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CAS No. : | 213697-53-1 | MDL No. : | MFCD02183572 |
Formula : | C26H36NP | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZEMZPXWZVTUONV-UHFFFAOYSA-N |
M.W : | 393.54 | Pubchem ID : | 2734217 |
Synonyms : |
|
Num. heavy atoms : | 28 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.54 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 0.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 128.21 |
TPSA : | 16.83 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -3.83 cm/s |
Log Po/w (iLOGP) : | 4.51 |
Log Po/w (XLOGP3) : | 6.86 |
Log Po/w (WLOGP) : | 7.19 |
Log Po/w (MLOGP) : | 5.94 |
Log Po/w (SILICOS-IT) : | 6.88 |
Consensus Log Po/w : | 6.28 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 1.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -6.59 |
Solubility : | 0.000101 mg/ml ; 0.000000258 mol/l |
Class : | Poorly soluble |
Log S (Ali) : | -7.02 |
Solubility : | 0.0000373 mg/ml ; 0.0000000948 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -7.93 |
Solubility : | 0.00000457 mg/ml ; 0.0000000116 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 4.32 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-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 |
---|---|---|
73% | In methanol; for 0.25h;Heating / reflux; | 50 ml of degassed, anhydrous methanol were heated to reflux temperature, and 2.00 g (5.1 mmol) of <strong>[213697-53-1]N-[2'-(dicyclohexylphosphino)-1,1'-biphenyl-2-yl]-N,N-dimethylamine</strong> were added slowly to the methanol until the phosphine compound was completely dissolved. Subsequently, 0.8 g (3.7 mmol) of copper(II) bromide was added to the solution in portions. After the copper bromide had been added, the solution was heated to reflux temperature for a further 15 min, and then the solution was cooled. After the solution had been cooled, a solid precipitated out and was filtered off, and was washed with a little ethanol and diethyl ether and subsequently dried. 1.5 g (1.4 mmol, M=1073.8 g/mol) of the abovementioned compound were obtained. The structure was checked by an FD-MS analysis (m/e=1074). The yield was 73% of theory. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.0% | In dichloromethane; for 20h; | CH2Cl2 (25 ml) was added to a Schlenk flask containing 2-(N,N-dimethylamino)-2'-(dicyclohexylphosphino)biphenyl (2.00 g, 5.10 mmol) and (DME)NiBr2 (1.23 g, 4.0 mmol) in a dry box. A dark blue solution formed immediately upon mixing. This solution was stirred for 20 hours. Then, it was filtered and recrystallized from CH2Cl2/pentane. The product was washed three times with an additional 15 ml of pentane and dried for 1 hour under vacuum. A blue powder was isolated in 49.0% yield. The product was soluble in CH2Cl2. IH NMR indicates that it is paramagnetic. Anal. Calcd for (C26H36NPBr2Ni) : C, 51.02% ; H, 5.94% ; N, 2.29% ; P, 5.06%. Found: C, 50.72% ; H, 6.10% ; N, 2.12% ; P, 5.02%. The IR (cm-1, KBr): 272, v (Ni-Br). This compound has also been characterized by x-ray crystallography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; | (COD)PdCl2 (2.0 g, 7.0 mmol) was mixed with tetramethyltin (1.16 ml, 8.4 mmol) in CH2Cl2 (50 ml) at room temperature. The mixture was stirred overnight until the bright yellow color of the precursor had vanished. The resulting mixture was filtered through Celite yielding a pale yellow solution. The solvent was removed from the that solution, leaving behind an off-white solid, (COD)PdClMe, which was washed twice with diethyl ether and dried under vacuum. A solution of the white (COD)PdClMe complex (0.775 g, 0.0029 mol dissolved in CH2Cl2) was reacted with 2-(N,N-dimethylamino)-2'-(dicyclohexylphosphino)biphenyl (1.78 g, 0.0045 mol). As a result, a light yellow palladium complex formed. 1H NMR (250 MHz, CD2Cl2, delta, ppm) : 0.88-2.94 m (22H, 2xC6H11) ; 1.06 d (3H, PdCH3, JPH = 2.5 Hz); 2.87 s (6H, 2xCH3); 6.75-7.68 m (8H, 2xC6H4). Anal. Calcd for (C27H39NPClPd) : C, 58.91% ; H, 7.16% ; N, 2.55% ; P, 5.63%. Found: C, 59.21% ; H, 7.31% ; N, 2.38% ; P, 5.41%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate;palladium diacetate; In diethyl ether; toluene; | 2-Amino-4-p-tolyl-quinoline-3-carbonitrile 2-Amino-4-bromo-quinoline-3-carbonitrile (248 mg, 1 mmol), 4-Methylphenyl boronic acid (204 mg, 1.5 mmol), Palladium(II)acetate (11 mg, 0.05 mmol), 2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (39 mg, 0.10 mmol), and K3PO4 (425 mg, 2 mmol) were suspended in 4 ml of toluene (Argon atmosphere) and heated to 100 C. for 21 h. The reaction mixture was taken up in diethyl ether, washed with aq. NaOH and brine, and dried over Na2SO4. The solvent was evaporated and the title compound (46 mg, 18%), MS: m/e=259.9 (M++H), was isolated from the residue by column chromatography (silica gel, Dichloromethane/Methanol=100:0-85:15). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With triethylamine; In ethyl acetate; N,N-dimethyl-formamide; | (1S)-{1-(1H-Indol-3-ylmethyl)-2-[5-(3-phenyl-isoquinolin-6-yl)-pyridin-3-yloxy]-ethyl}-carbamic Acid Tert-Butyl Ester To a solution of Example 80E (150 mg, 0.28 mmol), (1,1,1-tributylstannyl)benzene (137 mg, 0.57 mmol), tris(dibenzylideneacetone)-dipalladium (27 mg, 0.028 mmol) and 2-dicyclohexylphosphino-2'-dimethylamino-1,1'-biphenyl (22 mg, 0.057 mmol) in dry DMF (10 ml) triethyl amine was added under N2. The resulting solution was stirred 3 hours at 100 C. The reaction solution was partitioned between ethylacetate and water. The organic layer was washed (brine), dried (Na2SO4), filtered and concentrated under vacumm. Purification on silica gel with 60% ethyl acetate/hexane to provide the title compound (70 mg, 47%). MS (DCI/NH3) m/e 571 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethyl acetate; N,N-dimethyl-formamide; | Example 234G 5-(4-Methoxy-benzyloxy)-2-pyridin-4-yl-[1,7]naphthyridine Example 234F (164 mg, 0.55 mmol), 4-tributylstannylpyridine (401 mg, 1.09 mmol), Pd2 dba3 (50 mg, 0.06 mmol), and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (43 mg, 0.11 mmol) were combined in a 10 mL round bottom flask with a stirbar. The atmosphere of the flask was evacuated and replaced with argon twice. DMF (2 mL) and Et3N (0.5 mL, 3.27 mmol) were added and the reaction mixture warmed to 100 C. for 5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and Et2O, and filtered through Celite. The filtrate was washed twice with H2O and once with brine. Silica gel was added and the volatiles removed by rotary evaporation. Flash chromatography (70-100% EtOAc/hexanes-2-5% MeOH/CH2Cl2 gave 92 mg (49%) of as a yellow solid. Rf=0.39 (10% MeOH/CH2Cl2), 1H NMR (400 MHz, DMSO-D6) delta ppm 3.79 (s, 3H) 5.37 (s, 2H) 7.01 (m, 2H) 7.53 (m, 2H) 8.21 (d, J=5.83 Hz, 2H) 8.43 (m, 2H) 8.64 (d, J=8.59 Hz, 1H) 8.80 (d, J=4.30 Hz, 2H) 9.13 (s, 1H), 13C NMR (100 MHz, DMSO-D6) delta ppm 55.1, 70.3, 113.9, 121.3, 122.1, 122.6, 126.0, 128.1, 129.6, 131.3, 142.7, 144.6, 145.8, 148.4, 150.5, 155.5, 159.2; Anal Calcd for C21H17N3O2: C, 73.45; H, 4.99; N, 12.24. Found: C: 73.32, H: 5.10, N: 12.17. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With potassium fluoride; nitrogen; 2-amino-5,6-dihydrobenzo[d]thiazol-7(4H)-one; In 1,2-dimethoxyethane; palladium diacetate; | N-16-(5-Chloro-2-thienyl)-1,3-benzothiazol-2-yl]-N'-ethylurea This is an alternative procedure for making the compound of Example 314. A 40 ml pressure tube was charged with about 32 mg 5-chlorothiophene-2-boronic acid, about 50 mg N-(6-bromo-1,3-benzothiazol-2-yl)-N'-ethylurea and about 30 mg potassium fluoride as base. About 3 ml ethylene glycol dimethyl ether was added and the suspension was vacuum purged and released to nitrogen three times. The catalyst solution was prepared in a separate flask as follows: about 31 mg of Pd(OAc)2 and about 110 mg of 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl were charged followed by about 6 ml ethylene glycol dimethyl ether. The flask was vacuum purged and released to nitrogen 3 times followed by stirring to complete solution. An appropriate amount of catalyst solution (about 10-50 mol percent catalyst) was then transferred to the pressure tube. The pressure tube was then evacuated then released to nitrogen atmosphere three times, sealed tightly and heated to about 85-90 C. for about 12-20 hours. Upon cooling to room temperature the now clear solution was purified by preparative HPLC to yield about 33% of N-[6-(5-chloro-2-thienyl)-1,3-benzothiazol-2-yl]-N'-ethylurea. 1H NMR 1.1 (t, 3H), 3.2 (m, 2H), 6.75 (m, 1H), 7.18 (d, 1H), 7.38 (m, 1H), 7.6 (m, 2H), 8.19 (d, 1H), 10.75 (br s, 1H); LC/MS 3.86 min, 338 (M+1), 336 (M-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); In 1,2-dimethoxyethane; n-heptane; ethyl acetate; | Preparation 123 Preparation of benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate To an 250 ml r.b-flask was sequentially added benzyl (3R,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate (4.9714 g, 21.04 mmol), chloride (3.949 g, 23.15 mmol), Pd2(dba)3 (10 mol %, 1.926 g), 2-dicyclohexylphosphino-2'-(N,N-dimethyl amino)biphenyl (20 mol %, 1.656 g), and DME (110 ml). Cs2CO3 (9.57 g) was then added and the reaction mixture was stirred at 80 C. for 20 hr. It was cooled, diluted with Et2O (100 ml), poured into NaHCO3 (80 ml), extracted with CH2Cl2 (150 ml*3), dried (MgSO4), and concentrated. Purification via biotage chromatography (35% EtOAc in heptane) provided the title compound. 