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CAS No. : | 4383-25-9 | MDL No. : | MFCD00465456 |
Formula : | C13H19N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IYWYMFZAZUYNLC-UHFFFAOYSA-N |
M.W : | 189.30 | Pubchem ID : | 204463 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.54 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 60.94 |
TPSA : | 12.03 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.25 cm/s |
Log Po/w (iLOGP) : | 2.76 |
Log Po/w (XLOGP3) : | 3.1 |
Log Po/w (WLOGP) : | 2.96 |
Log Po/w (MLOGP) : | 2.94 |
Log Po/w (SILICOS-IT) : | 3.21 |
Consensus Log Po/w : | 3.0 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.09 |
Solubility : | 0.155 mg/ml ; 0.000821 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.02 |
Solubility : | 0.18 mg/ml ; 0.000953 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.29 |
Solubility : | 0.00966 mg/ml ; 0.0000511 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.14 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-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 |
---|---|---|
8 mg | With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Inert atmosphere | General procedure: To generate Compound 1, cyclohexylamine (0.5M in MeOH) was combined with benzaldehyde (0.5M in MeOH) and stirred for 3h at 64°C. The mixture was cooled to rt, followed by two additions of sodium cyanoborohydride (0.5M in EtOH), each followed by stirring at rt for 30m. The mixture was then heated to 64°C for 6h. The reaction mixture was worked-up with water and extracted three times with CH2Cl2. The organic fractions were pooled, dried with magnesium sulfate, and reduced in vacuo. Thesecondary amine was then solubilized in dry CH2Cl2 and combined with 4-chloro-benzoylchloride. Equivalents were based upon the assumption that the secondary amine was formed in 100percent yield. Dimethylaminopyridine (0.1equiv) was solubilized in dry CH2Cl2 and added directly to the stirring solution of secondary amine, followed by addition of diisopropylethylamine (1.1equiv). The reaction was then capped, purged with nitrogen gas, and stirred at rt overnight. The reaction mixture was then reduced in vacuo to an oil, which was resolubilized and purified using reverse phase preparative HPLC (isocratic elution: 75percent acetonitrile, 25percent water). Following preparative HPLC, compound purity was determined using reverse phase analytical HPLC. Compounds were purified to an average purity of greater than 95percent (supplementary Table 1).For Compound 1: IR (thin film from CDCl3): 2935, 2858, 2246, 1624, 1495, 1418, 1091, 908, 838, 734 cm−1; 1H NMR (400MHz, CDCl3) δ 7.52 (4H), 7.36 (4H), 7.20 (2H), 4.55 (1H), 3.65 (1H), 1.80 (4H), 1.47 (4H), 1.06 (2H); 13C NMR (75MHz, CDCl3) δ 171.2, 142.5, 139.0, 135.2, 128.7, 128.4, 127.7, 126.8, 77.17, 59.4, 59.4, 44.6, 32.0, 30.8, 25.7, 25.1, 25.1, 9.29; HRMS m/z calculated for (M+H); 328.1390, found: 328.1477 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
158 mg | With sodium tetrahydroborate; In methanol; toluene; at 20℃; for 1h; | General procedure: An oven dried 10 mL round bottom flask equipped with a stir bar was brought into the glove box with a reflux condenser. The flask was charged with [RuHCl(CO)(HN(CH2CH2PPh2)2)] (4) (6.0 mg, 0.01 mmol, 1 mol %), KOH (8.2 mg, 0.15 mmol, 15 mol %), and toluene (1.0 mL), an amine (1 mmol, 1.0 equiv), and an alcohol (1 mmol, 1.0 equiv) in that order. After all reagents had been added to the flask, the reflux condenser was attached and secured with a Keck clamp. The top of the condenser was sealed with a septum and the whole apparatus was removed from the glove box. Onceoutside the glove box, the apparatus was subjected to nitrogen flow by inserting an inlet needle supplying a positive pressure of nitrogen into the septum, and an outlet needle connected to an oil bubbler. When the transformation was deemed complete on the basis of analysis by GC-MS (CI), the reaction mixture was allowed to cool to rt. 5 mL MeOH was added, and the resulting mixture was stirred until the solution was homogeneous. NaBH4 (95 mg, 2.5 mmol, 2.5 equiv) was added through the top of the flask,exposing the reaction to the atmosphere. The solution was stirredfor 1 h at rt. After 1 h, 3.5 mL 1 M HCl was added dropwise. The solution was then diluted with 50 mL of EtOAc, washed with 1 M KOH (350 mL), and finally brine (350 mL). The organic layer wasthen dried with MgSO4 and the excess solvent was removed in vacuo. The resulting residue was subjected to flash chromatography. |
With sodium tetrahydroborate; In ethanol; at 70℃;Green chemistry; | General procedure: To an equimolar mixture of benzaldehyde (0.5 g, 4.7 mmol), aniline (0.44 g, 4.7 mmol), in 5 ml ethanol was added sulfated polyborate (5wt%, 0.050 g) and stirred in an oil bath preheated to 70 C after 1 minute/TLC monitored for imines, added NaBH4 (0.349 g, 9.423 mmol) and completion of the reaction monitored by thin-layer chromatography. Upon completion of the reaction, cooled to room temperature and quenched in water/NaHCO3, and the product extracted by ethyl acetate; The organic layer was dried over sodium sulfate and condensed in a vacuum to get pure products. The products obtained were known compounds identified by 1H NMR spectroscopy, and the analytical data compared with the literature values. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With bis(trimethylsilyl)amide yttrium(III); 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane; In toluene; at 140℃; for 21h;Inert atmosphere; | Under nitrogen protection, N-cyclohexylbenzamide (0.5 mmol), pinacol borane (3.0 mmol), rare earth catalyst bistrimethylsilylamino yttrium (15 mol%) and solvent toluene ( 3ml) was stirred and mixed; after the mixing was uniform, the reaction was performed at a temperature of 140 C. for 21 h to obtain N-benzylcyclohexylamine; the final product yield was 82%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With formic acid; Cp*IrCl(N-(phenyl(pyridin-2-yl)methyl)methanesulfonamide)complex; In ethyl acetate; at 40℃; for 18h;Inert atmosphere; | Under an inert gas atmosphere, dehydrated ethyl acetate (5 mL), cyclohexanone (MW: 98.14) (518 μL, 5.0 mmol), and benzylamine (MW: 107.15) (627 μL, 5.75 mmol) were added in a 20-mL Schlenk and cooled with ice. Formic acid (MW: 46.03) (566 μL, 15.0 mmol) was added and stirred for about 5 min, then the ice bath was removed, catalyst 3 (MW: 624.22) (3.12 mg, 0.005 mmol, S/C=1000) was added, and the mixture was stirred at 40 C. for 18 h. After distilling off the solvent, 1 M KOH (15 mL) was added, and the mixture was extracted with dichloromethane (40 mL). The organic layer was dried over sodium sulfate, filtered, and diluted in a 50-mL measuring flask. Five mL of the solution was taken, the solvent was distilled off, and quantification by 1H-NMR was carried out using coumarin as the internal standard substance. The yield of the obtained cyclohexylbenzylamine was 100%. |
