-dimethoxyethane at 100℃; for 48h; Inert atmosphere; Sealed tube; | |
91% | With tris((1E,4E)-1,5- diphenylpenta-1,4-dien-3-one) dipalladium; potassium-t-butoxide; 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride In 1,4-dioxane at 100℃; | |
91% | With potassium-t-butoxide; 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride In 1,4-dioxane at 100℃; | |
90% | With (2-phenyl-1H-inden-3-yl)-dicyclohexylphosphinium tetrafluoroborate; Palladium(0) bis(dibenzylideneacetone); sodium tertiary butoxide In 1,2-dimethoxyethane at 20 - 120℃; Inert atmosphere; | |
90% | With C46H56Cl2N3O2PPd; potassium-t-butoxide In 1,4-dioxane at 100℃; for 24h; Inert atmosphere; Glovebox; Sealed tube; | |
89% | With tris((1E,4E)-1,5- diphenylpenta-1,4-dien-3-one) dipalladium; di-tert-butylneopentylphosphonium tetrafluoroborate; sodium tertiary butoxide In toluene; xylene at 120℃; for 4h; | |
88% | With water monomer; potassium carbonate In <i>tert</i>-butyl alcohol at 110℃; for 0.25h; Inert atmosphere; | 53 EXAMPLE FIFTY-THREE: General Procdure for Ligand Screen for Aniline and 4- Chloroanisole (Figure 18); An oven dried test tube, which was equipped with a magnetic stir bar and fitted with a teflon septum, was charged with Pd(OAc)2 (1 mol %) and the ligand (1, 21, or 22) (3 mol %). The vessel was evacuated and backfilled with argon (this process was repeated a total of 3 times) and t-BuOH (2 mL) and degassed H2O (4 mol %) were added via syringe. After addition of the water, the solution was heated to 110 0C for 1.5 min. A second oven dried test tube, which was equipped with a magnetic stir bar and fitted with a Teflon septum, was charged with K2Cθ3 (1.4 mmol). The vessel was evacuated and backfilled with argon (this process was repeated a total of 3 times) and then the 4-chloroanisole (123 uL, 1.0 mmol) and aniline (110 uL, 1.2 mmol) were added via syringe and the activated catalyst solution was transferred from the first reaction vessel into the second via cannula. The solution was heated to 110 0C for 15 min and then was cooled to room temperature and dodecane was added as an internal standard. The reaction mixture was diluted with ethyl acetate, washed with water, and analyzed by GC. |
88% | With potassium-t-butoxide; C95H78Cl2N2PdS In 2-methyltetrahydrofuran at 80℃; | |
87% | With [PdCl2(N,N’-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene)]2(μ-bis(diphenylphosphino)ethane); potassium-t-butoxide In 1,4-dioxane at 110℃; for 0.166667h; Microwave irradiation; | General procedure for the NHC-Pd catalysed Buchwald-Hartwig amination General procedure: The aryl chloride (0.50 mmol), amine (0.60 mmol), KOtBu (0.75 mmol), NHC-Pd complex (0.0025 mmol) and dry dioxane (1.0 mL) were added into oven-dried microwave vial. The reaction mixture was irradiated in a microwave apparatus at 110 °C for 10 min. After the reaction mixture was cooled to room temperature, the product was filtered over Celite and washed with ethyl acetate.Then the filtrate was concentrated with a rotary evaporator, and the residue was then subjected to purification via flash column chromatography (eluent: ethyl acetate/petroleum ether) to give the corresponding pure products. |
86% | With dichloro(3-chloropyridinyl)(1,3-(diisopropylphenyl)-4,5-bis(dimethylamino)imidazol-2-ylidene)palladium(II); Cs2CO3 In 1,2-dimethoxyethane at 80℃; for 24h; Schlenk technique; Sealed tube; Inert atmosphere; | |
86% | With C46H52Cl3N3O2Pd; potassium 2-methyl-2-butoxide In toluene at 100℃; for 2h; Sealed tube; | |
84% | With sodium tertiary butoxide In toluene at 100℃; for 24h; | |
84% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2,6,6-tetramethyl-1-phenyl-4-phosphorinanol; sodium tertiary butoxide In 1,4-dioxane at 100℃; for 12h; Inert atmosphere; | |
82% | With NHC-Pd(II)-Im; potassium-t-butoxide In toluene for 4h; Inert atmosphere; Reflux; | 4.2. Experimental procedures General procedure: Under N2 atmosphere, KOtBu (114.0 mg, 1.0 mmol), NHC-Pd(II)-Im complex 1 (5.2 mg, 1.0 mol %), dry toluene (1.0 mL), chlorobenzene 2a (0.8 mmol), and aniline 3a (0.96 mmol) were successively added into a Schlenk reaction tube. The reaction mixture was stirred under reflux for 4 h. Then the solvent was removed under reduced pressure and the residue was purified by a flash chromatography on silica gel to give the pure product 4a. |
81% | With copper (II) acetate at 110℃; for 6h; | |
80% | With sodium tertiary butoxide In 1,4-dioxane at 80℃; Inert atmosphere; Sonication; | |
80% | With carbonyl(pentamethylcyclopentadienyl)cobalt diiodide; copper (II) acetate In neat (no solvent) at 100℃; for 4h; | |
79% | With dicyclohexylamino[(2,6-dimethyl)morpholin-4-yl]phenylphosphine; potassium-t-butoxide; palladium (II) chloride In toluene for 5h; Reflux; | |
78% | With ϖ-allylpalladium (II) chloride dimer; sodium tertiary butoxide In toluene at 100℃; for 20h; Inert atmosphere; Sealed tube; | |
77% | Stage #1: 4-chloromethoxybenzene; aniline With palladium diacetate; Sodium sulfate [anhydrous]; sodium tertiary butoxide; dicyclohexyl(2’,4’,6’-triisopropyl-[ 1,1’-bi-phenyl]-2-yl)phosphane for 1h; Milling; Stage #2: In water monomer; ethyl acetate for 0.0333333h; Milling; | 2. General Procedure General procedure: A mixture of substrate 2 (0.5 mmol), 1 (0.6 mmol), Pd(OAc)2 (2 mol%), Xphos (4 mol%), NaOtBu (2.0 equiv.) and Na2SO4 (2.0 g) were added to the 25 mL screw-capped stainless-steel vessel, along with two stainless steel balls ( = 1.4 cm). After that, the vessel was placed in the mixer mill, and the contents were ball milled at 30 Hz for 60 min. At the end of the reaction, small portion (3 mL) ethyl acetate and (3 mL) H2O were added in to the vessel and grinding for another 2 min at 30 Hz. Then, after the washing by brine, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by flash column chromatography on silica gel to give the desired product. |
75% | With (N,N'-diarylimidazol-2-ylidene)-based palladacycle; sodium tertiary butoxide In 1,4-dioxane at 70℃; for 2h; | |
73% | With oxalic acid hydrazide; phosphoric acid trihydrate; tetrabutylammonium bromide; 2,5-hexanedione; copper(II) oxide In water monomer at 120℃; for 24h; | |
66% | With 0.068 mol% Ni(II) and 0.026 mol% Pd(II) complexed in pyridine grafted demetalated chlorophyll b co-polymer modified SiO2 shell on Fe3O4 core at 120℃; for 12h; | |
55% | With ϖ-allylpalladium (II) chloride dimer; potassium-t-butoxide; 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydro-1H-imidazol-3-ium chloride In 1,4-dioxane at 100℃; for 1.5h; Inert atmosphere; | |
51% | With (2-mesityl-1H-inden-3-yl)-dicyclohexylphosphine; Palladium(0) bis(dibenzylideneacetone); sodium tertiary butoxide In 1,2-dimethoxyethane at 120℃; for 24h; Inert atmosphere; | 4.5. General procedures for palladium-catalyzed amination of aryl halides General procedure: Pd(dba)2/1-catalyzed amination of aryl halides: An oven-dried Schlenk tube equipped with a magnetic stirring bar was charged with Pd(dba)2 (5.8 mg, 0.010 mmol), ligand 1 (8.6 mg, 0.020 mmol) and tBuONa (134 mg, 1.4 mmol). The flask was capped with a rubber septum, evacuated, and then flushed with argon. This cycle was repeated three times. Amine (1.2 mmol), aryl halide (1.0 mmol) and DME (4 mL) were then successively added by syringe. The tube was stirred at room temperature for several minutes and then placed into a preheated oil bath (120 °C) for the time period as indicated in tables. After completion of reaction as judged by GC analysis, the reaction tube was allowed to cool to room temperature and the reaction mixture was adsorbed onto silica gel, and then purified by column chromatography (hexane/ethyl acetate as eluent) to afford the desired product. |
40% | With C28H29Cl2N3OPd; potassium-t-butoxide In toluene at 110℃; for 15h; Schlenk technique; Inert atmosphere; | General procedure for the catalytic amination General procedure: A Schlenk ask was charged with the required aryl chloride (0.25 mmol), amine (0.30 mmol), N-heterocyclic carbene-palladium(II) complex (2 mol%), KOtBu (1.3 equiv), and toluene (0.5 mL). The mixture was stirred at 110 C for 15 h under N2. After cooling, the mixture was evaporated and the product was isolated by preparative TLC on silica gel plates. The puried products were identied by 1H NMR spectra, and their analytical data are given in the Supporting Information. |
32% | With tris-(dibenzylideneacetone)dipalladium(0); di(dicyclohexylamino)phenylphosphine; potassium-t-butoxide In toluene for 32h; Reflux; Inert atmosphere; | 4.3. Typical C-N coupling of amines and aryl chlorides General procedure: A dried resealable Schlenk tube was charged with Pd2(dba)3 (0.03 mmol, 1 mol % of Pd), amine (3.0 mmol), ligand 1 (1 mol %) and KOtBu (4.5 mmol) in dried toluene (20 mL). The Schlenk tube was capped with a rubber septum, evacuated, and backfilled with nitrogen. This evacuation/backfill sequence was repeated two or three additional times. Aryl chloride (3.15 mmol) and toluene (2 mL×2) were added through the septum. After the septum was replaced with a Teflon screwcap, the mixture was refluxed until the starting amine had been completely consumed as judged by GC or TLC. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (10 mL×2), filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using n-hexane/dichloromethane (1/1, v/v) to afford C-N coupled product. |
20% | With tripotassium phosphate tribasic; copper (I) iodide In diethylene glycol at 150℃; for 16h; Sealed tube; | Synthesis of 1a-s and 2a-q; General Procedure General procedure: A 10 mL vial was charged with CuI (9.5 mg, 0.05 mmol), PSAP (30 mg,0.05 mmol, > 100 mesh), K3PO4 (424 mg, 2 mmol), aryl bromides (1mmol), amines (1.5 mmol), DEG (2 mL), and a magnetic stir bar. The vessel was sealed with a septum and placed into a preheated oil batchat 70 °C. The reaction mixture was held at this temperature for 14 hours. After cooling to r.t., the reaction mixture was filtered, and the precipitates were thoroughly washed with water and EtOAc (3 × 20mL). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Theresidue was purified using flash column chromatography on silica gel(eluting with petroleum ether/EtOAc) to afford the desired products. |
With 5-(di-tert-butylphosphino)-1′,3′,5′-triphenyl-1′H-[1,4′]bipyrazole; bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; sodium tertiary butoxide In toluene at 110℃; for 24h; | ||
With [tert-butyloxy]bis(N,N-diisopropylamino)phosphane; Palladium(0) bis(dibenzylideneacetone); sodium tertiary butoxide In toluene at 105℃; for 24h; Inert atmosphere; Schlenk technique; | ||
With methanol; trihexyl(tetradecyl)phosphonium hydroxide; (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-amino-ethyl)phenyl]palladium(II) chloride; dicyclohexyl(2’,4’,6’-triisopropyl-[ 1,1’-bi-phenyl]-2-yl)phosphane In 1,4-dioxane at 100℃; for 2h; Inert atmosphere; | ||
With potassium-t-butoxide In 2-methyltetrahydrofuran; dodecane at 70℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium t-butanolate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride In 1,4-dioxane at 100℃; | |
99% | With bis(η3-allyl-μ-chloropalladium(II)); potassium <i>tert</i>-butylate; 1,3-bis[(2,6-diisopropyl)phenyl]imidazolinium chloride In 1,4-dioxane at 100℃; for 1.5h; Inert atmosphere; | |
99% | With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3chloro-pyridyl)palladium(II) dichloride; caesium carbonate In 1,2-dimethoxyethane at 80℃; for 24h; Inert atmosphere; |
99% | With C36H45Cl2N3OPd; potassium <i>tert</i>-butylate In 1,4-dioxane at 90℃; for 1h; Inert atmosphere; Schlenk technique; | |
98% | With 1,1'-bis-(diphenylphosphino)ferrocene; [1,1′-bis(diphenylphosphino)ferrocene]bis(triphenylphosphite)nickel(0); sodium t-butanolate In toluene at 100℃; for 18h; Schlenk technique; Inert atmosphere; | |
98% | With C19H14N4NiO2; potassium <i>tert</i>-butylate In 1,4-dioxane at 90℃; for 4h; Inert atmosphere; Schlenk technique; | General procedure for the Buchwald-Hartwig reaction General procedure: Under an N2atmosphere, KOtBu (1.3 mmol), complex 1 (1 mol%),dioxane (2 ml), amines (1.3 mmol) and aryl chlorides (1.0 mmol)were successively added into a Schlenk tube. The mixture wasstirred vigorously at 90C for 4 h. Then the solvent was removedunder reduced pressure and the residue was purified by columnchromatography on silica gel (eluent:PE/EA = 15:1) to give the pureproducts. The reported yields are the average of two runs.The catalytic reactions have been given in Tables 4-7. The result-ing amines were identified by comparison of the1H and13C NMRdata with those previously reported (ESI). |
97% | With sodium hydride; 1,3-bis[(2,6-diisopropyl)phenyl]imidazolinium chloride; <i>tert</i>-butyl alcohol In 1,4-dioxane at 100℃; | |
96% | With [(N,N′-bis-(2,6-di(isopropyl)phenyl)imidazolidin-2-ylidene)PdCl2(indazole)]; potassium <i>tert</i>-butylate In toluene at 110℃; for 6h; Sealed tube; | |
96% | With potassium <i>tert</i>-butylate; C39H55Cl2N3Pd In tetrahydrofuran at 70℃; for 6h; Sealed tube; | |
90% | With C63H54Cl3N3OPd; potassium 2-methylbutan-2-olate In 1,4-dioxane at 100℃; for 2h; | |
88% | With potassium <i>tert</i>-butylate In toluene at 80℃; for 12h; Schlenk technique; | 1.1a Step 1a: Synthesis of raw material 4-methoxy-N-phenylaniline Add chlorobenzene (4mmol, 0.448g), p-anisidine (6mmol, 0.751g), potassium tert-butoxide (6mmol, 0.673g), 10mg[Pd] catalyst, 5mL toluene, and react at 80 in a 10mL Schlenk tube 12h. After the reaction, 700 mg of white solid was obtained by column chromatography with a yield of 88%. |