1H NMR (CDCl3) delta1.28 (m, 6 H), 2.65 (m, 4 H), 3.36 (m, 1 H), 3.63 (m, 1 H), 3.73 (m, 1 H), 4.00 (m, 1 H), 4.51 (m, 1 H), 4.64 (m, 1 H), 4.80 (m, 1 H), 5.18 (s, 2 H), 7.38 (m, 6 H), 7.74 (d, 1H); IR (liq.) 2969, 2344 (w), 1996 (w), 1952 (w), 1703 (s), 1691 (s), 1546, 1499 (s), 1449 (s), 1426 (s), 1395, 1359 (s), 1175, 1133, 1095, cm-1 HRMS (FAB) calcd for C20H26N4O3+H 371.2083, found 371.2089. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25 mg (18%) | With dimethyl amine;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; toluene; | Example 25 1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one To 3-bromo-1-(4-methoxyphenyl)-6-[4-(2-oxo-1-piperidinyl)phenyl]1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one (Example 21)(0.15 g, 0.3 mmol), dimethylamine (2M THF, 1.5 mL, 3 mmol), sodium t-butoxide (88 mg, 0.9 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (7 mg), was added toluene/dioxane (1:1) (15 mL) and the mixture was degassed with N2. Pd2(dba)3 was added and the reaction was heated to 85 C. for 24 h. The reaction was cooled, diluted with ethyl acetate and filtered through Celite. Purification by HPLC and freeze-drying afforded 25 mg (18%) of the title compound; HRMS (M+Na)+for C24H24NaN4O3 was 439.1726; 1H NMR (CDCl3) delta7.59 (s, 1H), 7.47 (d,j=8.8 Hz, 2H), 7.36 (d,j=8.8 Hz, 2H), 7.26 (d,j=9.1 Hz, 2H), 6.92 (d,j=9.2 Hz, 2H), 4.10 (t,j=6.6 Hz, 2H), 3.60 (m, 2H), 3.81 (s, 3H), 3.03 (t,j=6.6 Hz, 2H), 2.57 (m, 2H),1.94 (m, 4H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.38 g (98%) | With cesium fluoride;palladium diacetate; In 1,4-dioxane; ethyl acetate; | EXAMPLE 31A 3'-methoxy-6-methyl(1,1'-biphenyl)-3-carbonitrile A mixture of <strong>[21423-81-4]3-chloro-4-methylbenzonitrile</strong> (3.30 g, 20 mmol), 3-methoxyphenylboronic acid (4.56 g, 30 mmol), palladium acetate (89.8 mg, 0.4 mmol), 2-dicyclohexylphosphanyl-2'-dimethylaminobiphenyl (0.236 g, 0.6 mmol), and CsF (9.11 g, 60 mmol) in dioxane (60 mL) at room temperature was stirred for 12 hours, and concentrated. The concentrate was dissolved in ethyl acetate (10 mL), washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4:100 ethyl acetate/hexane to provide 4.38 g (98%) of the desired product. MS (DCI/NH3) m/z 241 (M+NH4)+; 1H NMR (CDCl3) delta7.55-7.52 (m, 2H), 7.38-7.33 (m, 2H), 6.94 (m, 1H), 6.86 (m, 1H), 6.80 (m, 1H), 3.84 (s, 3H), 2.32 (s, 3H). |
4.38 g (98%) | With cesium fluoride;palladium diacetate; In 1,4-dioxane; ethyl acetate; | EXAMPLE 31A 3'-methoxy-6-methyl(1,1'-biphenyl)-3-carbonitrile A mixture of <strong>[21423-81-4]3-chloro-4-methylbenzonitrile</strong> (3.30 g, 20 mmol), 3-methoxyphenylboronic acid (4.56 g, 30 mmol), palladium acetate (89.8 mg, 0.4 mmol), 2-dicyclohexylphosphanyl-2'-dimethylaminobiphenyl (0.236 g, 0.6 mmol), and CsF (9.11 g, 60 mmol) in dioxane (60 mL) at room temperature was stirred for 12 hours, and concentrated. The concentrate was dissolved in ethyl acetate (10 mL), washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4:100 ethyl acetate/hexane to provide 4.38 g (98%) of the desired product. MS (DCI/NH3) m/z 241 (M+NH4)+; 1H NMR (CDCl3) delta 7.55-7.52 (m, 2H), 7.38-7.33 (m, 2H), 6.94 (m, 1H), 6.86 (m, 1H), 6.80 (m, 1H), 3.84 (s, 3H), 2.32 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
269 mg (60%) | With sodium t-butanolate; In ethyl acetate; toluene; | REFERENCE EXAMPLE 85 1-(6-Chloro-3-pyridinyl)-4-ethylpiperazine A mixture of 5-bromo-2-chloropyridine (384 mg, 2.0 mmol), 1-ethylpiperazine (228 mg, 2.0 mmol), sodium tert-butoxide (576 mg, 6 mrnmol), tris(dibenzylideneacetone) dipalladium(0) (18.3 mg, 0.02 mmol), and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl (23.6 mg, 0.06 mmol) in 10 mL of toluene was heated at reflux for 1 hour and concentrated. The residue was purified by flash column chromatography, eluding with 5% methanol in ethyl acetate to provide 269 mg (60%) of 1-(6-chloro-3-pyridinyl)-4-ethylpiperazine as a brown semi-solid: MS 225.9 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cesium fluoride;palladium diacetate; In 1,4-dioxane; ethyl acetate; | EXAMPLE 54A methyl 4-(2-methyl-1,3-benzoxazol-5-yl)benzoate A room temperature solution of <strong>[19219-99-9]5-chloro-2-methyl-1,3-benzoxazole</strong> (110 mg, 0.71 mmol), CsF (325 mg, 2.14 mmol), Pd(OAc)2 (6.0 mg, 0.028 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (14 mg, 0.036 mmol) and 4-(methoxycarbonyl)phenylboronic acid (180 mg, 1.0 mmol) in dioxane (4 mL) was stirred for 18 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 15% ethyl acetate/hexanes to provide the desired product. 1H NMR (300 MHz, DMSO-d6) delta8.06 (d, 2H), 8.03 (d, 1H), 7.90 (d, 2H), 7.78 (d, 2H), 7.71 (dd, 1H), 7.29 (d, 2H), 3.90 (s, 3H), 2.65 (s, 3H). | |
With cesium fluoride;palladium diacetate; In 1,4-dioxane; ethyl acetate; | Example 54A methyl 4-(2-methyl-1,3-benzoxazol-5-yl)benzoate A room temperature solution of <strong>[19219-99-9]5-chloro-2-methyl-1,3-benzoxazole</strong> (110 mg, 0.71 mmol), CsF (325 mg, 2.14 mmol), Pd(OAc)2 (6.0 mg, 0.028 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (14 mg, 0.036 mmol) and 4-(methoxycarbonyl)phenylboronic acid (180 mg, 1.0 mmol) in dioxane (4 mL) was stirred for 18 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 15% ethyl acetate/hexanes to provide the desired product. 1H NMR (300 MHz, DMSO-d6) delta 8.06 (d, 2H), 8.03 (d, 1H), 7.90 (d, 2H), 7.78 (d, 2H), 7.71 (dd, 1H), 7.29 (d, 2H), 3.90 (s, 3H), 2.65 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; toluene; | d 7-(2-{1-[1-(3-Benzyloxy-phenyl)-2-ethoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester A solution of 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (0.20 g, 0.51 mmol), 7-(2-1-[1-(3-benzyloxy-phenyl)-2-ethoxycarbonyl-vinyl]-1H-indol-5-yloxy}-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (0.18 g, 0.56 mmol), potassium phosphate (0.16 g, 0.77 mmol), 2-dicyclohexylphosphino-2'(N,N-dimethylamino)biphenyl (0.03 g, 0.08 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.03 mg, 0.08 mmol) in 10% DMF/toluene (3 mL) was heated at 110 C. for 6 days under argon. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was purified by column chromatography with silica gel, eluding with hexane/ethyl acetate (4/1) to give the title compound (29%) as an E/Z isomeric mixture. 1H NMR (CDCl3) [E/Z mixture] delta7.36-7.22 (m, 7H), 7.10 (m, 4H), 6.86 (m, 3H), 6.75 (m, 1H), 6.58 (m, 1H), 6.22 (s, 1H), 5.00 (s, 2H), 4.40 (m, 2H), 4.01 (q, 2H, J=7.2 Hz), 3.78 (m, 2H), 3.22 (m, 2H), 2.75 (m, 2H), 1.85 (m, 2H), 1.52 (s, 9H), 1.01 (t, 3H, J=6.8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nitrogen; sodium carbonate; caesium carbonate;palladium diacetate; In tetrahydrofuran; dichloromethane; toluene; | EXAMPLE 1 (3R)-3-(4-Trifluoromethyl-phenylamino)-pentanenitrile A clean, dry and nitrogen gas purged 100 L glass tank was charged with (R)-3-aminopentanenitrile methanesulfonic acid salt (3000 g, 15.44 mol), sodium carbonate (2.8 kg, 26.4 mol), and methylene chloride (21 L). The heterogeneous mixture was stirred well for at least 2 hours. The mixture was filtered and the filter was rinsed with methylene chloride (3*2 L). The resulting filtrate was placed in a clean, dry, and nitrogen gas purged 50 L glass reaction tank. The methylene chloride was removed by distillation until the internal temperature reached 50-53 C. to afford the free-based amine as a thin oil. The tank was then cooled to room temperature and charged with toluene (20 L), chloro-4-(trifluoromethyl)benzene (4200 g, 23.26 mol), and cesium carbonate (7500 g, 23.02 mol). The solution was sparged with nitrogen gas for 1 hour. Near the time of completion of the sparging, fresh catalyst solution was prepared by charging a 2L round-bottom flask, equipped with stir bar and flushed with nitrogen gas, with 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (68 g, 0.17 mol), phenylboronic acid (28 g, 0.23 g), and tetrahydrofuran (1.2 L) followed by palladium acetate (26 g, 0.12 mol). The catalyst solution was stirred at room temperature under nitrogen atmosphere for 15 minutes. The catalyst solution was added to the 50L reaction tank with the use of a cannula (excluding air). The mixture was heated to 79 C. internal temperature under nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature and filtered through Celite. The solids were rinsed with toluene (3*2L) and the filtrate was collected. All filtrates were combined to afford a crude solution of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.30 g (16%) | With sodium t-butanolate;palladium diacetate; In hexane; toluene; | (3,5-dinitrophenyl)-2-pyridylamine. To a mixture of 3,5-dinitroaniline (1.3 g, 7.1 mmol), 2-bromopyridine (1.1 g, 7.1 mmol), palladium acetate (0.13 g, 0.57 mmol) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (0.28 g, 0.71 mmol) in toluene (20 mL) was added solid sodium tert-butoxide (0.75 g, 7.8 mmol) and the mixture heated at reflux temperature for 3 d. The reaction mixture was then concentrated and the product purified on silica gel using 2:1 hexane:ethyl acetate as eluent to give 0.30 g (16%) of pyridyl substituted compound as a red solid: Low resolution MS Calcd for C11H8N4O4: 260. Found: 260. |