98% | Example 15; Synthesis of cyclohexylbenzylamine by reductive amination reaction of cyclohexanone and benzylamine; Under an argon-gas atmosphere, 520 μL (5.0 mmol) of cyclohexanone (MW: 98.15), 572 μL (5.25 mmol) of benzylamine (MW: 107.15), and 0.5 mL of dehydrated ethyl acetate (Kanto Chemical Co., Inc.) were added to a 20-mL Schlenk tube and ice-cooled. 566 μL (15.0 mmol) of formic acid (MW: 46.03) was added and stirred for approximately 5 min, then the ice bath was removed, and as reaction examples 7-10, 0.005 mmol of each of the complexes of Ir-1, Ir-2, Rh-1 and Rh-2 shown in FIG. 1 was added and stirred at 40 C. for 18 hr. After the reaction was completed, a saturated sodium hydrogen carbonate solution was added and stirred for approximately 5 min, then the product was extracted with ether. The organic phase was analyzed by GC to calculate conversion rates the reaction yields. Results of the analysis were summarized in Table 2. | |
With Versatic 6; acetic acid; In tetrahydrofuran; at 20℃; for 0.0333333h; | EXAMPLE 3Reductive Amination of Cyclohexanone and Benzylamine with Na[(CH3CH2(CH3)2COO)3BH]One equivalent each of cyclohexanone and benzylamine are stirred into THF at 20 C. After the addition of one equivalent of acetic acid, two equivalents of Na[(CH3CH2(CH3)2COO)3BH] dissolved in THF are added. After two minutes the reduction is concluded (GC). |
98%Spectr. | With formic acid; Cp*IrCl((S)-5-((3-methyl-2,3-dihydro-1H-benzoimidazol-1-yl)methyl)pyrrolidin-2-one); In ethyl acetate; at 40℃; for 18h;Inert atmosphere; | Catalyst 2 to Schlenk of 20mL(MW: 592.17) 3.25mg (0.06mmol, S / C = 500) were charged, and was replaced with argon gasafter drying under reduced pressure. This ethyl acetate 3mL, benzyl amine (MW: 107.15) 375μL(9.0) mmol, formic acid (MW: 46.03) 340μL (9.0mmol), cyclohexanone (MW: 98.14) 310μL (3.0mmol) was added, followed by 18 hours heated with stirring at 40 C. The solvent wasconcentrated under reduced pressure, added 1M KOH 12 mL, and extracted withdichloromethane 50mL, dried organic layer with sodium sulfate, filtered, and filled up to 50mLvolumetric flask. The solution 5mL up a whole pipette, transferred to a 20mL round-bottomedflask, and concentrated under reduced pressure, coumarin as an internal standard (MW: 146.14)using a was subjected to a quantitative determination by H-NMR, the reaction yield 98 %Met. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydridoborate; In methanol; at 0 - 20℃; for 2h;Inert atmosphere; | Cyclohexanone (3 g, 30.4 mmol), benzylamine (4.36 mL, 39.5 mmol) and sieves (4 Å, 6 g) in CH2Cl2 (30 mL) were stirred at rt for 4 h. The mixture was then filtered on a celite pad, concentrated and treated with NaBH4 (1.73 g, 45.7 mmol) in MeOH (40 mL) at 0 ºC then at rt for 2 h. After elimination of methanol, brine was added and the mixture was extracted with CH2Cl2. The organics were dried and the solvent removed to yield a viscous oil which was treated with trichloroacetylchloride (5.11 mL, 45.5 mmol) and triethylamine (8.52 mL, 61.1 mmol) at rt overnight. Water was then added and the mixture extracted with CH2Cl2. The organics were dried, concentrated and purified by chromatography (hexane/CH2Cl2 50:50 to CH2Cl2) to yield 1d (9.8 g, 96%). IR (NaCl, neat): 3086, 3063, 3030, 2936, 2859, 1971, 1951, 1873, 1854, 1806, 1775, 1667, 1495, 1453, 1418, 1362, 1325, 1284, 1243, 1161, 1141, 1029, 997, 891, 840, 823, 811, 736, 700, 670, 605, 531 cm-1; 1H NMR (CDCl3, 400 MHz): d 1.07 (qt, 1H, J = 13.2, 3.6 Hz, H-4ax), 1.32 (dt, 2H, J = 13.2, 12.8 Hz, H-3ax and H-5ax), 1.49 (q, 2H, J = 12.4 Hz, H-2ax and H-6ax), 1.66 (d, 1H, J = 13.2 Hz, H-4eq), 1.80 (d, 2H, J = 12.8 Hz, H-3eq and H-5eq), 1.92 (d, 2H, J = 11.2 Hz, H-2eq and H-6eq), 4.47 (brt, 1H, J = 12.0 Hz, H-1), 4.60 (s, 2H, CH2Ar),7.17-7.34 (m, 5H, ArH); 13C NMR (CDCl3, 100 MHz): d 25.1 (C-4), 25.6 (C3 and C-5), 30.9 (C-2 and C-6), 47.8 (CH2Ar), 59.3 (C-1), 93.7 (CCl3), 126.3, 126.8, 128.4 (Ar-CH), 137.6 (ipso-C), 160.6 (CO). HRMS (ESI-TOF): Calcd for C15H19Cl3NO 334.0527 (M++1). Found 334.0530. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With C50H38ClN3O2P2RuS; potassium hydroxide; In toluene; at 100℃; for 12h; | General procedure: A 10 mL round-bottomed flask, with a stirring bar, was charged with 1-mol % of ruthenium(II) catalyst, 1 mmol of amine, 1.2 mmol of alcohol, 4 mmol of KOH and 3 mL of toluene. The reaction mixture was heated at 100 C with stirring for 10 h on an oil bath. Upon completion (as monitored by TLC), the reaction mixture was cooled to room temperature, quenched with water (3 mL) and the organic products were extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulphate; passed through a pad ofcelite using ethyl acetate and concentrated by rotary evaporator to afford the crude organic product. This product was purified by using preparative thin layer chromatography using 5% ethyl acetate-hexane susing as the eluent. The product conversion was determined by GC whereas a few representative compounds were characterized by 1HNMR spectroscopy (see Figs. S40-S44; Supplementary Information). The reported isolated yields are an average of two runs. |
91% | With trifuran-2-yl-phosphane; palladacycle; lithium hydroxide; In neat (no solvent); at 100℃; for 24h;Molecular sieve; Inert atmosphere; | General procedure: An oven dried Schlenk tube was charged with amine (3.0 mmol), alcohol (3.6 mmol), LiOH (1.5 mmol), palladacycle (6.0*10-3 mmol, 0.20 mol %), P(2-Fur)3 (12.0*10-3 mmol, 0.40 mol %) and activated 4 Å MS (100 mg) in argon atmosphere. The reaction mixture was stirred at 100 C for 24 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and washed with water followed by brine solution. The organic phase was dried over anhydrous sodium sulphate. After removal of the solvent, the crude was subjected to column chromatography on silica gel using ethyl acetate and n-hexane mixtures to afford the N-alkylated product. |