83% | With bis-triphenylphosphine-palladium(II) chloride; OHC6H4CHNC6H3F2; sodium t-butanolate In o-xylene for 12h; Inert atmosphere; Schlenk technique; Reflux; | |
80% | With palladium 10% on activated carbon; sodium t-butanolate; CyJohnPhos In tert-Amyl alcohol at 110℃; Inert atmosphere; | |
79% | With C31H26N4PPdS(1+)*Cl(1-); sodium t-butanolate In toluene at 110℃; for 18h; | 2.5.4. General procedure for C-N coupling reactions General procedure: In a typical run, an oven-dried 10 mL round bottom flask wascharged with a known mole percent of catalyst, NaOt-Bu(1.3 mmol), aryl amine (1.2 mmol) and aryl halide (1 mmol) withthe appropriate solvent(s) (4 mL). The flask was placed in a preheatedoil bath at required temp. After the specified time the flaskwas removed from the oil bath, water (20 mL) was added, and extraction with ether (4 10 mL) was done. The combined organiclayers were washed with water (3 10 mL), dried over anhydrousNa2SO4, and filtered. Solvent was removed under vacuum. The residuewas dissolved in hexane and analyzed by GC-MS using Elite-5columns, which are fused silica capillary columns coated with 5%diphenyl and 95% dimethyl polysiloxane. |
75% | With tris-(dibenzylideneacetone)dipalladium(0); di(dicyclohexylamino)phenylphosphine; potassium <i>tert</i>-butylate In toluene for 15h; Reflux; Inert atmosphere; | 4.3. Typical C-N coupling of amines and aryl chlorides General procedure: A dried resealable Schlenk tube was charged with Pd2(dba)3 (0.03 mmol, 1 mol % of Pd), amine (3.0 mmol), ligand 1 (1 mol %) and KOtBu (4.5 mmol) in dried toluene (20 mL). The Schlenk tube was capped with a rubber septum, evacuated, and backfilled with nitrogen. This evacuation/backfill sequence was repeated two or three additional times. Aryl chloride (3.15 mmol) and toluene (2 mL×2) were added through the septum. After the septum was replaced with a Teflon screwcap, the mixture was refluxed until the starting amine had been completely consumed as judged by GC or TLC. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (10 mL×2), filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using n-hexane/dichloromethane (1/1, v/v) to afford C-N coupled product. |
75% | With 0.068 mol% Ni(II) and 0.026 mol% Pd(II) complexed in pyridine grafted demetalated chlorophyll b co-polymer modified SiO2 shell on Fe3O4 core at 120℃; for 7h; | |
72% | With carbonyl(pentamethylcyclopentadienyl)cobalt diiodide; copper diacetate In neat (no solvent) at 100℃; for 4h; | |
60% | With tris-(dibenzylideneacetone)dipalladium(0); 2,4-dichloro-1,3-di-tert-butyl-1,3,2,4-diazadiphosphetidine; sodium t-butanolate In toluene at 120℃; for 24h; Inert atmosphere; | |
34% | With C26H22N3PPdS; sodium t-butanolate; XPhos at 145℃; for 24h; | |
55 %Chromat. | With C18H14N2Pd; sodium t-butanolate In 1,4-dioxane at 90℃; for 24h; | 4.7 General procedure for C-N coupling reactions 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 dioxane (4 mL). The flask was placed in a preheated oil bath at 90 °C. 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 hexane and analyzed by GC-MS. |
100 %Spectr. | With [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1, 1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate; potassium carbonate; tert-butyl XPhos at 110℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium hydroxide In water at 60℃; for 8h; Inert atmosphere; Sealed tube; | |
95% | With (1,3-bis(2,6-diisopropylphenyl)-3,4,5,6-tetrahydropyrimidin-2-ylidene)Pd(cinnamyl, 3-phenylallyl)Cl; sodium t-butanolate In neat (no solvent) at 110℃; for 12h; Inert atmosphere; Green chemistry; | |
92% | With tris(dibenzylideneacetone)dipalladium (0); di-tert-butylneopentylphosphonium tetrafluoroborate; sodium t-butanolate In toluene at 20℃; |
92% | With sodium t-butanolate In toluene at 20℃; | |
92% | With potassium phosphate; copper(l) iodide In diethylene glycol at 70℃; for 14h; Sealed tube; | Synthesis of 1a-s and 2a-q; General Procedure General procedure: A 10 mL vial was charged with CuI (9.5 mg, 0.05 mmol), PSAP (30 mg,0.05 mmol, > 100 mesh), K3PO4 (424 mg, 2 mmol), aryl bromides (1mmol), amines (1.5 mmol), DEG (2 mL), and a magnetic stir bar. The vessel was sealed with a septum and placed into a preheated oil batchat 70 °C. The reaction mixture was held at this temperature for 14 hours. After cooling to r.t., the reaction mixture was filtered, and the precipitates were thoroughly washed with water and EtOAc (3 × 20mL). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Theresidue was purified using flash column chromatography on silica gel(eluting with petroleum ether/EtOAc) to afford the desired products. |
91% | With potassium <i>tert</i>-butylate; palladium diacetate; XPhos In toluene at 80℃; for 7h; Inert atmosphere; | |
91% | With Pd(π-crotyl)(QPhos)Cl; sodium t-butanolate In toluene at 50℃; for 2h; Inert atmosphere; | |
91% | With potassium phosphate; copper(l) iodide; N′,N′-diphenyl-1H-pyrrole-2-carbohydrazide In diethylene glycol at 60℃; for 3h; Sealed tube; Molecular sieve; | |
90% | With potassium hydroxide; bis(tri-tert-butylphosphine)palladium(0); cetyltrimethylammonim bromide In water; toluene at 90℃; for 2h; | |
90% | With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In toluene at 90℃; Inert atmosphere; | |
89% | With C16H34ClPPd; sodium t-butanolate In toluene at 23℃; | |
87% | With potassium <i>tert</i>-butylate In para-xylene at 90℃; for 32h; Microwave irradiation; Inert atmosphere; regioselective reaction; | |
86% | With oxalic acid hydrazide; potassium hydroxide; tetrabutylammomium bromide; 2,5-hexanedione; copper(II) oxide In water at 25℃; for 96h; | |
85% | With palladium/alumina; C9H16N2*BF4(1-)*H(1+); potassium <i>tert</i>-butylate In toluene at 110℃; for 4h; Inert atmosphere; | |
84% | With di-tert-butyl{2′-isopropoxy-[1,1′-binaphthalen]-2-yl}phosphane; sodium t-butanolate In toluene at 110℃; for 16h; | |
83% | With tris(dibenzylideneacetone)dipalladium (0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 90 - 110℃; for 20h; | |
83% | With copper(l) iodide; N′-phenyl-1H-pyrrole-2-carbohydrazide; tetrabutylammomium bromide; potassium hydroxide In water at 130℃; for 0.0833333h; | |
83% | With C20H26N4O4; tetrabutylammomium bromide; copper(II) oxide; potassium hydroxide In water at 130℃; for 0.0833333h; Microwave irradiation; | |
83% | With potassium hydroxide In water at 20℃; for 6h; Green chemistry; | |
82% | Stage #1: 1-bromo-4-methoxy-benzene; aniline With tri-tert-butyl phosphine; sodium t-butanolate In hexane; toluene at 20℃; for 5h; Stage #2: With polymer-supported PPh2 In hexane; toluene at 20℃; for 14h; | |
82% | With 0.068 mol% Ni(II) and 0.026 mol% Pd(II) complexed in pyridine grafted demetalated chlorophyll b co-polymer modified SiO2 shell on Fe3O4 core at 120℃; for 7h; | |
80% | With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 120℃; | |
78% | With N-methoxy-1H-pyrrole-2-carboxamide; potassium phosphate; copper(II) acetate monohydrate at 90℃; for 12h; Sealed tube; | General Procedure A for synthesis of compounds 3a-3k, 4a-4x: General procedure: To a 10 mL sealed vial was added Cu(OAc)2·H2O (10 mg, 0.05mmol), N-methoxy-1H-pyrrole-2-carboxamide (7 mg, 0.05 mmol), aryl bromide (1.0 mmol), amine (3.0 mmol), K3PO4 (318 mg, 1.5 mmol),PEG-100 (2.0 g) and a magnetic stir bar. The reaction mixture was stirred in an oil bath preheated to 90 °C for 12 h. After allowing the mixture to cool to room temperature, the reaction mixture was extracted with ethyl acetate (3 × 25 mL) and water (20 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford the desired product. |
77% | With potassium hydroxide In N,N-dimethyl-formamide at 130℃; for 1.86667h; | |
76% | With tetrabutylammomium bromide; palladium diacetate; potassium carbonate; 2,6-bis(diphenylphosphino)pyridine In N,N-dimethyl acetamide at 135℃; for 4h; Inert atmosphere; | Typical experimental procedure for the Buchwald-Hartwig reaction General procedure: A round bottomedflask was charged with bromobenzene (4 mmol), aniline (4 mmol),TBAB (3 mmol), and K2CO3 (4 mmol) under a dry nitrogen atmosphere. A solution of (Ph2P)2py (0.05 mol % in 2 mL of DMAc) and a solution of palladiumacetate (0.025 mol % in 2 mL of DMAc) was added through a rubber septum,and the resulting mixture was heated at 135 C for the appropriate time. Uponcompletion of the reaction, the mixture was cooled to room temperature and quenched with H2O. After extraction with CH2Cl2 (3 20 mL), the combinedorganic layer was dried over MgSO4. The solvent was evaporated and the cruderesidue was purified by silica gel chromatography, using n-hexane/EtOAc aseluent to provide the desired product. The products were characterized byNMR spectroscopy |
75% | With potassium carbonate In methanol; water for 12h; Reflux; Inert atmosphere; | 2.3 General procedure for the N-arylation of aryl amines with aryl halides General procedure: In a 25ml round bottom flask a mixture of 4:1 methanol/water, aryl halide (1mmol), Resin-CuNPs (0.2g), K2CO3 (3mmol) and aryl amine (1.2mmol) were taken and heated at reflux temperature for 12-24h in an oil bath under inert conditions. Resin beads were filtered off at the end of reaction while the solution was still hot. After a work up with dichloromethane and water, the organic layer was separated, dried over anhydrous Na2SO4. The crude products obtained after removal of solvent (Scheme 1) were purified by column chromatography (ethyl acetate: hexane) and identified by mass or 1H NMR spectroscopy (see ESI). |
72% | With copper(l) iodide; tetrabutylammomium bromide; potassium hydroxide In water at 70℃; Green chemistry; | 2.4 General protocol for C-N coupling reaction General procedure: A 10 mL of vial was charged with CuI (10 mg, 0.05 mmol), PSP (0.25 mmol, size less than 90 μM), TBAB (40 mg, 0.25 mmol), base (1.0 mmol), aryl halides (0.5 mmol), arylamine (2.0 mmol), H2O (1.0 mL), and a magnetic stir bar. The vessel was sealed with a septum and placed into an oil bath, which was preheated to 70 °C (90 °C for alkyl amine, 120 °C for imidazole). The reaction mixture was stirred for another 16 h (8 h for imidazole). After allowing the mixture to cool to room temperature, the reaction mixture was filtrated, the precipitates were washed with water and ethyl acetate thoroughly. The filtrate was extracted with ethyl acetate (3×25 mL). The combined organic phases was washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatograph on silica gel to afford the desired products. |
70% | With Ni[3-(4-nitrophenyl)-1-picolyimidazolin-2-ylidene]2Cl2; potassium <i>tert</i>-butylate In tetrahydrofuran for 12h; Schlenk technique; Inert atmosphere; Reflux; | |
68% | With potassium <i>tert</i>-butylate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In N,N-dimethyl-formamide at 180℃; for 0.0666667h; microwave irradiation; | |
67% | With copper(l) iodide; potassium carbonate; pipecolic Acid In N,N-dimethyl-formamide at 110℃; for 24h; | |
67% | With tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene for 2h; Inert atmosphere; Reflux; | |
66% | With copper; caesium carbonate; methyl-alpha-D-glucopyranoside In water; dimethyl sulfoxide at 110℃; Sealed tube; Green chemistry; | General Procedure General procedure: All the reactions were carried out in DMSO-H 2 O (1:1, 2 mL) in asealed vessel. To a 10 mL hydrothermal synthesis reactor was chargedCu powder (6 mg, 0.1 mmol), MG (39 mg, 0.2 mmol), Cs 2 CO 3 (980 mg,3.0 mmol), nitrogen-containing heterocycle (1.5 mmol), amine (3.0mmol), and aryl halide (0.8 mmol). The reaction mixture was stirredfor a specified time at 100-110 °C. After TLC analysis confirmed thecomplete consumption of aryl halides, the mixture was cooled to r.t.(the pH was adjusted if the product was acidic), diluted with EtOAc(10 mL), filtered through a Celite pad, and washed with EtOAc (20-30mL). The organic layer was dried and concentrated. The residue waspurified by silica gel column chromatography to give the product. |
65% | With potassium <i>tert</i>-butylate at 100℃; for 12h; | |
63% | With bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; C40H43BN2P(1-)*C24H20P(1+); potassium <i>tert</i>-butylate In toluene Inert atmosphere; Schlenk technique; | 4.2 General Procedure A: Palladium-Catalyzed Coupling of Aryl Bromides with Amines Using Ligand 1 General procedure: Typically, [Pd(cinnamyl)Cl]2 (0.0031 g, 0.006 mmol), ligand 1 (0.0107 mg, 0.012 mmol), and KO(t-Bu) (0.081 g, 0.72 mmol) were loaded into a Schlenk tube. If a solid aryl bromide or amine was used, it was also added at this time. To the mixture of solids, the aryl bromide (0.6 mmol) and amine (0.72 mmol) were added via syringe (if liquid), followed by toluene (2 mL). The resulting mixture was stirred at room temperature for 1 min., then placed in a pre-heated, 80 °C oil bath and allowed to react for 12 h. After this time, the mixture was removed from the bath and cooled to room temperature, diluted with EtOAc (5 mL), and filtered through silica (1 × 4 cm column, ~10 mL), eluting with EtOAc (20 mL) or until the filtrate ran clear. The volatiles were removed from the filtrate via rotary evaporation and the resulting residue was subjected to flash chromatography on silica gel (8 × 2 cm column, ~25 mL silica). Specific details related to the synthesis, yield and characterization of each coupled product are described below in Section 4.8. |
52% | With potassium hydroxide; copper(II) oxide In water at 130℃; for 0.0833333h; microwave irradiation; | |
50% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 100℃; for 24h; Inert atmosphere; Sealed tube; | |
With chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(ll); sodium t-butanolate In toluene at 22.4℃; for 0.1h; Inert atmosphere; | ||
With [tert-butyloxy]bis(N,N-diisopropylamino)phosphane; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene at 105℃; for 5h; Inert atmosphere; Schlenk technique; | ||
161.4 mg | With [Cu(N,N'-bis(diisopropylphosphino)-N,N'-dimethyl-2,6-diaminopyridine)Br]; potassium <i>tert</i>-butylate In tetrahydrofuran at 110℃; for 16h; Inert atmosphere; Sealed tube; | |
20 %Chromat. | With [{(η7-C7H6PtBu2)Ti(η5-C5H5)}Pd(allyl)Cl]; potassium 2-methylbutan-2-olate In toluene at 80℃; for 14h; Glovebox; Schlenk technique; Inert atmosphere; | |
100 %Chromat. | With tri-tert-butyl phosphine; bis(dibenzylideneacetone)-palladium(0); sodium t-butanolate In toluene at 20℃; for 1h; Inert atmosphere; | |
30 %Chromat. | With C31H37ClN3NiO2(1-)*Li(1+); lithium hexamethyldisilazane In dimethyl sulfoxide at 110℃; for 3h; Inert atmosphere; Sealed tube; | 2.4 General Amination Procedure of Aryl Halides Using Different Amines General procedure: A representative amination method using chlorobenzene,pentylamine, and KOtBuin DMSO is described here. Allother amination reactions including different aryl halides,primary (1°) and secondary (2°) amines, solvents and baseswere performed using a similar method. A 4mL reactionvial containing a magnetic stir bar was charged with 1.4mLof anhydrous DMSO. The reaction vial, after being sealed with a septum and parafilm, was purged with Ar for 10min.Chlorobenzene [0.4mL, 3.9mmol, 2.25 equivalent (eq.)],pentylamine (0.21mL, 1.8mmol, 1.0eq.), anhydrous powderedKOtBu(70mg, 0.63mmol, 0.3eq.), and 2 (2mg,0.2mol%) were added sequentially. The reaction mixturewas stirred for 5min while continually purging with Ar. Thevial was then sealed with a Teflon screw cap. The reactionmixture was stirred for 3h at 110°C in a preheated oil bath,then allowed to cool to room temperature and filtered bypassing through Celite to remove the base and the catalyst.30L of the solution was then dissolved in 1mL absolute ethanol, and 10μL of decane was added as an internalstandard. Turn over number (TON) was determined usingGC-MS. |
>99 %Chromat. | With 4-methyl-pent-3-en-2-one; [(di-tert-butylneopentylphosphine)PdCl2]2; sodium t-butanolate In toluene at 22℃; for 15h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With Fe3O4 magnetic nanoparticles-supported EDTA-copper(II) complex In water at 50℃; for 2h; Green chemistry; | |
97% | With potassium carbonate In ethanol; water at 20℃; for 8h; | |
95% | With potassium carbonate In water at 20℃; | General procedure for the preparation of arylated amines indicate solvent/ratio for chromatography: General procedure: In a typical example, phenylboronic acid 1 (1.22 g, 1 mmol) was charged in the flask containing K2CO3 (2 equiv) in water as solvent (2 mL). To this was added aniline 2 (0.93 g, 1 mmol) and Cu-Mn catalyst, and the reaction mixture was allowed to stir at room temperature. The completion of the reaction was monitored by TLC. After completion, the base was neutralized using 2 N HCl and the catalyst was filtered off, thorough washings of water were given, extracted with ethyl acetate, and the organic layer was separated and dried under reduced vacuum. The crude product obtained was purified on silica gel column chromatography (solvents, ratio?), to obtain white crystalline product diphenylamine 3a (1.60 g) with 95% yield. All reactions were similarly carried out. |
95% | With triethylamine In N,N-dimethyl-formamide at 60℃; for 2h; | General procedure for Chan-Lam coupling General procedure: In a 50 cm3 round-bottom flask, phenylboronic acid(1.2 mmol), primary amine (1.0 mmol), triethyl amine(2.0 mmol), and 80 mg (0.018 mol% of Cu) Cu-ACP-Am-Fe3O4SiO2 were mixed in 5 cm3 DMF and the reactionwas allowed to stir at 60 °C temperature for 2 h in aerobiccondition. Reactions was monitored by thin-layer chromatography(TLC) using aluminum-backed silica gel 60 (F254)plates. After completion of the reaction, the catalyst wasseparated magnetically using bar magnet. Finally, the resultingsolution was extracted with ethyl acetate and dried overanhydrous Na2SO4.The solvent was removed under reducedpressure and the product was purified by silica gel columnchromatography. |
94% | With [copper(II)]2-β-cyclodextrin complex In water at 20℃; for 5h; chemoselective reaction; | |
94% | With C21H16CuN2O2; potassium carbonate In water at 28℃; for 16h; | General procedure for the N-arylation of anilines with aryl boronic acids General procedure: A 50 mL round bottomed flask was charged with amine (0.5 mmol), arylboronicacid (0.75 mmol), K2CO3 (1.5 mmol, 207 mg), C-1 complex (20 mol %, 39.15 mg) in 3 mL of water at room temperature. The reaction mixture was stirred with a magnetic stirrer for appropriate time. The progress of the reaction was monitored by TLC. After the completion of the reaction, the mixture was diluted with 20 mL of water and extracted with diethylether (3*20 mL). The combined organic layer were washed with brine and dried over by anhydrous Na2SO4 and evaporated in a rotary evaporator under reduced pressure. The crude was purified by column chromatography on silica gel (hexane/ethyl acetate, 9:1) to afford the desired product. |
93% | With ammonium cerium (IV) nitrate; copper diacetate In toluene at 20℃; for 12h; | |
92% | With potassium carbonate In water at 20℃; for 5h; | Preparation of diphenylamine; typical procedure General procedure: To a stirred solution of phenylboronic acid (1.0 mmol), aniline (1.0 mmol), and K2CO3 (2.0 mmol) in deionized H2O (10 mL) at room temperature was added an aqueous suspension of FePd nanowires (3.0 mol % in 3 mL of H2O). The mixture was stirred at room temperature for 5h. After completion of the reaction (as monitored by TLC), 2 M HCl was added and the catalyst was separated by applying an external magnet. The catalyst was washed with EtOAc. The mixture was extracted with EtOAc (2 * 20 mL), dried, and concentrated. The residue was subjected to gel permeation chromatography to afford pure product. |
92% | With potassium carbonate In methanol; water at 20℃; for 8h; | Typical Procedure: N-Arylation of Aniline with PhenylboronicAcid General procedure: In a 50 mL round-bottomed flask, aniline (0.5 mmol), phenylboronicacid (1 mmol), K2CO3 (1.5 mmol), nanocatalyst (30 mol%with respect to aniline substrate) were added and stirred inMeOH-H2O (1:1) under air at r.t. for the required time, monitoringby TLC. After completion, the mixture was diluted with H2O,and the product was extracted with EtOAc (3×). The combined extracts were washed with brine (3×) and dried over Na2SO4.The product was purified by column chromatography (60-120mesh silica gel, eluting with EtOAc-hexane solvent). |
92% | With copper immobilized at polyimide covalent organic framework In methanol; water at 20℃; for 8h; | |
89% | With [Cu0.5(1-isopropylimidazole)2]2[V4O11]; potassium carbonate In methanol at 20℃; for 16h; Sealed tube; | |
86% | With C37H35NiO2P2S2(1+)*F6P(1-); 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 60℃; for 10h; | |
83% | With copper(II) acetate monohydrate; silica gel; potassium carbonate In neat (no solvent) for 1.5h; Milling; Green chemistry; | |
80% | With [2,2]bipyridinyl; nickel(II) chloride hexahydrate; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 20h; | |
78% | With [Ni(bis(2-acetylthiophene)oxaloyldihydrazone(-2H))(H2O)2]2*2H2O; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 40℃; for 15h; | 2.6. General procedure for C N cross-coupling General procedure: A 10 ml borosilicate vial containing arylboronic acid I (1 mmol),N-nucleophile II (2 mmol), complex (15 mol%), DBU (2 mmol) andacetonitrile (1 ml) was stirred at 40C. The progress of the reactionwas monitored by TLC using ethyl acetate and n-hexane as elu-ent. After completion of reaction, the reaction mixture was filteredto remove the heterogeneous metal catalyst and the filtrate wastreated with ethyl acetate (5 ml) and water (5 ml). The separatedorganic layer was washed twice with water (2 × 5 ml), dried overanhydrous sodium sulfate and concentrated to yield a residue. Theresidue was purified by silica gel column chromatography usinghexane/ethyl acetate to yield clean product III. |
76% | With potassium phosphate; 4,4'-dimethyl-2,2'-bipyridines; [Ni(DHASICy)CpCl] In N,N-dimethyl-formamide; toluene at 70℃; for 8h; | 3. Typical procedure for the [Ni(DHASICy)CpCl] catalyzed Chan-Lam coupling. General procedure: A flask was charged with [Ni(DHASICy)CpCl] (4.3 mg, 7.5 μmol), 4,4’-dimethyl-2,2’-bipyridyl (1.4 mg, 7.5 μmol), K3PO4 (159.2 mg, 0.75 mmol), phenylboronic acid (91.4 mg, 0.75 mmol), and a stir bar at r.t. (if an amine was solid, it was added to the flask at this point). Solvent (DMF:75 μL, toluene: 0.925 mL (1.425 mL in the case of solid amine)) was added to the resultant vessel at r.t. and stirred well. Amine (0.375 mmol) in toluene (0.3 mL) was added using a syringe, and an additional 0.2 mL of toluene was used to rinse the flask which had been charged with amine (skipped this process in the case of solid amine). The resultant flask was capped with a reflux condenser and the reaction solution was then heated at 70 for 8 h. The reaction was quenched with H2O (5 mL) at r.t., and the resultant mixture was extracted with EtOAc (10 mL ×3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (30 mL) to afford the cross-coupling product. |
72% | With N-(pyrid-2-yl)benzamide; nickel(II) acetate tetrahydrate; N,N,N',N'-tetramethylguanidine In toluene at 60℃; for 24h; | General procedure for Chan-Lam cross-coupling reaction: General procedure: The 25 mL RB flask was charged with arylboronic acid (1 mmol), N-nucleophile (2 mmol), Ni(OAc)2*4H2O/1a (10 mol % of Ni(II) salt and 20 mol % of 1a), TMG (2 mmol), and toluene (1 ml). The reaction mixture was stirred at 60 °C for 24 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed with brine water. The combined organic phase was dried over anhydrous Na2SO4. After removal of the solvent, the residue was subjected to column chromatography on silica gel using hexane to afford the Chan-Lam product in high purity. |
70% | With triethylamine In dichloromethane at 40℃; for 20h; | |
63% | With potassium acetate In N,N-dimethyl-formamide at 20℃; for 15h; | |
56% | With pyridine; copper diacetate In dichloromethane at 20℃; for 72h; | |
25% | With sodium tosylate In toluene at 80℃; for 18h; Sealed tube; Green chemistry; | |
90 %Spectr. | With L-arginine; palladium dichloride In ethanol; water at 25℃; for 3h; Green chemistry; | General procedure for the amination of phenylboronic acid in thepresence of the PdCl2/l-arginine catalytic system General procedure: Amine (1.0 mmol), phenylboronic acid (1.1 mmol), L-arginine (1 mmol) and PdCl2 (1 mol%) were taken in a 25 ml single neckround-bottomed flask to which 3 ml of water/EtOH (1:1) wasadded. The reaction mixture was stirred for appropriate time at room temperature (Table 2). The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was washed with EtOAc (215 ml) and the organic phase separated, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude material was purified by column chromatography over silica gel to afford the corresponding product in high purity. |
65 %Chromat. | With C21H25CuN3O6S In dichloromethane at 20℃; | |
With C13H11N2O3S(1-)*CF3O3S(1-)*Cu(2+); oxygen In methanol at 50℃; for 12h; | ||
87 %Chromat. | With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 60℃; | |
100 %Chromat. | With C14H11CuF3N2O6S2; oxygen In methanol at 50℃; for 12h; | |
90 %Chromat. | With potassium carbonate In ethanol; water at 70℃; for 2.5h; | |
99 %Chromat. | With C32H32Cl2Cu2N4O4; triethylamine In ethanol for 5h; | 2.5.1. General procedure for C-N coupling reactions General procedure: In a typical run, an oven-dried 10 ml round bottom flask was charged with a known mole percent of catalyst and base, phenylboronic acid (1.2 mmol) and aniline (1.0 mmol) with ethanol (5 ml). The mixture was stirred at ambient temp (25 °C). After the specified time (5 h)stirring was stopped, water (20 ml) was added, and extraction with ether (2×10 ml) was done. The combined ether extract was 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. |
55 %Spectr. | With C30H25N4O(1-)*3C2H3O2(1-)*2Cu(2+) In methanol at 20℃; for 24h; | |
82 %Chromat. | With Cu(at)Ag nanoparticles on TiO2 incorporated nitrogen doped graphene oxide In water at 80℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With C31H26N4PPdS(1+)*Cl(1-); sodium t-butanolate In toluene at 95℃; for 9h; | 2.5.4. General procedure for C-N coupling reactions General procedure: In a typical run, an oven-dried 10 mL round bottom flask wascharged with a known mole percent of catalyst, NaOt-Bu(1.3 mmol), aryl amine (1.2 mmol) and aryl halide (1 mmol) withthe appropriate solvent(s) (4 mL). The flask was placed in a preheatedoil bath at required temp. After the specified time the flaskwas removed from the oil bath, water (20 mL) was added, and extraction with ether (4 10 mL) was done. The combined organiclayers were washed with water (3 10 mL), dried over anhydrousNa2SO4, and filtered. Solvent was removed under vacuum. The residuewas dissolved in hexane and analyzed by GC-MS using Elite-5columns, which are fused silica capillary columns coated with 5%diphenyl and 95% dimethyl polysiloxane. |
100% | With [Pd(N-(naphthyl)-salicylaldimine(-2H))(triphenylphosphine)]; sodium t-butanolate at 145℃; for 15h; | |
96% | With C26H22N3PPdS; sodium t-butanolate; XPhos at 145℃; for 16h; |
