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CAS No. : | 872-53-7 | MDL No. : | MFCD00060798 |
Formula : | C6H10O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VELDYOPRLMJFIK-UHFFFAOYSA-N |
M.W : | 98.14 | Pubchem ID : | 70106 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.83 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 29.04 |
TPSA : | 17.07 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.0 cm/s |
Log Po/w (iLOGP) : | 1.55 |
Log Po/w (XLOGP3) : | 1.27 |
Log Po/w (WLOGP) : | 1.38 |
Log Po/w (MLOGP) : | 1.0 |
Log Po/w (SILICOS-IT) : | 1.87 |
Consensus Log Po/w : | 1.41 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.18 |
Solubility : | 6.45 mg/ml ; 0.0657 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.23 |
Solubility : | 5.81 mg/ml ; 0.0592 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.9 |
Solubility : | 12.3 mg/ml ; 0.125 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.2 |
Signal Word: | Danger | Class: | 3 |
Precautionary Statements: | P210-P302+P352-P305+P351+P338 | UN#: | 1989 |
Hazard Statements: | H225-H315-H319-H335 | Packing Group: | Ⅱ |
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 |
---|---|---|
89% | Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; Stage #2: at 0 - 20℃; for 64 h; |
Step 1. (2E)- and (2Z)-3-Cyclopentylacrylonitrile To a solution of 1.0 M potassium tert-butoxide in THF (235 mL) at 0 °C was added dropwise a solution of diethyl cyanomethylphosphonate (39.9 mL, 0.246 mol) in THF (300 mL). The cold bath was removed and the reaction was warmed to room temperature followed by recooling to 0 °C, at which time a solution of cyclopentanecarbaldehyde (22.0 g, 0.224 mol) in THF (60 mL) was added dropwise. The bath was removed and the reaction warmed to ambient temperature and stirred for 64 hours. The mixture was partitioned between diethyl ether and water, the aqueous was extracted with three portions of ether, followed by two portions of ethyl acetate. The combined extracts were washed with brine, then dried over sodium sulfate, filtered and concentrated in vacuo to afford a mixture containing 24.4 g of olefin isomers which was used without further purification (89percent). 1H NMR (400 MHz, CDCl3): δ 6.69 (dd, 1H, trans olefin), 6.37 (t, 1H, cis olefin), 5.29 (dd, 1H, trans olefin), 5.20 (d, 1H, cis olefin), 3.07-2.95 (m, 1H, cis product), 2.64-2.52 (m, 1H, trans product), 1.98-1.26 (m, 16H). |
67% | Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 3 h; Cooling with ice Stage #2: at 0 - 20℃; |
Under ice-cooling conditions, 5.9g of diethyl cyanomethylphosphonate was dissolved in 100mL anhydrous tetrahydrofuran. 5.6g of potassium tert-butoxide was added portionwise in the solution and was stirred at room temperature for three hours. The temperature was reduced to 0°C and cyclopentanecarbaldehyde was added dropwise to the reaction solution and reacted overnight at room temperature. TLC was used to monitor reaction completion. 100ml of saturated ammonium chloride solution was added to quench the reaction. After distilling off the solvent, the residue was extracted with ethyl acetate then washed with water. The organic phase was washed with 100mL each of saturated sodium chloride solution 3 times. The organic phase was dried over anhydrous anhydrous magnesium sulfate overnight. The mixture was filtered and the solvent was distilled off under reduced pressure to give a crude product. The product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:1) to give 2.5g of intermediate 5a as a colorless liquid, yield: 67percent. |
46% | With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 49 h; | To a solution of Potassium t-butoxide (1.23 g, 10.37 mmol) in THF (20 mL) at 0 °C was added diethyl cyanomethylphosphonate 34b (1.96 g, 10.87 mmol) dropwise over a period of 10 mins. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C and added a solution ofcyclopentanecarbaldehyde 34a (0.97 g, 9.88 mmol) in THF (10 mL). The reaction mixture was allowed to warm to room temperature and stirred for 48 h. The reaction was diluted with water (10 mL and extracted with ethyl acetate (3 x 30 ml). The ethyl acetate layers were combined and washed with brine (25 ml), dried concentrated in vacuum. The residue obtained was purified by flash column chromatography (silica gel 20 g, eluting with 0-50percent ethyl acetate in hexane) to furnish 3-cyclopentylacrylonitrile 34c (0.55 g, 46percent) as a colorless oil; 1HNMR (300 MHz, DMSO) δ 6.85 (dd, J= 8.1, 16.3, 0.4H), 6.66 - 6.51 (m, 0.6H), 5.67 (dd, J= 1.2, 16.3, 0.4H), 5.56 (dd, J= 0.6, 10.8, 0.6H), 2.86 (dq, J= 8.1, 16.5, 0.6H), 2.60 (dt, J= 8.3, 16.7, 0.4H), 1.79 (m, 2H), 1.70 - 1.50 (m, 4H), 1.42 - 1.29 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.2% | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.5 h; Inert atmosphere Stage #2: at 0 - 20℃; for 1 h; Inert atmosphere |
Under nitrogen, a suspension of (cyanomethyl)triphenylphosphanium bromide (12 g, 31.49 mmol) in anhydrous THF (100 mL) was cooled to 0° C., a solution of 2.5 M n-BuLi in n-hexane (13 mL, 34.64 mmol) was added dropwise. The mixture was stirred at 0° C. for another 30 minutes, then cyclopentane-carbaldehyde (3.1 g, 31.49 mmol) was added, and the mixture was warmed to the room temperature and stirred for further 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (100 mL×3). The organic layers were combined, washed with water (60 mL×3) and saturated brine (60 mL) in sequence, dried over anhydrous sodium sulfate. The mixture was filtrated, the filtrate was concentrated in vacuum, the residue was purified by silica column chromatography (petroleum ether:ethyl acetate=10:1) to give colorless oil 3-b (1.0 g, yield: 26.2percent). LC-MS (ESI): m/z=122 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In toluene; at 25℃; for 48h; | General procedure: To a stirred solution of aldehyde or imine (6, 1 mmol) in toluene (2 mL) were added PdO-Fe3O4 (50 mg, 1.2 mol % of Pd) and PMHS (2 mmol, 0.12 mL). The resulting mixture was stirred at room temperature during two days. The catalyst was removed by a magnet and the resulting mixture was quenched with water and extracted with EtOAc. The organic phases were dried over MgSO4, followed by evaporation under reduced pressure to remove the solvent. The corresponding products 3a or 7 were purified by chromatography on silica gel (hexane/ethyl acetate). |
90% | With sodium tetrahydroborate; In methanol; at 0 - 25℃; for 2h; | NaBH4 (15.51 mg, 0.41 mmol) was added portion-wise to a solution of cyclopentanecarboxaldehyde(200 mg, 2.03 mmol) in methanol (4.0 mL) cooled at 0 C. The mixture was stirred for 1 h at 0 C,then the temperature was raised until 25 C and the reaction was kept under stirring for anotherhour. The solution was quenched with a saturated solution of NH4Cl (4.0 mL), methanol wasevaporated under reduced pressure and the aqueous layer was extracted with ethyl acetate (3 x 5mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated.The resulting residue was purified by flash chromatography on silica gel (1:10 ethylacetate/petroleum ether) to afford 14d as a colorless oil (90% yield). 1H NMR (400 MHz, CDCl3): delta3.43 (d, J = 6.2 Hz, 2H), 2.05 - 1.98 (s, 1H), 1.69 - 1.66 (m, 2H), 1.56 - 1.47 (m, 3H), 1.29 (s, 1H), 1.20- 1.14 (m, 3H). |
39% | With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; tris[3,5-bis(trifluoromethyl)phenyl]-borane; In 1,4-dioxane; at 100℃; for 12h;Glovebox; | General procedure: In a glovebox, aldehydes (0.25 mmol) and the Hantzsch ester 1 (95 mg, 0.38 mmol) were added to asolution of tris[3,5-bis(trifluoromethy)phenyl]borane (9) (8.1 mg, 12.5 mumol) in 1 mL of anhydrous1,4-dioxane. The reaction mixture was stirred at 25 or 100 C for 12 h. An internal standard (biphenylor mesitylene) was added to the reaction mixture and filtrated through a cotton plug. The resultingsolution was analyzed with gas chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Preparation 1 : ethyl 3-cyclopentylacrylate; Sodium ethoxide 21 wt% in ethanol (600 ml_, 1.6 mol) was added dropwise over 1 hour to a O0C solution of triethyl phosphonoacetate (343 g, 1.5 mol) in 2- methyltetrahydrofuran (3.1 L). The reaction was allowed to stir for 30 min and cyclopentancarboxaldehyde (163 ml_, 1.5 mol) was added dropwise over 1 h. The reaction was then allowed to warm to room temperature for 16 h. The reaction mixture was filtered through celite to remove insolubles. The filtrate was extracted 3 times with water (750 ml_), 3 times with saturated aqueous sodium bicarbonate (750 ml_), and 2 times with saturated aqueous ammonium chloride (500 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to an orange oil. The crude oil was purified via silica chromatography using 5% ethyl acetate in heptane to yield the title compound (218.6 g, 83%) as colorless oil. 1H NMR (400 MHz, DMSO-dbeta) delta ppm 1.12 (1 H, d, J=5.9 Hz), 1.21 (1 H, m), 1.20 (2 H, t, J=7.0 Hz), 1.34 (1 H, ddd, J=12.3, 5.9, 2.1 Hz), 1.56 (1 H, dt, J=7.3, 3.6 Hz), 1.64 (1 H, ddd, J=8.8, 4.7, 4.5 Hz), 1.80 (2 H, m), 1.93 (1 H, m), 2.60 (1 H, m, J=8.0, 8.0, 8.0, 8.0, 7.8 Hz), 3.31 (1 H, s), 4.10 (2 H, q, J=7.0 Hz), 5.82 (1 H, d, J=15.6 Hz), 6.86 (1 H, dd, J=15.6, 7.8 Hz) | |
83% | Sodium ethoxide 21 wt% in ethanol (600 mL, 1.6 mol) was added dropwise over 1 h to a 0 oC solution of triethyl phosphonoacetate sup-1 (343 g, 1.5 mol) in 2-methyltetrahydrofuran (3.1 L). The reaction was allowed to stir for 30 min and cyclopentanecarboxaldehyde (163 mL, 1.5 mol) was added dropwise over 1 h. The reaction was then allowed to warm to room temperature for 16 h. The reaction mixture was filtered through Celite to remove insoluble materials. The filtrate was extracted 3 x water (750 mL), 3 x saturated aqueous sodium bicarbonate (750 mL), and 2 x saturated aqueous ammonium chloride (500 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give an orange oil. The crude oil was purified via silica chromatography using 5% ethyl acetate in heptane to yield sup-2 (218.6 g, 83%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) delta 6.86 (1H, dd, J=15.6, 7.8 Hz), 5.82 (1H, d, J=15.6 Hz), 4.10 (2H, q, J=7.0 Hz), 3.31 (1H, s), 2.60 (1H, m), 1.93 (1H, m), 1.80 (2H, m), 1.64 (1H, ddd, J=8.8, 4.7, 4.5 Hz), 1.56 (1H, dt, J=7.3, 3.6 Hz), 1.34 (1H, ddd, J=12.3, 5.9, 2.1 Hz), 1.20 (2H, t, J=7.0 Hz), 1.21 (1H, m), 1.12 (1H, d, J=5.9 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Step 1. (2E)- and (2Z)-3-Cyclopentylacrylonitrile To a solution of 1.0 M potassium tert-butoxide in THF (235 mL) at 0 °C was added dropwise a solution of diethyl cyanomethylphosphonate (39.9 mL, 0.246 mol) in THF (300 mL). The cold bath was removed and the reaction was warmed to room temperature followed by recooling to 0 °C, at which time a solution of cyclopentanecarbaldehyde (22.0 g, 0.224 mol) in THF (60 mL) was added dropwise. The bath was removed and the reaction warmed to ambient temperature and stirred for 64 hours. The mixture was partitioned between diethyl ether and water, the aqueous was extracted with three portions of ether, followed by two portions of ethyl acetate. The combined extracts were washed with brine, then dried over sodium sulfate, filtered and concentrated in vacuo to afford a mixture containing 24.4 g of olefin isomers which was used without further purification (89percent). 1H NMR (400 MHz, CDCl3): delta 6.69 (dd, 1H, trans olefin), 6.37 (t, 1H, cis olefin), 5.29 (dd, 1H, trans olefin), 5.20 (d, 1H, cis olefin), 3.07-2.95 (m, 1H, cis product), 2.64-2.52 (m, 1H, trans product), 1.98-1.26 (m, 16H). | |
67% | Under ice-cooling conditions, 5.9g of diethyl cyanomethylphosphonate was dissolved in 100mL anhydrous tetrahydrofuran. 5.6g of potassium tert-butoxide was added portionwise in the solution and was stirred at room temperature for three hours. The temperature was reduced to 0°C and cyclopentanecarbaldehyde was added dropwise to the reaction solution and reacted overnight at room temperature. TLC was used to monitor reaction completion. 100ml of saturated ammonium chloride solution was added to quench the reaction. After distilling off the solvent, the residue was extracted with ethyl acetate then washed with water. The organic phase was washed with 100mL each of saturated sodium chloride solution 3 times. The organic phase was dried over anhydrous anhydrous magnesium sulfate overnight. The mixture was filtered and the solvent was distilled off under reduced pressure to give a crude product. The product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:1) to give 2.5g of intermediate 5a as a colorless liquid, yield: 67percent. | |
