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CAS No. : | 1013-88-3 |
Formula : | C13H11N |
M.W : | 181.23 |
SMILES Code : | N=C(C1=CC=CC=C1)C2=CC=CC=C2 |
MDL No. : | MFCD00001760 |
InChI Key : | SXZIXHOMFPUIRK-UHFFFAOYSA-N |
Pubchem ID : | 136809 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
450 mg (53%) | With hydrogenchloride; caesium carbonate;palladium diacetate; In tetrahydrofuran; ethyl acetate; toluene; | An alternative route to the synthesis of compound 470D is as follows. A mixture of compound 470B (1.17 g, 5.02 mmol), benzophenone imine (1.05 mL, 6.26 mmol), palladium acetate (25 mg, 0.11 mmol), rac-2,2'-bis(diphenylphosphino)-1,1' binaphthyl (100 mg, 0.161 mmol) and cesium carbonate (2.30 g, 7.06 mmol) in 20 mL of toluene was heated at 100 C. for 20 h. The reaction mixture was diluted with ethyl ether (200 mL) and filtered through Celite. After concentrating the filtrate, the residue was dissolved in 120 mL of THF and treated with 40 mL of 1N HCl. After standing for 2 h at room temperature, the mixture was partitioned between ethyl acetate (150 mL) and 0.25 N NaOH (160 mL). After washing with brine (100 mL), the organic layer was dried over magnesium sulfate. The organic layer was filtered and ~50 g of celite was added to the filtrate. After concentration in vacuo, the powdery residue was purified by flash chromatography on a 5*15 cm silica gel column eluding with 1 L each of 1:1 ethyl acetate:hexane, 6:4 ethyl acetate:hexane and 8:2 ethyl acetate:hexane to give 450 mg (53%) of 470D as a yellow powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | 3-Amino-5-bromo-1-methyl-1H-pyridin-2-one (2) A 48-mL seal tube equipped with a magnetic stirring bar was charged with benzophenone imine (0.43 g, 2.4 mmol), 3,5-dibromo-1-methyl-1H-pyridin-2-one (1) (0.51 g, 2.0 mmol), Pd(OAc)2 (0.025 g, 0.040 mmol), rac-BINAP (0.082 g, 0.13 mmol), and Cs2CO3 (0.92 g, 2.8 mmol) in dioxane (15 mL). After the mixture was degassed for 15 min., it was heated at 95 C. for 16 h. Then, the reaction mixture was cooled to room temperature and poured into H2O (10 mL). To this was added dichloromethane and the layers were separated. The aqueous phase was extracted with dichloromethane (3*10 mL), and the combined organic extracts were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude product was dissolved in 1 N HCl/MeOH (3 mL) and stirred for 1 h at room temperature. Then, to the reaction mixture was added sat. NaHCO3 (10 mL) and dichloromethane (10 mL), and the phases were separated. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-10% MeOH in dichloromethane/ether (1/1), to afford 0.22 g (54%) of 3-amino-5-bromo-1-methyl-1H-pyridin-2-one (2) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.8% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 100℃; for 4h; | To a solution of 6-bromo-[l,2,4]triazolo[1,5-a]pyridine (700 mg, 3.5350 mmol), diphenylmethanimine (1.28 g, 7.06 mmol) and t-BuONa (680 mg, 7.076 mmol) in toluene (50 mL) were added BINAP (221 mg, 0.3549 mmol) and Pd2(dba)3 (167 mg, 0.1769 mmol). The mixture was degassed for 5 min and refilled with N2 and then stirred at 100 C for 4 h. The reaction was quenched with water (100 mL), and extracted with EtOAc (100 mLx 3). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 5/1 to 1/1) to give the title compound as a yellow solid (1.01 g, 95.8%) .MS (ESI, pos. ion) m/z: 299.2 [M+H]+;1H NMR (400 MHz, CDCl3) d (ppm): 8.21 (s, 1H), 8.04 (d, 7 = 1.2 Hz, 1H), 7.79-7.73 (m, 2H), 7.50 (dd, J= 8.4, 2.9 Hz, 2H), 7.42 (t, J= 7.5 Hz, 2H), 7.31 (t, J= 6.2 Hz, 3H), 7.14 (dd, J= 7.7, 1.7 Hz, 2H), 7.03 (dd, J= 9.4, 2.0 Hz, 1H). |