94% | With potassium hydroxide; copper(II) oxide In dimethyl sulfoxide at 110℃; for 1.5h; | |
94% | With 0.068 mol% Ni(II) and 0.026 mol% Pd(II) complexed in pyridine grafted demetalated chlorophyll b co-polymer modified SiO2 shell on Fe3O4 core at 120℃; for 5.5h; | |
93% | With C29H25CuIN3OPPd; sodium t-butanolate In toluene at 40℃; for 24h; | |
93% | With Pd(tris[2-(diphenylphosphino)ethyl]phosphine tetrasulfide)(dibenzylideneacetone); caesium carbonate In isopropyl alcohol at 80℃; for 2h; | General experimental procedure for arylation of amines and phenols General procedure: To a stirred solution of aryl halide (1.2mmol) and [Pd(pp3S4)(dba)] (1mol %) in isopropanol (2.5ml) was added nitrogen/oxygen nucleophile (1mmol) followed by Cs2CO3 (2mol %) in the atmosphere of air. The mixture was heated to 80°C and the progress of the reaction was monitored by TLC. After completion, the solvent was evaporated through rotavapour and the crude mixture was washed with dichloromethane-H2O and the organic phase was separated and dried over Na2SO4. The dichloromethane was evaporated followed by flash column purification on silica gel of the crude to obtain the pure products. The products were characterized using 1H, 13C NMR spectroscopy and GC-MS spectroscopy. The characterization data were in good agreement with those described in the literature. |
91% | With potassium hydroxide; air; cadmium(II) acetate dihydrate; ethylene glycol In dimethyl sulfoxide at 110℃; for 1.5h; | |
89% | Stage #1: iodobenzene With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene for 0.75h; Inert atmosphere; Stage #2: 4-methoxy-aniline In toluene at 90℃; for 14h; Inert atmosphere; | |
88% | With nickel(II) chloride hexahydrate; triethylamine at 125℃; for 0.333333h; Microwave irradiation; Neat (no solvent); | General procedure for preparation of N-arylated amines 3: Aryl halide (1 mmol), amine (1.5 mmol), NiCl2·6H2O (10 mol % relative to aryl halide) and triethylamine (1.4 equiv) were taken in a 10 mL pressurized microwave vial with snap on cap. The reaction mixture was subjected to microwave exposure for 20 min at 300 W at appropriate temperature as indicated above. The progress of the reaction was monitored by TLC (Thin Layer Chromatography). After the reaction was completed, the reaction mixture was diluted with DCM and the insoluble catalyst was recovered and recycled without loss of activity. The filtrate was concentrated and subjected to column chromatography with n-hexane and ethyl acetate (2-10% depending upon the product) as eluent to afford the pure product. |
88% | With CuMoO4; caesium carbonate In dimethyl sulfoxide at 90℃; for 22h; Inert atmosphere; | |
86% | With copper(l) iodide; 2,2'-dihydroxybiphenyl; tetra(n-butyl)phosphonium malonate In 1,4-dioxane at 25℃; for 12h; Inert atmosphere; | |
86% | With potassium <i>tert</i>-butylate; copper In N,N-dimethyl-formamide at 170℃; for 24h; Inert atmosphere; | 2.2.6 4-methoxy-N-phenylaniline (7) A DMF solution (15mL) of p-anisidine 6 (200mg, 1.6mmol), Cu (29.60mg, 0.2mmol), tBuOK (198.5mg, 1.6mmol) and iodobenzene (0.090mL, 0.8mmol) was stirred under argon atmosphere at 170°C for 24h. Then, the solution was extracted with CH2Cl2 and purified by column chromatography (silica gel, 10% EtOAc/hexane) to give a yellow solid in 86% yield. 1H NMR (300MHz, CDCl3): δ (ppm)=7.19 (t, J=7.9Hz, 2H), 7.06 (d, J=8.9Hz, 2H), 6.81-6.90 (m, 5H), 3.78 (s, 3H). 13C NMR (75MHz, CDCl3). δ (ppm)=155.13, 145.08, 135.66, 129.21, 122.06, 119.43, 115.54, 114.57, 55.47. HRMS (APCI): calcd for C13H13NO [M+H]+ 200.1075, found 200.1067. |
85% | With iron(III) chloride; caesium carbonate; copper(II) oxide; 1,1'-bi-2-naphthol In N,N-dimethyl-formamide at 90℃; for 12h; Inert atmosphere; | |
85% | With palladium 10% on activated carbon; sodium t-butanolate; CyJohnPhos In <i>tert</i>-butyl alcohol at 80℃; Inert atmosphere; | |
85% | With toluene-4-sulfonic acid at 165℃; for 0.583333h; Ionic liquid; Microwave irradiation; | 4.1 General procedure for the MW-assisted C-N cross coupling General procedure: In a new sealed pressure regulation 10-mL pressurized vial were placed aryl halide (1 mmol), p-toluenesulfonic acid (1 mmol, 0.172 g), [DBU][HOAc] (1.5 mL), N-nucleophile (2 mmol), and a Teflon-coated magnetic stir bar. The vessel was closed with a snap-on cap, stirred at room temperature for 5 min and then placed into the MW cavity. Microwave irradiation of 100 W at a set temperature of 165°C was used and the reaction mixture was held under these conditions for the specified time. After completion of the reaction (monitored through TLC), the mixture was cooled to room temperature and was poured to a vessel containing distilled water. This was extracted with ethyl acetate (3*10 mL) and the combined organic phase was washed with brine (2*10 mL), dried over Na2SO4, and was concentrated under rotary vacuum evaporator. The crude product was purified by column chromatography using a mixture of ethyl acetate/n-hexane as eluent. |
85% | With potassium carbonate In methanol; water Reflux; Green chemistry; | |
82% | With copper(l) iodide; potassium carbonate; <i>L</i>-proline In dimethyl sulfoxide at 90℃; for 36h; | |
82% | With copper(l) iodide; potassium carbonate; <i>L</i>-proline In dimethyl sulfoxide at 90℃; for 36h; | |
82% | With C24H22N6Ni; sodium t-butanolate In N,N-dimethyl-formamide; acetonitrile at 45℃; for 24h; Inert atmosphere; Schlenk technique; | |
78% | With caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane for 48h; Reflux; | |
77% | With copper(l) iodide; C19H19N5O; potassium carbonate In water at 100℃; for 24h; Green chemistry; | |
76% | With potassium phosphate; tris(1,10-phenanthroline)ruthenium(II) complex; [Ni(2,2′:6′,2''-terpyridine)(pyridine)(CH3CN)2](PF6)2 In acetonitrile for 24h; Irradiation; | |
67% | With lanthanum(III) oxide; potassium hydroxide; N,N`-dimethylethylenediamine In dimethyl sulfoxide at 110℃; for 12h; Inert atmosphere; | |
60% | With potassium hydroxide In neat (no solvent) at 90℃; for 8h; | |
57% | With hydrazine hydrate; [Ru(1,2-bis(diphenylphosphino)benzene )(CO)2Cl2] at 130℃; for 24h; | |
54% | With iron(III) oxide; <i>L</i>-proline; sodium t-butanolate In dimethyl sulfoxide at 135℃; for 24h; | |
51% | With iron(III) oxide; copper acetylacetonate; caesium carbonate In water; dimethyl sulfoxide at 150℃; for 0.5h; sealed vial; Microwave irradiation; | |
38% | With copper(l) iodide; cesium acetate In dimethyl sulfoxide at 90℃; for 24h; Inert atmosphere; | |
31% | Stage #1: 4-methoxy-aniline With copper(II) acetate monohydrate In dimethyl sulfoxide at 20℃; for 0.5h; Stage #2: With phenylhydrazine In dimethyl sulfoxide at 20℃; for 0.5h; Stage #3: iodobenzene In dimethyl sulfoxide at 20 - 90℃; | |
100 %Chromat. | With C18H14N2Pd; sodium t-butanolate In 1,4-dioxane at 90℃; for 12h; | 4.7 General procedure for C-N coupling reactions 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 dioxane (4 mL). The flask was placed in a preheated oil bath at 90 °C. 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 hexane and analyzed by GC-MS. |
76 %Chromat. | With copper(l) iodide; cesium fluoride; pyrrole-2-carboxyl acid In dimethyl sulfoxide at 50℃; for 24h; Inert atmosphere; Glovebox; Sealed tube; | |
With potassium carbonate at 110℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With tris(dibenzylideneacetone)dipalladium (0); dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; 1-methyl-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine In toluene at 150℃; for 0.25h; microwave irradiation; | |
98% | With sodium t-butanolate; DavePhos In toluene at 105℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With lithium diisopropyl amide In tetrahydrofuran at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dicyclohexyl(2′,4′,6′-tri-isopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphane; chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl]palladium(ll); sodium tertiary butoxide In toluene at 110℃; Inert atmosphere; | |
98% | With sodium tertiary butoxide; dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine In toluene at 110℃; for 1h; | |
97% | With C29H25CuIN3OPPd; sodium tertiary butoxide In toluene at 40℃; for 24h; |
97% | With C54H70NO5PPdS; sodium tertiary butoxide In tetrahydrofuran; toluene at 110℃; for 24h; Sealed tube; Inert atmosphere; | |
96% | With dicyclohexyl(2′,4′,6′-tri-isopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphane; C47H63NO2PPd(2+)*CH3O3S(1-); sodium tertiary butoxide In toluene at 100℃; for 0.0833333h; | |
96% | With dicyclohexyl(2′,4′,6′-tri-isopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphane; [(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′- triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate methanesulfonate; sodium tertiary butoxide In toluene at 100℃; for 0.0833333h; Inert atmosphere; | 4 General Procedure for Catalyzed Arylation of Primary Amines General procedure: An oven-dried, resealable tube equipped with a magnetic stir bar and Teflon septum was charged with OMsBrettPhos precatalyst (0.01-0.5 mol %), BrettPhos (0.01-0.5 mol %) NaOt-Bu (115 mg, 1.20 mmol, 1.20 eq), aryl halide (1.00 mmol, 1.00 eq) and amine (1.20 mmol, 1.20 eq) if they are solids. The tube was evacuated and backfilled with argon. This process was repeated three times. Then the aryl halide and amine were added if they are liquid, followed by dioxane (1 mL). The reaction was heated at 100° C. and monitored by thin-layer chromatography or gas chromatography, observing the disappearance of aryl halide. After completion the reaction was cooled to room temperature, diluted with ethyl acetate, and filtered through a plug of Celite. The solvent was removed via rotary evaporation and the crude product was then purified by flash chromatography. See FIG. 14. |
95% | With potassium hydroxide In lithium hydroxide monohydrate at 20℃; for 6h; Green chemistry; | |
94% | With 0.068 mol% Ni(II) and 0.026 mol% Pd(II) complexed in pyridine grafted demetalated chlorophyll b co-polymer modified SiO2 shell on Fe3O4 core at 120℃; for 6h; | |
91% | With tripotassium phosphate tribasic; copper (I) iodide; N',N'-diphenyl-1H-pyrrole-2-carbohydrazide In diethylene glycol at 50℃; for 1h; Sealed tube; | |
91% | With Cupric sulfate; N',N'-diphenyl-1H-pyrrole-2-carbohydrazide; potassium carbonate In ethanol at 20℃; for 48h; Sealed tube; | 1 Synthesis of Ν-p-methoxyphenylaniline The 234 mg (1mmol) 4 - iodo anisole, 93 mg (1mmol) aniline, 25 mg (0.1mmol) CuSO4· 5H2O, 14 mg (0.1mmol) ligand L1, 138mg (1mmol) K2CO3, 2 ml EtOH, add 10 ml reaction tube, sealing, 20 °C reaction under the condition 48h. After the stop of the reaction, water, extracted with ethyl acetate, washing, saturated salt water washing, after drying with anhydrous sodium sulfate, filtered, the filtrate is distilled under reduced pressure, purification by silica gel column column chromatography separation, to be N - methoxy phenylaniline 181 mg, yield 91%. |
90% | With tripotassium phosphate tribasic; copper (I) iodide In diethylene glycol at 70℃; for 14h; Sealed tube; | Synthesis of 1a-s and 2a-q; General Procedure General procedure: A 10 mL vial was charged with CuI (9.5 mg, 0.05 mmol), PSAP (30 mg,0.05 mmol, > 100 mesh), K3PO4 (424 mg, 2 mmol), aryl bromides (1mmol), amines (1.5 mmol), DEG (2 mL), and a magnetic stir bar. The vessel was sealed with a septum and placed into a preheated oil batchat 70 °C. The reaction mixture was held at this temperature for 14 hours. After cooling to r.t., the reaction mixture was filtered, and the precipitates were thoroughly washed with water and EtOAc (3 × 20mL). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Theresidue was purified using flash column chromatography on silica gel(eluting with petroleum ether/EtOAc) to afford the desired products. |
90% | With potassium hydroxide In N,N-dimethyl-formamide at 100℃; for 5h; Inert atmosphere; Green chemistry; | |
85% | With potassium carbonate In ethanol; lithium hydroxide monohydrate at 20℃; UV-irradiation; Green chemistry; | |
84% | With copper(II) bis(2,4-pentanedionate); potassium hydroxide In glycerol at 100℃; for 15h; Inert atmosphere; Green chemistry; | General procedure for the synthesis of secondary amines General procedure: To a 25 ml round bottomed flask containing glycerol (5 ml) were added aryl halide (1 mmol), amine (1.5 mmol), Cu(acac)2 (2 mol %), and KOH (2 mmol). The resulting mixture was heated at 100 C for 15 h under N2 atmosphere. After completion, the reaction mixture was cooled to room temperature and was extracted with diethylether to isolate the reaction products. The combined organic layers were washed twice with brine solution (10 ml 2) and dried over anhydrous sodium sulfate followed by the evaporation of solvent under reduced pressure to yield the crude product. The remaining glycerol layer containing copper catalyst was reused for recycling experiments. The crude product was purified by column chromatography over silica gel using ethyl acetate and hexane (2:8) as eluents; conversion and selectivity of the product was determined by GC-MS results |
83% | With [Cu8(H){S2P(OiPr)2}6](PF6); Cs2CO3 In N,N-dimethyl-formamide at 120℃; for 24h; | |
