* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; potassium <i>tert</i>-butylate In toluene at 85℃; for 4 h;
3.16 g (20.0 mmol) of 4-bromopyrine, 2.79 g (30.0 mmol) of aniline, 0.37 g (0.4 mmol) of Pd2(dba)3, 0.08 g (0.4 mmol) of PtBu3, and 2.88 g (30.0 mmol) of KOtBu were dissolved in 60 mL of toluene to obtain a solution, which was then stirred at about 85° C. for about 4 hours. The reaction solution was cooled to room temperature, followed by three times of extraction with 50 mL of water and 50 mL of diethylether. The organic phase was collected, and was dried using magnesium sulfate to evaporate the solvent. The residue was separated and purified using silica gel column chromatography to obtain 1.49 g of Intermediate I-3 (Yield: 88percent) This compound was identified using LC-MS.
78%
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate In toluene at 100℃; for 24 h;
Step 4: Add aniline (0.75 g, 8 mmol) to the reactor.4-bromopyridine (1.05 g, 6.67 mmol),Pd2(dba)3 (0.17g, 0.2mmol),P(t-Bu)3 (0.14, 0.67 mmol),NaOt-Bu (2.24g, 20mmol),Toluene solution 100mL,Reaction at 100 ° C for 24 h,After the reaction, the organic phase was extracted with diethyl ether and water.The organic layer was dried over MgSO 4Concentrated organic matter,Column chromatographyRecrystallization gave Intermediate 17-4 (0.89 g, 78percent).
Reference：
[1] Patent: CN102850322, 2016, B, . Location in patent: Paragraph 0150-0153
[2] Patent: CN108822041, 2018, A, . Location in patent: Paragraph 0073; 0074; 0078
2
[ 626-61-9 ]
[ 62-53-3 ]
[ 22961-45-1 ]
Reference：
[1] Macromolecules, 2012, vol. 45, # 10, p. 4205 - 4215
[2] ChemSusChem, 2015, vol. 8, # 6, p. 1083 - 1087
[3] Journal of the Chemical Society, 1945, p. 927
[4] Journal of the Chemical Society, 1942, p. 726
[5] Chemistry - An Asian Journal, 2017, vol. 12, # 18, p. 2364 - 2368
3
[ 504-24-5 ]
[ 108-86-1 ]
[ 22961-45-1 ]
Yield
Reaction Conditions
Operation in experiment
91%
With tetrabutylammomium bromide; palladium diacetate; potassium carbonate; 2,6-bis(diphenylphosphino)pyridine In N,N-dimethyl acetamide at 135℃; for 4 h; Inert atmosphere
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 percent in 2 mL of DMAc) and a solution of palladiumacetate (0.025 mol percent 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
Reference：
[1] Tetrahedron Letters, 2014, vol. 55, # 30, p. 4098 - 4101
[2] Angewandte Chemie - International Edition, 2014, vol. 53, # 27, p. 7010 - 7013[3] Angew. Chem., 2014, vol. 126, # 27, p. 7130 - 7133,4
[4] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3014 - 3017
4
[ 7379-35-3 ]
[ 62-53-3 ]
[ 22961-45-1 ]
Yield
Reaction Conditions
Operation in experiment
40%
With potassium carbonate In isopropyl alcohol for 24 h; Reflux; Green chemistry
General procedure: A mixture of the corresponding aryl amine (9.74 mmol), 4-chloropyridin-1-ium chloride (1.21 g,8.12 mmol), anhydrous potassium carbonate (3.45 g, 25 mmol) and supported Cu(I) catalyst (100 mg,0.22 mmol of Cu, 2.7 mol percent of Cu) was refluxed in isopropyl alcohol (40 mL) for 24 h under openatmosphere conditions. After 24 h, reaction mixture was filtered to remove potassium salts andcatalyst. The solid was stirred in 50 mL of water until dissolution of potassium salts, catalyst wasfiltered off, washed twice with water (10 mL), methanol (10 mL), dried in vacuum and stored forfurther use. Diethyl ether (100 mL) was added to the product containing filtrate and the solutionwas then washed with 100 mL of water (three times). Organic phase was dried using anhydroussodium sulfate and solvents were removed under reduced pressure. Product(s) was/were separatedby flash chromatography on silica gel using methanol-dichloromethane (1:9) mixture as a mobile phase.Yields of products are listed in Table 2.