46% | With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 49h; | To a solution of Potassium t-butoxide (1.23 g, 10.37 mmol) in THF (20 mL) at 0 °C was added diethyl cyanomethylphosphonate 34b (1.96 g, 10.87 mmol) dropwise over a period of 10 mins. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C and added a solution ofcyclopentanecarbaldehyde 34a (0.97 g, 9.88 mmol) in THF (10 mL). The reaction mixture was allowed to warm to room temperature and stirred for 48 h. The reaction was diluted with water (10 mL and extracted with ethyl acetate (3 x 30 ml). The ethyl acetate layers were combined and washed with brine (25 ml), dried concentrated in vacuum. The residue obtained was purified by flash column chromatography (silica gel 20 g, eluting with 0-50percent ethyl acetate in hexane) to furnish 3-cyclopentylacrylonitrile 34c (0.55 g, 46percent) as a colorless oil; 1HNMR (300 MHz, DMSO) delta 6.85 (dd, J= 8.1, 16.3, 0.4H), 6.66 - 6.51 (m, 0.6H), 5.67 (dd, J= 1.2, 16.3, 0.4H), 5.56 (dd, J= 0.6, 10.8, 0.6H), 2.86 (dq, J= 8.1, 16.5, 0.6H), 2.60 (dt, J= 8.3, 16.7, 0.4H), 1.79 (m, 2H), 1.70 - 1.50 (m, 4H), 1.42 - 1.29 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With 1-hydroxycyclohexyl phenyl ketone; sodium hydroxide In 1,2-dimethoxyethane at 80℃; Sealed tube; chemoselective reaction; | |
95% | With Co4HP2Mo15V3O62; N-(4-sulfonic acid)butyl triethylammonium tetrafluoroborate; dihydrogen peroxide In lithium hydroxide monohydrate at 20℃; for 2h; Green chemistry; | |
88% | With 2-mesityl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium tetrafluoroborate; 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine In acetonitrile at 20℃; |
84% | With NHPI; oxygen In acetonitrile at 30℃; for 3h; Schlenk technique; | 10 Example 10: Synthesis of cyclopentanoic acid 5 mol% NHPI was added to a 25 mL Schlenk reaction tube, dried under vacuum for 15 minutes, and oxygen was bubbled in an oxygen atmosphere.2 mL of acetonitrile and 1.0 equivalent of cyclopentyl formaldehyde were added in this order, and an oxygen balloon was connected, and a glass stopper was placed on the reaction tube.Into the oil bath, react at 30 ° C for 3 h. After the reaction is completed, it is concentrated under reduced pressure and separated by column chromatography. The eluent is petroleum ether / ethyl acetate /Dichloromethane (v: v: v = 2: 1:1) gave cyclopentanoic acid. Yield 84%, yellow liquid; |
84% | With NHPI; oxygen In acetonitrile at 30℃; for 3h; Schlenk technique; | |
With poly[4-(diacetoxyiodo)styrene]; 2,2,6,6-tetramethyl-1-piperidinyloxy free radical In propan-2-one at 20℃; for 24h; | ||
With 4-acetylamino-2,2,6,6-tetramethyl-1-piperidinoxy In acetonitrile at 20℃; Electrolysis; | ||
With NHPI; oxygen In lithium hydroxide monohydrate; acetonitrile at 100℃; for 0.2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | General procedure: To a round bottom flask was added DCM (20 mL), aniline (8 mmol) and aldehyde (8 mmol). The resulted solution was stirred at room temperature for 4 h. Then, NaBH(OAc)3 (16 mmol) was added. The suspension was stirred at room temperature. After the complete consumption of aniline (monitored by TLC), the reaction mixture was diluted with DCM (10 mL), and washed with saturated aqueous sodium carbonate (3×10 mL) and water (2×10 mL). Then, the organic layer was washed with saturated brine and dried over anhydrous Na2SO4. The product was obtained using silica gel flash chromatography column. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: aqueous Ca(OH)2 2: phosphorus (III)-bromide / 150 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: diethyl ether 2: chromic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: Zn, I2 / benzene; diethyl ether 2: H2 / Pd-C / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; lithium bromide; In tetrahydrofuran; at 20℃; for 16h; | A solution of cyclopentanecaboxaldehyde (0.069 g, 0.70 mmol), benzyl (diethylethyl phosphono) acetate (0.100 g, 0.35 mmol), lithium bromide (0.030 g, 0.35 mmol), and triethylamine (0.049 mL, 0.35 mmol) in THF (1 mL) at room temperature was stirred for 16 hours, quenched with water, stirred for 15 minutes, diluted with ethyl acetate, washed sequentially with pH 7 buffer and brine, dried [(MGS04),] filtered, and concentrated to provide the desired product. MS [(ESI)] m/e 231 [(M+H) +.] | |
With triethylamine; lithium bromide; In tetrahydrofuran; at 20℃; for 16h; | benzyl (2E)-3-cyclopentylacrylate A solution of cyclopentanecaboxaldehyde (0.069 g, 0.70 mmol), benzyl (diethylethyl phosphono)acetate (0.100 g, 0.35 mmol), lithium bromide (0.030 g, 0.35 mmol), and triethylamine (0.049 ML, 0.35 mmol) in THF (1 ML) at room temperature was stirred for 16 hours, quenched with water, stirred for 15 minutes, diluted with ethyl acetate, washed sequentially with PH 7 buffer and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI) m/e 231 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid; In dichloromethane;Molecular sieve; | A solution of (11 (3, 16A)-11, 16,17, 21-tetrahydroxypregna-1, 4-DIENE-3, 20-dione (300mg), cyclopentanecarboxaldehyde (126mg), and PARA-TOLUENESULPHONIC ACID (96mg) in DICHLOROMETHANE (5ML) was stirred in the presence of molecular sieves (300mg) overnight. Saturated sodium bicarbonate solution (5ML) was added and the organic phase was separated using a phase separating cartridge and then evaporated to dryness. The residue (166mg) was purified on a Waters Spherisorb S5W 20x250mm preparative HPLC column, eluting with 70% ethyl acetate/ methanol/0. 880 ammonia (60: 0.5 : 0.5) : 30% heptane. and a flow rate of 20ml/min. Appropriate fractions were combined and evaporated to give 5mg of the (S) isomer product and 28mg of the (R) isomer product (examples 1 and 2 respectively). Compounds were analysed by'H NMR in CDCI3 and the stereochemistry at the 22 position was assigned.; General Chromatographic purification was performed on a Waters Spherisorb S5W 20x250mm preparative HPLC column, eluting with 45% to 70% ethyl acetate/methanol/0. 880 ammonia (60: 0.5 : 0.5) : 30 to 55% heptane mixtures and a flow rate of 20ML/MIN. Appropriate fractions were combined and evaporated to provide purified product. LCMS was conducted on a Luna C18 (2) 2x150mm 3um column eluting with water (solvent A), acetonitile (solvent B) and 2% TFA in water (solvent C) using the following elution gradient 0 min 70% A, 25% B and 5% C to 20 min 35% A, 60% B and 5% C at a flow rate of 0.3 ML/MIN and a column temperature of 30C. An injection volume of 5TL was used and UV detection was at 245nm. The mass spectra were recorded on a Fisons VG Plafform spectrometer using ELECTROSPRAY positive and negative mode (ES+ve and ES-ve). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.4% | Prep(167a): (21(at)-4-(tert-butoxycarbonyl)-1-(cyclopentylmethyl)piperazine-2-carboxylic acid In a round bottom flask, <strong>[192330-11-3](2R)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid</strong> (1.50 g, 6.52 mmol) in THF (20 mL) was dissolved, then cyclopentanecarbaldehyde (0.70 mL, 7.62 mmol) with acetic acid (1.20 mL) was added and then stirred for 0.5 hours. Next, NaBH(OAc)3 (2.07 g, 9.77 mmol) was added over 5 minutes and then stirred for 12 hours. The mixture was filtered though a cellose filter. The mother liquid was concentrated and placed on the high vacuum to afford (2R)-4-(tert-butoxycarbonyl)-1- (cyclopentylmethyl)piperazine-2-carboxylic acid as a white solid (1.98 g, 97.4%). 1 H NMR (400 MHz, DMSO-d6) No. ppm: 3.48-3.40 (m, 1 H), 3.36-3.25 (m, 2H), 3.12-3.00 (m, 2H), 2.28-2.24 (m, 1 H), 2.17 (bs, 1H), 2.08-2.08-2.01 (m, 1H), 1.69-1.59 (m, 2H), 1.55-1.44 (m, 4H), 1.38 (s, 9H), 1.35-1.20 (m, 2H), 1.14- 1.06 (m, 1 H). LCMS (ESI) : m/z. 313.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.5% | Stage #1: 3-amino-3-isopropyl-1-(4-trifluoromethylphenyl)-propenone; spiro[3.5]nonane-6,8-dione With trifluoroacetic acid In di-isopropyl ether at 20℃; for 0.166667h; Stage #2: cyclopentanealdehyde In di-isopropyl ether for 18h; Heating / reflux; water collecting trap; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | Stage #1: 3-amino-3-cyclopentyl-1-(4-trifluoromethylphenyl)-propenone; spiro[2.5]octane-5,7-dione With trifluoroacetic acid In di-isopropyl ether at 20℃; for 0.166667h; Stage #2: cyclopentanealdehyde In di-isopropyl ether for 18h; Heating / reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With pyrrolidine; In methanol; at 20 - 55℃; | Preparation 36; N-(6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide; A mixture of 6-acetamido-i-tetralone (Ryan Scientific) (200 mg, 0.98 mmol) and cyclopentanecarboxaldehyde (0.21 ml_, 1.9 mmol) in methanol (2 mL) was treated with pyrrolidine (0.25 mL, 2.9 mmol) at room temperature for 1 hour then heated at 55 0C overnight. The mixture was cooled to room temperature, treated with 1N hydrogen chloride (4 mL) was filtered thru a Chem Elute tube (CE101 1) eluting with 90% dichloromethane / 10% ethyl acetate and condensed filtrate to give (E)-N-(6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (200 mg, 0.71 mmol, 72%n yield) as a tan foam. 1H NMR (400 MHz, DMSOd6) delta ppm 1.25 - 1.44 (m, 2 H), 1.52 - 1.76 (m, 4 H), 1.77 - 1.90 (m, 2H), 2.08 (s, 3 H), 2.70 - 2.92 (m, 5 H), 6.63 (d, J=9.67 Hz, 1 H), 7.49 (dd, J=8.59, 2.15 Hz, 1 H), 7.59 - 7.66 (m, 1 H), 7.86 (d, J=8.59 Hz, 1 H), 10,23 (s, 1 H). ES-MS m/z 284 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With pyrrolidine In methanol at 20℃; for 20h; | 18 methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate; To a solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (3.4 g, 16.7 mmol) in methanol (30 mL) was added cyclopentanecarboxaldehyde (3.3 g, 33.3 mmol) and pyrrolidine (2.78 mL, 33.3 mmol). The solution was stirred for twenty hours at ambient temperature. The reaction was recharged with 0.5 mL of cyclopentanecarboxaldehyde. The resulting precipitate was collected by vacuum filtration to provide methyl 6-(cyclopentylmethylene)-5-oχo-5,6,7,8- EPO tetrahydroϖaphthalene-2-carboxylate as a solid (2.8 g, 60% yield). LC/MS on4.6x50mm C-18 column, tR = 6.71 minutes (10 to 90% acetonitrile/water over 8 minutes at 2 mL/minute with detection 254 nm, at 50 0C); ES-MS m/z 285 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 - 1.39 (m, 2 H), 1.52 - 1.74 (m, 4 H), 1.76 - 1.89 (m, 2 H), 2.77 (t, J=5.77 Hz, 2 H), 2.79 - 2.90 (m, 1 H), 2.97 (t, J=6.44 Hz, 2 H), 3.85 (s, 3 H)1 6.71 (d, J=9.94 Hz, 1 H), 7.88 (d, J=6.44 Hz, 1 H), 7.91 (s, 1 H)1 7.98 (d, J=8.06 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 12h; | A solution of N-ethyl -6 -methoxy-2-[(methoxymethoxy)methyl]pyridin-3-amine (7.20 g, 31.8 mmol) and cyclopentane carbaldehyde (3.75 g, 38.2 mmol) in 1,2-dichloroethane (240 mL) was added with sodium triacetoxyborohydride (88.75 g, 41.3 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was added with water, and extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate; and concentrated under reduced pressure. The resulting residue was purified by using silica gel column chromatography (hexane:ethyl acetate = 8:1) to obtain N-(cyclopentylmethyl)-N-ethyl-6-methoxy-2-[(methoxymethoxy)methyl]pyridin-3-amine (8.39 g, 86%) as pale yellow oil. 1H-NMR (400 MHz, CDCl3) delta : 0.94 (3H, t, J = 7.1 Hz), 1.05-1.23 (2H, m), 1.34-1.70 (6H, m), 1.82 (1H, m), 2.78 (2H, d, J = 7.5 Hz), 2.90 (2H, q, J = 7.1 Hz), 3.47 (3H, s), 3.93 (3H, s), 4.76 (2H, s), 4.85 (2H, s), 6.67 (1H, d, J = 8.8 Hz), 7.46 (1H, d, J = 8.8 Hz) |
86% | With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 12h; | A solution of N-ethyl-6-methoxy-2-[(methoxymethoxy)methyl]pyridin-3-amine (7.20 g, 31.8 mmol) and cyclopentanecarbaldehyde (3.75 g, 38.2 mmol) in 1,2-dichloroethane (240 mL) was added with sodium triacetoxyborohydride (8.75 g, 41.3 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was added with water, and extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain N-(cyclopentylmethyl)-N-ethyl-6-methoxy-2-[(methoxymethoxy)methyl]pyridin-3-amine (8.39 g, 86%) as pale yellow oil. 1H-NMR (CDCl3) delta: 0.94 (3H, t, J=7.1 Hz), 1.05-1.23 (2H, m), 1.34-1.70 (6H, m), 1.82 (1H, m), 2.78 (2H, d, J=7.5 Hz), 2.90 (2H, q, J=7.1 Hz), 3.47 (3H, s), 3.93 (3H, s), 4.76 (2H, s), 4.85 (2H, s), 6.67 (1H, d, J=8.8 Hz), 7.46 (1H, d, J=8.8 Hz). |