83% | With potassium hydroxide In dimethyl sulfoxide at 140℃; for 14h; Inert atmosphere; | General procedure for the N-arylation of aromatic amineswith aryl halide General procedure: In an oven dried 100 mL round bottom flask, Cu-grafted cat-alyst (0.05 g), aryl halide (1 mmol), aromatic amines (1.2 mmol),KOH (1 mmol), and 10 mL DMSO were stirred under nitrogen atmo-sphere, at 140C. The reaction mixtures were collected at differenttime intervals and identified by GC-MS and quantified by GC.After the completion of the reaction, the catalyst was filtered offand washed with water followed by acetone and dried in oven.The filtrate was extracted with ethyl acetate (3 × 20 mL) and thecombined organic layers were dried with anhydrous Na2SO4byvacuum. The filtrate was concentrated by vacuum and the result-ing residue was purified by column chromatography on silica gelto provide the desired product. |
82% | With C104H96N16O8Pd2(4+)*4NO3(1-); sodium tertiary butoxide In toluene at 110℃; for 16h; | Experimental procedure for Buchwald-Hartwig coupling reaction General procedure: In a 50 mL round bottom flask, the mixture of iodobenzene (2 mmol), amine (2.4 mmol), t-BuONa (3 mmol), and 1 as catalyst (0.05 mol %) was taken in toluene (10 mL). The reaction mixture was then heated to 110°C and continued for 12-18 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction the aqueous reaction mixture was extracted with ethyl acetate, washed with brine, dried over MgSO4, concentrated, and purified by column chromatography on silica gel which afforded corresponding coupling products (yield 75-96%). |
81% | With potassium hydroxide In dimethyl sulfoxide at 140℃; for 14h; Inert atmosphere; | 2.4. General procedure for the amination of aromatic amines with aryl halides General procedure: In an oven dried 100 mL RB flask, polymer supported Cu(II)catalyst (50 mg, 0.0098 mmol), aryl halide (1 mmol), aromatic amines (1.2 mmol), KOH (1 mmol), and 10 ml DMSO were stirred under nitrogen atmosphere, at 140 °C. The reaction mixtures were collected at different time intervals and identified by GCMS and quantified by GC. After the completion of the reaction, the catalyst was filtered off and washed with water followed by acetone and dried in oven. The filtrate was extracted with ethyl acetate(3 x 20 mL) and the combined organic layers were dried with anhydrous Na2SO4 by vacuum. The filtrate was concentrated by vacuum and the resulting residue was purified by column chromatography on silica gel to provide the desired product. |
80% | With potassium carbonate In methanol; lithium hydroxide monohydrate for 12h; Reflux; Inert atmosphere; | 2.3 General procedure for the N-arylation of aryl amines with aryl halides General procedure: In a 25ml round bottom flask a mixture of 4:1 methanol/water, aryl halide (1mmol), Resin-CuNPs (0.2g), K2CO3 (3mmol) and aryl amine (1.2mmol) were taken and heated at reflux temperature for 12-24h in an oil bath under inert conditions. Resin beads were filtered off at the end of reaction while the solution was still hot. After a work up with dichloromethane and water, the organic layer was separated, dried over anhydrous Na2SO4. The crude products obtained after removal of solvent (Scheme 1) were purified by column chromatography (ethyl acetate: hexane) and identified by mass or 1H NMR spectroscopy (see ESI). |
80% | With nickel(II) chloride ethylene glycol dimethyl ether complex; Ir[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]2(4,4'-di-tert-butyl-2,2'-bipyridyl)PF6; triethylamine; 4,4'-di-tert-butyl-2,2'-bipyridine In acetonitrile at 23 - 25℃; for 24h; Sealed tube; Irradiation; chemoselective reaction; | |
79% | With potassium hydroxide In N,N-dimethyl-formamide at 130℃; for 1.63333h; | |
78% | With copper (I) iodide; tetrabutylammonium bromide; potassium hydroxide In lithium hydroxide monohydrate at 70℃; for 16h; Green chemistry; | 2.4 General protocol for C-N coupling reaction General procedure: A 10 mL of vial was charged with CuI (10 mg, 0.05 mmol), PSP (0.25 mmol, size less than 90 μM), TBAB (40 mg, 0.25 mmol), base (1.0 mmol), aryl halides (0.5 mmol), arylamine (2.0 mmol), H2O (1.0 mL), and a magnetic stir bar. The vessel was sealed with a septum and placed into an oil bath, which was preheated to 70 °C (90 °C for alkyl amine, 120 °C for imidazole). The reaction mixture was stirred for another 16 h (8 h for imidazole). After allowing the mixture to cool to room temperature, the reaction mixture was filtrated, the precipitates were washed with water and ethyl acetate thoroughly. The filtrate was extracted with ethyl acetate (3×25 mL). The combined organic phases was washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatograph on silica gel to afford the desired products. |
78% | With copper (I) iodide; C19H19N5O; potassium carbonate In lithium hydroxide monohydrate at 100℃; for 24h; Green chemistry; | |
78% | With 1,1,3,3-tetramethylguanidine In acetonitrile for 24h; Inert atmosphere; Sealed tube; Sonication; Irradiation; | |
77% | With potassium hydroxide In dimethyl sulfoxide at 120℃; for 14h; Inert atmosphere; | General procedure for the copper-catalyzed N-arylation of amines with aryl iodides To a mixture of 0.05 g catalyst and aryl iodide (1.0 mmol) in9.0 cm3 DMSO, amine (1.2 mmol) and KOH (1.5 mmol)was added and the mixture was vigorously stirred at 120 Cfor appropriate time under a dry nitrogen atmosphere. Afterthe completion of the reaction, the catalyst was filtered offand washed with water followed by acetone and dried inoven. The filtrate was extracted with ethyl acetate(3 9 20 cm3) and the combined organic layers were driedwith anhydrous Na2SO4 by vacuum. The filtrate was concentratedby vacuum and the resulting residue was purifiedby column chromatography on silica gel to provide thedesired product. All the products are known and the spectroscopicdata (FT-IR and NMR) and melting points wereconsistent with those reported in the literature [26]. |
73% | With potassium hydroxide In dimethyl sulfoxide; <i>tert</i>-butyl alcohol at 110℃; for 24h; | |
72% | With potassium hydroxide In dimethyl sulfoxide at 130℃; for 18h; | |
71% | With copper (I) iodide; N-acetyl-D-glucosamine; Cs2CO3 In lithium hydroxide monohydrate; dimethyl sulfoxide at 110℃; for 24h; | |
66% | With potassium carbonate In lithium hydroxide monohydrate; dimethyl sulfoxide at 110℃; for 24h; | |
65% | With copper (I) iodide; 2,2'-dihydroxybiphenyl; tetrabutylphosphonium malonate In 1,4-dioxane at 25℃; for 12h; Inert atmosphere; | |
60% | With copper(II) oxide; potassium hydroxide In dimethyl sulfoxide; <i>tert</i>-butyl alcohol at 110℃; for 24h; Inert atmosphere; | |
60% | With copper (I) iodide; N,N′-di-β-D-glucopyranosylethylenediamine; Cs2CO3 In lithium hydroxide monohydrate at 100℃; for 24h; | General procedure of CuI/L5 catalyzed Ullmann-type C-N coupling of aryl halides andnitrogen nucleophiles in water General procedure: To a stirred solution of H2O (5 ml) were added CuI (0.1 mmol, 19 mg), aryl halides (1.0 mmol),nitrogen nucleophiles (1.2 mmol), Cs2CO3 (2 mmol, 651 mg) and L5 (0.1 mmol) were added tothe solution, subsequently the mixture was heated to 100 °C under air and stirred for 24 h. Whenthe reaction was finished, the mixture was cooled and partitioned by adding the ethyl acetate (20ml) and water (20 ml). Then, the organic phase was separated and the aqueous phase wasextracted with ethyl acetate (20 ml) twice. The combined organic phases were washed withsaturated brine, dried over Na2SO4, and concentrated in vacuo. Then the crude product waspurified by column chromatography through silica gel, eluting with ethyl acetate/petroleum ethersolvent mixture, to give the pure product. |
23% | With Cs2CO3; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane for 144h; Reflux; | |
22% | With potassium hydroxide; copper(II) oxide In dimethyl sulfoxide at 110℃; for 1.2h; | |
58 %Chromat. | With potassium-t-butoxide; oxygen In N,N-dimethyl-formamide at 45℃; for 24h; Irradiation; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With di-tert-butyl{2′-isopropoxy-[1,1′-binaphthalen]-2-yl}phosphane; potassium phosphate; palladium diacetate; phenylboronic acid In butan-1-ol at 110℃; for 15h; Inert atmosphere; | |
77% | With (R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl di-t-butylphosphine; bis(tri-ortho-tolylphosphine)palladium(0); sodium t-butanolate In toluene at 25℃; for 24h; Inert atmosphere; | |
69% | With sodium t-butanolate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride In 1,4-dioxane at 110℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium <i>tert</i>-butylate; DavePhos In toluene at 80℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With caesium carbonate In toluene at 100℃; for 15 - 20h; | 2.6.15 Pd(OAc)2/2-Catalyzed Amination of Aryl Iodides (Table 6). General Procedure: An oven-dried Schlenk flask equipped with a magnetic stirring bar was charged with Pd(OAc)2 (x mol %, see Table 6) and NaO-t-Bu (1.5 mmol) or Cs2CO3 (1.5 mmol). Amine (1.2 mmol) and aryl iodide (1.0 mmol) were also added at this time if they were solids. The flask was capped with a rubber septum, evacuated and then flushed with argon. This cycle was repeated three times. Ligand 2 (2x mol %, see Table 6) was then added via syringe from a stock solution. Aryl iodide (if a liquid, 1.0 mmol), amine (if a liquid, 1.2 mmol) and toluene (3 mL) were then successively added by syringe. The reaction mixture was heated at a temperature indicated in Table 6 until the starting material had been completely consumed as judged by TLC (15-20 hours). The mixture was cooled to room temperature, adsorbed onto silica gel and then purified by column chromatography (hexanes/ethyl acetate as eluent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 2-[2-(dicyclohexylphosphino)-phenyl]-1-methyl-1H-indole; palladium diacetate; potassium carbonate; phenylboronic acid In <i>tert</i>-butyl alcohol at 110℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: triethoxy(4-methoxyphenyl)silane With tetrabutyl ammonium fluoride; copper diacetate; tris(pentafluorophenyl)phosphine In dichloromethane; water at 20℃; for 0.0833333h; Molecular sieve; Stage #2: aniline With oxygen In dichloromethane; water at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In xylene at 80℃; for 22h; | 3 EXAMPLE 3N',iV",N'"-Triphenyl-N',N",N'"-(tri-4-methoxyphenyl)melem 4A mixture of cyameluric chloride (831 mg, 3.01 mmol) and N-4-methoxyphenyl- phenylamine (4.19 g, 21.1 mmol) in xylenes (50 mL) was heated at 80 °C for 22 h. The resulting dark coloured mixture was collected on a sintered glass funnel to give a solid residue. The residue was washed with H2O (two times) and then EtOH (two times). The residue was taken up in CH2Cl2, filtered and concentrated to give a solid residue. The residue was purified by flash chromatography (EtOAc/CH2Cl2, gradient; 0:100, 2.5:97.5 then 4:96) to yield N',iV",N'"-triphenyl-N',N",N'"-(tri-4-methoxyphenyl)melem 4 (1.68 g, 73%) as a pale orange solid. A portion of this material was further purified by, firstly, recrystallisation (CH2Cl2/toluene) and, secondly, by sublimation (350 °C, 0.025 mBar): rap. 487 - 496 °C (DSC); Rf0.17 (5:95 EtOAc/CH2Cl2); 1H NMR(CD2Cl2, 400 MHz) £3.77 (s, 9H), 6.88 (d, J= 8.8 Hz, 6H), 7.16 (d, J= 8.8 Hz, 6H), 7.20 - 7.29 (m, 9H), 7.33 - 7.40 (m, 6H); 13C NMR (CD2Cl2, 100 MHz) 555.91, 115.20, 127.82, 128.07, 129.26, 129.92, 136.05, 143.52, 159.22, 165.37; HRMS (EI) m/z 763.2891 C45H35Ni0O3 [M-H]+" requires 763.2888. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 4-methoxy-aniline With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 20℃; for 0.166667h; Inert atmosphere; Stage #2: phenyl 1H-imidazole-1-sulfonate In toluene at 105℃; for 17h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With indium; copper diacetate In methanol at 70℃; for 3h; | Typical procedure: A mixture of phenyl azide (0.1 g, 1 mmol), phenyl boronic acid (0.1 g, 1 mmol), indium metal (1.5 mmol, granule) in methanol was taken in a round bottom flask. To this solution, Cu(OAc)2 (1 mmol) was added and the resulting mixture was allowed to stir under reflux at 70 °C for the appropriate time (Table 1). After complete conversion as confirmed by TLC, the mixture was filtered through a pad of Celite with an excess of methanol. Removal of the solvent followed by purification on silica gel (Merck, 100-200 mesh, ethyl acetate/hexane, 2:98) afforded pure diphenyl amine (0.112 g) in 80% yield. |
67% | In 5,5-dimethyl-1,3-cyclohexadiene at 140℃; Inert atmosphere; | General Procedure for synthesis of 3 General procedure: The flask was charged with organoboronic acids 1 (1 mmol) and xylene (5 ml) under nitrogen. The mixture was heated to 100 °C and the solution of organic azides (1.5 mmol) in xylene (5 ml) was added slowly. After this, the mixture was heated to 140 °C and then stirred at this temperature for 24-48 h. The mixture was then cooled to room temperature and CH3OH (2 ml) was added. The resulting mixture was stirred for another 10 minute. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using petroleum ether/ethyl acetate as the eluent to afford 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With di-tert-butyl{2′-isopropoxy-[1,1′-binaphthalen]-2-yl}phosphane; potassium phosphate; palladium diacetate; phenylboronic acid In butan-1-ol at 110℃; for 15h; Inert atmosphere; | |
77% | With 2-[2-(dicyclohexylphosphino)-phenyl]-1-methyl-1H-indole; palladium diacetate; potassium carbonate; phenylboronic acid In <i>tert</i>-butyl alcohol at 110℃; for 24h; Inert atmosphere; | |