With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; potassium <i>tert</i>-butylate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride In 1,4-dioxane at 100℃; for 20h; Inert atmosphere;
65%
With zinc(II) nitrate hexahydrate In tetrahydrofuran at 75℃; for 24h; Sealed tube; Green chemistry;
With C48H56ClN3Pd; potassium <i>tert</i>-butylate In tetrahydrofuran at 70℃; for 24h; Schlenk technique; Inert atmosphere;
With tris(dibenzylideneacetone)dipalladium (0); potassium <i>tert</i>-butylate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride In 1,4-dioxane at 100℃; for 3h;
40%
With potassium carbonate In isopropyl alcohol for 24h; Reflux; Green chemistry;
3.2. General Synthetic Procedure for C-N Coupling of Aryl Amine with 4-Chloropyridin-1-ium Chloride
General procedure: A mixture of the corresponding aryl amine (9.74 mmol), 4-chloropyridin-1-ium chloride (1.21 g,8.12 mmol), anhydrous potassium carbonate (3.45 g, 25 mmol) and supported Cu(I) catalyst (100 mg,0.22 mmol of Cu, 2.7 mol % of Cu) was refluxed in isopropyl alcohol (40 mL) for 24 h under openatmosphere conditions. After 24 h, reaction mixture was filtered to remove potassium salts andcatalyst. The solid was stirred in 50 mL of water until dissolution of potassium salts, catalyst wasfiltered off, washed twice with water (10 mL), methanol (10 mL), dried in vacuum and stored forfurther use. Diethyl ether (100 mL) was added to the product containing filtrate and the solutionwas then washed with 100 mL of water (three times). Organic phase was dried using anhydroussodium sulfate and solvents were removed under reduced pressure. Product(s) was/were separatedby flash chromatography on silica gel using methanol-dichloromethane (1:9) mixture as a mobile phase.Yields of products are listed in Table 2.
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
78%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 95℃; for 24h; Inert atmosphere;
With potassium phosphate; XPhos In toluene for 20h; Heating;
With potassium carbonate In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; 1,2,4-Trichlorobenzene
R.2 Synthesis of 1-[4-(4-pyridylamino)phenyl]-2-chloropropanone STR12
Reference Example 2 Synthesis of 1-[4-(4-pyridylamino)phenyl]-2-chloropropanone STR12 4-pyridylaminobenzene (9.00 g) and aluminium chloride (21 g) were suspended in 1,2,4-trichlorobenzene (45 mL). To the mixture solution, 2-chloropropionyl chloride (5.7 mL) was dropped by heating at 70° C. and stirring over ca. one minute. After dropping, the mixture was heated to 80° C., followed by reaction with the temperature maintained for one hour. The reacted mixture was diluted with dichloromethane (500 mL). Next, ice-water (20 mL) was carefully added to the solution, and sufficiently stirred. To the resultant solution, anhydrous potassium carbonate was added for drying until the viscosity of the solution disappeared. After the drying agent was removed by filtration, the solution was concentrated under reduced pressure to obtain a crude product. This product was finally purified by a silica gel column chromatography (solvent: chloroform→5% methanol/chloroform) to obtain the captioned compound (12.34 g). Yield was 89.5%. 1 H-NMR (250 MHz, DMSO-d6) δ:9.41 (1H, s) 8.33 (2H, d) 8.00 (2H, d) 7.30 (2H, d) 7.10 (2H, d) 5.71 (1H, q) 1.61 (3H, d)
11 Preparation of N,N,N'-triphenyl-N'-4-pyridinylurea
EXAMPLE 11 Preparation of N,N,N'-triphenyl-N'-4-pyridinylurea A solution of 8.51 g (0.05 mol) of N-phenyl-4-pyridinamine in 400 ml of chloroform is mixed with 11.5 g (0.11 mol) of triethylamine. To this mixture is added, dropwise with stirring, a solution of 11.6 G (0.05 mol) of diphenylcarbamic chloride in chloroform. The mixture is then heated under reflux for 72 hours, cooled, and partitioned between water and chloroform. The combined chloroform extracts are dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated to an oil which is dissolved in diethyl ether, filtered, and washed with 2M NaOH and water. The ether solution is concentrated to give a solid which is recrystallized from ethyl acetate to yield N,N,N-triphenyl-N'-4-pyridinylurea, mp 156°-157° C.
