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CAS No. : | 6276-03-5 | MDL No. : | MFCD00001130 |
Formula : | C14H10O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HTPXFGUCAUTOEL-UHFFFAOYSA-N |
M.W : | 210.23 | Pubchem ID : | 80468 |
Synonyms : |
|
Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P362-P403+P233-P501 | UN#: | |
Hazard Statements: | H315-H319-H335 | Packing Group: | |
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 |
---|---|---|
95.5% | With thionyl chloride for 2h; Heating; | |
91% | With thionyl chloride for 10h; Heating; | |
With thionyl chloride |
With pyridine; thionyl chloride In diethyl ether | ||
With thionyl chloride for 3h; Heating; | ||
With oxalyl dichloride In dichloromethane for 2h; | 4 EXAMPLE 4 To a suspension of 1-fluorenecarboxylic acid (184 mg) and oxalyl chloride (0.2 ml) in dichloromethane (4 ml) was added N,N-dimethylformamide (0.01 ml), and the mixture was stirred for 2 hours.. The resultant solution was evaporated to give a crude acid chloride.. To a suspension of 3-pyridazin-3-yl-phenylamine (150 mg) and pyridine (0.21 ml) in dichloromethane (2 ml) was dropwise added a solution of the acid chloride obtained above in dichloromethane. (5 ml) followed by stirring for an hour.. The mixture was diluted with dichloromethane and washed with an aqueous solution of sodium hydrogen carbonate and brine.. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure.. The residue was purified by a silica gel column chromatography eluding with 2% methanol in dichloromethane to give N-(3-(pyridazin-3-yl)phenyl)-9H-fluorene-1-carboxamide (44 mg, 13.8%).NMR (DMSO-d6, δ): 4.24 (2H, s). 7.3-7.5(2H, m), 7.5-7.7 (3H, m), 7.7-7.9 (3H, m), 7.99 (1H, dd, J=7.0 Hz, 1.8 Hz), 8.1-8.3 (2H, m), 8.70 (1H, t, J=3.6 Hz), 9.24 (1H, dd, J=4.9 Hz, 1.5 Hz), 10.54 (1H, s) APCI-Mass m/z: 364 (M+1). | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1.5h; Inert atmosphere; | ||
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 12h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; amalgamated zinc; acetic acid | ||
With sodium hydroxide; hydrazine hydrate; trimethyleneglycol at 205℃; | ||
With sodium amalgam; water |
With phosphorus; hydrogen iodide; acetic acid | ||
With sodium hydroxide; hydrazine hydrate In diethylene glycol Heating; | ||
With phosphorus; hydrogen iodide; acetic acid In water for 48h; Heating / reflux; | 2 A mixture of 9-fluorenone-1-caboxylic acid (6 g, 26.8 mmol), a 55% HI solution HI (10.5 mL) and red phosphorous (9,6 g, 310 mmol) in 400 mL acetic acid was refluxed for 48 h, then concentrated. Following addition of 200 mL of water; the mixture was stirred overnight and filtered. The cake was treated in 200 mL water and 5 mL concentrated NaOH and filtered to remove residual phosphorous. The filtrate was adjusted to pH 2 with 4 N HCl to give a suspension that was filtered, washed with, dried in vacuum to afford 5.47 g of compound 8 as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 4.25 (2H, s), 7.35 (2H, m), 7.55 (1H, t), 7.63 (1H, d), 7.92 (1H, d), 7.96 (1H, d), 8.2 (1H, d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | In tetrahydrofuran; diethyl ether for 3h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With diborane In tetrahydrofuran for 29h; Heating; | |
