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CAS No. : | 6737-42-4 | MDL No. : | MFCD00003050 |
Formula : | C27H26P2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LVEYOSJUKRVCCF-UHFFFAOYSA-N |
M.W : | 412.44 | Pubchem ID : | 81219 |
Synonyms : |
|
Num. heavy atoms : | 29 |
Num. arom. heavy atoms : | 24 |
Fraction Csp3 : | 0.11 |
Num. rotatable bonds : | 8 |
Num. H-bond acceptors : | 0.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 132.56 |
TPSA : | 27.18 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -4.39 cm/s |
Log Po/w (iLOGP) : | 4.41 |
Log Po/w (XLOGP3) : | 6.23 |
Log Po/w (WLOGP) : | 5.64 |
Log Po/w (MLOGP) : | 6.89 |
Log Po/w (SILICOS-IT) : | 8.54 |
Consensus Log Po/w : | 6.34 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -6.41 |
Solubility : | 0.000162 mg/ml ; 0.000000392 mol/l |
Class : | Poorly soluble |
Log S (Ali) : | -6.59 |
Solubility : | 0.000107 mg/ml ; 0.000000259 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -11.29 |
Solubility : | 0.0000000021 mg/ml ; 0.0 mol/l |
Class : | Insoluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 3.0 |
Synthetic accessibility : | 5.58 |
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 |
---|---|---|
80% | With indium(III) bromide; 1,1,3,3-Tetramethyldisiloxane In toluene at 100℃; for 22 h; Inert atmosphere; Sealed tube | General procedure: In a sealed tube containing a solution of the phosphine oxide derivative (5 mmol) in anhydrous toluene (1M) was added InBr3 (1 mol percent, 0.05 mmol) and the TMDS (1.5 equiv., 7.5 mmol). The reactionnal mixture was stirred at 100 °C during 7 to 40 h depending on the substrate (the reaction was monitored by 31P NMR). After complete consumption and evaporation of toluene the phosphine was purified by flash chromatography on silica gel with pure cyclohexane) to afford the desired phosphine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.36% | Stage #1: at 50℃; Stage #2: at 0 - 80℃; Stage #3: With oxygen In methanol; water |
General Procedure: A 2 l four-necked flask equipped with an effective condenser, a stirrer and a dropping funnel was filled with 500 ml of dry THF which was then deoxygenated for 1 h by transmitting of dry nitrogen. Then 100 g (0.382 mol) of triphenylphosphine was added, and the mixture was stirred till a clear solution was obtained, wherein 6 g (0.856 mol) of freshly prepared ultra-fine lithium flushed with THF was added a little at a time in high purity argon current. The addition rate of the lithium was limited by keeping an exothermic reaction temperature below 50 °C. When the loading of the lithium was completed, the resultant crimson solution was cooled to 0 °C, and a solution of 50 g (0.442 mol) of 1,3-dichloropropane or 62.3 g (0.442 mol) of 1,5-dichloropentane in 50 ml of THF was added by drops to the reaction mass with the temperature kept at 0 °C. When dripping was over, the color of the reaction mass turned light-brown. The mixture was boiled at the flask temperature of 80 °C for 3 h. After the mixture got self-cooled to room temperature, 750 ml of deoxygenated methanol was added to it. The mass was cooled to 0 °C, and 125 ml of oxygen-free water was rapidly added by drops into a vigorously stirred mass. The suspension of the deposited diphosphines 1 or 2 was settled at 0 °C for a short time possible, a solution was decanted from them. The residuum was filtered under nitrogen, rinsed with 5 x 25 ml of cold diethyl ether and dried in vacuum for 20 h. Obtained: 21.54 g (yield 35percent as compared with Ph3P) 1,3-bis(diphenylphosphine)propane (1) or 29.4 g (yield 35percent as compared with Ph3P) 1,5-bis(diphenylphosphine)pentane (2) in the form of white amorphous powders with melting temperatures 61-63 and 41-44 °C respectively that agreed with the literature data [24]. 1H and 31P NMR spectra corresponded to a structure of the compounds and are given in Table 3. When compound 1 was synthesized using not deoxygenated methanol and water, a by process of formation of 1,3-bis(diphenylphosphine)propanemonoxide (3) was observed. In this case a mixture of compounds 1 and 3 was a caramel-like, non-crystallizing mass which was subsequently cut by way of fractional recrystallization from the benzene/methanol mixture. Obtained: 8.4 g of compound 1 (yield 13.6percent) and 5.2 g of compound 3 (yield 6.36percent as compared with Ph3P) with melting temperatures 121-124 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | Stage #1: at 50℃; Inert atmosphere Stage #2: at 0 - 80℃; Inert atmosphere |
General Procedure: A 2 l four-necked flask equipped with an effective condenser, a stirrer and a dropping funnel was filled with 500 ml of dry THF which was then deoxygenated for 1 h by transmitting of dry nitrogen. Then 100 g (0.382 mol) of triphenylphosphine was added, and the mixture was stirred till a clear solution was obtained, wherein 6 g (0.856 mol) of freshly prepared ultra-fine lithium flushed with THF was added a little at a time in high purity argon current. The addition rate of the lithium was limited by keeping an exothermic reaction temperature below 50 °C. When the loading of the lithium was completed, the resultant crimson solution was cooled to 0 °C, and a solution of 50 g (0.442 mol) of 1,3-dichloropropane or 62.3 g (0.442 mol) of 1,5-dichloropentane in 50 ml of THF was added by drops to the reaction mass with the temperature kept at 0 °C. When dripping was over, the color of the reaction mass turned light-brown. The mixture was boiled at the flask temperature of 80 °C for 3 h. After the mixture got self-cooled to room temperature, 750 ml of deoxygenated methanol was added to it. The mass was cooled to 0 °C, and 125 ml of oxygen-free water was rapidly added by drops into a vigorously stirred mass. The suspension of the deposited diphosphines 1 or 2 was settled at 0 °C for a short time possible, a solution was decanted from them. The residuum was filtered under nitrogen, rinsed with 5 x 25 ml of cold diethyl ether and dried in vacuum for 20 h. Obtained: 21.54 g (yield 35percent as compared with Ph3P) 1,3-bis(diphenylphosphine)propane (1) or 29.4 g (yield 35percent as compared with Ph3P) 1,5-bis(diphenylphosphine)pentane (2) in the form of white amorphous powders with melting temperatures 61-63 and 41-44 °C respectively that agreed with the literature data [24]. 1H and 31P NMR spectra corresponded to a structure of the compounds and are given in Table 3. When compound 1 was synthesized using not deoxygenated methanol and water, a by process of formation of 1,3-bis(diphenylphosphine)propanemonoxide (3) was observed. In this case a mixture of compounds 1 and 3 was a caramel-like, non-crystallizing mass which was subsequently cut by way of fractional recrystallization from the benzene/methanol mixture. Obtained: 8.4 g of compound 1 (yield 13.6percent) and 5.2 g of compound 3 (yield 6.36percent as compared with Ph3P) with melting temperatures 121-124 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With indium(III) bromide; 1,1,3,3-Tetramethyldisiloxane; In toluene; at 100℃; for 22h;Inert atmosphere; Sealed tube; | General procedure: In a sealed tube containing a solution of the phosphine oxide derivative (5 mmol) in anhydrous toluene (1M) was added InBr3 (1 mol %, 0.05 mmol) and the TMDS (1.5 equiv., 7.5 mmol). The reactionnal mixture was stirred at 100 C during 7 to 40 h depending on the substrate (the reaction was monitored by 31P NMR). After complete consumption and evaporation of toluene the phosphine was purified by flash chromatography on silica gel with pure cyclohexane) to afford the desired phosphine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With triethylamine;palladium diacetate; In methanol; DMF (N,N-dimethyl-formamide); at 80℃; for 48h; | Example 45 methyl 4-(7-chloro-3-{2-[4-fluoro-2-(trifluoromethyl)anilino]-2-oxoethyl}-6-methyl-2-oxo-2H-chromen-4-yl)benzoate palladium acetate (89.8 mg), <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (206 mg) and triethylamine (1 ml) were added to a solution of 2-[4-(4-bromophenyl)-7-chloro-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide (1.17 g) in methanol (10 ml) and DMF (20 ml), and the mixture was stirred at 80C for 2 days under carbon monoxide atmosphere (atmospheric pressure).. The reaction solvent was concentrated to distill off under reduced pressure, water was added, and an organic material was extracted with a mixed solvent of chloroform and methanol.. The extract was washed with an aqueous saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate-chloroform = 5:1:3?4:1:1) to obtain the title compound (0.559 g, yield 49%). mp: 202-204C(hexane-ethyl acetate): NMR (CDCl3) delta: 2.28 (3H, s), 3.43 (2H, s), 3.98 (3H, s), 6.81 (1H, s), 7.21-7.27 (1H, m), 7.32 (1H, dd, J = 8.4, 3.0 Hz), 7.43-7.46 (3H, m), 7.97 (1H, dd, J = 9.0, 4.8 Hz), 8.17 (1H, s), 8.24 (2H, d, J = 8.7 Hz). IR (KBr): 3258, 1719. Elemental analysis for C27H18NO5ClF4Calculated (%): C, 59.19; H, 3.31; N, 2.56. Found (%): C, 59.09; H, 3.40; N, 2.60. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With hydrogenchloride; triethylamine;palladium diacetate; In N,N-dimethyl-formamide; | Preparation 39 4-(3-Acetylphenyl)-1-hexanoyl-3,4-dimethylpiperidine To a solution of 1-hexanoyl-3,4-dimethyl-4-(trifluoromethanesulfonyloxyphenyl)piperidine (Preparation 28, 2.1 g, 4.7 mmol)) in N,N-dimethyl- formamide (15 mL) at room temperature were added sequentially, triethylamine (0.57 g, 5.6 mmol), butyl vinyl ether (3.0 mL, 23.4 mmol), <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (69 mg, 0.17 mmol) and palladium(II) acetate (31 mg, 0.14 mmol). The mixture was heated at 80 C. under a nitrogen atmosphere for 18 h and then allowed to cool to room temperature. After the addition of 2 N HCl (20 mL), the mixture was stirred vigorously for 30 minutes and then poured onto dichloromethane (50 mL). The two layers were separated and the aqueous layer was extracted with dichloromethane (3*20 mL). The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluding with ethyl acetate:hexane (1:2 and then 2:1). The title compound was isolated as clear oil (900 mg, 58%). NMR (CDCl3, selected data from a 1:1 mixture of rotamers): 0.55-0.65 (m, 3H), 0.85-0.95 (m, 3H), 1.20-1.38 (m, 4H), 1.42 (s, 3H), 1.57-1.78 (m, 3H), 2.08-2.48 (m, 4H), 2.60 (s, 3H), 2.92 (m, 0.5H), 3.15 (m, 0.5H), 3.39 (m, 0.5H), 3.60 (m, 1H), 3.90 (m, 0.5H), 4.41 (m, 0.5H), 4.73 (m, 0.5H), 7.41-7.53 (m, 2H), 7.79 (d, 1H), 7.85 (s, 1H). MS (thermospray): M/Z (MH+) 330.4; C21H31NO2+H requires 330.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; trifluorormethanesulfonic acid; triethylamine;carbon monoxide; tetrakis(triphenylphosphine)palladium (0); In ethanol; dichloromethane; N,N-dimethyl-formamide; | Step 1 Synthesis of 7-ethoxycarbonylisoquinoline: 0.89 g (6.1 mmol) of <strong>[7651-83-4]7-hydroxyisoquinoline</strong> was dissolved in 15 ml of dichloromethane. 1.1 ml of pyridine and 1.3 ml (7.7 mmol) of anhydrous trifluoromethanesulfonic acid were added to the obtained solution under cooling with ice, and they were stirred at 0 C. for 1 hour. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain an oily product. This oily product was dissolved in 10 ml of DMF. 0.4 ml (2.9 mmol) of triethylamine, 50 mg (0.04 mmol) of tetrakistriphenylphosphine palladium, 16 mg (0.04 mmol) of 1,3-bis(diphenylphosphino)propane and 5 ml of ethanol were added to the obtained solution, and they were stirred in the presence of carbon monoxide at 70 C. overnight. The solvent was evaporated, and the residue was purified by the silica gel column chromatography to obtain the title compound. Yield: 196 mg (0.97 mmol) (16%) MS (ESI, m/z) 202 (MH+) H-NMR (CD3Cl) delta 1.48 (3H, t), 4.47 (2H, q), 7.70 (1H, d), 7.88 (1H, d), 8.30 (1H, dd), 8.62 (1H, d), 8.74 (1H, s), 9.37 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine;palladium diacetate; In ethanol; hexane; N,N-dimethyl-formamide; | Ethyl-2,2,4,4-tetramethyl chroman-6-carboxylate (Compound 23) A solution of 6-bromo-2,2,4,4-tetramethylchroman (synthesis is described in U.S. Pat. No. 6,252,090)(2.2 g, 8.08 mmol), palladium acetate (0.145 g, 0.65 mmol) and <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (0.267 g, 0.65 mmol) in a mixture of N,N-dimethylformamide (25 mL), ethanol (20 mL) and triethyl amine (7 mL) was heated at 90 C. under an atmosphere of carbon monoxide overnight. The volatiles were distilled off in vacuo and the residue was diluted with water and extracted with ethyl acetate. The combined organic extract was washed with brine (*1), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent to afford the title compound (1.9 g, 90%). 1H NMR (300 MHz, CDCl3): delta8.00 (d, 1H, J=2.3 Hz), 7.76 (dd, 1H, J=2.1, 8.5 Hz), 6.79 (d, 1H, J=8.5 Hz), 4.33 (q, 2H, J=7.1 Hz), 1.85 (s, 2H), 1.36 (s, 6H), 1.37 (s, 6H), 1.39-1.33 (m, 3H). |