27.b Preparation of N,N-bis-(4-Fluorophenyl)-N'-phenyl-N'-4-pyridinylurea
(b) Preparation of N,N-bis-(4-fluorophenyl)-N'-phenyl-N'-4-pyridinylurea. bis-(4-Fluorophenyl)carbamic chloride 5.35 g, 0.02 mol) is dissolved, together with 2.0 g of triethylamine in 100 ml of chloroform. To this mixture is added 3.4 g (0.02 mol) of N-phenyl-4-pyridinamine. The resulting mixture is heated under reflux for eight hours after which the solution is cooled to room temperature, washed three times with brine solution, dried, and evaporated. The solid residue is recrystallized from diisopropyl ether to yield 4.5S g of N,N-bis-(4-fluorophenyl)-N'-phenyl-N'-4-pyridinylurea, mp 187°-191° C.
Stage #1: N-phenylpyridin-4-amine With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 1h;
Stage #2: carbon disulfide In tetrahydrofuran at 20℃; for 16h;
Stage #3: cyanomethyl bromide In tetrahydrofuran for 24h;
Stage #1: N-phenylpyridin-4-amine With phosphorus trichloride In tetrahydrofuran at 20℃; for 1.5h;
Stage #2: (R,R)-TADDOL With triethylamine In tetrahydrofuran at 0℃; for 24h;
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; potassium <i>tert</i>-butylate In toluene at 85℃; for 4h;
1 Synthesis of Intermediate I-3
3.16 g (20.0 mmol) of 4-bromopyrine, 2.79 g (30.0 mmol) of aniline, 0.37 g (0.4 mmol) of Pd2(dba)3, 0.08 g (0.4 mmol) of PtBu3, and 2.88 g (30.0 mmol) of KOtBu were dissolved in 60 mL of toluene to obtain a solution, which was then stirred at about 85° C. for about 4 hours. The reaction solution was cooled to room temperature, followed by three times of extraction with 50 mL of water and 50 mL of diethylether. The organic phase was collected, and was dried using magnesium sulfate to evaporate the solvent. The residue was separated and purified using silica gel column chromatography to obtain 1.49 g of Intermediate I-3 (Yield: 88%) This compound was identified using LC-MS.
78%
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate In toluene at 100℃; for 24h;
1.4
Step 4: Add aniline (0.75 g, 8 mmol) to the reactor.4-bromopyridine (1.05 g, 6.67 mmol),Pd2(dba)3 (0.17g, 0.2mmol),P(t-Bu)3 (0.14, 0.67 mmol),NaOt-Bu (2.24g, 20mmol),Toluene solution 100mL,Reaction at 100 ° C for 24 h,After the reaction, the organic phase was extracted with diethyl ether and water.The organic layer was dried over MgSO 4Concentrated organic matter,Column chromatographyRecrystallization gave Intermediate 17-4 (0.89 g, 78%).
73%
With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene for 2h; Inert atmosphere; Reflux;
Synthesis of htermediate 7
Under a nitrogen atmosphere, 2-bromopyridine (1.58 g,10 mmol) and aniline (2.79 g, 30 mmol) were mixed anddissolved in toluene (40 mE). Then t-l3uONa (2.88 g, 30mmol), Pd(OAc)2 (45 mg, 0.2 mmol), and I3INAP (0.25 g, 0.4 mmol) were added and refluxed for 2 irs.After the reaction was terminated, the reactants werecooled to normal temperature, and MC (150 mE) and H20(150 mE) were added. The MC layer was extracted, driedover anhydrous MgSO4, concentrated, and purified by column chromatography eluting with Hex:EA=4: 1, to obtainIntermediate 7 (1.24 g, 73%).Intermediate 7 MS(FAI3): 170(M+)
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; potassium <i>tert</i>-butylate In toluene at 85℃; for 4h;
1 Synthesis of Intermediate I-4
2.55 g (15.0 mmol) of Intermediate I-3, 2.83 g (10.0 mmol) of 4-bromoiodobenzene, 0.18 g (0.2 mmol) of Pd2(dba)3, 0.04 g (0.4 mmol) of PtBu3, and 1.44 g (15.0 mmol) of KOtBu were dissolved in 40 mL of toluene to obtain a solution, which was then stirred at about 85° C. for about 4 hours. The reaction solution was cooled to room temperature, followed by three times of extraction with 30 mL of water and 30 mL of diethylether. The organic phase was collected, and was dried using magnesium sulfate to evaporate the solvent. The residue was separated and purified using silica gel column chromatography to obtain 2.04 g of Intermediate I-4 (Yield: 63%) This compound was identified using LC-MS
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 C13H11N2O3S(1-)*CF3O3S(1-)*Cu(2+); oxygen In methanol at 50℃; for 12h;
98 %Chromat.