Yield | Reaction Conditions | Operation in experiment |
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With cesium fluoride; In 1,4-dioxane; ethyl acetate; | EXAMPLE 275C methyl 6-cyano-5-(1-naphthyl)nicotinate A mixture of Example 275B (800 mg, 4 mmol), 1-naphthaleneboronic acid (1.5 g, 8.7 mmol), palladium(I) acetate (17 mg, 0.08 mmol), 2-dimethylamino-2'-dicyclohexylphosphino-biphenyl (44 mg, 0.11 mmol), and CsF (2 g, 13 mmol) in dioxane (20 mL) at room temperature was stirred for 48 hours, treated with ethyl acetate, washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 9:1/hexanes:ethyl acetate to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
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500 mg (36%) | With potassium phosphate; trichlorophosphate;tris(dibenzylideneacetone)dipalladium (0); In 1,2-dimethoxyethane; sodium hydrogencarbonate; | EXAMPLE 219 8-(Benzyloxy)-4-[(2-chloro-4-fluoro-5-methoxyphenyl)amino]-7-methoxybenzo[g]quinoline-3-carbonitrile A mixture of 8-benzyloxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile (11.4 g, 31.9 mmol) and phosphorus oxychloride (147 g, 959 mmol) is heated under reflux for one hour. After cooling to room temperature, the reaction mixture is evaporated under vacuum to remove the volatiles. The residue is carefully slurried in cold saturated aqueous sodium bicarbonate solution (500 mL). The solids are collected by filtration, washed thoroughly with saturated aqueous sodium bicarbonate solution and water and dried to give 11.7 grams of crude 8-(benzyloxy)-4-chloro-7-methoxybenzo[g]quinoline-3-carbonitrile as a light orange solid. A mixture of 8-(benzyloxy)-4-chloro-7-methoxybenzo[g]quinoline-3-carbonitrile (1.00 g, 2.7 mmol), 2-chloro-4-fluoro-5-methoxyaniline (560 mg, 3.2 mmol), tris(dibenzylideneacetone)dipalladium(O) (240 mg, 0.26 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (330 mg, 0.84 mmol) and K3PO4 (860 mg, 4.1 mmol) in 15 mL of ethylene glycol dimethyl ether is heated at 80 C. for 3 hours. An additional 5% of all reagents is added and the mixture is heated at 80 C. for 2 hours then cooled to room temperature and partitioned between aqueous sodium bicarbonate and methylene chloride. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by column chromatography eluding with 1:1 hexane/ethyl acetate yields 500 mg (36%) of 8-(benzyloxy)-4-[(2-chloro-4-fluoro-5-methoxyphenyl)amino]-7-methoxybenzo[g]quinoline-3-carbonitrile as a yellow solid, mp 248-250 C. dec. MS 514.2 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; In 1,2-dimethoxyethane; diethyl ether; water; pentane; | A. 4-[4-Isopropyl-piperazin-1-yl]-benzoic acid methyl ester Tris-(dibenzylidene-acetone)-dipalladium (0.05 mmol), (2'-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (0.1 mmol) and potassium carbonate (4.6 mmol) are suspended in 1,2-dimethoxyethane (10 ml) in an oxygen-free atmosphere (N2). 4-Bromo-benzoic acid methyl ester (3.3 mmol) and 1-isopropyl-piperazine (3.9 mmol) are added and the stirred mixture is heated under reflux for 28 hours. After cooling the solvent is evaporated and water is added to the residue, which is then extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with (CH2Cl2/MeOH=95:5) as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A pale-brown powder with Rf=0.23 (CH2Cl2/MeOH=95:5) is obtained. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium t-butanolate; In diethyl ether; ethyl acetate; toluene; | A. 4-(4-Benzyl-piperazin-1-yl)-benzoic acid methyl ester Tris-(dibenzylidene-acetone)-dipalladium (0.03 mmol), (2'-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (0.9 mmol) and NaOtBu (6.5 mmol) are suspended in toluene (20 ml) in an oxygen-free atmosphere (N2). 4-Bromo-benzoic acid methyl ester (4.65 mmol) and 1-(benzyl)-piperazine (5.6 mmol) are added and the stirred mixture is heated under reflux for 4 hours. After cooling, a mixture of ethylacetate and diethylether is added and the mixture is filtered. Then the solvent is evaporated and the residue is suspended in diethylether and the solid filtered of and dried (vacuum). A pale powder with mp. 105-107 C., Rf=0.67 (CH2Cl2/MeOH=95:5) is obtained. |
Yield | Reaction Conditions | Operation in experiment |
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With NaH; In toluene; mineral oil; | Example 54H 4-benzyloxy-2-[7-(tert-butyl-dimethyl-silanyloxy)-naphthalen-1-ylamino]-benzoic Acid Benzyl Ester A mixture of benzyl-2-bromo-4-benzyloxybenzoate (285 mg, 0.717 mmol), 2-(tertbutyldimethylsilyloxy)-8-aminonaphthalene (196 mg, 0.717 mmol), tris-(dibenzylideneacetone)dipalladium (4 mg, 0.004 mmol), (2'-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (6 mg, 0.015 mmol) and 60% NaH in mineral oil (45 mg, 1.1 mmol) in toluene (3 mL) was heated to reflux under N2 for 1 hour, poured into water (10 mL) acidified to a pH <3with aqueous 1M HCl and extracted with diethyl ether (3*5 mL). The combined ether layers were washed with brine (1*5 mL), dried (MgSO4), filtered, concentrated under reduced pressure and purified silica gel eluding with 10% ethyl acetate/hexanes to provide the titled compound. |
Yield | Reaction Conditions | Operation in experiment |
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39 mg (75%) | With ammonium hydroxide; triethylamine; cesium fluoride; In 1,2-dimethoxyethane; chloroform; | EXAMPLE 44 4-(5-m-TOLYL-BENZOOXAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE Et3N (5 muL) was added to a solution of palladium (II) acetate (0.7 mg, 3.1 mumol) and 2-(N,N-dimethylamino)-2'-dicyclohexylphosphinobiphenyl (1.8 mg, 4.65 mumol) in 1,2-dimethoxyethane (0.5 mL) under a nitrogen atmosphere at RT. 4-(5-Bromo-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane (50 mg, 0.155 mmol, prepared in example 9), m-tolylboronic acid (32 mg, 0.233 mmol) and CsF (70 mg, 0.465 mmol) were added to the solution and the mixture was heated in an oil bath (temp=80 C.) for a period of 16 h. The reaction mixture was cooled to RT, filtered through a pad of celite and concentrated in vacuo. The crude residue was purified by chromatography (Biotage, 12L) eluding with 4% MeOH in CHCl3 with 1 mL of NH4OH per L to give 39 mg (75%) of the title compound as a film: 1H NMR (CDCl3, 400 MHz) delta 7.55 (d, 1H, J=1.7 Hz), 7.40-7.38 (m, 2H), 7.33-7.26 (m, 2H), 7.22-7.19 (m, 1H), 7.14 (d, 1H, J=7.4 Hz), 4.54-4.52 (m, 1H), 3.94 (t, 2H, J=5.8 Hz), 3.19-3.12 (m, 4H), 3.06-2.99 (m, 2H), 2.41 (s, 3H), 2.20-2.13 (m, 2H), 1.86-1.78 (m, 2H); 13C NMR (CDCl3, 100 MHz) delta 162.2, 148.6, 144.3, 141.9, 138.5, 138.0, 128.9, 128.4, 127.8, 124.6, 119.8, 114.8, 108.7, 57.3, 50.4, 46.5, 44.4, 27.0, 21.8; MS (Cl) m/z 334,1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
palladium diacetate; In 1,4-dioxane; | a 4-(4-Trifluoromethyl)-acetophenone A suspension of 3.44 g 4-bromoacetophenone, 4.94 g 4-trifluoroboronic acid, 7.88 g cesiumfluoride, 80 mg palladium acetate and (2'-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (Buchwalds' ligand), in 100 ml dioxane is heated under nitrogen. When the reaction is complete, the suspension is filtered over Hyflo, the filtrate is evaporated and purified by filtration over silicagel (hexane-ethyl acetate 7:3) to obtain 4-(4'-trifluoromethyl-phenyl)-acetophenone a yellowish solid, m.p. 114-116 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; 1,1,1,3,3,3-hexamethyl-disilazane;Pd2dba3; In toluene; | A. (2-Chloro-4-trifluoromethylphenyl)-acetic acid A solution of LiHMDS in toluene was prepared by the addition of n-BuLi (357 mL of a 1.6 M solution in hexanes, 571 mmol) to a cold (-78 C.) solution of HMDS (120.5 mL, 571 mmol) in toluene (700 mL). After 30 min, the reaction mixture was allowed to warm up to 10 C. over 1 h. The solution was then transferred via a cannula to a flame-dried, three-neck flask under N2 containing Pd2dba3 (4.18 g, 4.57 mmol) and (2'-dicyclohexylphosphanylbiphenyl-2-yl)-dimethylamine (3.77 g, 9.59 mmol). The mixture was stirred for 15 min at 15 C., cooled to -10 C. and t-butylacetate (70.5 mL, 525.4 mmol) was added dropwise. After 10 min, <strong>[141738-80-9]3-chloro-4-iodobenzotrifluoride</strong> (70 g, 228.4 mmol) was added and the reaction mixture was warmed up to 28 C. After stirring at this temperature for 1.5 h, the mixture was filtered through silica gel, using toluene as eluent, and the solvent was removed in vacuo. The residue was purified using flash chromatography (silica gel, 98:2 hexanes:EtOAc) to yield (2-chloro-4-trifluoromethylphenyl)-acetic acid tert-butyl ester as a solid. | |
