Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 38235-77-7 | MDL No. : | MFCD00015010 |
Formula : | C15H17N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZYZHMSJNPCYUTB-CYBMUJFWSA-N |
M.W : | 211.30 | Pubchem ID : | 1268086 |
Synonyms : |
|
Num. heavy atoms : | 16 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 68.31 |
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) : | -5.32 cm/s |
Log Po/w (iLOGP) : | 2.96 |
Log Po/w (XLOGP3) : | 3.19 |
Log Po/w (WLOGP) : | 3.06 |
Log Po/w (MLOGP) : | 3.6 |
Log Po/w (SILICOS-IT) : | 3.64 |
Consensus Log Po/w : | 3.29 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.45 |
Solubility : | 0.0748 mg/ml ; 0.000354 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.11 |
Solubility : | 0.162 mg/ml ; 0.000769 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -5.81 |
Solubility : | 0.000325 mg/ml ; 0.00000154 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.45 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | General procedure: BuLi (1.55 equiv)was added dropwise to a stirred solution of therequisite amine (1.60 equiv) in THF at 78 C and the resultantsolutionwas stirred at 78 C for 30 min. A solution of the requisitea,b-unsaturated ester (1.0 equiv) in THFwas then added via cannula and the resultant mixture was stirred at 78 C for 2 h. ()-CSO 4(1.60 equiv) was then added and the reaction mixture was allowedto warm to rt over 14 h. Satd aq NH4Cl was then added and thereaction mixture was stirred at rt for 5 min, then concentrated invacuo. The residue was partitioned between CH2Cl2 and 10% aqcitric acid and the aqueous layer was extracted with three portionsof CH2Cl2. The combined organic extracts werewashed sequentiallywith satd aq NaHCO3 and brine, then dried and concentrated invacuo. The residue was then dissolved in Et2O and the resultantsolution was filtered, then concentrated in vacuo. Following the general procedure, BuLi (2.5Min hexanes, 15.2 mL,38.01 mmol) and (R)-N-benzyl-N-(a-methylbenzyl)amine (8.26 g,39.1 mmol, >99:1 er) were reacted with 2 (5.00 g, 24.5 mmol,>99:1 dr) and 4 (9.55 g, 41.7 mmol) in THF (200 mL) at 78 C togive 6 in >99:1 dr. Purification via flash column chromatography(eluent 30e40 C petrol/Et2O, 15:1) gave 6 as a pale yellow solid(9.77 g, 93%, >99:1 dr);29 mp 85e88 C; {lit.28 mp 87e88 C}; [a]D2326.7 (c 1.0, CHCl3); {lit.28 [a]D25 27.2 (c 1.0, CHCl3)}; dH (400 MHz,CDCl3) 1.20 (9H, s, CMe3), 1.18e1.22 (3H, obsc d, C(a)Me), 2.91 (1H,br s, OH), 3.92 (1H, d, J 14.9, NCHAHBPh), 4.22 (1H, d, J 14.9,NCHAHBPh), 4.27e4.33 (2H, m, C(a)H, C(3)H), 4.49 (1H, d, J 3.0,C(2)H), 7.21e7.61 (15H, m, Ph). | |
93% | BuLi (2.5M in hexanes, 15.2mL, 38.0mmol) was added dropwise to a stirred solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine43 (8.26g, 39.1mmol, >99:1 er) in THF (100mL) at -78C and stirring was continued at -78C for 30min. A solution of 1244 (5.00g, 24.5mmol, >99:1 dr) in THF (100mL) was then added via cannula and the resultant mixture was stirred at -78C for 2h. (-)-CSO 3 (8.97g, 39.1mmol) was then added and stirring was continued as the reaction mixture was allowed to warm to rt over 15h. Satd aq NH4Cl (5mL) was added and the reaction mixture was stirred at rt for 5min then concentrated in vacuo. The residue was partitioned between CH2Cl2 (100mL) and 10% aq citric acid (100mL), and the aqueous layer was extracted with CH2Cl2 (3×40mL). The combined organic extracts were washed sequentially with satd aq NaHCO3 (100mL) and brine (100mL), then dried and concentrated in vacuo. The residue was dissolved in Et2O (100mL), the insoluble CSO residues were filtered off, and the filter cake was washed with Et2O (2×50mL). The filtrate was concentrated in vacuo and the process was repeated. Purification via flash column chromatography (eluent 30-40C petrol/Et2O, 15:1) gave 14 as a pale yellow solid (9.77g, 93%, >99:1 dr);30b mp 85-88C; {lit.45 mp 87-88C}; [alpha]23D[alpha]D23 -26.7 (c 1.0 in CHCl3); {lit.45 [alpha]25D[alpha]D25 -27.2 (c 1.0 in CHCl3)}; deltaH (400MHz, CDCl3) 1.26-1.29 (12H, m, C(alpha)Me, CMe3), 2.91 (1H, br s, OH), 3.92 (1H, d, J 14.9, NCHAHBPh), 4.22 (1H, d, J 14.9, NCHAHBPh), 4.27-4.33 (2H, m, C(alpha)H, C(3)H), 4.49 (1H, d, J, 3.0, C(2)H), 7.21-7.61 (15H, m, Ph). | |
91% | tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(alpha-methylbenzyl)amino]-3-phenylpropanoate 3 BuLi (2.5?M in hexanes, 15.5?mL, 38.8?mmol) was added dropwise to a stirred solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine (8.25?g, 39.2?mmol, >99:1 er) in THF (60?mL) at -78?C and the resultant mixture was stirred at -78?C for 30?min. A solution of 26 (5.00?g, 24.5?mmol, >99:1 dr [(E):(Z)]) in THF (60?mL) was then added dropwise via cannula and the resultant mixture was stirred at -78?C for 2?h (-)-CSO (9.00?g, 39.3?mmol) was then added and the resultant mixture was allowed to warm to rt and stirred at rt for 16?h, then concentrated in vacuo. The residue was partitioned between CH2Cl2 (100?mL) and 10% aq citric acid (100?mL), and the aqueous layer was extracted with CH2Cl2 (3?*?40?mL). The combined organic extracts were washed sequentially with satd aq NaHCO3 (100?mL) and brine (100?mL), then dried and concentrated in vacuo. The residue was dissolved in Et2O (100?mL) and filtered, and the filter cake was washed with Et2O (2?*?100?mL), then the combined organic extracts were concentrated in vacuo. Purification via flash column chromatography (eluent 30-40?C petrol/Et2O, 20:1) gave 3 as a white solid (9.04?g, 91%, >99:1 dr); [ 22 ] mp 86-90?C; {lit [ 22 ]. mp 85-88?C}; -24.8 (c 1.0 in CHCl3); {lit [22]. [alpha]23D [alpha]D23 -26.7 (c 1.0 in CHCl3)}; deltaH (400MHz, CDCl3) 1.26 (3H, d, J 6.9, C(alpha)Me), 1.28 (9H, s, CMe3), 2.91 (1H, br s, OH), 3.92 (1H, d, J 14.9, NCHAHBPh), 4.22 (1H, d, J 14.9, NCHAHBPh), 4.27-4.33 (2H, m, C(3)H, C(alpha)H), 4.49 (1H, d, J 3.0, C(2)H), 7.21-7.61 (15H, m, Ph). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium(II) perchlorate; S-(+)-1-benzyl-3-hydroxymethyl-4-methyl-1,4-dihydropyridine In acetonitrile at 45℃; for 72h; Yield given. Yields of byproduct given. Title compound not separated from byproducts; | ||
With formic acid; N1-(2,4,6-trimethylphenylsulfonyl)-(1S,2S)-1,2-diamino-1,2-diphenylethane-η6-benzene complex with ruthenium chloride; triethylamine In dichloromethane at 28℃; for 36h; Yield given. Yields of byproduct given. Title compound not separated from byproducts; | ||
With (-)-(4S)-2-(2- |
With [Rh(R,R-1,2-diphenylphosphinyloxycyclohexane)COD]BF4; hydrogen; benzylamine In methanol at 20℃; | ||
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; hydrogen; (R<SUB>p</SUB>)-t-butyl(phenyl)phosphine oxide In toluene at 0℃; for 120h; Title compound not separated from byproducts; | ||
With hydrogen In dichloromethane at 25℃; for 12h; Title compound not separated from byproducts; | ||
With hydrogen In ethanol at 20℃; | ||
With (S)-[2-(hydroxydiphenylmethyl)pyrrolidin-1-yl]( pyridin-2-yl)methanone; trichlorosilane In dichloromethane at 20℃; | ||
With potassium <i>tert</i>-butylate; hydrogen In isopropyl alcohol at 50 - 65℃; | ||
With potassium <i>tert</i>-butylate; hydrogen In isopropyl alcohol; <i>tert</i>-butyl alcohol at 60℃; Title compound not separated from byproducts.; | ||
With trichlorosilane In chloroform at -10℃; for 24h; Title compound not separated from byproducts.; | ||
With hydrogen; triphenylphosphine In dichloromethane for 48h; | ||
With formic acid In dichloromethane for 1h; | ||
11 % ee | With hydrogen; triethylamine In methanol at 40℃; for 24h; | 64 Example 23 Preparation of Optically Active N-Acetylphenylalanine Using Rhodium metal complex catalyst The atmosphere in a 25 mL-recovery flask was substituted with nitrogen, and 3 mL of deoxygenized methanol and triethylamine (20.9 μL, 0.15 mmol) were added to the flask as the reaction solvent. α-Acetamidocinnamic acid (0.20 g, 0.98 mmol) and [Rh(CLPL-S)(COD)]BF4 (3.95 mg, 0.0049 mmol) were weighed in a 50 mL-Pyrex (registered trade name) test tube for autoclaving, the tube was put into an autoclave together with a stirrer in the tube, and the atmosphere in the autoclave was substituted with nitrogen. The reaction solvent in a volume of 2 mL was added to the mixture, the atmosphere in the autoclave was sufficiently substituted with hydrogen, and then pressurized with 2 MPa of hydrogen, and the reaction mixture was stirred at 40° C. for 22 hours. After 22 hours, the atmosphere in the autoclave was returned to ordinary pressure, and the reaction mixture was concentrated in an evaporator. The concentrated residue was added with 5 mL of 2 M aqueous sodium hydroxide for dissolution, and the solution was washed with 5 mL of ethyl acetate. The aqueous layer was separated, and added with diluted hydrochloric acid until pH of the aqueous layer became lower than 2, and the produced oil was extracted with 10 mL of ethyl acetate. The organic layer was concentrated in an evaporator to obtain (R)-N-acetylphenylalanine quantitatively. 1H NMR (300 MHz, CD3OD): δ 7.25-7.12 (m, 5H), 4.58 (dd, J=4.8, 8.9 Hz, 1H), 3.15 (dd, J=5.1, 13.8 Hz, 1H), 2.89 (dd, J=9.0, 13.8 Hz, 1H), 1.89 (s, 3H) |
29 % ee | With hydrogen; triethylamine In methanol at 40℃; for 24h; | 65 Example 23 Preparation of Optically Active N-Acetylphenylalanine Using Rhodium metal complex catalyst The atmosphere in a 25 mL-recovery flask was substituted with nitrogen, and 3 mL of deoxygenized methanol and triethylamine (20.9 μL, 0.15 mmol) were added to the flask as the reaction solvent. α-Acetamidocinnamic acid (0.20 g, 0.98 mmol) and [Rh(CLPL-S)(COD)]BF4 (3.95 mg, 0.0049 mmol) were weighed in a 50 mL-Pyrex (registered trade name) test tube for autoclaving, the tube was put into an autoclave together with a stirrer in the tube, and the atmosphere in the autoclave was substituted with nitrogen. The reaction solvent in a volume of 2 mL was added to the mixture, the atmosphere in the autoclave was sufficiently substituted with hydrogen, and then pressurized with 2 MPa of hydrogen, and the reaction mixture was stirred at 40° C. for 22 hours. After 22 hours, the atmosphere in the autoclave was returned to ordinary pressure, and the reaction mixture was concentrated in an evaporator. The concentrated residue was added with 5 mL of 2 M aqueous sodium hydroxide for dissolution, and the solution was washed with 5 mL of ethyl acetate. The aqueous layer was separated, and added with diluted hydrochloric acid until pH of the aqueous layer became lower than 2, and the produced oil was extracted with 10 mL of ethyl acetate. The organic layer was concentrated in an evaporator to obtain (R)-N-acetylphenylalanine quantitatively. 1H NMR (300 MHz, CD3OD): δ 7.25-7.12 (m, 5H), 4.58 (dd, J=4.8, 8.9 Hz, 1H), 3.15 (dd, J=5.1, 13.8 Hz, 1H), 2.89 (dd, J=9.0, 13.8 Hz, 1H), 1.89 (s, 3H) |
23 % ee | With hydrogen; triethylamine In methanol at 40℃; for 24h; | 66 Example 23 Preparation of Optically Active N-Acetylphenylalanine Using Rhodium metal complex catalyst The atmosphere in a 25 mL-recovery flask was substituted with nitrogen, and 3 mL of deoxygenized methanol and triethylamine (20.9 μL, 0.15 mmol) were added to the flask as the reaction solvent. α-Acetamidocinnamic acid (0.20 g, 0.98 mmol) and [Rh(CLPL-S)(COD)]BF4 (3.95 mg, 0.0049 mmol) were weighed in a 50 mL-Pyrex (registered trade name) test tube for autoclaving, the tube was put into an autoclave together with a stirrer in the tube, and the atmosphere in the autoclave was substituted with nitrogen. The reaction solvent in a volume of 2 mL was added to the mixture, the atmosphere in the autoclave was sufficiently substituted with hydrogen, and then pressurized with 2 MPa of hydrogen, and the reaction mixture was stirred at 40° C. for 22 hours. After 22 hours, the atmosphere in the autoclave was returned to ordinary pressure, and the reaction mixture was concentrated in an evaporator. The concentrated residue was added with 5 mL of 2 M aqueous sodium hydroxide for dissolution, and the solution was washed with 5 mL of ethyl acetate. The aqueous layer was separated, and added with diluted hydrochloric acid until pH of the aqueous layer became lower than 2, and the produced oil was extracted with 10 mL of ethyl acetate. The organic layer was concentrated in an evaporator to obtain (R)-N-acetylphenylalanine quantitatively. 1H NMR (300 MHz, CD3OD): δ 7.25-7.12 (m, 5H), 4.58 (dd, J=4.8, 8.9 Hz, 1H), 3.15 (dd, J=5.1, 13.8 Hz, 1H), 2.89 (dd, J=9.0, 13.8 Hz, 1H), 1.89 (s, 3H) |
40 - 73 % ee | With hydrogen In dichloromethane at 0 - 25℃; for 0.5 - 16h; | 61; 62; 63; 65 0.01 Molar equivalent of transition metal compound and 0.012 molar equivalent of ligand were dissolved under argon in degassed CH2Cl2 (0.015 M) and stirred at room temperature for {fraction (1/2)} hour. After adding one molar equivalent of substrate in degassed CH2Cl2 (0.15 M) under argon, the mixture obtained was hydrogenated in an autoclave at the appropriate temperature under hydrogen pressure. Conversion and ee were determined by chromatography |
75 % ee | With hydrogen; benzylamine In dichloromethane at 25℃; for 16h; | 67 0.01 Molar equivalent of transition metal compound and 0.012 molar equivalent of ligand were dissolved under argon in degassed CH2Cl2 (0.015 M) and stirred at room temperature for {fraction (1/2)} hour. After adding one molar equivalent of substrate in degassed CH2Cl2 (0.15 M) under argon, the mixture obtained was hydrogenated in an autoclave at the appropriate temperature under hydrogen pressure. Conversion and ee were determined by chromatography |
58 % ee | With hydrogen; benzylamine In dichloromethane at 25℃; for 16h; | 69 0.01 Molar equivalent of transition metal compound and 0.012 molar equivalent of ligand were dissolved under argon in degassed CH2Cl2 (0.015 M) and stirred at room temperature for {fraction (1/2)} hour. After adding one molar equivalent of substrate in degassed CH2Cl2 (0.15 M) under argon, the mixture obtained was hydrogenated in an autoclave at the appropriate temperature under hydrogen pressure. Conversion and ee were determined by chromatography |
75 % ee | With phthalimide; hydrogen In dichloromethane at 25℃; for 16h; | 66 0.01 Molar equivalent of transition metal compound and 0.012 molar equivalent of ligand were dissolved under argon in degassed CH2Cl2 (0.015 M) and stirred at room temperature for {fraction (1/2)} hour. After adding one molar equivalent of substrate in degassed CH2Cl2 (0.15 M) under argon, the mixture obtained was hydrogenated in an autoclave at the appropriate temperature under hydrogen pressure. Conversion and ee were determined by chromatography |