Multi-step reaction with 3 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 1.5 h / 20 °C / Inert atmosphere 2: dmap; triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 3: 3,4-thiene-2,3-diylbis(dicyclohexylphosphine); nickel(II) acetylacetonate dihydrate / 1,4-dioxane; hexane / 16 h / 170 °C / Inert atmosphere; Sealed tube |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With potassium permanganate; sulfuric acid; iodine In acetic acid at 100℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bromine Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.5% | With acetic acid In tetrahydrofuran; methanol; water | 29 1-Fluorenemethanol 1-Fluorenemethanol A solution of 1-fluorenecarboxylic acid (10.0 g, 47.6 mmol) in THF (150 mL) at 0° C. was charged With a 1M solution of BH3 -THF complex in THF (80 mL, 80 mmol). The reaction mixture was stored overnight at room temperature then quenched with 30 mL of 10% AcOH in methanol. After dilution with water (100 mL), the water layer was extracted with ethyl acetate (3*50 mL). The combined organic extracts were washed with 10% potassium carbonate solution, water, brine, dried over magnesium sulfate and evaporated. The residue (white crystals) was washed with ether and dried to afford 1-fluorenemethanol (6.4 g, 68.5%). |
59% | With lithium aluminium tetrahydride In tetrahydrofuran for 1h; Ambient temperature; | |
33% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 1h; |
With lithium aluminium tetrahydride In diethyl ether Heating; | ||
Multi-step reaction with 2 steps 1: H2SO4 2: LiAlH4 | ||
With borane-THF In tetrahydrofuran at 20℃; for 16.5833h; | 2 Compound 9 Compound 9 To a slurry of compound 8 (5.47 g, 26 mmol) in 50 mL dry THF, was added dropwise a 1 M solution BH3-THF (28 mL) at room temperature over a 35 minutes period. The mixture was stirred at room temperature for 16 h then quenched by brine. The organic layer was washed with brine, dried over MgSO4, concentrated to give 4.5 g of compound 9 as a yellow solid. 1H NMR (400 MHz, CHCl3) δ 3.9(2H, s), 4.85 (2H, s), 7.35 (4H, m), 7.55 (1H, d), 7.75 (1H, d), 7.8 (1H, d). | |
In tetrahydrofuran; water | 1-Fluorenylmethanol 1-Fluorenylmethanol To a cooled (0°), stirred, solution of 1-fluorenecarboxylic acid (2.10 g, 10.0 mmol) in dry tetrahydrofuran (20 ml) under argon was added lithium aluminium hydride (0.19 g, 5 mmol) added in portions over 10 minutes. After a further 1 hour, water was added cautiously until effervescence ceased. The reaction mixture was partitioned between ethyl acetate and water and filtered. The organic layer was washed with saturated sodium hydrogen carbonate solution followed by water and dried over MgSO4. Evaporation of solvent gave crude product. δH (CDCl3 containing CD3 OD) 3.87 (2H, s), 4.81 (2H, s), 7.2-7.75 (7H, m) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In tetrahydrofuran at 20℃; for 40h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: 9H-fluorene-1-carboxylic acid With isocyanate de chlorosulfonyle In dichloromethane at 0℃; Stage #2: With triethylamine In dichloromethane at 20℃; | |
Multi-step reaction with 2 steps 1: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 12 h / 20 °C / Schlenk technique; Inert atmosphere 2: bis(1,5-cyclooctadiene)nickel (0); triphenylphosphine / toluene / 1 h / 110 °C / Schlenk technique; Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 23℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 9H-fluorene-1-carboxylic acid With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In chloroform at 20℃; for 0.0833333h; Stage #2: 3-spiro[2,3-dihydro-1H-indene-1,4'-piperidine]-1-ylpropane-1-amine In chloroform at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: thionyl chloride / 3 h / Heating 2: aq. NaHCO3 / CHCl3 / 1 h / 20 °C / pH 8 - 9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: thionyl chloride / 3 h / Heating 2: aq. NaHCO3 / CHCl3 / 1 h / 20 °C / pH 8 - 9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 59 percent / LiAlH4 / tetrahydrofuran / 1 h / Ambient temperature 2: 64 percent / pyridinium dichromate, silica gel / CH2Cl2 / 7 h | ||
Multi-step reaction with 2 steps 1: 91 percent / B2H6 / tetrahydrofuran / 29 h / Heating 2: 88 percent / pyridinium chlorochromate on neutral alumina / hexane / 8 h / Ambient temperature | ||
Multi-step reaction with 2 steps 1: SOCl2 2: palladium/charcoal; xylene / Hydrogenation |