With n-butyllithium; 1,1,1,3,3,3-hexamethyl-disilazane; In toluene; | A. (2-Chloro-4-trifluoromethylphenyl)-acetic Acid A solution of LiHMDS in toluene was prepared by the addition of n-BuLi (357 mL of a 1.6 M solution in hexanes, 571 mmol) to a cold (-78 C.) solution of HMDS (120.5 mL, 571 mmol) in toluene (700 mL). After 30 min, the reaction mixture was allowed to warm up to 10 C. over 1 h. The solution was then transferred via a cannula to a flame-dried, three-neck flask under N2 containing Pd2 dba3 (4.18 g, 4.57 mmol) and (2'-dicyclohexylphosphanylbiphenyl-2-yl)-dimethylamine (3.77 g, 9.59 mmol). The mixture was stirred for 15 min at 15 C., cooled to -10 C. and t-butylacetate (70.5 mL, 525.4 mmol) was added dropwise. After 10 min, <strong>[141738-80-9]3-chloro-4-iodobenzotrifluoride</strong> (70 g, 228.4 mmol) was added and the reaction mixture was warmed up to 28 C. After stirring at this temperature for 1.5 h, the mixture was filtered through silica gel, using toluene as eluent, and the solvent was removed in vacuo. The residue was purified using flash chromatography (silica gel, 98:2 hexanes:EtOAc) to yield (2-chloro-4-trifluoromethylphenyl)-acetic acid tert-butyl ester as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The crude material was placed into a round bottomed flask, and the flask was purged with argon. THF (2 mL) was added, and the mixture was cooled to 0 C. with stirring. A solution of BH3 in THF (7 mL, 1M, 7.0 mmol) was added dropwise to the mixture. The mixture was stirred at 0 C. for 1.5 h, then warmed to room temperature and stirred for 19 h. Acetic acid (4 mL) was added and the mixture was stirred at room temperature for 6h. The mixture was then diluted with ether (50 mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (50 mL), the layers were separated, and the aqueous phase was extracted with ether (50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 555 mg of 2 which was judged to be 93% pure by GC analysis. | ||
1.23 g (79%) | An oven-dried Schlenk flask was cooled to room temperature under an argon purge, and was charged with tetrakis(triphenylphosphine)palladium (289 mg, 0.25 mmol, 5 mol %) sodium carbonate (2.86 g, 27 mmol), and 1 (1.0 g, 5.0 mmol). The flask was purged with argon and DME (50 mL), ethanol (2 mL), water (15 mL), and 2-bromoiodobenzene (0.83 mL, 6.05 mmol) were added through a rubber septem. The mixture was heated to 85 C. with stirring for 3 days. The mixture was cooled to room temperature, diluted with ether (100 mL), and poured into a separatory funnel. The layers were separated and the organic phase was washed with 1M NaOH (2*50 mL), washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 1.23 g (79%) of 2 as a colorless oil. | |
The crude material was placed into a round bottomed flask, and the flask was purged with argon. THF (2 mL) was added, and the mixture was cooled to 0 C. with stirring. A solution of BH3 in THF (7 mL, 1M, 7.0 mmol) was added dropwise to the mixture. The mixture was stirred at 0 C. for 1.5 h, then warmed to room temperature and stirred for 19 h. Acetic acid (4 mL) was added and the mixture was stirred at room temperature for 6 h. The mixture was then diluted with ether (50 mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (50 mL), the layers were separated, and the aqueous phase was extracted with ether (50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 555 mg of 2 which was judged to be 93% pure by GC analysis. |
1.23 g (79%) | An oven-dried Schlenk flask was cooled to room temperature under an argon purge, and was charged with tetrakis(triphenylphosphine)palladium (289 mg, 0.25 mmol, 5 mol %) sodium carbonate (2.86 g, 27 mmol), and 1 (1.0 g, 5.0 mmol). The flask was purged with argon and DME (50 mL), ethanol (2 mL), water (15 mL), and 2-bromoiodobenzene (0.83 mL, 6.05 mmol) were added through a rubber septem. The mixture was heated to 85 C. with stirring for 3 days. The mixture was cooled to room temperature, diluted with ether (100 mL), and poured into a separatory funnel. The layers were separated and the organic phase was washed with 1M NaOH (2*50 mL), washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 1.23 g (79%) of 2 as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A round bottomed flask was purged with argon and charged with alcohol 1 (1.78 g, 7.0 mmol), dichloromethane (28 mL), triethylsilane (1.5 mL, 9.1 mmol), and trifluoroacetic acid (1.1 mL, 14.7 mmol). The mixture was stirred at room temperature for 1.5 h, then was quenched with solid potassium carbonate (ca 2 g). The mixture was diluted with ether (50 mL) and transferred to a separatory funnel. The mixture was washed with saturated aqueous NaHCO3 (50 mL), and the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford a mixture of 2 and 1-(2-bromophenyl)cyclohexene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.01 g (95%) | tris-(dibenzylideneacetone)dipalladium(0); In toluene; | N-(4-Cyanophenyl)morpholine.11 An oven-dried resealable Schlenk tube was purged with argon and charged with Pd2(dba)3 (11.5 mg, 0.025 mmol, 5 mol % Pd), 2 (14.8 mg, 0.075 mmol, 7.5 mol %), NaOt-Bu (68 mg, 0.71 mmol) and 4-chlorobenzonitrile (69 mg, 0.50 mmol). The tube was purged with argon then DME (0.5 mL) and morpholine (53 muL, 0.61 mmol) were added through a rubber septum. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for 26 h, then diluted with EtOAc, filtered through celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 91 mg (96%) of a tan solid. Amination using 0.05 mol % Pd. An oven-dried resealable Schlenk tube was purged with argon and charged with Pd2(dba)3 (2.3 mg, 0.0025 mmol, 0.05 mol % Pd), ligand 2 (2.9 mg, 0.0075 mmol, 0.075 mol %), and NaOt-Bu (1.34 g, 13.9 mmol). Toluene (10 mL), di-n-butylamine (2.00 mL, 11.9 mmol), and 4-chlorotoluene (1.18 mL, 10.0 mmol) were added and the mixture was degassed using three freeze-pump-thaw cycles. The reaction vessel was placed under argon, sealed with a teflon screw cap, and stirred in a 100 C. oil bath for 20 h after which time GC analysis showed the aryl halide had been completely consumed. The reaction mixture was cooled to room temperature, diluted with ether (100 mL) and extracted with 1 M HCl (3*100 mL). The combined aqueous acid phase was basified with 3N NaOH, then extracted with ether (3*150 mL). The ethereal extracts were dried over anhydrous sodium sulfate, filtered and concentrated to afford 2.01 g (95%) of di-n-butyltoluidine6 as a pale yellow oil. |
2.01 g (95%) | tris-(dibenzylideneacetone)dipalladium(0); In toluene; | N-(4-Cyanophenyl)morpholine.11 An oven-dried resealable Schlenk tube was purged with argon and charged with Pd2(dba)3 (11.5 mg, 0.025 mmol, 5 mol % Pd), 2 (14.8 mg, 0.075 mmol, 7.5 mol %), NaOt-Bu (68 mg, 0.71 mmol) and 4-chlorobenzonitrile (69 mg, 0.50 mmol). The tube was purged with argon then DME (0.5 mL) and morpholine (53 muL, 0.61 mmol) were added through a rubber septum. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for 26 h, then diluted with EtOAc, filtered through celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 91 mg (96%) of a tan solid. Amination using 0.05 mol % Pd. An oven-dried resealable Schlenk tube was purged with argon and charged with Pd2(dba)3 (2.3 mg, 0.0025 mmol, 0.05 mol % Pd), ligand 2 (2.9 mg, 0.0075 mmol, 0.075 mol %), and NaOt-Bu (1.34 g, 13.9 mmol). Toluene (10 mL), di-n-butylamine (2.00 mL, 11.9 mmol), and 4-chlorotoluene (1.18 mL, 10.0 mmol) were added and the mixture was degassed using three freeze-pump-thaw cycles. The reaction vessel was placed under argon, sealed with a teflon screw cap, and stirred in a 100 C. oil bath for 20 h after which time GC analysis showed the aryl halide had been completely consumed. The reaction mixture was cooled to room temperature, diluted with ether (100 mL) and extracted with 1 M HCl (3*100 mL). The combined aqueous acid phase was basified with 3N NaOH, then extracted with ether (3*150 mL). The ethereal extracts were dried over anhydrous sodium sulfate, filtered and concentrated to afford 2.01 g (95%) of di-n-butyltoluidine6 as a pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
210 mg (79%) | With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; | 1,1-Bis(4-methylphenyl)-3-methyl-2-butanone. An oven-dried Schlenk tube was cooled under an argon purge and charged with Pd2(dba)3 (13.7 mg, 0.015 mmol, 3 mol % Pd), 2 (14.1 mg, 0.036 mmol, 3.6 mol %), and NaOtBu (211 mg, 2.2 mmol). The flask was purged with argon, and toluene (3 mL) was added with stirring. The flask was then charged with 4-chlorotoluene (0.24 mL, 2.0 mmol), 3-methyl-2-butanone (0.105 mL, 1.0 mmol), and additional toluene (3 mL). The reaction mixture was stirred at room temperature for 2 min, then heated to 80 C. with stirring for 22 h at which time GC analysis showed the starting aryl chloride had been completely consumed. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NH4Cl (5 mL), diluted with ether (20 mL), and poured into a separatory funnel. The layers were separated and the aqueous phase was extracted with ether (10 mL). The combined organic fractions were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 210 mg (79%) of a white solid: mp 48-51 C.; 1H NMR (300 MHz, CDCl3) delta 7.00-7.18 (m, 8H), 5.22 (s, 1H), 2.79 (p, 1H, J=6.8 Hz), 2.31 (s, 6H), 1.10 (d, 6H, J=6.8 Hz); 13C NMR (125 MHz, CDCl3) delta 212.3, 136.6, 135.8, 129.24, 129.16, 128.9, 128.7, 61.4, 40.7, 21.0, 18.6; IR (neat, cm-1) 2972, 1718, 1513, 1038, 803. Anal Calcd for C14H20O: C, 85.67; H, 8.32. Found: C, 86.02; H, 8.59. |
