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CAS No. : | 1123-25-7 | MDL No. : | MFCD00001463 |
Formula : | C8H14O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | REHQLKUNRPCYEW-UHFFFAOYSA-N |
M.W : | 142.20 | Pubchem ID : | 70744 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.88 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 39.97 |
TPSA : | 37.3 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) : | -5.58 cm/s |
Log Po/w (iLOGP) : | 1.59 |
Log Po/w (XLOGP3) : | 2.23 |
Log Po/w (WLOGP) : | 2.04 |
Log Po/w (MLOGP) : | 1.57 |
Log Po/w (SILICOS-IT) : | 1.76 |
Consensus Log Po/w : | 1.84 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.06 |
Solubility : | 1.24 mg/ml ; 0.0087 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.65 |
Solubility : | 0.319 mg/ml ; 0.00225 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.27 |
Solubility : | 7.62 mg/ml ; 0.0536 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.5 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | To a stirring solution Of LiAlH4 (20 mmol) in anhydrous THF (10 mL) at 40C was added 1-methyl-cyclohexanecarboxylic acid (i, 7.0 mmol) in 50 mL of THF dropwise over a period of 1 hour. The solution was stirred at refluxing temperature under N2 for 6 hours. The solution was cooled to 40C by ice bath, and 1 mL of 1 N NaOH (1 mL) followed by H2O (2 mL) was slowly added to the solution to quench the reaction. The solution was stirred at 23 0C for 1 hour and then filtered to remove solid material. The solution was concentrated. Purification by flash silica gel chromatography (ethyl acetate/hexanes, 1:2) gave the product, (l-methyl-cyclohexyl)-methanol (ii), in 82% yield | |
Step 2 The methyl ester 50.03 from above was dissolved in methylene chloride (100 mL) and cooled to-78C, under nitrogen atmosphere. DIBAL (1.0 M solution in methylene chloride, 200 mL) was added dropwise over 2 h period. The reaction mixture was warmed to room temperature over 16 h. The reaction mixture was cooled to 0C and MeOH (5-8 mL) was added dropwise. A solution of aqueous 10% sodium potassium tartarate (200 mL) was slowly added with stirring. Diluted with methylene chloride (100 mL) and separated the organic layer (along with some white precipitate). The organic layer was washed with 1 N HCI (250 mL), brine (200 mL), dried (Na2SO4) and concentrated to provide the alcohol 50.04 (11.00 g) as a clear oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 40℃; for 7.5h;Large scale; | Step 4, 120 kg of 1-methylcyclohexanoic acid, 600 kg of dichloromethane and 1 kg of N,N-dimethylformamide (DMF) catalyst are added to the chlorination kettle, and the temperature is raised to 40 C to reflux the reaction. 130 kg of thionyl chloride was added dropwise, and thionyl chloride was added in 1.5 hours. After the completion of the dropwise addition, the reflux reaction was continued for 6 hours, and the sulfur dioxide and hydrogen chloride gas formed by the reflux reaction were absorbed by 30% sodium hydroxide alkaline water. After the reflux reaction is completely completed, the dichloromethane is recovered under normal pressure (can be recycled), and after the dichloromethane is recovered, the excess thionyl chloride is recovered at a temperature of 80 C and a negative pressure of -0.087 MPa. After 6 hours, 1-methylcyclohexanecarboxylic acid chloride was obtained after the recovery. Wherein, the weight of 1-methylcyclohexanoyl chloride is 134 kg, the content is 98%, the yield is 98%. A specific process for chlorinating 1-methylcyclohexanoic acid to obtain 1-methylcyclohexanoyl chloride is shown in the formula (4). |