54 % ee | With phthalimide; hydrogen In dichloromethane at 25℃; for 16h; | 68 0.01 Molar equivalent of transition metal compound and 0.012 molar equivalent of ligand were dissolved under argon in degassed CH2Cl2 (0.015 M) and stirred at room temperature for {fraction (1/2)} hour. After adding one molar equivalent of substrate in degassed CH2Cl2 (0.15 M) under argon, the mixture obtained was hydrogenated in an autoclave at the appropriate temperature under hydrogen pressure. Conversion and ee were determined by chromatography |
76 % ee | With hydrogen; iodine In dichloromethane at 0℃; for 2h; | 64 0.01 Molar equivalent of transition metal compound and 0.012 molar equivalent of ligand were dissolved under argon in degassed CH2Cl2 (0.015 M) and stirred at room temperature for {fraction (1/2)} hour. After adding one molar equivalent of substrate in degassed CH2Cl2 (0.15 M) under argon, the mixture obtained was hydrogenated in an autoclave at the appropriate temperature under hydrogen pressure. Conversion and ee were determined by chromatography |
With formic acid; triethylamine In dichloromethane at 30℃; for 24h; Schlenk tube; | 4 In a 20-ml Schlenk tube, 28 mg (0.05 mmol) of RuCl((R,R)-Msdpen) (p-TMS-toluene) (S/C=100), 1.04 g (5 mmol) of the title imine, 10 ml of dichloromethane, and 2.5 ml of a formic acid-triethylamine (5:2) azeotropic mixture were mixed, and the mixture was allowed to react for 24 hours at 30° C. The yield and optical purity were measured by GC analysis, and as a result, optically active N-benzyl-1-phenethylamine, which was the target amine, was obtained at a yield of 86% and an optical purity of 76% ee | |
62 % ee | With ortho-difluorobenzene; (S)-4-(pentafluorophenyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]borepine tetrahydrofuran; Dimethylphenylsilane at 20℃; Overall yield = 54 %; Overall yield = 22.8 mg; | |
Multi-step reaction with 2 steps 1: C21H34BN2O2(1+)*C2F6NO4S2(1-) / 34 h / 20 °C 2: methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | To a solution of (R)-(+)-1-phenylethanamine (48.47 g, 0.40 mol) in toluene (300 mL), was added benzaldehyde (43.51 g, 0.41 mol). The resulting solution was heated at reflux. Stirring was then continued at reflux for around 3 h and water was removed by azeotropic distillation with a Dean-Stark trap during refluxing. After the reaction was complete, the solvent was removed by vacuum distillation to give a residue as pale yellow oil, which was then dissolved in anhydrous methanol (300 mL). The solution was cooled down to 0 C with an ice bath, and the powdered NaBH4 (15.52 g, 0.41 mol) was added in portions over 0.5 h. After the addition was complete, the mixture was stirred at 0 C for a further 2 h, and the reaction was traced by TLC (EtOAc/hexane = 1:6). When the reaction was complete, methanol was removed by vacuum distillation. The solid residue was then partitioned between toluene (300 mL) and water (150 mL). Two phases were separated, and the aqueous phase was extracted twice with toluene (2 × 75 mL). The extracts were combined and dried over anhydrous MgSO4. Evaporation of toluene under vacuum gave an oily residue, which was dissolved in ethanol (250 mL). Concentrated hydrochloric acid (40 mL, 12 M, 0.48 mol) was added, and the mixture was heated at reflux for 2 h. After the solution was concentrated to dryness, a residue was obtained as a pale yellow solid. A mixed solvent of ethyl acetate (100 mL) and hexane (200 mL) was added. The suspension was stirred at reflux for 2 h. After the suspension was cooled to room temperature, the off-white solid was collected on Buchner funnel by suction, and was rinsed with a mixed solvent (EtOAc/hexane = 1:3). The solid was then partitioned between ethyl acetate (400 mL) and aqueous sodium hydroxide (250 mL, 20% w/v). Two phases were separated and the aqueous phase was extracted twice with ethyl acetate (2 × 100 mL). After the combined extracts were dried over anhydrous MgSO4, evaporation of the solvent under vacuum afforded (R)-N-benzyl-1-phenylethanamine (78.1 g, 0.37 mol) as colorless oil in 92% yield. inlMMLBox (c 1.2, EtOH) {lit.63 inlMMLBox (c 1.1, EtOH)}. 1H NMR (CDCl3) delta 1.40 (d, J = 6.6 Hz, 3H), 3.63 (d, J = 13.1 Hz, 1H), 3.69 (d, J = 13.1 Hz, 1H), 3.84 (q, J = 6.6 Hz, 1H), 7.24-7.40 (m, 10H). MS m/z (%) 212 (M++1, 100), 196 (56), 91 (48). | |
90% | With sodium tetrahydroborate; iron(III) trifluoromethanesulfonate; In dichloromethane; at 20℃; for 0.0833333h; | General procedure: In typical experimental procedure, to the CH2Cl2 solution (3 ml) of benzaldehyde (0.001 mol) and aniline (0.001mol) were added sodium borohydride (0.001 mol) and Fe(OTf)3 (1 mol% ), and the mixture was allowed to react for 5 min., at room temperature. After that 1 ml methanol was added for complete conversion. The progress of reaction was monitored by TLC. After completion of the reaction, solvent completely distilled at 40 C. Then the reaction mixture was quenched with 5% aqueous NaHCO3 solution and reaction mixture was extracted with dichloromethane twice (2x10 mL). The resulted organic layer was washed with water followed by Na2SO4 drying. The solvent was evaporated under reduced pressure and the crude material was purified by silica gel colum chromatography eluting with 2-10% EtOAc in hexane. All the products were characterized by IR, NMR and Mass spectroscopy. All the new compounds gave satisfactory spectroscopic data in accordance with their structure. |
88% | General procedure: To a stirred solution of aldehyde/3-formyl-indole-2-carboxylic acid (1.0 mmol) and amine/aniline (1.0mmol) in ethanol (4 mL), tris(pentafluorophenyl)borane(1 mol%) was added. After 15 min, NaBH4 (2.0 mmol) was added at room temperature. On completion of the reaction (as monitored by TLC), the reaction mixture was quenched with water, later extracted with ethylacetate. Organic layer was dried under vacuum and column chromatography was carried out for the purification product (Silica gel, n-hexane/ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; mono-sulphonated (2S,4S)-bis-(diphenylphosphino)pentane (2b); hydrogen In ethyl acetate var. solvents, di-sulphonated phosphine (2c); other imines; | ||
With hydrogen In methanol; benzene at 20℃; for 18h; reactions of derivatives under var. conditions; | ||
With hydrogen; potassium iodide In methanol; benzene at 20℃; for 90h; Yield given. Yields of byproduct given. Title compound not separated from byproducts; |
With chiral dimethoxyborane; magnesium bromide In tetrahydrofuran a) 0 deg C, 2 h, b) r.t. 25 h; Yield given. Yields of byproduct given. Title compound not separated from byproducts; | ||
With chiral dialkoxyborane (1a); magnesium bromide In tetrahydrofuran at 0 - 20℃; for 24h; Yield given. Yields of byproduct given. Title compound not separated from byproducts; | ||
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; mono-sulphonated (2S,4S)-bis-(diphenylphosphino)pentane (2b); hydrogen In ethyl acetate at 20℃; Yield given; | ||
With (R,R,R)-bis(1-methyl-4,5,6,7-tetrahydroindene)titanium; hydrogen at 65℃; Yield given. Yields of byproduct given. Title compound not separated from byproducts; | ||
With n-butyllithium; (R,R)-ethylene-1,2-bis(η5-4,5,6,7-tetrahydro-1-indenyl)zirconium dichloride (R)-1,1'-binaphth-2,2'-diolate; phenylsilane; hydrogen In tetrahydrofuran; hexane at 65℃; for 23h; Yield given. Yields of byproduct given. Title compound not separated from byproducts; | ||
With chloro(1,5-cyclooctadiene)iridium(I) dimer; hydrogen; 1,1′-binaphthalene-2,2′-diylbis[bis(4-methylphenyl)phosphine]; benzylamine 1.) CH3OH, 25 deg C, 1 h, 2.) CH3OH, 60 kg/cm2, 20 deg C, 18 h; Multistep reaction. Title compound not separated from byproducts; | ||
With hydrogen In dichloromethane at 23℃; Yield given. Yields of byproduct given. Title compound not separated from byproducts; | ||
With n-butyllithium; (R)-<2,2'-biphenyldiylbis(3,4-dimethylcyclopentadienyl)>titanium dichloride; hydrogen In hexane; toluene at 80℃; for 12h; Yield given; Yields of byproduct given. Title compound not separated from byproducts; | ||
With hydrogen In dichloromethane at 20℃; for 12h; Title compound not separated from byproducts; | ||
With D-mannitol phosphinite-phosphite derivative; hydrogen In dichloromethane at 25℃; for 16h; Title compound not separated from byproducts; | ||
With polymethylhydrosiloxane In methanol at 20℃; for 6h; | ||
With formic acid; triethylamine In dichloromethane at 20℃; for 48h; optical yield given as %ee; | ||
With 2,6-dimethylpyridine; C13H30N2O2S2; trichlorosilane In dichloromethane at -20℃; for 24h; Inert atmosphere; optical yield given as %ee; | ||
With formic acid; C25H27ClN2O2RuS; triethylamine In dichloromethane at 25℃; for 24h; optical yield given as %ee; enantioselective reaction; | ||
With N,N'-dimethyl-(R)-1,1'-binaphthyldiamine-bis-2-pyridinecarboxyamide; trichlorosilane In chloroform at 0℃; for 12h; Inert atmosphere; optical yield given as %ee; stereoselective reaction; | ||
With C34H26N4O2; trichlorosilane In dichloromethane at 0℃; for 12h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; | ||
Stage #1: N-benzyl-N-(1-phenylethylidene)amine With C16H17ClN2O2; trichlorosilane In dichloromethane Inert atmosphere; Stage #2: With sodium hydrogencarbonate In chloroform; water Saturated solution; optical yield given as %ee; enantioselective reaction; | ||
29 % ee | With hydrogen; benzylamine In methanol at 20 - 30℃; for 18h; | 20 Example 20: (jR)-A'-Benzyl-l-phenylethylamine; In a 15 mL autoclave in an argon atmosphere bis(l,5-cyclooctadiene)-di(iridium(I)dichloride) 98% (6.7 mg, 0.010 mmol), (+)-ligand la (11.0 mg, 0.020 mmol), benzylamine(5.6 mg, 0.052 mmol) and JV-benzyl-A/"-(l-phenylethylidene)amine (0.21 g, 1.0 mmol) isdissolved in degassed methanol (5 mL) and stirred for Ih at room temperature. Afterflushing the autoclave with argon hydrogenation is carried out during 17 h at 30 °C and at50 bar hydrogen pressure. The reaction solution is directly analysed by GC for conversion(column: HP-101 25 m / 0.2 mm) and enantiomeric excess (column: Macherey-Nagel,Nucleodex Beta-PM CC200/4). Conversion is 100% at an ee of 29%. |
10 % ee | With hydrogen; benzylamine In methanol at 20 - 30℃; for 16h; | 21 Example 21: (S)-N-Benzyl-l-phenylethylamine; In a 15 mL autoclave in an argon atmosphere bis(l,5-cyclooctadiene)-di(iridium(I)di-chloride) 98% (6.7 mg, 0.010 mmol), (+)-ligand Ic (5.7 mg, 0.010 mmol), benzylamine(5.6 mg, 0.052 mmol) and Ar-benzyl-JV-(l-phenylethylidene)amine (0.21 g, 1.0 mmol) isdissolved in degassed methanol (5 mL) and stirred for Ih at room temperature. Afterflushing the autoclave with argon hydrogenation is carried out during 15 h at 30 °C and at50 bar hydrogen pressure. The reaction solution is directly analysed by GC for conversion(column: HP-101 25 m / 0.2 mm) and enantiomeric excess (column: Macherey-Nagel,Nucleodex Beta-PM CC200/4). Conversion is 100% at an ee of 10%. |
Stage #1: N-benzyl-N-(1-phenylethylidene)amine With C29H50IrNO2P(1+)*C32H12BF24(1-) In dichloromethane at -20℃; for 1h; Inert atmosphere; Autoclave; Stage #2: With hydrogen In dichloromethane at -20℃; for 6h; Autoclave; optical yield given as %ee; | ||
With C32H33F3N2O4RuS2; hydrogen In methanol at 40℃; for 15h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; | ||
With formic acid; (p-cymene)ruthenium(II) chloride; triethylamine In acetonitrile at 20℃; for 24h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; | ||
With hydrido[bis(pentafluorophenyl)]{2-[(2,2,4,7-tetramethyl-3,4-dihydroquinolinium-1(2H)-yl)methyl]phenyl}borate(1-); hydrogen In tert-butyl methyl ether at 20℃; for 12h; enantioselective reaction; | ||
With formic acid; C28H34IrN2(1+)*F6P(1-); triethylamine In dichloromethane at 20℃; Inert atmosphere; enantioselective reaction; | ||
With C37H38N2O6PRuS; hydrogen In methanol; dichloromethane at 40℃; for 10h; Autoclave; optical yield given as %ee; enantioselective reaction; | ||
27 % ee | With C51H62Br2N2P2Ru; potassium <i>tert</i>-butylate; hydrogen In toluene at 40℃; for 24h; Autoclave; Overall yield = 83 %; Overall yield = 917.3 mg; | |
72 % ee | With 1,1,1-trifluoro-N-(4-oxido-2,6-bis(2,4,6-triisopropylphenyl)dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-yl)methanesulfonamide; benzo[1,3,2]dioxaborole In pentane at -78 - -22℃; for 24h; Inert atmosphere; Schlenk technique; Overall yield = 95%; Overall yield = 200 mg; enantioselective reaction; | General procedure for the N-acylation of amines 3a-3k General procedure: 5 mg of amine 3 was dissolved in 0.6 mL dichloromethane and 10 µL acteylchloride was added at 0 °C. The mixture was stirred at room temperature overnight and then concentrated in vacuum. The residue was dissolved in diethyl ether and filtered over a short plug of silica gel. Concentration in high vacuum afforded the pure acylated amine, which was used for chiral HPLC analysis. |
59 % ee | With trichlorosilane; C28H28N2O7 In dichloromethane at 0℃; for 24h; Overall yield = 53 %; enantioselective reaction; | General experimental procedure for the the enantioselective reduction of imines with trichlorosilane catalyzed by 5 General procedure: To a stirred solution of imine 6 (0.5 mmol) and catalyst 5 (25 mg, 0.05 mmol) in dry CH2Cl2 (2 mL) was added the trichlorosilane (0.1 ml, 1 mmol) at 0°C and the reaction mixture was stirred at 0°C for 24 h. Saturated NaHCO3 (2 ml) was then added and extracted with CH2Cl2 (3*5 ml). The combined organic phases were washed with saturated brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography through silica gel, eluting with a 1:99 ethyl acetate/petroleum ether solvent mixture to give pure 7. The ee value of the reduction product was determined by HPLC on a chiral column (Daicel, Chiralpak, OD-H). |
With trichlorosilane; C52H40O2P2S4 In dichloromethane at 0℃; for 24h; Inert atmosphere; Schlenk technique; Overall yield = 43 %; Optical yield = 22 %ee; stereoselective reaction; | ||
5 % ee | With trichlorosilane; C32H43N5O12 In toluene at 20℃; for 24h; Overall yield = 56 %; enantioselective reaction; | General experimental procedure for the asymmetric reductionof imines with trichlorosilane catalyzed by an organocatalyst General procedure: To a stirred solution of imine 10 (0.5 mmol) and organocatalyst (0.05 mmol) in toluene (2 mL) was added trichlorosilane (0.15 ml,1.5 mmol) at room temperature and the reaction mixture wasstirred at room temperature for 24 h. Next, saturated NaHCO3(2 ml) was added and extracted with ethyl acetate (3 * 10 ml).The combined organic phases were washed with brine, and driedover anhydrous MgSO4. Afterward the organic phase wasevaporated under reduced pressure to give the crude product,which was purified by column chromatography through silicagel, eluting with 1:99 EtOAc/PE solvent mixture, to give pure product 11. The ee value of the reduction product was determined byHPLC on a chiral column (Daicel, Chiralpak, OD). |
With trichlorosilane; C16H24N2O2S In dichloromethane at -20℃; for 48h; Inert atmosphere; Overall yield = 91 %; Optical yield = 89 %ee; enantioselective reaction; | ||