With C14H11CuF3N2O6S2; oxygen In methanol at 50℃; for 12h;
With tris-(dibenzylideneacetone)dipalladium(0); potassium <i>tert</i>-butylate; XPhos In toluene for 24h; Inert atmosphere; Reflux;
9,9-dimethyl-N2,N7-diphenyl-10-(6-phenylpyridin-3-yl)-N2,N7-di(pyridin-4-yl)-9,10-dihydroacridine-2,7-diamine
To a flask charged with 2,7-dibromo-9,9-dimethyl-10-(6-phenylpyridin-3-yl)-9,10-dihydroacridine (1.04 g, 2.00 mmol), iV-phenylpyridin-4-amine (817 mg, 4.80 mmol), tris(dibenzylideneacetone) dipalladium (73 mg, 0.08 mmol), 220 (dicyclohexylphosphino)-2',4',6'-tri-?'-propyl-l,l'-biphenyl (X-PHOS) (114 mg, 0.24 mmol), and potassium f-butoxide (897 mg, 8.0 mmol) under a N2 atmosphere was added toluene (30 mL) at room temperature. The flask was attached to a reflux condenser and heated to reflux. After 24 h, the crude reaction mixture was cooled to rt, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over 25 MgSCv The resulting solution was filtered and concentrated. The resulting residue was purified via silica gel chromatography, eluted with CH2CI2, then EtOAc, then EtOAc:Et3N = 98:2, to afford the product as a yellow solid in 57% yield. The material was recrystallized from C^C^/hexane to afford an off-white solid.
With methanesulfonic acid In sulfolane at 170℃; for 10h; Inert atmosphere;
D23
General procedure: 42.2 g (20 mmol) of the compound A001 (raw material A), 18.3 g (10 mmol) of the compound B001 (raw material B) and 400 mL of methanesulfonic acid were added at 25 ° C to an 1 L three-necked flask equipped with stirring blades, and stirring was started. After introducing nitrogen into the flask, heating of the flask was started with an oil bath. Over 30 minutes, the internal temperature of the flask was raised, and after reaching 170 ° C, the internal temperature of the flask was maintained at 170 ° C for 3 hours to react the compound A 001 and the compound B 001. (The temperature reached by raising the internal temperature of the flask is defined as T1 ° C and the time maintained at T1 ° C is defined as H1 hours. In the example A01, T1 ° C is 170 ° C and H1 hour is 3 hours.) Thereafter, the oil bath was removed and the internal temperature of the flask was cooled to 25 °Cover 1.5 hours, and then the stirring was stopped. 2000 g of ice and 1000 g of water were placed in a 3 L beaker equipped with stirring blades, and stirring was started. The reaction solution of the 1 L three-necked flask was poured therein, and stirred for 1 hour to obtain a suspension. This suspension was filtered, and the crystals separated by filtration were washed with 500 mL of water. This crystal was dried in an air dryer at 50 ° C for 15 hours to obtain 38.9 g (6.6 mmol) of triarylmethane derivative C001 (yield 66%).
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate In toluene at 100℃; for 24h;
1.5
Step5: Add in the reactorIntermediate 17-4 (1.36 g, 8 mmol),17-3 (3.0 g, 6.67 mmol),Pd2 (dba) 3 (0.17 g, 0.2 mmol),P(t-Bu)3 (0.14, 0.67 mmol),NaOt-Bu (2.24g, 20mmol),Toluene solution 100mL,Reaction at 100 ° C for 24 h,After the reaction, the organic phase was extracted with diethyl ether and water.The organic layer was dried over MgSO 4Concentrated organic matter, column chromatography,Recrystallization gave Intermediate 17-5 (2.43 g, 74%).