With thionyl chloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; | 1-Methylcyclohexanecarbonyl chloride (Beilstein 918, 9II10) prepared from 1-methylcyclohexane-carboxylic acid (0.75 g, 0.0052 mol) and thionyl chloride (0.76 mL, 0.010 mol) was added to a solution of the ethyl amine derivative prepared in the preceding paragraph (1.5 g, 0.0047 mol). Diisopropylethylamine (0.87 mL, 0.005 mol) in 50 mL of methylene chloride was also added. After 2 hours the solution was washed with water, saturated NaHCO3, dried over anhydrous Na2 SO4 and evaporated. The product was crystallized from ethyl acetate/hexane. MP 132-134 C. Rf 0.63 silica, EtOAc/hexane 1:1. IR 1652 cm-1. 1 H NMR (DMSO-d6): delta 1.08 (s, 3H), 1.1-1.5 (m, 10 H), 2.58-2.65 (m, 2H), 2.7-2.78 (m, 2H), 3.0-3.17 (m, 4H), 6.35 (t, 1H), 6.4 (d, 1 H), 6.95-6.98 (s, 1H), 6.99-7.02 (d, 1H), 7.19-7.22 (t, 2H), 7.3-7.45 (m, 4H), 7.6-7.64 (d, 1H). | |
With thionyl chloride; for 3h;Heating / reflux; | 25.0 g 1-Methyl-cyclohexanecarboxylic acid was refluxed in 200 ml thionylchloride for three hours. The cooled reaction mixture was evaporated in vacuo. The residue was dissolved in 200 ml tetrahydrofuran and added dropwise to 300 ml of an ice cooled 33% ammonia solution. After completion of the addition the mixture was evaporated in vacuo, the residue dissolved in 200 ml water and extracted five times with portions of 200 ml of ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure to provide 25.0 g 1-Methyl-cyclohexanecarboxylic acid amide as an oil.C8H15NO (141.21), MS (ESI): 142.2 (M+H+). |
With oxalyl dichloride; | Example 2; Preparation of oxazoline substrates: Carboxylic acids were converted to their acid chlorides using either oxalyl chloride (6a, 7a, 9a-13a, 15a, 15d, 17a) or thionyl chloride (8a, 14a, 14c, 16a, 16d). See Broady, S. D.; Rexhausen, J. E.; Thomas, E. J. J. Chem. Soc, Perkin Trans. 1,1999, 1083. The acid chlorides were then reacted with (iS)-tert-leucinol or {R)-tert-Qudmo to form amides which were subsequently cyclized to oxazolines using triphenylphosphine. See Kawasaki, K.; Katsuki, T. Tetrahedron, 1997, 53, 6337; and Zhang, X.; Lin, W.; Gong, L.; Mi, A.; Cui, X.; Jiang, Y.; Choi, M. C. K.; Chan, A. S. C. Tetrahedron Lett. 2000, 43, 1535; | |
With thionyl chloride; In dichloromethane; at 0 - 20℃; for 3h; | Preparation of i-Methyl-cyclohexanecarbonyl chloride; A solution of 1-Methyl-cyclohexanecarboxylic acid (1.5 g, 10.5 mmol) in dry DCM (15 ml.) was cooled to O0C, SOCI? (2.28 mL, 31.6 mmol) was added. The reaction mixture was allowed to rt, maintained for 3 h and then was concentrated to obtain the crude product (1.70 g). The crude was directly used in the next step without any purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
hydrogenchloride; In water; for 16h;Heating / reflux; | Preparation of Intermediate 50.01 Step 1 To a solution of 50.02 (15 g) in MeOH (150 mL) was added conc HCI (3-4 mL) and the mixture was refluxed for 16 h. The reaction mixture was cooled to room temperature and concentrated. The residue was taken in diethyl ether (250 mL) and washed with cold saturated sodium bicarbonate solution, and brine. The organic layer was dried (Na2SO4) and concentrated to afford the methyl ester 50.03 (12.98 g) which was carried forward without further purification. | |
hydrogenchloride; In water; for 16h;Heating / reflux; | PREPARATION OF P3 MOIETIES Preparation of Intermediate 50.01 Step 1 To a solution of 50.02 (15 g) in MeOH (150 mL) was added conc HO (3-4 mL) and the mixture was refluxed for 16 h. The reaction mixture was cooled to room temperature and concentrated. The residue was taken in diethyl ether (250 mL) and washed with cold saturated sodium bicarbonate solution, and brine. The organic layer was dried (Na2SO4) and concentrated to afford the methyl ester 50.03 (12.98 g) which was carried forward without further purification. | |