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 12h; | A solution of 3-ethylamino-6-methoxy-2-(methoxymethyloxy)methylpyridine (7.20 g, 31.8 mmol) and cyclopentanecarboaldehyde (3.75 g, 38.2 mmol) in 1,2-dichloroethane (240 mL) was added with sodium triacetoxyborohydride (8.75 g, 41.3 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was added with water, and extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain 3-(N-cyclopentylmethyl-N-ethyl)amino-6-methoxy-2-(methoxymethyloxy)methylpyridine (8.39 g, 86%) as pale yellow oil.1H-NMR (CDCl3) delta: 0.94 (3H, t, J=7.1 Hz), 1.05-1.23 (2H, m), 1.34-1.70 (6H, m), 1.82 (1H, m), 2.78 (2H, d, J=7.5 Hz), 2.90 (2H, q, J=7.1 Hz), 3.47 (3H, s), 3.93 (3H, s), 4.76 (2H, s), 4.85 (2H, s), 6.67 (1H, d, J=8.8 Hz), 7.46 (1H, d, J=8.8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With hydroxylamine hydrochloride; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In ethyl acetate; N,N-dimethyl-formamide at 100℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | e) N-Benzyl-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-l-yll-2-cyclopentyl- acetamide; To a solution of 5.0 g (20.47 mmol) (2-amino-4,5-difluoro-phenyl)-carbamic acid tert- butyl ester (Example 73, intermediate g) in 50 ml methanol, 2.21 g (22.57 mmol) cyclopentanecarbaldehyde (commercially available) were added. After stirring for 5 min. at room temperature, 3.2 g (20.5 mmol) p-chlorobenzoic acid and 2.5 ml (20.47 mmol) benzyl isocyanide (commercially available) were added. After stirring for 19 h, 38.38 ml (153.52 mmol) 4 M hydrochloric acid in dioxane were added dropwise over 5 min. After 5 h the solution was poured on 500 ml saturated aqueous sodium bicarbonate solution and the phases were separated. The organic layer was extracted three times with ethyl acetate and the combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n- heptane : ethyl acetate (100 : 0 to 50 : 50). Light yellow foam (97%). MS (Turbo Spray): m/z = 480.1 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With hydrogen;palladium 10% on activated carbon; In ethyl acetate; under 760.051 Torr; for 3h; | Step 1: A mixture of nitrobenzene 40 (0.5 g, 1.6 mmol) and cyclopentanecarbaldehyde (0.15 ml, 1.6 mmol) in EtOAc was degassed and saturated with argon. 10% Pd/C (0.40 g) was added to this solution and the resulting mixture was stirred under H2 at 1 atm for 3 hrs. The reaction mixture was filtered through Celite, concentrated under reduced pressure. Purification by flash chromatography(40% to 50 % EtOAc - hexanes gradient) gave aniline 41 as a yellow semi-solid. Yield (0.4 g, 68%); 1H NMR (400 MHz, DMSO-J6) delta 7.86-7.80 (m, 4H), 6.90 (t, J = 8.0 Hz, IH), 6.36 (s, IH), 6.33 (d, J = 5.6 Hz, 2H), 5.40 (t, J = 5.6 Hz, IH), 3.59 (t, J= 7.2 Hz, 2H), 2.86 (t, J= 6.4 Hz, 2H), ), 2.50-2.45 (m, 2H), 2.09 (quintet, J= 7.6 Hz, IH), 1.86 (quintet, J= 7.6 Hz, 2H), 1.76-1.72 (m, 2H), 1.57-1.47 (m, 4H), 1.23-1.08 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | A solution of 0.87 ml of cyclopentanecarboxaldehyde (8.15 mmol; Aldrich) in 10 ml of tetrahydrofuran is added to 18 ml of a commercially available 0.5 M solution of ethynylmagnesium bromide in tetrahydrofuran (10 mmol, Aldrich) cooled beforehand to 0 C. The mixture is then stirred for 2 hours at ambient temperature and a saturated solution of NH4Claq is added. The mixture is extracted with ethyl acetate and the organic phases are then combined, washed with a saturated solution of NaClaq, dried over sodium sulphate, filtered, and concentrated under vacuum. 0.931 g of (+-)-1-cyclopentylprop-2-yn-1-ol is obtained in the form of a light brown oil with a yield of 92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-amino-3-cyclopentyl-1-(4-trifluoromethylphenyl)-propenone; spiro[3.5]nonane-6,8-dione With trifluoroacetic acid at 20℃; for 0.166667h; Stage #2: cyclopentanealdehyde at 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With C64H94N6O4S2; In dichloromethane; at 20℃; | General procedure: In a typical experiment, a,a-disubstituted aldehyde(0.40 mmol), maleimides (0.20 mmol), and catalyst (0.03 mmol,15 mol%) in CH2Cl2 (0.5 mL) were stirred magnetically at room temperatureuntil the maleimide was consumed (monitored by TLC).The corresponding product was obtained after column chromatography(silica gel, eluent n-hexane/EtOAc). The enantiomeric excessof the products was determined by chiral HPLC analysis using chiralcolumns. All products were identified by spectroscopic data. Racemicsamples of the Michael adducts were prepared using racemiccatalyst. Compounds 6a'-6i' , 6m' and 6r' are known. The analyticaland spectroscopic data are in accordance with those reported. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With pyrrolidine In methanol at 20℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With pyrrolidine; In methanol; at 0 - 20℃;Inert atmosphere; | Step 2: methyl 6-(3-cyclopentylacryloyl)-2-methoxynicotinate; To a solution of methyl 6-acetyl-2-methoxynicotinate (1.2g, 5.74mmol) and cyclopentanecarboxaldehyde (1.22mL, 11.5mmol) in methanol (3OmL) at 0C under nitrogen was added pyrrolidine (0.58OmL, 6.88mmol). After 10 min, the reaction was allowed to warm up to room temperature and stirred for 2 h. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, concentrated, and purified by silica gel column chromatography eluting with a gradient of 0%-20% ethyl acetate/ heptane to obtain the title compound as a solid (0.38g, 69%). 1 H NMR (500 MHz, CHLOROFORM-d) delta ppm 1.27 (1 H, t, J=7.1 Hz), 1.50 (1 H, m), 1.51 (1 H, dd, J=7A, 5.0 Hz), 1.58 (3 H, s), 1.67 (1 H, td, J=7.6, 3.2 Hz), 1.75 (1 H, m), 1.92 (1 H, m), 2.77 (1 H, m, J= 8.1 Hz), 3.94 (3 H, s), 4.14 (2 H, s), 7.23 (1 H, dd, J=15.6, 8.3 Hz), 7.48 (1 H, m), 7.75 (1 H, d, J=7.8 Hz), 8.28 (1 H, d, J=7.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With dmap; (1R,2R)-trans-1-amino-2-(2-hydroxybenzamide)cyclohexane; In dichloromethane; at 20℃; for 48h; | General procedure: To a solution of 10, 11, ent-11 or 15 (0.04 mmol), the nitroalkene 13 (0.2 mmol) and DMAP (7.3 mg,0.06 mmol) in CH2Cl2 (0.3 mL) was added the aldehyde 12 (0.4 mmol) and the mixture was stirredat rt until completion (TLC). The reaction was quenched with HCl 2N (10 mL) and the mixture wasextracted with AcOEt (3 10 mL). The organic phase was washed with sat. NaHCO3 (2 10 mL),dried over MgSO4, and the solvent was evaporated (15 Torr) to get the crude product, which waspurified by silica gel chromatography (n-hexane/AcOEt gradients). Known adducts 14 were identifiedby comparison of their NMR data with those of the literature (Supplementary Materials NMR spectra).Their enantiomeric excesses were determined by chiral HPLC using the conditions described in eachcase (Supplementary Materials HPLC chromatograms). Not described compounds 14ad and 14aehave been fully characterized. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium <i>tert</i>-butylate / tetrahydrofuran / 49 h / 0 - 20 °C 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 20 °C 3: potassium acetate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 3 h / 120 °C / microwave | ||
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / 0 °C / Inert atmosphere 1.2: 1 h / 0 - 20 °C / Inert atmosphere 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 18 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: cyclopentanealdehyde; (R)-1-(1-Naphthyl)ethylamine In dichloromethane at 20℃; for 0.5h; Molecular sieve; Stage #2: 1-(trimethylsiloxy)-1-methoxy-1,3-butadiene With tin(II) trifluoromethanesulfonate In dichloromethane at -78 - -30℃; optical yield given as %de; diastereoselective reaction; | General procedure for 'One-pot' vinylogous Mannich reactions: (S,E)-methyl 5-((R)-1-(naphthalen-1-yl)ethylamino)-5-cyclohexylpent-2-enoate (4a): To a round-bottomed flask containing (R)-1-naphthalen-1-yl-ethylamine (3) (186 mg, 1.1 mmol, 1.1 equiv) in dried DCM (0.1 M) solution added 4AMS (500 mg/mmol) followed by cyclohexane-carbaldehyde (2a) (112 mg, 1 mmol, 1 equiv). After stirring at room temperature for 30 mins, (1-methoxy-buta-1,3-dienyloxy)-trimethyl-silane (1) (258 mg, 1.5 mmol, 1.5 equiv) was added and the mixture solution was cooled to -78 °C. Tin (II) triflate (412 mg, 1 mmol, 1 equiv) was then added and the reaction was stirred at this temperature for 8 h. The reaction temperature was raised to -30 °C and kept at the same temperature overnight. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate and removed the solid via filtration. The reaction mixture was then extracted with ethyl acetate (15 ml × 5). The combined organic phase was dried over sodium sulfate. After concentration, the crude product was purified by silica gel chromatography (ethyl acetate/hexane = 5/1) to afford the product (258 mg, 71% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.6% | With piperidine; pyridine; at 20 - 80℃; for 6h; | Step 1: 3-cyclopentyl Acrylic Acid 660 mL of cyclopentanecarbaldehyde and 500 g of malonic acid were added to 1 L of pyridine, and 13.4 mL of piperidine was added dropwise thereto and the resulting mixture was stirred at room temperature to react for 1 hour. Then the temperature was raised to 80 C. and the stirring was continued for 5 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to distill off the pyridine, and then 2.6 L of purified water was added thereto and the pH was adjusted to 2?5 with concentrated hydrochloric acid. Then, the resulting mixture was extracted with ethyl acetate (1.7 L*3), and the organic layers were combined, and washed sequentially with 1 L of water and 1L of saturated brine. To the combined organic layer was added 4 L of 9% sodium hydroxide (1.3 L*3) and stirred, and the aqueous layers were combined and cooled down to 0?5 C., and then concentrated hydrochloric acid was added dropwise thereto to adjust the pH to 2?5 and the resulting mixture was extracted by adding 2.6 L of ethyl acetate. The aqueous layer was washed with ethyl acetate (1.3 L*2), and the organic layers were combined, washed with 2.6 L of purified water and then with 2.6 L of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-cyclopentyl acrylic acid (650 g, 96.6%). 1H-NMR (500 MHz, CDCl3): delta=11.24 (bs, 1H), 7.08 (dd, J=15.6, 8.0 Hz, 1H), 5.81 (dd, J=15.5, 1.2 Hz, 1H), 2.64 (dd, J=8.1, 7.6 Hz, 1H), 1.92?1.81 (m, 2H), 1.71 (ddq, J=12.5, 6.5, 2.9 Hz, 2H), 1.68?1.58 (m, 2H), 1.48?1.37 (m, 2H); MS (ES):141.09 (M+H+). |
93% | With piperidine; pyridine; at 20 - 80℃; for 9h; | Cyclopentyl-carbaldehyde (344.4 g, 3.51 mol, 1.17 eq.) was added dropwise to a solution of 5M propandioic acid (312 g, 3.0 mol, 1.0 eq.) in pyridine at room temperature. After the completion of the addition, the resulting mixture was stirred for 10 minutes. Then, piperidine (6.2 g, 0.075 mol, 0.025 eq.) was slowly added dropwise. After the completion of the addition, the resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was heated to 70 C to 80 C, stirred for 8 hours, and concentrated under reduced pressure to evaporate the solvent. The residue was adjusted with concentrated hydrochloric acid to pH 3.0, and extracted with ethyl acetate three times. The organic phases were combined, and washed with 2.5M sodium hydroxide solution five times. The aqueous phase was adjusted with concentrated hydrochloric acid to pH 3.0, and extracted with ethyl acetate three times. The organic layers were combined, washed with water three times, washed with saturated salt solution, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-cyclopentyl-acrylic acid (391.2 g, yield: 93 %). 1H NMR (500 MHz, CDCl3) delta:7.08 (dd, J=15.6, 8.1 Hz, 1H), 5.81 (dd, J=15.6, 1.1 Hz, 1H), 11.25 (s, 1H), 2.64 (m, 1H), 1.63 (m, 2H), 1.42 (m, 2H), 1.86 (m, 2H), 1.72 (m, 2H); HRMS (ESI) calcd. for C8H12O2[M-H]- 139.0765; Found: 139.0760. |