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / 0 - 20 °C 2: dipyridinium dichromate; silica gel / dichloromethane / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 91 percent / SOCl2 / 10 h / Heating 2: tetrahydrofuran / 1 h / -70 deg C -> room temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 91 percent / SOCl2 / 10 h / Heating 2: tetrahydrofuran / 1 h / -70 deg C -> room temperature 3: NH2OH*HCl, NaOAc / H2O / 2 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 91 percent / B2H6 / tetrahydrofuran / 29 h / Heating 2: 88 percent / pyridinium chlorochromate on neutral alumina / hexane / 8 h / Ambient temperature 3: ZnI2 / CH2Cl2 / 1 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 91 percent / SOCl2 / 10 h / Heating 2: tetrahydrofuran / 1 h / -70 deg C -> room temperature 3: NH2OH*HCl, NaOAc / H2O / 2 h / Heating 4: 95 percent / H2, conc. HCl / Pd/C / methanol / 21 h / 2280 Torr / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 91 percent / B2H6 / tetrahydrofuran / 29 h / Heating 2: 88 percent / pyridinium chlorochromate on neutral alumina / hexane / 8 h / Ambient temperature 3: ZnI2 / CH2Cl2 / 1 h / Ambient temperature 4: LiAlH4 / tetrahydrofuran / 3 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 38 percent / tetrahydrofuran; diethyl ether / 3 h / Ambient temperature 2: CuBr2 / ethyl acetate; CHCl3 / 3.5 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 38 percent / tetrahydrofuran; diethyl ether / 3 h / Ambient temperature 2: CuBr2 / ethyl acetate; CHCl3 / 3.5 h / Heating 3: dimethylformamide / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: CrO3; acetic acid 2: sodium hydroxide; trimethylene glycol; aqueous hydrazine hydrate / 205 °C | ||
Multi-step reaction with 2 steps 1: chromium (VI)-oxide; aqueous acetic acid 2: sodium hydroxide; trimethylene glycol; aqueous hydrazine hydrate / 205 °C | ||
Multi-step reaction with 2 steps 1: chromium (VI)-oxide; aqueous acetic acid 2: amalgamated zinc; aqueous hydrochloric acid; acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: hydrogen chloride; methanol 2: ethanol; aqueous hydrazine hydrate 3: aqueous hydrochloric acid; acetic acid; aqueous sodium nitrite solution | ||
Multi-step reaction with 2 steps 1: SOCl2 2: NaN3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: H2SO4 2: LiAlH4 3: PBr3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: H2SO4 2: LiAlH4 3: PBr3 4: H2S, NaOEt / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.7% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 24h; | 28 EXAMPLE 28 To a suspension of 9H-fluorene-1-carboxylic acid (106 mg) and 3-(4,5-dimethylimidazol-1-yl)aniline (94 mg) in dichloromethane (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (135 mg) and 4-dimethylaminopyridine (31 mg), and the mixture was stirred for 24 hours.. The mixture was diluted with dichloromethane and washed with water and brine.. The mixture was dried over magnesium sulfate and evaporated under reduced pressure.. The residue was triturated with methanol, and the insoluble material was collected by filtration and dried to give N-[3-(4,5-dimethylimidazol-1-yl)-phenyl]-9H-fluorene-1-carboxamide (123 mg, 64.7%). APCI-mass m/z: 380 (M+1) NMR (DMSO-d6, δ); 2.13 (6H, s), 4.20 (2H, s), 7.15 (1H, d, J=8.4 Hz), 7.3-7.5 (6H, m), 7.75 (1H, d, J=6.9 Hz), 7.8-7.9 (2H, m), 7.98 (1H, d, J=6.6 Hz), 8.13 (1H, d, J=6.9 Hz), 10.57 (1H, s): |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29.2% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 24h; | 27 EXAMPLE 27 To a suspension of 9H-fluorene-1-carboxylic acid (79 mg) and 3-(4-methylimidazol-1-yl)aniline (65 mg) in dichloromethane (2 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (101 mg) and 4-dimethylaminopyridine (23 mg), and the mire was stirred for 24 