With hydrogenchloride; In water; for 16h;Heating / reflux; | To a solution of 50.02 (15 g) in MeOH (150 mL) was added conc HCI (3-4 mL) and the mixture was refluxed for 16 h. The reaction mixture was cooled to room temperature and concentrated. The residue was taken in diethyl ether (250 mL) and washed with cold saturated sodium bicarbonate solution, and brine. The organic layer was dried (Na2SO4) and concentrated to afford the methyl ester 50.03 (12.98 g) which was carried forward without further purification. |
With hydrogenchloride; In water; for 16h;Heating / reflux; | To a solution of 5.02 (15 g) in MeOH (150 mL) was added conc HCI (3- 4 mL) and the mixture was refluxed for 16 h. The reaction mixture was cooled to room temperature and concentrated. The residue was taken in diethyl ether (250-mL) and washed with cold saturated sodium bicarbonate solution, and brine. The organic layer was dried (Na2S04) and concentrated to afford the methyl ester 50. 03 (12.98 g) which was carried forward without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: HCl / 16 h / Heating 2.1: LAH / CH2Cl2 / 16 h / -78 - 20 °C 3.1: PCC / CH2Cl2 / 16 h / 0 - 20 °C 4.1: CHCl3 / 2 h / 20 °C 5.1: CHCl3 / 16 h / 0 - 20 °C 6.1: HCl / methanol / 72 h / 0 - 20 °C 6.2: HCl / H2O / 48 h / Heating 7.1: H2 / Pd/C / methanol / 16 h / 20 °C 8.1: NaOH / dioxane; H2O / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; ammonium chloride; In tetrahydrofuran; diethyl ether; | 1-methylcyclohexane-1-carboxylic acid (10 g) in tetrahydrofuran was added dropwise to a stirred solution of lithium aluminium hydride (2.5 g) in tetrahydrofuran. After 1 h, saturated aqueous ammonium chloride then dilute hydrochloric acid were added, and the mixture was extracted with chloroform (x 3). The combined organic phase was dried (Na2SO4) and evaporated to yield the title alcohol as a colourless syrup (8 g), single component by g.c.-m.s. 4 Tetrahydrothiophene-2-methanol: the title alcohol was prepared from <strong>[19418-11-2]tetrahydrothiophene-2-carboxylic acid</strong> (J.T. Wrobel and E. Hejchman, Synthesis 1987, 452) by reduction with lithium aluminium hydride in ether (S. Ikegami, Tetrahedron 1974, 30 , 2087). 5 (RS)-2-Cyclohexene-1-methanol: cyclohexenone (10 g) was added dropwise to a solution of lithium aluminium hydride (2 g) in diethyl ether (50 ml) and the mixture was stirred at ambient temperature for 2 h. Saturated ammonium chloride solution (150 ml) was added, followed by hydrochloric acid (2 M) to dissolve the grey precipitate, and the mixture was extracted with chloroform (x 3), dried (MgSO4) and evaporated to a syrup. Fractional distillation under reduced pressure gave 2-cyclohexen-1-ol as a liquid, a single component by g.c.-m.s. The resulting 2-cyclohexen-1-ol (4 g) was converted to the title alcohol by the method of W. C. Still et al., (J. Am. Chem. Soc., 100 (1978) 1927-8, and after purification by flash crhomatography (silica; eluant ethyl acetate/light petroleum ether, 1:4) was obtained as a colourless liquid (2.5 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In methanol; diethyl ether; hexane; at 20℃; | Preparation 23Methyl 1-methylcvclohexane carboxylateTreat a solution of 1-methylcyclohexane carboxylic acid (7.11 g, 50.0 mmol) in MeOH (1O mL) and Et2O (40 mL) dropwise with trimethylsilyldiazomethane (2.0 M/hexanes; 26 mL, 52 mmol). Stir the reaction mixture at room temperature overnight, then concentrate under reduced pressure to yield the title compound as a clear, pale yellow oil (7.811 g, 50 mmol; 100%). MS(ES): m/z = 156 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Example 5.1; O-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)ethyl]-N-[(1-methylcyclohexyl)carbonyl]-L-tyrosine To a solution of 