90% | With triethylamine;palladium diacetate; In ethanol; hexane; N,N-dimethyl-formamide; | Ethyl-2,2,4,4-tetramethyl chroman-6-carboxylate (Compound 23) A solution of 6-bromo-2,2,4,4-tetramethylchroman (synthesis is described in U.S. Pat. No. 6,252,090)(2.2 g, 8.08 mmol), palladium acetate (0.145 g, 0.65 mmol) and <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (0.267 g, 0.65 mmol) in a mixture of N,N-dimethylformamide (25 mL), ethanol (20 mL) and triethyl amine (7 mL) was heated at 90 C. under an atmosphere of carbon monoxide overnight. The volatiles were distilled off in vacuo and the residue was diluted with water and extracted with ethyl acetate. The combined organic extract was washed with brine (*1), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent to afford the title compound (1.9 g, 90%). 1H NMR (300 MHz, CDCl3): delta8.00 (d, 1H, J=2.3 Hz), 7.76 (dd, 1H, J=2.1,8.5 Hz), 6.79 (d, 1H, J=8.5 Hz), 4.33(q, 2H, J=7.1 Hz), 1.85 (s, 2H), 1.36(s, 6H), 1.37 (s, 6H), 1.39-1.33(m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With hydrogenchloride; triethylamine; In water; acetonitrile; | Example 111 Preparation of 2,6-dimethyl-4-[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzyl]amino]carbonyl]benzoic Acid To a solution of trifluoromethanesulfonic acid, 2,6-dimethyl-4-[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzyl]amino]carbonyl]phenyl ester (Example 105, 562 mg, 1.09 mmol) in acetonitrile (7 mL) and water (1 mL) at 25 C. was added palladium (II) acetate (24 mg, 0.109 mmol), <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (45 mg, 0.109 mmol), followed by triethylamine (2.18 mmol, 0.303 mL). The reaction was then pressurized to 40 psi with carbon monoxide and heated to 80 C. for 4 h. The mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL) containing 1 mL of triethylamine. The separated aqueous layer was re-extracted with ethyl acetate (2*50 mL) and the combined organic layers were discarded. The aqueous phase was adjusted with 1N hydrochloric acid solution to pH 2 and extracted with ethyl acetate (100 mL). The organic extract was washed with water (25 mL) and brine (25 mL), dried (MgSO4), filtered and evaporated under reduced pressure to yield 2,6-dimethyl-4-[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzyl]amino]carbonyl]benzoic acid (1.7 g, 71% yield) as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; ammonium hydroxide; carbon monoxide; triethylamine;Pd(OAc)2; In methanol; dichloromethane; dimethyl sulfoxide; | Step 2: 5-(hydroxymethyl)isoquinoline (15) To a solution of 2 g (9.6 mmol) of the 1:1 mixture of 5 and <strong>[58794-09-5]7-bromoisoquinoline</strong> in 7 mL DMSO and 15 mL MeOH was added 0.4 g (1 mmol) 1,3-bis(diphenylphosphino)propane, 0.2 g (0.9 mmol) Pd(OAc)2, and 5 mL (36 mmol) Et3N. Carbon monoxide gas was bubbled through the solution for 5 minutes, and then the reaction was heated under a CO atmosphere for 36 h. The reaction mixture was cooled, diluted with 300 mL EtOAc, washed with 200 mL saturated sodium bicarbonate solution and 200 mL brine, then dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (4*12 cm silica gel, linear gradient 1-4% MeOH containing 10% saturated aqueous NH4OH/CH2Cl2 afforded 1.3 g of 5- and 7-carboxymethyl isoquinoline as an inseparable mixture. To a -78 C. solution of 1.2g (6.4 mmol) 5- and 7-carboxymethyl isoquinoline in 50 mL CH2Cl2 was added 15 mL (15 mmol, IM solution in CH2Cl2) diisobutulaluminum hydride. After 30 min at -78 C. the reaction was quenched with 10 mL IM HCl, allowed to warm to room temperature, diluted with 250 mL EtOAc, and brought to pH>10 with 250 mL saturated sodium bicarbonate solution. The layers were mixed and separated and the EtOAc layer was washed with 250 mL brine, then dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (4*12 cm silica gel, linear gradient 3-10% MeOH containing 10% NH4OH/ CH2Cl2 followed by purification of mixed fractions (3*12 cm silica gel, linear gradient 3-10% MeOH containing 10% NH4OH/CH2Cl2) afforded 5-hydroxymethylisoquinoline 15 as the higher Rf isomer: 1H NMR(400 mHz, CDCl3) 9.25 (s, 1H); 8.57 (d, IH, J=5.94 Hz); 7.92 (d, 1H, J=8.23 Hz); 7.90 (d, 1H, J=6.04 Hz); 7.76 (d, 1H, J=6.22Hz); 7.59 (dd, 1H, J=7.13 and 8.05 Hz); 5.16 (s, 2H). The lower Rf isomer is the 7-isomer. 1H NMR(400 mHz, CDCl3) 9.22 (s, 1H); 8.51 (d, 1H, J=5.76 Hz); 7.95 (br s, 1H); 7.83 (d, 1H, J=8.41 Hz); 7.71 (dd, 1H, J=8.5 and 1.65 Hz); 7.65 (d, 1H, J=5.76 Hz); 4.92 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With CO; triethylamine;palladium diacetate; In methanol; dimethyl sulfoxide; | D. 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-1-benzoic acid methyl ester To a solution of trifluoro-methanesulfonic acid 4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-phenyl ester (10.0 g, 19.8 mmol) in a Parr pressure bottle in MeOH (69 mL) were added DMSO (62 mL) and triethylamine (21.8 mL, 157 mmol). To the reaction mixture were added palladium acetate (2.2 g, 9.1 mmol) and <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e(3.75 g, 9.1 mmol). The mixture was shaken under 40 psi of CO at 70 C. for 4 hours. The reaction mixture was cooled to room temperature and was diluted with diethyl ether (600 mL). The ether layer was washed with water (5*60 mL), dried (MgSO4) and concentrated. The crude residue was purified by flash chromatography with hexanes/EtOAc (1:1) to afford 6.9 g (85% yield) of 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid methyl ester. 1H-NMR (400 MHz, CDCl3) delta 7.91 (d, 2H), 7.32 (d, 2H), 7.28-7.16 (comp, 6H),), 6.82 (d,, 1H), 6.79 (s, 1 H), 6.68 (dd, 1H), 3.86 (s, 3H), 3.74 (s, 3H), 3.38 (s, 2H), 2.47-2.44 (comp, 8H); MS (M+1) 416.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine;palladium diacetate; In methanol; dimethyl sulfoxide; | A. 4-(7-{2-[tert-Butoxycarbonyl-(tetrahydro-pyran-4-yl)-amino]-ethylamino}-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl)-3,5-dichloro-benzoic acid methyl ester A suspension of methanesulfonic acid 4-(7-{2-[tert-butoxycarbonyl-(tetrahydro-pyran-4-yl)-amino]-ethylamino}-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl)-3,5-dichloro-phenyl ester (188 mg, 0.276 mmol) from Example 134, step B, <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (30 mg 0.073 mmol), triethylamine (0.10 mL), and palladium(II) acetate (25 mg, 0.11 mmol) in methanol (3.5 mL)/dimethylsulfoxide (3.5 mL) was degassed with a stream of carbon monoxide and then shaken for 4 hours at 70 C. under 40 psi carbon monoxide. The mixture was filtered through Celite, diluted with ethyl acetate and washed with water, dried (Na2SO4), concentrated under reduced pressure, and chromatographed (3:1 to 1:1 hexanes/ethyl acetate) to afford the product (144 mg, 88%): +APcI MS (M+1)+592; 1H NMR (CDCl3) delta: 8.04 (s, 2H), 5.83 (br s, 1H), 3.92 (s, 3H), 2.43 (s, 3H), 2.24 (s, 3H), 1.53 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With carbon monoxide; triethylamine;palladium diacetate; In methanol; | Step B Preparation of methyl 4-cyano-3-(trifluoromethoxy) benzoate Through a solution of the product from Step A (3.82 g, 14.4 mmol), palladium(II) acetate (150 mg, 0.4 wt %), 1,3-bis(diphenylphosphino)propane (300 mg), and triethylamine (3.5 mL) in 30 mL of MeOH and 15 mL of DMSO was bubbled carbon monoxide gas for 6 hours. The reaction was heated to 80 C. and stirred under a balloon of carbon monoxide. After ca. 16 hours, another additional portions of palladium(II) acetate (100 mg) and 1,3-bis(diphenylphosphino)propane (200 mg) were added, and the solution was stirred for an additional 20 hours. The mixture was diluted with EtOAc and extracted with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (20% EtOAc/hexane) gave the titled product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With carbon monoxide; triethylamine;palladium diacetate; In methanol; dimethyl sulfoxide; | (c) Methyl 3,4-dimethoxy-1-naphthalenecarboxylate A solution of 1-bromo-3,4-dimethoxylnaphthalene (3.72 g, 13.9 mmol), <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (0.29 g, 0.7 mmol), palladium acetate (0.16 g, 0.70 mmol), triethylamine (4.85 mL, 34.8 mmol), MeOH (11.5 mL) and DMSO (17 mL) was heated to 75 C. Carbon monoxide was bubbled through the solution for 30 min and the mixture heated under CO (1 atm) for 23 h. The mixture was diluted with brine and extracted with EtOAc (3*70 mL). The organic layers were dried (MgSO4), filtered, and concentrated. Column chromatography gave methyl 3,4-dimethoxy-1-naphthalenecarboxylate as a yellow oil (2.93 g, 85%). 1H NMR (CDCl3) delta 8.89 (m, 1H), 8.21 (m, 1H), 8.06 (s, 1H), 7.52 (m, 2H), 4.06 (s, 3H), 4.02 (s, 3H), 4.00 (s, 3H); MS (APCI) m/z 247 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine;palladium diacetate; In methanol; N,N-dimethyl-formamide; | Preparation 12 A mixture of 4-[2-(tert-butoxycarbonylamino)ethyl]-phenyl trifluoromethanesulfonate (6.11 g, 16.6 mmol), palladium(II) acetate (745 mg, 3.32 mmol), <strong>[6737-42-4]1,3-bis-(diphenylphosphino)propane</strong> (1.37 g, 3.32 mmol), triethylamine (6.94 ml, 49.8 mmol), and MeOH (24ml) in DMF (60 ml) was purged for 30 min with carbon monoxide. The mixture was stirred under carbon monoxide atmosphere at 78 C. for 3 hours. After cooling the mixture to room temperature, the reaction mixture was diluted with EtOAc, washed with water, 1N-hydrochloric acid, water, saturated sodium hydrogencarbonate, water and brine successively, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 4:1-3:1) to give methyl 4-[2-(tert-butoxycarbonylamino)ethyl]benzoate (3.52 g, 76%). IR (KBr, cm-1): 3371, 2978, 2947, 1722, 1680, 1525, 1277 1H-NMR (CDCl3, delta): 1.43 (9H, s), 2.86 (2H, t, J=7.0 Hz),3.32-3.45 (2H, m), 3.91 (3H, s), 4.45-4.63 (1H, m), 7.27 (2H, d, J=8.3 Hz), 7.98 (2H, d, J=8.3 Hz) MS (m/z): 1 80 (M-C5H9O2+2H)+ |
Yield | Reaction Conditions | Operation in experiment |
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95% | With triethylamine;palladium diacetate; In N,N-dimethyl-formamide; | C 4-Methoxytricyclo[7.2.1.02,7]dodeca-2(7),3,5,10-tetraene Trifluoro-methanesulfonic acid 2-cyclopent-3-enylmethyl-5-methoxy-phenyl ester (2.00 g, 5.95 mmol) was dissolved in DMF (10 mL) under a N2 atmosphere and treated with triethylamine (0.91 g, 8.92 mmol) and <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (0.37 g, 0.89 mmol). This mixture was stirred and degassed (3 vacuum/N2 purge cycles), and then treated with palladium acetate (93 mg, 0.42 mmol). After stirring for 20 min. the mixture was warmed to 100 C. for 18 hours, cooled and poured into brine (30 mL). The resulting mixture was extracted with EtOAc (4*10 mL) and the combined organic layer was washed with sat. aq. NaHCO3 soln. (10 mL), H2O (10 mL), brine (10 mL), dried (MgSO4), filtered and evaporated to an oil. The oil was chromatographed on Silica gel (2%CH2Cl2/hexanes) to provide product as an oil (1.05 g, 95%). (TLC 10%EtOAc/hexanes Rf 0.52). 1H NMR (CDCl3) delta6.94 (d, J=8.0 Hz, 1H), 6.68 (dd, J=8.0,2.8 Hz, 1H), 6.59 (d, J=2.8 Hz, 1H), 6.23 (dd, J=5.5,2.8 Hz,1H), 5.79 (dd, J=5.5,2.6 Hz, 1H), 3.77 (s, 3H), 3.28 (m, 1H), 2.96-2,89 (m, 2H), 2.49 (d, J=15.5 Hz, 1H), 2.19 (m, 1H), 1.85 (d, J=10.5 Hz, 1H). 13C NMR (CDCl3) 156.94, 144.07, 138.95, 131.24, 131.21, 126.34, 111.73, 111.45, 55.22, 45.10, 40.18, 38.47, 29.49. GCMS m/e 186 (M+). |