hours.. The mix e was diluted with dichloromethane, washed with water and brine.. The mixture was dried over magnesium sulfate and evaporated under reduced pressure.. The residue was triturated with methanol, and the insoluble material was collected by filtration and dried to give N-[3-(4-methylimidazol-1-yl)-phenyl]-9H-fluorene-1-carboxamide (40 mg, 29.2%). APCI-mass m/z: 366 (M+1) NMR (DMSO-d6 δ; 2.18 (3H, s), 4.21 (2H, s), 7.3-7.8 (9H, m), 7.98 (1H, d, J=6.5 Hz), 8.0-8.1 (2H, m), 8.13 (1H, d, J=7.3 Hz), 10.53 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium In tetrahydrofuran; hexane; dichloromethane; N,N-dimethyl-formamide | (Z)-9-[4-[4-(2,3-Dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]-2-butenyl]-N-propyl-9H-fluorene-9-carboxamide, monohydrochloride STR227 (Z)-9-[4-[4-(2,3-Dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]-2-butenyl]-N-propyl-9H-fluorene-9-carboxamide, monohydrochloride STR227 Butyllithium (8.4 mL, 2.5M in hexane, 21 mmol) was added dropwise over 10 min to a solution of fluorenecarboxylic acid (Aldrich Chemical Co.) (2.10 g, 10 mmol) in THF (50 mL) at 0° C. under argon. During addition of the first equivalent of BuLi, the reaction became thick with a white precipitate which became yellow and cleared after addition of the second equivalent. The reaction was stirred at 0° C. for 20 min, then cis-1,4-dichloro-2-butene (1.2 mL, 11 mmol) was added dropwise over 5 min. The reaction lightened in color during addition and was stirred at 0° C. for 3 h, then poured into 1N HCl (50 mL) and extracted with CH2 Cl2 (3*50 mL). The combined organic layers were washed with brine (30 mL) then dried over MgSO4. Evaporation provided 3.5 g of a yellow oil containing crystalline solid. The crude residue was triturated with hexane (20 mL). The supernatant was decanted, and the residue pumped under high vacuum to give 2.93 g of a tan solid. To a suspension of the crude acid prepared above (1.42 g, 4.77 mmol) and N,N-dimethylformamide (5 drops) in CH2 Cl2 (15 mL) at RT under argon was added oxalyl chloride (3.6 mL, 2.0M in CH2 Cl2, 7.16 mmol). The reaction bubbled for 10 min, then the reaction was stirred at RT for 1.5 h, at which time all solids had dissolved. The reaction was concentrated in vacuo to give an orange oil. The crude acid chloride was dissolved in CH2 Cl2 (15 mL) and cooled to 0° C. Propylamine (1.2 mL, 14.3 mmol) was added dropwise over 1 min, and the reaction was stirred at 0° C. for 10 min. The reaction was partitioned between EtOAc (50 mL) and water (20 mL). The organic layer was washed with 1N HCl (2*20 mL) and brine (20 mL), then dried over MgSO4. Evaporation gave 1.7 g of an orange oil, which was purified by flash chromatography on silica gel (150 g) eluding with CH2 Cl2 to give title compound (1.38 g, 84%) as a pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; H2; ammonia; lithium In ethanol; water; acetic acid | 12.A A. A. 1,2,3,4,4a,9a-Hexahydrofluorene-1-carboxylic acid A solution of 21.0 g (0.10 mole) of fluorene-1-carboxylic acid in 25 ml of absolute ethanol is added to 500 ml of liquid ammonia and the solution treated portionwise with 4.2 g (0.60 mole) of lithium cut in small pieces. After evaporation of the NH3, the residue is cooled in ice and treated first with water and then with sufficient conc. HCl to render it strongly acidic. The crude partially reduced product is filtered off and dissolved in acetic acid. Reduction of the solution over 1 g of PtO2 under up to 55 psi of H2 is complete after about 1 equivalent of H2 is taken up. The solution is freed of catalyst and taken to dryness. Recrystallization from hexane affords the desired product, mp 138°-139°. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In oxalyl dichloride; dichloromethane | 171 Preparation 171 Preparation 171 To a solution of 9H-fluorene-1-carboxylic acid (0.49g) in dichloromethane (2ml) were added in turn oxalyl chloride (0.4ml) and a catalytic amount of N,N-dimethylformamide (2drops) at ambient temperature. After stirring at ambient temperature for 1 hour, the reaction mixture was evaporated in vacuo, and the residue was added in dichloromethane (5ml) to give a solution of 9H-fluorene-1-carboxyl chloride. To a solution of 5-amino-methyl nicotinic acid (0.53g) in dichloromethane (5ml) were added pyridine (1.0ml) and the acid chloride solution at 0°C. After stirring at 0°C for 1 hour, the reaction mixture was diluted with dichloromethane, washed with aqueous potassium carbonate (10%) and brine, and dried over potassium carbonate. Evaporation gave a residue which was triturated with diisopropyl ether to give 5-[(9H-fluorene-1-carbonyl)-amino]-nicotinic acid methyl ester (0.492g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap In dichloromethane | 175 Example 175 Example 175 To a suspension of 9H-fluorene-1-carboxylic acid (835mg) and 3-methyl-N2-(2-pyridylmethyl)-2,5-pyridyldiamine (845mg) in dichloromethane (30ml) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.14g) and 4-dimethylaminopyridine (242mg) and stirred for 18 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 150g, eluding with 1-4% methanol/dichloromethane) to give N-[5-methyl-6-[methyl(2-pyridylmethyl)amino]-3-pyridyl]-9H-fluorene-1-carboxamide (1.14g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; N,N-dimethyl-formamide | 91 Example 91 Example 91 To a suspension of 9H-fluorene-1-carboxylic acid (147mg) in dichloromethane (3ml) was added oxalyl chloride (0.2ml) and N,N-dimethylformamide (0.01ml). The mixture was stirred for 2 hours and evaporated to give crude 9H-fluorene-1-carboxylic acid chloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 9H-fluorene-1-carboxylic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In 1-methyl-pyrrolidin-2-one; dichloromethane for 0.5h; Stage #2: C34H36N3O3Pol With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one; dichloromethane at 20℃; for 24h; Stage #3: With chlorotriisopropylsilane; trifluoroacetic acid In dichloromethane at 20℃; for 1h; | B.5 EXAMPLE B.5 [0218] Fluorene-4-carboxylic acid (0.00023 mole) in 1 ml of 1/1 mixture of DCM/NMP was added to PyBOP (0.00046 mole) in DCM (1 ml). This mixture was stood for 30 minutes, then added to the resin of example A.30. DCM (5 ml) was added, followed by DIPEA (0.00057 mole). The reaction mixture was shaken for 24 hours at room temperature, then filtered, washed three times with DCM, three times with first methanol, followed by secondly DCM. A mixture of TFA/DCM/TIS (4 ml; 75/23/2) was added and the mixture was shaken for one hour at room temperature. The mixture was filtered, the filter residue was washed with 2 ml of a mixture of TFA/DCM/TIS (75/23/2) and with DCM (2 ml). The filtrate was blown dry at 50 C. under a gentle stream of nitrogen. The residue was dissolved in DCM (5 ml), then blown dry once more. This fraction was purified by high performance liquid chromatography over Hyperprep RP-C18 BDS (100 g, 100 Å, 8 μm; eluent: [(0.5% NH4OAc in H2O)/CH3CN 90/10)]/CH3OH/CH3CN (0 minute) 75/25/0, (10 minutes) 0/50/50, (16 minutes) 0/0/100, (18.10-20.00 minutes) 75/25/0). The pure fractions were collected and the organic solvent was evaporated. The aqueous concentrate was extracted with DCM/aqueous potassium carbonate solution, then separated over Extrelut. The organic phase was blown dry under nitrogen at 50 C. The residue was dried further under vacuum at 60 C., yielding 0.0046 g of the compound identified as No. 29 in the following table F-1. Compounds identified as No. 30 to No. 36 in the following table F-1 were similarly prepared while using the same experimental procedure and replacing fluorene-4-carboxylic