85% | With sodium hydroxide; In toluene; at 110℃; for 12h; | General procedure: To 20-mL colorimetrictube was added 1a (46.5 mg, 0.5 mmol), 2a (81 mg,0.75 mmol), AgMnO2 nanorod catalyst (10 mg), NaOH(30.0 mg, 0.75 mmol), and toluene (3.0 mL). The mixturewas refluxed in air for 12 h and then cooled to room temperature.The resulting solution was directly purified bycolumn chromatography with petroleum ether/ethyl acetateas eluent to give the desired product |
80% | With C26H29ClIrN4O(1+)*F6P(1-); potassium tert-butylate; In toluene; at 110℃; for 48h;Inert atmosphere; Schlenk technique; Molecular sieve; | General procedure: Alcohol (1.00 mmol)and amine (1.10 mmol) were weighed into an oven-dried Schlenkflask containing 4Å molecular sieves (60 mg). tBuOK (0.50 mmol)was added, followed by dry toluene (0.50 mL). The mixture wasput under an atmosphere of nitrogen, and catalyst (0.01 mmol)was added before stoppering the flask and immersing it in a pre-heated oil bath (110C) for 48 h. Then, the solvent was evaporatedand the crude solid was purified by column chromatography using petroleum ether and triethylamine. The analytical data of all products are consistent with the data reported in literature [6j,8,11e]. |
77.7% | With W4 Raney nickel; In 5,5-dimethyl-1,3-cyclohexadiene; for 6h;Reflux; | General procedure: The prepared grades of R-Ni were weighed in water after considering its specific gravity. The residual water was removed using dean stark apparatus. (0043) All the reactions were carried out in a 2-neck round bottom flask, attached with a condenser. Typically, reaction was carried out by stirring and refluxing the reaction mixture of amine and alcohol with pretreated R-Ni in 20ml solvent. After reaction completion, reaction mixture was cooled and filtered using Whatman filter paper 40. The solvent was removed in vacuo. The mixture thus obtained was purified using column chromatography. The purified compounds obtained were characterized by IR, NMR, LC-MS and melting or boiling point. The analytical data obtained of the known compounds are in agreement to the reported literature. |
52% | In neat (no solvent); at 145℃; for 48h;Inert atmosphere; Sealed tube; | General procedure: Synthesis of N-phenylbenzylamine (3a): Under nitrogen atmosphere, to a 15-mL Pyrex glass screw-cap tube were added 1a (930 mg, 10 mmol), 2a (1080 mg, 10 mmol), and the Pt-Sn/γ-Al2O3 catalyst (195 mg, 0.05 mol % Pt). The resultant mixture was stirred in the sealed tube at 145 C for 8 h. After cooled to ambient temperature, the catalyst was removed by centrifugation and washed with Et2O (25 mL). The combined supernatant was concentrated under reduced pressure and then subjected to purification by silica gel column chromatography (eluent: petroleum ether (60-90 C)/EtOAc = 20:1, v/v), affording product 3a as a pale brown liquid (1740 mg, 95%). |
47% | With 2,2,4,4,6,6-hexachloro-1,3,5-triaza-2,4,6-triphosphorine; at 200℃; for 24h;Schlenk technique; Inert atmosphere; | General procedure: aniline 372.5mg (4mmol), and 4-methylbenzyl alcohol 244.3mg (2mmol), and 0.5mL of 1,2,4-trimethylbenzene (reaction solvent) were housed in a Schlenk flask. Then, to the flask was added 1,3,5-triazole-2,4,6-triphosphorine-2,2,4,4,6,6- chloride 34.8mg (0.1mmol), of these the mixture, under an argon gas atmosphere, was carried out with stirring for 24 hours at 160 . Thereafter, the procedure of Experimental Example 1-1, was obtained are shown (4-methylbenzyl) phenylamine following. The yield was 76%. Instead of aniline, using cyclohexylamine 396.7mg (4mmol),Instead of 4-methylbenzyl alcohol, with benzyl alcohol 216.3mg (2mmol), except that the reaction temperature was changed to 200 C., the procedure of Experimental Example 3-1, benzyl cyclohexylamine below Obtained. The yield was 47%. |
40% | With chloro(η5-pentamethylcyclopentadienyl)(L-prolinato)iridium(III); In toluene; at 150℃; for 72h; | The reaction of further alcohols (Al) with further aminating agents (Am) is shown in table (6) below. The reaction was carried out in toluene as solvent in the presence of 2 mol % of Cp*Ir(Pro)Cl as catalyst. The reaction conditions and yields are shown in table (6) below. |
86%Chromat. | With CuO#NiO; at 140℃; for 15h;Inert atmosphere; | [0044] With reference to the conditions used in Examples 9-16, 60-150 mg of catalyst D obtained in Example 4 was weighted and added into a 40 mL glass reaction tube provided with a magnetic stirring apparatus containing 5 mmol amines having different structures and 5 mmol alcohols having different structures, respectively. After sealed, the tube was purged with N2 to replace the air in the system for three times. Next, the system was heated and stirred. The temperature was raised to 80-180 C. and then kept for 6-36 hours. The reaction was then stopped and the system was cooled down to the room temperature. The catalyst was obtained from the reaction mixture by filtration. Agilent 7890A (30 m×0.25 mm×0.33 μm capillary column, hydrogen flame ionization detector) gas chromatograph was used for quantitatively analyzing the reaction mixture. The other byproducts were qualitatively analyzed with Agilent 6890/5973 Gas Chromatography-Mass Spectrometer (equipped with NIST Mass Spectral Database chemical workstation, 30 m×0.25 mm×0.33 μm capillary column). Each of the analysis results was shown in Table 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With lithium; In tetrahydrofuran; at 25℃; for 2h;Inert atmosphere; | General procedure: A mixture of lithium sand (21 mg, 3.0 mmol) and DTBB (26 mg, 0.1 mmol) in THF (2 mL) was stirred at room temperature under nitrogen atmosphere. When the reaction mixture turned dark green (5-20 min), indicating the formation of the lithium arenide, a solution of the primary amine (1.0 mmol) in THF (2 mL) was slowly added by syringe, followed by the addition of the corresponding aldehyde (1.0 mmol) in THF (2 mL). After total conversion of the starting material (TLC, GC-MS), the resulting suspension was diluted with ethyl ether (10 mL) and washed with H2O (3 × 10 mL). The combined extracts were dried over anhydrous Na2SO4 and evaporated (20 mbar). The resulting residue was purified by flash column chromatography (silica gel, hexane-ethyl acetate) to give the corresponding secondary amine. |