39% | With (1,3-bis(2,6-diisopropylphenyl)imidazolidene)Ni(styrene)2; lithium tert-butoxide In 1,4-dioxane for 3h; Inert atmosphere; Heating; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate In toluene at 100℃; for 24h; Glovebox; Inert atmosphere; | 1.1 1. Synthesis of Intermediate 1 To a 250mL two-necked flask, add the first compound (3.12g, 10mmol), the second compound (4.38g, 22mmol), tris(dibenzylideneacetone)dipalladium (180mg, 0.2mmol) and tri-tert-butylphosphine tetrafluoro borate (116 mg, 0.4 mmol), then NaOtBu (2.40 g, 25 mmol) was added to the glove box, and toluene (100 mL) that had been dehydrated and deoxygenated in advance was added under a nitrogen atmosphere, and the reaction was carried out at 100 ° C for 24 hours, and cooled. After reaching room temperature, the reaction solution was poured into ice water (200 mL), extracted with dichloromethane three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was spin-dried, added with silica gel for sample preparation, and separated and purified by column chromatography to obtain the intermediate The mass of body 1 was 4.72 g, a pale yellow powdery solid, the yield was 86%, |
67% | With tri-tert-butyl phosphine; palladium diacetate; sodium t-butanolate In toluene for 1h; Inert atmosphere; Reflux; | |
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate In toluene Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: (±)-7-(4-methoxyphenyl)-7-azabicyclo[4.1.0]heptan-2-one With 4-nitro-benzoic acid In acetonitrile at 80℃; for 1h; Inert atmosphere; Stage #2: With sodium carbonate In acetonitrile Inert atmosphere; regioselective reaction; | General experimantal procedure for the synthesis of aryl amines: General procedure: In a srew capped 5.0 ml vessel, a mixture of aziridine (0.50 mmol) and p-NBA (0.38 mmol) in 1.0 ml of acetonitrile was heated at 80 oC for desired time under argon. After complete reaction (TLC), 5.0 ml concentrated solution of sodiumcarbonate was added and stirred for few minutes. The solution was extracted with ethylacetate (20.0 x 2 ml) and washed with brine. Evaporation of the organic layer followed by small silica gel column chromatography (eluted with hexanes/ethylacetate) to afford pure desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tris-(dibenzylideneacetone)dipalladium(0); Nonafluorobutanesulfonyl fluoride; caesium carbonate; XPhos In toluene at 105℃; for 15h; Inert atmosphere; | |
60% | Stage #1: 4-methoxy-phenol With sodium hydride In acetonitrile at 20℃; for 0.5h; Stage #2: With 2,2-dichloro-1,3-dicyclohexylimidazolidine-4,5-dione In acetonitrile at 20℃; for 1h; Stage #3: aniline With copper(l) iodide; triethylamine In acetonitrile at 80℃; for 24h; | General Procedure for the One-Pot Cross-Coupling ofPhenols and Amines Using DCID Catalyzed by CuI General procedure: Typically for the synthesis of 5a, to an oven-dried 25 mL roundbottomflask containing dry MeCN (5 mL) were added phenol (1mmol) and NaH (0.024 g, 1 mmol). The reaction mixture stirredfor 30 min at room temperature, and then DCID (0.330 g, 1mmol) was added. The reaction mixture was stirred for 1 h atroom temperature, and completion of the reaction was monitoredby TLC. After completion of the reaction, amines (1.6mmol), Et3N (0.101 g, 1 mmol), and CuI (0.038 g, 20 mol%) wereadded, and the reaction mixture was stirred at 80 °C for 24 h(TLC monitoring). For the purification of products, chromatographyon silica gel was performed (EtOAc-heptane, 1:3). Structureof the diaryl amines was confirmed by comparison ofmelting point and NMR spectra reported in the literature (seeSupporting Information). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With styrene; Au-Pd/Al2O3 In 1,3,5-trimethyl-benzene at 130℃; for 24h; Schlenk technique; Inert atmosphere; | |
81% | With dmap; oxygen; palladium diacetate In toluene at 135℃; for 37h; Sealed tube; | |
91 %Chromat. | With gold-palladium bimetallic nanoparticles supported on TiO2 In 1,3,5-trimethyl-benzene at 160℃; for 12h; Inert atmosphere; Schlenk technique; |
With palladium on activated charcoal; toluene-4-sulfonic acid In 1,3,5-trimethyl-benzene at 160℃; for 18h; Inert atmosphere; Schlenk technique; | ||
With styrene; 10 wt% Pd(OH)2 on carbon In toluene at 140℃; Flow reactor; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In dichloromethane at 20℃; for 6h; Molecular sieve; | General experiment procedure of aromatization General procedure: To a solution of compound 2(0.108 g, 0.5 mmol) in solvent (8 mL) was added amine (0.6 mmol) and 4A molecule sieve (4 g). The mixture was stirred at room temperature, tracked byTLC. After compound 2 disappeared, the mixture was filtered and the filtrate was concentrated, the products were obtained by flash chromatography using petroleum ether and ethyl acetate (5/1 to 3/1, V/V) as eluent. All the productshave been previously reported in references and were conformed by comparing melting points and 1H NMR or MS data and spectra with literatures. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With iron(II) phthalocyanine; copper(l) chloride In acetonitrile at 0℃; | 3 Synthesis of 4-methoxydiphenylamine Reaction flask was added 4-methoxyaniline 0.123 g (1 mmol), phenylhydrazine 0.16 g(1.5 mmol), FePc 0.057 g (0.1 mmol), CuCl0.01 g (0.1 mmol) and 10 ml of acetonitrile0 °C reaction; TLC until complete reaction was followed over; after the reaction, thecrude product obtained was purified by column chromatography (petroleum ether: ethylacetate = 100: 1) to give the desired product (90% yield). |
80% | With tetrabenzoporphyrinatocobalt(II); copper diacetate In acetonitrile at 0℃; for 13h; chemoselective reaction; | 3.3 4.2.1. General procedure for N-arylation of amines (2) with arylhydrazines (1). General procedure: Into a 25 mL round-bottom flask, amine (2) (1 mmol), Cu(OAc)2 (0.02 g, 0.1 mmol) and acetonitrile (4 mL) were added, the mixture was stirred and cooled to 0 °C. Then, CoPc (0.057 g, 0.1 mmol) was added, the solution of arylhydrazine (1) (2 mmol) in acetonitrile (2 mL) was added successively at a rate of 0.2 mmol per hour while stirring for 13 h in air. After completion of the reaction monitored by TLC analysis (developing solvent: ethyl acetate/petroleum ether (1:8)), the mixture was filtered, concentrated, and the residue was further purified by column chromatography using ethyl acetate/petroleum ether (1:100) as eluent to afford N-aryl amine 3. |
73% | Stage #1: 4-methoxy-aniline With copper diacetate In acetonitrile at -5℃; for 0.25h; Stage #2: With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In acetonitrile at -5℃; for 0.0833333h; Stage #3: phenylhydrazine In acetonitrile at -5℃; for 3.33333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With SingaCycle-A3; potassium hexamethylsilazane In 1,4-dioxane; toluene at 100℃; for 12h; Schlenk technique; Inert atmosphere; | |
89% | With bis(1,5-cyclooctadiene)nickel (0); sodium hexamethyldisilazane; 1,2-bis-(dicyclohexylphosphino)ethane In toluene at 100℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With copper; potassium carbonate In nitrobenzene at 210℃; for 24h; Inert atmosphere; | 2.2.7 9-butyl-N3,N6-bis(4-methoxyphenyl)-N3,N6-diphenyl-9H-carbazole-3,6-diamine (8) A mixture of 5 (237.5mg, 0.5mmol), 7 (209.2mg, 1.1mmol), K2CO3 (276.4mg, 2.0mmol), and Cu (36.5mg, 0.2mmol) dissolved in nitrobenzene (15mL) was stirred under argon atmosphere at 210°C for 24h. The solution was then extracted with CH2Cl2 and purified by column chromatography (silica gel, 50% CH2Cl2/hexane) to give a green solid in 62% yield. 1H NMR (300MHz, DMSO-d6): δ (ppm)=7.82 (s, 2H), 7.56 (d, J=8.8Hz, 2H), 7.20 (d, J=8.8Hz, 2H), 7.14 (t, J=7.8Hz, 4H), 7.04 (d, J=8.5Hz, 4H), 6.86 (d, J=8.8Hz, 4H), 6.71-6.77 (m, 6H), 4.22-4.40 (m, 2H), 3.69 (s, 6H), 1.68-1.78 (m, 2H), 1.27-1.40 (m, 2H), 0.89 (t, J=7.34Hz, 3H). 13C NMR (75MHz, DMSO-d6): δ (ppm)=155.36, 149.12, 140.79, 138.95, 137.80, 128.96, 126.29, 125.53, 122.74, 119.50, 118.85, 118.69, 114.83, 110.50, 55.19, 42.35, 30.90, 19.90, 13.77. HRMS (APCI): calcd for C42H39N3O2 [M+H]+ 618.3121, found 618.3116. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With styrene; 5%-palladium/activated carbon; 10 wt% Pd(OH)2 on carbon; hydrogen In cyclohexanone; toluene at 140℃; for 168h; | 1-2; 1-3 Pd / C (100mg, Pd: 5wt%, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., Product Name: Palladium-Activated Carbon (5%)) and Celite (1.00g, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., Product name: Celite No.545) is mixed well and mixed well. The resulting mixture is used as the first catalyst cartridge. It was housed in (inner diameter 5.0 mm, length 100 mm). Similarly, Pd (OH) 2 / C (855mg, Pd: 20wt%, 50% water content, Made by Fujifilm Wako Pure Chemical Industries, Ltd., Product name: Palladium hydroxide-activated carbon (Pd 20%) (approx. 50% hydrous)) And Celite (8.55g, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., Product name: Celite No.545) is mixed well and mixed well. The resulting mixture is used in a second catalyst cartridge. It was housed in (inner diameter 10.0 mm, length 200 mm). The prepared first and second catalyst cartridges were connected to the multi-stage continuous flow reactor shown in FIG. 2, respectively. Heat the first catalyst cartridge to 140 ° C and Hydrogen gas is circulated from the top at a flow rate of 5.0 ml / min to perform pretreatment reduction of the catalyst, and then at 140 ° C. and 0.2 MPa. Toluene solution containing phenol (0.24M) at a flow rate of 0.10 ml / min, Hydrogen gas was supplied at a flow rate of 5.0 ml / min. The reaction solution was collected from the outlet of the pressure control valve and analyzed by gas chromatography. After confirming that the reaction has stabilized Supply the reaction solution containing unreacted hydrogen gas to the gas-liquid separator, A toluene solution of cyclohexanone from which hydrogen had been removed was obtained. Toluene solution containing this cyclohexanone and p-anisidine (0.20M) and styrene (0.40M) Toluene solution containing Preheated piping set to 140 ° C, 0.5 MPa via the mixing section (Inner diameter 1.0 mm, length 100 cm) and continuously supplied to the second catalyst cartridge. The reaction solution is collected every 30 minutes from the outlet of the pressure control valve. Analysis by gas chromatography was performed. After confirming that the series of reactions was stabilized from the analysis results, The reaction solution was collected from the outlet of the reactor for 168 hours. The solvent was distilled off from the reaction solution thus obtained under reduced pressure. By sufficiently drying the obtained white solid under reduced pressure, The desired 4-methoxydiphenylamine (38.6 g) was obtained (yield 96%). |
74% | With palladium 10% on activated carbon; sodium formate; trifluoroacetic acid In toluene at 140℃; for 24h; Inert atmosphere; | |
61% | Stage #1: phenol With sodium hydride In acetonitrile at 20℃; for 0.5h; Stage #2: With 2,2-dichloro-1,3-dicyclohexylimidazolidine-4,5-dione In acetonitrile at 20℃; for 1h; Stage #3: 4-methoxy-aniline With copper(l) iodide; triethylamine In acetonitrile at 80℃; for 24h; | General Procedure for the One-Pot Cross-Coupling ofPhenols and Amines Using DCID Catalyzed by CuI General procedure: Typically for the synthesis of 5a, to an oven-dried 25 mL roundbottomflask containing dry MeCN (5 mL) were added phenol (1mmol) and NaH (0.024 g, 1 mmol). The reaction mixture stirredfor 30 min at room temperature, and then DCID (0.330 g, 1mmol) was added. The reaction mixture was stirred for 1 h atroom temperature, and completion of the reaction was monitoredby TLC. After completion of the reaction, amines (1.6mmol), Et3N (0.101 g, 1 mmol), and CuI (0.038 g, 20 mol%) wereadded, and the reaction mixture was stirred at 80 °C for 24 h(TLC monitoring). For the purification of products, chromatographyon silica gel was performed (EtOAc-heptane, 1:3). Structureof the diaryl amines was confirmed by comparison ofmelting point and NMR spectra reported in the literature (seeSupporting Information). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With η5‐cyclopentadienyl‐η3‐1‐phenylallylpalladium; potassium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 80℃; for 24h; Inert atmosphere; | 3 Example 3 General procedure: I n this Example, an aryl fluorosulfonate is reacted with aniline as shown in Equation 7: Equation 7 [0051] The present Example is performed in a nitrogen- filled glovebox. To each of 12 30 mL vials are added one of the aryl fluorosulfonates selected from Table 1 where R in Equation 7 represents one or more groups joined to the aryl ring as shown (2.50 mmol), Xantphos (0.017 g; 0.03 mmol); potassium carbonate (0.691 g; 5.00 mmol), and 1,4-dioxane (5 mL). To each stirring mixture is added aniline (274 uL) and CpPd (cinnamyl) (0.007 g in 100 uL 1,4-dioxane). Each reaction mixture is heated at 80 °C for 12 to 24 hours. The reaction mixture is cooled to room temperature and adsorbed onto silica gel. The product is purified by flash chromatography (ISCO, manufactured by Teledyne) and the volatiles are removed by vacuum to reveal the desired product having yields recorded in Table 1. |
66% | With η5‐cyclopentadienyl‐η3‐1‐phenylallylpalladium; potassium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 80℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With cobalt(II) phthalocyanine; copper diacetate In dichloromethane at 20℃; | 27 Synthesis of 4-methoxydiphenylamine Aniline reaction flask was added 0.093 g (1 mmol), 4- hydrazino anisole 0.179 g(1.3 mmol), CoPc 0.057 Ke (0.1 mmol), Cu (OAc) 2 0.02 g (0.1 mmol) and 10 ml of methylenechloride, 20 °C reaction; TLC until the reaction was followed completely finished; thecrude product after the reaction was subjected to column chromatography (petroleumether: ethyl acetate = 100: 1) to give the target product (92% yield). |