210 mg (79%) | With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; | 1,1-Bis(4-methylphenyl)-3-methyl-2-butanone. An oven-dried Schlenk tube was cooled under an argon purge and charged with Pd2(dba)3 (13.7 mg, 0.015 mmol, 3 mol % Pd), 2 (14.1 mg, 0.036 mmol, 3.6 mol %), and NaOtBu (211 mg, 2.2 mmol). The flask was purged with argon, and toluene (3 mL) was added with stirring. The flask was then charged with 4-chlorotoluene (0.24 mL, 2.0 mmol), 3-methyl-2-butanone (0.105 mL, 1.0 mmol), and additional toluene (3 mL). The reaction mixture was stirred at room temperature for 2 min, then heated to 80 C. with stirring for 22 h at which time GC analysis showed the starting aryl chloride had been completely consumed. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NH4Cl (5 mL), diluted with ether (20 mL), and poured into a separatory funnel. The layers were separated and the aqueous phase was extracted with ether (10 mL). The combined organic fractions were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 210 mg (79%) of a white solid: mp 48-51 C.; 1H NMR (300 MHz, CDCl3) delta 7.00-7.18 (m, 8H), 5.22 (s, 1H), 2.79 (p, 1H, J=6.8 Hz), 2.31 (s, 6H), 1.10 (d, 6H, J=6.8 Hz); 13C NMR (125 MHz, CDCl3) delta 212.3, 136.6, 135.8, 129.24, 129.16, 128.9, 128.7, 61.4, 40.7, 21.0, 18.6; IR (neat, cm-1) 2972, 1718, 1513, 1038, 803. Anal Calcd for C14H20O: C, 85.67; H, 8.32. Found: C, 86.02; H, 8.59. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
170 mg (89%) | With cesium fluoride;palladium diacetate; In tetrahydrofuran; 1,4-dioxane; | 4-Hexylanisole.21 An oven-dried resealable Schlenk tube was capped with a rubber septum, cooled under an argon purge, charged with 1-hexene (0.19 mL, 1.5 mmol), and cooled to 0 C. A solution of 9-BBN in THF (3 mL, 1.5 mmol, 0.5 M) was added, the flask was stirred at 0 C. for 15 min, then warmed to room temperature and stirred for 5 h. 4-Chloroanisole (0.12 mL, 1.0 mmol) was added, the septum was removed, and palladium acetate (4.4 mg, 0.02 mmol, 2 mol %), ligand 2 (11.9 mg, 0.03 mmol, 3 mol %), and cesium fluoride (456 mg, 3.0 mmol) were added under a stream of argon. The septum was replaced and the flask was purged with argon for 30 s. Dioxane (2 mL) was added, the septum was removed, the tube was sealed with a teflon screw cap, and the mixture was stirred at rt for 2 min. The reaction mixture was then heated to 50 C. with stirring for 22 h, at which time GC analysis showed the aryl chloride had been completely consumed. The mixture was cooled to room temperature, diluted with ether (20 mL), and poured into a separatory funnel. The mixture was washed with 1 M aqueous NaOH (20 mL), the layers were separated, and the aqueous phase was extracted with ether (20 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography to afford 170 mg (89%) of a colorless oil: 1H NMR (300 MHz, CDCl3) delta 7.09 (d, 2H, J=8.8 Hz), 6.82 (d, 2H, J=8.6 Hz), 3.78 (s, 3H), 2.54 (t, 2H, J=7.5 Hz), 1.54-1.60 (m, 2H), 1.28-1.35 (m, 6H), 0.88 (t, 3H, J=6.8 Hz); 13C NMR (125 MHz, CDCl3) delta 157.6, 135.0, 129.2, 113.6, 55.2, 35.0, 31.73, 31.70, 28.9, 22.6, 14.1; IR (neat, cm-1) 2926, 1513, 1243, 1038, 822. Anal Calcd for C13H20O: C, 81.20; 11, 10.48. Found: C, 81.19; H, 10.62. |
170 mg (89%) | With cesium fluoride;palladium diacetate; In tetrahydrofuran; 1,4-dioxane; | 4-Hexylanisole.21 An oven-dried resealable Schlenk tube was capped with a rubber septum, cooled under an argon purge, charged with 1-hexene (0.19 mL, 1.5 mmol), and cooled to 0 C. A solution of 9-BBN in THF (3 mL, 1.5 mmol, 0.5 M) was added, the flask was stirred at 0 C. for 15 min, then warmed to room temperature and stirred for 5 h. 4-Chloroanisole (0.12 mL, 1.0 mmol) was added, the septum was removed, and palladium acetate (4.4 mg, 0.02 mmol, 2 mol %), ligand 2 (11.9 mg, 0.03 mmol, 3 mol %), and cesium fluoride (456 mg, 3.0 mmol) were added under a stream of argon. The septum was replaced and the flask was purged with argon for 30 s. Dioxane (2 mL) was added, the septum was removed, the tube was sealed with a teflon screw cap, and the mixture was stirred at rt for 2 min. The reaction mixture was then heated to 50 C. with stirring for 22 h, at which time GC analysis showed the aryl chloride had been completely consumed. The mixture was cooled to room temperature, diluted with ether (20 mL), and poured into a separatory funnel. The mixture was washed with 1 M aqueous NaOH (20 mL), the layers were separated, and the aqueous phase was extracted with ether (20 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography to afford 170 mg (89%) of a colorless oil: 1H NMR (300 MHz, CDCl3) delta 7.09 (d, 2H, J=8.8 Hz), 6.82 (d, 2H, J=8.6 Hz), 3.78 (s, 3H), 2.54 (t, 2H, J=7.5 Hz), 1.54-1.60 (m, 2H), 1.28-1.35 (m, 6H), 0.88 (t, 3H, J=6.8 Hz); 13C NMR (125 MHz, CDCl3) delta 157.6, 135.0, 129.2, 113.6, 55.2, 35.0, 31.73, 31.70, 28.9, 22.6, 14.1; IR (neat, cm-1) 2926, 1513, 1243, 1038, 822. Anal Calcd for C13H20O: C, 81.20; H, 10.48. Found: C, 81.19; H, 10.62. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
163 mg (80%) | tris-(dibenzylideneacetone)dipalladium(0); In toluene; | 2-Methyl-4-(3,5-xylyl)-3-pentanone. An oven-dried resealable Schlenk tube was charged with NaHMDS (238 mg, 1.3 mmol) under nitrogen in a Vacuum Atmospheres glovebox. The tube was capped with a teflon screw cap and removed from the glovebox. The screwcap was removed and Pd2(dba)3 (13.7 mg, 0.015 mmol, 3 mol % Pd) and 2 (14.1 mg, 0.036 mmol, 3.6 mol %) were added under a stream of argon. The tube was capped with a rubber septum and toluene (3 mL) was added with stirring. The flask was then charged with 5-bromo-m-xylene (0.135 mL, 1.0 mmol), 2-methyl-3-pentanone (0.15 mL, 1.2 mmol), and additional toluene (3 mL). The septum was replaced with a teflon screw cap and the reaction mixture was stirred at room temperature for 22 h until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction was quenched with 5 mL of saturated aqueous NH4Cl, diluted with ether (20 mL), and poured into a separatory funnel. The layers were separated, and the aqueous phase was extracted with ether (10 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 163 mg (80%) of a colorless oil. GC and NMR analysis showed the material obtained was a mixture of the desired product and a regioisomer containing the aryl group at the 2-position of the ketone (46/1 ratio by GC analysis; 40/1 ratio by 1H NMR analysis). NMR data are given for the major product only. 1H NMR (250 MHz, CDCl3) delta 6.88 (s, 1H), 6.81 (s, 2H), 3.83 (q, 1H, J=6.9 Hz), 2.68 (p, 1H, J=6.9 Hz), 2.29 (s, 6H), 1.34 (d, 3H, J=6.9 Hz), 1.07 (d, 3H, J=7.0 Hz), 0.92 (d, 3H, J=6.6 Hz); 13C NMR (125 MHz, CDCl3) delta 214.7, 140.7, 138.3, 128.6, 125.7, 50.9, 39.0, 21.2, 19.3, 18.2, 18.1; IR (neat, cm-1) 2972, 1710, 1101, 849. Anal (for the mixture) Calcd for C14H20O: C, 82.3; H, 9.87. Found: C, 82.09; H, 9.85. |
163 mg (80%) | tris-(dibenzylideneacetone)dipalladium(0); In toluene; | 2-Methyl-4-(3,5-xylyl)-3-pentanone. An oven-dried resealable Schlenk tube was charged with NaHMDS (238 mg, 1.3 mmol) under nitrogen in a Vacuum Atmospheres glovebox. The tube was capped with a teflon screw cap and removed from the glovebox. The screwcap was removed and Pd2(dba)3 (13.7 mg, 0.015 mmol, 3 mol % Pd) and 2 (14.1 mg, 0.036 mmol, 3.6 mol %) were added under a stream of argon. The tube was capped with a rubber septum and toluene (3 mL) was added with stirring. The flask was then charged with 5-bromo-m-xylene (0.135 mL, 1.0 mmol), 2-methyl-3-pentanone (0.15 mL, 1.2 mmol), and additional toluene (3 mL). The septum was replaced with a teflon screw cap and the reaction mixture was stirred at room temperature for 22 h until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction was quenched with 5 mL of saturated aqueous NH4Cl, diluted with ether (20 mL), and poured into a separatory funnel. The layers were separated, and the aqueous phase was extracted with ether (10 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to give 163 mg (80%) of a colorless oil. GC and NMR analysis showed the material obtained was a mixture of the desired product and a regioisomer containing the aryl group at the 2-position of the ketone (46/1 ratio by GC analysis; 40/1 ratio by 1H NMR analysis). NMR data are given for the major product only. 1H NMR (250 MHz, CDCl3) delta 6.88 (s, 1H), 6.81 (s, 2H), 3.83 (q, 1H, J=6.9 Hz), 2.68 (p, 1H, J=6.9 Hz), 2.29 (s, 6H), 1.34 (d, 3H, J=6.9 Hz), 1.07 (d, 3H, J=7.0 Hz), 0.92 (d, 3H, J=6.6 Hz); 13C NMR (125 MHz, CDCl3) delta 214.7, 140.7, 138.3, 128.6, 125.7, 50.9, 39.0, 21.2, 19.3, 18.2, 18.1; IR (neat, cm-1) 2972, 1710, 1101, 849. Anal (for the mixture) Calcd for C14H20O: C, 82.3; H, 9.87. Found: C, 82.09; H, 9.85. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | tris(dibenzylideneacetone)dipalladium (0); In acetone; toluene; | Reference example 8-1 1-[2-Nitro-4-(trifluoromethyl)phenyl]acetone To a solution of 1-chloro-2-nitro-4-trifluoromethylbenzene (5.38 g, 23.41 mmol) in toluene (46 ml) were added acetone (10.3 ml, 140.46 mmol), phenol (441 mg, 4.68 mmol), calcium phosphate (12.42 g, 58.52 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (369 mg, 0.94 mmol) and tris(dibenzylideneacetone)dipalladium(O) (214 mg, 0.23 mmol) successively and the mixture was stirred for 9 hours at 50C. After being cooled to room temperature, the reaction mixture was filtered by silica gel with ethyl acetate and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to give the subject compound (4.59 g, 79 %). 