83 % ee | With (S)-N-isopropyl-N-methyl-2-ammonium-2'-bis(pentafluorophenyl)hydroborate-1,1'-binaphthyl; hydrogen In tert-butyl methyl ether at 25℃; for 20h; Schlenk technique; Overall yield = 80 %; enantioselective reaction; | |
78 % ee | With (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diylhydrogenphosphate; (C5(CH3)5)Ir(NHCH(C6H5)CH(C6H5)NSO2C6(CH3)5); isopropyl alcohol In toluene at 80℃; for 24h; Inert atmosphere; Sealed tube; enantioselective reaction; | |
17 % ee | With Dimethylphenylsilane; C32H12BF24(1-)*C36H40PRuS(1+) In benzene at 20℃; for 18h; Inert atmosphere; Glovebox; Sealed tube; Overall yield = 56 %; Overall yield = 13 mg; enantioselective reaction; | |
Stage #1: N-benzyl-N-(1-phenylethylidene)amine With trimethylaluminum; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane; 3,3'-bis-(3,5-bis-trifluoromethyl-phenyl)-[1,1']binaphthalenyl-2,2'-diol In toluene Stage #2: Solvolysis; Optical yield = 13 percent ee; enantioselective reaction; | ||
83 % ee | With [Ir(cycloocta-1,5-diene)](BF4); hydrogen; C11H20NOP In dichloromethane at -78 - 20℃; for 24h; Schlenk technique; Autoclave; | |
2 % ee | With [Ir(cycloocta-1,5-diene)](BF4); hydrogen; methylphenyl-p-tolylphosphine borane In dichloromethane at -78 - 20℃; for 24h; Schlenk technique; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | General procedure: (S)-N-Benzyl-1-phenylethylamine (8.5 mL, 8.59 g, 40.6 mmol) was dissolved in anhyd THF (130 mL) and cooled to -78 C; 1.6 M BuLi in n-hexane (23.6 mL, 37.8 mmol) was slowly added dropwise and the color changed from pale rose to pink. The mixture was stirred at -78 C for 30 min, and then a solution of tert-butyl (E)-oct-2-enoate (4; 5 g, 25.5 mmol) in anhyd THF (20 mL) was added. The solution was stirred at -78 C under argon for 3 h. Subsequently sat. aq NH4Cl (50mL) was added, and the solution was allowed to warm up to r.t. THF was evaporated in vacuo. H2O (150 mL) was added to the residue, and the solution was extracted with CH2Cl2 (3 × 100 mL). The combined organic extracts were washed with brine (200 mL) and dried (MgSO4), and the solvent was evaporated in vacuo to yield a yellow, slightly viscous liquid (13.3 g), which was purified by flash chromatography (cyclohexane-EtOAc, 19:1) to give a colorless oil; yield: 8.35 g (80%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | BuLi (1.55 equiv)was added dropwise to a stirred solution of therequisite amine (1.60 equiv) in THF at 78 C and the resultantsolutionwas stirred at 78 C for 30 min. A solution of the requisitea,b-unsaturated ester (1.0 equiv) in THFwas then added via cannula and the resultant mixture was stirred at 78 C for 2 h. ()-CSO 4(1.60 equiv) was then added and the reaction mixture was allowedto warm to rt over 14 h. Satd aq NH4Cl was then added and thereaction mixture was stirred at rt for 5 min, then concentrated invacuo. The residue was partitioned between CH2Cl2 and 10% aqcitric acid and the aqueous layer was extracted with three portionsof CH2Cl2. The combined organic extracts werewashed sequentiallywith satd aq NaHCO3 and brine, then dried and concentrated invacuo. The residue was then dissolved in Et2O and the resultantsolution was filtered, then concentrated in vacuo. 4.3. tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(a-methylbenzyl)amino]butanoate 5 Following the general procedure, BuLi (2.4Min hexanes, 4.54 mL,10.9 mmol) and (R)-N-benzyl-N-(a-methylbenzyl)amine (2.39 g,11.3 mmol, >99:1 er) were reacted with 1 (1.00 g, 7.03 mmol, >99:1dr) and 4 (2.74 g, 12.0 mmol) in THF (120 mL) at 78 C to give 5 in>99:1 dr. Purification via flash column chromatography (eluent30e40 C petrol/Et2O, 10:1) gave 5 as a yellow solid (2.29 g, 91%,>99:1 dr);9,28 mp 89e94 C; {lit.28 mp 88e89 C}; [a]D23 35.5 (c 1.0,CHCl3); {lit.28 [a]D25 35.2 (c 1.0, CHCl3)}; dH (400 MHz, CDCl3) 1.08(3H, d, J 7.0, C(4)H3), 1.32 (3H, d, J 6.8, C(a)Me), 1.36 (9H, s, CMe3),2.92 (1H, d, J 6.5, OH), 3.25 (1H, qd, J 7.0, 2.6, C(3)H), 3.87 (1H, d, J14.7, NCHAHBPh), 3.97e4.04 (3H, m, C(2)H, C(a)H, NCHAHBPh),7.18e7.50 (10H, m, Ph). | |
91% | BuLi (2.4M in hexanes, 4.54mL, 10.9mmol) was added dropwise to a stirred solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine43 (2.39g, 11.3mmol, >99:1 er) in THF (60mL) at -78C and stirring was continued at -78C for 30min. A solution of 13 (1.00g, 7.03mmol, >99:1 dr) in THF (60mL) was then added via cannula and the resultant mixture was stirred at -78C for 2h. (-)-CSO 3 (2.59g, 11.3mmol) was then added and stirring was continued as the reaction mixture was allowed to warm to rt over 15h. Satd aq NH4Cl (5mL) was added and the reaction mixture was stirred at rt for 5min then concentrated in vacuo. The residue was partitioned between CH2Cl2 (100mL) and 10% aq citric acid (100mL), and the aqueous layer was extracted with CH2Cl2 (3×40mL). The combined organic extracts were washed sequentially with satd aq NaHCO3 (100mL) and brine (100mL), then dried and concentrated in vacuo. The residue was dissolved in Et2O (100mL), the insoluble CSO residues were filtered off, and the filter cake was washed with Et2O (2×50mL). The filtrate was concentrated in vacuo and the process was repeated. Purification via flash column chromatography (eluent 30-40C petrol/Et2O, 10:1) gave 15 as a yellow solid (2.29g, 91%, >99:1 dr);45 mp 89-94C; {lit.45 mp 88-89C}; [alpha]23D[alpha]D23 -35.5 (c1.0 in CHCl3); {lit.45 [alpha]25D[alpha]D25 -35.2 (c 1.0 in CHCl3)}; deltaH (400MHz, CDCl3) 1.08 (3H, d, J 7.0, C(4)H3), 1.32 (3H, d, J 6.8, C(alpha)Me), 1.36 (9H, s, CMe3), 2.92 (1H, app d, J 6.5, OH), 3.25 (1H, qd, J 7.0, 2.6, C(3)H), 3.87 (1H, d, J 14.7, NCHAHBPh), 3.97-4.04 (3H, m, C(2)H, C(alpha)H, NCHAHBPh), 7.18-7.50 (10H, m, Ph). | |
89% | BuLi (2.5?M in hexanes, 22.7?mL, 56.8?mmol) was added dropwise to a stirred solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine (12.0?g, 56.5?mmol, >99:1 er) in THF (60?mL) at -78?C and the resultant mixture was stirred at -78?C for 30?min. A solution of 15 (5.00?g, 35.3?mmol, >99:1 dr [(E):(Z)]) in THF (60?mL) was then added dropwise via cannula and the resultant mixture was stirred at -78?C for 2?h (-)-CSO (13.0?g, 58.8?mmol) was then added and the resultant mixture was allowed to warm to rt and stirred at rt for 16?h, then concentrated in vacuo. The residue was partitioned between CH2Cl2 (100?mL) and 10% aq citric acid (100?mL), and the aqueous layer was extracted with CH2Cl2 (3?*?40?mL). The combined organic extracts were washed sequentially with satd aq NaHCO3 (100?mL) and brine (100?mL), then dried and concentrated in vacuo. The residue was dissolved in Et2O (100?mL) and filtered, and the filter cake was washed with Et2O (2?*?100?mL), then the combined organic extracts were concentrated in vacuo. Purification via flash column chromatography (eluent 30-40?C petrol/Et2O, 20:1) gave 1 as a white solid (11.6?g, 89%, >99:1 dr); [ 22 ] mp 90-93?C; {lit [ 22 ]. mp 89-94?C}; -36.8 (c 1.0 in CHCl3); {lit [22]. [alpha]23D [alpha]D23 -35.5 (c 1.0 in CHCl3)}; deltaH (400MHz, CDCl3) 1.08 (3H, d, J 7.0, C(4)H3), 1.32 (3H, d, J 6.8, C(alpha)Me), 1.36 (9H, s, CMe3), 2.92 (1H, d, J 6.5, OH), 3.25 (1H, qd, J 7.0, 2.6, C(3)H), 3.87 (1H, d, J 14.7, NCHAHBPh), 3.97-4.04 (3H, m, C(2)H, C(alpha)H, NCHAHBPh), 7.18-7.50 (10H, m, Ph). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | n-BuLi (2.5 M in hexanes, 9.22 mL, 23.1 mmol) was added dropwise to a stirred solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine (5.03 g, 23.8 mmol) in THF (60 mL) at -78 C, and the resultant mixture was stirred at -78 C for 30 min. A solution of 22 (2.50 g, 14.9 mmol) in THF (30 mL) was then added via cannula and the resultant mixture was stirred at -78 C for 2 h. (-)-CSO (5.80 g, 25.3 mmol) was then added and the reaction mixture was allowed to warm to rt over 12 h. Satd. aq. NH4Cl (10 mL) was then added, and the resultant mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 (200 mL) and the resultant solution was washed sequentially with 10% aq. citric acid (200 mL), satd. aq. NaHCO3 (200 mL) and brine (200 mL), then dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30-40 C petrol/Et2O, 20:1) gave 24 as a pale yellow oil (4.06 g, 69%, >99:1 dr);4,18 [alpha]D25 -63.1 (c 1.0 in CHCl3); {lit. [alpha]D25 -62.6 (c 1.0 in CHCl3)}; deltaH (400 MHz, CDCl3) 1.34 (9H, s, CMe3), 1.37 (3H, d, J 6.8, C(alpha)Me), 1.71 (3H, d, J 6.3, C(6)H3), 2.94 (1H, br s, OH), 3.54 (1H, dd, J 9.1, 2.6, C(3)H), 3.76 (1H, d, J 14.4, NCHAHBPh), 3.97 (1H, d, J 14.4, NCHAHBPh), 4.08 (1H, br s, C(2)H), 4.23 (1H, q, J 6.8, C(alpha)H), 5.55 (1H, dq, J 15.4, 6.3, C(5)H), 5.66-5.72 (1H, m, C(4)H), 7.19-7.42 (10H, m, Ph). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: (R)-N-benzyl-1-phenylethylamine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: dodec-2-enoic acid ethyl ester In tetrahydrofuran; hexane at -78℃; for 2.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: methyl (E)-oct-2-enoate With n-butyllithium In tetrahydrofuran Stage #2: (R)-N-benzyl-1-phenylethylamine Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | General procedure: BuLi (1.55 equiv)was added dropwise to a stirred solution of therequisite amine (1.60 equiv) in THF at 78 C and the resultantsolutionwas stirred at 78 C for 30 min. A solution of the requisitea,b-unsaturated ester (1.0 equiv) in THFwas then added via cannula and the resultant mixture was stirred at 78 C for 2 h. (-)-CSO 4(1.60 equiv) was then added and the reaction mixture was allowedto warm to rt over 14 h. Satd aq NH4Cl was then added and thereaction mixture was stirred at rt for 5 min, then concentrated invacuo. The residue was partitioned between CH2Cl2 and 10% aqcitric acid and the aqueous layer was extracted with three portions of CH2Cl2. The combined organic extracts werewashed sequentiallywith satd aq NaHCO3 and brine, then dried and concentrated invacuo. The residue was then dissolved in Et2O and the resultantsolution was filtered, then concentrated in vacuo. Following the general procedure, BuLi (2.3Min hexanes, 2.02 mL,4.63 mmol) and (R)-N-benzyl-N-(a-methylbenzyl)amine (1.15 g, 4.78 mmol, >99:1 er) were reacted with 31 (700 mg, 2.99 mmol,>99:1 dr) and 4 (1.17 g, 5.08 mmol) in THF (20 mL) at 78 C to give36 in >99:1 dr. Purification via flash column chromatography (eluent30e40 C petrol/Et2O, 10:1) gave 36 as a yellow oil (1.18 g, 85%,>99:1 dr); [a]D20 24.5 (c 1.0, CHCl3); nmax (ATR) 3497 (OeH), 1722(C]O); dH (400 MHz, CDCl3) 1.26 (9H, s, CMe3), 1.22e1.37 (3H, obscd, C(a)Me), 3.16 (1H, br s, OH), 3.83 (3H, s, OMe), 3.97 (1H, d, J 15.0,NCHAHBPh), 4.26 (1H, d, J 15.0, NCHAHBPh), 4.30e4.41 (2H, m,C(3)H, C(a)H), 4.52e4.57 (1H, m, C(2)H), 6.96 (2H, d, J 7.8, C(30)H,C(50)H), 7.45 (2H, d, J 7.8, C(20)H, C(60)H), 7.25e7.64 (10H, m, Ph); dC(100 MHz, CDCl3) 14.6 (C(a)Me), 27.8 (CMe3), 52.3 (NCH2Ph), 55.2(OMe), 57.5 (C(a)), 64.8 (C(3)), 73.7 (C(2)), 82.0 (CMe3), 113.5 (C(30),C(50)), 128.2 (C(20), C(60)), 126.7, 126.9, 128.2, 128.2, 128.3, 131.2(o,m,p-Ph), 130.5 (C(10)), 142.1, 144.5 (i-Ph), 159.1 (C(40)), 172.4(C(1)); m/z (ESI) 462 ([MH], 100%); HRMS (ESI) C29H36NO4([MH]) requires 462.2639; found 462.2628. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: (R)-N-benzyl-1-phenylethylamine With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.25h; Stage #2: methyl (E)-hex-2-enoate In tetrahydrofuran; hexane at -78℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | To a stirred solution of (R)-(+)-N-benzyl-N--methylbenzylamine (685 mg, 3.2 mmol) in THF (10 mL) was slowly added nBuLi (201 mg, 3.0 mmol) at -78 C. The resulting pink solution was stirred for 45 min followed by slow addition of ethyl trans-2-pentanoate (267 mg, 2.1 mmol) in 3 mL of THF. After stirring for 2 h at -78 C, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (20 mL × 3). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The residual oil was purified by column chromatography on silica gel (hexane / ethyl acetate 20/1) to give 423 mg (61 %) of (3R,7R)-Ethyl-N-(-methylbenzyl benzyl)-3-aminopentanoate (2). The several spectral data of 2 were matched with those of the literature values. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With n-butyllithium In tetrahydrofuran; hexane at -78℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: (R)-N-benzyl-1-phenylethylamine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: tert-butyl (E)-3-(4-methoxyphenyl)prop-2-enoate In tetrahydrofuran; hexane at -78℃; for 3h; Further stages.; | |
88.4% | Stage #1: (R)-N-benzyl-1-phenylethylamine With n-butyllithium In tetrahydrofuran; hexane at -78℃; Stage #2: tert-butyl (E)-3-(4-methoxyphenyl)prop-2-enoate In tetrahydrofuran; hexane at -78℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sec.-butyllithium; In tetrahydrofuran; cyclohexane; at -78℃; for 5.5h; | Step Three: To a solution of (R)-(+)-N-benzyl-alpha-methylbenzylamine (0.70 g, 3.3 mmol) in THF (6.7 mL) cooled to -78 C. under a dry nitrogen atmosphere, sec-BuLi (4.22 mL, 1.3M in cyclohexane, 5.5 mmol) was added dropwise. The resulting mixture was stirred at -78 C. for 30 minutes and then a solution of 75 (0.62 g, 2.74 mmol) in THF (3.4 mL) was added dropwise by syringe. The mixture was stirred at -78 C. for 5 hours and then quenched with glacial AcOH (2 mL) in THF (5 mL). The reaction mixture was warmed to room temperature, poured into a 1:1 mixture of saturated aqueous NaHCO3:EtOAc. The organic layer was washed with H2O (2 times) and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 1:5 ethyl actetate:hexanes to give 76 (1.2 g, 100%). This material still contained minor impurities but was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (+)-2,6'-bis(diphenylphosphino)-2'-methoxy-1,1'-biphenyl; hydrogen;bis(1,5-cyclooctadiene)-di(iridium(I)-dichloride); In methanol; at 20 - 30℃; under 37503.8 Torr; for 18h; | In a 15 mL autoclave in an argon atmosphere bis(1,5-cyclooctadiene)-di(iridium(I)-dichloride) 98% (6.7 mg, 0.010 mmol), (+)-ligand Ia (11.0 mg, 0.020 mmol), benzylamine (5.6 mg, 0.052 mmol) and N-benzyl-N-(1-phenylethylidene)amine (0.21 g, 1.0 mmol) is dissolved in degassed methanol (5 mL) and stirred for 1h at room temperature. After flushing the autoclave with argon hydrogenation is carried out during 17 h at 30 C and at 50 bar hydrogen pressure. The reaction solution is directly analysed by GC for conversion (column: HP-101 25 m / 0.2 mm) and enantiomeric excess (column: Macherey-Nagel, Nucleodex Beta-PM CC200/4). Conversion is 100% at an ee of 29%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10 % ee | Stage #1: N-benzyl-N-(1-phenylethylidene)amine With benzylamine In methanol at 20℃; for 1h; Stage #2: With hydrogen In methanol at 30℃; for 15h; | 14 Example 14: (1S)-Ar-Benzyl-l-phenylethylamine; In a 15 mL autoclave in an argon atmosphere bis(l,5-cyclooctadiene)-di(iridium(I)di-chloride) 98% (6.7 mg, 0.010 mmol), (+)-ligand Ic (5.7 mg, 0.010 mmol), benzylamine(5.6 mg, 0.052 mmol) and A^-benzyl-A/-(l-phenylethylidene)amine (0.21 g, 1.0 mmol) isdissolved in degassed methanol (5 mL) and stirred for Ih at room temperature. Afterflushing the autoclave with argon hydrogenation is carried out during 15 h at 30 °C and at50 bar hydrogen pressure. The reaction solution is directly analysed by GC for conversion(column: HP-101 25 m / 0.2 mm) and enantiomeric excess (column: Macherey-Nagel,Nucleodex Beta-PM CC200/4). Conversion is 100% at an ee of 10%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | BuLi (2.4 M, 4.50 mL, 10.9 mmol) was added to a stirred solution of 2229 (2.37 g, 11.3 mmol) in THF (30 mL) at -78 C. The resultant solution was stirred at -78 C for 30 min before the addition of a solution of 15 (1.00 g, 7.00 mmol) in THF (20 mL) at -78 C via cannula. The reaction mixture was stirred for 2 h, (-)-CSO21 (2.74 g, 12.0 mmol) was added and the reaction mixture was allowed to warm to rt over 12 h. The reaction mixture was then quenched with satd aq NH4Cl (5 mL) and concentrated in vacuo. The residue was partitioned between 10% aq citric acid (50 mL) and CH2Cl2 (50 mL) and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed sequentially with satd aq NaHCO3 (100 mL) and brine (100 mL), then dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30-40 C petrol/Et2O, 9:1) gave 25 as a white crystalline solid (1.50 g, 58%, >99:1 dr);31 mp 85-88 C; -27.9 (c 1.0 in CHCl3); {lit.31 -34.4 (c 1.0 in CHCl3)}; deltaH (400 MHz, CDCl3) 1.08 (3H, d, J 7.0, C(4)H3), 1.32 (3H, d, J 6.7, C(alpha)Me), 1.36 (9H, s, CMe3), 3.02 (1H, br s, OH), 3.24-3.27 (1H, m, C(3)H), 3.95 (1H, ABd, J 15.0, NCHA), 4.05-4.12 (3H, m, C(alpha)H, C(2)H, NCHB), 7.21-7.36 (8H, m, Ph), 7.48 (2H, dd, J 7.6, 0.5, Ph). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | To a solution of (R)-(+)-N-benzyl-ox-methylbenzylamine (0.70 g, 3.3 mmol) in THF (6.7 mL) cooled to -78 C. under a dry nitrogen atmosphere, see-BuLi (4.22 mL, 1.3M in cyclohexane, 5.5 mmol) was added dropwise. The resulting mixture was stirred at -78 C. for 30 minutes and then a solution of 170 (0.62 g, 2.74 mmol) in THF (3.4 mL) was added dropwise by syringe. The mixture was stirred at -78 C. for 5 hours and then quenched with glacial AcOH (2 mL) in THF (5 mL). The reaction mixture was warmed to room temperature, poured into a 1:1 mixture of saturated aqueous NaHCO3:EtOAc. The organic layer was washed with H2O (2 times) and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 1:5 ethyl actetate:hexanes to give 171 (1.2 g, 100%). This material still contained minor impurities but was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | General procedure: BuLi (1.55 equiv) was added dropwise to a solution of the requisite amine (1.6 equiv) in THF at -78 C. The resultant pink solution was stirred at -78 C for 30 min before the addition of a solution of the requisite alpha,beta-unsaturated ester (1.0 equiv) in THF at -78 C. The reaction mixture was then stirred at -78 C for 2 h before the addition of satd aq NH4Cl. The reaction mixture was then allowed to warm to rt and concentrated in vacuo. The residue was partitioned between H2O and Et2O and the aqueous layer was extracted with Et2O. The combined organic extracts were then washed sequentially with 10% aq citric acid, satd aq NaHCO3 and brine, then dried and concentrated in vacuo. | |
80% | To a stirred solution of [(R)- (+)-N-BENZYL-A-METHYLBENZYLAMINE] (4. [0ML,] [19MMOL)] in THF [(20ML)] [AT-78C] was added n-butyl lithium (1.6M in hexanes, 12.5mL, [20MMOL)] and the resulting mixture was allowed to warm to room temperature over. 10 min. before recooling to -78C. A solution of trans-3-fluorocinnamic acid [TERT-BUTYL] ester (3.74g, 16.8mmol) in THF (20mL) was added and the resulting mixture was stirred at-78C for 2h then quenched by the addition of saturated aqueous ammonium chloride solution (25mL). After warming to room temperature the organic phase was washed with water (2 x [50ML)] and brine, dried [(MGSO4)] and evaporated. The crude product was purified by Bond Elut (isohexane then 2% ethyl acetate in isohexane) to give the sub-title compound as a gum (5.85g, 80%). [1H] NMR [(400MHZ,] [CDC13)] : 1.23 (s, 9H), 1.27 (d, 3H), 2.48 (m, 2H), 3.67 (s, 2H), [3.] 97 (q, 1H), 4.40 (dd, 1H), 6.93 (ddd, 1H), 7. [1-7.] 4 (m, 13H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With RuH(BH4)[(S,S)-xylskewphos][(S,S)-dpen]; hydrogen; sodium t-butanolate; In toluene; at 40℃; under 7600.51 Torr; for 15h;Autoclave; Inert atmosphere; | A glass autoclave was charged with RuH(BH4)[(S,S)-xylskewphos] [(S,S)-dpen] (0.88 mg, 1.0 mumol), N-(1-phenylethylidene)benzylamine (209 mg, 1.0 mmol), and NaOC(CH3)3 (10.1 mg, 105 mumol) and flushed with argon. 0.26 mL of toluene was added thereto, and the autoclave was degassed and then flushed with hydrogen. It was charged with hydrogen until the pressure reached 10 atm, and a reaction was started by stirring in a water bath at 40 C. 15 hours later the pressure was returned to normal pressure. From 1H NMR and HPLC of the product, it was found that 90% ee (R)-N-benzyl-1-phenylethylamine was formed in a yield of 99%. The spectral data of the amine compound obtained were as follows. 1H NMR (400 MHz, CDCl3) delta 1.37 (d, J=6.4 Hz, 3H, CHCH3), 3.59 (d, J=12.8 Hz, 1H, CHHPh), 3.66 (d, J=13.3 Hz, 1H, CHHPh), 3.81 (q, J=6.4 Hz, 1H, CHNH), 7.14-7.40 (m, 10H, aromatic H); 13C NMR (100 MHz, CDCl3) delta 24.5, 51.6, 57.5, 126.7, 126.8, 126.9, 128.1, 128.3, 128.4, 140.6, 145.6; HPLC (column, CHIRALCEL OD-H; solvent, hexane/2-propanol/NHEt2=99.5/0.5/0.1; flow rate, 0.5 mL/min; temperature, 30 C.; UV wavelength, 254 nm; tR of (R)-N-benzyl-1-phenylethylamine 24.1 min.; tR of (S)-N-benzyl-1-phenylethylamine 30.1 min.); specific rotation [alpha]25D +43.7 (c 1.03, CHCl3); literature value, [alpha]20D +23.7/(c 1.35, C2H5OH, (R)) J. Org. Chem. 1990, 55, 1086. |
With phosphoric acid; C37H38N2O6PRuS; hydrogen; In methanol; dichloromethane; at 40℃; under 38002.6 Torr; for 10h;Autoclave; | General procedure: A 50 mL glass-lined stainless-steel reactor equipped with a magnetic stirrer bar was charged with Ru-catalyst (R,R)-10h (2.8 mg, 0.004 mmol), corresponding ketimine (0.2 mmol), and phosphoric acid HH (2.5 mg, 0.01 mmol) in a mixed solvent (1 mL, CH2Cl2/MeOH=4:1, v/v) under nitrogen atmosphere in a glove box. The autoclave was closed, and the final pressure of the hydrogen gas was adjusted to 50 atm after purging the autoclave with hydrogen gas several times. The reaction mixture was stirred at 40 C for 10 h. Then the hydrogen gas was carefully released and the conversion was determined by 1H NMR. The enantiomeric excesses were determined by HPLC with a chiral AD-H column after the amine products were converted to the corresponding N-Boc protected products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 3,3'-bis(9-anthryl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate; diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate In toluene at 57℃; for 120h; Inert atmosphere; Dean-Stark trap; optical yield given as %ee; enantioselective reaction; | ||
Stage #1: acetophenone; benzylamine at 150℃; for 0.666667h; Molecular sieve; Microwave irradiation; Stage #2: With [(S)-2-(hydroxydiphenylmethyl)-pyrrolidin-1-yl]-(1-methyl-1H-imidazol-2-yl)methanone; trichlorosilane In dichloromethane at 0℃; for 8h; Molecular sieve; optical yield given as %ee; enantioselective reaction; | ||
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 17h; Inert atmosphere; Overall yield = 56 %Spectr.; Optical yield = 16 %ee; | 18 Synthesis of N-benzyl-1-phenylethanamine Catalyst 2 to Schlenk of20mL (MW: 592.17) 3.04mg (0.006mmol, S / C = 500) were charged, and was replaced withargon gas after drying under reduced pressure. This ethyl acetate, 3mL, benzyl amine (MW:107.15) 375μL (3.45mmol), formic acid (MW: 46.03) 340μL (9.0mmol), acetophenone (MW:120.15) 349μL (3. 0mmol) was added, followed by heating for 17 hours with stirring at 40 ° C.The solvent was concentrated under reduced pressure, added 1M KOH 12 mL, and extractedwith dichloromethane 50mL, dried organic layer with sodium sulfate, filtered, and filled up to50mL volumetric flask. The solution 5mL up a whole pipette, 20mL transferred to a roundbottomedflask, and concentrated under reduced pressure, coumarin as an internal standard(MW: 146.14) using was subjected to a quantitative determination by H-NMR, the reactionyield 56 %Met. When the optical purity was measured of the obtained compound was 16% ee |
With formic acid; sodium formate; C34H38ClIrN2O3 In 2-methyltetrahydrofuran for 16h; Sealed tube; Overall yield = 97 percent; Optical yield = 10 percent ee; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | BuLi (1.6 M in hexanes, 9.9 mL, 15.8 mmol) was added to a stirred solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine (3.36 g, 15.9 mmol) in THF (25 mL) at -78 C and the resulting pink solution was stirred at -78 C for 30 min. A solution of 12 (3.77 g, 10.6 mmol) in THF (5 mL) was then added dropwise and the resultant mixture was stirred at -78 C for 1 h. Satd aq NH4Cl (4 mL) was then added and the mixture was allowed to warm to rt. The reaction mixture was poured into brine (150 mL) and extracted with Et2O (3×50 mL). The combined organic extracts were dried and concentrated in vacuo to give 10 in 98:2 dr. Purification via flash chromatography (eluent 30-40 C petrol/Et2O, 10:3) gave 10 as a viscous, colourless oil (5.11 g, 85%, >99:1 dr); C34H50N2O5 requires C, 72.05; H, 8.9; N, 4.9%; found C, 72.25; H, 8.5; N, 5.0%; [alpha]D21 -23.9 (c 2.0 in CHCl3); numax (film) 2970, 2930, 1730 (CO), 1700 (CO), 1600, 1495, 1455, 1245; deltaH (500 MHz, DMSO-d6, 363 K) 0.81 (6H, t, J 7.4, OCH(CH2CH3)2), 1.34 (3H, d, J 6.9, C(alpha)Me), 1.44 (15H, s, CMe3, C(2')Me2), 1.46-1.57 (4H, m, OCH(CH2CH3)2), 1.76 (1H, dd, J 9.4, 3.7, C(4)HA), 1.79 (1H, dd, J 9.4, 4.2, C(4)HB), 2.11 (2H, m, C(2)H2), 2.89 (1H, dd, J 9.5, 9.5, C(4')HA), 3.50-3.55 (1H, m, C(3)H), 3.54 (1H, dd, J 9.8, 5.8, C(4')HB), 3.57 (1H, d, J 15.1, NCHAHBPh), 3.85 (1H, d, J 15.1, NCHAHBPh), 3.91 (1H, q, J 6.9, C(alpha)H), 4.23-4.28 (1H, m, C(5')H), 4.56-4.61 (1H, m, OCHEt2), 7.41-7.21 (10H, m, Ph); deltaC (50 MHz, CDCl3) 9.6 (OCH(CH2CH3)2), 19.7 (C(alpha)Me), 24.3, 25.2, 26.3, 27.3 (C(2')Me2), 26.3 (OCH(CH2CH3)2), 28.5 (CMe3), 37.0 (C(2)), 37.0 (C(4)), 37.1, 49.8 (C(3), NCH2Ph), 50.9, 51.2 (C(4')), 57.5 (C(alpha)), 70.3, 70.7 (C(5')), 76.5 (OCHEt2), 79.0, 79.9 (CMe3), 92.9 (C(2')), 126.8, 127.3, 128.4 (o,m,p-Ph), 140.9 (i-Ph), 151.8, 152.5 (NCO), 172.1 (C(1)); m/z (CI+) 567 ([M+H]+, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99%; 98% | General procedure: 4.4. Typical procedure for the preparation of (RS)-methyl arylsulfinates (RS)-2Compound (R,SS)-1a (3.35 g, 9.99 mmol) was dissolved in toluene (20 mL), after which methanol (0.96 g, 29.96 mmol) was added, and the mixture was cooled to -5 C with a salt-ice bath. A solution of BF3·OEt2 (2.13 g, 15.01 mmol) in toluene (10 mL) was added dropwise over 5 min, and the mixture was stirred at -5 C for around 2.5 h. The reaction was monitored by TLC (EtOAc/hexane = 1:6). After the mixture was diluted with toluene (50 mL), the reaction was quenched by adding an aqueous saturated solution of NaHCO3 (20 mL). The organic phase was separated, and then washed successively with an aqueous solution of citric acid (20 mL, 15% w/v) and aqueous saturated solution of NaHCO3 (5 mL). The organic solution was dried over anhydrous MgSO4. The solvent was removed by vacuum distillation to afford (RS)-methyl benzenesulfinate (RS)-2a (1.54 g, 9.86 mmol) as a colorless oil in 99% yield. All aqueous phases were combined and adjusted to pH 10 by adding powdered KOH. The resulting aqueous mixture was then twice extracted with ethyl acetate (2 × 50 mL). The organic extracts were combined and dried over anhydrous MgSO4. Removal of the solvent by vacuum distillation gave a pale yellow oily residue. After flash chromatography through a short column (5-8 cm) of silica gel, pure (R)-N-benzyl-1-phenylethanamine (2.07 g, 9.80 mmol) was recovered in 98% yield and could be re-used in the preparation of compounds 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98%; 99% | General procedure: 4.4. Typical procedure for the preparation of (RS)-methyl arylsulfinates (RS)-2Compound (R,SS)-1a (3.35 g, 9.99 mmol) was dissolved in toluene (20 mL), after which methanol (0.96 g, 29.96 mmol) was added, and the mixture was cooled to -5 C with a salt-ice bath. A solution of BF3·OEt2 (2.13 g, 15.01 mmol) in toluene (10 mL) was added dropwise over 5 min, and the mixture was stirred at -5 C for around 2.5 h. The reaction was monitored by TLC (EtOAc/hexane = 1:6). After the mixture was diluted with toluene (50 mL), the reaction was quenched by adding an aqueous saturated solution of NaHCO3 (20 mL). The organic phase was separated, and then washed successively with an aqueous solution of citric acid (20 mL, 15% w/v) and aqueous saturated solution of NaHCO3 (5 mL). The organic solution was dried over anhydrous MgSO4. The solvent was removed by vacuum distillation to afford (RS)-methyl benzenesulfinate (RS)-2a (1.54 g, 9.86 mmol) as a colorless oil in 99% yield. All aqueous phases were combined and adjusted to pH 10 by adding powdered KOH. The resulting aqueous mixture was then twice extracted with ethyl acetate (2 × 50 mL). The organic extracts were combined and dried over anhydrous MgSO4. Removal of the solvent by vacuum distillation gave a pale yellow oily residue. After flash chromatography through a short column (5-8 cm) of silica gel, pure (R)-N-benzyl-1-phenylethanamine (2.07 g, 9.80 mmol) was recovered in 98% yield and could be re-used in the preparation of compounds 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98%; 98% | General procedure: 4.4. Typical procedure for the preparation of (RS)-methyl arylsulfinates (RS)-2Compound (R,SS)-1a (3.35 g, 9.99 mmol) was dissolved in toluene (20 mL), after which methanol (0.96 g, 29.96 mmol) was added, and the mixture was cooled to -5 C with a salt-ice bath. A solution of BF3·OEt2 (2.13 g, 15.01 mmol) in toluene (10 mL) was added dropwise over 5 min, and the mixture was stirred at -5 C for around 2.5 h. The reaction was monitored by TLC (EtOAc/hexane = 1:6). After the mixture was diluted with toluene (50 mL), the reaction was quenched by adding an aqueous saturated solution of NaHCO3 (20 mL). The organic phase was separated, and then washed successively with an aqueous solution of citric acid (20 mL, 15% w/v) and aqueous saturated solution of NaHCO3 (5 mL). The organic solution was dried over anhydrous MgSO4. The solvent was removed by vacuum distillation to