acid by the appropriate reactive acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With Et3SiB(C6F5)4 In chlorobenzene at 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Stage #1: 9H-fluorene-1-carboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 20 - 50℃; for 1h; Stage #2: guanidine hydrochloride With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 3h; Cooling with ice; | 5.1.1 N-(Diaminomethylene)-9H-fluorene-2-carboxamide (4) To a solution of 9H-fluorene-2-carboxylic acid (15, 520mg, 2.47mmol) in DMF (6mL) was added 1,1′-carbonyldiimidazole (CDI) (440mg, 2.71mmol) at room temperature, the reaction mixture was stirred at 50°C for 1h, then allowed to cool. This mixture was added under ice-cooling to a solution which had been prepared by addition of NaH (55% dispersion in mineral oil; 500mg, 12.5mmol) to DMF (6mL) solution of guanidine hydrochloride (1.18g, 12.3mmol) and stirring at room temperature for 1h, and the reaction mixture was stirred at room temperature for 2h. The reaction mixture was concentrated in vacuo and added CHCl3 and water. The aqueous layer was extracted with CHCl3, and the combined organic layer was washed with 1M NaOH aq, dried over MgSO4. After evaporation in vacuo, the resultant residue was purified by silica gel column chromatography (EtOAc), recrystalization from MeOH to give the title compound 4 (140mg, 23%) as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 1.5 h / 20 °C / Inert atmosphere 2: dmap; triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With 2,2,6,6-tetramethyl-piperidine-N-oxyl; chloro(1,5-cyclooctadiene)rhodium(I) dimer; copper diacetate; cesium fluoride In toluene at 120℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 9H-fluorene-1-carboxylic acid In dichloromethane at 0℃; for 0.5h; Schlenk technique; Stage #2: With (bis-(2-methoxyethyl)amino)sulfur trufluoride In dichloromethane at 0℃; for 0.5h; Schlenk technique; | 3.2.2. Representative Procedure for the Synthesis of Acyl Fluorides from Carboxylic Acids General procedure: To a 20 mL of Schlenk tube charged with a magnetic stir bar, were successively added carboxylic acid (3.0 mmol) and CH2Cl2 (15 mL). After the mixture was stirred at 0 °C for 30 min, Deoxo-Fluorreagent (608 L, 3.3 mmol, 1.1 equiv) was slowly added to the reaction mixture. After the reaction mixture was stirred at 0 °C for 30 min, the solution was slowly poured into saturated NaHCO3,extracted with CH2Cl2 (3 15 mL), and dried over MgSO4. The crude product was purified by flash chromatography on silica gel to aord the corresponding acyl fluorides 1 [36]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate; sodium hydrogencarbonate; triphenylphosphine In N,N-dimethyl-formamide at 20℃; for 48h; Molecular sieve; Inert atmosphere; Sealed tube; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; copper(II) acetate dihydrate In o-xylene at 150℃; for 6h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With copper(II) acetate dihydrate; [(Rh(η-C5H5)I2)n] In o-xylene at 150℃; for 6h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; copper(II) acetate dihydrate In o-xylene at 150℃; for 6h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With copper(II) acetate dihydrate; [(Rh(η-C5H5)I2)n] In o-xylene at 150℃; for 6h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 18h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: bis(1,5-cyclooctadiene)nickel (0); bis(dicyclohexylphosphino)methane / toluene / 24 h / 150 °C / Inert atmosphere; Schlenk technique; Sealed tube 2: toluene; N,N-dimethyl-formamide / 4 h / 90 °C / Inert atmosphere; Schlenk technique; Sealed tube |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis(1,5-cyclooctadiene)nickel (0); bis(dicyclohexylphosphino)methane In toluene at 150℃; for 24h; Inert atmosphere; Schlenk technique; Sealed tube; |