100% | General procedure: To generate Compound 1, cyclohexylamine (0.5M in MeOH) was combined with benzaldehyde (0.5M in MeOH) and stirred for 3h at 64C. The mixture was cooled to rt, followed by two additions of sodium cyanoborohydride (0.5M in EtOH), each followed by stirring at rt for 30m. The mixture was then heated to 64C for 6h. The reaction mixture was worked-up with water and extracted three times with CH2Cl2. The organic fractions were pooled, dried with magnesium sulfate, and reduced in vacuo. Thesecondary amine was then solubilized in dry CH2Cl2 and combined with 4-chloro-benzoylchloride. Equivalents were based upon the assumption that the secondary amine was formed in 100% yield. Dimethylaminopyridine (0.1equiv) was solubilized in dry CH2Cl2 and added directly to the stirring solution of secondary amine, followed by addition of diisopropylethylamine (1.1equiv). The reaction was then capped, purged with nitrogen gas, and stirred at rt overnight. The reaction mixture was then reduced in vacuo to an oil, which was resolubilized and purified using reverse phase preparative HPLC (isocratic elution: 75% acetonitrile, 25% water). Following preparative HPLC, compound purity was determined using reverse phase analytical HPLC. Compounds were purified to an average purity of greater than 95% (supplementary Table 1). | |
98% | With 1.1 wt% Pd/NiO; hydrogen; In ethanol; at 25℃; under 760.051 Torr; for 10h; | benzaldehyde (106 mg, 1 mmol), cyclohexanamine (99 mg, 1 mmol) and 20 mg 1.1 wt% Pd/NiO were added into a 50 mL reaction tube and reacted at 25 C under hydrogen atmosphere for 10 h. The crude mixture was purified by filtration and after direct rotary evaporation. Following the procedure above,N-benzylcyclohexanamine was obtained (185mg, Isolated yield = 98%). |
93% | With ammonium acetate; In benzene; for 1.5h;Reflux; | To a 50-mL round-bottomed flask containing ammonium formate (0.69 g, 11 mmol) was added piperonal (1.65 g, 11 mmol) followed by pyrrolidine (0.78 g, 11 mmol) and toluene (20 mL). The mixture was magnetically stirred and heated at reflux with continuous removal of the water formed (Dean-Stark trap). The mixture was then cooled to room temperature and the solvent was removed by rotary evaporation. The crude product was purified by distillation under reduced pressure and afforded the amine. |
86% | In toluene; at 25℃; for 24h; | General procedure: To a stirred solution of aldehyde (2, 1 mmol) in toluene (2 mL) were added PdO-Fe3O4 (50 mg, 1.2 mol % of Pd), PMHS (2 mmol, 0.12 mL) and the corresponding amine (1 or 4, 1 mmol). The resulting mixture was stirred at room temperature or at 130 C until the end of reaction. 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 3 or 5 were purified by chromatography on silica gel (hexane/ethyl acetate). |
70.1% | With titanium isopropoxide; sodium tetrahydridoborate; In methanol; at 20 - 80℃; for 4h;Inert atmosphere; | 2.12 g of cyclohexylamine, 2.5 g of benzaldehyde, 70 ml of methanol,3.7 g of tetraisopropyl titanate and 2.50 g of sodium borohydride.N2 protection, at room temperature cyclohexylamine benzaldehyde were added to mix,Drop in tetraisopropyl titanate manually. After stirring for 1h, the temperature was raised to 80 C and the reaction was stopped after stirring for 3h.Cooling, sodium borohydride in batches, the temperature controlled at below 10 .After adding, stirring 10-20min, quenched by adding sodium bicarbonate solution.Methanol was decanted, 100ml sodium bicarbonate solution was added,Dichloromethane extraction, drying,Spin dry. Column chromatography, yield: 70.1%. |
61.8% | After 1 g (9.423 mmol) of benzaldehyde was dissolved in 10 mL of methanol, 0.934 g (9.423 mmol) of cyclohexylamine was added thereto and reacted at room temperature for 1 hour. 0.53 g (14.13 mmol) of sodium borohydride was slowly added thereto and stirred for 1 hour. The degree of progress of reaction was confirmed by TLC. When the reaction did not proceed further, 40 mL of water was added to the mixture, and the mixture was extracted twice with 30 mL of methylene chloride. The extracts were combined, dried with anhydrous magnesium sulfate to remove water, and then distilled under reduced pressure. The resulting reaction product was separated using a silica gel-filled column with a mixed solvent of ethyl acetate and n-hexane as a mobile phase, to thereby obtain a colorless liquid of benzyl-cyclohexyl-amine. Yield: 61.8% .1H NMR (300 MHz, CDCl3) δ 7.32 (m, 5H), δ 3.77 (s, 2H), δ 3.16 (m, 1H), δ 1.90 (m, 10H) . | |
92%Chromat. | With hydrogen; In water monomer; at 80℃; under 22502.3 Torr; for 8h;Inert atmosphere; Autoclave; Green chemistry; | General procedure: To a 100 mL autoclave were added aldehyde (2.5 mmol) and amine (2.5 mmol) results the formation of imine, then catalyst(1 mol%), and water (15 mL) were added and reactor was closed. The reactor was then purged 3 times with nitrogen and finally reaction mixture was pressurized to 30 bar of hydrogen pressure. The reactor was heated to 80 C and stirred for 8 h at 500 rpm. After completion, the reactor was cooled to room temperature and the remaining hydrogen gas was carefully removed. The catalyst was separated from reaction mixture by using magnet. The product from aqueous phase was extracted with ethyl acetate. The ethyl acetate layer wase vaporated in vacuum by rotary vapour to obtain the product. All the products are well known in literature and were confirmed by GC (Perkin Elmer, Clarus 400) (BP-10 GC column, 30 m × 0.32 mm ID, film thickness 0.25 mm) and GCMS (Shimadzu GC-MS QP 2010) |
With triisopropyltin triflate[18b]; hydrogen; In 1,2-dichloro-benzene; at 180℃; under 7500.75 Torr; for 14h; | General procedure: A solution of imine (0.2 mmol) and, if necessary*, collidine (2.6 pL, 0.02 mmol) in 1,2- dichlorobenzene (0.7 mL) was added to iPr3SnOTf in a Wilmad high pressure NMR tube fitted with a PV-ANV PTFE valve. The solution was freeze-pump-thaw degassed once. H2 was admitted (after complete thawing) up to a pressure of 10 bar at RT. The reaction mixturewas heated in an Al bead bath, and the results are presented in Table 1.