afford (RS)-methyl benzenesulfinate (RS)-2a (1.54 g, 9.86 mmol) as a colorless oil in 99% yield. All aqueous phases were combined and adjusted to pH 10 by adding powdered KOH. The resulting aqueous mixture was then twice extracted with ethyl acetate (2 × 50 mL). The organic extracts were combined and dried over anhydrous MgSO4. Removal of the solvent by vacuum distillation gave a pale yellow oily residue. After flash chromatography through a short column (5-8 cm) of silica gel, pure (R)-N-benzyl-1-phenylethanamine (2.07 g, 9.80 mmol) was recovered in 98% yield and could be re-used in the preparation of compounds 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98%; 98% | General procedure: 4.4. Typical procedure for the preparation of (RS)-methyl arylsulfinates (RS)-2Compound (R,SS)-1a (3.35 g, 9.99 mmol) was dissolved in toluene (20 mL), after which methanol (0.96 g, 29.96 mmol) was added, and the mixture was cooled to -5 C with a salt-ice bath. A solution of BF3·OEt2 (2.13 g, 15.01 mmol) in toluene (10 mL) was added dropwise over 5 min, and the mixture was stirred at -5 C for around 2.5 h. The reaction was monitored by TLC (EtOAc/hexane = 1:6). After the mixture was diluted with toluene (50 mL), the reaction was quenched by adding an aqueous saturated solution of NaHCO3 (20 mL). The organic phase was separated, and then washed successively with an aqueous solution of citric acid (20 mL, 15% w/v) and aqueous saturated solution of NaHCO3 (5 mL). The organic solution was dried over anhydrous MgSO4. The solvent was removed by vacuum distillation to afford (RS)-methyl benzenesulfinate (RS)-2a (1.54 g, 9.86 mmol) as a colorless oil in 99% yield. All aqueous phases were combined and adjusted to pH 10 by adding powdered KOH. The resulting aqueous mixture was then twice extracted with ethyl acetate (2 × 50 mL). The organic extracts were combined and dried over anhydrous MgSO4. Removal of the solvent by vacuum distillation gave a pale yellow oily residue. After flash chromatography through a short column (5-8 cm) of silica gel, pure (R)-N-benzyl-1-phenylethanamine (2.07 g, 9.80 mmol) was recovered in 98% yield and could be re-used in the preparation of compounds 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | n-BuLi (2.5 M in hexanes, 15.0 mL, 37.5 mmol) was added dropwise to a stirred solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine (8.04 g, 38.1 mmol) in THF (120 mL) at -78 C, and the resultant mixture was stirred at -78 C for 30 min. A solution of 22 (4.00 g, 23.8 mmol) in THF (80 mL) was then added via cannula and the resultant mixture was stirred at -78 C for 2 h. Satd. aq. NH4Cl (20 mL) was then added and the reaction mixture was allowed to warm to rt over 15 min, then partitioned between Et2O (100 mL) and H2O (100 mL). The aqueous layer was extracted with Et2O (3*100 mL) and the combined organic extracts were washed sequentially with 10% aq. citric acid (500 mL), satd. aq. NaHCO3 (500 mL) and brine (500 mL), then dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30-40 C petrol/Et2O, 20:1) gave 23 as a pale yellow oil (7.22 g, 80%, 98:2 dr);3-5,16,17 [alpha]D25 -22.2 (c 2.0 in CHCl3); {lit. [alpha]D24 -23.3 (c 2.04 in CHCl3)}; deltaH (400 MHz, CDCl3) 1.37 (9H, s, CMe3), 1.38 (3H, d, J 6.8, C(alpha)Me), 1.70 (3H, d, J 4.6, C(6)H3), 2.22 (1H, dd, J 14.2, 9.2, C(2)HA), 2.35 (1H, dd, J 14.2, 5.5, C(2)HB), 3.66 (2H, app s, NCH2Ph), 3.73-3.78 (1H, m, C(3)H), 4.01 (1H, q, J 6.8, C(alpha)H), 5.52-5.54 (2H, m, C(4)H, C(5)H), 7.17-7.39 (10H, m, Ph). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | General procedure: BuLi (1.6 equiv) was added to a solution of the requisite amine (2.0 equiv) in THF at -78 C. After 30 min, a solution of the requisite substrate (1.0 equiv) in THF at -78 C was added dropwise via cannula. After a further 2 h, satd aq NH4Cl was added and the reaction mixture was allowed to warm to rt before being concentrated in vacuo. 10% aq Citric acid solution was then added and the resultant mixture was extracted with three portions of CH2Cl2. The combined organic extracts were washed with satd aq NaHCO3 and brine, then dried and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | General procedure: BuLi (1.6 equiv) was added to a solution of the requisite amine (2.0 equiv) in THF at -78 C. After 30 min, a solution of the requisite substrate (1.0 equiv) in THF at -78 C was added dropwise via cannula. After a further 2 h, satd aq NH4Cl was added and the reaction mixture was allowed to warm to rt before being concentrated in vacuo. 10% aq Citric acid solution was then added and the resultant mixture was extracted with three portions of CH2Cl2. The combined organic extracts were washed with satd aq NaHCO3 and brine, then dried and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | General procedure: BuLi (1.6 equiv) was added to a solution of the requisite amine (2.0 equiv) in THF at -78 C. After 30 min, a solution of the requisite substrate (1.0 equiv) in THF at -78 C was added dropwise via cannula. After a further 2 h, satd aq NH4Cl was added and the reaction mixture was allowed to warm to rt before being concentrated in vacuo. 10% aq Citric acid solution was then added and the resultant mixture was extracted with three portions of CH2Cl2. The combined organic extracts were washed with satd aq NaHCO3 and brine, then dried and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sodium tris(acetoxy)borohydride; In tetrahydrofuran; at 20℃; for 16h; | Step 1: NaBH(OAc)3 (3.31 g, 15.6 mmol) was added to a solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine (3.30 g, 15.6 mmol) and 26 (2.06 g, 10.4 mmol, >99:1 dr [(E)/(Z)]) in THF (40 mL) and the resultant solution was stirred at rt for 16 h. 1.0 M aq NaOH (10 mL) was then added and the aqueous layer was extracted with EtOAc (40 mL). The combined organic layers were then dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30-40 C petrol/Et2O, 15:1) gave tert-butyl (E,R)-7-[N-benzyl-N-(alpha-methylbenzyl)amino]hept-2-enoate as a pale yellow oil (3.22 g, 79%, >99:1 dr [(E)/(Z)]); C26H35NO2 requires C, 79.35; H, 9.0; N, 3.6%; found C, 79.2; H, 8.6; N, 3.5%; +18.9 (c 1.2 in CHCl3); numax (film) 1715 (CO); deltaH (400 MHz, CDCl3) 1.39 (3H, d, J 6.8, C(alpha)Me), 1.41-1.49 (4H, m, C(5)H2, C(6)H2), 1.51 (9H, s, CMe3), 2.00-2.06 (2H, app q, J 6.9, C(4)H2), 2.31-2.40 (1H, m, C(7)HA), 2.48-2.57 (1H, m, C(7)HB), 3.51 (1H, d, J 14.0, NCHAHBPh), 3.59 (1H, d, J 14.0, NCHAHBPh), 3.93 (1H, q, J 6.8, C(alpha)H), 5.69 (1H, d, J 15.6, C(2)H), 6.82 (1H, dt, J 15.6, 6.9, C(3)H), 7.22-7.43 (10H, m, 2×Ph); deltaC (100 MHz, CDCl3) 14.8 (C(alpha)Me), 25.6, 26.9 (C(5), C(6)), 28.2 (CMe3), 31.7 (C(4)), 48.7 (C(7)), 54.4 (NCH2Ph), 57.7 (C(alpha)), 79.9 (CMe3), 122.9 (C(2)), 126.6, 127.9, 128.0, 128.1, 128.5 (o,m,p-Ph), 140.9, 143.8 (i-Ph), 148.0 (C(3)), 166.2 (C(1)); m/z (ESI+) 394 ([M+H]+, 100%).Step 2: CAN (1.06 g, 1.91 mmol) was added to a solution of tert-butyl (E,R)-7-[N-benzyl-N-(alpha-methylbenzyl)amino]hept-2-enoate (250 mg, 0.64 mmol, >99:1 dr [(E)/(Z)]) in MeCN/H2O (v/v 5:1, 10 mL) and the resultant mixture was stirred at rt for 16 h. The reaction mixture was then diluted with Et2O (20 mL), satd aq NaHCO3 was added (20 mL), and stirring was continued for a further 30 min. The aqueous layer was extracted with Et2O (2×20 mL) and the combined organic extracts were dried and concentrated in vacuo. Purification via flash column chromatography (gradient elution, 0?30% Et2O in 30-40 C petrol) gave 29 as a colourless oil (157 mg, 81%, >99:1 dr [(E)/(Z)]); +64.8 (c 1.0 in CHCl3); numax (film) 3382 (N-H), 1714 (CO), 1652 (CC); deltaH (400 MHz, CDCl3) 1.36 (3H, d, J 6.6, C(alpha)Me), 1.41-1.52 (4H, m, C(5)H2, C(6)H2), 1.48 (9H, s, CMe3), 2.11-2.17 (2H, app q, J 6.9, C(4)H2), 2.38-2.45 (1H, m, C(7)HA), 2.47-2.49 (1H, m, C(7)HB), 3.75 (1H, q, J 6.6, C(alpha)H), 5.72 (1H, d, J 15.6, C(2)H), 6.83 (1H, dt, J 15.6, 6.9, C(3)H), 7.23-7.36 (5H, m, Ph); deltaC (100 MHz, CDCl3) 24.3 (C(alpha)Me), 25.8 (C(5)), 28.1 (CMe3), 29.8 (C(6)), 31.8 (C(4)), 47.5 (C(7)), 58.4 (C(alpha)), 80.0 (CMe3), 123.2 (C(2)), 126.5, 128.4, 126.8 (o,m,p-Ph), 145.7 (i-Ph), 147.6 (C(3)), 166.1 (C(1)); m/z (ESI+) 304 ([M+H]+, 100%); HRMS (ESI+) C19H30NO2+ ([M+H]+) requires 304.2271; found 304.2283. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | General procedure: BuLi was added dropwise to a stirred solution of the requisite amine in the THF at -78 C. After 30 min, a solution of the requisite alpha,beta-unsaturated ester in THF was added via cannula. The reaction mixture was stirred at -78 C for 2 h and then satd aq NH4Cl was added. The resultant mixture was concentrated in vacuo and extracted with three portions of Et2O. The combined organic extracts were dried and concentrated in vacuo. The residue was dissolved in CH2Cl2, the resultant solution was washed with 10% aq citric acid, satd aq NaHCO3 and brine, then dried and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | BuLi (2.5 M, 2.80 mL, 7.00 mmol) was added dropwise to a stirred solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine (1.46 mL, 7.00 mmol) in THF (5 mL) at -78 C and the resultant mixture was stirred at this temperature for 30 min. A solution of 23 (1.10 g, 4.38 mmol) in THF (15 mL) at -78 C was then added dropwise. The reaction mixture was stirred at -78 C for 2 h then satd aq NH4Cl (2 mL) was added. The resultant mixture was diluted with Et2O (40 mL) and washed with 10% aq citric acid (2×30 mL). The aqueous layer was extracted with Et2O (2×40 mL) and the combined organic extracts were washed with satd aq NaHCO3 (50 mL) and brine (50 mL), then dried and concentrated in vacuo to give 26 in >99:1 dr. Purification via flash column chromatography (eluent 30-40 C petrol/Et2O/Et3N, 50:50:1) gave 26 as a yellow oil (1.67 g, 82%, >99:1 dr); +3.4 (c 1.2 in CHCl3); numax (ATR) 3063, 3026, 3004, 2971, 2930 (C-H), 1725 (CO),1642 (CC); deltaH (400 MHz, CDCl3) 1.35 (3H, d, J 6.8, C(alpha)Me), 1.42 (9H, s, CMe3), 1.48-1.59 (1H, m, C(4)HA), 1.60-1.73 (1H, m, C(4)HB), 1.89-1.94 (2H, m, C(2)H2), 2.44 (1H, td, J 11.6, 5.3, C(5)HA), 2.94 (1H, td, J 11.6, 4.6, C(5)HB), 3.08 (2H, dd, J 13.9, 6.8, N'(CHAHBCHCH2)2), 3.18 (2H, dd, J 13.9, 6.2, N'(CHAHBCHCH2)2),3.33-3.39 (1H, m, C(3)H), 3.50 (1H, d, J 14.7, NCHAHBPh), 3.72-3.86 (2H, m, NCHAHBPh, C(alpha)H), 5.13-5.25 (4H, m, N'(CH2CHCH2)2), 5.83-5.97 (2H, m, N'(CH2CHCH2)2), 7.22-7.46 (10H, m, Ph); deltaC (100 MHz, CDCl3) 20.2 (C(alpha)Me), 28.1 (CMe3), 30.0 (C(4)), 37.8 (C(2)), 50.1 (NCH2Ph), 51.4 (C(5)), 52.5 (C(3)), 56.8 (N(CH2CHCH2)2), 58.0 (C(alpha)), 80.0 (CMe3), 117.9 (N'(CH2CHCH2)2), 126.6, 127.0, 127.9, 128.1, 128.2, 128.3 (o,m,p-Ph), 135.2 (N'(CH2CHCH2)2), 141.5, 147.7 (i-Ph), 171.9 (C(1)); m/z (ESI+) 463 ([M+H]+, 100%); HRMS (ESI+) C30H43N2O2+ ([M+H]+) requires 463.3319; found 463.3302. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | BuLi (2.5 M, 26.5 mL, 66.4 mmol) was added dropwise to a stirred solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine (13.9 mL, 66.4 mmol) in THF (40 mL) at -78 C and the resultant mixture was stirred at this temperature for 30 min. A solution of 24 (12.5 g, 41.5 mmol) in THF (150 mL) at -78 C was then added dropwise. The reaction mixture was stirred at -78 C for 2 h then satd aq NH4Cl (15 mL) was added. The resultant mixture was diluted with Et2O (250 mL) and washed with 10% aq citric acid (2×150 mL). The aqueous layer was extracted with Et2O (2×200 mL) and the combined organic extracts were washed with satd aq NaHCO3 (500 mL) and brine (500 mL), then dried and concentrated in vacuo to give 27 in >99:1 dr. Purification via flash column chromatography (eluent 30-40 C petrol/Et2O/Et3N, 66:34:1) gave 27 as a colourless oil (18.7 g, 88%, >99:1 dr); -2.9 (c 1.3 in CHCl3); numax (ATR) 3062, 3027, 2975, 2930, 2801 (C-H), 1723 (CO), 1643, (CC), 1602 (CC, aromatic); deltaH (400 MHz, CDCl3) 1.32 (3H, d, J 7.1, C(alpha)Me), 1.44 (9H, s, CMe3), 1.55-1.65 (1H, m, C(4)HA), 1.66-1.76 (1H, m, C(4)HB), 1.87-1.96 (2H, m, C(2)H2), 2.39-2.51 (1H, m, C(5)HA), 2.86-2.99 (1H, m, C(5)HB), 3.06 (1H, dd, J 13.9, 6.8, N'CHAHBCHCH2), 3.19 (1H, dd, J 13.9, 5.9, N'CHAHBCHCH2), 3.32-3.42 (1H, m, C(3)H), 3.51 (1H, d, J 14.9, NCHAHBPh), 3.53 (1H, d, J 13.5, N'CHAHBPh), 3.70 (1H, d, J 13.5, N'CHAHBPh), 3.78-3.86 (2H, m, NCHAHBPh, C(alpha)H), 5.16-5.29 (2H, m, N'CH2CHCH2), 5.89-6.02 (1H, m, N'CH2CHCH2), 7.20-7.45 (15H, m, Ph); deltaC (100 MHz, CDCl3) 20.2 (C(alpha)Me), 28.1 (CMe3), 30.4 (C(4)), 37.9 (C(2)), 50.1 (NCH2Ph), 51.7 (C(5)), 52.6 (C(3)), 56.9 (N'CH2CHCH2), 58.0 (C(alpha)Me), 58.3 (N'CH2Ph), 80.0 (CMe3), 117.2 (N'CH2CHCH2), 126.6, 126.8, 127.0 (p-Ph), 128.0, 128.1, 128.2, 128.3, 128.3, 129.0 (o,m-Ph), 136.1 (N'CH2CHCH2), 139.6, 141.6, 142.8 (i-Ph), 172.0 (C(1)); m/z (ESI+) 513 ([M+H]+, 100%); HRMS (ESI+) C34H45N2O2+ ([M+H]+) requires 513.3476; found 513.3460. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | BuLi (2.5 M, 15 mL, 37.5 mmol) was added dropwise to a stirred solution of (R)-N-benzyl-N-(-methylbenzyl)amine (7.92 g, 37.5 mmol) in THF (50 mL) at 78 C. After stirring for 30 min, a solution of 6 (3.40 g, 12.5 mmol) in THF (50 mL) was added dropwise via cannula at 78 C. After stirring for a further 2 h at 78 C, satd aq NH4Cl (50 mL) was added. The reaction mixture was then allowed to warm to rt and concentrated in vacuo. The residue was dissolved in CH2Cl2 (50 mL) and the resultant solution was sequentially washed with 10% aq citric acid (30 mL), satd aq NaHCO3 (30 mL) and brine (30 mL), then dried and concentrated in vacuo. Purification via flash column chromatography (eluent 3040 ºC petrol/Et2O, 20:1) gave 9 as a colourless oil (5.25 g, 87%, >99:1 dr); +10.2 (c 1.0 in CHCl3); max (ATR) 2976 (C-H), 1721 (C=O); H (400 MHz, CDCl3) 1.14 (3H, d, J 7.1, C()Me), 1.43 (9H, s, CMe3), 1.982.00 (2H, m, C(2)H2), 2.64 (1H, dd, J 12.8, 5.0, C(4)HA), 2.76 (1H, dd, J 12.8, 9.1, C(4)HB), 3.58 (1H, d, J 14.9, NCHACHBPh), 3.673.74 (1H, m, C(3)H), 3.81 (1H, q, J 7.1, C()H), 3.92 (1H, d, J 14.9, NCHACHBPh), 6.876.99 (2H, m, Ar), 7.227.37 (10H, m, Ph); C (100 MHz, CDCl3) 19.6 (C()Me), 27.9 (CMe3), 32.4 (C(2)), 37.5 (C(4)), 50.0 (NCH2Ph), 54.4 (C(3)), 57.6 (C()), 80.4 (CMe3), 104.8 (dd, J 28, 20, C(3')), 119.4 (dd, J 19, 7, C(6')), 123.6 (d, J 19, C(1')), 126.8, 127.1, 127.9, 128.0, 128.2, 128.3 (o,m,p-Ph), 140.6, 142.1 (i-Ph), 146.1 (d, J 209, CF), 148.6 (d, J 203, CF), 153.9 (d, J 226, CF), 171.5 (C(1)); m/z (ESI+) 506 ([M+Na]+, 63%), 484 ([M+H]+, 100%); HRMS (ESI+) C29H33F3NO2+ ([M+H]+) requires 484.2458; found 484.2458. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | General procedure: BuLi (1.55 equiv) was added dropwise to a solution of the requisite amine (1.6 equiv) in THF at -78 C. The resultant pink solution was stirred at -78 C for 30 min before the addition of a solution of the requisite alpha,beta-unsaturated ester (1.0 equiv) in THF at -78 C. The reaction mixture was then stirred at -78 C for 2 h before the addition of satd aq NH4Cl. The reaction mixture was then allowed to warm to rt and concentrated in vacuo. The residue was partitioned between H2O and Et2O and the aqueous layer was extracted with Et2O. The combined organic extracts were then washed sequentially with 10% aq citric acid, satd aq NaHCO3 and brine, then dried and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | General procedure: BuLi (1.55 equiv) was added dropwise to a solution of the requisite amine (1.6 equiv) in THF at -78 C. The resultant pink solution was stirred at -78 C for 30 min before the addition of a solution of the requisite alpha,beta-unsaturated ester (1.0 equiv) in THF at -78 C. The reaction mixture was then stirred at -78 C for 2 h before the addition of satd aq NH4Cl. The reaction mixture was then allowed to warm to rt and concentrated in vacuo. The residue was partitioned between H2O and Et2O and the aqueous layer was extracted with Et2O. The combined organic extracts were then washed sequentially with 10% aq citric acid, satd aq NaHCO3 and brine, then dried and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | General procedure: BuLi (1.55 equiv) was added dropwise to a solution of the requisite amine (1.6 equiv) in THF at -78 C. The resultant pink solution was stirred at -78 C for 30 min before the addition of a solution of the requisite alpha,beta-unsaturated ester (1.0 equiv) in THF at -78 C. The reaction mixture was then stirred at -78 C for 2 h before the addition of satd aq NH4Cl. The reaction mixture was then allowed to warm to rt and concentrated in vacuo. The residue was partitioned between H2O and Et2O and the aqueous layer was extracted with Et2O. The combined organic extracts were then washed sequentially with 10% aq citric acid, satd aq NaHCO3 and brine, then dried and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | General procedure: BuLi (1.55 equiv) was added dropwise to a solution of the requisite amine (1.6 equiv) in THF at -78 C. The resultant pink solution was stirred at -78 C for 30 min before the addition of a solution of the requisite alpha,beta-unsaturated ester (1.0 equiv) in THF at -78 C. The reaction mixture was then stirred at -78 C for 2 h before the addition of satd aq NH4Cl. The reaction mixture was then allowed to warm to rt and concentrated in vacuo. The residue was partitioned between H2O and Et2O and the aqueous layer was extracted with Et2O. The combined organic extracts were then washed sequentially with 10% aq citric acid, satd aq NaHCO3 and brine, then dried and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | General procedure: BuLi (1.55 equiv) was added dropwise to a solution of the requisite amine (1.6 equiv) in THF at -78 C. The resultant pink solution was stirred at -78 C for 30 min before the addition of a solution of the requisite alpha,beta-unsaturated ester (1.0 equiv) in THF at -78 C. The reaction mixture was then stirred at -78 C for 2 h before the addition of satd aq NH4Cl. The reaction mixture was then allowed to warm to rt and concentrated in vacuo. The residue was partitioned between H2O and Et2O and the aqueous layer was extracted with Et2O. The combined organic extracts were then washed sequentially with 10% aq citric acid, satd aq NaHCO3 and brine, then dried and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | General procedure: BuLi (1.55 equiv) was added dropwise to a solution of the requisite amine (1.6 equiv) in THF at -78 C. The resultant pink solution was stirred at -78 C for 30 min before the addition of a solution of the requisite alpha,beta-unsaturated ester (1.0 equiv) in THF at -78 C. The reaction mixture was then stirred at -78 C for 2 h before the addition of satd aq NH4Cl. The reaction mixture was then allowed to warm to rt and concentrated in vacuo. The residue was partitioned between H2O and Et2O and the aqueous layer was extracted with Et2O. The combined organic extracts were then washed sequentially with 10% aq citric acid, satd aq NaHCO3 and brine, then dried and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | General procedure: BuLi (1.55 equiv) was added dropwise to a solution of the requisite amine (1.6 equiv) in THF at -78 C. The resultant pink solution was stirred at -78 C for 30 min before the addition of a solution of the requisite alpha,beta-unsaturated ester (1.0 equiv) in THF at -78 C. The reaction mixture was then stirred at -78 C for 2 h before the addition of satd aq NH4Cl. The reaction mixture was then allowed to warm to rt and concentrated in vacuo. The residue was partitioned between H2O and Et2O and the aqueous layer was extracted with Et2O. The combined organic extracts were then washed sequentially with 10% aq citric acid, satd aq NaHCO3 and brine, then dried and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | General procedure: BuLi (1.55 equiv) was added dropwise to a solution of the requisite amine (1.6 equiv) in THF at -78 C. The resultant pink solution was stirred at -78 C for 30 min before the addition of a solution of the requisite alpha,beta-unsaturated ester (1.0 equiv) in THF at -78 C. The reaction mixture was then stirred at -78 C for 2 h before the addition of satd aq NH4Cl. The reaction mixture was then allowed to warm to rt and concentrated in vacuo. The residue was partitioned between H2O and Et2O and the aqueous layer was extracted with Et2O. The combined organic extracts were then washed sequentially with 10% aq citric acid, satd aq NaHCO3 and brine, then dried and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | General procedure: BuLi (1.55 equiv) was added dropwise to a solution of the requisite amine (1.6 equiv) in THF at -78 C. The resultant pink solution was stirred at -78 C for 30 min before the addition of a solution of the requisite alpha,beta-unsaturated ester (1.0 equiv) in THF at -78 C. The reaction mixture was then stirred at -78 C for 2 h before the addition of satd aq NH4Cl. The reaction mixture was then allowed to warm to rt and concentrated in vacuo. The residue was partitioned between H2O and Et2O and the aqueous layer was extracted with Et2O. The combined organic extracts were then washed sequentially with 10% aq citric acid, satd aq NaHCO3 and brine, then dried and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | General procedure: BuLi (1.55 equiv) was added dropwise to a solution of the requisite amine (1.6 equiv) in THF at -78 C. The resultant pink solution was stirred at -78 C for 30 min before the addition of a solution of the requisite alpha,beta-unsaturated ester (1.0 equiv) in THF at -78 C. The reaction mixture was then stirred at -78 C for 2 h before the addition of satd aq NH4Cl. The reaction mixture was then allowed to warm to rt and concentrated in vacuo. The residue was partitioned between H2O and Et2O and the aqueous layer was extracted with Et2O. The combined organic extracts were then washed sequentially with 10% aq citric acid, satd aq NaHCO3 and brine, then dried and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10 g | at 0 - 50℃; | 2 Description 2: N-benzyl-1-phenylethanaminium 6-(tert-butoxycarbonyl)-6- azaspiro[2.5]octane-5-carboxylate (single unknown enantiomer) (D2) To an ice cooled solution of 6-(terf-butoxycarbonyl)-6-azaspiro[2.5]octane-5- carboxylic acid (racemic mixture) (D1 ) (41 g, 160.8 mmol) in anhydrous MeOH (400 ml) (f?)-N-benzyl-1 -phenylethanamine (34 g, 160.8 mmol) was added and the resulting reaction mixture was stirred at 0°C for 1 .5 hrs. The reaction mixture was warmed at RT and further stirred for 5 hours. Solvent was evaporated in vacuo to afford (f?)-N-benzyl-1 -phenylethanaminium 6-(tert-butoxycarbonyl)-6- azaspiro[2.5]octane-5-carboxylate (racemic salt) (75 g). To a solution of the above compound (75 g, 160.8 mmol) in anhydrous EtOH (400 ml), H20 (1 .2 L) was added and the resulting suspension was warmed to reflux untill the mixture turned into clear solution. The mixture was cooled slowly to 50°C until formation of a precipitate which was filtered at 50 °C. The aqueous layer was extracted with EtOAc twice, and the collected organic layers were dried over anhydrous Na2S04, filtered and evaporated in vacuo to afford 20 g of salt which was recrystallized from H20/EtOH (300/100 ml) at 50°C to afford the title compound (D2) (10 g). |
10 g | In methanol at 0 - 20℃; for 6.5h; | 2 N-benzyl-1-phenylethanaminium 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-5-carboxylate (single unknown enantiomer) To an ice cooled solution of 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-5-carboxylic acid (racemic mixture) (D1) (41 g, 160.8 mmol) in anhydrous MeOH (400 ml) (R)-N-benzyl-1-phenylethanamine (34 g, 160.8 mmol) was added and the resulting reaction mixture was stirred at 0° C. for 1.5 hrs. The reaction mixture was warmed at RT and further stirred for 5 hours. Solvent was evaporated in vacuo to afford (R)-N-benzyl-1-phenylethanaminium 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-5-carboxylate (racemic salt) (75 g). To a solution of the above compound (75 g, 160.8 mmol) in anhydrous EtOH (400 ml), H2O (1.2 L) was added and the resulting suspension was warmed to reflux until the mixture turned into clear solution. The mixture was cooled slowly to 50° C. until formation of a precipitate which was filtered at 50° C. The aqueous layer was extracted with EtOAc twice, and the collected organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to afford 20 g of salt which was recrystallized from H2O/EtOH (300/100 ml) at 50° C. to afford the title compound (D2) (10 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | General procedure: BuLi was added dropwise to a stirred solution of the requisiteamine in either THF or Et2O (as stated) at 78 C or 20 C, respectively,and stirring was continued for 30 min. A solution of therequisite a,b-unsaturated ester in either THF or Et2O (as stated) wasthen added via cannula and the reaction mixturewas stirred for 2 h(for THF) or 5 h (for Et2O). Satd aq NH4Cl was then added to thereaction mixture, which was then diluted with Et2O and H2O. Theaqueous layer was extracted with three portions of Et2O and thecombined organic extracts were washed sequentially with 10% aqcitric acid, satd aq NaHCO3 and brine, then dried and concentratedin vacuo. 4.27 tert-Butyl (3S,4S,5S,6R,alphaR)-3-[N-benzyl-N-(alpha-methylbenzyl)amino]-4,5,6,7-tetrahydroxy-4,5,6,7-di-O-isopropylideneheptanoate 54 Method A: Following general procedure 1, a solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine (129 mg, 0.611 mmol) in THF (5 mL) was reacted with BuLi (2.4 M, 0.25 mL, 0.59 mmol) and a solution of 22 (100 mg, 0.305 mmol, >99:1 dr) in THF (5 mL) at -78 C, which gave 54 in >99:1 dr. Purification via flash column chromatography (eluent 30-40 C petrol/Et2O, 10:1) gave 54 as a white solid (155 mg, 94%, >99:1 dr); mp 65-75 C; -18.8 (c 1.0 in CHCl3); numax (film) 1733 (C=O); deltaH (400 MHz, CDCl3) 1.25 (3H, s, MeCMe), 1.35 (3H, s, MeCMe), 1.36 (3H, s, MeCMe), 1.41 (3H, d, J 6.8, C(alpha)Me), 1.41 (9H, s, CMe3), 1.48 (3H, s, MeCMe), 2.19 (1H, dd, J 15.4, 4.4, C(2)HA), 2.47 (1H, dd, J 15.4, 8.2, C(2)HB), 3.69 (1H, d, J 15.0, NCHAHBPh), 3.85 (1H, dd, J 8.5, 6.1, C(7)HA), 3.88 (1H, d, J 15.0, NCHAHBPh), 3.99-4.05 (2H, m, C(5)H, C(7)HB), 4.06-4.10 (1H, m, C(alpha)H), 4.11 (1H, app dd, J 8.5, 6.8, C(3)H), 4.22 (1H, app dt, J 8.4, 6.1, C(6)H), 4.31 (1H, dd, J 6.5, 3.1, C(4)H), 7.19-7.37 (10H, m, Ph); deltaC (100 MHz, CDCl3) 17.2 (C(alpha)Me), 24.6, 25.5, 26.5, 26.8 (4 * MeCMe), 28.1 (CMe3), 37.1 (C(2)), 50.0 (NCH2Ph), 54.9 (C(3)), 59.4 (C(alpha)), 67.9 (C(7)), 73.3 (C(6)), 77.8 (C(4)), 78.7 (C(5)), 79.7 (CMe3), 108.1, 109.5 (2* MeCMe), 126.4, 126.7, 127.8, 128.0, 128.3, 128.4 (o,m,p-Ph), 141.9, 143.7 (i-Ph), 171.5 (C(1)); m/z (ESI+) 540 ([M+H]+, 100%); HRMS (ESI+) C32H46NO6+ ([M+H]+) requires 540.3320; found 540.3309. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | General procedure: BuLi was added to a solution of the requisite amine (1.6 equiv) in THF at -78C and the resultant mixture was stirred at -78C for 3 0min. A solution of the requisite alpha,beta-unsaturated ester (1.0 equiv) in THF at -78C was added via cannula and the resultant mixture was stirred at -78C for 2h. Satd aq NH4Cl was then added and the reaction mixture was allowed to warm to rt. The organic phase was washed with 10% aq citric acid (×2) and the combined aqueous layers were extracted with Et2O. The combined organic layers were washed sequentially with satd aq NaHCO3 and brine, then dried and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | n-BuLi (2.5 M in hexanes, 0.35 mL, 0.86 mmol) was added dropwise to a stirred solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine (188 mg, 0.89 mmol) in THF (5 mL) at -78 C, and the resultant mixture was stirred at -78 C for 30 min. A solution of 28 (128 mg, 0.56 mmol, >99:1 dr) in THF (5 mL) was then added via cannula and the resultant mixture was stirred at -78 C for 2 h. Satd. aq. NH4Cl (5 mL) was then added and the resultant mixture was allowed to warm to rt over 15 min, then partitioned between Et2O (10 mL) and H2O (10 mL). The aqueous layer was extracted with Et2O (3*25 mL) and the combined organic extracts were washed sequentially with 10% aq citric acid (50 mL), satd. aq. NaHCO3 (50 mL) and brine (50 mL), then dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30-40 C petrol/Et2O, 15:1) gave 29 as a colourless oil (214 mg, 87%, 99:1 dr); [alpha]D25 -33.6 (c 1.0 in CHCl3); numax (ATR) 1724 (C=O); deltaH (400 MHz, CDCl3) 1.12 (3H, t, J 7.1, OCH2Me), 1.22 (3H, t, J 7.1, OCH2Me), 1.41 (3H, d, J 7.1, C(alpha)Me), 1.46 (9H, s, CMe3), 1.99 (1H, dd, J 15.7, 4.3, C(2)HA), 2.33 (1H, dd, J 15.7, 7.8, C(2)HB), 3.42-3.58 (3H, m, OCH2Me, OCHAHBMe), 3.63 (1H, d, J 14.9, NCHAHBPh), 3.72-3.80 (2H, m, C(3)H, OCHAHBMe), 3.93 (1H, q, J 7.1, C(alpha)H), 3.99 (1H, d, J 14.9, NCHAHBPh), 4.45 (1H, d, J 4.8, C(4)H), 7.22-7.44 (10H, m, Ph); deltaC (100 MHz, CDCl3) 15.1, 15.4 (C(OCH2Me)2), 19.9 (C(alpha)Me), 28.1 (CMe3), 33.5 (C(2)), 51.2 (NCH2Ph), 55.0 (C(3)), 58.6 (C(alpha)), 62.7, 63.8 (C(OCH2Me)2), 79.7 (CMe3), 105.8 (C(4)), 126.4, 126.8, 127.9, 128.0, 128.1, 128.2 (o,m,p-Ph), 141.9, 143.2 (i-Ph), 171.8 (C(1)); m/z (ESI+) 442 ([M+H]+, 100%); HRMS (ESI+) C27H40NaO4+ ([M+H]+) requires 442.2952; found 442.2948. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | n-BuLi (2.5 M in hexanes, 1.90 mL, 4.82 mmol) was added dropwise to a stirred solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine (1.05 g, 4.98 mmol) in THF (25 mL) at -78 C, and the resultant mixture was stirred at -78 C for 30 min. A solution of 47 (865 mg, 3.11 mmol, >99:1 dr) in THF (10 mL) was then added via cannula and the resultant mixture was stirred at -78 C for 2 h. Satd. aq. NH4Cl (20 mL) was then added and the resultant mixture was allowed to warm to rt over 15 min, then partitioned between Et2O (100 mL) and H2O (100 mL). The aqueous layer was extracted with Et2O (3*100 mL) and the combined organic extracts were washed sequentially with 10% aq. citric acid (500 mL), satd. aq. NaHCO3 (500 mL) and brine (500 mL), then dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30-40 C petrol/Et2O, 10:1) gave 48 as a colourless oil (1.29 g, 91%, 99:1 dr); [alpha]D25 -42.2 (c 1.0 in CHCl3); numax (ATR) 1722 (C=O); deltaH (400 MHz, CDCl3) 1.17-1.25 (6H, m, C(OCH2Me)2), 1.37 (3H, d, J 7.1, C(alpha)Me), 1.42 (9H, s, CMe3), 1.64-1.70 (1H, m, C(4)HA), 1.73-1.79 (1H, m, C(4)HB), 1.89-1.91 (2H, m, C(2)H2), 3.35-3.42 (1H, m, OCHAHBMe), 3.47-3.62 (4H, m, C(3)H, OCH2Me, NCHAHBPh), 3.67-3.75 (1H, m, OCHAHBMe), 3.78-3.85 (2H, m, C(alpha)H, NCHAHBPh), 4.87 (1H, dd, J 8.1, 3.0, C(5)H), 7.23-7.44 (10H, m, Ph); deltaC (100 MHz, CDCl3) 15.2, 15.4 (C(OCH2Me)2), 19.9 (C(alpha)Me), 28.0 (CMe3), 37.1 (C(4)), 37.8 (C(2)), 50.0 (NCH2), 50.5 (C(3)), 58.0 (C(alpha)), 60.4, 61.0 (C(OCH2Me)2), 80.1 (CMe3), 100.9 (C(5)), 126.7, 127.0, 128.0, 128.1, 128.2, 128.3 (o,m,p-Ph), 141.5, 142.4 (i-Ph), 171.7 (C(1)); m/z (ESI+) 456 ([M+H]+, 100%); HRMS (ESI+) C28H41NNaO4+ ([M+Na]+) requires 478.2928; found 478.2931. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | At first, 468 mg of 1a (198.1 g/mol; 2.3 mmol) was dissolved in10 mL of dry THF in a round bottom flask. The flask was sealed,purged with Ar, and cooled to 78 C in a CO2-acetone bath. In a second pear-shaped flask, 1.89 g of (R)-(+)-N-benzyl-N-alpha-methylbenzylamine (CAS: 38235-77-7, viscous light yellow oil, 211.3 g/mol, 8.9 mmol) was dissolved in 10 mL of dry THF. This one was also sealed, purged with Ar, and cooled to -78 C. Once cooled, 5.3 mL of nBuLi (n-buthyllithium, CAS: 109-72-8, 64.1 g/mol, 8.51 mmol, 1.6 M solution) was added dropwise, turning the solution from colorless to a dark pink. The solution was stirred for 15 min at -78 C, warmed to 0 C in an ice bath along 30 min, and finally to -78 C again for 15 min. The pink solution was added dropwise over the substrate solution and the resulting mixture turned orange. Once the addition was finished, the resulting mixture was magnetically stirred for 3 h before quenching with an excess of satd NH4Cl. The solution turned from orange to yellow with precipitate. After 60 min, the yellow reaction mixture was extracted with AcOEt (3 times). The organic layers were combined and washed with water (3 times) and brine (1 time). The AcOEt washed solution was dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure affording a crude yellowish oil. This crude was redissolved in DCM, washed 3 times with a 10% citric acid (3 times), and dried again with anhydrous Na2SO4. Final filtration and solvent removal led to a viscous yellowish oil. Flash chromatography afforded 814 mg of product 3 (Hexanes/AcOEt 9:1, 84% yield). Rf = 0.61 (Hexanes/AcOEt, 1:1); [alpha]D20 = +4.6 (c 1.6, CHCl3); IR (film): numax = 2926 (C-H), 1732 (C=O), 1688 (C=O, 1452 (C-N), 1299, 1145 (C-O) cm-1; 1H NMR (200 MHz, CDCl3): delta = 7.46-7.26 (10H, CarH), 7.05 (dt, J = 15.5 7.1 Hz, 1H, H3), 5.83 (d, J = 15.7 Hz, 1H, H2), 3.84 (q, J = 7.0 Hz, 1H, CH(CH3)), 3.80 (AB, JAB = 15.0 Hz, 1H, NCHAH), 3.57-3.50 (4H, CO2CH3 and NCHHB), 3.35-3.25 (1H, m, H-7), 2.20-2.01 (6H, H-4, H-6 and H-8), 1.63-1.48 (2H, H-5), 1.35 (d, J = 7.0 Hz, 3H, CHCH3) ppm; 13C NMR (50 MHz, CDCl3): delta = 173.3 (s, C-1), 172.0 (s, C-9), 152.2 (d, C-3), 143.2 (s, Cipso), 141.6 (s, Cipso), 128.5 (d, Car), 128.4 (d, Car), 128.1 (d, Car), 127.3 (d, Car), 126.9 (d, Car), 121.0 (d, C-2), 58.3 (d, CHCH3), 53.8 (d, C-7), 51.7 (s, CO2CH3), 50.2 (t, CH2Car), 36.4 (t, C-8), 33.2 (t, C-4), 32.3 (t, C-6), 25.4 (t, C-5), 20.2 (q, CHCH3) ppm; HRMS (ESI): m/z (M+H) calcd for C25H31NO4, 410.2331; found, 410.2325, Delta = -0.98 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | At first, 1.48 g of 1b (158.0 g/mol; 9.37 mmol) was dissolved in60 mL of dry THF in a round bottom flask. The flask was sealed, purged with Ar, and cooled to 78 C in am CO2-acetone bath. In a second pear-shaped flask, 7.18 g of (R)-(+)-N-benzyl-N-alpha-methylbenzylamine (CAS: 38235-77-7, 211.3 g/mol, 34 mmol) was dissolved in 60 mL of dry THF. This one was also sealed, purged with Ar and cooled to -78 C. Once cooled, 16 mL of nBuLi (n-buthyllithium, CAS: 109-72-8, 64.1 g/mol, 32 mmol, 1.6 M solution) was added dropwise, turning the solution from colorless to a dark pink. The solution was stirred for 15 min at -78 C, warmed to 0 C in an ice bath for 30 min and finally to -78 C again for min. The pink solution was added dropwise over the substrate solution and the resulting mixture turned orange. Once the addition was finished, the resulting mixture was magnetically stirred for 3 h before quenching with an excess of satd NH4Cl. The solution turned from orange to yellow with precipitate. After 60 min, the yellow reaction mixture was extracted with AcOEt (3 times). The organic layers were combined and washed with water (3 times) and brine (1 time). The AcOEt washed solution was dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure affording a crude yellowish oil. This crude was redissolved in DCM, washed 3 times with a 10% citric acid (3 times) ,and dried again with anhydrous Na2SO4. Final filtration and solvent removal lead to a viscous yellowish oil. Flash chromatography afforded 2.66 g of product 2 (Hexanes/AcOEt 9:1, 77% yield). Rf = 0.55 (Hexanes/AcOEt, 1:1); [alpha]D20 = +8.1 (c 0.7, CHCl3); IR (neat): numax = 3431 (O-H), 2933 (C-H), 1730 (C=O), 1450, 1155 (C-O) cm-1; 1H NMR (400 MHz, CDCl3): delta = 7.43-7.22 (10H, CarH), 3.85 (q, J = 6.9 Hz, 1H, CHCH3), 3.79 (AB, JAB = 14.9 Hz, 1H, NCHAH), 3.62 (t, J = 6.3 Hz, 3H, H-7), 3.59-3.55 (1H, NCHHB), 3.55 (s, 3H, CO2CH3), 3.31 (m, 1H, H-3), 2.09 (ABX, JABX = 14.7 4.6 Hz, 1H, H-2A), 2.03 (ABX, JABX = 14.6 and 8.3 Hz, 1H, H-2B), 1.64-1.37 (6H, H-4, H-5 and H-6), 1.35 (d, J = 7.0 Hz, 3H, CHCH3) ppm; 13C NMR (50 MHz, CDCl3): delta = 173.5 (s, CO2CH3), 143.3 (s, Cipso), 141.8 (s, Cipso), 128.5 (d, Car), 128.4 (d, Car), 128.3 (d, Car), 128.1 (d, Car), 127.1 (d, Car), 126.9 (d, Car), 63.1 (t, C-7), 58.1 (d, CHCH3), 54.0 (d, C-3), 51.6 (q, CO2CH3), 50.1 (t, NCH2), 36.6 (t, C-2), 33.4 (t, C-6), 32.8 (t, C-4), 23.3 (t, C-5), 19.8 (q, CHCH3) ppm; HRMS (ESI): m/z (M+H) calcd for C23H32NO3, 370.2376; found, 370.2374, Delta = -0.73 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(alpha-methylbenzyl)amino]-3-(3'-fluorophenyl)propanoate 29 BuLi (2.2?M in hexanes, 15.9?mL, 34.9?mmol) was added dropwise to a stirred solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine (7.61?g, 36.0?mmol, >99:1 er) in THF (100?mL) at -78?C and the resultant mixture was stirred at -78?C for 30?min. A solution of 27 (5.00?g, 22.5?mmol, 96:4 dr [(E):(Z)]) in THF (100?mL) was then added dropwise via cannula and the resultant mixture was stirred at -78?C for 2?h (-)-CSO (10.3?g, 45.0?mmol) was then added and the resultant mixture was allowed to warm to rt and stirred at rt for 16?h, then concentrated in vacuo. The residue was partitioned between CH2Cl2 (100?mL) and 10% aq citric acid (100?mL), and the aqueous layer was extracted with CH2Cl2 (3?*?80?mL). The combined organic extracts were washed sequentially with satd aq NaHCO3 (100?mL) and brine (100?mL), then dried and concentrated in vacuo. The residue was dissolved in Et2O (100?mL) and filtered, and the filter cake was washed with Et2O (2?*?100?mL), then the combined organic extracts were concentrated in vacuo. Purification via flash column chromatography (eluent 30-40?C petrol/Et2O, 10:1) gave 29 as a pale yellow oil (6.23?g, 85%, >99:1 dr); [ 19 ] -19.4 (c 1.0 in CHCl3); {lit [19]. [alpha]20D [alpha]D20 -34.6 (c 1.0 in CHCl3)}; deltaH (400MHz, CDCl3) 1.22 (9H, s, CMe3), 1.19-1.22 (3H, obsc d, C(alpha)Me), 2.75 (1H, d, J 2.4, OH), 3.86 (1H, d, J 14.9, NCHAHBPh), 4.13 (1H, d, J 14.9, NCHAHBPh), 4.16-4.23 (2H, m, C(3)H, C(alpha)H), 4.39 (1H, dd, J 3.9, 2.4, C(2)H), 6.93-7.00 (1H, m, Ar) 7.17-7.39 (11H, m, Ar, Ph), 7.46-7.48 (2H, m, Ar). | |
82% | General procedure: BuLi (1.55 equiv)was added dropwise to a stirred solution of therequisite amine (1.60 equiv) in THF at 78 C and the resultantsolutionwas stirred at 78 C for 30 min. A solution of the requisitea,b-unsaturated ester (1.0 equiv) in THFwas then added via cannula and the resultant mixture was stirred at 78 C for 2 h. (-)-CSO 4(1.60 equiv) was then added and the reaction mixture was allowedto warm to rt over 14 h. Satd aq NH4Cl was then added and thereaction mixture was stirred at rt for 5 min, then concentrated invacuo. The residue was partitioned between CH2Cl2 and 10% aqcitric acid and the aqueous layer was extracted with three portions of CH2Cl2. The combined organic extracts werewashed sequentiallywith satd aq NaHCO3 and brine, then dried and concentrated invacuo. The residue was then dissolved in Et2O and the resultantsolution was filtered, then concentrated in vacuo. Following the general procedure, BuLi (2.3Min hexanes, 2.12 mL,4.88 mmol) and (R)-N-benzyl-N-(a-methylbenzyl)amine (1.22 g,5.04 mmol, >99:1 er) were reacted with 28 (700 mg, 3.15 mmol,>99:1 dr) and 4 (1.23 g, 5.36 mmol) in THF (20 mL) at 78 C to give 33 in >99:1 dr. Purification via flash column chromatography (eluent30e40 C petrol/Et2O, 10:1) gave 33 as a pale yellow solid(1.16 g, 82%, >99:1 dr); mp 73e79 C; [a]D20 34.6 (c 1.0, CHCl3);nmax (ATR) 3485 (OeH), 1724 (C]O); dH (400 MHz, CDCl3) 1.39 (9H,s, CMe3), 1.32e1.50 (3H, obsc d, C(a)Me), 3.20 (1H, br s, OH), 4.13(1H, d, J 15.0, NCHAHBPh), 4.37 (1H, d, J 15.0, NCHAHBPh), 4.41e4.50(2H, m, C(3)H, C(a)H), 4.61e4.70 (1H, m, C(2)H), 7.09e7.75 (14H, m,Ar, Ph); dC (100 MHz, CDCl3) 14.8 (C(a)Me) 27.4 (CMe3) 52.0(NCH2Ph), 57.3 (C(a)), 64.0 (C(3)), 73.1 (C(2)), 82.1 (CMe3), 114.4,116.8 (2d, J 21.5, C(20), C(40)), 125.5 (d, J 2.9, C(60)), 126.7, 127.0,128.0, 128.0, 128.2, 128.3 (o,m,p-Ph), 129.4 (d, J 7.6, C(50)), 141.1 (d, J6.7, C(10)), 143.9, 141.6 (i-Ph), 162.5 (d, J 245.1, C(30)), 172.0 (C(1)); dF(377 MHz, CDCl3) 112.9 (C(30)F); m/z (ESI) 450 ([MH], 100%);HRMS (ESI) C28H33FNO3 ([MH]) requires 450.2439; found450.2439. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | General procedure: BuLi (1.55 equiv)was added dropwise to a stirred solution of therequisite amine (1.60 equiv) in THF at 78 C and the resultantsolutionwas stirred at 78 C for 30 min. A solution of the requisitea,b-unsaturated ester (1.0 equiv) in THFwas then added via cannula and the resultant mixture was stirred at 78 C for 2 h. (-)-CSO 4(1.60 equiv) was then added and the reaction mixture was allowedto warm to rt over 14 h. Satd aq NH4Cl was then added and thereaction mixture was stirred at rt for 5 min, then concentrated invacuo. The residue was partitioned between CH2Cl2 and 10% aqcitric acid and the aqueous layer was extracted with three portions of CH2Cl2. The combined organic extracts werewashed sequentiallywith satd aq NaHCO3 and brine, then dried and concentrated invacuo. The residue was then dissolved in Et2O and the resultantsolution was filtered, then concentrated in vacuo. Following the general procedure, BuLi (2.3Min hexanes, 2.02 mL,4.63 mmol) and (R)-N-benzyl-N-(a-methylbenzyl)amine (1.15 g,4.78 mmol, >99:1 er) were reacted with 29 (700 mg, 2.99 mmol,>99:1 dr) and 4 (1.17 g, 5.09 mmol) in THF (20 mL) at 78 C to give34 in >99:1 dr. Purification via flash column chromatography (eluent30e40 C petrol/Et2O,10:1) gave 34 as a pale yellow oil (1.04 g,75%, >99:1 dr); [a]D20 30.8 (c 1.0, CHCl3); nmax (ATR) 3958 (OeH),1722 (C]O); dH (400 MHz, CDCl3) 1.23 (9H, s, CMe3), 1.17e1.26 (3H,obsc d, C(a)Me), 2.72 (1H, br s, OH), 3.79 (3H, s, OMe), 3.86 (1H, d, J15.0, NCHAHBPh), 4.12 (1H, d, J 15.0, NCHAHBPh), 4.19 (1H, d, J 3.1,C(3)H), 4.22 (1H, q, J 6.8, C(a)H), 4.37 (1H, d, J, 3.1, C(2)H), 6.77e7.57(14H, m, Ar, Ph); dC (100 MHz, CDCl3) 14.6 (C(a)Me), 27.8 (CMe3),52.4 (NCH2Ph), 55.2 (OMe), 57.4 (C(a)), 65.4 (C(3)), 73.5 (C(2)), 82.2(CMe3), 112.9, 115.8, 122.4, 126.7 (C(20), C(40), C(50), C(60)), 126.7,128.1, 128.1, 128.2, 128.3, 129.0 (o,m,p-Ph), 140.0 (C(10)), 141.9, 144.2(i-Ph), 159.4 (C(30)), 172.3 (C(1)); m/z (ESI) 462 ([MH], 100%);HRMS (ESI) C29H36NO4 ([MH]) requires 462.2639; found462.2636. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | General procedure: BuLi (1.55 equiv)was added dropwise to a stirred solution of therequisite amine (1.60 equiv) in THF at 78 C and the resultantsolutionwas stirred at 78 C for 30 min. A solution of the requisitea,b-unsaturated ester (1.0 equiv) in THFwas then added via cannula and the resultant mixture was stirred at 78 C for 2 h. (-)-CSO 4(1.60 equiv) was then added and the reaction mixture was allowedto warm to rt over 14 h. Satd aq NH4Cl was then added and thereaction mixture was stirred at rt for 5 min, then concentrated invacuo. The residue was partitioned between CH2Cl2 and 10% aqcitric acid and the aqueous layer was extracted with three portions of CH2Cl2. The combined organic extracts werewashed sequentiallywith satd aq NaHCO3 and brine, then dried and concentrated invacuo. The residue was then dissolved in Et2O and the resultantsolution was filtered, then concentrated in vacuo. Following the general procedure, BuLi (2.3Min hexanes, 2.12 mL,4.88 mmol) and (R)-N-benzyl-N-(a-methylbenzyl)amine (1.22 g,5.04 mmol, >99:1 er) were reacted with 30 (493 mg, 2.22 mmol,>99:1 dr) and 4 (865 mg, 3.77 mmol) in THF (20 mL) at 78 C togive 35 in >99:1 dr. Purification via flash column chromatography(eluent 30e40 C petrol/Et2O, 10:1) gave 35 as a pale yellow oil(819 mg, 82%, >99:1 dr); [a]D20 26.7 (c 1.0, CHCl3); nmax (ATR) 3499(OeH), 1723 (C]O); dH (400 MHz, CDCl3) 1.23 (9H, s, CMe3),1.19e1.31 (3H, obsc d, C(a)Me), 2.77 (1H, br s, OH), 3.85 (1H, d, J 15.0,NCHAHBPh), 4.11 (1H, d, J 15.0, NCHAHBPh), 4.16e4.25 (2H, m, C(3)H,C(a)H), 4.40e4.44 (1H, m, C(2)H), 7.01 (2H, app t, J 8.0, C(30)H,C(50)H), 7.38 (2H, app t, J 8.0, C(20)H, C(60)H), 7.20e7.52 (10H, m, Ph);dC (125 MHz, CDCl3) 14.7 (C(a)Me) 27.8 (CMe3) 52.2 (NCH2Ph), 57.5(C(a)), 64.7 (C(3)), 73.3 (C(2)), 82.4 (CMe3), 114.9 (d, J 21.5, C(30),C(50)), 126.8, 127.0, 128.0, 128.0, 128.3, 128.4 (o,m,p-Ph), 131.6 (d, J7.2, C(20), C(60)), 134.3 (C(10)), 141.9, 144.1 (i-Ph), 162.3 (d, J 246.4,C(40)), 172.2 (C(1)); dF (377 MHz, CDCl3) 114.7 (C(40)F); m/z (ESI)450 ([MH],100%); HRMS (ESI) C28H33FNO3 ([MH]) requires450.2439; found 450.2435.4.18. tert-Butyl (R,R,R)-2-hydroxy | |