95.8% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 100℃; for 4h;Inert atmosphere; | To <strong>[356560-80-0]6-bromo-[1,2,4]triazolo[1,5-a]pyridine</strong> (700 mg, 3.5350 mmol),Benzophenone imine (1.28g, 7.06mmol)And t-BuONa (680mg, 7.076mmol)Intoluene (50mL) solutionBINAP (221mg, 0.3549mmol)And Pd2(dba)3 (167 mg, 0.17690 mmol).The resulting mixture was degassed for 5 minutes.And charge N2,It was then stirred at 100 C for 4 hours.After the reaction,The reaction was quenched with water (100 mL).Extracted with EtOAc (100 mL×3).The combined organic phases were dried over anhydrous Na 2 SO 4 .Filter and concentrate under reduced pressure.The residue obtained was purified by silica gel column chromatography (EtOAc/EtOAc (v/v)The title compound was obtained as a yellow solid (1.01 g, 95.8%). |
69% | With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 80℃; | 6-Bromo-[l,2,4]triazolo[l,5-a]pyridine (300 mg, 1.5 mmol), bezophenone imine (326 mg, 1.8 mmol), Pd2(dba)3 (7 mg, 0.008 mmol), BINAP (14 mg, 0.02 mmol) and sodium terf-butoxide (202 mg, 2.1 mmol) were combined in toluene and heated at 80 0C overnight. The mixture was concentrated under reduced pressure and purified by Biotage SP4 (ethyl acetate / petroleum ether gradient) to give the desired product as a yellow crystalline solid (310 mg, 69 %). 1H NMR (400 MHz, DMSO-d6) delta ppm 7.21 (dd, J=9.39, 2.06 Hz, 1 H), 7.24 - 7.29 (m, 2 H), 7.32 - 7.40 (m, 3 H), 7.47 - 7.54 (m, 2 H), 7.55 - 7.62 (m, 1 H), 7.66 (d, J=8.70 Hz, 1 H), 7.68 - 7.74 (m, 2 H), 8.35 (s, 1 H), 8.41 (d, J=I.83 Hz, 1 H); m/z (ES+APCI)+ : 299 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.1% | With 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 150℃; for 0.333333h;Irradiation; | Preparation 59 N-(Diphenylmethylene)-5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazol-6-amine To a 10 mL microwave vial is added <strong>[1206800-24-9]6-bromo-5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazole</strong> (500 mg, 1.37 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (73 mg, 123 mumol) and Pd2(dba)3 (38 mg, 41 mumol). The mixture is suspended in toluene (5 mL, 47 mmol) and benzophenone imine (272 mg, 1.5 mmol) and sodium tert-butoxide (203 mg, 2.05 mmol) are added. The mixture is heated at 150 C. for 20 min in a microwave reactor. After cooling, the reaction solution is concentrated to give a brown oil which is dissolved in DCM (150 mL) and washed with saturated aqueous sodium chloride (2*50 mL). The aqueous layers are combined and extracted with DCM (1*50 mL), dried with Na2SO4, filtered and concentrated to give a brown residue. The residue is purified on a silica gel column eluding with hexanes (A) and EtOAc (B), gradient from 85%(A): 15%(B) to 50%(A):50%(B) over 50 min to give a yellow solid material as the title compound (574 mg, 90.1% yield). MS (m/z): 467.2 EtOAc (B), gradient from 85% (A): 15% (B) to 50% (A):50% (B) over 50 min to give a |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); bis[2-(diphenylphosphino)phenyl] ether; In toluene; at 80℃; for 2h; | 2-Amino-5-trifluoromethoxy pyridine (34); 2-Chloro-5-trifluoromethoxypyridine (6, 1.0 g, 5.0 mmol), benzophenone imine (1.09 g, 6.0 mmol, 1.2 eq), NaOtBu (0.72 g, 7.5 