93% | With piperidine; In pyridine; at 20 - 80℃; for 9h; | To a 5M solution of malonic acid (312 g, 3.0 mol, 1.0 eq.) in pyridine was added cyclopentanecarbaldehyde (344.4 g, 3.51 mol, 1.17 eq.) drop-wise at room temperature and stirred for 10 minutes; and then piperidine (6.2 g, 0.075 mol, 0.025 eq.) was slowly added drop-wise, and the reaction was stirred for additional 1 hour at room temperature. The reaction was warmed to 70?80 C. and stirred for 8 hours. The reaction mixture was concentrated under reduced pressure to evaporate the solvent, and the resulting residue was adjusted to pH 3.0 with the concentrated hydrochloric acid, and extracted with ethyl acetate three times. The organic phase was combined and washed with a 2.5M sodium hydroxide solution five times. The aqueous layer was adjusted to pH 3.0 with the concentrated hydrochloric acid and extracted with ethyl acetate three times. The organic layer was combined, washed with water three times, then washed with a saturated brine solution, dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure to afford 3-cyclopentylacrylic acid (391.2 g, yield: 93%). 1H NMR (500 MHz, CDCl3): delta 7.08 (dd, J=15.6, 8.1 Hz, 1H), 5.81 (dd, J=15.6, 1.1 Hz, 1H), 11.25 (s, 1H), 2.64 (m, 1H), 1.63 (m, 2H), 1.42 (m, 2H), 1.86 (m, 2H), 1.72 (m, 2H); HRMS (ESI) calcd. for C8H12O2[M-H]- 139.0765; Found: 139.0760. |
General procedure: To a stirred solution of cyclohexanecarboxyaldehyde (400 mL, 3.30 mmol) in pyridine (750 mL) were added malonic acid (290 g, 2.78 mol) and piperidine (7.5 mL, 75 mmol) at room temperature. After being stirred at ambient temperature for 1 h, the reaction mixture was heated at 80 C for 5 h, cooled to room temperature, poured into ice-cooled 3.0 M aqueous hydrochloric acid (1.2 L) and extracted with ethyl acetate. The organic layer was extracted with 2.0 M sodium hydroxide. The aqueous layer was washed with ethyl acetate, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to yield the title compound (442 g, 100%) as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With C64H94N6O4S2; In dichloromethane; at 20℃; | General procedure: In a typical experiment, a,a-disubstituted aldehyde(0.40 mmol), maleimides (0.20 mmol), and catalyst (0.03 mmol,15 mol%) in CH2Cl2 (0.5 mL) were stirred magnetically at room temperatureuntil the maleimide was consumed (monitored by TLC).The corresponding product was obtained after column chromatography(silica gel, eluent n-hexane/EtOAc). The enantiomeric excessof the products was determined by chiral HPLC analysis using chiralcolumns. All products were identified by spectroscopic data. Racemicsamples of the Michael adducts were prepared using racemiccatalyst. Compounds 6a'-6i' , 6m' and 6r' are known. The analyticaland spectroscopic data are in accordance with those reported. |
95% | With 2-([(1R,2R)-2-aminocyclohexyl]amino}[3,5-bis(trifluoromethyl)benzyl]amino}methylidene)-2,3-dihydro-1H-indene-1,3-dione; benzoic acid; In para-xylene; at 40℃; for 48h; | General procedure: To a solution of N-phenylmaleimide 4a (34.6 mg, 0.200 mmol) and acetone (73.4 muL, 1.00 mmol) in p-xylene (0.4mL) were added organocatalyst 3 (20.5mg, 0.040 mmol) and benzoic acid (2.5 mg, 0.020 mmol) at room temperature. After stirring in a closed tube at 40C for 48 h, the reaction mixture was directly purified by flash column chromatography on silica gel with a 3:2-1:1 mixture of hexane and AcOEt to afford 5a (37.3 mg, 81%) as a white powder. 4.3.18 (R)-1-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)cyclopentane-1-carbaldehyde 5r 4b [alpha]D19 = -12.7 (c 1.0, CHCl3). 91% ee; Enantiomeric excess was determined by HPLC with ChiralCel OD-H column (hexane/2-propanol = 75:25), flow rate = 0.5 mL/min; lambda = 210 nm; tmajor = 50.6 min, tminor = 35.9 min. |
92% | With 1-[(1R,2R)-2-aminocyclohexyl]-3-[4-(n-perfluorooctyl)phenyl]-thiourea; benzoic acid; In dichloromethane; at 20℃; for 76h; | General procedure: To a solution of 7a (277 mg, 1.60 mmol) and fluorous organocatalyst 3 (107 mg, 0.160 mmol) in 20 mL of CH2Cl2 was added isobutyl aldehyde (293 muL, 3.20 mmol) at room temperature. After stirring at room temperature for 22 h, the reaction mixture was evaporated under reduced pressure. Then, a 1:1 mixture of hexane and chloroform was added to the residue. The precipitated fluorous organocatalyst 3 was filtered, and washed with a 1:1 mixture of hexane and chloroform. The collected 3 was dried under reduced pressure, and was used in the next step without further purification. The filtrate was evaporated, and the residue was purified by flash column chromatography on silica gel with a 2:1 mixture of hexane and AcOEt to afford the pure 8a (343 mg, 87%) as a colorless powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sulfuric acid; In benzene; at 45℃; for 4.5h;Reflux; | The general procedure for the acid catalyzed robinson annulation reaction is as follows: Carbaldehyde (10 mmol), but-3-en-2-one (10 mmol) was refluxed in benzene (10 ml) with catalytic amount H2SO4 (0.05 ml) in a round bottom flask equipped with Dean-Stark trap. The mixture was first heated to 45 C. for 1.5 hrs, and then increased to reflux until no more H2O condensed from the reaction mixture (1.5 hr). Another equivalent of bu-3-2-one (10 mmol) was added and refluxed for an additional 1.5 hrs. The mixture was cooled down and 20 ml of 1M NaHCO3 was added and the organic phase was separated. The aqueous phase was extracted with benzene, and the combined organic phase was washed with brine and dried over MgSO4. The solid was filtered, and concentrated in vacuo to give crude dark brown oil which was separated by flash column chromatography (Ethyl acetate/Hexane=15% to 25%) to give spiro enone as yellow oil.Spiro[4.5]dec-6-en-8-one (65% Yield) 1H-NMR (360 MHz, CDCl3) delta 6.74 (d, J=7.2 Hz, 2H), 5.84 (d, J=7.2 Hz, 2H), 2.44 (t, J=7.2 Hz, 2H), 1.89 (t, J=7.2 Hz, 2H), 1.76-1.67 (m, 8H); 13C-NMR (90 MHz, CDCl3) delta 200.19, 159.78, 126.76, 44.32, 38.31, 35.59, 34.15, 24.73; ESI-MS: Calculated for C10H14O (M+H)+151.2. Found: 151.3 |
With sulfuric acid; In toluene; at 45℃; for 3.5h;Reflux; Dean-Stark; | (0451) To a solution of cyclopentanecarbaldehyde (Aldrich) (0.82 g, 8.36 mmol) in dry toluene (10 mL), methyl vinyl ketone (Alfa Aesar) (0.684 mL, 8.36 mmol) was added followed by a catalytic amount of concentrated H2SO4 (0.045 mL, 0.836 mmol). The mixture was heated at 45 C. for 1.5 hours, then refluxed for 1 hour using a Dean-Stark trap. The reaction mixture was cooled to room temperature and further methyl vinyl ketone (Alfa Aesar) (0.684 mL, 8.36 mmol) was added. The reaction mixture was heated at reflux for 1 hour, allowed to cool to room temperature and treated with an aqueous 1M NaHCO3 (30 mL) solution. The aqueous was extracted with toluene and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-20% EtOAc in iso-hexane afforded the title compound; (0452) 1H NMR (400 MHz, CDCl3) delta 6.74 (1H, d), 5.86 (1H, d), 2.45 (2H, t), 1.92 (2H, t), 1.80-1.71 (4H, br mults), 1.71-1.61 (4H, br mults). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With copper(II) sulfate; In 1,2-dichloro-ethane; at 60℃;Inert atmosphere; | General procedure: To a 20 ml scintillation vial (S)-(-)-2-Methyl-2-propanesulfinamide (0.36 g, 3mmol, 1 eq.), aldehyde (6 mmol, 2 eq.), copper(II) sulfate (1.43g, 9 mmol, 3 eq.) and 10 ml dichloroethane was added. The vial is then capped and placed on reaction block. The mixture is heated up to 60 C and stirred for overnight. The resulting mixture is filtered through celite. After evaporating solvent under reduced pressure,the blue colored residue is subjected to column chromatography using dichloromethane/methanol as eluent to afford the product in 69-99% yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyrrolidine In chloroform at 40℃; | ||
With para-methylbenzylamine In toluene at 25℃; | ||
With racemic primary amine thiourea organocatalyst In dichloromethane at 20℃; | Representative procedure for the Michael addition General procedure: In a typical experiment, a,a-disubstituted aldehyde(0.40 mmol), maleimides (0.20 mmol), and catalyst (0.03 mmol,15 mol%) in CH2Cl2 (0.5 mL) were stirred magnetically at room temperatureuntil the maleimide was consumed (monitored by TLC).The corresponding product was obtained after column chromatography(silica gel, eluent n-hexane/EtOAc). The enantiomeric excessof the products was determined by chiral HPLC analysis using chiralcolumns. All products were identified by spectroscopic data. Racemicsamples of the Michael adducts were prepared using racemiccatalyst. Compounds 6a'-6i' , 6m' and 6r' are known. The analyticaland spectroscopic data are in accordance with those reported. |
With para-methylbenzylamine In toluene at 25℃; | ||
With para-methylbenzylamine In toluene at 20℃; | General procedure: Reference racemic samples of adducts 10 were obtained by performing the reaction using 4-methylbenzylamine (20mol%) as the organocatalyst in toluene as the solvent at room temperature. | |
With para-methylbenzylamine In toluene at 25℃; for 30h; | ||
With 3-Amino-3-phenylpropionic acid; potassium hydroxide In dichloromethane at 20℃; for 48h; | ||
With para-methylbenzylamine In toluene at 20℃; | 3.1. General Information General procedure: All of the reagents and solvents employed were of the best grade available and were used withoutfurther purification. The 1H spectra were recorded at room temperature on a Bruker Oxford AV300at 300 MHz, using TMS as the internal standard. Absolute configuration for adducts 18 was determinedaccording to the order of elution of their enantiomers in chiral HPLC. Reference racemic samples ofadducts 18 were obtained by performing the conjugate addition reaction using 4-methylbenzylamine(20 mol%) as an organocatalyst in toluene as a solvent at room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With C64H94N6O4S2; In dichloromethane; at 20℃; | General procedure: In a typical experiment, a,a-disubstituted aldehyde(0.40 mmol), maleimides (0.20 mmol), and catalyst (0.03 mmol,15 mol%) in CH2Cl2 (0.5 mL) were stirred magnetically at room temperatureuntil the maleimide was consumed (monitored by TLC).The corresponding product was obtained after column chromatography(silica gel, eluent n-hexane/EtOAc). The enantiomeric excessof the products was determined by chiral HPLC analysis using chiralcolumns. All products were identified by spectroscopic data. Racemicsamples of the Michael adducts were prepared using racemiccatalyst. Compounds 6a'-6i' , 6m' and 6r' are known. The analyticaland spectroscopic data are in accordance with those reported. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sec.-butyllithium / cyclohexane; hexane; tetrahydrofuran / 0.25 h / -40 °C / Inert atmosphere 1.2: 1.25 h / -40 - 40 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 2.2: 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: N-(tert-butoxycarbonyl)-4-methoxy-2-methylaniline With sec.-butyllithium In tetrahydrofuran; hexane; cyclohexane at -40℃; for 0.25h; Inert atmosphere; Stage #2: cyclopentanealdehyde In tetrahydrofuran; hexane; cyclohexane at -40 - 40℃; for 1.25h; Inert atmosphere; | 17 tert-Butyl[2-(2-cyclopentyl-2-hydroxyethyl)-4-methoxyphenyl]carbamate To a solution of tert-butyl (4-methoxy-2-methylphenyl)carbamate (475 mg) in tetrahydrofuran (7 mL) was added dropwise sec-butyllithium (1.04 mol/L hexane-cyclohexane solution, 4.3 mL) at -40° C. under an argon atmosphere, and the mixture was stirred for 15 minutes. Then a solution of cyclopentanecarboxyaldehyde (0.256 mL) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred at -40° C. for 15 minutes and at room temperature for additional one hour. Water and 1 mol/L hydrochloric acid were added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (535 mg).1H-NMR (CDCl3) δ ppm:1.20-2.10 (19H, m), 2.70 (1H, dd, J=8.3, 14.0 Hz), 2.78 (1H, dd, J=2.9, 14.0 Hz), 3.55-3.70 (1H, m), 3.78 (3H, s), 6.69 (1H, d, J=3.0 Hz), 6.77 (1H, dd, J=3.0, 8.8 Hz), 7.40-7.70 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: piperidine / ethanol / Reflux 2: potassium carbonate / acetone / 20 °C | ||