With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate In toluene at 110℃; for 7h; Inert atmosphere;
1 Synthesis of Compound 001
N-phenylpyridin-4-amine (110 mmol) under nitrogen2-bromo-9,9-dimethyl--9H- fluorene (100mmol),O-phenanthroline (1.98g), cuprous iodide (1.90g),A substance such as cesium carbonate (38.6 g, 2 eq) was dissolved in toluene (300 mL) and heated at 110 ° C for 7 hours.It was cooled, filtered at room temperature, and the metal was removed, and the solvent was evaporated to give solid 001 (76 mmol, 76%).
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).
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate In toluene for 12h; Inert atmosphere; Reflux;
Synthesis of Compound 16
Under a nitrogen atmosphere, Compound 6 (3.69 g, 10 mmol) and Intermediate 7 (1.70 g, 10 mmol) were mixed and dissolved in toluene (50 mE). Then, Pd2dba3 (0.18 g, 0.2mmol), t-13u3P (0.4 ml, 0.4 mmol), and t-l3uONa (2.88 g, 30mmol) were added and refluxed for 12 irs.After the reaction was terminated, MC (250 mE) and H20(250 mE) were added. The MC layer was extracted, and theorganic layer was distilled under reduced pressure andpurified by column chromatography eluting with Hex:EA=2:1, to obtain Compound 16 (3.58 g, 76%).1H NMR (DMSO, 300 Hz): ö(ppm)=8.57-8.25 (d, 2H),8.21-8.10 (m, 1H), 8.10-7.75 (m, 2H), 7.72-6.90 (m, 13H),6.90-6.52 (m, 4H).Compound 16 MS(FAI3): 458(M+).
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate In toluene for 12h; Inert atmosphere; Reflux;
Synthesis of Compound 15
Under a nitrogen atmosphere, Compound 2 (3.43 g, 10mmol) and Intermediate 7 (1.70 g, 10 mmol) were mixed and dissolved in toluene (50 mE). Then Pd2dba3 (0.18 g, 0.2mmol), t-13u3P (0.4 ml, 0.4 mmol), and t-l3uONa (2.88 g, 30mmol) were added and refluxed for 12 irs.Afier the reaction was terminated, MC (250 mE) and H20 (250 mE) were added. The MC layer was extracted, and the organic layer was distilled under reduced pressure and purified by column chromatography eluting with Hex:EA=2:1, to obtain Compound 15 (3.29 g, 76%).1H NMR (DMSO, 300 Hz): ö(ppm)=8.55-8.25 (d, 2H),8.21-8.10 (m, 1H), 8.10-7.80 (m, 2H), 7.75-6.90 (m, 11H),6.90-6.55 (m, 4H). Compound 15 MS(FAI3): 432(M+).
With potassium hexamethylsilazane In tetrahydrofuran at 100℃; for 16h; Inert atmosphere;
1.1-1.13; 3 Example 1 (reaction conditions screening)
4-methoxypyridine 2a (0.5 mmol) and aniline 3a (0.75 mmol) were sequentially added to the reaction tube under N2 atmosphere.a mixture obtained by dissolving a base (0.75 mmol) of THF and a solvent (0.5 ml) in a concentration of 1.0 M in advance,Heat to T ° C, stir the reaction for about 16 h until the conversion of the raw materials is completed, and return to room temperature.Diluted with THF (3 ml) to the reaction mixture.Filtered on silica gel or diatomaceous earth, washed with THF,The crude product was concentrated in vacuo and subjected to silica gel column chromatography to give the corresponding product 1aa.