mmol, 1.5 eq), DPEphos (0.03 g, 0.05mmol, 0.01 eq), Pd2dba3 (0.07 g, 0.1 mmol, 0.02 eq) were introduced in dry toluene (15 mL) and the reaction mixture was heated at 80 0C and vigorously stirred for 2 h. GC monitoring indicated 100% conversion. The mixture was allowed to cool to ambient temperature before being filtrated on celite and washed with ethyl acetate. The filtrate was poured onto a 10% aqueous solution of citric acid (30 mL) and the reaction mixture was then vigorously stirred for 16 h at room temperature. GC of the organic phase indicated disappearance of starting reagent and formation of diphenylketone. The aqueous phase was adjusted to pH 9-10 with 5% sodium hydroxide (40 mL) and extracted with ethyl acetate (5 x 20 mL). The combined organic layers were dried over sodium sulfate before being evaporated to afford a crude yellow powder. Crystallization in hexane provided pure 2-amino-5-trifluoromethoxy pyridine (34, 0.36 g, 2.0 mmol, 40%) as colorless needles; m.p. 71 -73 0C.1H NMR (CDCl3, 300 MHz): delta = 7.91 (d, J = 2.7 Hz, 1 H), 7.23 (dd, J = 2.7, 8.9 Hz, 1 H), 6.39 (d, J= 8.9 Hz, 1 H), 4.49 (bs, 2 H). - 19F NMR (CDCl3, 282 MHz): delta = -58.9 - 13C NMR (CDCl3, 75 MHz): delta = 157.1, 141.4, 138.7, 131.6, 120.6 (q, J = 256 Hz), 108.7. - C6H5F3N2O (178): calcd. (%) C 40.46, H 2.83, N 15.73; found C 40.46, H 2.90, N 16.02. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium diacetate; caesium carbonate; triethylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; | EXAMPLE 47CN-(diphenylmethylene)-2-phenylquinolin-6-amineIn a 20 mL microwave tube was charged cesium carbonate (0.440 mL, 5.50 mmol), palladium(II) acetate (0.018 g, 0.079 mmol), and 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (0.068 g, 0.118 mmol) in dioxane (6.0 mL) to give a yellow suspension. The mixture was stirred for 10 minutes and then triethylamine (0.016 mL, 0.118 mmol) was added. The solution was stirred for another 10 minutes; and then8489667 1 <strong>[3894-25-5]6-bromo-2-phenylquinoline</strong> (1.1168 g, 3.93 mmol) and benzophenone imine (0.791 niL, 4.72 mmol) were added as a solution in dioxane (6.0 mL). The mixture was heated at 100 0C overnight. The mixture was cooled to room temperature and dilute with ethyl acetate. The organics were washed 2 x 100 mL with water, dried over magnesium sulfate, filtered, and concentrated onto silica gel. The reaction was purified by flash chromatography using an Argonaut Flashmaster Solo, 20g column (10% ethyl acetate:hexanes for 30 min) to afford a yellow oil. (ES I(+)) m/e 385.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; | Tert-butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate synthesized in Reference Example 17 (59.8 mg, 0.20 mmol, benzophenone imine (43.5 mg, 0.24 mmol), tris(dibenzylideneacetone)dipalladium (9.2 mg, 0.010 mmol), BINAP (12.5 mg, 0.020 mmol), and cesium carbonate (130.3 mg, 0.40 mmol) were suspended in toluene (1.0 mL), and the suspension was stirred at 100C overnight. The resultant reaction mixture was cooled to room temperature and then filtered through Celite, and the Celite was washed with ethyl acetate. The filtrate was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solid was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to yield the title compound (67 mg, 76%). |
76% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; | The <strong>[492431-11-5]tert-butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate</strong> (59.8 mg, 0.20 mmol) prepared in Referential Example 14, benzophenone imine (43.5 mg, 0.24 mmol), tris(dibenzylideneacetone)dipalladium (9.2 mg, 0.010 mmol), BINAP (12.5 mg, 0.020 mmol) and cesium carbonate (130.3 mg, 0.40 mmol) were suspended in toluene (1.0 mL). The reaction mixture was stirred at 100C overnight. The reaction mixture was cooled to room temperature and filtered through a Celite pad. The Celite pad was washed with ethyl acetate. The filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solid was filtered out, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (67 mg, yield: 76%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 3.08333h;Inert atmosphere; | Nitrogen was bubbled into a solution of compound 37 (1.0 g, 3.7 mmol, 1.0 eq), compound 38 (742 mg, 4.1 mmol, 1.1 eq), Pd2(dba)3 (340 mg, 0.37 mmol, 0.1 eq), Xantphos (454 mg, 0.78 mmol, 0.21 eq) and CS2CO3 (2.4 g, 7.4 mmol, 2 eq) in dioxane (20 mL) for 5 mins. The mixture was stirred at 110 C for 3 h. After completion, the mixture was cooled down to RT, diluted with DCM (50 mL) and filtered through a pad of Celite, rinsed with DCM (20 mL). The filtrate was dried over sodium sulfate, concentrated and purified by silica column to give the desired product as a yellow solid (0.5 g, 33%). NMR (300 MHz, CDCb): delta 7.36-7.25 (m, 10 H), 7.17 (d, J= 8.1 Hz, 1 H), 6.35 (d, J= 8.4 Hz, 1 H), 4.48 (s, 2 H), 3.70 (t, J= 6.0 Hz, 2 H), 2.92 (s, J= 6.0 Hz, 2 H), 1.50 (s, 9 H). LCMS: (M+H)+:413.9. |
With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃; for 48h; | To a round-bottomed flask equipped with a stirring bar, tert-butyl 2-chloro-7,8- dihydro-l,6-naphthyridine-6(5H)-carboxylate (1.09 g, 4.05 mmol), diphenyl-methanimine 26 (2.20 g, 12.14 mmol), Pd(OAc)2 (181.6 mg, 0.809 mmol), BINAP (503.8 mg, 0.809 mmol), CS2CO3 (6.59 g, 20.23 mmol) and toluene (16 mL) were added. The reaction mixture was heated at 110 C for 2 days. The reaction mixture was filtered and removed solvent in vacuo. The residue 158a was directly used in the next step. | |
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; | Intermediate W-1 was synthesized through the reaction of <strong>[1151665-15-4]tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate</strong> with benzophenone imine and tert-butoxysodium in the presence of a Pd catalyst and deprotection. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; at 100.0℃; for 16.0h;Inert atmosphere; | Add benzophenone imine (215 mg, 1.19 mmol), cesium carbonate (640 mg, 1.96 mmol), (±)-2,2'-bis(diphenylphosphino)-l, -binaphthalene (BINAP, 98 mg, 0.16 mmol), tris(dibenzylideneacetone)dipalladium [Pd2(dba)3, 90 mg, 0.098 mmol] to the solution of 3-bromo-5-(l, 1 -difluoroethyl)pyridine (200 mg, 0.9 mmol) in dioxane (10 mL), stir the resulting mixture under nitrogen atmosphere at 100C for 16 hrs. Cool the reaction mixture to room temperature, filter off the solid, concentrate the filtrate under reduced pressure, purify by flash chromatography (silica gel, EtOAc:PE=2:l) to yield the title compound (296 mg, 92%). MS: (M+l): 323. |
92% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100.0℃; for 16.0h;Inert atmosphere; | Add benzophenone imine (215 mg, 1.19 mmol), cesium carbonate (640 mg, 1.96 mmol), (+-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP, 98 mg, 0.16 mmol), tris(dibenzylideneacetone)dipalladium [Pd2(dba)3, 90 mg, 0.098 mmol] to the solution of <strong>[1108724-32-8]3-bromo-5-(1,1-difluoroethyl)pyridine</strong> (200 mg, 0.9 mmol) in dioxane (10 mL), stir the resulting mixture under nitrogen atmosphere at 100 C. for 16 hrs. Cool the reaction mixture to room temperature, filter off the solid, concentrate the filtrate under reduced pressure, purify by flash chromatography (silica gel, EtOAc:PE=2:1) to yield the title compound (296 mg, 92%). MS: (M+1): 323. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | In 1,4-dioxane; at 20℃; | General procedure: (The reagents were purchased fromAdamas and used without further purification.) A dry 3-mL flask was chargedwith relevant isatin 5 (0.3 mmol), tert-butyl 2-aminoacetate hydrochloride 7(0.3 mmol) and benzophenone imine 8 (0.36 mmol). The reaction mixture wasstirred at room temperature for the corresponding time. After the completionof the reaction, the reaction mixture was directly purified by silica gelchromatography (ethyl acetate/petroleum ether = 1:4) to give product 6. Asolution of 6 in EA/TFA (10:1) was stirred in a 10-mL flask under roomtemperature for 3 h. The solvent was removed under vacuum. The residue wasrecrystallized in diethyl ether/petroleum ether to give product 9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.3 g | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 16.0h;Inert atmosphere; Sonication; | To a degassed and purged with argon suspension of methyl 2-bromo-5-fluoro-pyridine-4- carboxylate (308 mg, 1.32 mmol) in 1,4-dioxane (6 mL) was added benzophenoneimine (0.266 mL, 1.58 mmol), tris(dibenzylideneacetone)dipalladium(0) (24.1 mg, 0.026 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (30.5 mg, 0.053 mmol) and cesium carbonate (602.0 mg, 0.053 mmol). The reaction mixture was flushed with argon, sonicated, caped and left to stir at 100C for 1 6h. The reaction mixture was cooled, diluted with ethyl acetate (15 mL), washed with water (15 mL), brine (15 mL), and evaporated under reduced pressure affording methyl 2-((diphenylmethylene)amino)-5-fluoroisonicotinate (230 mg). LCMS: MW (calcd): 334.1; MS (ES, m/z): 335.34 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 100℃; for 2h; | To a solution of 7-bromoimidazo[l,2-a]pyridine (5.50 g, 27.91 mmol) and diphenylmethanimine (10.00 g, 55.19 mmol) in toluene (200 mL) were added Pd2(dba)3 (97%, 1.30 g, 1.38 mmol), BINAP (1.70 g, 2.73 mmol) and t-BuONa (5.40 g, 56.19 mmol). The reaction mixture was stirred at 100 C for 2 hours and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v) = 1/20) to give the title compound as brown oil (8.00 g, yield 96%).MS (ESI, pos. ion) m/z: 298.2 [M+H]+;1H NMR (400MHz, CDCl3) d (ppm): 7.84 (d, 7 = 7.1 Hz, 1H), 7.75 (d, J = 7.4 Hz, 2H), 7.51 - 7.45 (m, 2H), 7.43 - 7.38 (m, 3H), 7.31 - 7.22 (m, 3H), 7.18 - 7.15 (m, 2H), 6.88 (d, J= 0.8 Hz, 1H), 6.30 (dd, J= 7.1, 1.9 Hz, 1H). |
96% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 100℃; for 2h; | To <strong>[808744-34-5]7-bromoimidazo[1,2-a]pyridine</strong> (5.50 g, 27.91 mmol)And benzophenone imine (10.00g, 55.19mmol)In toluene (200mL) was addedPd2(dba)3 (97%, 1.30g, 1.38mmol),BINAP (1.70g, 2.73mmol)And t-BuONa (5.40 g, 56.19 mmol).The reaction system was stirred at 100 C for 2 hours.After the reaction,Concentrate under reduced pressure.The residue obtained is purified by silica gel column chromatography (MeOH/DCM (v/v) = 1 / 20).The title compound was obtained as a brown oil ( 8.00 g, yield: 96%). |