Yield | Reaction Conditions | Operation in experiment |
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75.3% | With hydrogenchloride; sodium formate; N-ethyl-N,N-diisopropylamine;palladium diacetate; In dichloromethane; dimethyl sulfoxide; | Example 13 Synthesis of (S)-2-di(2-naphthyl)phosphinyl-2'-(trifluoromethanesulfonyloxy)-1,1'-binaphthyl (S)-2,2'-bis(trifluoromethanesulfonyloxy)-1,1'-binaphthyl (9.10 g, 16.5 mmol), palladium acetate (0.372 g, 1.65 mmol), <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (0.683 g, 1.65 mmol) and sodium formate (0.113 g, 1.65 mmol) were dissolved in DMSO (45 ml), and the resulting solution was stirred for 1.5 hours at room temperature. The solution was admixed with a solution made by dissolving di(2-naphthyl)phosphine oxide (6.00 g, 19.8 mmol) and diisopropylethylamine (5.8 ml, 33 mmol) in DMSO (55 ml). The resulting solution was stirred for 4 hours at 100 C. After cooling to room temperature, the reaction mixture was admixed with methylene chloride (75 ml). To the resulting solution, which was cooled in an ice/water bath, 2N hydrochloric acid (100 ml) was gradually added dropwise. The solution was then stirred for 30 minutes at room temperature. Then, the solution was separated into layers, and the aqueous layer was extracted with methylene chloride. The organic layers were combined into a single solution, and the solution was washed with water. After drying with anhydrous magnesium sulfate, the organic solution was concentrated. The solution was then purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:4 by volume) to obtain 8.45 g (yield: 75.3%) of the above captioned compound as yellowish white crystals. mp: 122 to 123 C.; [alpha]D24: -66.8 (c 1.00, toluene) 1 H-NMR(CDCl3)delta: 6.99-8.05(m, ArH) 31 P-NMR(CDCl3)delta: 29.03 CI-Mass spectrum m/z: 703(M+ +H) |
Yield | Reaction Conditions | Operation in experiment |
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65% | With hydrogenchloride; N-ethyl-N,N-diisopropylamine;palladium diacetate; In dichloromethane; dimethyl sulfoxide; | Example 3 Synthesis of (R)-2-diphenylphosphinyl-2'-trifluoromethanesulfonyloxy-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl (R)-2,2'-ditrifluoromethanesulfonyloxy-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl (3.0 g, 5.4 mmol), palladium acetate (121 mg, 0.54 mol) and <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (222 mg, 0.54 mmol) were dissolved in DMSO (25 ml). The solution was stirred for 1.5 hours at room temperature. The solution was admixed with a solution made by dissolving diphenylphosphine oxide (1.41 g, 7.0 mmol) and diisopropylethylamine (1.04 g, 8.1 mmol) in DMSO (15 ml). The resulting solution was stirred for 6 hours at 100 C. After concentrating, the solution was admixed with methylene chloride (40 ml) and 1N hydrochloric acid (20 ml). The solution was then stirred for 30 minutes at room temperature. Next, the solution was separated into layers, and the aqueous layer was extracted with methylene chloride. The organic layers were combined into a single solution, and the solution was washed with water. After drying with anhydrous magnesium sulfate, the solution was concentrated. The solution was then purified by silica gel column chromatography (hexane: ethyl acetate=4:1 to 1:1 by volume) to obtain 2.13 g (yield: 65%) of the above captioned compound as yellowish while crystals. mp: 148 to 150 C. [alpha]D24: -3.35 (c 1.00, toluene) 31 P-NMR(CDCl3)delta: 28.12(s) EI-Mass spectrum: m/z 610(M+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With triethylamine;palladium diacetate; In methanol; dimethyl sulfoxide; | 4-[Isopropyl-(7-isopropyl-3,3,6-trimethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid methyl ester (Compound 67) Following general procedure O and using 7-isopropyl-5-[isopropyl-(4-trifluoromethanesulfonyloxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 63, 0.052 g, 0. 107 mmol), triethyl amine (0.4 mL, 0.28 mmol), palladium(II)acetate (0.030 g, 0.13 mmol) and <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (0.041 g, 0.1 mmol) in a mixture of 3 mL of methanol, 2 mL of dimethylsulfoxide and 1 mL of 1,2-dichloroethane, the title compound (0.037 g, 84%) was obtained as a brown oil. 1 H NMR (300 MHz, CDCl3): delta 7.81 (d, 2H, J=9.2 Hz), 6.59 (s, 1H), 6.40 (d, 2H, J=9.2 Hz), 4.32 (heptet, 1H, J=6.6 Hz), 4.24 (s, 2H), 3.83 (s, 3H), 3.19 (heptet, 1H, J=7.0 Hz), 2.00 (s, 3H), 1.36-1.26 (m, 15H), 0.98 (d, 3H, J=6.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
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92% | With carbon monoxide; ammonia; triethylamine; In methanol; N,N-dimethyl-formamide; | e) Methyl (R)-3-(N-Cyclobutyl-N-isopropylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxylate (R)-3-(N-Cyclobutyl-N-isopropylamino)-8-fluoro-5-trifluoromethylsulfonyloxy-3,4-dihydro-2H-1-benzopyran (1.65 g, 4.01 mmol) was dissolved in a solution of DMF/methanol (6:2, 30 mL) and then degassed followed by the inlet of carbon monoxide (*3). With a slight positive pressure of carbon monoxide, palladium(II)-acetate (30 mg), <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (55 mg) and triethylamine (1.25 mL, 8.8 mmol) were added and the reaction mixture was degassed and subjected to carbon monoxide once again. The reaction was heated to 70 C. under carbon monoxide atmosphere with vigorous stirring for 6 h. The reaction was allowed to cool and the solvent was removed in vacuo. The remains were taken into a 2M solution of NH3 and then extracted, twice, with diethyl ether. The combined ether portions were dried (MgSO4), filtered, and the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent: 8% ethyl acetate/hexane) gave 1.18 mg (92% yield) of the title compound as a clear oil. [alpha]21D =-139.1 (C=0.1; CHCl3). GC-MS (70 eV) M=321 (3%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With carbon monoxide; ammonia; triethylamine; In methanol; N,N-dimethyl-formamide; | d) Methyl (R)-3-(N-Cyclobutyl-N-n-propylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5carboxylate (R)-3-(N-Cyclobutyl-N-n-propylamino)-8-fluoro-5-trifluoromethylsulfonyloxy-3,4dihydro-2H-1-benzopyran (1.00 g, 2.43 mmol) was dissolved in a solution of DMF/methanol (6:2, 20 mL) and then degassed followed by the inlet of carbon monoxide (*3). With a slight positive pressure of carbon monoxide, palladium(II)-acetate (18 mg), <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (25 mg) and triethylamine (0.75 mL, 5.3 mmol) were added and the reaction mixture was degassed and subjected to carbon monoxide once again. The reaction was heated to 70 C. under carbon monoxide atmosphere with vigorous stirring for 6 h. The reaction was allowed to cool and the solvent was removed in vacuo. The remains were taken into a 2M solution of NH3 and then extracted, twice, with diethyl ether. The combined ether portions were dried (MgSO4), filtered, and the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent: 15% ethyl acetate/hexane) gave 0.73 mg (94% yield) of the title compound as a clear oil. [alpha]21D =-130.1 (C=0.1; CHCl3). GC-MS (70 eV) M=321 (2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine; In methanol; N,N-dimethyl-formamide; | e) Methyl (R)-3-(N-Cyclopentyl-N-n-propylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxylate (R)-3-(N-Cyclopentyl-N-n-propylamino)-8-fluoro-5-trifluoromethylsulfonyloxy-3,4dihydro-2H-1-benzopyran (3.7 g, 8.7 mmol), DMF (50 mL), triethylamine (2.5 g, 25 mmol), methanol (4 g, 130 mmol), palladiuma(II)acetate (100 mg, 0.45 mmol) and 1,3<strong>[6737-42-4]bis(diphenylphosphino)propane</strong> (200 mg, 0.48 mmol) were placed in a round-bottomed flask. The solution was stirred at 75 C. in an atmosphere of carbon monoxide for 4 h. After evaporation of the solvent in vacuo and subjecting the crude to flash chromatography, 2.5 g (86 % yield) of the title compound as a colorless oil was isolated. GC/MS (70 eV) M=335 (20 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine;palladium diacetate; In methanol; N,N-dimethyl-formamide; | e) Methyl (R)-3-(N-Cyclohexyl-N-n-propylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxylate (R)-3-(N-Cyclohexyl-N-n-propylamino)-8-fluoro-5-trifluoromethylsulfonyloxy-3,4dihydro-2H-1-benzopyran (0.8 g, 1.8 mmol) (4), DMF (30 mL), triethylamine (0.5 g, 5 mmol), methanol (0.8 g, 13 mmol), palladium(II)acetate (30 mg, 0.14 mmol) and <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (60 mg, 0.14 mmol) were placed in a round-bottomed flask. The solution was stirred at 75 C. in an atmosphere of carbon monoxide for 4 h. After evaporation of the solvent in vacuo and subjecting the crude to flash chromatography, 0.6 g (76% yield) of the title compound as a colorless oil was isolated. GC/MS (70 eV) M=349 (30 %). |
Yield | Reaction Conditions | Operation in experiment |
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64% | With triethylamine;palladium diacetate; In methanol; chloroform; N,N-dimethyl-formamide; toluene; | Example 47 3-(N,N-Dipropylamino)-5-methyloxycarbonylthiochroman (3-(N,N-Dipropylamino)-5-trifluoromethanesulfonyl-thiochroman (620 mg, 1.6 mmol) was dissolved in 11 mL of DMF/methanol 6:2 and the solution was degassed for 15 min. Pd(OAc)2 (11 mg), 1,3-bis-diphenyl-phosphinopropane (19 mg), and triethylamine (0.48 mL, 0.35 g) were added to the reaction mixture. The mixture was heated to 70 C. under carbonmonoxide atmosphere and stirred for 5 hours. The solution was cooled, diluted with 30 mL of toluene, washed with saturated NaHCO3, dried (Na2 SO4) and evaporated in vacuo. Chromatography on silica (eluent: gradient CHCl3 ?10% EtOAc/CHCl3) gave 310 mg (64% yield) of the title compound (base) as a slightly yellow oil. 13C NMR: (200 MHz-CDCl3) PPM 168.2, 136.6, 134.8, 131.6, 130.1, 126.5, 125.7, 56.7, 52.5, 52.1, 30.4, 28.0, 22.3, 11.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With triethylamine;palladium diacetate; In N-methyl-acetamide; methanol; chloroform; toluene; | Example 22 3-Dipropylamino-5-methyloxycarbonylthiochroman 3-Dipropylamino-5-hydroxybenzothiopyran (EP 0222 996; 620 mg, 1.6 mmol) was dissolved in 11 mL of dimethylformamide/methanol (6:2) and the solution was degassed (10mm, 22 C., 15 min). Pd(OAc)2 (11 mg) 1,3-bis-diphenyl-phosphinopropane (19 mg), and triethylamine (0.48 mL, 0.35 g) were added to the reaction mixture. The mixture was heated to 70 C. under carbonmonoxide atmosphere and stirred for 5 hours. The solution was cooled, diluted with 30 mL of toluene, washed with saturated NaHCO3, dried with Na2 SO4, and evaporated in vacuo. Chromatography on silica by elution using a gradient CHCl3 ?10% EtOAc/CHCl3 gave 310 mg of the title compound (base) as a slightly yellow oil; Yield: 64%. 13 C NMR (200 MHz-CDCl3) PPM 168.2, 136.6, 134.8, 131.6, 130.1, 126.5, 125.7, 56.7, 52.5, 52.1, 30.4, 28.0, 22.3, 11.9. |
Yield | Reaction Conditions | Operation in experiment |