1-methylcyclohexanecarboxylic acid (44 mg, 0.3 1 mmol) in DMF (1 ml) were added TBTU (116 mg, 0.36 mmol), N-methylmorpholine (34 mul, 031 mmol) and methyl O-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)ethyl]-L-tyrosinate (100 mg, 0.28 mmol). The mixture was stirred at 30 C. for 30 hours. NaOH 6N (187 mul, 1.12 mol) was added. After stirring at 40 C. for 4 hours, the resulting mixture was purified by C18 reverse phase chromatography (basic conditions) to give the title compound (100 mg, 76%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Example 1; O-{2-[6-(methylamino)pyridin-2-yl]ethyl}-N-[(1-methylcyclohexyl)carbonyl]-L-tyrosine Examples 1.1 to 1.27To 1-methylcyclohexanecarboxylic acid (47 mg, 0.33 mmol) and TBTU (125 mg, 0.33 mmol) was added a solution of methyl O-{2-[6-(methylamino)pyridin-2-yl]ethyl}-L-tyrosinate (100 mg, 0.30 mmol) in DMF (1 ml). The reaction mixture was stirred at room temperature for 24 hours. Then 6N NaOH (0.34 ml, 2.00 mmol) was added and the mixture was stirred for 2 hours. After filtration the mixture was purified by C18 reverse phase chromatography (basic conditions) to afford example 1.1 as a solid (92 mg, 69%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Example 2; N-[(1-methylcyclohexyl)carbonyl]-O-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl]-L-tyrosine Examples 2.1 to 2.2 To 1-methylcyclohexanecarboxylic acid (44 mg, 0.31 mmol) and TBTU (118 mg, 0.31 mmol) was added a solution of methyl O-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl]-L-tyrosinate (100 mg, 0.28 mmol) in DMF (1 ml). The reaction mixture was stirred at room temperature for 24 hours. Then LiOH (52 mg, 1.13 mmol) and water (0.2 ml) were added and the mixture was stirred for 24 hours. After filtration the mixture was purified by C18 reverse phase chromatography (basic conditions) to afford example 2.1 as a solid (89 mg, 68%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 1-methylcyclohexanecarboxylic acid (32.0 mg, 0.222 mmol) in DCM (1.5 mL) was added one drop of DMF (cat.), followed by oxalyl chloride (37.0 mg, 0.228 mmol), while at ambient temperature and under a constant stream of nitrogen. Upon cessation of gas evolution, the reaction mixture was cooled to 0 C prior to the introduction of triethylamine (34.0 mg, 0.333 mmol) as a solution in DCM (2.0 mL), and then N-(3,5-difluorobenzyl)-2- [(4S)-3-methyl-2,5-dioxo-r,3'-dihydrospiro[imidazolidine-4,2'-inden]-5'-yl]amino}-2- oxoethanaminium chloride (50.0 mg, 0.111 mmol, Intermediate 1). After 1 hour the reaction mixture was applied directly to a silica gel column for purification, eluting with DCM:MeOH - 99:1 to 95:5. Product containing fractions were pooled and concentrated in vacuo to give the title compound. MS: mlz = 561 (M + 23(Na+)). HRMS: mlz = 539.2477; calculated mlz = 539.2464 for C29H33N4O4F2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(c) 2-Methyl-5-[(1 -methylcvclohexylcarbonylamino)methyllbenzoic acidTBTU (15 mmol; 4.9 g) was added to a mixture of 1 -methylcyclohexylcarboxylic acid (15 mmol; 2.2 g), TEA (9.6 mL) and DMF (130 mL) at rt. After 10 min a mixture of5-aminomethyl-2-methylbenzoic acid (6.3 g crude mixture with NaCI, see step (b) above) was added. After 3 h at rt the reaction mixture was concentrated, water was added and the formed precipitate was washed with water, dried and purified by preparative HPLC. Yield: 3.6 g (83%). MS [M+H]+ = 290; TLC: Rf = 0.49 (silica gel, DCM:EtOH 9:1 ). | ||