85% | With tetrabenzoporphyrinatocobalt(II); copper diacetate In acetonitrile at 0℃; for 13h; chemoselective reaction; | 3.23 4.2.1. General procedure for N-arylation of amines (2) with arylhydrazines (1). General procedure: Into a 25 mL round-bottom flask, amine (2) (1 mmol), Cu(OAc)2 (0.02 g, 0.1 mmol) and acetonitrile (4 mL) were added, the mixture was stirred and cooled to 0 °C. Then, CoPc (0.057 g, 0.1 mmol) was added, the solution of arylhydrazine (1) (2 mmol) in acetonitrile (2 mL) was added successively at a rate of 0.2 mmol per hour while stirring for 13 h in air. After completion of the reaction monitored by TLC analysis (developing solvent: ethyl acetate/petroleum ether (1:8)), the mixture was filtered, concentrated, and the residue was further purified by column chromatography using ethyl acetate/petroleum ether (1:100) as eluent to afford N-aryl amine 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium acetate; palladium diacetate; triphenylphosphine In toluene at 100℃; for 12h; Schlenk technique; Inert atmosphere; | General procedure: A Schlenk reaction tube was charged with Amine or amide 1 (1.2 mmol), aryltrimethylgermane 2 (1.0 mmol), Pd(OAc)2 (5 mol %), PPh3 (5 mol %), toluene (2.0 mL), under argon atmosphere at 100 °C for 12 h. After completion of the reaction, asindicated by TLC, the reaction mixture was extracted with diethyl ether (3×10 mL). The combined organic layer was washedby water and dried by Na2SO4. The solvent was removed in vacuo and the residue, further purification was carried out byshort column chromatography (silica gel 300400 mesh, petroleum ether / ethyl acetate as the eluent) to give the targetmolecules. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium acetate; palladium diacetate; triphenylphosphine In toluene at 100℃; for 12h; Schlenk technique; Inert atmosphere; | General procedure: A Schlenk reaction tube was charged with Amine or amide 1 (1.2 mmol), aryltrimethylgermane 2 (1.0 mmol), Pd(OAc)2 (5 mol %), PPh3 (5 mol %), toluene (2.0 mL), under argon atmosphere at 100 °C for 12 h. After completion of the reaction, asindicated by TLC, the reaction mixture was extracted with diethyl ether (3×10 mL). The combined organic layer was washedby water and dried by Na2SO4. The solvent was removed in vacuo and the residue, further purification was carried out byshort column chromatography (silica gel 300400 mesh, petroleum ether / ethyl acetate as the eluent) to give the targetmolecules. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With di-tert-butyl peroxide; palladium dichloride In dimethyl sulfoxide at 100℃; for 24h; Schlenk technique; | 3 Example 3 In a dry Schlenk reaction tube was added palladium chloride (0.025 mmol),Copper pentapentate (0.05 mmol),P-methoxydiphenylamine (0.25 mmol),The system was displaced three times under one atmosphere of carbon monoxide atmosphere.Then, the solvent was added successively to dry dimethylsulfoxide (1.0 mL)DTBP (0.75 mmol) and solvent dry dimethylsulfoxide (2.0 mL)The reaction was stopped at 100 ° C for 24 hours,After cooling to room temperature, ethyl acetate was added to the reaction system to quench the reaction, a saturated potassium carbonate solution (30.0 mL) was added, and the mixture was extracted with dichloromethane (20 × 3). The acridone derivative was isolated by column chromatography,Separation yield reached 81%. |
81% | With di-tert-butyl peroxide; copper(II) dipivaloate; palladium dichloride In dimethyl sulfoxide at 100℃; for 24h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With bis(acetylacetonato)palladium(II); dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine; 3K(1+)*O4P(3-)*1.2H2O In N,N-dimethyl-formamide at 130℃; for 24h; Sealed tube; Inert atmosphere; | |
64% | With bis(acetylacetonato)palladium(II); tripotassium phosphate "n" hydrate; BrettPhos In N,N-dimethyl-formamide at 130℃; for 24h; | |
33% | With bis(acetylacetonato)palladium(II); tripotassium phosphate "n" hydrate; dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine In N,N-dimethyl-formamide at 130℃; for 24h; Inert atmosphere; | 7 Example 1 General procedure: Under nitrogen, into a 15 mL screw vial tube, a stir bar,92 mg (0.60 mmol) of 4-nitroanisole,152 mg (0.90 mmol) of diphenylamine,9.1 mg (0.030 mmol) of palladium acetylacetonate (II),48 mg (0.090 mmol) of 2-dicyclohexylphosphino-3,6-dimethoxy-2 ', 4', 6'-triisopropylbiphenyl, 480 mg (1.8 mmol) of tripotassium phosphate n-And 3 mL of heptane were added.After closing the vial tube tightly,And the mixture was heated and stirred at 130 ° C. for 24 hours.Then, the reaction solution was cooled to room temperature.Ethyl acetate was added to the reaction solution, and the mixture was filtered through celite.The filtrate was concentrated and the obtained residue was dissolved in diethyl ether (10 mL), And a 30% hydrogen peroxide aqueous solution (1.5 mL) was added.After stirring at room temperature for 10 minutes, diethyl ether (20 mL × 3). The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by medium pressure column chromatography (activated calcium oxide (activated, neutral, Brokmann Activity I), developing solvent = hexane / ethyl acetate) To obtain 100 mg of the objective 4-methoxytriphenylamine as a white powder (yield 61%). |
29% | With potassium phosphate; 18-crown-6 ether; C36H45ClN2O2Pd In 1,4-dioxane at 130℃; for 12h; Glovebox; | |
27% | With palladium(II) acetylacetonate; tripotassium phosphate "n" hydrate; 2-(2,4,6-trimethylphenyl)-5-(2,4,6-triisopropylphenyl)-2H-imidazo[1,5-a]pyridinium chloride In 1,4-dioxane; water at 130℃; for 12h; Inert atmosphere; | 28-34 Example 1 General procedure: Under a nitrogen atmosphere, in a 4 mL screw vial tube,Stir bar,4-nitroanisole 31 mg (0.20 mmol),Phenylboronic acid 37 mg (0.30 mmol),Palladium acetylacetonate (II)0.60 mg (2.0 μmol),2- (2,4,6-trimethylphenyl) -5- (2,4,6-triisopropylphenyl) -2H-imidazo [1,5-a] pyridinium chloride1.9 mg (4.0 μmol),Tripotassium phosphate n-hydrate 139 mg (0.60 mmol),18-Crown-6 5.3 mg (0.020 mmol),1 mL of 1,4-dioxane and 20 μL of n-tridecane as an internal standard substance were added.After the vial tube was tightly capped, it was heated and stirred at 130 ° C. for 12 hours.By the heating, 2- (2,4,6-trimethylphenyl) -5- (2,4,6-triisopropylphenyl) -2H-imidazo [1,5-a] pyridinium chloride is dehydrochlorinated. Thus, an N-heterocyclic carbene compound represented by the above formula (2-1) was produced.Next, the reaction solution is cooled to room temperature, and a part of the reaction solution is collected.When diluted with ethyl acetate and analyzed by gas chromatography, 4-methoxybiphenyl was detected in a yield of 59%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate In acetonitrile at 20℃; for 72h; Inert atmosphere; Irradiation; | 2 Embodiment 2 This embodiment of a method for preparing a 4-aminobutyrate derivative includes the following steps: In a nitrogen atmosphere,19.9 mg (0.1 mmol) of 4-methoxydiphenylamine, at room temperature,31.2 mg (0.3 mmol) of styrene and51.3 mg (0.45 mmol) of ethyl diazoacetate dissolved in5mL acetonitrile,Then add 0.01 mmol[Ir(dF-CF3-ppy)2dtbbpy]PF6 and mix well.Place it in the blue LED light for 72 hours.After the reaction was completed, the reaction solvent was concentrated and dried by a rotary evaporator, and then a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 10:1 was used as an eluent to perform silica gel column chromatography to separate and obtain the corresponding 4 -Aminobutyric acid derivatives,The structural formula is: the product purity is 99%, and the yield is 60%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 110℃; for 24h; Molecular sieve; Inert atmosphere; Schlenk technique; | General procedure for the synthesis of amines General procedure: To a mixture of PhN=NNHTs (1 mmol), boronic acid (1.5 mmol) 4 Å MS (0.25 g) and freshly distilled DBU (3 mmol), dry toluene (2 mL) was added in a Schlenk flask under nitrogen atmosphere. The tube was caped tightly and heated at 110 °C for 24 h. After completion of reaction, water was added to the reaction mixture and extracted with EtOAc. The EtOAc layer was separated, washed with brine, dried over Na2SO4, and evaporated. Purification of the crude product by flash chromatography over silica gel (230-400 mesh) with petroleum ether-EtOAc as eluent gave the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With cesium fluoride In acetonitrile at 100℃; for 14h; Inert atmosphere; | General procedure for synthesis of aromatic amines General procedure: A mixture of benzyne precursor (0.1 mmol) and p-toluenesulfonyl isocyanate (0.24 equiv.) and cesium fluoride (0.3 equiv.) in acetonitrile (0.1 M) was heated at 100°C for 14h. The reaction was quenched with H2O and extracted with ethyl acetate (3 x 2 ml). The combined organic extract was dried over anhydrous sodium sulfate (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate In toluene at 100℃; | 14 Product 3-6 Synthetic Example In a round bottom flask5,5 '- (5-bromo-1,3-phenylene) bis (1-phenyl-1H-indole)(12.95 g, 24 mmol),4-methoxy-N-phenylaniline (3.99 g, 20 mmol),Pd2 (dba) 3 (0.03-0.05 mmol),P (t-Bu) 3 (0.1 eq.),NaOt-Bu (3 eq.),toluene (10.5 mL / 1 mmol) is added and the reaction proceeds at 100 ° C.After the reaction was completed, the reaction mixture was extracted with ether and water. The organic layer was dried over MgSO 4 and concentrated. The resulting organic material was subjected to silicagel column and recrystallization to obtain 8.29 g (yield: 63%) of the product. |
63% | With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate In toluene at 100℃; | 14 Synthetic Example of Product 3-6 In a round bottom flask 5,5'-(5-bromo-1,3-phenylene)bis(1-phenyl-1H-indole) (12.95g, 24mmol), 4-methoxy-N-phenylaniline (3.99g, 20mmol), Pd2(dba)3 (0.03~0.05 mmol), P(t-Bu)3 (0.1 eq.), NaOt-Bu (3 eq.),toluene (10.5 mL / 1 mmol) is added and the reaction proceeds at 100 ° C.After the reaction was completed, the reaction mixture was extracted with ether and water. The organic layer was dried over MgSO 4 and concentrated. The resulting organic material was subjected to silicagel column and recrystallization to obtain 8.29 g (yield: 63%) of the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 62% 2: 24% | With copper(II) acetate monohydrate; triethylamine In acetonitrile at 20℃; for 24h; | N-Arylation of Amines 3; General Procedure General procedure: A 10 mL vial was charged with the substrate amine 1 (0.2 mmol), NaBPh4 or NaBAr4 (0.1 mmol), and Cu(OAc)2·H2O (0.2 equiv) in MeCN (2 mL). To this mixture was added Et3N (2.0 equiv). The reaction mixture was then stirred at r.t. for 24 h. After completion of the reaction as monitored by TLC, the mixture was then concentrated through a rotary evaporator to yield the product, which was purified by direct flash column chromatography (Tables 2 and 3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: N-(4-methoxyphenyl)phenylamine With N,N,N,N,N,N-hexamethylphosphoric triamide; potassium <i>tert</i>-butylate at 60℃; for 2h; Inert atmosphere; Stage #2: (4-bromophenyl)(phenyl)methanone at 120℃; for 6h; Inert atmosphere; | 5 Example 5: Preparation of a compound of formula (VIII) 3.98 g (20 mmol) of 4-methoxyphenylaniline and 2.47 g (22 mmol) of potassium t-butoxide were placed in a 250 mL two-necked flask, protected with nitrogen, and 15 mL of HMPA was added thereto, and the mixture was stirred at 60 ° C for 2 h. 5.72 g (22 mmol) of 4-bromobenzophenone was added in portions and reacted at 120 ° C for 6 h. The mixture was extracted with saturated brine and EtOAc. The organic solvent was distilled off under reduced pressure to give a crude material. Purified by column chromatography,Ethyl acetate / petroleum ether was used as an eluent to give an orange powder, yield 86%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: N-(4-methoxyphenyl)phenylamine With N,N,N,N,N,N-hexamethylphosphoric triamide; potassium <i>tert</i>-butylate at 60℃; for 2h; Inert atmosphere; Stage #2: bis(4-bromophenyl)methanone at 120℃; for 6h; Inert atmosphere; | 7 xample 7: Preparation of a compound of formula (X) 3.98 g (20 mmol) of 4-methoxyphenylaniline and 2.47 g (22 mmol)Potassium tert-butoxide was placed in a 250 mL two-necked flask, protected with nitrogen, 15 mL of HMPA was added, and stirred at 60 for 2 h. 7.44 g (22 mmol) of 4,4'-dibromobenzophenone was added in portions and reacted at 120 ° C for 6 h. The organic solvent was evaporated under reduced pressure, and then evaporated and evaporated. Purified by column chromatography,Ethyl acetate/petroleum ether as eluent,A yellow powder was obtained in a yield of 76%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: N-(4-methoxyphenyl)phenylamine; C22H8Br2Cl2O2 With sodium t-butanolate In toluene for 0.5h; Reflux; Stage #2: With tetrakis(triphenylphosphine) palladium(0) In toluene for 3h; Reflux; | Synthesis of Compound 18 10.7 g (20 mmol) of Compound 3-A, 100 mmol of sodium-t-butoxide, 40 mmol of 4-methoxy-N-phenylaniline and 200 mL of toluene were mixed, refluxed, heated for 30 minutes, 0.2 mmol of tetrakistriphenylphosphinepalladium was added, followed by stirring for 3 hours in a reflux state. After the reaction, the reaction solution returned to room temperature was extracted with water, and the organic layer was recrystallized twice with chloroform to give 11.1 g of compound 4-O (yield 72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium phosphate In toluene at 80℃; for 15h; Inert atmosphere; | Representative Procedure for the Synthesis of Phosphoryl Ynamines 2 fromBromo(phosphoryl)ethyne 