Multi-step reaction with 2 steps 1: piperidine / ethanol / 6 h / Reflux 2: potassium carbonate / acetone / 1 h / 0 - 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | [01726] Step 1 : Synthesis of methyl 5-chloro-3-((cyclopentylmethyl) amino)-2- methylbenzoate[01727] To a stirred solution of methyl 3-amino-5-chloro-2-methyl benzoate (3.0 g, 15 mmol) and cyclopentanecarbaldehyde (2.2 g, 22 mmol) in methanol (30 mL), acetic acid ( 1 .8 g, 30 mmol) was added and reaction stirred at room temperature for 8 h. Then sodiumcyanoborohydride (2.4 g, 37 mmol) was added at 0C and the reaction stirred overnight at room temperature. On completion, the solvent was removed under reduced pressure and the crude material was purified by column chromatography to afford the title compound (4.2 g, 99%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With copper(II) sulfate; In dichloromethane; at 20℃; for 71h; | General procedure: Aryl or alkylaldehyde ( 1.2 eq.) was added to a stirred suspension of (S)-t-butylsulfinylamide ( 1.0 eq.) and flame-dried CuS04 (2.2 eq.) in dry CH2C12. The resulting mixture was stirred at rt for 69 h. The reaction mixture was filtered through a pad of Celite and the pad was extracted with CH2C12. The combined organic extracts were concentrated under reduced pressure yielding the crude product. Purification by repeated flash chromatography (Si02) using EtOAc-cyclohexane as eluent gave the desired product. |
78% | With copper(II) sulfate; In dichloromethane; at 20℃; for 71h; | (R,E)-N-(Cyclopentylmethylene)-2-methylpropane-2-sulfinamide The title compound was synthesized according to General Method H utilizing cyclopentanecarboxaldehyde (15.0 g, 152.8 mmol, 1.0 eq.), (R)-t-butylsulfinylamide (24.1 g, 198.7 mmol, 1.3 eq.), and flame-dried CuSO4 (73.2 g, 458.5 mmol, 3.0 eq.). The resulting mixture was stirred at rt for 71 h. The reaction mixture was filtered through a pad of Celite and the pad was rinsed with CH2Cl2 (5*100 mL). The combined organic extracts were concentrated under reduced pressure yielding a clear yellow oil (37.2 g). Purification by flash chromatography (SiO2, h=6 cm, Ø=10 cm) using 1:9 EtOAc-cyclohexane as eluent gave the product (23.8 g, 78% isolated yield) as a clear pale yellow oil. 1H NMR (300 MHz, CDCl3) delta ppm 7.99 (d, J=5.5 Hz, 1H), 3.02-2.87 (m, 1H), 1.97-1.78 (m, 2H), 1.78-1.55 (m, 6H), 1.18 (s, 9H). |
78% | With copper(II) sulfate; In dichloromethane; at 20℃; for 71h; | (R,E)-N-(Cyclopentylmethylene)-2-methylpropane-2-sulfinamide o The title compound was synthesized according to General Method H utilizing /f N cyclopentanecarboxaldehyde (15.0 g, 152.8 mmol, 1.0 eq.), (R)-t-butylsulfinylamide (24.1 g, 198.7 mmol, 1.3 eq.), and flame-dried CuS04 (73.2 g, 458.5 mmol, 3.0 eq.). The resulting mixture was stirred at rt for 71 h. The reaction mixture was filtered through a pad of Celite and the pad was rinsed with CH2C12 (5 x 100 mL). The combined organic extracts were concentrated under reduced pressure yielding a clear yellow oil (37.2 g). Purification by flash chromatography (Si02) using 1 :9 EtOAc-cyclohexane as eluent gave the product (23.8 g, 78% isolated yield) as a clear pale yellow oil. NMR (300 MHz, CDCI3) delta ppm 7.99 (d, J = 5.5 Hz, 1H), 3.02-2.87 (m, 1H), 1.97-1.78 (m, 2H), 1.78-1.55 (m, 6H), 1.18 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.3% | A solution of (5-bromopyridin-3-yl)methanamine (LIV) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL×3), combined organic layers were dried over MgSO4 and concentrated in vacuo to give 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine ( LV) (1.23 g, 4.57 mmol, 79.3% yield) as a brown oil. ESIMS found for C12H17BrN2 m/z 269 (M+H). | |
79.3% | With methanol; sodium cyanoborohydride; at 20℃; for 2h; | A solution of (5-bromopyridin-3-yl)methanamine (LVIII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL×3), combined organic layers were dried over MgSO4 and concentrated in vacuo to give 1-(5-bromopyridin-3-ye-N-(cyclopentylmethyl)methanamine (LIX) (1.23 g, 4.57 mmol, 79.3% yield) as a brown oil. ESIMS found for C12H17BrN2 m/z 269 (M+H). |
79.3% | Step 4 A solution of (5-bromopyridin-3-yl)methanamine (XXXII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL*3), combined organic layers were dried over MgSO4 and concentrated in vacuo to give 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XXXIII) (1.23 g, 4.57 mmol, 79.3% yield) as a brown oil. ESIMS found for C12H17BrN2 m/z 269 (M+H). |
79.3% | Step 4 (0832) A solution of (5-bromopyridin-3-yl)methanamine (XLVII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL×3), combined organic layers were dried over MgSO4 and concentrated in vacuo to give 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XLVIII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. 1H NMR (CDCl3, 400 MHz) delta ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6 Hz. 1H), 2.53 (d, J=7.2 Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J=2.0 Hz, 1H); ESIMS found for C12H17BrN2 m/z 269.1 (M+H). | |
79.3% | Step 4 A solution of (5-bromopyridin-3-yl)methanamine (XLVIII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL*3), combined organic layers were dried over MgSO4 and concentrated in vacuo to give 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XLIX) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. 1H NMR (CDCl3, 400 MHz) delta ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6 Hz. 1H), 2.53 (d, J=7.2 Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J=2.0 Hz, 1H); ESIMS found for C12H17BrN2 m/z 269.1 (M+H). | |
79.3% | A solution of (5-bromopyridin-3-yl)methanamine (XL VIII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over MgSO4 and concentrated in vacuo to give 1-(5-broromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XLIX) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. 1H NMR (CDCl3, 400 MHz) delta ppm 1.07- 1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6Hz. 1H), 2.53 (d, J=7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J=2.0Hz, 1H); ESIMS found for C12H17BrN2 mlz 269.1 (M+H). | |
79.3% | A solution of (5 -bromopyridin-3 -yl)methanamine (XLVI) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over Mg504 and concentrated in vacuo to give 1 -(5 -bromopyridin-3 -yl)-N-(cyclopentylmethyl)methanamine (XLVII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. ?H NMR (CDC13, 400 MHz) ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6Hz. 1H), 2.53 (d, J=7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J2.OHz, 1H); ESIMS found for C,2H,7BrN2 mlz 269.1 (M+H). | |
79.3% | A solution of(5-bromopyridin-3-yl)methanamine (XLVII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq)in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over MgSO4 and concentrated in vacuo to give 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XLVIII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. ?H NMR (CDC13, 400 MHz) ppm 1.07-1.23 (m, 2H), 1.47- 1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt,J=7.6Hz. 1H), 2.53 (d,J=7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J2.OHz, 1H); ESIMS found for C,2H,7BrN2 mlz 269.1 (M+H). | |
79.3% | A solution of (5-bromopyridin-3-yl)methanamine (XLVII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over Mg504 and concentrated in vacuo to give 1 -(5 -bromopyridin-3 -yl)-N-(cyclopentylmethyl)methanamine (XLVIII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. ?H NMR (CDC13, 400 MHz) ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6Hz. 1H), 2.53 (d, J7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J2.OHz, 1H); ESIMS found for C,2H,7BrN2 mlz 269.1 (M+H). | |
79.3% | j0667j A solution of (5 -bromopyridin-3 -yl)methanamine (LXIV) (1.30 g, 5.8 mmol,1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq)in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol,6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solventwas removed under reduced pressure and the residue was diluted in water (20 mL) and extractedwith DCM (10 mL x 3), combined organic layers were dried over Mg504 and concentrated in vacuoto give 1 -(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (LXV) (1.23 g, 4.57 mmol,79.3% yield) as a yellow oil. ?H NMR (CDC13, 400 MHz) ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m,4H), 1.70-1.84 (m, 2H), 2.02 (spt, J7.6Hz. 1H), 2.53 (d, J7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H),8.47 (s, 1H), 8.56 (d, J2.OHz, 1H); ESIMS found for C,2H,7BrN2 mlz 269.1 (M+H). | |
79.3% | A solution of (5 -bromopyridin-3 -yl)methanamine (XL VII) ( 1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBCN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over MgS04 and concentrated in vacuo to give l-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XL VIII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. NMR (CDC13, 400 MHz) delta ppm 1.07-1.23 (m, 2H), 1.47- 1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6Hz. 1H), 2.53 (d, J=7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J=2.0Hz, 1H); ESIMS found for Ci2Hi7BrN2 mlz 269.1 (M+H). | |
79.3% | j0644j A solution of (5 -bromopyridin-3 -yl)methanamine (XLVI) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq)in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over MgSO4 and concentrated in vacuo to give 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XLVII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. ?HNMR(CDC13, 400 MHz) ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6Hz. 1H), 2.53 (d, J=7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H),8.47 (s, 1H), 8.56 (d, J2.OHz, 1H); ESIMS found for C12H17BrN2 mlz 269.1 (M+H). | |
79.3% | [0667] A solution of (5-bromopyridin-3-yl)methanamine (LXIV) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBLLCN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over MgSC>4 and concentrated in vacuo to give l-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (LXV) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. NMR (CDC13, 400 MHz) delta ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6Hz. 1H), 2.53 (d, J=7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J=2.0Hz, 1H); ESIMS found for Ci2Hi7BrN2 mlz 269 A (M+H). | |
79.3% | A solution of (5-bromopyridin-3-yl)methanamine (XL VII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBCN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over MgS04 and concentrated in vacuo to give l-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XL VIII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. NMR (CDC13, 400 MHz) delta ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6Hz. IH), 2.53 (d, J=7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, IH), 8.47 (s, IH), 8.56 (d, J=2.0Hz, IH); ESIMS found for Ci2Hi7BrN2 mlz 269 A (M+H). | |
79.3% | A solution of (5-bromopyridin-3-yl)methanamine (XL VII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBCN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over MgSC>4 and concentrated in vacuo to give l-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XL VIII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. NMR (CDC13, 400 MHz) delta ppm 1.07-1.23 (m, 2H), 1.47- 1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6Hz. 1H), 2.53 (d, J=7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J=2.0Hz, 1H); ESIMS found for Ci2Hi7BrN2 mlz 269.1 (M+H). | |
79.3% | A solution of (5-bromopyridin-3-yl)methanamine (XLVII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBCN ( 1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM ( 10 mL x 3), combined organic layers were dried over MgSC>4 and concentrated in vacuo to give l-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XL VIII) ( 1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. NMR (CDC13, 400 MHz) delta ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6Hz. IH), 2.53 (d, J=7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, IH), 8.47 (s, IH), 8.56 (d, J=2.0Hz, IH); ESIMS found for Ci2Hi7BrN2 mlz 269.1 (M+H). | |
79.3% | A solution of (5-bromopyridin-3-yl)methanamine (LXIV) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBCN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over MgSC>4 and concentrated in vacuo to give l-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (LXV) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. NMR (CDC , 400 MHz) delta ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6Hz. IH), 2.53 (d, J=7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, IH), 8.47 (s, IH), 8.56 (d, J=2.0Hz, IH); ESIMS found for Ci2Hi7BrN2 mlz 269.1 (M+H). | |