TBTU (15 mmol; 4.9 g) was added to a mixture of 1-methylcyclohexylcarboxylic acid (15 mmol; 2.2 g), TEA (9.6 mL) and DMF (130 mL) at rt. After 10 min a mixture of 5-aminomethyl-2-methylbenzoic acid (6.3 g crude mixture with NaCl, see step (b) above) was added. After 3 h at rt the reaction mixture was concentrated, water was added and the formed precipitate was washed with water, dried and purified by preparative HPLC. Yield: 3.6 g (83%). MS [M+H]+=290; TLC: Rf=0.49 (silica gel, DCM:EtOH 9:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With naphthalene-1,4-dicarbonitrile; phenanthrene; In water; acetonitrile; at 20℃; for 18h;Irradiation; Inert atmosphere; | General procedure: An aqueous acetonitrile (CH3CN/H2O = 9:1) solution containing 2, 3, Phen, and electron-acceptorin Pyrex vessels (18 mm x 180 mm) was purged with argon for10 min. The mixture was irradiated with 400 W high-pressure mercury lamp, and then concentrated under reduced pressure. The product was purified by silica gel column chromatography using hexane and EtOAc as eluents to yield 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With dipotassium peroxodisulfate; silver nitrate In water; acetonitrile at 60℃; for 24h; Inert atmosphere; Schlenk technique; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 0.1h;Inert atmosphere; | To a solution of 18 (7.0 mg, 0.023 mmol, 1.0 equiv) in THF (1 mE) was added 1 -methylcyclohexanecarboxylic acid (16.6 mg, 0.116 mmol, 5.0 equiv) and triphenylphosphane (30.6 mg, 0.116 mmol, 5.0 equiv) at room temperature. Then DIAD (23 IL, 0.116 mmol, 5.0 equiv) was slowly added during 1 minute. The reaction mixture was stirred at room temperature for 5 minutes before water (5 mE) was added. The mixture was extracted with Et20 (3x10 mE) and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the crude product by flash colunm chromatography (silica gel, hexanes/ EtOAc=50: 1 -30: 1) afforded 19 (4.4 mg, 45%) as a colorless oil.Physical state: colorless oilR1=0.2 (Hex/EtOAc=20: 1; anisaldehyde)HRMS (m/z): calcd for C28H40NaO3, [M+Na], 447.2875. found, 447.2884.[a]D=+16.4 (c=0.44, CH2C12)?H NMR (600 MHz, Chioroform-d) oe 6.04 (s, 1H), 5.62 (s,1H), 4.82 (s, 1H), 3.51 (d, J=11.7 Hz, 1H), 2.47 (s, 1H), 2.45(dd, J=15.9, 3.4 Hz, 1H), 2.18-2.08 (m, 1H), 2.01 (d, J=12.3Hz, 2H), 1.96-1.87 (m, 1H), 1.82 (dt, J=15.7, 5.8 Hz, 1H),1.77 (d, J=1.3 Hz, 3H), 1.67 (ddd, J=15.7, 9.1, 2.6 Hz, 1H),1.59 (s, 4H), 1.58-1.51 (m, 2H), 1.38-1.19 (m, 6H), 1.14 (s,3H), 1.07 (s, 3H), 1.04 (s, 3H), 1.01 (d, J=7.1 Hz, 3H), 0.85(dd, J=12.1, 8.4 Hz, 1H), 0.69 (td, J=8.8, 6.3 Hz, 1H).?3CNMR (151 MHz, Chloroform-d) oe 208.3, 178.1, 138.0,136.9, 131.8, 122.2, 85.9, 75.4, 49.3, 45.4, 43.4, 41.4, 40.0,35.7,30.5,28.8,25.8,24.3,23.5,23.4,23.4,22.9, 16.7, 15.6,15.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12 mg | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 16h; | [0390] N-methyl-1-(2,3,5-trifluorophenyl)methanamine (37 mg, 0.211 mmol), which was prepared from 2,3,5-trifluorobenzaldehyde and methanamine hydrochloride according to the procedure outlined for compound 13, and 1 -methylcyclohexanecarboxylic acid (30 mg, 0.211 mmoL) were dissolved in dry DMF (lml), 2-(7-Aza-1H-benzotriazole- [0391] 1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(1 19.7 mg, 0.315 mmoL) and N,N-Diisopropylethylamine (54.2 mg, 0.42 mmoL) were added to the solution. The mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 12 mg of desired compound 65 as colorless oil ( yield =19.5% )1H NMR:(CDC13, 400 M Hz) (ppm) 6.80-6.82 (m, 1 H), 6.72-6.76 (m, 1 H), 4.65 (s, 2 H), 3.10 (s, 3 H), 2.06-2.11 (m, 2 H), 1.36-1.54 (m, 8 H), 1.27 (s, 3 H).LCMS (ESI) [M+H] calad for C16H20F3N0, 300.1; found 300.