98%
With potassium hexamethylsilazane In tetrahydrofuran at 100℃; for 16h; Inert atmosphere; Schlenk technique; Sealed tube; Green chemistry;
With tri-tert-butyl phosphine; palladium diacetate; sodium t-butanolate In toluene at 115℃; for 24h; Inert atmosphere; Sonication;
2.1; 2.2
In a 500 ml three-necked flask, N-phenylpyridin-4-amine (17.02 g, 100 mmol) and 4'-bromo-4-iodobiphenyl (35.90 g, 100 mmol), toluene (200 mL) and were added. Sodium tert-butaoxide (28.83 g, 300 mmol), the air was removed by ultrasonication, and palladium acetate (0.07 g, 0.3 mmol) and tri-tert-butylphosphine (0.18 g, 0.6 mmol) were added under a nitrogen atmosphere, and the mixture was heated and refluxed at 115 ° C for 24 hours. , TLC monitors the completion of the reaction;After cooling to room temperature, wash twice with water, separate the liquid, and the organic phase is dried with anhydrous magnesium sulfate, filtered, and the filtrate is added to activated carbon for decoloration at 115 ° C for 45 minutes, filtered hot, and the filtrate is concentrated under reduced pressure and then concentrated with acetic acid. The ester was recrystallized twice to give the intermediate N-(4'-bromo-[1,1'-biphenyl]-4-yl)-N-phenylpyridin-4-amine 30.89 g, 77% yield ;
With SingaCycle-A1; potassium hexamethylsilazane In toluene at 100℃; for 24h; Schlenk technique; Inert atmosphere;
Amination with Azaarylamines and Diaryl Sulfides/Sulfoxides(Table 2); General Procedure 2
General procedure: KHMDS (90 mg, 0.45 mmol), azaarylamine (0.18 mmol), diaryl sulfide/sulfoxide (0.15 mmol), and SingaCycle-A1 (5.0 mg, 0.0075 mmol,5 mol%) were sequentially added to a Schlenk tube under a nitrogen atmosphere. Toluene (1.0 mL) was added and the resulting mixture was heated at 100 °C for 24 h. The reaction mixture was poured into H2O and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was dried over sodium sulfate and the solvent was removedunder reduced pressure. Chromatographic purification of thecrude oil using 25% ethyl acetate in hexane as the eluent provided the corresponding product 3.
With SingaCycle-A1; potassium hexamethylsilazane In toluene at 100℃; for 24h; Schlenk technique; Inert atmosphere;
Amination with Azaarylamines and Diaryl Sulfides/Sulfoxides(Table 2); General Procedure 2
General procedure: KHMDS (90 mg, 0.45 mmol), azaarylamine (0.18 mmol), diaryl sulfide/sulfoxide (0.15 mmol), and SingaCycle-A1 (5.0 mg, 0.0075 mmol,5 mol%) were sequentially added to a Schlenk tube under a nitrogen atmosphere. Toluene (1.0 mL) was added and the resulting mixture was heated at 100 °C for 24 h. The reaction mixture was poured into H2O and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was dried over sodium sulfate and the solvent was removedunder reduced pressure. Chromatographic purification of thecrude oil using 25% ethyl acetate in hexane as the eluent provided the corresponding product 3.
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate In toluene at 110℃; for 10h; Inert atmosphere;
3.5
Under the protection of nitrogen, dissolve Intermediate 4 (10.08mmol) and reactant E-058 (10.08mmol) in 100.00ml of toluene solution, add tris(dibenzylideneacetone)dipalladium (0.11mmol), tri-tert-butyl phosphine (0.60mmol), sodium tert-butoxide (20.16mmol); warm up to 110°C, and stir the mixture for 10h, use diatomaceous earth to filter while it is hot to remove the salt and catalyst, the filtrate was cooled to room temperature, washed with water three times, the organic phase was retained, and then the aqueous phase was extracted with ethyl acetate; after the organic phases were combined, they were dried with anhydrous magnesium sulfate. And use a rotary evaporator to remove the solvent; use amixed solution of dichloromethane and petroleum ether (V dichloromethane: Vpetroleum ether = 10: 4), the remaining material was purified by column chromatography to obtain a luminescent auxiliary material (6.70 g, yield: 84.79%, Mw: 784.04).