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92% | With triethylamine;palladium diacetate; In methanol; N,N-dimethyl-formamide; | Example 54 3-(N-isopropyl-N-n-propylamino)-5-methyloxycarbonylthiochroman 3-(N-isopropyl-N-n-propylamino)-5-trifluoromethanesulfonylthiochroman (0.97 g, 2.44 mmol) was dissolved in 17 mL of DMF/methanol 6:2 and the solution was degassed for 15 min. Pd(OAc)2 (17 mg), 1,3-bis-diphenyl-phosphinopropane (29 mg) and triethylamine (0.54 g, 0.75 mL, 5.4 mmol) were added to the reaction mixture. The mixture was heated to 70 C. under carbonmonoxide atmosphere and stirred for 4 hours. The solution was cooled, diluted with toluene, dried (Na2 SO4) and washed with saturated NaHCO3, evaporated in vacuo. Chromatography on silica (eluent: 5% EtOAc/hexane) gave 0.69 g (92% yield) of the title compound (base) as a clear oil. MS 307. 13 C NMR: (200 MHz-CDCl3) PPM 168.3, 137.0, 134.8, 131.6, 130.1, 126.5, 125.7, 53.9, 52.2, 48.9, 47.3, 32.7, 30.1, 23.8, 21.1, 11.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine;PdOAc2; In N-methyl-acetamide; methanol; | Example 2 3-Dipropylamino-5-methyloxycarbonylchroman 3-Dipropylamino-5-trifluoromethanesulfonylchroman (Example 1; 4.43 g, 11.6 mmol) was dissolved in 80 mL dimethylformamide/methanol 6:2 and the solution was degassed (10 mm Hg, 20 C., 15 min). PdOAc2 (76 mg, 0.34 mmol), 1,3-bis-diphenylphosphinopropane (141 mg, 0.34 mmol) and triethylamine (3.5 mL, 25 mmol) were then added. The mixture was heated to 70 C. under CO atmosphere and stirred for 5 hours. The solution was cooled, diluted with toluene (200 mL), washed with aqueous NaHCO3, dried with Na2 SO4 and evaporated to dryness. The oil was purified by flash chromatography (silica gel) by elution with ethyl acetate/hexane 1:8. Yield: 76%, Mp 150-152 C. (HCl-salt). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With ammonia; triethylamine;palladium diacetate; In methanol; diethyl ether; N,N-dimethyl-formamide; | Example 80 (R)-8-Fluoro-5-methoxycarbonyl-3-(N,N-di-n-propylamino)chroman (R)-8-Fluoro-3-(N,N-di-n-propylamino)-5-trifloromethanesulfonyloxychroman (0.95 g, 2.4 mmol), triethylamine (0.53 g, 5.2 mmol), 1,3bis-(diphenylphosphino)propane (100 mg, catalytic amount), palladium(II)acetate (50 mg, catalytic amount) and DMF/MeOH (18 mL, 6:2) were mixed in a 50 mL three necked round bottom flask. The flask was evacuated followed by the inlet of CO (repeated three times). The reaction mixture was stirred at 70 C. for 7 hours. The solvent was removed in vacuo and the residue was dissolved in diethyl ether/2M NH3. The layers were separated and the water phase was extracted once with ether. The combined ether layers were dried (MgSO4) and the solvent was removed in vacuo to give a brown oily residue which was purified by flash chromatography (SiO2, CH2 Cl2 /EtOAC, 20:1) to give 650 mg of the title compound as a clear oil (87% yield). [alpha]21 -92 (c 10 mg/mL MeOH). Mass spectrum (70 eV) m/z (relative intensity) 309(20, M+), 281(18), 280(100), 56(10), 43(22), 42(12), 41(16). |
Yield | Reaction Conditions | Operation in experiment |
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95% | With triethylamine;palladium diacetate; In methanol; diethyl ether; ammonia; N,N-dimethyl-formamide; | d (R)-2-N,N-Dibenzylamino-5 methoxycarbonylchroman (R)-2-N,N-Dibenzylamino-5-trifluoromethanesulfonyloxychroman (1.8 g, 3.8 mmol) and triethylamine (0.8 g, 8.3 mmol) were dissolved in a solution of DMF/MeOH (20 mL, 6:2) in a three necked round bottom flask. The flask was evacuated, followed by inlet of CO gas (repeated three times). Palladium(II)acetate (28 mg, catalytic amount) and 1,3-bis(diphenylphosphino)-propane (60 mg, catalytic amount) were added and the reaction mixture was stirred at 75 C. for 6 hours. The solvent was removed in vacuo to give a brownish oily residue. The oil was dissolved in diethyl ether/NH3 (2M). The layers were separated and the water phase was extracted once with diethyl ether. The combined ether layers were dried (MgSO4). The solvent was removed in vacuo to give a brown oily residue which was purified by flash chromatography (SiO2, CH2 Cl2 /hexane, 1:1) to give the title compound in 95% yield (1.4 g). [alpha]D21 -147 (c 5 mg/mL, MeOH). Mass spectrum (70 eV) m/z (relative intensity) 388(25), 387(100, M+), 297(10), 296(62), 264(27), 132(40), 91(79). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.5% | With nitrogen; triethylamine;palladium diacetate; In methanol; N,N-dimethyl-formamide; | Preparation 6 cis-(+-)-2,3,3a,4,5,9b-hexahydro-9-carbomethoxy-3-(n-propyl)-1H-benz[e]indole (A-7,Chart A) A solution of 3.27 g (9 mmol) triflate A-6 and 2.5 mL (18 mmol) triethylamine in 10 mL methanol and 30 mL DMF was degassed with nitrogen through a syringe (10 min). Carbon monoxide was then introduced mid bubbled for 10 min. During this time, a solution of 202 mg (0.9 mmol) palladium acetate and 445 mg (1.08 mmol) <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e in 10 mL DMF was dissolved and degasseal with for 10 min with nitrogen. This solution was added to the reaction, heated to 70 C. and carbon monoxide bubbled through the refluxing solution overnight. Nitrogen was bubbled through the solution and then it was quenched with NaHCO3 (satd). The mixture was extracted with ethyl acetate (3*500 mL) and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to yield an oil. The oil was flash chromatographed on 500 g silica gel 60 (230-400 mesh) eluding with hexane/ethyl acetate (4:1). Homogeneous fractions were combined and concentrated to yield the title compound A-7 as an oil (1.9 g, 77.5%): NMR (CDCl3, TMS)delta7.65-7.62(d,J=9 Hz, 1H); 7.26-7.08 (m, 2H) 4.18-4.09 (q,J=9 Hz, 1H); 3.87 (s, 3H); 3.08-1.37 (m, 13H); 0.95-0.90 (t, J=7 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
bis(triphenylphosphine)palladium(II)-chloride; In methanol; dimethyl sulfoxide; | iii. Methyl 4-methoxycarbonylphenylacetate. To a solution of methyl 4-trifluoromethylsulfonyloxyphenylacetate (6 g) dissolved in dimethyl sulfoxide (30 mL) and methanol (5 mL) was added 1,3-bis(diphenylphosphino)propane (0.25 g) and bis(triphenylphosphine)palladium(II) chloride (0.43 g). The reaction was placed under a carbon monoxide atmosphere and the solution heated at 60 C. for 24 h. The reaction was diluted with ethyl acetate, washed (1N hydrochloric acid, water, brine), dried (MgSO4), and evaporated to give an oil which was purified by chromatography, eluding with diethyl ether:hexane (7:3), to afford the di-ester (3.15 g); TLC: Rf =0.32, diethyl ether:hexane (30:70). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With hydrogenchloride; N-ethyl-N,N-diisopropylamine;palladium diacetate; In dichloromethane; dimethyl sulfoxide; | (2) Synthesis of (R)-2'-diphenylphosphinyl-2-trifluoromethanesulfonyloxy-1,1'-binaphthyl In 100 ml of dimethyl sulfoxide (DMSO) were dissolved 11 g (20 mmol) of (R)-2,2'-bis[trifluoromethanesulfonyloxy]-1,1'-binaphthyl, 0.225 g (50 mol %) of palladium acetate, and 0.43 g (50 mol %) of <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e. This solution was stirred at room temperature for 1.5 hours. Thereto was added a solution prepared by dissolving 8.08 g (40 mmol) of diphenylphosphine oxide and 20 ml of diisopropylethylamine in 100 ml of dimethyl sulfoxide (DMSO). The resultant mixture was stirred at 100 C. for 12 hours. After the reaction mixture was cooled to room temperature, 75 ml of methylene chloride was added thereto. This solution was cooled in an ice bath, and 100 ml of 2 N hydrochloric acid was gradually added dropwise thereto. The resultant mixture was stirred at room temperature for 30 minutes and then subjected to liquid separation. The aqueous layer was extracted with methylene chloride. The resultant organic layer was collected, washed with water, and then dried with anhydrous magnesium sulfate. The dried organic layer was concentrated for solvent removal, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/4 by volume). As a result, 11.5 g (yield, 96%) of the target compound was obtained as yellowish white crystals. [alpha]D24 44.45 (c 0.50, CHCl3) 1H NMR (CDCl3) delta 7.0-8.01 (m, aromatic) 31P NMR (CDCl3) delta 28.73 (s) |
96% | With hydrogenchloride; N-ethyl-N,N-diisopropylamine;palladium diacetate; In dichloromethane; dimethyl sulfoxide; | (2) Synthesis of (R)-2'-diphenylphosphinyl-2-(trifluoromethanesulfonyloxy]-1,1'-binaphthyl In 100 ml of dimethyl sulfoxide were dissolved 11 g (20 mmol) of (R)-2,2'-bis(trifluoromethanesulfonyloxy]-1,1'-binaphthyl, 0.225 g (50 mol %) of palladium acetate, and 0.43 g (50 mol %) of <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e. This solution was stirred at room temperature for 1.5 hours. Thereto was added a solution prepared by dissolving 8.08 g (40 mmol) of diphenylphosphine oxide and 20 ml of diisopropylethylamine in 100 ml of dimethyl sulfoxide. The resultant mixture was stirred at 100 C. for 12 hours. After the reaction mixture was cooled to room temperature, 75 ml of methylene chloride was added thereto. This solution was cooled in an ice bath, and 100 ml of 2 N hydrochloric acid was gradually added dropwise thereto. The resultant mixture was stirred at room temperature for 30 minutes and then subjected to liquid separation. The aqueous layer was extracted with methylene chloride. The resultant organic layer was collected, washed with water, and then dried with magnesium sulfate. The dried organic layer was concentrated for solvent removal, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to 1/4 by volume). As a result, 11.5 g (yield, 96%) of the target compound was obtained as yellowish white crystals. [alpha]D24 44.45 (c 0.50, CHCl3) 1H NMR (CDCl3) delta 7.0-8.01 (m, aromatic) 31P NMR (CDCl3) delta 28.73 (s) |
83% | With sodium formate; sodium hydrogencarbonate; N-ethyl-N,N-diisopropylamine;palladium diacetate; In water; argon; dimethyl sulfoxide; toluene; acetonitrile; | (2) Synthesis of (R)-2-diphenylphosphinyl-2'-trifluoromethanesulfonyloxy-1,1'-binaphthyl: In a 100-ml 4-necked flask, 2.74 g (4.98 mmol) of (R)-2,2'-bis(trifluoromethanesulfonyloxy)-1,1'-binaphthyl prepared in the step (1) and 1.99 g (9.82 mmol) of diphenylphosphine oxide (Tokyo) were dissolved in 20 ml of dimethylsulfoxide in an argon stream, to which 110 mg (0,491 mmol) of palladium acetate, 203 mg (0,491 mmol) of <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e, 5.1 ml of ethyldiisopropylamine (Ald) and 33 mg (0,491 mmol) of sodium formate (NACALAI) were combined to stir them for 20 minutes at room temperature. Thereafter, the resultant solution was stirred for 19 hours at 90 C. and then cooled back to room temperature. The solution was added with 250 ml of ether and 150 ml of water, and the mixture was stirred to separate an organic layer andan aqueous layer. After the separation, the organic layer was washed four times with 125 ml of water, twice with 125 ml of 5% diluted hydrochloric acid, twice with 50 ml of water, once with 125 ml of a saturated aqueous solution of sodium hydrogencarbonate and lastly with 125 ml of a brine. The thus-washed organic layer was dried on anhydrous magnesium sulfate, and the solvent was distilled off. The residue was then purified by column chromatography on silica gel making use o#a 3:1 (solvent ratio, the same shall apply hereinafter) mixture of toluene and acetonitrile as a developing solvent, thereby obtaining 2.51 g (yield: 83%) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine; In methanol; N,N-dimethyl-formamide; | e) Methyl (R)-3-(N-Cyclopentyl-N-n-propylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxylate (R)-3-(N-Cyclopentyl-N-n-propylamino)-8-fluoro-5-trifluoromethylsulfonyloxy-3,4-dihydro-2H-1-benzopyran (3.7 g, 8.7 mmol), DMF (50 mL), triethylamine (2.5 g, 25 mmol), methanol (4 g, 130 mmol), palladium(ll)acetate (100 mg, 0.45 mmol) and <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (200 mg, 0.48 mmol) were placed in a round-bottomed flask. The solution was stirred at 75 C. in an atmosphere of carbon monoxide for 4 h. After evaporation of the solvent in vacuo and subjecting the crude to flash chromatography, 2.5 g (86% yield) of the title compound as a colorless oil was isolated. GC/MS (70 eV) M=335 (20 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With triethylamine;palladium diacetate; In methanol; diethyl ether; N,N-dimethyl-formamide; | a) Methyl (R)-8-fluoro-3-(N-isopropyl-N-n-propylamino)-3,4 -dihydro-2H-1-benzopyran-5-carboxylate (R)-8-Fluoro-3-(N-isopropyl-N-n-propylamino)-5-trifluoromethanesulfonyloxy-3,4-dihydro-2H-1-benzopyran (2.4 g, 6.0 mmol), triethylamine (1.3 g, 12.9 mmol), 1,3-bis (diphenylphosphino)propane (95 mg, catalytic amount), palladium(II)acetate (48 mg, catalytic amount) and DMF/MeOH (30 mL, 3:1) were mixed in a 50 mL three necked round bottom flask. The flask was evacuated followed by the inlet of CO (repeated two times). The reaction mixture was stirred at 70 C. for 7.5 hours. The solvent was removed in vacuo and the residue was dissolved in diethyl ether/sat. NaHCO3. The layers were separated and the water phase was extracted once with ether. The combined ether layers were dried (MgSO4) and the solvent was removed in vacuo to give a crude which was purified by flash chromatography (SiO2, hexane/EtOAC, 9:1) to give 1.3 g of the title compound (71% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine;palladium diacetate; In methanol; N,N-dimethyl-formamide; | e) Methyl (R)-3-(N-Cyclohexyl-N-n-propylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxylate (R)-3-(N-Cyclohexyl-N-n-propylamino)-8-fluoro-5-trifluoromethylsulfonyloxy-3,4-dihydro-2H-1-benzopyran (0.8 g, 1.8 mmol) (4), DMF (30 mL), triethylamine (0.5 g, 5 mmol), methanol (0.8 g, 13 mmol), palladium(II)acetate (30 mg, 0.14 mmol) and <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (60 mg, 0.14 mmol) were placed in a round-bottomed flask. The solution was stirred at 75 C. in an atmosphere of carbon monoxide for 4 h. After evaporation of the solvent in vacuo and subjecting the crude to flash chromatography, 0.6 g (76% yield) of the title compound as a colorless oil was isolated. GC/MS (70 eV) M=349 (30 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine;palladium diacetate; In methanol; water; dimethyl sulfoxide; | EXAMPLE 124 Methyl 1,1-dimethyl-3-oxo-indan-5-carboxylate (LXVII) A solution of trifluoromethanesulfonic acid 1,1-dimethyl-3-oxo-indan-5-yl ester (3.08 g, 10.0 mmol), triethylamine (2.02 g, 20.0 mmol), palladium acetate (0.11 g, 0.50 mmol) and 1,3<strong>[6737-42-4]bis(diphenylphosphino)propane</strong> (<strong>[6737-42-4]dppp</strong>, 0.21 g, 0.50 mmol) in 30 mL of anhydrous dimethylsulfoxide and 20 mL of methanol was saturated with carbon monoxide for 10 min, and then stirred under a balloon filled with carbon monoxide at 65-70 C. for 2 hours. Methanol was evaporated, and the resulting solution was diluted with 50 mL of water, extracted with ethyl ether (40 mL*4). The combined extracts were dried over magnesium sulfate and evaporated, The residue was purified by flash chromatography (EtOAc:hexane=1:20 to 1:5) to give 1.98 g (91% yield) of the title compound as light yellow solids; 1 H-NMR (CDCl3) delta1.45 (s, 6H), 2.65 (s, 2H), 3.94 (s, 3H), 7.58 (dd, J=8.1 Hz, 1 H), 8.30 (dd, J=1.6, 8.1 Hz, 1H), 8.36 (d, J=1.6 Hz, 1H); MS m/e 219 (MH+). Anal. calcd. for C13 H14 O3: C, 71.54; H, 6.47, Found: C, 71.71; H, 6.46. |
91% | With triethylamine;palladium diacetate; In methanol; water; dimethyl sulfoxide; | EXAMPLE 124 Methyl 1,1-dimethyl-3-oxo-indan-5-carboxylate (LXVII) A solution of trifluoromethanesulfonic acid 1,1-dimethyl-3-oxo-indan-5-yl ester (3.08 g, 10.0 mmol), triethylamine (2.02 g, 20.0 mmol), palladium acetate (0.11 g, 0.50 mmol) and <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (<strong>[6737-42-4]dppp</strong>, 0.21 g, 0.50 mmol) in 30 mL of anhydrous dimethylsulfoxide and 20 mL of methanol was saturated with carbon monoxide for 10 min, and then stirred under a balloon filled with carbon monoxide at 65-70 C. for 2 hours. Methanol was evaporated, and the resulting solution was diluted with 50 mL of water, extracted with ethyl ether (40 mL*4). The combined extracts were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (EtOAc:hexane=1:20 to 1:5) to give 1.98 g (91% yield) of the title compound as light yellow solids; 1 H-NMR (CDCl3) delta 1.45 (s, 6H), 2.65 (s, 2H), 3.94 (s, 3H), 7.58 (dd, J=8.1 Hz, 1H), 8.30 (dd, J=1.6, 8.1 Hz, 1H), 8.36 (d, J=1.6 Hz, 1H); MS m/e 219 (MH+). Anal. calcd. for C13 H14 O3: C, 71.54; H, 6.47. Found: C, 71.71; H,6.46. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
~ 94 - ~ 95%; ~ 5% | With potassium carbonate;palladium diacetate; In butan-1-ol; at 100℃; for 22h; | Al.10: 4-[N-(Methyl')-N-^er/butyloxycarbonyl')aminol-l-methyl-lH-imidazof4,5- clpyridine -6- carboxylic acid; 60 EPO <DP n="62"/>A1.10A mixture of A1.9 (0.52 g; 1.8 mmol), palladium acetate (45 mg; 0.2 mmol), l,3-bis-(diphenylphosphino)propane (83 mg; 0.2 mmol), potassium carbonate (355 mg; 2.6 mmol) and rc-butanol (10 ml) was stirred briskly at 100 C. under an atmosphere of carbon monoxide. After 2 hrs, additional palladium acetate (45 mg;0.2 mmol) and l,3-bis-(diphenylphosphino)propane (83 mg; 0.2 mmol) were added and heating was continued for 2 hrs. At this time, additional palladium acetate (22 mg; 0.1 mmol) and l,3-bis-(diphenylphosphino)propane (43 mg; 0.1 mmol) were added and heating was continued for 18 hrs. After cooling to rt, methanol (40 ml) was added, followed by decolorizing carbon. After standing 10 minutes, the mixture was filtered through Celite and the filtrate was concentrated. After co-evaporating the residue from heptane (2 x 20 ml), methanol (20 ml) and IN NaOH (4 ml) were added. The resulting solution was stirred 1.5 hr at room temperature, after which time the methanol was removed in vacuo. The aqueous residue was washed with ethyl acetate (25 ml). After diluting with water (50 ml), the aqueous layer was transferred to a flask containing chloroform (50 ml). While stirring the biphasic mixture, the ph of the aqueous layer was adjusted to ~4 with 10% citric acid solution. The layers were separated and the aqueous layer was extracted with chloroform (25 ml). The combined organic layer was washed with water (50 ml), dried (MgSO4) and concentrated to afford 0.58 g (99+%; contains -5% 1,3-bis- (diphenylphosphino)propanedioxide) as an off-white solid. HPLC (A): 95%, ret. time= 1.06 min., LC/MS (M+H)+ = 207.17 (minus Boc-group). 1H-NMR (CDCl3) delta: 8.23 (IH, s), 8.08 (IH, s), 3.96 (3H, s), 3.50 (3H, s), 1.45 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With triethylamine;palladium diacetate; In N,N-dimethyl-formamide; | Preparation 39 4-(3-Acetylphenyl)-1-hexanoyl-3,4-dimethylpiperidine To a solution of 1-hexanoyl-3,4-dimethyl-4-(trifluoromethanesulfonyloxyphenyl)piperidine (Preparation 28, 2.1 g, 4.7 mmol)) in N,N-dimethylformamide (15 mL) at room temperature were added sequentially, triethylamine (0.57 g, 5.6 mmol), butyl vinyl ether (3.0 mL, 23.4 mmol), <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (69 mg, 0.17 mmol) and palladium(II) acetate (31 mg, 0.14 mmol). The mixture was heated at 80C under a nitrogen atmosphere for 18 h and then allowed to cool to room temperature. After the addition of 2 NHCl (20 mL), the mixture was stirred vigorously for 30 minutes and then poured onto dichloromethane(50 mL). The two layers were separated and the aqueous layer was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated in vacuo.The residue was purified by column chromatography on silica gel eluding with ethyl acetate: hexane (1:2 and then 2:1). The title compound was isolated as clear oil (900 mg, 58%). NMR (CDCl3, selected data from a 1:1 mixture of rotamers): 0.55-0.65 (m, 3H), 0.85-0.95 (m, 3H), 1.20-1.38 (m, 4H), 1.42 (s, 3H), 1.57-1.78 (m, 3H), 2.08-2.48 (m, 4H), 2.60 (s, 3H), 2.92 (m, 0.5H), 3.15 (m, 0.5H), 3.39 (m, 0.5H), 3.60 (m, 1H), 3.90 (m, 0.5H), 4.41 (m, 0.5H), 4.73 (m, 0.5H), 7.41-7.53 (m, 2H), 7.79 (d, 1H), 7.85 (s, 1H). MS (thermospray): M/Z (MH+) 330.4; C21H31NO2+ H requires 330.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With formic acid; triethylamine;palladium diacetate; In ethyl acetate; N,N-dimethyl-formamide; | Step 2 A mixture of 5-(4-fluorobenzoyl)-6-trifluoromethylsulfonyloxy-2-methylsulfonyl-naphthalene (0.3 g, 0.63 mmol), [prepared as described in step 1 above], formic acid (0.096 ml, 2.5 mmol), triethylamine(0.36 ml, 2.5 mmol), palladium acetate (14 mg, 0.06 mmol), and 1,3-bis (diphenylphosphino)propane (0.10 g, 0.03 mmol) in DMF (10 ml) was stirred at room temperature. After 16 h, the reaction mixture was poured into brine and extracted into ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (gradient elution 10-30% ethyl acetate / hexanes) and then recrystallized from ethyl acetate -hexanes to give 0.1 g of 5-(4-fluoro-benzoyl)-2-methylsulfonylnaphthalene as a solid (48% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; triethylamine;palladium diacetate; In methanol; dichloromethane; dimethyl sulfoxide; acetonitrile; | EXAMPLE 10 Preparation of (S)-N-(tert.butoxycarbonyl)-N-propyl-6-methoxy-5-methoxycarbonyl-1,2,3,4-tetrahydro-2-naphthylamine A solution of (S)-N-(tert.butoxycarbonyl)-N-propyl-6-methoxy-5-hydroxy-1,2,3,4-tetrahydro-2-naphthylamine (1.4 g; 4.17 mmoles), prepared as described in example 9, in acetonitrile (42 ml) was added at room temperature with K2CO3 (1.15 g, 8.34 mmoles) and, dropwise, with a solution of N-phenyltrifluoromethansulfonimide (1.78 g; 5 mmoles) in acetonitrile (10 ml). The reaction mixture was heated to 55 C. for 19 hours, then the solvent was evaporated under reduced pressure. The residue was added with methylene chloride and water. The phases were separated and the organic one was washed with water, anhydrified over Na2SO4 and the solvent evaporated under reduced pressure. The residue was dissolved in dimethylsulfoxide (13 ml) and methanol (5 ml) and the solution was added, under N2 at room temperature, with triethylamine (1.1 ml, 7.87 mmoles), palladium acetate (53 mg; 0.236 mmole) and 1,3-bisdiphenylphosphinopropane (97 mg; 0.236 mmole). The reaction mixture was then heated to 70 C. under CO pressure (9 bar) for 90 hours during which further palladium acetate (18 mg, 0.080 mmole) and 1,3-bisdiphenylphosphinopropane (33 mg, 0.080 mmole) were added in one portion. After cooling to room temperature the mixture was poured into water and methylene chloride. The phases were separated and the organic one was washed with water, anhydrified over Na2SO4 and evaporated to dryness under reduced pressure. The resulting crude was purified by silica gel chromatography (eluent: petrolatum:ethyl acetate=90:10). There was obtained 1.08 g of (S)-N-(tert.butoxycarbonyl)-N-propyl-6-methoxy-5-methoxycarbonyl-1,2,3,4-tetrahydro-2-naphthylamine. 1H-NMR (200 MHz, CDCl3) delta (ppm): 0.86 (t, 3H), 1.44 (t, 9H); 1.46-2.00 (m, 4H); 2.71-3.13 (m, 6H); 3.78 (s, 3H); 3.89 (s, 3H), 3.90-4.27 (m, 1H); 6.71 (d, 1H); 7.03 (d, 1H). Mass (electronic impact): 377 (M)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With potassium carbonate;palladium diacetate; In methanol; dimethyl sulfoxide; ethyl acetate; | EXAMPLE 102 4-(3,5-Dichloro-pyridin-4-ylmethyl)-7-methoxy-phthalazin-1-carboxylic acid methyl ester A suspension of 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (9.7 g, 27 mmoles), prepared as described in example 45, in DMSO/CH3OH (80/40 ml) was added with K2CO3 (7.4 g, 54 mmoles), palladium acetate (0.31 g, 1.4 mmoles) and 1,3-bis(diphenylphosphine)propane (0.75 g, 1.82 mmoles). The mixture was placed in autoclave under CO atmosphere (8 bar) and heated at 50 C. After 4 hours the mixture was poured into water (10 volumes) and extracted four times with ethyl acetate. The organic phase was washed with aqueous NaCl and discoloured with charcoal, filtered and dried to give a solid which was flash chromatographed (eluent: petrolatum/ethyl acetate 1:1) to give 5 g of the title compound (yield: 49%). 1H-NMR (CDCl3) delta: 8.48(s,2H); 8.22-7.55(m,3H); 4.91(s,2H); 4.02 and 4.01(2s,6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; N-Bromosuccinimide; triethylamine; In tetrahydrofuran; dichloromethane; water; trifluoromethanesulfonic acid anhydride; N,N-dimethyl-formamide; | (c) Bromomethyl-(6-methoxy-[1,5]-naphthyridin-4-yl)-ketone The naphthyridine (18b) (10 g, 0.057 mol) in dichloromethane (200 ml) containing 2,6-lutidine (9.94 ml, 0.086 mol) and 4-dimethylaminopyridine (0.07 g, 0.0057 mol) was cooled in ice and treated with trifluoromethanesulfonic anhydride (10.5 ml, 0.063 mol). After stirring for 2.5 hours the mixture was washed with saturated ammonium chloride solution, dried, evaporated and purified on silica (dichloromethane). The triflate (13.2 g, 0.044 mol) in DMF (200 ml) with triethylamine (12 ml, 0.086 mol) butyl vinyl ether (22 ml, 0.17 mol), palladium (II) acetate (0.97 g, 0.0044 mol) and 1,3-bis(diphenylphosphino)propane (1.77 g, 0.0044 mol) was heated at 60 C. for 3 hours then evaporated and chromatographed on silica gel (dichloromethane) to give a yellow solid (10.7 g, 95%). This was dissolved in THF (250 ml), water (40 ml) and treated with N-bromosuccinimide (7.4 g. 0.042 mol) for 1 hour, then evaporated and chromatographed on silica gel (dichloromethane) to give the ketone (10.42 g, 98%). | |