79.3% | A solution of (5-bromopyridin-3-yl)methanamine (XLVII) (1.30 g, 5.8mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over Mg504 and concentrated in vacuo to give 1 -(5 -bromopyridin-3 -yl)-N-(cyclopentylmethyl)methanamine (XLVIII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. ?H NMR (CDC13, 400 MHz) ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.61-Tz. 1H), 2.53 (d, J7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J2.OHz, 1H); ESIMS found for C,2H,7BrN2 mlz 269.1 (M+H). | |
79.3% | A solution of (5-bromopyridin-3-yl)methanamine (LXIV) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBLLCN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over MgSC>4 and concentrated in vacuo to give l-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (LXV) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. NMR (CDC13, 400 MHz) delta ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6Hz. 1H), 2.53 (d, J=7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J=2.0Hz, 1H); ESIMS found for Ci2Hi7BrN2 mlz 269 A (M+H). | |
79.3% | A solution of (5-bromopyridin-3-yl)methanamine (XL VI) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBCN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over MgSC>4 and concentrated in vacuo to give l-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XL VII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. NMR (CDCI3, 400 MHz) delta ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6Hz. 1H), 2.53 (d, J=7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J=2.0Hz, 1H); ESIMS found for Ci2Hi7BrN2 mlz 269 A (M+H). | |
79.3% | Step 4 [0647] A solution of (5-bromopyridin-3-yl)methanamine (XL VII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBCN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over MgS04 and concentrated in vacuo to give l-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XL VIII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. NMR (CDCI3, 400 MHz) delta ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6Hz. IH), 2.53 (d, J=7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, IH), 8.47 (s, IH), 8.56 (d, J=2.0Hz, IH); ESIMS found for Ci2Hi7BrN2 mlz 269 A (M+H). | |
79.3% | A solution of (5-bromopyridin-3-yl)methanamine (XLVII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH ( 15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over MgSO4 and concentrated in vacuo to give 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XLVIII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. 1H NMR (CDCl3, 400 MHz) delta ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6Hz. IH), 2.53 (d, J=7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, IH), 8.47 (s, IH), 8.56 (d, J=2.0Hz, IH); ESIMS found for C12H17BrN2 m/z 269.1 (M+H). | |
79.3% | Step 4 [0648] A solution of (5-bromopyridin-3-yl)methanamine (XL VII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBCN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over MgS04 and concentrated in vacuo to give l-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XL VIII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. NMR (CDC13, 400 MHz) delta ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6Hz. IH), 2.53 (d, J=7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, IH), 8.47 (s, IH), 8.56 (d, J=2.0Hz, IH); ESIMS found for Ci2Hi7BrN2 mlz 269 A (M+H). | |
79.3% | [0644] A solution of (5-bromopyridin-3-yl)methanamine (XL VI) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBCN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over MgSC>4 and concentrated in vacuo to give l-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XL VII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. NMR (CDC13, 400 MHz) delta ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6Hz. 1H), 2.53 (d, J=7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J=2.0Hz, 1H); ESIMS found for Ci2Hi7BrN2 mlz 269.1 (M+H). | |
79.3% | A solution of (5-bromopyridin-3-yl)methanamine (XL VII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBCN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over MgS04 and concentrated in vacuo to give l-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XL VIII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. NMR (CDC13, 400 MHz) delta ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6Hz. IH), 2.53 (d, J=7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, IH), 8.47 (s, IH), 8.56 (d, J=2.0Hz, IH); ESIMS found for Ci2Hi7BrN2 mlz 269 A (M+H). | |
79.3% | A solution of(5-bromopyridin-3-yl)methanamine (XLVII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL x 3), combined organic layers were dried over Mg504 and concentrated in vacuo to give 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XLVIII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. ?H NMR (CDC13, 400 MHz) ppm 1.07-1.23 (m, 2H), 1.47- 1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt,J=7.6Hz. 1H), 2.53 (d,J7.2Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J2.OHz, 1H); ESIMS found for C,2H,7BrN2 mlz 269.1 (M+H). | |
79.3% | A solution of (5-bromopyridin-3-yl)methanamine (LXII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL×3), combined organic layers were dried over MgSO4 and concentrated in vacuo to give 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (LXIII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. 1H NMR (CDCl3, 400 MHz) delta ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6 Hz, 1H), 2.53 (d, J=7.2 Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J=2.0 Hz, 1H); ESIMS found for C12H17BrN2 m/z 269.1 (M+H). | |
79.3% | Step 4 A solution of (5-bromopyridin-3-yl)methanamine (XLVII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL*3), combined organic layers were dried over MgSO4 and concentrated in vacuo to give 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XLVIII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. 1H NMR (CDCl3, 400 MHz) delta ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6 Hz. 1H), 2.53 (d, J=7.2 Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J=2.0 Hz, 1H); ESIMS found for C12H17BrN2 m/z 269.1 (M+H). | |
79.3% | Step 4 (0835) A solution of (5-bromopyridin-3-yl)methanamine (XLVII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL×3), combined organic layers were dried over MgSO4 and concentrated in vacuo to give 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (XLVIII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. 1H NMR (CDCl3, 400 MHz) delta ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6 Hz. 1H), 2.53 (d, J=7.2 Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J=2.0 Hz, 1H); ESIMS found for C12H17BrN2 m/z 269.1 (M+H). | |
79.3% | Step 4 (0856) A solution of (5-bromopyridin-3-yl)methanamine (LXII) (1.30 g, 5.8 mmol, 1.0 eq), cyclopentanecarbaldehyde (0.57 g, 5.8 mmol, 1.0 eq) and TEA (0.60 g, 5.8 mmol, 1.0 eq) in MeOH (15 mL) was stirred at room temperature for 2 h. Then NaBH3CN (1.98 g, 34.6 mmol, 6.0 eq) was added and the mixture was stirred at the same temperature for another 3 h. The solvent was removed under reduced pressure and the residue was diluted in water (20 mL) and extracted with DCM (10 mL×3), combined organic layers were dried over MgSO4 and concentrated in vacuo to give 1-(5-bromopyridin-3-yl)-N-(cyclopentylmethyl)methanamine (LXIII) (1.23 g, 4.57 mmol, 79.3% yield) as a yellow oil. 1H NMR (CDCl3, 400 MHz) delta ppm 1.07-1.23 (m, 2H), 1.47-1.67 (m, 4H), 1.70-1.84 (m, 2H), 2.02 (spt, J=7.6 Hz, 1H), 2.53 (d, J=7.2 Hz, 2H), 3.80 (s, 2H), 7.86 (s, 1H), 8.47 (s, 1H), 8.56 (d, J=2.0 Hz, 1H); ESIMS found for Cl2H17BrN2 m/z 269.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
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To a suspension of 3,3-dibromo-l-trifluoromethyl-propane (2.35 g, 8.72 mmol) in H20 was added sodium acetate (1.67 g, 20.4 mmol). The mixture was heated at 100 C for 30 min.and then cooled to room temperature. A solution of cyclopentanecarboxaldehyde (1 g, 10.2 mmol) in 4.8 ml of MeOH was added to the reaction mixture followed by NH4OH (4.8 ml, 20% in H20). The reaction was stirred at room temperature overnight. The mixture was extracted 3 with EtOAc. The combined organics were washed with brine, dried over MgS04, filtered and concentrated. The crude product was used directly for the next step. |
Yield | Reaction Conditions | Operation in experiment |
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With C64H94N6O4S2; In dichloromethane; at 20℃; | General procedure: In a typical experiment, a,a-disubstituted aldehyde(0.40 mmol), maleimides (0.20 mmol), and catalyst (0.03 mmol,15 mol%) in CH2Cl2 (0.5 mL) were stirred magnetically at room temperatureuntil the maleimide was consumed (monitored by TLC).The corresponding product was obtained after column chromatography(silica gel, eluent n-hexane/EtOAc). The enantiomeric excessof the products was determined by chiral HPLC analysis using chiralcolumns. All products were identified by spectroscopic data. Racemicsamples of the Michael adducts were prepared using racemiccatalyst. Compounds 6a'-6i' , 6m' and 6r' are known. The analyticaland spectroscopic data are in accordance with those reported. | |
With C64H94N6O4S2; In dichloromethane; at 20℃; | General procedure: In a typical experiment, a,a-disubstituted aldehyde(0.40 mmol), maleimides (0.20 mmol), and catalyst (0.03 mmol,15 mol%) in CH2Cl2 (0.5 mL) were stirred magnetically at room temperatureuntil the maleimide was consumed (monitored by TLC).The corresponding product was obtained after column chromatography(silica gel, eluent n-hexane/EtOAc). The enantiomeric excessof the products was determined by chiral HPLC analysis using chiralcolumns. All products were identified by spectroscopic data. Racemicsamples of the Michael adducts were prepared using racemiccatalyst. Compounds 6a'-6i' , 6m' and 6r' are known. The analyticaland spectroscopic data are in accordance with those reported. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With racemic primary amine thiourea organocatalyst; In dichloromethane; at 20℃; | General procedure: In a typical experiment, a,a-disubstituted aldehyde(0.40 mmol), maleimides (0.20 mmol), and catalyst (0.03 mmol,15 mol%) in CH2Cl2 (0.5 mL) were stirred magnetically at room temperatureuntil the maleimide was consumed (monitored by TLC).The corresponding product was obtained after column chromatography(silica gel, eluent n-hexane/EtOAc). The enantiomeric excessof the products was determined by chiral HPLC analysis using chiralcolumns. All products were identified by spectroscopic data. Racemicsamples of the Michael adducts were prepared using racemiccatalyst. Compounds 6a'-6i' , 6m' and 6r' are known. The analyticaland spectroscopic data are in accordance with those reported. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With C13H28N2; benzoic acid; In neat (no solvent); at 4℃; for 19h;Green chemistry; | General procedure: Typical procedure for the asymmetric Michael reaction: The a,a-disubstitutedaldehyde (1.6 mmol) and nitroolefin (0.4 mmol) were added to a mixture of thediamine catalyst 1c (8.5 mg, 0.04 mmol) and benzoic acid (4.9 mg, 0.04 mmol).The reaction mixture was stirred at 4 C for the time as indicated in the Tables2 and 3. The reaction mixture was stirred until complete conversion of thenitroolefin (monitored by TLC) and then was purified by flash columnchromatography on silica gel (ethyl acetate/hexanes = 1:10) to afford thepure Michael product. The enantiomeric excess (ee) of the products 4a-j and5a-e was determined by chiral HPLC analysis. |
90% | General procedure: To a mixture of catalyst 1 (20 mol%) and alpha,alpha-disubstituted aldehyde (4 mmol) was added PhCOOH (10 mol%) and stirred for 20 min at 0C. Next, nitroolefin (1 mmol) was added to the resulting mixture and stirred for the appropriate time (Tables 4 and 5) at 0C. After completion of the reaction (monitored by TLC), the mixture was purified by silica-gel column chromatography to afford the desired product. Relative and absolute configurations of the products were determined by comparison of 1H NMR, 13C NMR, and specific rotation values with those reported in the literature.8 | |