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate In toluene at 90℃; for 5h; Inert atmosphere;
2.3
(3) Under the protection of nitrogen, compound D-033 (30.00mmol) and compound E-033 (30.00mmol)were dissolved in toluene solution, and tris(dibenzylideneacetone)dipalladium (0.30mmol) was added.Butylphosphine (1.50mmol) and sodium tert-butoxide (60.00mmol), stir well, warm up to 90, and reflux for5h; after the reaction is over, lower the temperature slightly, filter with diatomaceous earth to remove salt andcatalyst, After the filtrate was cooled to room temperature, it was washed with water three times, the organicphase was retained, and then the aqueous phase was extracted with ethyl acetate; after the organic phases werecombined, anhydrous magnesium sulfate was used for drying, and the solvent was removed using a rotaryevaporator to obtain solid organics.Use a small amount of dichloromethane to completely dissolve the solidorganic matter, and then slowly add dropwise to the petroleum ether solution, stir evenly, precipitateprecipitation, suction filtration to obtain the solid, successively rinse with absolute ethanol, petroleum ether,and dry to prepare Intermediate 3 (7.28 g, yield: 83.63%);
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate In toluene at 90℃; for 5h; Inert atmosphere;
3.3
(3) Under the protection of nitrogen, dissolve compound D-057 (30.00mmol) and compound E-057(30.00mmol) in 130.00ml toluene solution, add tris(dibenzylideneacetone)dipalladium (0.30mmol), Tri-tert-butylphosphine (1.50mmol) and sodium tert-butoxide (60.00mmol), stir well, heat up to 90°C, and reflux for5h; after the reaction, lower the temperature slightly, filter with diatomaceous earth to remove the salt and Thecatalyst, the filtrate is cooled to room temperature, washed three times with water, the organic phase isretained, and then the aqueous phase is extracted with ethyl acetate; after the organic phases are combined,they are dried with anhydrous magnesium sulfate, and the solvent is removed with a rotary evaporator toobtain solid organics .Use a small amount of dichloromethane to completely dissolve the solid organic matter,and then slowly add dropwise to the petroleum ether solution, stir evenly, precipitate precipitation, suctionfiltration to obtain the solid, successively rinse with absolute ethanol, petroleum ether, and dry to prepareIntermediate 3 (9.19g, yield: 83.66%);
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium tertiary butoxide In toluene at 110℃; for 3h;
1.2.3 Synthesis of Compound P-29
After Sub 1-14 (5 g, 6.0 mmol), Sub 2-3 (1.03 g, 6.0 mmol), Pd2(dba)3 (0.17 g, 0.2 mmol), P(t-Bu)3 (0.1 g, 0.5 mmol), NaO(t-Bu) (1.74 g, 18.1 mmol), toluene (mL) were placed in a round bottom flask, the mixture was heated under reflux at 110° C. for 3 hours. When the reaction was completed, the reaction product was diluted with distilled water at room temperature and extracted with methylene chloride and water. Then, the organic layer was dried with MgSO4 and concentrated. After the concentrate was dissolved in toluene and was applied to silica filter. Then, the resultant was concentrated and recrystallized with toluene and acetone to obtain the product P-29 (4.47 g, 77%).
77%
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium tertiary butoxide In toluene at 110℃; for 3h;
1.2.3 Synthesis of Compound P-29
After Sub 1-14 (5 g, 6.0 mmol), Sub 2-3 (1.03 g, 6.0 mmol), Pd2(dba)3 (0.17 g, 0.2 mmol), P(t-Bu)3 (0.1 g, 0.5 mmol), NaO(t-Bu) (1.74 g, 18.1 mmol), toluene (mL) were placed in a round bottom flask, the mixture was heated under reflux at 110° C. for 3 hours. When the reaction was completed, the reaction product was diluted with distilled water at room temperature and extracted with methylene chloride and water. Then, the organic layer was dried with MgSO4 and concentrated. After the concentrate was dissolved in toluene and was applied to silica filter. Then, the resultant was concentrated and recrystallized with toluene and acetone to obtain the product P-29 (4.47 g, 77%).
With tri-tert-butyl phosphine; palladium diacetate; sodium t-butanolate In toluene at 80℃;
Preparation of Intermediate Fused Compounds
General procedure: 1-1 (58.19 g, 187 mmol), Pd(C2H3O2)2 (0.4 g (1.83 mmol), Pt-Bu3 (0.37 g, 1.83 mmol) and NaOt-Bu (22.8 g, 238 mmol) dissolved in 1000 mL of toluene. After stirring at 80 ° C. for 4 hours, the reaction solution was cooled to room temperature, extracted three times with 300 mL of water and 300 mL of diethyl ether, dried the collected organic layer over anhydrous magnesium sulfate, and evaporated the solvent to give a silica residue. Intermediate 4-1 (34.45 g, yield 80%) was obtained by separation and purification by gel and chromatography, and the resulting compound was confirmed by LC-MS.
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