1H NMR (CDCl3, 400 MHz) delta 8.40 (d, 1H, J = 1.2 Hz), 7.85 (dd, 1H, J = 8.0, 1.2 Hz), 7.44 (d, 1H, J = 8.0 Hz), 4.22 (s, 2H), 2.37 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100 mg (50%) | With potassium phosphate;palladium diacetate; In ethyl acetate; toluene; | b 5-Methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoimidazole-1-carboxylic acid tert-butyl ester and 5-Methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoimidazole-1-carboxylic acid tert-butyl ester To a dry reaction vial fitted with a stir bar and a Teflon-lined screw cap, a mixture of 5-chloro-6-methyl-benzoimidazole-1-carboxylic acid tert-butyl ester and 5-chloro-6-methyl-benzoimidazole-3-carboxylic acid tert-butyl ester (150 mg, 0.56 mmol, as prepared in Example 30, step a), 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (284 mg, 1.12 mmol, Aldrich Chemical Company), (2'-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (17.7 mg, 0.045 mmol, Strem Chemicals Inc, Newburyport, Mass.), Pd(OAc)2 (6.7 mg, 0.03 mmol. Strem Chemicals Inc, Newburyport, Mass.), and K3PO4 (238 mg, 1.12, mmol) were added. The vial was capped, purged with argon, and then suspended in toluene (3 mL). After stirring for 18 hr at 95 C., the reaction was allowed to cool and then filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified using preparative thin layer chromatography (1:3 EtOAc/hexanes, 2000mu SiO2 plate) to afford 100 mg (50%) of the title compound (1:1 mixture of regioisomers) as a yellow oil. ESI-MS (m/z): Calcd. for C19H27BN2O4: 358.2; found: 303.2 (M-tBu), 259.3 (M-Boc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dimethoxyethane; hexane; ethyl acetate; | EXAMPLE 50 tert-Butyl (2E)-3-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridin-2-yl}prop-2-enoate A mixture of tert-butyl (2E)-3-(7-chloro-6-cyanothieno[3,2-b]pyridin-2-yl)prop-2-enoate (1.29 g, 3.74 mmol), <strong>[98446-49-2]2,4-dichloro-5-methoxyaniline</strong> (862 mg, 4.49 mmol), Tris(dibenzylideneacetone)-dipalladium(0) (343 mg, 0.37 mmol), potassium phosphate (1.29 g, 5.61 mmol) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (456 mg, 1.16 mmol) in 36 mL of ethylene glycol dimethyl ether is heated at 90 C. for 3 hours. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The aqueous layer is extracted with additional ethyl acetate and the organic layers are combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluding with a gradient of hexane to 40% ethyl acetate in hexane to provide 974 mg of tert-butyl (2E)-3-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridin-2-yl}prop-2-enoate as a light tan solid, mp 224 C. dec; 1H NMR (DMSO-d6) delta 1.48 (s, 9H), 3.85 (s, 3H), 6.26 (d, J=16 Hz, 1H), 7.37 (s, 1H), 7.75 (d, J=16 Hz, 1H), 7.78 (s, 1H), 7.91 (s, 1H), 8.62 (s, 1H), 9.80 (s, 1H); MS 476.0, 478.0 (M+H)+. Analysis for C22H19Cl2N3O3S-0.4 H2O: Calcd: C, 54.64; H, 4.13; N, 8.69. Found: C, 54.51; H, 3.96; N, 8.50. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; aniline; trifluoroacetic acid; In dichloromethane; caesium carbonate; | 60 mg of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate are placed in a Personal Chemistry SmithProcessVial tube with a maximum volume of 5 ml. 404 mg of cesium carbonate, 35.9 mg of 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 12.1 mg of tris(dibenzylideneacetone)dipalladium[0] and 29 mul of aniline are then added. 4 ml of 1,2-dimethoxyethane are then added. The tube is sealed with the stopper provided for this purpose and the reaction is subjected to microwave radiation for 5 minutes at 120 C. The other parameters are those recommended by the constructor. The catalyst is filtered through Celite 535 and the four reaction crudes are pooled, concentrated to dryness under reduced pressure in the rotary evaporator and purified by preparative LC/MS (conditions A). The fractions containing the protected intermediate compound are pooled and concentrated under reduced pressure. The yellow oil obtained is dissolved in 2 ml of dichloromethane and then 500 mul of trifluoroacetic acid are added. The solution is stirred for 2 hours at ambient temperature, until the starting product has disappeared. 10 ml of dichloromethane and 10 ml of a saturated sodium hydrogencarbonate solution are then added. When no more gas is being given off, the organic phase is dried over magnesium sulfate and the solvent is concentrated to dryness under reduced pressure and a rotary evaporator. 18.6 mg of 2-methylsulfonyl-N-(3-phenylamino-1H-indazol-5-yl)benzenesulfonamide are obtained in the form of a yellow oil (analytical LC/MS analysis: Tr=3.49 minutes; [M+H]+=443.09). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium tert-butylate; acetic acid;palladium diacetate; In tetrahydrofuran; | Step C Preparation of 1-(6-Methyl-pyridin-2-yl)-2-quinolin-6-yl-ethanone To a solution of <strong>[612-57-7]6-chloro-quinoline</strong> (2.08 g, 12.3 mmol) in tetrahydrofuran (50 mL) was added 1-(6-methyl-pyridin-2-yl)-ethanone of Step B (2.0 g, 14.8 mmol, 1.1 equiv), palladium acetate (0.055 g, 0.25 mmol, 0.02 equiv), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (0.197 g, 0.50 mmol, 0.04 equiv), and potassium tert-butoxide (3.76 g, 30.75 mmol, 2.2 equiv). The resulting reaction mixture was heated to 80 C. for 18 hours, then cooled down to 20 C., and slowly treated with acetic acid (3 mL). The resulting solids were filtered off, and the mother liquor was concentrated in vacuo. Silica gel chromatography (3:1 hexane/acetone) yielded the title compound (2.52 g, 78%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride;tris-(dibenzylideneacetone)dipalladium(0); In toluene; | Production Example 33 Under a nitrogen gas flow, to a mixture of 1.0 g of methyl trans-4-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]cyclohexanecarboxylate, 10 mL of toluene, 593.8 mg of 4,4-dimethylpiperidine, 206.4 mg of 2'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine and 779.4 mg of potassium phosphate, was added 150.8 mg of tris(dibenzylideneacetone)dipalladium, followed by stirring for 15 hours at 100 C. To the reaction mixture were added 100 mL of DCM and 30 mL of 1M hydrochloric acid, and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (chloroform:methanol=100:0-97:3), to obtain 350 mg of methyl 4-{5-[4-(4,4-dimethylpiperidin-1-yl)phenyl]-1,3,4-thiadiazol-2-yl}cyclohexanecarboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; | Example 4 N-(4-Methoxybenzyl)-3H-benzo[d]imidazol-5-amine The compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), 4-methoxybenzylamine (165 mg; 0.156 ml; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd2 dba3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1; Yield: 0.058 g (22.9%); MS m/z: 254.3 [M+H]+; 1H-NMR (500 MHz, DMSO d6): delta 3.69 (s, 3H); 4.19 (d, 2H, 3J=5.8 Hz); 5.97-5.99 (br m, 1H); 6.46 (br s, 1H); 6.57-6.59 (m, 1H); 6.64 (br s, 1H); 6.85-6.86 (m, 2H); 7.27-7.29 (m, 2H); 7.79 (s, 1H); 11.77 (br s, 1H); HPLC METHOD [A]: rt 10.12 min (95.6%) Alternatively the compound was synthesized starting from benzimidazol-5-amine (2.66 g; 20 mmol; 1 eq.), 4-methoxybenzaldehyde (3.26 g; 2.9 ml; 24 mmol; 1.2 eq.), NaBH4 (1.14 g; 30 mmol; 1.5 eq.) and 5 N NaOH (20 ml; 100 mmol; 5 eq.) according to method 2; Yield: 4.53 g (89.5%); MS m/z: 254.3 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.096 mg (39.8%) | In tetrahydrofuran; | Example 9 N-(4-Fluorobenzyl)-3H-benzo[d]imidazol-5-amine The compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), 4-fluorobenzylamine (150 mg; 0.137 ml; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd2 dba3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1; Yield: 0.096 mg (39.8%); MS m/z: 242.4 [M+H]+; 1H-NMR (500 MHz, DMSO d6): delta 4.25 (s, 2H); 6.04 (br s, 1H); 6.50 (s, 1H); 6.59 (dd, 1H, 4J=1.2 Hz, 3J=8.5 Hz); 7.09-7.13 (m, 2H); 7.26 (d, 1H, 3J=8.5 Hz); 7.38-7.41 (m, 2H); 7.83 (s, 1H); 11.88 (br s, 1H); HPLC (METHOD [A]): rt 11.21 min (99.2%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; | Example 6 N-(4-Chlorobenzyl)-3H-benzo[d]imidazol-5-amine The compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), 4-chlorobenzylamine (170 mg; 0.146 ml; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd2 dba3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1; Yield: 0.064 g (24.9%); MS m/z: 258.3 [M+H]+; 1H-NMR (500 MHz, DMSO d6): delta 4.26 (d, 2H, 3J=5.8 Hz); 6.13 (br s, 1H); 6.43 (br s, 1H); 6.58-6.59 (m, 1H); 7.16-7.17 (m, 1H); 7.33-7.35 (m, 2H); 7.37-7.39 (m, 2H); 7.81 (br s, 1H); 11.78 (br s, 1H); HPLC (METHOD [A]): rt 11.80 min (92.7%) Alternatively the compound was synthesized starting from benzimidazol-5-amine (2.66 g; 20 mmol; 1 eq.), 4-chlorobenzaldehyde (3.09 g; 22 mmol; 1.1 eq.), NaBH4 (1.14 g; 30 mmol; 1.5 eq.) and 5 N NaOH (20 ml; 100 mmol; 5 eq.) according to method 2; Yield: 3.94 g (76.7%); MS m/z: 258.3/260.3 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.058 g (24.5%) | In tetrahydrofuran; | Example 8 N-(4-Methylbenzyl)-3H-benzo[d]imidazol-5-amine The compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), 4-methylbenzylamine (145 mg; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd2 dba3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1; Yield: 0.058 g (24.5%); MS m/z: 238.3 [M+H]+; 1H-NMR (500 MHz, DMSO d6): delta 2.24 (s, 3H); 4.21 (s, 2H); 5.97 (br s, 1H); 6.49 (s, 1H); 6.59 (dd, 1H, 4J=1.8 Hz, 3J=8.5 Hz); 7.08-7.10 (m, 2H); 7.24-7.26 (m, 3H); 7.82 (s, 1H); 11.82 (br s, 1H); HPLC (METHOD [A]): rt 11.87 min (96.2%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.127 g (41%) | In tetrahydrofuran; | Example 10 N,N-Dibenzyl-1H-benzo[d]imidazol-5-amine The compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), dibenzylamine (0.231 ml; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd2 dba3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1 but purified by flash chromatography on silica using a CHCl3/MeOH gradient; Yield: 0.127 g (41%); 314.1 MS m/z: [M+H]+; 1H-NMR (500 MHz, DMSO d6): delta 4.67 (s, 4H); 6.70 (br s, 1H); 6.73 (dd, 1H, 4J=2.4 Hz, 3J=8.9 Hz); 7.19-7.23 (m, 2H); 7.28-7.33 (m, 9H); 7.90 (s, 1H); 11.91 (br s, 1H); HPLC (METHOD [A]): rt 14.79 min (99.2%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.150 g (67.3%) | In tetrahydrofuran; | Example 2 N-Benzyl-1H-benzo[d]imidazol-5-amine The compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), benzylamine (128 mg; 0.127 ml; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd2 dba3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1; Yield: 0.150 g (67.3%); MS m/z: 224.5 [M+H]+; 1H-NMR (500 MHz, DMSO d6): delta 4.33 (s, 2H); 6.64 (d, 1H, 4J=2.1 Hz); 6.98 (dd, 1H; 4J=2.1 Hz, 3J=8.9 Hz); 7.23-7.38 (m, 5H); 7.51 (d, 1H, 3J=8.9 Hz); 8.07 (s, 1H); HPLC (METHOD [A]): rt 22.19 min (80.6%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.064 g (22.6%) | In tetrahydrofuran; | Example 5 N-(3,4-Dimethoxybenzyl)-3H-benzo[d]imidazol-5-amine The compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), 3,4-dimethoxybenzylamine (201 mg; 0.181 ml; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd2 dba3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1; Yield: 0.064 g (22.6%); MS m/z: 284.1 [M+H]+; 1H-NMR (500 MHz, DMSO d6): delta 3.69 (s, 3H); 3.71 (s, 3H); 4.17 (d, 2H, 3J=5.8 Hz); 5.96 (br s, 1H); 6.48 (br s, 1H); 6.58-6.60 (m, 1H); 6.85-6.89 (m, 2H); 6.99 (s, 1H); 7.27-7.29 (m, 1H); 7.80 (s, 1H); 11.78 (br s, 1H); HPLC (METHOD [A]): rt 8.92 min (100%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.069 mg (29.1%) | In tetrahydrofuran; | Example 7 N-(1-Phenylethyl)-3H-benzo[d]imidazol-5-amine The compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), 1-phenylethylamine (145 mg; 0.154 ml; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd2 dba3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1; Yield: 0.069 mg (29.1%); MS m/z: 238.1 [M+H]+; 1H-NMR (500 MHz, DMSO d6): delta 1.42 (d, 3H, 3J=7.0 Hz); 4.44 (quin, 1H, 3J=6.7 Hz); 5.97 (br s, 1H); 6.34 (br s, 1H); 6.59-6.60 (m, 1H); 7.13-7.16 (m, 1H); 7.24-7.28 (m, 3H); 7.38-7.39 (m, 2H); 7.77 (s, 1H); 11.74 (br s, 1H); HPLC (METHOD [A]): rt 11.42 min (90.3%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.051 g (21.5%) | In tetrahydrofuran; | Example 3 N-Phenethyl-1H-benzo[d]imidazol-5-amine The compound was synthesized starting from 5-bromobenzimidazole (200 mg; 1 mmol; 1 eq.), phenylethylamine (146 mg; 0.152 ml; 1.2 mmol; 1.2 eq.), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol %), Pd2 dba3 (9 mg; 0.01 mmol; 0.01 eq.; 1 mol %) and lithiumbis(trimethylsilyl)amide 1 M in THF (2.2 ml; 2.2 mmol; 2.2 eq.) according to method 1; Yield: 0.051 g (21.5%); MS m/z: 238.3 [M+H]+; 1H-NMR (500 MHz, DMSO d6): delta 2.86 (t, 2H, 3J=7.6 Hz); 3.25 (t, 2H, 3J=7.6 Hz); 6.59 (dd, 1H, 4J=2.1 Hz, 3J=8.5 Hz); 6.62 (br s, 1H); 7.18-7.22 (m, 1H); 7.27-7.31 (m, 5H); 7.92 (s, 1H); HPLC (METHOD [A]): rt 11.20 min (84.4%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.565 g (54.1%) | With aniline; In tetrahydrofuran; | Example 1 N-Phenyl-1H-benzo[d]imidazol-5-amine The compound was synthesized starting from 5-bromobenzimidazole (1.0 g; 5 mmol; 1 eq.), aniline (559 mg; 0.547 ml; 6 mmol; 1.2 eq.), lithiumbis(trimethylsilyl)amide 1M in THF (11 ml; 11 mmol; 2.2 eq.), 2-dicyclohexylphos-phino-2"-(N,N-dimethylamino)biphenyl) (45 mg; 0.12 mmol; 0.024 eq.; 2.4 mol %), Pd2 dba3 (45 mg; 0.05 mmol; 0.01 eq.; 1 mol %) and THF (5 ml) according to method 1; Yield: 0.565 g (54.1%); MS m/z: 210.2 [M+H]+; 1H-NMR (500 MHz, DMSO d6): delta 6.72-6.75 (m, 1H); 6.94-6.96 (m, 1H); 7.00-7.02 (m, 2H); 7.16-7.19 (m, 2H); 7.25 (br s, 1H); 7.47 (d, 1H, 3J=8.5 Hz); 7.98 (br s, 1H); 8.04 (s, 1H); 12.13 (br s, 1H); HPLC (METHOD [A]): rt 10.62 min (87.0%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In dichloromethane; at 20℃; for 0.5h; | A solution of 1 (0.1 mmol) and DCPAB (0.20 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 30 min. The product was separated by passing through a short silicagel column with CH2Cl2/ethyl acetate (1:1, v/v) as eluent. The second band was collected and afforded complex 2. Red solid, 89% yield. Found: C, 58.92; H, 6.10; N 3.92.Calc. for C38H48ClFeN2OPPd: C, 58.70; H, 6.22; N, 3.73%. IR (KBr, cm-1): 2925, 2851, 1599 (C=N), 1447, 1315, 1264,1106, 1052, 1002, 808, 752.1H NMR (400 MHz, CDCl3) delta 9.89 (1H, brs, OH), 7.98 (1H, m, ArH), 7.21-7.37 (5H, m,ArH), 7.04-7.09 (2H, m, ArH), 4.24 (1H, s, C5H3), 4.07-4.14 (6H, m, C5H5+C5H3), 3.92 (1H, s, C5H3), 2.56 (3H, s, CH3), 2.51 (3H, s, CH3), 2.17 (3H, s, CH3), 2.35 (2H, m, PCy2), 1.76-1.06 (20H, m, Cy). 31P{1H}NMR (162 MHz, CDCl3) delta 67.15, 65.54. MS-ESI+ [m/z]: 741.2 (M+-Cl). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); 4-tert-butylpiperidine hydrochloride; sodium t-butanolate; In 1,4-dioxane; at 120℃; for 0.75h;Microwave irradiation; | 1005881 Prepared using General Procedure ii. Into a degassed solution of tert-butyl (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoate (INT14) (50 mg, 0.09 mmol), sodium tert-butoxide (18 mg, 0.19 mrnol) and 4-tert- butylpiperidine HCI (23 rng. 0.11 mmoi) in dioxane (2.5 mL) were added Pd2(dba)3 (9 mg, 0.01 rnmol) and 2-dicyclohexylphosphino-2 ?-(VN-dirnethy1amino)biphenyl (6 rng, 0.015 mrnol). The reaction mixture was heated for 45 mm at 120C in a microwave reactor. The mixture was diluted with EA and washed with NaHCO3. The organic layer was dried over Na2SO4, concentrated, and purified by preparatory HPLC. The isolated intermediate was deprotected using General Procedure 8 to provide 2.9 mg (6%) of (S)2-(4-(teri-butvl)benzamido)-3-(4-(5-(4-(tert-butyl)piperidin- 1 -yl)pyrimidin-2-yl)phenyl)propanoic acid (Compound 253). LCMS-ESI (m/z) calculated for C33H42N403:542.7; found 543.3 [M±Hf, 1R = 10.79 mm (Purity). ?H NMR (400 MHz. CDCl) oe 8.52 (s, 2H). 8.23 (d, J= 8.0 Hz, 2H), 7.72 (d, J 8.4 Hz, 2H), 7.44 (dd, J 11.3, 8.4 Hz, 4H), 6.79 (d, J 6.8 Hz, 1H), 5.18 (d, J 6.5 Hz, 111), 3.89 (d, J 11.9 Hz. 2H), 3.47 (d, J5.2 Hz, 2H), 2.83 (t, J= 11.5 Hz, 2H), 1.88 (d, J= 12.0 Hz, 2H), 1.52 - 1.37 (m, 2H),1.34 (s, 9H), 1.24 (dcl, J 24.7, 12.8 Hz, IH), 0.92 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In tetrahydrofuran; for 1h;Inert atmosphere; Schlenk technique; | (r3-1-tBu-indenyl)2(ji-Cl)2Pd2 (3d) (0.300 g, 0.48 mmol) and <strong>[213697-53-1]DavePhos</strong> (0.3 78 g, 0.96 mmol) were added to a 100 mL Schlenk flask and placed under an atmosphere of nitrogen. THF (20 mL) was added to the flask via cannula. The resulting solution was stirred for 60 minutes, during which time the reaction mixture became homogeneous. The mixture was opened to air and 90% of the solvent was evaporated under reduced pressure.Pentane was added to precipitate solid from solution. A red-orange solid, which contained two isomers in an approximately 1:1 ratio, was collected via vacuum filtration. Yield: 0.622 g, 88%.?H NMR (CDC13, 600 MHz): Isomer A: 7.78-7.74 (m, 1H), 7.48-7.40 (m, 3H), 7.39-7.34 (m, 2H), 7.19 (d, J = 7.52 Hz, 1H), 7.08-6.96 (m, 3H), 6.89-6.85 (m, 1H), 6.68 (d, J= 7.34 Hz,1H), 6.33 (d, J = 2.82 Hz, 1H), 4.45 (d, J = 2.66 Hz 1H), 2.55 (s, 6H), 1.54 (s, 9H),1.22-0.76 (m, 22H) ppm. Isomer B: 7.70-7.66 (m, 1H), 7.48-7.40 (m, 3H), 7.29-7.27 (m, 2H),7.17 (d, J = 7.58 Hz, 1H), 7.08-6.96 (m, 3H), 6.84-6.81 (m, 1H), 6.75 (d, J = 7.31 Hz, 1H),6.48 (d, J = 2.78 Hz, 1H), 4.55 (d, J = 2.71 Hz, 1H), 2.62 (s, 6H), 2.29-1.66 (m, 22H), 1.55 (s,9H) ppm. ?3C{?H} NMR (CDC13, 150 MHz): 150.96, 150.92, 143.95, 143.63, 139.44,139.28, 138.18, 138.04, 137.88, 137.77, 133.77, 133.72, 133.53, 133.48, 132.38, 132.26,128.96, 125.96, 125.89, 125.80, 125.70, 124.16, 123.91, 120.78, 120.71, 120.56, 120.25,118.23, 118.13, 43.96, 43.67, 34.58, 34.48, 34.34, 34.18, 34.13, 31.75, 31.73, 31.13, 30.39,30.17, 29.73, 29.70, 29.14, 29.02, 28.17, 27.23, 27.04, 26.93, 26.06, 25.98, 25.78, 25.61 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; lithium tert-butoxide; In 1,4-dioxane; at 138℃; for 36h;Schlenk technique; Inert atmosphere; | In a 25 mL Schlenk tube,The addition of 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl (<strong>[213697-53-1]DavePhos</strong>) 77.9 mg (0.2 mmol),(1,5-cyclooctadiene) rhodium (I) dimer 2.5 mg (2.5% of moles of starting material), lithium tert-butoxide48 mg (0.6 mmol) was added, and argon was replaced three times with 1 mL of 1,4-dioxane and 175 mg (1.0 mmol) of 2-fluorobromobenzene under argon.138 C for 36 hours,After cooling to room temperature, the solvent was distilled off under reduced pressure, separated by a 200-300 mesh silica gel column, Petroleum