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With triethylamine; In acetonitrile; at 70℃; | General procedure: BBR (3.71 g, 10 mmol) was heated at 195-210 C for 10-15 min under vacuum (30-40 mmHg)to afford the black oil, which was acidified with ethanol/concentrated HCl (95:5). The solvent wasremoved by evaporation and the residue was collected and then purified by flash chromatographyover silica gel using CH2Cl2/CH3OH as the gradient eluent, giving the title compound 1 (2.85 g, 80%)as an orange solid.To a stirred solution of 1 (100 mg, 0.28 mmol) in anhydrous CH3CN, triethylamine (175 muL,1.26 mmol) was added and heated to 70 C. Then the RCOX/RSO2Cl (1.1-1.2 eq) was added andstirred for 5-6 h. The mixture was cooled to precipitate completely, filtrated and washed with CH2Cl2to afford target compounds 2a-k and 3a-f. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With caesium carbonate; 9-(2-mesityl)-10-methylacridinium perchlorate; In dichloromethane; for 1h;Irradiation; Inert atmosphere; Sealed tube; | General procedure: A dry tube equipped with a stirring bar was charged with the carboxylic acid 1a-l (0.2 mmol, 1.0 equiv), 2a (4.0 mg, 10 mumol, 5 mol%), Cs2CO3 (66 mg, 0.1 mmol, 1.0 equiv), and the requisite nitrosoarene (0.4 mmol, 2.0 equiv). The tube was capped with a Supelco aluminum crimp seal with septum (PTFE/butyl) and it was evacuated and refilled with N2 (3 ×). CH2Cl2 (anhydrous and degassed by bubbling through with N2 for 20 min; 4.0 mL) was added. The N2 inlet was then removed and the cap sealed with parafilm. The mixture was stirred at r.t. for 1 h in front of blue LEDs. The tube was opened to air and the mixture was diluted with CH2Cl2 (5 mL) and brine (5 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were dried (MgSO4), filtered, and evaporated. Purification by column chromatography on silica gel gave 3a-o. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-methyl-pyrrolidin-2-one; tris-(dibenzylideneacetone)dipalladium(0); disodium hydrogenphosphate; C42H34F10IrN4; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; at 20℃;Irradiation; | Take 2-methyl-cyclohexylcarboxylic acid (0.2 mmol),4-methoxystyrene (0.8 mmol), ruthenium catalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.001 mmol),Palladium catalyst Pd2(dba)3 (0.002 mmol), Xantphos (0.002 mmol) and Na2HPO4 (0.2 mmol) were dissolved in NMP (2 mL).Reactive overnight at room temperature under illumination (provided by a 36W Blue LED light)After the reaction was completed, it was quenched with water and extracted with ethyl acetate three times.The organic phase was combined, and concentrated to give a colorless oily liquid (29.5 mg, 64%), which was compound 4, and the ratio of Z/E configuration was analyzed by 1H-NMR using diphenylmethane as an internal standard. The ratio is 90/10. | |
With tris-(dibenzylideneacetone)dipalladium(0); disodium hydrogenphosphate; Ir[dF(CF3)ppy]2(dtbbpy)PF6; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1-methyl-pyrrolidin-2-one; at 20℃;Irradiation; | compound 4 of the formula:Take 2-methyl-cyclohexylcarboxylic acid (0.2 mmol),4-methoxystyrene (0.8 mmol), ruthenium catalystIr[dF(CF3)ppy]2(dtbbpy)PF6 (0.001 mmol), palladium catalyst Pd2(dba)3 (0.002 mmol), Xantphos(0.002 mmol) and Na2HPO4 (0.2 mmol) dissolved in NMP (2 mL), under light (provided by 36W Blue LED) room temperatureThe reaction was completed overnight, and after completion of the reaction, it was quenched with water and extracted three times with ethyl acetate.A colorless oily liquid (29.5 mg, 64%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Carboxylic acid 3 (0.2 mmol, 1 equiv.) and HATU (0.2 mmol, 1 equiv.) were dissolved in 1 mL DCE in a one dram vial charged with a stir bar. DIPEA (0.1 mL, 0.6 mmol, 3 equiv.) was added and the resulting solution was stirred at RT for 10 minutes. Amine 2 (0.2 mmol, 1 equiv.) was added to the mixture. The reaction solution was heated to 45 C and stirred overnight. Upon completion the reaction mixture was condensed and loaded onto a 60g C-18 cartridge and purified over a gradient of 5-95% ACN/H2O. The fractions containing