87% | General procedure: To a mixture of catalyst 1 (15 mol %), and alpha,alpha-disubstituted aldehyde (4 mmol) was added p-NO2-C6H4COOH (10 mol %) and stirred for 20 min at 0 C. Nitroolefin (1 mmol) was added to the resulting mixture and stirred for the appropriate time (Tables 4 and 5) at 0 C. After completion of the reaction (monitored by TLC), the mixture was purified by silica-gel column chromatography to afford the desired product. Relative and absolute configurations of the products were determined by comparison of 1H NMR, 13C NMR, and specific rotation values with those reported in the literature. 6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With C13H28N2; benzoic acid; In neat (no solvent); at 4℃; for 12h;Green chemistry; | General procedure: Typical procedure for the asymmetric Michael reaction: The a,a-disubstitutedaldehyde (1.6 mmol) and nitroolefin (0.4 mmol) were added to a mixture of thediamine catalyst 1c (8.5 mg, 0.04 mmol) and benzoic acid (4.9 mg, 0.04 mmol).The reaction mixture was stirred at 4 C for the time as indicated in the Tables2 and 3. The reaction mixture was stirred until complete conversion of thenitroolefin (monitored by TLC) and then was purified by flash columnchromatography on silica gel (ethyl acetate/hexanes = 1:10) to afford thepure Michael product. The enantiomeric excess (ee) of the products 4a-j and5a-e was determined by chiral HPLC analysis. |
95% | General procedure: To a mixture of catalyst 1 (20 mol%) and alpha,alpha-disubstituted aldehyde (4 mmol) was added PhCOOH (10 mol%) and stirred for 20 min at 0C. Next, nitroolefin (1 mmol) was added to the resulting mixture and stirred for the appropriate time (Tables 4 and 5) at 0C. After completion of the reaction (monitored by TLC), the mixture was purified by silica-gel column chromatography to afford the desired product. Relative and absolute configurations of the products were determined by comparison of 1H NMR, 13C NMR, and specific rotation values with those reported in the literature.8 | |
93% | General procedure: To a mixture of catalyst 1 (15 mol %), and alpha,alpha-disubstituted aldehyde (4 mmol) was added p-NO2-C6H4COOH (10 mol %) and stirred for 20 min at 0 C. Nitroolefin (1 mmol) was added to the resulting mixture and stirred for the appropriate time (Tables 4 and 5) at 0 C. After completion of the reaction (monitored by TLC), the mixture was purified by silica-gel column chromatography to afford the desired product. Relative and absolute configurations of the products were determined by comparison of 1H NMR, 13C NMR, and specific rotation values with those reported in the literature. 6 |
91% | General procedure: To a mixture of catalyst 1 (20 mol%), and aldehyde (4 mmol) in water (0.5 mL) was added PhCOOH (10 mol%) and stirred for 20 min. at 0 C or at rt. Then, nitroolefin (1 mmol) was added to the resulting mixture and stirred for appropriate time (Tables 7-10) at 0 C or at rt. After completion of the reaction (monitored by TLC),the mixture was purified by silica-gel column chromatography to afford the desired product. Relative and absolute configurations ofthe products were determined by comparison of 1H NMR, 13C NMR and specific rotation values with those reported in the literature.8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | General procedure: To a mixture of catalyst 1 (20 mol%) and alpha,alpha-disubstituted aldehyde (4 mmol) was added PhCOOH (10 mol%) and stirred for 20 min at 0C. Next, nitroolefin (1 mmol) was added to the resulting mixture and stirred for the appropriate time (Tables 4 and 5) at 0C. After completion of the reaction (monitored by TLC), the mixture was purified by silica-gel column chromatography to afford the desired product. Relative and absolute configurations of the products were determined by comparison of 1H NMR, 13C NMR, and specific rotation values with those reported in the literature.8 | |
91% | General procedure: To a mixture of catalyst 1 (15 mol %), and alpha,alpha-disubstituted aldehyde (4 mmol) was added p-NO2-C6H4COOH (10 mol %) and stirred for 20 min at 0 C. Nitroolefin (1 mmol) was added to the resulting mixture and stirred for the appropriate time (Tables 4 and 5) at 0 C. After completion of the reaction (monitored by TLC), the mixture was purified by silica-gel column chromatography to afford the desired product. Relative and absolute configurations of the products were determined by comparison of 1H NMR, 13C NMR, and specific rotation values with those reported in the literature. 6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | General procedure: To a mixture of catalyst 1 (20 mol%) and alpha,alpha-disubstituted aldehyde (4 mmol) was added PhCOOH (10 mol%) and stirred for 20 min at 0C. Next, nitroolefin (1 mmol) was added to the resulting mixture and stirred for the appropriate time (Tables 4 and 5) at 0C. After completion of the reaction (monitored by TLC), the mixture was purified by silica-gel column chromatography to afford the desired product. Relative and absolute configurations of the products were determined by comparison of 1H NMR, 13C NMR, and specific rotation values with those reported in the literature.8 | |
90% | General procedure: To a mixture of catalyst 1 (15 mol %), and alpha,alpha-disubstituted aldehyde (4 mmol) was added p-NO2-C6H4COOH (10 mol %) and stirred for 20 min at 0 C. Nitroolefin (1 mmol) was added to the resulting mixture and stirred for the appropriate time (Tables 4 and 5) at 0 C. After completion of the reaction (monitored by TLC), the mixture was purified by silica-gel column chromatography to afford the desired product. Relative and absolute configurations of the products were determined by comparison of 1H NMR, 13C NMR, and specific rotation values with those reported in the literature. 6 | |
89% | General procedure: To a mixture of catalyst 1 (20 mol%), and aldehyde (4 mmol) in water (0.5 mL) was added PhCOOH (10 mol%) and stirred for 20 min. at 0 C or at rt. Then, nitroolefin (1 mmol) was added to the resulting mixture and stirred for appropriate time (Tables 7-10) at 0 C or at rt. After completion of the reaction (monitored by TLC),the mixture was purified by silica-gel column chromatography to afford the desired product. Relative and absolute configurations ofthe products were determined by comparison of 1H NMR, 13C NMR and specific rotation values with those reported in the literature.8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-(1,3-dioxolan-2-yl)ethyl(triphenyl)phosphonium bromide With n-butyllithium In tetrahydrofuran; hexane at -30℃; for 0.75h; Inert atmosphere; Stage #2: cyclopentanealdehyde In tetrahydrofuran; hexane at 20℃; for 16.5h; Overall yield = 65 %; Overall yield = 0.84 g; | 20.1 Step 1. Preparation of 2- [(Z)-3 -cyclopentylallyl]- 1,3 -dioxolane and 2-[(E)-3 - cyclopentylallyl]- 1 ,3-dioxolane Under nitrogen atmosphere, to a cooled (-30 °C) solution of commercially available 2- (1,3-dioxolan-2-yl)-ethyl(triphenyl)-phosphonium bromide (3.48 g, 7.9 mmol) in dry THF (82mL), n-BuLi (2.5 M in Hexane, 3.1 mL, 7.9 mmol) was added dropwise. The solution was stirred at -30 °C for 45 mm, then cyclopentanecarboxaldehyde (0.76 mL, 7.14 mmol) in dry THF (5.0 mL) was added dropwise. The reaction mixture was stirred for 30 mm and then at r.t. for 16 h. Then, the solution was diluted with CH2C12 (100 mL) and washed with sat. NH4C1 solution (3 x 50 mL). The organic layer was dried over Na2504, filtered and concentrated to dryness giving anoily residue (2.91 g). Purification by typical silica gel flash chromatography (CH2C12) afforded the pure title compounds (0.84 g, 65%), as a mixture (ratio 7:93) of E/Z diastereoisomers. ‘H NMR (DMSO-d6): ö 5.54-5.31 (m, 3H), 5.30-5.23 (m, 1H, major), 4.77 (t, 1H, J= 4.7 Hz, major), 4.78 (t, 1H, J= 6.0 Hz, minor), 3.92-3.7 1 (m, 8H), 2.72-2.60 (m, 1H, major), 2.35 (dd, 1H, J= 4.8, 1.5 Hz, major), 2.33 (dd, 1H, J= 4.8, 1.5 Hz, major), 2.27-2.23 (m, 2H, minor),1.77-1.68 (m, 4H), 1.66-1.46 (m, 9H), 1.28-1.11 (m, 4H). | |
86 % de | Stage #1: 2-(1,3-dioxolan-2-yl)ethyl(triphenyl)phosphonium bromide With n-butyllithium In tetrahydrofuran; hexane at -30℃; for 0.75h; Inert atmosphere; Stage #2: cyclopentanealdehyde In tetrahydrofuran; hexane at 20℃; for 16h; Inert atmosphere; Overall yield = 65 %; Overall yield = 0.84 g; | 2-[(Z)-3-cyclopentylallyl]-1,3-dioxolane and 2-[(E)-3-cyclopentylallyl]-1,3-dioxolane (53). Under nitrogen atmosphere, to a cooled (-30 °C) solution of commercially available 2-(1,3-dioxolan-2-yl)-ethyl(triphenyl)-phosphonium bromide (3.48 g, 7.9 mmol) in dry THF (82 mL), n-BuLi (2.5 M inHexane, 3.1 mL, 7.9 mmol) was added dropwise. The solution was stirred at -30 °C for 45 min, thencyclopentanecarboxaldehyde (0.76 mL, 7.14 mmol) in dry THF (5.0 mL) was added dropwise. Thereaction mixture was stirred for 30 min and then at room temperature for 16 h. Then, the solution wasdiluted with CH2Cl2 (100 mL) and washed with sat. NH4Cl solution (3 x 50 mL). The organic layer wasdried over Na2SO4, filtered and concentrated to dryness giving an oily residue (2.91 g). Purification bytypical silica gel flash chromatography (100% CH2Cl2) afforded the pure title compounds (0.84 g,65%), as a mixture (ratio 7:93) of E/Z diastereoisomers. 1H NMR (DMSO-d6): δ 5.54-5.31 (m, 3H),5.30-5.23 (m, 1H, major), 4.77 (t, 1H, J = 4.7 Hz, major), 4.78 (t, 1H, J = 6.0 Hz, minor), 3.92-3.71(m, 8H), 2.72-2.60 (m, 1H, major), 2.35 (dd, 1H, J = 4.8, 1.5 Hz, major), 2.33 (dd, 1H, J = 4.8, 1.5 Hz,major), 2.27-2.23 (m, 2H, minor), 1.77-1.68 (m, 4H), 1.66-1.46 (m, 9H), 1.28-1.11 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
430 mg | Stage #1: 5-bromo-3-fluoro-2-methoxypyridine With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 1.5h; Inert atmosphere; Stage #2: cyclopentanealdehyde In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere; | 65.A A) (5-bromo-3-fluoro-2-methoxypyridin-4-yl)(cyclopentyl)methanol A) (5-bromo-3-fluoro-2-methoxypyridin-4-yl)(cyclopentyl)methanol [0539] To a solution of DIEA (0.827 mL) in THF (90 mL) was added 1.6 M n-butyllithium hexane solution (3.64 mL) at -78°C, and the mixture was stirred under argon atmosphere at -78°C for 30 min. To the reaction mixture was added a solution of 5-bromo-3-fluoro-2-methoxypyridine (1.00 g) in THF (30 mL) at -78°C, and the mixture was stirred under argon atmosphere at -78°C for 1 hr. To the reaction mixture was added cyclopentanecarbaldehyde (0.572 g) at -78°C, and the mixture was stirred under argon atmosphere at -78°C for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution at -78°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (430 mg). MS (ESI+): [M+H]+ 304.0. MS (ESI+), found: 304.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.2% | Under nitrogen, a suspension of (cyanomethyl)triphenylphosphanium bromide (12 g, 31.49 mmol) in anhydrous THF (100 mL) was cooled to 0° C., a solution of 2.5 M n-BuLi in n-hexane (13 mL, 34.64 mmol) was added dropwise. The mixture was stirred at 0° C. for another 30 minutes, then cyclopentane-carbaldehyde (3.1 g, 31.49 mmol) was added, and the mixture was warmed to the room temperature and stirred for further 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (100 mL×3). The organic layers were combined, washed with water (60 mL×3) and saturated brine (60 mL) in sequence, dried over anhydrous sodium sulfate. The mixture was filtrated, the filtrate was concentrated in vacuum, the residue was purified by silica column chromatography (petroleum ether:ethyl acetate=10:1) to give colorless oil 3-b (1.0 g, yield: 26.2percent). LC-MS (ESI): m/z=122 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 3,3-dibromo-1,1,1-trifluoropropan-2-one (8.1 g, 30 mmol) and sodium acetate (8.1 g, 60 mmol) in water (54 mL) was heated to reflux for 30 mins, and then the mixture was cooled to room temperature. Cyclopentanecarbaldehyde (2.65 g, 27 mmol) and Ammonium Hydroxide (33 mL) in methanol (135 mL) was added. The mixture was stirred at room temperature overnight. Upon the completion, methanol was removed and the aqueous was extracted with ethyl acetate (50 mL x 2). The combined organic phase was dried and concentrated. The crude (5.5 g) was used without further purification for next step.LC-MS (m/z) = 205 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With potassium acetate; In 2,2,2-trifluoroethanol; at 90℃; for 24h; | A mixture of ethyl 3-oxobutanoate (0.4 g, 3 mmol), cyclopentanecarbaldehyde (0.38 g, 3 mmol), 1,3-thiazole-2-carboximidamide HCl salt (0.49 g, 3 mmol) and KOAc (0.59 g, 6 mmol) in CF3CH2OH (10 mL) was stirred for 24 hours at 90 C. After being cooled, it was partitioned (EtO Ac-brine). The organic was dried (Na2SO4), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/petroleum ether) to give the desired compound as a yellow solid (0.33 g, 31%). ESIMS m/z = 320.