*collidine only required when aniline (PhNH2) is the reagent amine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73%; 8% | With 4,4'-di-tert-butylbiphenyl; lithium; In tetrahydrofuran; at 25℃; for 5h;Inert atmosphere; | General procedure: A mixture of lithium sand (21 mg, 3.0 mmol) and DTBB (26 mg, 0.1 mmol) in THF (2 mL) was stirred at room temperature under nitrogen atmosphere. When the reaction mixture turned dark green (5-20 min), indicating the formation of the lithium arenide, a solution of the primary amine (1.0 mmol) in THF (2 mL) was slowly added by syringe, followed by the addition of the corresponding aldehyde (1.0 mmol) in THF (2 mL). After total conversion of the starting material (TLC, GC-MS), the resulting suspension was diluted with ethyl ether (10 mL) and washed with H2O (3 × 10 mL). The combined extracts were dried over anhydrous Na2SO4 and evaporated (20 mbar). The resulting residue was purified by flash column chromatography (silica gel, hexane-ethyl acetate) to give the corresponding secondary amine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With ammonium formate; acetic acid;palladium-carbon; In methanol; ethyl acetate; | Step C 1(R)-Amino-2(R)-phenyl-3(R)-t-butyldimethylsilyloxymethylcyclohexane STR137 To a solution of the <strong>[4383-25-9]cyclohexylbenzylamine</strong> (100 mg, 0.24 mmol) from step B in 1:1 EtOAc/MeOH (5 mL) was added 10% Pd/C (100 mg), ammonium formate (303 mg, 4.8 mmol) and acetic acid (209 mg, 3.5 mmol). The mixture was stirred at room temperature for 5 days, filtered thru celite, washed with methanol and concentrated in vacuo. The residue was purified by column chromatography (20 g silica gel 60, 20 mm diam. column, 2.5-8% MeOH/CH2 Cl2) to afford a yellow oil (25 mg, 33%). 1 H NMR (CDCl3, 500 MHz) δ 7.19-7.34 (m, 5H), 3.44 (dd, 1H, J=2.5, 7.3 Hz), 3.25 (dd, 1H, J=3.7, 6.2 Hz), 3.10 (bs, 1H), 2.70 (dd, 1H, J=2.8, 9.1 Hz), 2.22-2.30 (m, 3H), 1.99-2.03 (m, 1H), 1.92 (d, 1H, J=11.7 Hz), 1.61-1.78 (m, 3H), 1.29-1.38 (m, 1H), 0.83 (s, 9H), -0.11 (s, 3H), -0.18 (s, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
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80% | To this imine (37.4 g; 0.2 mole) was added phosphorous acid (16.4 g; 0.2 mole) and the mixture stirred while heating. The reaction mixture became a homogeneous liquid at 70 and at 95-100 a vigorous reaction took place. After keeping at 110-130 for 30 minutes the mixture was cooled and diluted with water. Basification with NaOH and extraction with benzene gave after evaporation of the solvent N-benzylcyclohexylamine (80%). Distillation gave pure N-benzylcyclohexylamine bp 120-125/3 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tert.-butylhydroperoxide;Rh2(cap)4; In acetonitrile; at 20℃; for 16h;Product distribution / selectivity; | Example 7 Oxidation of Secondary AminesRh2(cap)4/tert-Butyl hydroperoxide can be used under anhydrous conditions to mediate the oxidation of secondary amine, as shown below: N-Phenylbenzylamine (1) was selected to determine suitable conditions for oxidation with TBHP catalyzed by Rh2(cap)4 at 1.0 mol % catalyst loading (Table 1). Previously described conditions for benzylic oxidation (entry 1)9b gave complete conversion of 1, but benzylidineaniline (2) was accompanied by its hydrolysis product benzaldehyde (3). Benzaldehyde formation with complete substrate conversion was diminished in the absence of NaHCO3 (entry 2). Attempts to decrease the extent of hydrolysis even further using molecular sieves or anhydrous MgSO4 were unsuccessful (entries 3 and 4) because they significantly limited the oxidation of 1. Methanol, the solvent of choice for the oxidation of N-aryl tertiary amines,10 was found be effective (entry 5); however, when <strong>[4383-25-9]N-<strong>[4383-25-9]cyclohexylbenzylamine</strong></strong> was submitted to reaction under the same conditions, no imine product was obtained at room temperature (entry 6), and only trace amounts were obtained at temperatures up to 60 C. However, the use of acetonitrile as the solvent gave optimal results for both N-phenyl- and <strong>[4383-25-9]N-<strong>[4383-25-9]cyclohexylbenzylamine</strong></strong> substrates (entries 7 and 8) with quantitative conversion, chromatographically pure product in high yield, and the absence of hydrolysis. We assume that steric effects in the two solvents are responsible for the difference in reaction outcomes (entries 6 and 8). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64%Chromat.; 35%Chromat. | With 2 wtpercent ruthenium immobilized in calcium hydroxyapatite; In 1,3,5-trimethyl-benzene; at 130℃; for 48h;Inert atmosphere; | General procedure: All reactions were performed in glass batch reactors under inertargon atmosphere and were stirred magnetically. Ru/HAP is usedwithout further activation. Unless stated otherwise, a Ru/HAP with2 wt% Ru was used. For a standard reaction 1 mL of mesitylenesolvent, 0.5 mmol of amine and 2 mmol of alcohol were added tothe vial containing 3 mol% of Ru/HAP (15 mol Ru, 75 mg of the2 wt% catalyst). As an internal standard tetradecane (0.25 mmol)was added and appropriate response factors were determined. Thebatch reactor was then thoroughly flushed with argon to minimizeoxidation of substrates with residual oxygen, before the reactionwas started at 130C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With N-chloro-succinimide; In dichloromethane; at -10 - 20℃; for 0.25h;Inert atmosphere; | General procedure: All chlorinations were achieved using a modified procedure of Gottlich in which a flame dried and N2 purged flask was charged with amine (1 mmol) and dry and degassed CH2Cl2 (10 mL). The reaction solution was cooled to -10C and treated with N-chlorosuccinimide (1.5 mmol) stirred for 10 min and then allowed to warm to RT, where it was stirred for 5min. At this point most reactions were complete by TLC analysis, solvent was removed in vacuo and the residue subjected to column chromatography (1:9 EtOAc/hexane), Rf's shown below. While most N-chloramines reported are new mass spectral analysis invariably failed to provide meaningful results with data corresponding to loss of the chloride observed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In diethyl ether |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With C22H27ClN3Ru(1+)*F6P(1-); hydrogen; In isopropyl alcohol; at 80℃; under 45004.5 Torr; for 12h; | General procedure: All of the hydrogenation reactions were performed at constant pressures using a stainless steel 50mL Parr hydrogenation reactor. The reactor was flushed three times with hydrogen gas at 2-4bar prior to the addition of catalyst and substrate. Catalyst 1 (0.02mmol), nitrile (1mmol), and dodecane (1mmol) in case of symmetrical amine synthesis or, catalyst 1 (0.02mmol), nitrile (1mmol), amine (3mmol) and dodecane (1mmol) in case of asymmetrical amine synthesis were dissolved in iPrOH (5mL) under a nitrogen atmosphere. The solution was then injected into the reactor against a flow of hydrogen gas. The hydrogen gas was adjusted to 60bar. The temperature of the system was maintained at 80C using a thermostat. Small aliquots of the reaction mixture were withdrawn after 12h with a syringe and diluted with 2mL of EtOAc and passed through a very short column of silica and subjected to GC-MS analysis. A few selected secondary amines were purified by flash chromatography and characterized by 1H and 13C NMR spectra. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44%; 56% | With Mg-Al hydrotalcite supported copper; at 180℃; for 15h; | General procedure: A mixture of ketone/amine and alcohol in required molar ratio along with the catalyst was taken in a 50 mL reaction tube of reaction station at desired temperature under stirring for required reaction time. Afterwards the reaction mixture was cooled and diluted with dichloromethane (5 mL). The catalyst was filtered to recover it from the liquid phase. The reaction mixture was analyzed by gas chromatography (Agilent 5975) having a HP-5 (60 m) capillary column with a programmed oven temperature from 50 to 280 C, a 0.5 cm3/min flow rate of N2 as carrier gas and FID detector. The conversion of substrate (ketone/amine) was calculated on the basis of its weight percent. The products formed in the reactions were characterized by GC-MS analysis. The values in parenthesis given in all tables are selectivity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.8 g | With triethylamine; In methanol; at 20℃;Inert atmosphere; | Cyclohexanone (3 g, 30.4 mmol), benzylamine (4.36 mL, 39.5 mmol) and sieves (4 Å, 6 g) in CH2Cl2 (30 mL) were stirred at rt for 4 h. The mixture was then filtered on a celite pad, concentrated and treated with NaBH4 (1.73 g, 45.7 mmol) in MeOH (40 mL) at 0 ºC then at rt for 2 h. After elimination of methanol, brine was added and the mixture was extracted with CH2Cl2. The organics were dried and the solvent removed to yield a viscous oil which was treated with trichloroacetylchloride (5.11 mL, 45.5 mmol) and triethylamine (8.52 mL, 61.1 mmol) at rt overnight. Water was then added and the mixture extracted with CH2Cl2. The organics were dried, concentrated and purified by chromatography (hexane/CH2Cl2 50:50 to CH2Cl2) to yield 1d (9.8 g, 96%). IR (NaCl, neat): 3086, 3063, 3030, 2936, 2859, 1971, 1951, 1873, 1854, 1806, 1775, 1667, 1495, 1453, 1418, 1362, 1325, 1284, 1243, 1161, 1141, 1029, 997, 891, 840, 823, 811, 736, 700, 670, 605, 531 cm-1; 1H NMR (CDCl3, 400 MHz): d 1.07 (qt, 1H, J = 13.2, 3.6 Hz, H-4ax), 1.32 (dt, 2H, J = 13.2, 12.8 Hz, H-3ax and H-5ax), 1.49 (q, 2H, J = 12.4 Hz, H-2ax and H-6ax), 1.66 (d, 1H, J = 13.2 Hz, H-4eq), 1.80 (d, 2H, J = 12.8 Hz, H-3eq and H-5eq), 1.92 (d, 2H, J = 11.2 Hz, H-2eq and H-6eq), 4.47 (brt, 1H, J = 12.0 Hz, H-1), 4.60 (s, 2H, CH2Ar),7.17-7.34 (m, 5H, ArH); 13C NMR (CDCl3, 100 MHz): d 25.1 (C-4), 25.6 (C3 and C-5), 30.9 (C-2 and C-6), 47.8 (CH2Ar), 59.3 (C-1), 93.7 (CCl3), 126.3, 126.8, 128.4 (Ar-CH), 137.6 (ipso-C), 160.6 (CO). HRMS (ESI-TOF): Calcd for C15H19Cl3NO 334.0527 (M++1). Found 334.0530. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37 mg | With dmap; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Inert atmosphere; | General procedure: General procedure: To generate Compound 1, cyclohexylamine (0.5M in MeOH) was combined with benzaldehyde (0.5M in MeOH) and stirred for 3h at 64C. The mixture was cooled to rt, followed by two additions of sodium cyanoborohydride (0.5M in EtOH), each followed by stirring at rt for 30m. The mixture was then heated to 64C for 6h. The reaction mixture was worked-up with water and extracted three times with CH2Cl2. The organic fractions were pooled, dried with magnesium sulfate, and reduced in vacuo. Thesecondary amine was then solubilized in dry CH2Cl2 and combined with 4-chloro-benzoylchloride. Equivalents were based upon the assumption that the secondary amine was formed in 100% yield. Dimethylaminopyridine (0.1equiv) was solubilized in dry CH2Cl2 and added directly to the stirring solution of secondary amine, followed by addition of diisopropylethylamine (1.1equiv). The reaction was then capped, purged with nitrogen gas, and stirred at rt overnight. The reaction mixture was then reduced in vacuo to an oil, which was resolubilized and purified using reverse phase preparative HPLC (isocratic elution: 75% acetonitrile, 25% water). Following preparative HPLC, compound purity was determined using reverse phase analytical HPLC. Compounds were purified to an average purity of greater than 95% (supplementary Table 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8 mg | With dmap; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Inert atmosphere; | General procedure: To generate Compound 1, cyclohexylamine (0.5M in MeOH) was combined with benzaldehyde (0.5M in MeOH) and stirred for 3h at 64C. The mixture was cooled to rt, followed by two additions of sodium cyanoborohydride (0.5M in EtOH), each followed by stirring at rt for 30m. The mixture was then heated to 64C for 6h. The reaction mixture was worked-up with water and extracted three times with CH2Cl2. The organic fractions were pooled, dried with magnesium sulfate, and reduced in vacuo. Thesecondary amine was then solubilized in dry CH2Cl2 and combined with 4-chloro-benzoylchloride. Equivalents were based upon the assumption that the secondary amine was formed in 100% yield. Dimethylaminopyridine (0.1equiv) was solubilized in dry CH2Cl2 and added directly to the stirring solution of secondary amine, followed by addition of diisopropylethylamine (1.1equiv). The reaction was then capped, purged with nitrogen gas, and stirred at rt overnight. The reaction mixture was then reduced in vacuo to an oil, which was resolubilized and purified using reverse phase preparative HPLC (isocratic elution: 75% acetonitrile, 25% water). Following preparative HPLC, compound purity was determined using reverse phase analytical HPLC. Compounds were purified to an average purity of greater than 95% (supplementary Table 1).For Compound 1: IR (thin film from CDCl3): 2935, 2858, 2246, 1624, 1495, 1418, 1091, 908, 838, 734 cm-1; 1H NMR (400MHz, CDCl3) δ 7.52 (4H), 7.36 (4H), 7.20 (2H), 4.55 (1H), 3.65 (1H), 1.80 (4H), 1.47 (4H), 1.06 (2H); 13C NMR (75MHz, CDCl3) δ 171.2, 142.5, 139.0, 135.2, 128.7, 128.4, 127.7, 126.8, 77.17, 59.4, 59.4, 44.6, 32.0, 30.8, 25.7, 25.1, 25.1, 