With dmap; N-Bromosuccinimide; triethylamine; In tetrahydrofuran; dichloromethane; water; trifluoromethanesulfonic acid anhydride; N,N-dimethyl-formamide; | (b) Bromomethyl-(6-methoxy-[1,5]-naphthyridin-4-yl)-ketone The naphthyridine (31a) (10 g, 0.057 mol) in dichloromethane (200 ml) containing 2,6-lutidine (9.94 ml, 0.086 mol) and 4-dimethylaminopyridine (0.07 g, 0.0057 mol) was cooled in ice and treated with trifluoromethanesulfonic anhydride (10.5 ml, 0.063 mol). After stirring for 2.5 hours the mixture was washed with saturated ammonium chloride solution, dried, evaporated and purified on silica (dichloromethane). The triflate (13.2 g, 0.044 mol) in DMF (200 ml) with triethylamine (12 ml, 0.086 mol) butyl vinyl ether (22 ml, 0.17 mol), palladium (II) acetate (0.97 g, 0.0044 mol) and 1,3-bis(diphenylphosphino)propane (1.77 g, 0.0044 mol) was heated at 60 C. for 3 hours then evaporated and chromatographed on silica gel (dichloromethane) to give a yellow solid (10.7 g, 95%). This was dissolved in THF (250 ml), water (40 ml) and treated with N-bromosuccinimide (7.4 g, 0.042 mol) for 1 hour, then evaporated and chromatographed on silica gel (dichloromethane) to give the ketone (10.42 g, 98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With hydrogenchloride; triethylamine;palladium diacetate; In N-methyl-acetamide; | 7-Acetyl-3-(tert-butyloxycarbonyl)-2,3,4,5-tetrahydro-1H-3-benzazepine To a stirred solution of 3-(tert-butyloxycarbonyl)-7-trifluoromethylsulfonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine (10 g, 25.3 mmol) in anhydrous dimethylformamide (100 ml) under argon at room temperature, was added triethylamine (7.05 ml, 50.6 mmol), butyl vinyl ether (16.4 ml, 126.6 mmol), <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (0.412 g, 1 mmol) and palladium acetate (0.202 g, 0.9 mmol) sequentially. The resultant mixture was heated at 85 C. for 1.5 h and cooled to room temperature. 4% Aqueous hydrochloric acid (150 ml) was added and stirring continued for 0.5 h. The reaction mixture was extracted with dichloromethane (3*300 ml) and the combined organics washed with water (4*500 ml), dried (Na2SO4) and evaporated in vacuo to afford a brown gum. Chromatography on silica gel with 0-30% ethyl acetate-hexane gradient elution gave the title compound (5.8 g, 79%) as a colourless solid. 1H NMR (CDCl3) delta:1.49 (9H, s), 2.58 (3H, s), 2.96 (4H, m), 3.57 (4 H, m), 7.21 (1H, d, J=8 Hz), 7.72 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.5% | With triethylamine;palladium diacetate; In methanol; dimethyl sulfoxide; | (1) A mixture of tert-butyl (6-bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (synthesised according to the method similar to that in Example 74 (7)) (2.41 g, 5 mmol), <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (0.21 g, 0.5 mmol) and triethylamine (0.77 ml, 5.5 mmol) in dimethyl sulfoxide (30 ml) and methanol (20 ml) was stirred under a carbon monoxide atmosphere at room temperature for 10 min. To the obtained mixture was added palladium acetate (0.11 g, 0.5 mmol) and the mixture was stirred with heating under a carbon monoxide atmosphere at 60 C. for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 4-butoxy-3-{{(tert-butoxycarbonyl)amino}methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylate (1.92 g, 83.5%) as crystals. Melting point 148-149 C. Elemental analysis for C25H36N2O6 Calculated: C, 65.20; H, 7.88; N, 6.08. Found: C, 65.30; H, 7.67; N, 6.17. 1H-NMR(CDCl3) delta: 0.97 (6H, d, J=6.8 Hz), 1.05 (3H, t, J=7.3 Hz), 1.47 (9H, S), 1.56-1.71 (2H, m), 1.83-1.93 (2H, m), 2.05-2.25 (1H, m), 3.89 (2H, t, J=6.6 Hz), 3.99 (3H, s), 4.01 (2H, d, J=7.6 Hz), 4.53 (2H, d, J=5.4 Hz), 4.77 (1H, bs), 8.09 (1H, dd, J=1.9, 8.4 Hz), 8.40 (1H, d, J=1.9 Hz), 8.47 (1H, d, J=8.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With hydrogenchloride; In ethanol; dichloromethane; for 3h;Reflux; | The solution of <strong>[6737-42-4]dppp</strong> (1.2373g, 3mmol)in 15ml CH2Cl2 was added to a solution of PdCl2(0.5320g, 3mmol) that dissolved in 2 cm3 ethanoland 2cm3 concentrate HCl. The mixture was reuxfor 3 hrs. And then the solvent was evaporate at roomtemperature to give pale yellow precipitate. A smallportion of this complex was dissolve in CH2Cl2 and setto slow evaporation at room temperature after a oneweek, the yellow colored needle crystals were formedsuitable for single-crystal diffraction analysis15. TheMelting point is 277C, yield is 1.664gm (94%),formula: [Pd(k2-<strong>[6737-42-4]dppp</strong>)Cl2] and M.wt.is 589.72gm/mole.as shown in Figure 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | In tetrahydrofuran; at 130℃; for 0.1h;Inert atmosphere; Microwave irradiation; | General procedure: In a 10mL dry microwave reactor were introduced [CpFe(CO)2I] (49mg, 0.16mmol) and the ligand (0.16mmol, 1 eq.) in degassed THF (1mL) under argon atmosphere. The homogeneous solution was placed in a microwave reactor with a power fixed at 150W, for 6min at 130C. The dark green solution was filtered through a pad of deactivated alumina (3% H2O). Then, the cake was washed with EtOH. The complex was recovered in the EtOH and transferred in a Schlenk tube under argon atmosphere. The solvent was removed under vacuum and the crude product was washed with dry and degassed Et2O (3×10mL). The supernatant liquid was removed with Pasteur pipette and the resulting solid was dried under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sodium tetrahydroborate; In propan-1-ol; at 90℃; under 760.051 Torr; for 0.333333h;Microwave irradiation; Inert atmosphere; Green chemistry; | General procedure: The reactions were run in a CEM Corp. MARS microwave fitted with a fiber optic temperature probe and a port on top for a reflux condenser.1 mmol of Mo(CO)6 and dppe (0.425 g, 1.1 mmol) were combined with 20 mL of 1-propanol in a two-neck 100 mL RB flask. To this mixture was added NaBH4 (0.128 g, 3.3 mmol). The flaskwas placed in themicrowave and a reflux condenser attached through a hole in the top of the microwave. The mixture was sparged with nitrogen. The mixture was heated under nitrogen at 400 W for 1.5 min to reach reflux temperature. Once the reflux temperature was reached the microwave power was reduced and the temperature maintained for 18 min. The mixture was cooled to room temperature and 2-4 mL of water was added to the reaction to dissolve excess NaBH4 and promote product precipitation. The reaction was cooled -10 C for several hours. The light yellow complex was filtered in air and washed with 2×5 mL of petroleum ether/diethyl ether(1:1) mixture resulting in 580 mg of Mo(CO)4dppe after drying, a 95% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium tetrahydroborate; at 120℃; under 760.051 Torr; for 0.666667h;Microwave irradiation; Inert atmosphere; Green chemistry; | General procedure: The reactions were run in a CEM Corp. MARS microwave fitted with a fiber optic temperature probe and a port on top for a reflux condenser.1 mmol of Mo(CO)6 and dppe (0.425 g, 1.1 mmol) were combined with 20 mL of 1-propanol in a two-neck 100 mL RB flask. To this mixture was added NaBH4 (0.128 g, 3.3 mmol). The flaskwas placed in themicrowave and a reflux condenser attached through a hole in the top of the microwave. The mixture was sparged with nitrogen. The mixture was heated under nitrogen at 400 W for 1.5 min to reach reflux temperature. Once the reflux temperature was reached the microwave power was reduced and the temperature maintained for 18 min. The mixture was cooled to room temperature and 2-4 mL of water was added to the reaction to dissolve excess NaBH4 and promote product precipitation. The reaction was cooled -10 C for several hours. The light yellow complex was filtered in air and washed with 2×5 mL of petroleum ether/diethyl ether(1:1) mixture resulting in 580 mg of Mo(CO)4dppe after drying, a 95% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In dichloromethane; at 20℃; for 0.833333h; | General procedure: Diphosphine ligand (2.0 mmol) was dissolved in 10 mL of dichloromethane and the solution was added dropwise to a stirred solution of RuCl2(PPh3)3 (1.0 mmol) in 10 mL of dichloromethane. The reaction mixture was stirred approximately for 50 min at room temperature. The brown solution was filtered to remove the insoluble impurities. The solvent was reduced by a vacuum and the product was then precipitated by adding n-hexane. The yellow solid was filtered and washed three times with 20 mL of diethyl ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | 1,3-Bis(diphenylphosphino)propane (<strong>[6737-42-4]dppp</strong>) (680 mg, 1.65 mmol) and [Ru(benzene)Cl2]2 (408.2 mg, 0.816 mmol) were weighed and charged into a 100-mL Schlenk flask and then the gas in the flask was substituted with nitrogen gas. DMF (30 mL) was added thereto under nitrogen atmosphere; the mixture was heated in an oil bath at 120C under nitrogen atmosphere for 4.0 hours and then cooled to an oil bath temperature of 60C; and DMF was removed by vaporization under reduced pressure (1 mmHg). Dichloromethane (25mL) and 1,2-diphenylethylenediamine (dpen) (350 mg, 1.65 mmol) were added thereto, and the mixture was heated in an oil bath at 40C for 2. 0 hours. Dichloromethane was removed by vaporization under reduced pressure (1 mmHg), and NaBH4 (1.56 g, 41.2 mmol), toluene (15 mL) and ethanol (15 mL) were added thereto. The mixture was heated in an oil bath at 65C for 5 minutes and then, stirred at room temperature for 30 minutes. The reaction solution was Celite-filtered, and the filtrate was evaporated under reduced pressure (1 mmHg). Toluene (50 mL) was added to the residue obtained, and the mixture was stirred for 30 minutes while heated in an oil bath at 40C. The reaction solution was Celite-filtered, and the filtrate was evaporated under reduced pressure (1 mmHg), to give a powder. The powder obtained was further dried under reduced pressure (1 mmHg), to give 1. 