product were identified by LC-MS and condensed under vacuum to give the final product 4. The final product was characterized by NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / Reflux 1.2: 0 °C 2.1: pyridinium chlorochromate; silica gel / dichloromethane / 20 °C 3.1: triphenylphosphine / dichloromethane / 0 - 20 °C 4.1: caesium carbonate / dimethyl sulfoxide / 12 h / 115 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With silver hexafluoroantimonate; tert-butylammonium hexafluorophosphate(V); 1,8-diazabicyclo[5.4.0]undec-7-ene; In dichloromethane; at 20℃; for 3h;Electrolysis; Molecular sieve; | General procedure: With no precautions to exclude air or moisture, the ElectraSyn vial (5 ml) with a stir bar was charged with carboxylic acid (0.2 mmol, 1.0 equiv.), alcohol (0.6 mmol, 3.0 equiv.), 2,4,6-collidine (0.6 mmol, 3.0 equiv.), nBu4NPF6 (0.3 mmol, 1.5 equiv.), 3 A molecular sieves (150 mg), AgPF6 (0.3 mmol, 1.5 equiv.) and CH2Cl2 (3.0 ml). The ElectraSyn vial cap equipped with anode (graphite) and cathode (graphite) were inserted into the mixture. After pre-stirring for 15 min, the reaction mixture was electrolysed at a constant current of 10 mA for 3 h. The ElectraSyn vial cap was removed, and electrodes were rinsed with Et2O (2 ml), which was combined with the crude mixture. Then, the crude mixture was further diluted with Et2O (30 ml). The resulting mixture was washed with 2 M HCl (20 ml) and NaHCO3 (aq.) (20 ml), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative thin-layer chromatography to furnish the desired product. Full experimental details and characterization of new compounds can be found in the Supplementary Information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With silver hexafluoroantimonate; tert-butylammonium hexafluorophosphate(V); 1,8-diazabicyclo[5.4.0]undec-7-ene; In dichloromethane; at 20℃; for 3h;Electrolysis; Molecular sieve; | General procedure: With no precautions to exclude air or moisture, the ElectraSyn vial (5 ml) with a stir bar was charged with carboxylic acid (0.2 mmol, 1.0 equiv.), alcohol (0.6 mmol, 3.0 equiv.), 2,4,6-collidine (0.6 mmol, 3.0 equiv.), nBu4NPF6 (0.3 mmol, 1.5 equiv.), 3 A molecular sieves (150 mg), AgPF6 (0.3 mmol, 1.5 equiv.) and CH2Cl2 (3.0 ml). The ElectraSyn vial cap equipped with anode (graphite) and cathode (graphite) were inserted into the mixture. After pre-stirring for 15 min, the reaction mixture was electrolysed at a constant current of 10 mA for 3 h. The ElectraSyn vial cap was removed, and electrodes were rinsed with Et2O (2 ml), which was combined with the crude mixture. Then, the crude mixture was further diluted with Et2O (30 ml). The resulting mixture was washed with 2 M HCl (20 ml) and NaHCO3 (aq.) (20 ml), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative thin-layer chromatography to furnish the desired product. Full experimental details and characterization of new compounds can be found in the Supplementary Information. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With piperazine; 9-(2-chlorophenyl)acridine; tetrakis(acetonitrile)copper(I)tetrafluoroborate In dichloromethane at 25 - 27℃; for 14h; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; caesium carbonate In dimethyl sulfoxide at 40℃; for 1h; Glovebox; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; caesium carbonate In dimethyl sulfoxide at 40℃; for 1h; Glovebox; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; caesium carbonate In dimethyl sulfoxide at 40℃; for 1h; Glovebox; Inert atmosphere; Irradiation; |
Tags: 1123-25-7 synthesis path| 1123-25-7 SDS| 1123-25-7 COA| 1123-25-7 purity| 1123-25-7 application| 1123-25-7 NMR| 1123-25-7 COA| 1123-25-7 structure
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