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With magnesium methanolate In methanol at 60℃; | General procedure for the synthesis of compounds 1, 4-22, 27-29 General procedure: The synthesis of 5,6-dehydrokawain analogues were performed based on the method reported by McCracken, S. T. et al.2 Magnesium methoxide was prepared by gently heating Mg (156 mg) in anhydrous MeOH. 4-Methoxy-6-methyl-2-pyrone (3)3 (0.30 g, 2.1 mmol) or other 2-pyrones and each aldehyde (2.2 mmol) were added to the solution. The reaction mixture was heated at reflux for 3-6 hours, cooled, and dried in vacuo. The residual material was then suspended in acetic acid (3.3 M, 30 mL) and extracted with ethyl acetate for three times. The combined organic layer was washed with water and dried in vacuo. Purification of the compounds was conducted by preparative HPLC. NMR spectra were recorded on a JEOL JNM-ECZ400S in CDCl3. HRMS was recorded on a Thermo scientific Q Exactive instrument. Mp were recorded on a Yanagimoto micro melting point apparatus. The 1H and 13C NMR data observed for 11,4, 33, 73, 83, 105, 222, 256, 266 were agreed with those previously reported in the literature. The 1H NMR data of 247 and 278 were in agreement with literature values. |
17% | With magnesium In methanol at 60℃; for 5h; | 1 Compound 15: 6 - [(E) -2-Cyclopentylvinyl] -4-methoxy-2H-pyran-2-one (formula (15)) Metal Mg was heated in methanol (60 ° C.) and suspended. 4-methoxy-6-methyl-2-pyrone (0.20 g) and cyclopentanecarboxaldehyde (0.24 ml, 2.2 mmol) were added thereto, and the mixture was heated at 60 ° C. for 5 hours. After cooling, it was acidified with acetic acid and extracted with ethyl acetate. The extract was concentrated under reduced pressure and then purified by reverse phase preparative HPLC (mobile phase: water-acetonitrile = 3: 7).Yield: 17%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 10 steps 1.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 0 °C / Inert atmosphere 1.2: 0 - 30 °C / Inert atmosphere 2.1: acetonitrile / 30 °C 3.1: lithium hydroxide monohydrate / tetrahydrofuran; water / 30 °C 4.1: (1S,2R)-1-amino-2-indanol / isopropyl alcohol / 20 °C 5.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 5.2: 0.5 h 6.1: phosphorus pentoxide / tetrahydrofuran / 60 - 70 °C / Inert atmosphere 7.1: isopropylmagnesium chloride / tetrahydrofuran / 1 h / -15 - 5 °C / Inert atmosphere 7.2: -5 - 5 °C / Inert atmosphere 8.1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / tetrahydrofuran; water / 50 - 60 °C / Inert atmosphere 9.1: hydrogenchloride / tetrahydrofuran; water / 20 °C / Reflux 10.1: phosphoric acid / isopropyl alcohol / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: cyclopentanealdehyde; N-(7-chloroquinolin-4-yl)ethylenediamine In N,N-dimethyl-formamide at 90℃; Stage #2: [(p-methylphenyl)sulfonylmethyl]isonitrile With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 12h; | 13 4.3 General procedure for the synthesis of (5-22) General procedure: Aldehyde (1equiv. 0.48mmol) and amine (1equiv. 0.48mmol) were dissolved in DMF (10mL) and heat the reaction mixture at 90°C for 6-8h. Then Potassium carbonate (2equiv. 0.96mmol) and TOSMIC (1equiv. 0.48mmol) were added to the reaction mixture, continue stirring at 90°C for 12h. The Completion of the reaction was monitored by TLC, then cool the reaction mixture to room temperature, then add 20mL water and extract with EtOAc (3×20mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. Then obtained crude was purified by column chromatography using 60-120 mesh in Methanol/Chloroform as eluent, afforded the title compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With tris(2-diphenylphosphinoethyl)phosphine; hydrogen; cobalt(II) fuoride; potassium carbonate In ethanol at 140℃; for 24h; Glovebox; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | General procedure: To a stirred solution of 5 (1 equiv.) in THF (~20 mL) was added dropwise a 2.0 M solution of lithium diisopropylamide (LDA) in THF/heptane/ethylbenzene (2.2 equiv.) at -78 C. The reaction mixture was stirred for 30 min at 0 C followed by dropwise addition of aldehyde (1.2equiv.). The solution was stirred for 16 h at room temperature, quenched by a saturated aqueous solution of NH4Cl and extracted with ethyl acetate. The organic phase was dried with MgSO4, evaporated, and the residue was purified by silica gel column chromatography |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.1% | 5.0 ml (1.45 M in n-hexane, 7.19 mmol, 1.05 eq.) of an n-butyl lithium solution is slowly dropped into a solution of 1.00 g (6.85 mmol, 1.0 eq.) of <strong>[16986-24-6]1,7-dicarba-closo-dodecaborane</strong>(12) in 50 ml of diethyl ether at 0 C. After 30 minutes, the solution is heated to room temperature. After three hours, the solution is cooled again to 0 C., and 0.62 ml (0.67 mg, 6.85 mmol, 1.0 eq.) of cyclopentaldehyde is dropped in. The solution is then heated to room temperature. After 24 hours, 20 ml of distilled water is added to the white suspension, which is acidulated by means of concentrated hydrochloric acid and then extracted three times by means of 20 ml of diethyl ether on each occasion. The combined organic phases are washed by means of 20 ml of saturated sodium chloride solution and dried by means of magnesium sulfate, and the solvent is then removed under reduced pressure. The residue is purified by column chromatography (eluent: hexane/ethyl acetate 5:1 v/v). A white solid is obtained. Yield: 0.5 g (2.06 mmol, 30.1%) Rfvalue: 0.74 (eluent: hexane/ethyl acetate 5:1 v/v) Melting point: 50.2-51.3 C. 1H NMR (CDCl3): δ=1.25-3.10 (br m, 10H, BH), 1.36 (m, 2H, 2-CH2a), 1.46 (m, 2H, 1-CH2a), 1.66 (m, 2H, 2-CH2b), 1.78 (m, 2H, 1-CH2b), 1.94 (br s, 1H, 4-OH), 2.08 (dt, 1H, 3-CH, 3JHH=8.2 Hz, 3JHH=3.6 Hz), 2.92 (br s, 1H, 6-CH), 3.81 (d, 1H, 4-CH, 3JHH=3.6 Hz) ppm. 11Bv in cm-1): 3,591 (m), 3,486 (s), 3,060 (m), 2,955 (s), 2,868 (m), 2,603 (s), 1,450 (w), 1,385 (m), 1,131 (s), 1,009 (m), 817 (w), 732 (m), 707 (w), 669 (w), 608 (w). Elementary Analysis: Calculated for C8H22B10O1: C=39.64% H=9.15%. Found: C=39.77% H=9.10%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | In methanol at 80℃; for 0.5h; | General procedure for the synthesis of compounds (12-43). General procedure: First, 0.5 g of 2-hydrazinoadenosine (11) and different aralkyl or alkylaldehyde compounds (1.1 equivalent) were combined in methanol(30 ml) and heated by microwave at 80 °C for 30 min. The crudeproducts (12-13, 17, 19, 21-32, and 35-39) were precipitated frommethanol, and the other products (14-16, 18, 20, 33-34, and 40-43) were purified from the reaction mixture using silica gel column chromatography. All the crude products were further purified by MPLC on reverse phase C18 material to yield the products(12-43). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 0 - 20℃; for 1h; | General procedure: A solution of compound 29a (60 mg, 0.25 mmol), cyclopropanecarboxaldehyde(24 muL, 0.37 mmol) and AcOH (56 muL, 0.98 mmol) inCH2Cl2 (2.5 mL) was treated with NaBH(OAc)3 (420 mg, 2.0 mmol) at0 C, and the mixture was stirred at room temperature for 1 h. Theresulting mixture was partitioned between AcOEt (50 mL) and saturatedaqueous NaHCO3 (30 mL), and the organic phase was washedwith saturated aqueous NaCl, dried (Na2SO4), filtered, and concentratedin vacuo. The residue was purified by silica gel columnchromatography (MeOH/CHCl3; 1:99 to 13:87) to afford compound 1(61 mg, 83%) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With dipotassium peroxodisulfate; iron(III)-acetylacetonate; di-tert-butyl peroxide In ethyl acetate at 120℃; for 2h; Sealed tube; | |
62% | With dipotassium peroxodisulfate; iron(III)-acetylacetonate; di-tert-butyl peroxide In ethyl acetate at 120℃; for 12h; | 6 Example 6 The benzoyl formic acid (30.0mg, 0.2mmol), Fe(acac)3 (21.2mg, 0.06mmol),Cyclopentyl formaldehyde (98.0mg, 1.0mmol), DTBP (58.5mg, 0.4mmol),K2S2O8 (81.1mg, 0.3mmol) and a stirring rod were put into the reaction tube, and ethyl acetate 1mL was added as a solventClose the reaction tube. Place the reaction tube in an oil bath at 120 ° C, start stirring, and perform constant temperature reaction for 12 hours.After cooling the reaction mixture to room temperature, the solid residue was filtered through a short silica gel column and washed with 10 mL of ethyl acetate.After evaporating the solvent in vacuo, the crude product was subjected to column chromatography with petroleum ether: ethyl acetate = 70: 1 as the eluent to obtain a pure product.Colorless oil, 62% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Method A: To a solution of <strong>[118753-66-5]tert-butyl 4-aminopiperazine-1-carboxylate</strong> 4 or tert-butyl piperazine-1-ylcarbamate 8 (201mg, 1.0mmol) in CH2Cl2 (5mL) were added the aldehydes (1.2mmol or 2.4mmol) and AcOH (72mg, 1.2mmol or 144mg, 2.4mmol). After stirring for 0.5h at room temperature, NaBH(OAc)3 (255mg, 1.2mmol, or 510mg, 2.4mmol) was added and then stirred for another 1-2h. The reaction mixture was washed with brine and saturated NaHCO3 aq. The organic phase was dried with anhydrous Na2SO4 and then filtered. The filtrate was concentrated to produce the crude 5 or 9 in a yield of 61%-72%. To the aboved crude in CH2Cl2 (10mL) was added TFA (1mL). After stirring for 1.5-2h at room temperature, the reaction mixture was then concentrated to produce the crude 6 or 10 in a yield of 65%-72%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Method A: To a solution of <strong>[118753-66-5]tert-butyl 4-aminopiperazine-1-carboxylate</strong> 4 or tert-butyl piperazine-1-ylcarbamate 8 (201mg, 1.0mmol) in CH2Cl2 (5mL) were added the aldehydes (1.2mmol or 2.4mmol) and AcOH (72mg, 1.2mmol or 144mg, 2.4mmol). After stirring for 0.5h at room temperature, NaBH(OAc)3 (255mg, 1.2mmol, or 510mg, 2.4mmol) was added and then stirred for another 1-2h. The reaction mixture was washed with brine and saturated NaHCO3 aq. The organic phase was dried with anhydrous Na2SO4 and then filtered. The filtrate was concentrated to produce the crude 5 or 9 in a yield of 61%-72%. To the aboved crude in CH2Cl2 (10mL) was added TFA (1mL). After stirring for 1.5-2h at room temperature, the reaction mixture was then concentrated to produce the crude 6 or 10 in a yield of 65%-72%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With iodine In ethanol for 6h; Reflux; | 2-cyclopentylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(3H)-one (3) (Scheme 15) [00498] A mixture of 3-aminothieno[2,3-b]pyridine-2-carboxamide (1) (483 mg, 2.5 mmol, 1 equiv), cyclopentanecarbaldehyde (2) (490 mg, 5 mmol, 2 equiv) and iodine (762 mg, 3 mmol, 1.2 equiv) was refluxed in 10 mL of EtOH for 6h. Reaction mixture was cooled to rt and carefully poured into a preliminary prepared solution of K2CO3 (1.5 g) and Na2S203*5H20 (3 g) in 50 mL of water. The precipitate formed was filtered, washed with water, cold EtOH, cold MTBE and dried to afford the target product (3) as a grey solid (625 mg, 92%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With lithium methanolate; ammonia; lithium perchlorate In N,N-dimethyl-formamide at 20℃; for 8h; Electrochemical reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Tags: 872-53-7 synthesis path| 872-53-7 SDS| 872-53-7 COA| 872-53-7 purity| 872-53-7 application| 872-53-7 NMR| 872-53-7 COA| 872-53-7 structure
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P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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