9.29; HRMS m/z calculated for (M+H); 328.1390, found: 328.1477 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.4%; 34.6% | With W4 Raney nickel; In 5,5-dimethyl-1,3-cyclohexadiene;Reflux; | General procedure: The prepared grades of R-Ni were weighed in water after considering its specific gravity. The residual water was removed using dean stark apparatus. (0043) All the reactions were carried out in a 2-neck round bottom flask, attached with a condenser. Typically, reaction was carried out by stirring and refluxing the reaction mixture of amine and alcohol with pretreated R-Ni in 20ml solvent. After reaction completion, reaction mixture was cooled and filtered using Whatman filter paper 40. The solvent was removed in vacuo. The mixture thus obtained was purified using column chromatography. The purified compounds obtained were characterized by IR, NMR, LC-MS and melting or boiling point. The analytical data obtained of the known compounds are in agreement to the reported literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37.5%; 62.5% | With W4 Raney nickel; In 5,5-dimethyl-1,3-cyclohexadiene;Reflux; | General procedure: The prepared grades of R-Ni were weighed in water after considering its specific gravity. The residual water was removed using dean stark apparatus. (0043) All the reactions were carried out in a 2-neck round bottom flask, attached with a condenser. Typically, reaction was carried out by stirring and refluxing the reaction mixture of amine and alcohol with pretreated R-Ni in 20ml solvent. After reaction completion, reaction mixture was cooled and filtered using Whatman filter paper 40. The solvent was removed in vacuo. The mixture thus obtained was purified using column chromatography. The purified compounds obtained were characterized by IR, NMR, LC-MS and melting or boiling point. The analytical data obtained of the known compounds are in agreement to the reported literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89%Chromat. | With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; 1,3-bis-(diphenylphosphino)propane; potassium carbonate; In toluene; at 110℃; for 12h;Molecular sieve; Inert atmosphere; Schlenk technique; | General procedure: Ruthenium complex (0.015 mM), diphosphine ligand (0.07 mM), potassium carbonate (0.03 mM), and activated molecular sieves 3Å (0.1 g) were added to the reaction flask. The mixture was exposed to nitrogen for 10 min. Amine (1.0 mM), benzyl alcohol (1.0 mM), and dry toluene as solvent (1.0 mL) were added and refluxed for 12 h. After filtration, the reaction mixture was extracted three times with 5% hydrochloric acid solution, then the pH of the combined aqueous phase was adjusted to nine by the addition of dilute sodium hydroxide solution. The aqueous phase was extracted with dichloromethane and dried over MgSO4 prior to the injection to GC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 2,3-dicyano-5,6-dichloro-p-benzoquinone; In dichloromethane; water; at 20℃; for 12h; | General procedure: To astirred solution of the N-allyllic amine (1 mmol) dissolved in 9 mL ofCH2Cl2 and 1 mL of water, DDQ (1.2 equiv) was added intermittentlyin 3-4 portions. Reaction progress was monitored by TLC. Upon consumption ofthe starting material,2,3-dichloro-5,6-dicyanohydroquinone (DDQH2) was removed byfiltration. A saturated NaHCO3 solution was added to the filtrateand the aqueous phase was extracted twice with CH2Cl2 (2x 15 mL). Drying over Na2SO4, evaporation to dryness gavea material that was purified by flash column chromatography using neutral orbasic alumina as stationary phaseand hexane-CH2Cl2(3:7) as eluent. The compound was characterized by comparison with authentic samplesand by spectral data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With [(nBu3Sn)2WO4]; dihydrogen peroxide; In methanol; water; at 20℃; for 5h;Catalytic behavior; | General procedure: Four mol% (33 mg) of organometallic coordinationpolymer [(nBu3Sn)2WO4], was added to a stirred solutionof methanol (2 mL) and amine (1.0 mmol) and theresultant suspension was stirred for 2 min. To this, 3-4 mmol aqueous hydrogen peroxide (30 wt%) was added,after which the reaction mixture was stirred at r.t., untilcompletion of the reaction as indicated by thin-layerchromatography (TLC). The catalyst was filtered andwashed with acetone several times. Excess hydrogenperoxide was decomposed by adding small portions ofsodium hydrogen sulphite. The solution was extractedwith dichloromethane. The combined organic extractswere dried over anhydrous sodium sulfate. The mixturewas filtered and the solvent was removed by a rotaryevaporator and the crude residue was purified bypreparative thin-layer chromatography using ethyl acetateand n-hexane (1:4) as eluents to give correspondingnitrone or oxime derivatives. All the products are knowncompounds (except 7b) and were characterized bycomparison of their IR, 1H NMR and 13C NMR spectroscopicdata and respective melting points with the reportedvalues. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate;Cooling with ice; | Into a 1-L Erienmeyer flask with stirrer bar were charged 360 mL (ca. 3.5 equiv) of cyclohexylamine and 500 mL of ethyl acetate and the solution was cooled in an ice bath. To the stirred solution was added drop wise in ca. 2.0 h 153.9 g (107.0 mL; 0.9 mol) of benzyl bromide and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was filtered with the aid of 500 mL of toluene. The filtrate was washed with water and brine, dried over sodium sulfate, and after filtration volatiles were evaporated. Residual cyclohexylamine was removed by co-evaporation with toluene. This gave 186.6 g (98%) of product as a colorless liquid sufficiently pure for the next step. It contained less than 2% of bis-alkylation product (<5 3.60). 1H NMR δ 1.01 -1.32 (m, 6 H) and 1.53-1.93 (m, 5 H) (c-Hex and N-H), 2.46 (tt, 1 H, HC-N), 3.78 (s, 2 H, CH2Ph), 7.20-7.55 (m, 5 H, Ph); 13C NMR <5 25.19, 26.40 and 33.77 (c-Hex), 51.25 (HC-N), 56.36 (CH2Ph), 126.96, 128.23 and 128.52 (C-H, Ph), 141.23 (q-C, Ph). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68%; 22%; 12% | With iodine; sodium carbonate; In chloroform; at 60℃; for 24h; | General procedure: To a solution of N,N-diisopropyl-p-bromobenzylamine (1.0 mmol, 270.2 mg) in CHCl3 (2.0 mL) was added I2 (1.5 mmol,380.7 mg) and Na2CO3 (2.0 mmol, 212.0 mg) at room temperature, and the mixture was stirred for 24 h at 60 C. The reaction mixture was cooled to room temperature and quenched by satd aq Na2SO3 (10 mL), and extracted with CHCl3 (20 mL 3). Then, the organic layer was dried over Na2SO4. After removal of the solvent under reduced pressure, the yield was determined by 1H NMR analysis (89%). The residue was purified by short column chromatography on neutral silica gel (AcOEt/EtOH = 7:3) to afford N-isopropyl-p-bromobenzylamine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With C27H31ClN3Ru(1+)*Br(1-); hydrogen; In isopropyl alcohol; at 80℃; under 45004.5 Torr; for 12h; | General procedure: All of the hydrogenation reactions were performed at constant pressures using a stainless steel 50mL Parr hydrogenation reactor. The reactor was flushed three times with hydrogen gas at 2-4bar prior to the addition of catalyst and substrate. Catalyst 1 (0.02mmol), nitrile (1mmol), and dodecane (1mmol) in case of symmetrical amine synthesis or, catalyst 1 (0.02mmol), nitrile (1mmol), amine (3mmol) and dodecane (1mmol) in case of asymmetrical amine synthesis were dissolved in iPrOH (5mL) under a nitrogen atmosphere. The solution was then injected into the reactor against a flow of hydrogen gas. The hydrogen gas was adjusted to 60bar. The temperature of the system was maintained at 80C using a thermostat. Small aliquots of the reaction mixture were withdrawn after 12h with a syringe and diluted with 2mL of EtOAc and passed through a very short column of silica and subjected to GC-MS analysis. A few selected secondary amines were purified by flash chromatography and characterized by 1H and 13C NMR spectra. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With dmap; In toluene; at 20℃; for 15h; | General procedure: To a solution of freshly distilled α-hydroxy cyclobutanone (1.338 mmol, 0.116 g) or α-hydroxy cyclopentanone (1.338 mmol, 0.134 g), DMAP (0.0896 mmol, 0.0109 g) in dry Toluene (1.0 mL) at room temperature was added dropwise the benzylamine (0.448 mmol), and the mixture was stirred for 15 h. The crude reaction mixture was directly loaded on silica gel column without aqueous work-up and pure products were obtained by flash column chromatography (silica gel, mixture of petroleum ether/ether, 5:11:1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36%; 15% | With ammonium cerium (IV) nitrate; In water; acetonitrile; at 20℃; for 1h; | General procedure: To a solution of 34.5 mg (0.099 mmol) of 3be (Z/E=73/27) in 1.0 mL of MeCN 0.20 mL of water were added followed by 155.7 mg (0.28 mmol) of (NH4)2[Ce(NO3)6]. The reaction mixture was stirred at room temperature for 1 h, diluted with satd. NaHCO3 and satd. Na2SO3 and stirred for additional 10 min. Resulted mixture was extracted with CH2Cl2, combined extracts were dried over K2CO3 and concentrated. The residue was purified by flash column chromatography (n-hexane/EtOAc=1/1) affording 22.4 mg of 11b as a yellowish liquid (Z/E=72/28, yield 97%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A 4-ml screw neck vial was charged with gem-fluorohalocyclopropane (0.50 mmol) and CuX (0.10 mmol). In a stream of argon MeCN (0.50 mL) was added. The vial was quickly sealed and the reaction mixture was stirred at 100 C for 5 h. GC analysis of a reaction aliquot showed the completion of the cyclopropane isomerization. Next, HNR2 or HNR2·HCl (0.60 mmol) and K2CO3 (1.5 mmol) were added and the reaction mixture was stirred at room temperature for additional 2 h. The desired product was isolated as written above. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50%; 64%; 31% | With ammonium cerium (IV) nitrate; In water; acetonitrile; at 20℃; for 1h; | General procedure: To a solution of 34.5 mg (0.099 mmol) of 3be (Z/E=73/27) in 1.0 mL of MeCN 0.20 mL of water were added followed by 155.7 mg (0.28 mmol) of (NH4)2[Ce(NO3)6]. The reaction mixture was stirred at room temperature for 1 h, diluted with satd. NaHCO3 and satd. Na2SO3 and stirred for additional 10 min. Resulted mixture was extracted with CH2Cl2, combined extracts were dried over K2CO3 and concentrated. The residue was purified by flash column chromatography (n-hexane/EtOAc=1/1) affording 22.4 mg of 11b as a yellowish liquid (Z/E=72/28, yield 97%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
110.3 g | With Oxone; potassium hydrogencarbonate; In water; acetone; at 40℃; for 3.5h; | General procedure: Product of Step 1 dissolved in 450 mL of acetone was added to a 2-L beaker containing a mechanically stirred solution/suspension of 250 g of sodium bicarbonate in 450 mL of water. 460 g of Oxone (1.13 mole equiv) was added in small portions of ca. 10 g in the course of 1 h; small portions of crushed ice were occasionally added to maintain the temperature below ca. 40 C. After Oxone addition was complete, stirring was continued for 1 h. Next, 400 mL of ethyl acetate was added and after stirring for 5 min the reaction mixture was allowed to phase separate, where after the top layer was decanted; this was repeated 3 times with 200-mL portions of ethyl acetate. Next, the combined organic phases were washed twice with brine, dried over sodium sulfate, and after filtration solvents were removed by evaporation to leave a reddish liquid that may crystallize on standing. Yield 70.6 g (85% or 70% over 2 steps). The product obtained is sufficiently pure for further use; According to the general recipe disclosed in Example 1 using the crude product of Step 1 and 410 g of potassium bicarbonate in 500 mL of acetone and 1000 mL of water, then adding portion wise at ambient temperature 700 g of Oxone in 2.5 h (500 mL of ethyl acetate used in the first extraction now added at 60% completion of Oxone addition to counteract foaming due to precipitation of the nitrone formed), gave crude product, which was recrystallized from n-heptane-ethyl acetate (7:1 v/v). Yield: 1 10.3 g (60%) of nitrone as a single isomer. 1H NMR δ 1.1 1 -1.39 (m, 3 H), 1.60 (m, 1 H) and 1.83-2.12 (m, 6 H) (c-Hex), 3.79 (tt, 1 H, HC-N), 7.28-7.38 (m, 3H, Ph), 7.38 (s, 1 H, HC=N), 8.21 (m, 2 H, Ph); 13C NMR δ 25.12, 25.12 and 31.22 (c-Hex), 75.69 (HC-N), 128.48, 128.59 and 130.06 (C-H, Ph), 130.95 (q-C, Ph), 132.19 (C=N). |
Tags: 4383-25-9 synthesis path| 4383-25-9 SDS| 4383-25-9 COA| 4383-25-9 purity| 4383-25-9 application| 4383-25-9 NMR| 4383-25-9 COA| 4383-25-9 structure
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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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