ether: ethyl acetate = 100: 1, and dried in vacuo to give 55.5 mg of a colorless viscous product in 57% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; lithium tert-butoxide; In 1,4-dioxane; at 138℃; for 36h;Schlenk technique; Inert atmosphere; | In a 25 mL Schlenk tube,The addition of 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl (<strong>[213697-53-1]DavePhos</strong>) 77.9 mg (0.2 mmol),(1,5-cyclooctadiene) chlorineRhodium (I) dimer 2.5 mg (2.5% mol of raw material), lithium tert-butoxide48 mg (0.6 mmol) was added, and argon was replaced three times. Under 1 mL of 1,4-dioxane was added under argon, 67 mg of 4-trifluoromethylbromobenzene (0.3 mmol).138 C for 36 hours,After cooling to room temperature, the solvent was distilled off under reduced pressure, separated by a 200-300 mesh silica gel column, Petroleum ether: ethyl acetate = 100: 1 and dried in vacuo to give 92.3 mg of product as a white solid in 86% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; lithium tert-butoxide; In 1,4-dioxane; at 138℃; for 36h;Schlenk technique; Inert atmosphere; | 25 mL of Schlenk tube, 2-dicyclohexylphosphino-2 & apos ;-( N, N-dimethylamino) biphenyl (<strong>[213697-53-1]DavePhos</strong>) 77.9 mg (0.2 mmol),(1,5-cyclooctadiene) chlorineRhodium (I) dimer 2.5 mg (2.5% mol of raw material), lithium tert-butoxide48 mg (0.6 mmol) was added, and argon was replaced three times. Under argon, 1 mL of 1,4-dioxane was added, 3-trifluoromethylbromobenzene (67.5 mg (0.3 mmol).138 C for 36 hours,After cooling to room temperature, the solvent was distilled off under reduced pressure, separated by a 200-300 mesh silica gel column, Petroleum ether: ethyl acetate = 100: 1 and dried in vacuo to give 95.4 mg of product as a white solid in 89% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; lithium tert-butoxide; In 1,4-dioxane; at 138℃; for 36h;Schlenk technique; Inert atmosphere; | 25 mL of Schlenk tube, 2-dicyclohexylphosphino-2 & apos ;-( N, N-dimethylamino) biphenyl (<strong>[213697-53-1]DavePhos</strong>) 77.9 mg (0.2 mmol),(1,5-cyclooctadiene) chlorineRhodium (I) dimer 2.5 mg (2.5% mol of raw material), lithium tert-butoxide48 mg (0.6 mmol) was added, and argon was replaced three times, and 1 mL of 1,4-dioxane was added under argon, 54.6 mg of 4-cyanobromobenzene (0.3 mmol).138 C for 36 hours,After cooling to room temperature, the solvent was distilled off under reduced pressure, separated by a 200-300 mesh silica gel column, Petroleum ether: ethyl acetate = 50: 1 and dried in vacuo to give 74.4 mg of product as a pale yellow solid in 75% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; lithium tert-butoxide; In 1,4-dioxane; at 138℃; for 36h;Schlenk technique; Inert atmosphere; | 25 mL of Schlenk tube, 2-dicyclohexylphosphino-2 & apos ;-( N, N-dimethylamino) biphenyl (<strong>[213697-53-1]DavePhos</strong>) 77.9 mg (0.2 mmol),(1,5-cyclooctadiene) chlorineRhodium (I) dimer 2.5 mg (2.5% mol of raw material), lithium tert-butoxide48 mg (0.6 mmol), argon was replaced three times, and 1 mL of 1,4-dioxane was added under argon.3,5-dimethylbromobenzene (55.5 mg) (0.3 mmol).138 C for 36 hours,After cooling to room temperature, the solvent was distilled off under reduced pressure, separated by a 200-300 mesh silica gel column, Petroleum ether: ethyl acetate = 100: 1, dried in vacuo to give 65.8 mg of product as a white solid in 66% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; lithium tert-butoxide; In 1,4-dioxane; at 138℃; for 36h;Schlenk technique; Inert atmosphere; | In a 25 mL Schlenk tube,The addition of 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl (<strong>[213697-53-1]DavePhos</strong>) 77.9 mg (0.2 mmol),(1,5-cyclooctadiene) chlorineRhodium (I) dimer 2.5 mg (2.5% mol of raw material), lithium tert-butoxide48 mg (0.6 mmol), argon was replaced three times, and 1 mL of 1,4-dioxane was added under argon.3,5-Bis-trifluoromethyl bromobenzene87.9 mg (0.3 mmol).138 C for 36 hours,After cooling to room temperature, the solvent was evaporated under reduced pressure and chromatographed on silica gel at 200-300 mesh Column separation, petroleum ether: ethyl acetate = 100: 1, and dried in vacuo to give 100.8 mg of product as a white solid in 83% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; lithium tert-butoxide; In 1,4-dioxane; at 138℃; for 36h;Schlenk technique; Inert atmosphere; | In a 25 mL Schlenk tube,The addition of 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl (<strong>[213697-53-1]DavePhos</strong>) 77.9 mg (0.2 mmol),(1,5-cyclooctadiene) chlorineRhodium (I) dimer 2.5 mg (2.5% mol of raw material), lithium tert-butoxide48 mg (0.6 mmol) was added, and argon was replaced three times with 1 mL of 1,4-dioxane under argon, 62.1 mg of 2-bromonaphthalene (0.3 mmol).138 C for 36 hours,After cooling to room temperature, the solvent was distilled off under reduced pressure, separated by a 200-300 mesh silica gel column, Petroleum ether: ethyl acetate = 100: 1 and dried in vacuo to give 90.7 mg of product as a white solid in 87% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; lithium tert-butoxide; In 1,4-dioxane; at 138℃; for 36h;Schlenk technique; Inert atmosphere; | In a 25 mL Schlenk tube,The addition of 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl (<strong>[213697-53-1]DavePhos</strong>) 77.9 mg (0.2 mmol),(1,5-cyclooctadiene) chlorineRhodium (I) dimer 2.5 mg (2.5% mol of raw material), lithium tert-butoxide48 mg (0.6 mmol), argon was replaced three times, and 1 mL of 1,4-dioxane was added under argon.4-bromo-N-methylindole63.0 mg (0.3 mmol).138 C for 36 hours,After cooling to room temperature, the solvent was evaporated under reduced pressure and chromatographed on silica gel at 200-300 mesh Column separation, petroleum ether: ethyl acetate = 100: 1, and dried in vacuo to give 80.8 mg of product as a white solid in 77% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; lithium tert-butoxide; In 1,4-dioxane; at 150℃; for 36h;Schlenk technique; Inert atmosphere; | In a 25 mL Schlenk tube,The addition of 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl (<strong>[213697-53-1]DavePhos</strong>) 77.9 mg (0.2 mmol),(1,5-cyclooctadiene) chlorineRhodium (I) dimer 2.5 mg (2.5% mol of raw material), lithium tert-butoxide48 mg (0.6 mmol), argon was replaced three times, and 1 mL of 1,4-dioxane was added under argon.9-bromoanthracene 257.1 mg (1.0 mmol)The 150 C for 36 hours,After cooling to room temperature, the solvent was distilled off under reduced pressure, separated by a 200-300 mesh silica gel column, Petroleum ether: ethyl acetate = 100: 1, and dried in vacuo to give 47.9 mg of product as a white solid in 42% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; lithium tert-butoxide; In 1,4-dioxane; at 138℃; for 36h;Schlenk technique; Inert atmosphere; | In a 25 mL Schlenk tube,The addition of 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl (<strong>[213697-53-1]DavePhos</strong>) 77.9 mg (0.2 mmol)(1,5-cyclooctadiene) chlorineRhodium (I) dimer 2.5 mg (2.5% mol of raw material), lithium tert-butoxide48 mg (0.6 mmol), argon was replaced three times, and 1 mL of 1,4-dioxane was added under argon.3,5-dimethoxy bromobenzene65.1 mg (0.3 mmol).138 C for 36 hours,After cooling to room temperature, the solvent was evaporated under reduced pressure and chromatographed on silica gel at 200-300 mesh Column separation, petroleum ether: ethyl acetate = 100: 1, and dried in vacuo to give 79.4 mg of product as a white solid in 75% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; lithium tert-butoxide; In 1,4-dioxane; at 138℃; for 36h;Schlenk technique; Inert atmosphere; | In a 25 mL Schlenk tube,The addition of 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl (<strong>[213697-53-1]DavePhos</strong>) 77.9 mg (0.2 mmol),(1,5-cyclooctadiene) chlorineRhodium (I) dimer 2.5 mg (2.5% mol of raw material), lithium tert-butoxide48 mg (0.6 mmol) was added, and argon was replaced three times. Under argon, 1 mL of 1,4-dioxane was added, and 32.5 mg of 3-fluorobromobenzene (0.3 mmol).138 C for 36 hours,After cooling to room temperature, the solvent was distilled off under reduced pressure, separated by a 200-300 mesh silica gel column, Petroleum ether: ethyl acetate = 100: 1 and dried in vacuo to give 66.6 mg of product as a white solid in 68% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With chloro(1,5-cyclooctadiene)rhodium(I) dimer; lithium tert-butoxide; In 1,4-dioxane; at 138℃; for 36h;Schlenk technique; Inert atmosphere; | 25 mL of Schlenk tube, 2-dicyclohexylphosphino-2 & apos ;-( N, N-dimethylamino) biphenyl (DavePhos) 77.9 mg (0.2 mmol),(1,5-cyclooctadiene) chlorineRhodium (I) dimer 2.5 mg (2.5% mol of raw material), lithium tert-butoxide48 mg (0.6 mmol), argon was replaced three times, and 1 mL of 1,4-dioxane was added under argon.3-isopropyl bromobenzene59.7 mg (0.3 mmol).138 C for 36 hours,After cooling to room temperature, the solvent was distilled off under reduced pressure, separated by a 200-300 mesh silica gel column, Petroleum ether: ethyl acetate = 100: 1, and dried in vacuo to give 81.5 mg of a colorless viscous product in 80% yield. |
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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