1 g of RuH (eta1-BH4) (<strong>[6737-42-4]dppp</strong>) (dpen) (Complex 16) . Yield was 90 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium tetrahydroborate; In tetrahydrofuran; at 125℃; under 760.051 Torr; for 0.333333h;Microwave irradiation; Inert atmosphere; Green chemistry; | General procedure: The reactions were run in a CEM Corp. MARS microwave fitted with a fiber optic temperature probe and a port on top for a reflux condenser.1 mmol of Mo(CO)6 and dppe (0.425 g, 1.1 mmol) were combined with 20 mL of 1-propanol in a two-neck 100 mL RB flask. To this mixture was added NaBH4 (0.128 g, 3.3 mmol). The flaskwas placed in themicrowave and a reflux condenser attached through a hole in the top of the microwave. The mixture was sparged with nitrogen. The mixture was heated under nitrogen at 400 W for 1.5 min to reach reflux temperature. Once the reflux temperature was reached the microwave power was reduced and the temperature maintained for 18 min. The mixture was cooled to room temperature and 2-4 mL of water was added to the reaction to dissolve excess NaBH4 and promote product precipitation. The reaction was cooled -10 C for several hours. The light yellow complex was filtered in air and washed with 2×5 mL of petroleum ether/diethyl ether(1:1) mixture resulting in 580 mg of Mo(CO)4dppe after drying, a 95% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium tetrahydroborate; In tetrahydrofuran; at 125℃; under 760.051 Torr; for 0.333333h;Microwave irradiation; Inert atmosphere; Green chemistry; | General procedure: The reactions were run in a CEM Corp. MARS microwave fitted with a fiber optic temperature probe and a port on top for a reflux condenser.1 mmol of Mo(CO)6 and dppe (0.425 g, 1.1 mmol) were combined with 20 mL of 1-propanol in a two-neck 100 mL RB flask. To this mixture was added NaBH4 (0.128 g, 3.3 mmol). The flaskwas placed in themicrowave and a reflux condenser attached through a hole in the top of the microwave. The mixture was sparged with nitrogen. The mixture was heated under nitrogen at 400 W for 1.5 min to reach reflux temperature. Once the reflux temperature was reached the microwave power was reduced and the temperature maintained for 18 min. The mixture was cooled to room temperature and 2-4 mL of water was added to the reaction to dissolve excess NaBH4 and promote product precipitation. The reaction was cooled -10 C for several hours. The light yellow complex was filtered in air and washed with 2×5 mL of petroleum ether/diethyl ether(1:1) mixture resulting in 580 mg of Mo(CO)4dppe after drying, a 95% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sodium tetrahydroborate; In propan-1-ol; at 90℃; under 760.051 Torr; for 0.333333h;Microwave irradiation; Inert atmosphere; Green chemistry; | General procedure: The reactions were run in a CEM Corp. MARS microwave fitted with a fiber optic temperature probe and a port on top for a reflux condenser.1 mmol of Mo(CO)6 and dppe (0.425 g, 1.1 mmol) were combined with 20 mL of 1-propanol in a two-neck 100 mL RB flask. To this mixture was added NaBH4 (0.128 g, 3.3 mmol). The flaskwas placed in themicrowave and a reflux condenser attached through a hole in the top of the microwave. The mixture was sparged with nitrogen. The mixture was heated under nitrogen at 400 W for 1.5 min to reach reflux temperature. Once the reflux temperature was reached the microwave power was reduced and the temperature maintained for 18 min. The mixture was cooled to room temperature and 2-4 mL of water was added to the reaction to dissolve excess NaBH4 and promote product precipitation. The reaction was cooled -10 C for several hours. The light yellow complex was filtered in air and washed with 2×5 mL of petroleum ether/diethyl ether(1:1) mixture resulting in 580 mg of Mo(CO)4dppe after drying, a 95% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium tetrahydroborate; at 120℃; under 760.051 Torr; for 0.666667h;Microwave irradiation; Inert atmosphere; Green chemistry; | General procedure: The reactions were run in a CEM Corp. MARS microwave fitted with a fiber optic temperature probe and a port on top for a reflux condenser.1 mmol of Mo(CO)6 and dppe (0.425 g, 1.1 mmol) were combined with 20 mL of 1-propanol in a two-neck 100 mL RB flask. To this mixture was added NaBH4 (0.128 g, 3.3 mmol). The flaskwas placed in themicrowave and a reflux condenser attached through a hole in the top of the microwave. The mixture was sparged with nitrogen. The mixture was heated under nitrogen at 400 W for 1.5 min to reach reflux temperature. Once the reflux temperature was reached the microwave power was reduced and the temperature maintained for 18 min. The mixture was cooled to room temperature and 2-4 mL of water was added to the reaction to dissolve excess NaBH4 and promote product precipitation. The reaction was cooled -10 C for several hours. The light yellow complex was filtered in air and washed with 2×5 mL of petroleum ether/diethyl ether(1:1) mixture resulting in 580 mg of Mo(CO)4dppe after drying, a 95% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In dichloromethane; at 20℃; for 1h; | <strong>[6737-42-4]dppp</strong> (0.619g, 1.50mmol) was dissolved in dichloromethane (40mL) and 1 (0.562g, 1.50mmol) was slowly added. Then, the reaction mixture was stirred for 1h at ambient temperature. The resulting yellow solution was filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was washed with Et2O (3×5mL) and dried under vacuum to yield a yellow solid (0.850g, 85%). 1H NMR (CDCl3): delta 7.7-7.2 (m, 20H, CH, Ph), 5.3 (s, 1H, CH), 2.9-2.7 (m, 6H, CH2), 1.6 (6H, CH3). 13C NMR (CDCl3): delta 187.4 (s, C=O), 139.0 (d, o-CH, Ph), 132.6 (d, p-CH, Ph), 129.5 (d, m-CH, Ph), 128.5 (s, C, Ph), 100.1 (d, CH), 26.0 (q, CH3), 26.0 (t, CH2), 23.7 (t, CH2). 31P NMR (CDCl3): delta 37.5. 11B ((CD3)2CO): delta-0.54 (quintet, BF4). Anal. Calcd for C32H33BF4O2P2Pd: C, 54.53; H, 4.72%. Found: C, 54.60; H, 4.79%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | In dichloromethane; at 20℃; for 0.5h; | General procedure: [Cu(MeCN)4]PF6 (75 mg, 0.20mmol) was added to dppp (82 mg, 0.20mmol) in 5mL of dichloromethane. Then, bpy (32 mg, 0.20mmol) was added and the solution immediately changed to yellow. The reaction mixture was stirred for 30 min at room temperature. Diethyl ether was added to the solution to precipitate the product as a yellow solid, which was filtered and washed with diethyl ether: yield, 126 mg (0.162mmol, 81percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In tetrahydrofuran; at 130℃; for 0.0583333h;Inert atmosphere; Microwave irradiation; | General procedure: Method A: In a 10 mL dry microwave reactor were introduced [CpFe(naphthalene)][PF6] (63 mg, 0.16 mmol) and the ligand (0.16 mmol) under an argon atmosphere. Then, a mixture of degassed THF and CH3CN (1.5 mL, 2:1) was added. The homogeneous solution was placed in a microwave reactor (40 W) at 130 C for 3.5 minutes. The crude red solution was filtered through a pad of deactivated alumina (3% H2O) with dry and degassed CH3CN. This solution was transferred in a Schlenk tube under argon atmosphere. The solvent was removed under vacuum and the crude product was dissolved in 1 mL of dry and degassed CH3CN. The naphthalene was eliminated by hot extraction with pentane (60 C). The complex was precipitated with Et2O and dried under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In acetonitrile; at 20℃; for 1h; | General procedure: A solution of 1a (136 mg, 0.4 mmol) and triphenylphosphine (105 mg, 0.4 mmol) in CH3CN (2.0 mL) was stirred at room temperature for 1 h. The corresponding phosphonium salt was formed quantitatively. To the reaction mixture K2CO3 (111 mg, 0.8 mmol) was added,and the reaction mixture was stirred at room temperature for 12 h. After the usual aqueous extractive workup and column chromatographic purification process (hexanes/Et2O/CH2Cl2, 3:1:1) compound 2a was isolated as a white solid, 181 mg (98%). Other compounds were synthesized similarly, and the selected spectroscopic data of 2a, 2d, 2i, 3a, and 4a are as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In acetonitrile; at 20℃; for 1h; | General procedure: A solution of 1a (136 mg, 0.4 mmol) and triphenylphosphine (105 mg, 0.4 mmol) in CH3CN (2.0 mL) was stirred at room temperature for 1 h. The corresponding phosphonium salt was formed quantitatively. To the reaction mixture K2CO3 (111 mg, 0.8 mmol) was added,and the reaction mixture was stirred at room temperature for 12 h. After the usual aqueous extractive workup and column chromatographic purification process (hexanes/Et2O/CH2Cl2, 3:1:1) compound 2a was isolated as a white solid, 181 mg (98%). Other compounds were synthesized similarly, and the selected spectroscopic data of 2a, 2d, 2i, 3a, and 4a are as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | General procedure: All the complexes were prepared according to the following general procedure. In a solution of PdCl2 (0.5mmol) in 20mL of methanol, the appropriate amount of the respective solid diphosphine is added (0.5mmol). After stirring for 30min, 1mmol of the selected thiole, deprotonated with KOH in 20mL of methanol, is added and the reaction mixture is stirred for 48h under moderate heating (60C). The resulting solution is filtrated for the removal of any residual solids and the filtrate is left to stand in air after the addition of a small amount of a 1:1 mixture of CH2Cl2/CHCl3. Slow evaporation of the solvent gave the products in the form of crystals which were filtered off and dried under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In dichloromethane; at 20℃; for 2h; | General procedure: DMPE (102 muL, 0.616 mmol) was slowly added to a yellow suspension of [Pd(TFA)2(TMEDA)] (0.138 g, 0.31 mmol) in CH2Cl2 (3 mL). An initial suspension turned gray. After stirring the reaction mixture for 2 h at room temperature, the solvent was removed under vacuum, and washed with n-hexane. The crude solid was recrystallized from CH2Cl2/hexane to give [Pd(P~P)2](TFA)2 (P~P = DMPE), 2 (0.192 g, 99%). Complexes 3-8 were analogously prepared. Analytical and spectroscopic data are available as Supporting Information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In chloroform; at 30℃; for 3h; | General procedure: A solution of dppm (0.131 g, 0.34 mmol) in CHCl3 (10 ml) was added to a suspension of complex 1 (0.145 g, 0.34 mmol) in CHCl3 (15 ml). The resulting yellow solution formed was stirred at 30 C for 3 h and then left for slow evaporation at room temperature. The yellow precipitate was filtered off, washed with CHCl3 and dried under vacuum (Scheme 3). The related complexes [Pd(Sac-CH2O)2(dppe)] (3), [Pd(Sac-CH2O)2(<strong>[6737-42-4]dppp</strong>)] (4), [Pd(Sac-CH2O)2(dppmS2)] (5) and [Pd(Sac-CH2O)2(-dppeO2)] (6) were prepared and isolated in a similar manner. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In tetrahydrofuran; at 80℃;Inert atmosphere; | FeCl as starting material2(thf)3/2(0.289 g, 1.23 mmol) and under an argon atmosphere THF (6.0 mL), 1,3- bis [diphenylphosphino] propane (0.507 g, 1.23 mmol) was added .The following operations were also carried out under an argon atmosphere.It was allowed to react overnight at 80 .The reaction was cooled to ambient temperature and filtered.It washed 3 times with white powder obtained with diethyl ether, and dried under vacuum.To give the title compound as a white powder (0.591 g, 89% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | General procedure: A solution of [Cu(CH3CN)4](ClO4) (35.3mg, 0.108mmol) and 1,2-bis(diphenylphosphino)ethane (dppe) (43.2mg, 0.108mmol) in CH2Cl2 (10mL) was stirred for 30min at room temperature. A solution of Hbmp (22.6mg, 0.108mmol) in CH2Cl2 (5mL) was added, and this mixture was stirred for another 2h to give a light-yellow solution. The solvent was evaporated to dryness at reduced pressure. The residue was dissolved in a mixture of acetone/dichloromethane (1:5 v/v), and slow diffusion of petroleum ether into the above solution gave light-yellow crystals of 2 (69.4mg, 0.090mmol, 83%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In chloroform; at 20℃; for 3h; | To the solution of 0.124g (0.1mmol) complex 3 in CHCl3 (10mL), <strong>[6737-42-4]bis(diphenylphosphino)propane</strong> (<strong>[6737-42-4]dppp</strong>) (0.041g, 0.1mmol) was added, and the resulting solution was stirred for 3h at room temperature (RT). After that, the solvent was evaporated and the residue was treated with 15mL CH2Cl2/ n-hexane (1:3) to give 3b as the yellow solid. (0056) Yield (82%), M.p. 164C (dec.), IR (KBr, cm-1); nu (CO)=1621,1H NMR (400MHz, CDCl3, ppm): delta=2.00-2.70 (m, CH2 (<strong>[6737-42-4]dppp</strong>)), 4.54, 5.41 (m, CHP, meso-rac), 6.57, 6.91, 7.06, 7.20, 7.37, 7.45, 7.53, 7.63, 7.82, 7.92, 8.52 (m, C6H4, C6H4CO, PPh2, meso-rac); 31P{1H} NMR (161.97MHz, CDCl3, ppm): delta=-2.76,-2.55, 11.22, 13.66, 24.09, 24.33, 25.02, 25.22 (<strong>[6737-42-4]dppp</strong> and CHP, meso-rac isomers). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | In methanol; dichloromethane; at 20℃; for 5h; | Follow a similar procedure as 2, <strong>[6737-42-4]dppp</strong> (0.2mmol, 0.0825g) and Bphen (0.2mmol, 0.0665g) were added into the stirring solution of AgClO4 (0.2mmol, 0.0415g) in a mixture of CH2Cl2 (5ml) and CH3OH (5ml) for 5h at ambient temperature. The insoluble residues were removed by filtration, and the brown filtrate was evaporated slowly at room temperature for about one week to yield white crystals. Yields: 77%. Anal. Calc. for C102H84Ag2Cl2N4O8P4: elemental analysis: C, 64.32; H, 4.41; N, 2.94%. Measured value: C, 64.76; H, 4.52; N, 2.91%. IR (cm-1, KBr pellets): 3435m, 3051m, 2928w, 1965w, 1619m, 1588m, 1560s, 1517s, 1491s, 1434vs, 1424s, 1384s, 1308m, 1270w, 1233m, 1182m, 1097vs, 1026m, 999m, 954m, 854s, 829s, 767vs, 737vs, 701vs, 623vs, 593m, 574m, 547m, 509s, 479s, 441m. 1H NMR (600MHz, CDCl3, 298K): delta=1.5 (br, 4H, <strong>[6737-42-4]dppp</strong>-CH2CH2CH2), 2.7 (br, 8H, <strong>[6737-42-4]dppp</strong>-CH2CH2CH2), 7.0-7.6 (m, with solvent signal peak overlap, <strong>[6737-42-4]dppp</strong>-ph, Bphen-ph), 7.7 (br, 4H, H5,6-Bphen), 8.9 (br, 4H, H2,9-Bphen)ppm. 31P NMR (243MHz, CDCl3): delta=4.79 (d, JAg-P=430Hz), -5.93 (d, JAg-P=233Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.1% | Step 1, to 10. 0g sponge palladium by adding aqua regia (concentrated hydrochloric acid and concentrated nitric acid in a 3: 1 volume ratio of the system), Until the sponge palladium completely dissolved to the dissolved solution by adding a percentage of concentration of 37% concentrated hydrochloric acid to the solution is notThe filtrate was filtered while the brown nitroxide was retreated and the resulting filtrate was concentrated to a palladium level of 0. 3 g / mLAcid solution;Step 2: 45. Ogl, 3-bis (diphenylphosphino) propane was added to 400 mL of N, N-dimethylformamide, heatedTo 50 C to give a solution of bis (diphenylphosphino) alkane in N, N-dimethylformamide;[0024] Step 3: To a solution of N, N-dimethylformamide in bis (diphenylphosphino) alkane as described in step 2 under stirringThe solution of the chloropalladic acid in step 1 was added dropwise, and the reaction was carried out under the condition of stirring at a temperature of 50 C for 60 min.After the reaction solution is cooled and filtered to obtain a filter cake;[0025] Step 4: Wash the filter cake in step 3 with absolute ethanol, and then, at a temperature of 50 C,0. 08 MPa, the dried filter cake was vacuum dried for 3 h to give a pale yellow powder, 1,3-bis (diphenylphosphino) propane diPalladium chloride complex (C27H26Cl2P2Pd) 54. 4 g, yield 98. 1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With triisobutylaluminum; In diethyl ether; hexane; toluene; at 20℃; for 24h;Inert atmosphere; | The Ni(<strong>[6737-42-4]dppp</strong>)2 reagent used in these reactions can be prepared, for example, by the method of B. Corain el al., J. Organomet. Chem. 1971, 28, 133-136. Briefly, to a vigorously stirred mixture of 1.50 g (5.84 mmol) of nickel(II) bis(acetylacetonate) (Ni(acac)2) and 4.82 g (11.7 mmol) of <strong>[6737-42-4]1,3-bis(diphenylphosphino)propan</strong>e (<strong>[6737-42-4]dppp</strong>) in 80 ml of ether and 15 ml of toluene, a solution of i-Bu3Al (19.8 ml of 1.0 M solution in hexanes, 19.8 mmol) was added slowly over a 1 h period (by syringe pump) under Ar atmosphere. The resulting mixture was stirred at room temperature for 24 h. During this period the solution's color changed from bright green to bright red. The reaction mixture was left unperturbed for an additional 24 h, and the resulting precipitate was filtered under argon, and washed with excess ether to give 3.5 g (68%) of the product as a bright-orange solid material, mp 281 C., decomp. (lit. mp 281-283 C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium hydroxide; In 1,4-dioxane; at 110℃; for 20h;Inert atmosphere; | A 50 ml three-necked flask equipped with a stirring reflux device was charged with 1 mmol of 2-diphenylphosphineaniline, 1.5 mmol of p-bromobenzyl alcohol, 1 mmol of bis Dicyclohexylphosphine propane,mmol RuCl2 (PPh3) 3,1 mmol potassium hydroxide, 20 ml dioxane, the temperature was 110 C, heated for 20h under a nitrogen atmosphere, cooledHowever, filtration and recrystallization of the resulting solid from a mixed solvent of CH 2 Cl 2 and petroleum ether gave product 6 in a yield of 87%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 15%; 65%; 13% | With air; In 1,4-dioxane; water; at 20℃; for 2h;Inert atmosphere; | A mixture of 1 (200 mg, 0.752 mmol), 2c (155 mg, 0.376 mmol),DMSO (2.0 mL), and H2O (0.1 mL) was stirred for 1 h. Addition ofwater (?8 mL) gave a precipitate, which was centrifuged off, washedwith water (4 ×5 mL), and dried. The aqueous fraction was extractedwith chloroform (3 × 15 mL). The extracts were dried over MgSO4,filtered, and evaporated. The residue was purified by TLC to give betaines3c (35 mg, 14%) and 4c (287 mg, 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.9% | A mixture of [Ni(H2O)6](BF4)2 (100mg, 2.94×10-4mol) and <strong>[6737-42-4]dppp</strong> (121mg, 2.94×10-4mol) in CH3CN (10ml) was stirred. The color of the solution turned to brown from blue. After 3h, 2-pySH (63.5mg, 5.87×10-4mol) was added and the solution was stirred overnight. The resulting red-brown solution was evacuated to dryness. The crude product was purified by recrystallization from H2O/acetone. Orange plate crystals were recrystallized and were collected by filtration with a yield of 112mg (50.9%). Anal. Calc. for C32H30NNiP2SBF4: C, 57.53; H, 4.53; N, 2.10. Found: C, 57.63; H, 4.47; N, 2.09%. 1H NMR ((CD3)2SO, 400MHz) delta 7.81 (d, Ar-H, 8H); 7.56-7.49 (m, Ar-H, 13H); 6.77 (d, Ar-H, 1H); 6.54 (t, Ar-H, 1H); 6.10 (d, Ar-H, 1H);2.67 (br, PCH2CH2CH2P, 4H); 1.85 (br, PCH2CH2CH2P, 2H). 1H NMR (CD3CN, 400MHz) delta 7.83-7.78 (m, Ar-H, 8H); 7.56-7.44 (m, Ar-H, 13H); 6.69 (d, Ar-H, 1H); 6.44 (t, Ar-H, 1H); 6.25 (d, Ar-H, 1H); 2.54 (m, PCH2CH2CH2P, 4H) (The peak of PCH2CH2CH2P could not be identified due to residual solvent or water.). 31P{1H} NMR(CD3CN, 161MHz) delta 13.04 (br); 3.59 (br). UV-Vis (CH3CN) lambdamax, nm (epsilon, dm3mol-1cm-1) 274 (2.38×104), 292sh (2.17×104), 326sh (9.13×103), 373 (3.2×103). ESI-Mass: m/z 580 (calc. for M-BF4=580). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In 5,5-dimethyl-1,3-cyclohexadiene; at 70 - 110℃; | A solution of DPPP (29.7 mg, 0.072 mmol) in xylene (1.5 mL) was added dropwise to a solution of [Rh2(cod)2(mu2-Cl)2] (35.5 mg, 0.036 mmol) in xylene (1 mL) at 70 C. The temperature was raised to 110 C and the resulting red mixture was stirred for 3 h. The solvent was removed under vacuum at 110 C and the residue dried under vacuum overnight in order to remove traces of free cod. The product was recrystallised from THF/n-hexane to give a red powder: Yield 95% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In N,N-dimethyl-formamide; at 105℃; for 24h;Sealed tube; | A solution of perfluorinated iodide 19 (1.44 g, 3.03 mmol, 2.5 equiv) and DPPP (22; 500 mg, 1.21 mmol, 1.0 equiv) in DMF (5 mL) was stirred in a tightly closed reaction tube for 24 h at 105 C. The mixture was diluted with MTBE (20 mL); the crude product precipitated and was collected by filtration. The residue was recrystallized (MTBE, 50mL) to furnish product 8a (1.07 g, 0.786 mmol, 65%) as a colorless solid; mp 165 C. IR (ATR): 2911 (w), 2875 (w), 1739 (w), 1438 (w), 1228 (s), 1189 (s), 1143 (s), 1116 (s), 737 (m), 689 cm-1 (m). 1H NMR (500 MHz, CD3OD): delta = 1.65-1.82 (m, 2 H), 2.34-2.60 (m, 4H), 3.42-3.57 (m, 4 H), 3.58-3.73 (m, 4 H), 7.65-7.83 (m, 8 H), 7.83-7.98 (m, 12 H). 13C{1H} NMR (125 MHz, CD3OD): delta = 12.61-15.32 (m, 2 CH2; HMQC), 14.14-18.85 (m, CH2; HMQC), 19.56-24.98 (m, 2 CH2; HMQC), 25.10 (t, J = 22.3 Hz, 2 CH2), 116.87-117.56 (m, 4 C), 131.67-131.77 (m, 8CH), 134.42-134.49 (m, 8 CH), 136.73-136.84 (m, 4 CH). 31P{1H} NMR (203 MHz, CD3OD): delta = 27.69 (s). 19F{1H} NMR (470 MHz, CD3OD): delta = -82.42 (tt, J = 10.4 Hz, J = 2.6 Hz), -114.79 to -115.17 (m), -122.66 to -123.04 (m), -123.49 to -123.76 (m), -123.76 to -124.08 (m), -127.18 to -127.42 (m). HRMS (ESI): m/z [M - 2 I-] calcd for C43H34F26P2: 553.0855; found: 553.0842. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In methanol; dichloromethane; at 20℃; for 6h; | A mixture of CuBr (28.7mg, 0.2mmol) and <strong>[6737-42-4]dppp</strong> (82.5mg, 0.2mmol) with an excess of batho (66.5mg, 0.2mmol) were dissolved in CH2Cl2 (5mL) and CH3OH (5mL) solution, stirred at room temperature for 6h. The insoluble residues were removed by filtration, and the filtrate was evaporated slowly at room temperature to yield yellow crystalline products. Yield: 80%. Anal. Calc. for C53H50BrCuN2O2P2: C, 66.84; H, 5.29; N, 2.94. Found: C, 66.97; H, 5.15; N, 2.88%. IR (KBr disc, cm-1): 3378s, 3048w, 2858w, 2580w, 1616w, 1556m, 1515m, 1433s, 1414m, 1229m, 1026s, 998w, 767m, 740s, 698vs, 513s, 482m. 1H NMR (600MHz, CDCl3, 298K): delta 7.87-8.98 (d, 6H, batho CH), 7.56-7.68 (m, 10H, batho CH), 7.41-7.24 (m, 20H, <strong>[6737-42-4]dppp</strong> CH), 2.91-2.81 (m, 4H, CH2), 2.78-2.63 (m, 2H, CH2); 31P NMR (400MHz, CDCl3, 298K): -12.25, -14.84. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In methanol; dichloromethane; at 20℃; for 6h; | General procedure: A mixture of CuBr (28.7mg, 0.2mmol) and <strong>[6737-42-4]dppp</strong> (82.5mg, 0.2mmol) with an excess of batho (66.5mg, 0.2mmol) were dissolved in CH2Cl2 (5mL) and CH3OH (5mL) solution, stirred at room temperature for 6h. The insoluble residues were removed by filtration, and the filtrate was evaporated slowly at room temperature to yield yellow crystalline products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | A mixture of [Cu(CH3CN)4]ClO4 (98.3mg, 0.3mmol) and <strong>[6737-42-4]dppp</strong> (123.7mg, 0.3mmol) were dissolved in CH2Cl2 (6mL). After stirring for 4h at room temperature, the CH2Cl2 solution was concentrated to half its original volume and dry diethyl ether (5ml) was added. Then a white precipitate was obtained. After that, the mixture of the above-mentioned white precipitate and neo (62.6mg, 0.3mmol) were dissolved in CH3CN (7mL) and CH2Cl2 (3mL) solution, stirred for another 6h. The yellow powder of the mixed-ligand complex [Cu(<strong>[6737-42-4]dppp</strong>)(neo)]ClO4 was obtained. Yield: 83%. Anal. Calc. for C41H38ClCuN2O4P2: C, 62.84; H, 4.89; N, 3.57. Found: C, 62.76; H, 4.74; N, 3.54%. IR (KBr disc, cm-1): 3428m, 3053w, 2053m, 1586w, 1552w, 1461m, 1434vs, 1394m, 1372s, 1259w, 1218s, 1095w, 1070w, 804w, 745s, 696s, 512m, 433w. 1H NMR (600MHz, CDCl3, 298K) delta 8.52-7.78ppm (m, 6H, neo CH), 7.25-7.06ppm (m, 20H, <strong>[6737-42-4]dppp</strong> CH), 3.17-2.57ppm (m, 4H, CH2), 2.43-2.11ppm (m, 2H, CH2);2.13ppm (s, 6H, CH3); 31P NMR (400MHz, CDCl3, 298K): -17.08ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium acetate; In dimethyl sulfoxide; at 60℃; for 24h;Schlenk technique; | Accurate weighing1,3-bis(diphenylphosphino)propane (0.1237 g, 0.3 mmol), potassium acetate (0.1325 g,1.35 mmol) was added to a 25 mL Schlenk reaction flask followed by 2-methylbromobenzene (128 muL, 0.9 mmol), solventIt was dimethyl sulfoxide (2 mL) and reacted at 60 C for 24 h. After completion of the reaction, it was extracted with ethyl acetate/water and dried over anhydrous sodium sulfate.The organic phase was removed under reduced pressure. EtOAc (EtOAc/EtOAc)80%. |
Tags: 6737-42-4 synthesis path| 6737-42-4 SDS| 6737-42-4 COA| 6737-42-4 purity| 6737-42-4 application| 6737-42-4 NMR| 6737-42-4 COA| 6737-42-4 structure
[ 14221-01-3 ]
Tetrakis(triphenylphosphine)palladium
Similarity: 0.91
[ 13991-08-7 ]
1,2-Bis(diphenylphosphino)benzene
Similarity: 0.81
[ 14694-95-2 ]
Tris(triphenylphosphine)chlororhodium
Similarity: 0.81
[ 40691-33-6 ]
Dichlorobis(tri-o-tolylphosphine)palladium(II)
Similarity: 0.79
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