1 and Diarylamines: Synthesis ofDiphenyl-(2-diphenylaminoethynyl)phosphine oxide (2a). General procedure: To a 50 mL of two-neck round-bottomed flask charged with a magnetic stirrer bar, were successively added 1-Bromo(2-diphenylphosphoryl)ethyne (1) (305 mg, 1.0 mmol), diphenylamine(203 mg, 1.2 mmol, 1.2 equiv), K3PO4 (637 mg, 3.0 mmol, 3.0 equiv) and dehydrated toluene (5mL). After the mixture was stirred at 80 C for 15 h, the reaction mixture was quenched with 1 mL of saturated NH4Cl aq., and extracted with ethyl acetate and H2O, and dried over brine and MgSO4. The crude product was purified by flash chromatography (hexane/EtOAc, 1:2) to afford the corresponding phosphoryl ynamine 2a (240 mg) in 61% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In acetonitrile at 20℃; for 12h; | 2.1.2. General procedure for the synthesis of 3-(4-methoxyphenyl)thiourea derivatives (1-9) General procedure: A solution of commercially available (4-methoxyphenyl)aniline (0.003 mol, 0.40 g) in anhydrous acetonitrile (6 ml) was treated with a corresponding isothiocyanate (0.003 mol). The mixture was stirred at room temperature for 12 h. After that, the solvent was evaporated. The solid residue was crystallized from acetonitrile or purified by column chromatography (chloroform: methanol;9.5:0.5 vol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In acetonitrile at 20℃; for 12h; | 2.1.2. General procedure for the synthesis of 3-(4-methoxyphenyl)thiourea derivatives (1-9) General procedure: A solution of commercially available (4-methoxyphenyl)aniline (0.003 mol, 0.40 g) in anhydrous acetonitrile (6 ml) was treated with a corresponding isothiocyanate (0.003 mol). The mixture was stirred at room temperature for 12 h. After that, the solvent was evaporated. The solid residue was crystallized from acetonitrile or purified by column chromatography (chloroform: methanol;9.5:0.5 vol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In acetonitrile at 20℃; for 12h; | 2.1.2. General procedure for the synthesis of 3-(4-methoxyphenyl)thiourea derivatives (1-9) General procedure: A solution of commercially available (4-methoxyphenyl)aniline (0.003 mol, 0.40 g) in anhydrous acetonitrile (6 ml) was treated with a corresponding isothiocyanate (0.003 mol). The mixture was stirred at room temperature for 12 h. After that, the solvent was evaporated. The solid residue was crystallized from acetonitrile or purified by column chromatography (chloroform: methanol;9.5:0.5 vol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | In acetonitrile at 20℃; for 12h; | 2.1.2. General procedure for the synthesis of 3-(4-methoxyphenyl)thiourea derivatives (1-9) General procedure: A solution of commercially available (4-methoxyphenyl)aniline (0.003 mol, 0.40 g) in anhydrous acetonitrile (6 ml) was treated with a corresponding isothiocyanate (0.003 mol). The mixture was stirred at room temperature for 12 h. After that, the solvent was evaporated. The solid residue was crystallized from acetonitrile or purified by column chromatography (chloroform: methanol;9.5:0.5 vol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | In acetonitrile at 20℃; for 12h; | 2.1.2. General procedure for the synthesis of 3-(4-methoxyphenyl)thiourea derivatives (1-9) General procedure: A solution of commercially available (4-methoxyphenyl)aniline (0.003 mol, 0.40 g) in anhydrous acetonitrile (6 ml) was treated with a corresponding isothiocyanate (0.003 mol). The mixture was stirred at room temperature for 12 h. After that, the solvent was evaporated. The solid residue was crystallized from acetonitrile or purified by column chromatography (chloroform: methanol;9.5:0.5 vol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In acetonitrile at 20℃; for 12h; | 2.1.2. General procedure for the synthesis of 3-(4-methoxyphenyl)thiourea derivatives (1-9) General procedure: A solution of commercially available (4-methoxyphenyl)aniline (0.003 mol, 0.40 g) in anhydrous acetonitrile (6 ml) was treated with a corresponding isothiocyanate (0.003 mol). The mixture was stirred at room temperature for 12 h. After that, the solvent was evaporated. The solid residue was crystallized from acetonitrile or purified by column chromatography (chloroform: methanol;9.5:0.5 vol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.5% | Stage #1: Acetanilid With sodium hydride In mineral oil at 40℃; for 0.5h; Stage #2: 1-bromo-4-methoxy-benzene at 20 - 40℃; for 2.5h; Stage #3: In methanol at 110℃; for 1h; | 2; 5 Example 2 In a four-necked flask equipped with a thermometer, a reflux condenser, a stirrer, and a nitrogen introduction tube, at room temperature of 25 ° C,Add 200g of tetramethylurea and 4.8g (0.12mol) of 60% sodium hydride to control the material temperature not to exceed 40 ,While stirring, 15.0 g (0.11 mol) of acetanilide was added in three batches, and the reaction was further stirred at 40 ° C. for 30 minutes to prepare an acetanilide sodium salt solution.At 20 ° C, 18.7 g (0.1 mol) of 4-bromoanisole was added to the reaction bottle within 60 minutes,Control the temperature of the material ≤ 40 , after the addition is complete, continue to stir at 40 for 90 minutes.After adding 15g of methanol, the temperature was raised to 110 ° C within 30 minutes while distilling off the low-boiling fraction,And, continue to keep warm at 110 for 30 minutes, and then, the temperature is controlled in the range of 90 ~ 100 ,Under vacuum conditions, tetramethylurea was distilled off to obtain a reaction mixture containing the target product 4-methoxydiphenylamine. Add 200 g of water to the reaction mixture containing 4-methoxydiphenylamine, stir well to dissolve soluble substances, and filter to obtain crude 4-methoxydiphenylamine.4-Methoxydiphenylamine crude product after methanol recrystallization, centrifugal separation, drying, etc.deal with,The target product 4-methoxydiphenylamine 18.9g, purity 99.5% (gas chromatography analysis), reaction yield 94.5%(Based on 4-bromoanisole). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With bis(1,5-cyclooctadiene)nickel (0); sodium hexamethyldisilazane; 1,2-bis-(dicyclohexylphosphino)ethane In toluene at 100℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium hydroxide; In dimethyl sulfoxide; at 130℃; for 36.0h;Sealed tube; Inert atmosphere; | General procedure: To a mixture of iodobenzene (1.0 mmol), guanidine nitrate(0.5 mmol), and KOH (3.0 mmol) in DMSO (2 mL), Cu/Cu2O (25 mg)was added. The resulting mixture was then sealed and stirred for 36 h at130 C. After completion of the reaction, the reaction mixture wascooled to room temperature, diluted with water followed by extractionusing ethyl acetate. The organic phase was dried over anhydrousNa2SO4. The crude residue was obtained after evaporation of the solventon rotavapor. The residue was purified by column chromatographywith ethyl acetate and pet-ether as eluent to give the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 85% 2: 12% | With copper(II) acetate monohydrate; potassium carbonate at 110℃; for 8h; Inert atmosphere; | Synthesis of 4a-p; General Procedure B General procedure: To a solution of aromatic amine (1.53 mmol), Cu(OAc)2·H2O (0.13 mmol), K2CO3(3.84 mmol) in DEG (3 mL) were added aryl halides (1.28 mmol). The flask wasevacuated and backfilled with argon (3×), and the resulting mixture was heated in an oilbath with appropriate temperature under rapid stirring for the indicated time. After thecomplete consumption of aryl halide as monitored by TLC, the flask was cooled to r.t.The flask was opened to air, and the reaction mixture (if the product was acidic, themixture was acidified) was extracted with ethyl acetate (3×10 mL), and the organiclayer was washed with water (2×10 mL) and once with brine (10 mL), dried withmagnesium sulfate and concentrated in vacuo. The product was purified by columnchromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate In toluene at 110℃; for 1h; | Preparation of intermediate 7-iodo-N,N-diphenylpyrido[2,3,4,5-lmn]phenanthridin-2-amine (A-1) General procedure: In the reaction vessel, 3-0 substance (200.2g, 75mmol), sodium tetrabutoxide (21.62g, 225mmol), toluene (500mL),Diamine (12.69g75mmol),Pd2(dba)3 (2.06g, 2.25mmol) and tritetrabutyl phosphine (0.36mL, 15mmol) were added and reacted at 110° C. for 1 hour. The reaction solution was cooled, washed with water, and the palladium catalyst was removed with a silica filter, evaporated to dryness, and recrystallized with methylene chloride/petroleum ether to obtain A-1 (14.92 g, 40%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium acetate; [(2,6-bis(2,4,6-triisopropylphenyl)phenyl)dicyclohexylphosphine](allyl-η3)palladium(II) chloride In <i>tert</i>-butyl alcohol at 100℃; for 12h; Inert atmosphere; Sealed tube; | 33 Example 22-33 General procedure: In the pressure tube, under nitrogen atmosphere, Aryl halide (1.0 mmol), Amine (1.2 mmol), potassium acetate (1.3 mmol), 0.5 mmol%[(TPhos)Pd(all)Cl] And 75 uL of dodecane (as an internal standard for GC analysis) were dissolved in 2.0 mL of anhydrous solvent. The tube was sealed and placed at 100°C to react for 12 hours. Add dichloromethane and diatomaceous earth to aid filtration, Analyze by gas chromatography, The product was separated by (petroleum ether/ethyl acetate) column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium <i>tert</i>-butylate In toluene at 100℃; for 12h; Schlenk technique; | 1.1c Step 1c: Synthesis of the probe ligand provided by the present invention Add 4-methoxy-N-phenylaniline (2.2mmol, 0.44g), 4'-(4-chlorophenyl)-2,2':6',2”-terpyridine ( 2mmol, 0.68g), potassium tert-butoxide (3mmol, 0.336g), 10mg [Pd] catalyst, 5mL toluene, and reacted for 12h at 100°C. After the reaction, 710mg of light yellow solid was obtained by column chromatography and the yield was 70%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate In toluene at 110℃; for 10h; | 2.2 Step 2: Add intermediate 61-C (35mmol) and reactant 61-D (42mmol) to the reaction vessel and dissolve in 200ml of toluene, then add Pd2(dba)3(0.35mmol), P(t-Bu)3 (1.75 mmol), t-BuONa (77 mmol). After the addition, the reaction temperature was slowly raised to 110° C., and the mixture was stirred for 10 h. Use diatomaceous earth to filter while hot to remove salts and catalysts. After the filtrate is cooled to room temperature, distilled water is added to the filtrate for washing. After separation, the organic phase is retained, and the aqueous phase is extracted with ethyl acetate. Next, the combined organic layer was dried using magnesium sulfate, and the solvent was removed using a rotary evaporator. The volume ratio of dichloromethane: petroleum ether was 1: (1-9) as the eluent, and the remaining material was purified by column chromatography to obtain compound 61 (19.3 g, yield 78%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With phenylsilane; copper diacetate; 1,4-di(diphenylphosphino)-butane In toluene; acetonitrile at 60℃; for 30h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate In toluene at 100℃; for 24h; Glovebox; Inert atmosphere; | 4.1 1. Synthesis of Intermediate 1 Into a 250mL two-necked flask, add the first compound (3.52g, 10mmol), the second compound (4.78g, 24mmol), tris(dibenzylideneacetone)dipalladium (0.18g, 0.2mmol) and tri-tert-butylphosphine tetramine Fluoroborate (0.12 g, 0.4 mmol), then NaOtBu (2.88 g, 30 mmol) was added to the glove box, toluene (100 mL) which had been dehydrated and deoxygenated in advance was added under nitrogen atmosphere, and the reaction was carried out at 100 ° C for 24 hours , cooled to room temperature, poured the reaction solution into ice water (200 mL), extracted three times with dichloromethane, combined the organic phases, dried over anhydrous sodium sulfate, filtered, spin-dried the solvent, added silica gel for sample preparation, and separated and purified by column chromatography. The mass of the obtained intermediate 1 was 5.07 g, a pale yellow solid, the yield was 86% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With bis(1,5-cyclooctadiene)nickel (0); 3,4-bis(dicyclohexylphosphino)thiophene In toluene at 150℃; for 24h; Sealed tube; | General procedure for the Buchwald-Hartwig amination employing solidamines General procedure: An oven-dried vial was charged with the corresponding carbamate(0.5 mmol, 1.0 eq.), the corresponding amine (0.5 mmol, 1.0 eq.), Ni(cod)2 (5 mol%)and dcypt (10 mol%). Thereafter PhMe (2.5 ml) was added and the vial was sealed.The reaction mixture was stirred at 150 °C for 24 h. After that the reaction wasallowed to cool to room temperature and opened to air. The volatiles were removedunder reduced pressure, and purification via flash column chromatographyafforded the title compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With tris(2,2′-bipyridyl)ruthenium(II) chloride; Sodium hydrogenocarbonate In acetonitrile at 20℃; for 8h; Inert atmosphere; Irradiation; | 3 Example 3 Under light conditions, diphenylamine derivative 1c (1equiv), diazonium trivalent iodine reagent 2a (1.5equiv), ruthenium terpyridine chloride (2% mmol), sodium bicarbonate (1equiv) and acetonitrile (2mL) were added to 15mL In the reaction tube, the mixture was stirred at room temperature for 8 hours, and separated by silica gel column chromatography to obtain the target compound 3c in a yield of 72%. |
Tags: 1208-86-2 synthesis path| 1208-86-2 SDS| 1208-86-2 COA| 1208-86-2 purity| 1208-86-2 application| 1208-86-2 NMR| 1208-86-2 COA| 1208-86-2 structure
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