82% | tert-Butyl (R,R,R)-2-hydroxy-3-[N-benzyl-N-(alpha-methylbenzyl)amino]-3-(4'-fluorophenyl)propanoate 30 BuLi (2.2?M in hexanes, 15.9?mL, 34.9?mmol) was added dropwise to a stirred solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine (7.61?g, 36.0?mmol, >99:1 er) in THF (100?mL) at -78?C and the resultant mixture was stirred at -78?C for 30?min. A solution of 28 (5.00?g, 22.5?mmol, 96:4 dr [(E):(Z)]) in THF (100?mL) was then added dropwise via cannula and the resultant mixture was stirred at -78?C for 2?h (-)-CSO (10.3?g, 45.0?mmol) was then added and the resultant mixture was allowed to warm to rt and stirred at rt for 16?h, then concentrated in vacuo. The residue was partitioned between CH2Cl2 (100?mL) and 10% aq citric acid (100?mL), and the aqueous layer was extracted with CH2Cl2 (3?*?80?mL). The combined organic extracts were washed sequentially with satd aq NaHCO3 (100?mL) and brine (100?mL), then dried and concentrated in vacuo. The residue was dissolved in Et2O (100?mL) and filtered, and the filter cake was washed with Et2O (2?*?100?mL), then the combined organic extracts were concentrated in vacuo. Purification via flash column chromatography (eluent 30-40?C petrol/Et2O, 10:1) gave 30 as a pale yellow oil (6.03?g, 82%, >99:1 dr); [alpha]D25 -27.0 (c 1.0 in CHCl3); {lit [19]. [alpha]20D [alpha]D20 -26.7 (c 1.0 in CHCl3)}; deltaH (400MHz, CDCl3) 1.20 (9H, s, CMe3), 1.19-1.22 (3H, obsc d, J 6.9, C(alpha)Me), 2.75 (1H, br s, OH), 3.82 (1H, d, J 15.2, NCHAHBPh), 4.10 (1H, d, J 15.2, NCHAHBPh), 4.13-4.22 (2H, m, C(3)H, C(alpha)H), 4.40 (1H, d, J 2.7, C(2)H), 6.99 (2H, app t, J 8.6, C(3?)H, C(5?)H), 7.16-7.49 (10H, m, Ph), 7.36 (2H, app t, J 7.3, C(2?)H, C(6?)H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | BuLi (2.2?M in hexanes, 20.7?mL, 45.6?mmol) was added dropwise to a stirred solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine (9.95?g, 47.0?mmol, >99:1 er) in THF (100?mL) at -78?C and the resultant mixture was stirred at -78?C for 30?min. A solution of 16 (5.00?g, 29.4?mmol, >99:1 dr [(E):(Z)]) in THF (100?mL) was then added dropwise via cannula and the resultant mixture was stirred at -78?C for 2?h (-)-CSO (13.5?g, 58.8?mmol) was then added and the resultant mixture was allowed to warm to rt and stirred at rt for 16?h, then concentrated in vacuo. The residue was partitioned between CH2Cl2 (100?mL) and 10% aq citric acid (100?mL), and the aqueous layer was extracted with CH2Cl2 (3?*?80?mL). The combined organic extracts were washed sequentially with satd aq NaHCO3 (100?mL) and brine (100?mL), then dried and concentrated in vacuo. The residue was dissolved in Et2O (100?mL) and filtered, and the filter cake was washed with Et2O (2?*?100?mL), then the combined organic extracts were concentrated in vacuo. Purification via flash column chromatography (eluent 30-40?C petrol/Et2O, 10:1) gave 2 as a pale yellow solid (8.26?g, 71%, >99:1 dr); [ 19 ] mp 78-83?C; lit [19]. mp 82-86C}; [alpha]25D [alpha]D25 -28.1 (c 1.0 in CHCl3); {lit [19]. [alpha]23D [alpha]D23 -32.2 (c 1.0 in CHCl3)}; deltaH (400MHz, CDCl3) 0.77 (3H, d, J 6.6, C(4)MeA), 1.15 (3H, d, J 6.6, C(4)MeB), 1.35 (3H, d, J 7.1, C(alpha)Me), 1.52 (9H, s, CMe3), 2.07 (1H, d septet, J 9.8, 6.6, C(4)H), 2.91 (1H, d, J 2.7, OH), 3.18 (1H, app d, J 9.8, C(3)H), 3.61 (1H, d, J 14.9, NCHAHBPh), 3.68 (1H, app d, J 2.7, C(2)H), 3.92 (1H, q, J 7.1, C(alpha)H), 4.33 (1H, d, J 14.9, NCHAHBPh) 7.21-7.53 (10H, m, Ph). | |
56% | General procedure: BuLi (1.55 equiv)was added dropwise to a stirred solution of the requisite amine (1.60 equiv) in THF at 78 C and the resultant solution was stirred at 78 C for 30 min. A solution of the requisitea,b-unsaturated ester (1.0 equiv) in THFwas then added via cannula and the resultant mixture was stirred at 78 C for 2 h. (-)-CSO 4(1.60 equiv) was then added and the reaction mixture was allowedto warm to rt over 14 h. Satd aq NH4Cl was then added and thereaction mixture was stirred at rt for 5 min, then concentrated invacuo. The residue was partitioned between CH2Cl2 and 10% aqcitric acid and the aqueous layer was extracted with three portions of CH2Cl2. The combined organic extracts werewashed sequentiallywith satd aq NaHCO3 and brine, then dried and concentrated invacuo. The residue was then dissolved in Et2O and the resultantsolution was filtered, then concentrated in vacuo. Following the general procedure, BuLi (2.3Min hexanes, 1.98 mL,4.56 mmol) and (R)-N-benzyl-N-(a-methylbenzyl)amine (1.14 g,4.70 mmol, >99:1 er) were reacted with 57 (500 mg, 2.94 mmol,>99:1 dr) and 4 (1.15 mg, 5.00 mmol) in THF (20 mL) at 78 C togive 65 in >99:1 dr. Purification via flash column chromatography(eluent 30e40 C petrol/Et2O, 10:1) gave 65 as a white solid(658 mg, 56%, >99:1 dr);28 mp 82e86 C; [a]D23 32.2 (c 1.0, CHCl3);nmax (ATR) 3498 (OeH), 1716 (C]O); dH (400 MHz, CDCl3) 0.77 (3H,d, J 6.7, C(4)MeA), 1.14 (3H, d, J 6.7, C(4)MeB), 1.35 (3H, d, J 7.0,C(a)Me), 1.52 (9H, s, CMe3), 2.07 (1H, d septet, J 9.8, 6.7, C(4)H), 2.91(1H, d, J 2.9, OH), 3.18 (1H, app d, J 9.8, C(3)H), 3.60 (1H, d, J 15.7,NCHAHBPh), 3.68 (1H, app d, J 2.9, C(2)H), 3.91 (1H, q, J 7.0, C(a)H),4.32 (1H, d, J 15.7, NCHAHBPh), 7.18e7.57 (10H, m, Ph); dC (100 MHz,CDCl3) 20.0, 22.3 (C(4)Me2), 20.9 (C(a)Me), 27.8 (C(4)), 28.1 (CMe3),52.0 (NCH2Ph), 58.1 (C(a)), 64.1 (C(3)), 70.9 (C(2)), 82.8 (CMe3),126.4, 127.1, 128.0, 128.4, 128.4, 128.6 (o,m,p-Ph), 142.5, 142.5 (i-Ph),175.4 (C(1)); m/z (ESI) 398 ([MH], 100%); HRMS (ESI)C25H35NNaO3 ([MNa]) requires 420.2509; found 420.2513. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83 % ee | With cyclopentyl methyl ether; 2'-(bis(3,5-bis(trifluoromethyl)phenyl)phosphanyl)-3',6'-dimethoxy-N2,N2,N6,N6-tetramethyl-[1,1'-biphenyl]-2,6-diamine; sodium t-butanolate In 1,4-dioxane at 60℃; for 16h; Inert atmosphere; Overall yield = 68 %; Overall yield = 230 mg; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | BuLi (2.30 M in hexanes, 14.0 mL, 32.3 mmol) was added dropwise to a stirred solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine (5.36 g, 33.3 mmol, >99:1 er) in THF (30 mL) at -78 C. After stirring for 30 min, a solution of 14 (3.50 g, 20.8 mmol, >99:1 dr) in THF (10 mL) at -78 C was added dropwise via cannula. The reaction mixture was left to stir at -78 C for 2 h, before the addition of satd aq NH4Cl (10 mL). The resultant mixture was allowed to warm to rt and then extracted with CH2Cl2 (3*200 mL). The combined organic extracts were washed sequentially with 10% aq citric acid (200 mL) and satd aq NaHCO3 (200 mL), then dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30-40 C petrol/EtOAc, 19:1) gave 15 as a pale yellow oil (6.08 g, 89%, >99:1 dr);12,31 [alpha]D20 -4.7 (c 1.0 in CHCl3); {lit.12,31 [alpha]D24 -1.7 (c 3.4 in CHCl3)}; deltaH (500 MHz, CDCl3) 1.37 (3H, d, J 6.7, C(alpha)Me), 1.41 (9H, s, CMe3), 1.70 (3H, d, J 5.2, C(6)H3), 2.26 (1H, dd, J 14.2, 8.4, C(2)HA), 2.42 (1H, dd, J 14.2, 6.4, C(2)HB), 3.12-3.14 (2H, m, CH2CH=CH2), 3.80-3.85 (1H, m, C(3)H), 4.01 (1H, q, J 6.7, C(alpha)H), 5.00 (1H, dd, J 10.2, 1.5, CH2CH=CHAHB), 5.08 (1H, dd, J 17.0, 1.5, CH2CH=CHAHB), 5.45-5.50 (2H, m, C(4)H, C(5)H), 5.78 (1H, ddt, J 17.0, 10.2, 6.2, CH2CH=CH2), 7.20-7.39 (5H, m, Ph). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | BuLi (2.5 M in hexanes, 1.23 mL, 3.08 mmol) was added dropwise via syringe to a stirred solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine (0.67 mL, 3.18 mmol, >99:1 er) in THF (8 mL) at -78 C. After stirring at -78 C for 30 min, a solution of 18 (390 mg, 1.99 mmol, >99:1 dr [(E):(Z)]) in THF (8 mL) at -78 C was added dropwise via cannula. The reaction mixture was left to stir at -78 C for 2 h, then satd aq NH4Cl (10 mL) was added. The resultant mixture was allowed to warm to rt and stirred at rt for 15 min, then concentrated in vacuo. The residue was partitioned between CH2Cl2 (10 mL) and 10% aq citric acid (10 mL). The aqueous layer was extracted with CH2Cl2 (2*20 mL) and the combined organic extracts were washed sequentially with satd aq NaHCO3 (20 mL), H2O (20 mL) and brine (20 mL), then dried and concentrated in vacuo to give 20 in >99:1 dr. Purification via flash column chromatography (eluent 30-40C petrol/Et2O, 20:1) gave 20 as a pale yellow oil (787mg, 97%, 99:1 dr); [alpha]D20 +6.5 (c 1.0 in CHCl3); numax (ATR) 1726 (C=O), 1640 (C=C); deltaH (400MHz, CDCl3) 1.37 (3H, d, J 7.0, C(alpha)Me), 1.43 (9H, s, CMe3), 1.46-1.63 (4H, m, C(4)H2, C(5)H2), 1.87-2.06 (4H, m, C(2)H2, C(6)H2), 3.31-3.38 (1H, m, C(3)H), 3.52 (1H, d, J 15.0, NCHAHBPh), 3.81-3.87 (2H, m, C(alpha)H, NCHAHBPh), 4.96-5.05 (2H, m, C(8)H2), 5.79-5.89 (1H, m, C(7)H), 7.25-7.47 (10H, m, Ph); deltaC (100MHz, CDCl3) 20.5 (C(alpha)Me), 26.3 (C(5)), 28.1 (CMe3), 33.0 (C(4)), 33.7 (C(6)), 37.7 (C(2)), 50.1 (C(3)), 53.8 (NCH2Ph), 58.3 (C(alpha)), 80.0 (CMe3), 114.4 (C(8)), 126.6, 127.0, 128.0, 128.2, 128.3 (o,m,p-Ph), 139.1 (C(7)), 142.0, 140.7 (i-Ph), 172.2 (C(1)); m/z (ESI+) 408 ([M+H]+, 100%); HRMS (ESI+) C27H38NO2+ ([M+H]+) requires 408.2897; found 408.2898. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | BuLi (2.5 M in hexanes, 1.85 mL, 4.26 mmol) was added dropwise via syringe to a stirred solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine (0.92 mL, 4.40 mmol, >99:1 er) in THF (10 mL) at -78 C. After stirring at -78 C for 30 min, a solution of 8 (500 mg, 2.75 mmol, >99:1 dr [(E):(Z)]) in THF (10 mL) at -78 C was added dropwise via cannula. The reaction mixture was left to stir at -78 C for 2 h, then satd aq NH4Cl (10 mL) was added. The resultant mixture was allowed to warm to rt and stirred at rt for 15 min, then concentrated in vacuo. The residue was partitioned between CH2Cl2 (10 mL) and 10% aq citric acid (10 mL). The aqueous layer was extracted with CH2Cl2 (2*20 mL) and the combined organic extracts were washed sequentially with satd aq NaHCO3 (20 mL), H2O (20 mL) and brine (20 mL), then dried and concentrated in vacuo to give 19 in >99:1 dr. Purification via flash column chromatography (eluent 30-40 C petrol/Et2O, 100:1) gave 19 as a pale yellow oil (959 mg, 89%, >99:1 dr); 14l [alpha]D20 +8.7 (c 1.0 in CHCl3); {lit.14l [alpha]D26 +8.1 (c 0.9 in CHCl3)}; deltaH (400MHz, CDCl3) 1.25 (3H, d, J 7.0, C(alpha)Me), 1.28-1.39 (1H, m, C(4)HA), 1.31 (9H, s, CMe3), 1.46 (1H, app dtd,J 14.9, 9.3, 5.0, C(4)HB), 1.74-1.82 (2H, m, C(2)H2), 2.00-2.09 (1H, m, C(5)HA), 2.26-2.34 (1H, m, C(5)HB), 3.27 (1H, app tt, J 8.7, 4.4, C(3)H), 3.39 (1H, d, J 15.0, NCHAHBPh), 3.67-3.75 (2H, m, C(alpha)H, NCHAHBPh), 4.83-4.94 (2H, m, C(7)H2), 5.70 (1H, app ddt, J 17.1, 10.3, 6.5, C(6)H), 7.12-7.35 (10H, m, Ph). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | BuLi (2.5 M in hexanes, 2.16 mL, 5.40 mmol) was added dropwisevia syringe to a stirred solution of (R)-N-benzyl-N-(a-methylbenzyl)amine (1.14 g, 5.40 mmol, >99% ee) in THF (20 mL) at78 C. The resultant pink solution was stirred for 30 min at78 C. A solution of 32 {500 mg, 1.80 mmol, >99:1 dr [(E):(Z)ratio] in THF (5 mL) at 78 C was then added dropwise via cannula.The resultant solution was stirred at 78 C for 2 h thenquenched with satd aq NH4Cl (20 mL). The resultant mixture wasdiluted with Et2O (20 mL). The aqueous layer was extracted withEt2O (3 50 mL). The combined organics were dried and concentratedin vacuo. Purification via flash column chromatography (eluent5?10% Et2O in pentane) gave 34 as a colourless oil (855 mg,93%, >99:1 dr) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine In dichloromethane at 0 - 20℃; for 14h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | At first, 52 n-BuLi 12.4ml (19.9mmol) of 1.6M was added dropwise to a stirred solution of 5.1g (22.0mmol) of 53 N-benzyl-N-alpha-methylbenzylamine (R)-1 in 15ml of 54 THF at -78C under an N2 atmosphere and the resulting solution stirred for 30min. Subsequently a solution of the alpha,beta-unsaturated diester 55 2 (2.3g, 11.0mmol), dissolved in 8ml of THF was added dropwise to the lithium amide solution via cannula and stirred at -78C for 4h before the addition of saturated 56 aqueous NH4Cl (18mL) and warming to room temperature. The crude reaction mixture was partitioned between DCM and brine and the organic layers concentrated in vacuo. The residue was partitioned between DCM and 10% citric acid solution, organic layer washed in succession with aqueous NaHCO3 solution and brine, dried and concentrated in vacuo. Purification via column chromatography on silica (1:4, EtAcO: Hexane) gave 10 3 (4.5g, 86%) as a clear oil; [alpha]D26=+3.9 (c 1.9, CHCl3); IR (neat): numax=3459, 2947, 1738, 1435, 1028; 1H NMR (400MHz, CDCl3): delta=0.85(1H, m, H-4A), 1.20-1.30(1H, m, H-3A), 1.30(1H, m, H-5A), 1.36(3H, d, J=6.8Hz, C(alpha)Me), 1.65(1H, m, H-3B), 1.73(1H, m, H-4B), 1.95(1H, m, H-5B), 1.95(1H, m, H-6), 2.01(1H, dd, J=11.8, 10.3Hz, H-8A), 2.15(1H, dd, J=11.8, 2.8Hz, H-8B), 2.29(1H, dd, J=11.4, 11.0Hz, H-1), 3.12(1H, ddd, J=11.0, 11.0, 3.6Hz, H-2), 3.41(3H, s, OCH3), 3.63(3H, s, OCH3), 3.64(1H, AB, J=13.6Hz, NCHAHPh), 3.83(1H, AB, J=13.6Hz, NCHHBPh), 3.96(1H, c, J=6.8Hz, C(alpha)H), 7.15-7.35(10H, m, Ar-H) ppm; 13C NMR (200MHz, CDCl3): delta=16.1(CH3, C(alpha)Me), 24.5(CH2, C-3), 28.5(CH2, C-5), 30.2(CH2, C-4), 37.3(CH, C-6), 39.4(CH2, C-8), 49.9(CH2, NCH2Ph), 51.2(CH3, OCH3), 51.4(CH3, OCH3), 54.5(CH, C-1), 56.8(CH, C(alpha)), 58.6(CH, C-2), 126.4-129.1(10H, C-Ar), 140.6(C, Cipso), 144.1(C, Cipso), 172.4(C, COOMe), 174.1(C, COOMe) ppm; HRMS (ESI): m/z (M+H) calcd for C26H34NO4, 424.2488; found, 424.2486 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | BuLi (2.5?M in hexanes, 28.3?mL, 70.7?mmol) was added dropwise to a stirred solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine (15.4?g, 73.0?mmol, >99:1 er) in THF (203?mL) at -78 C. The reaction mixture was stirred at -78 C for 30?min, then a solution of 23 (9.04?g, 45.6?mmol, >99:1 dr [(E):(Z)]) in THF (101?mL) was added dropwise at -78 C and the resultant mixture was stirred at -78 C for 2?h. (-)-CSO 9 (16.2?g, 70.7?mmol) was added and the resultant mixture was allowed to warm to rt and stirred at rt for 18?h. The reaction mixture was then concentrated in vacuo and partitioned between CH2Cl2 (100?mL) and 10% aq citric acid (100?mL). The aqueous layer was extracted with CH2Cl2 (3?*?100?mL), and the combined organic extracts were washed with satd aq NaHCO3 (200?mL), then dried and concentrated in vacuo. The residue was triturated with Et2O (200?mL), then filtered and concentrated in vacuo. Purification via flash column chromatography (eluent 30-40 C petroleum ether/EtOAc, 98:2) gave 32 as a colourless oil (16.3?g, 84%, >99:1 dr); -27.0 (c 1.0 in CHCl3); numax 3501 (br, O-H), 1719 (C=O); deltaH (400?MHz, CDCl3) 0.80 (3H, t, J 7.3, C(8)H3), 1.08 (3H, d, J 6.9, C(alpha)Me), 1.17-1.50 (6H, m, C(5)H2, C(6)H2, C(7)H2), 1.34 (9H, s, CMe3), 1.60-1.75 (2H, m, C(4)H2), 2.84 (1H, d, J 6.1, OH), 3.12 (1H, ddd, J 8.6, 4.8, 1.8, C(3)H), 3.60 (1H, d, J 15.4, NCHAHBPh), 3.81-3.92 (2H, m, C(2)H, C(alpha)H), 4.18 (1H, d, J 15.4, NCHAHBPh), 7.10-7.40 (10H, m, Ph); deltaC (100?MHz, CDCl3) 14.6 (C(8)), 19.9 (C(alpha)Me), 23.1, 26.8, 27.8 (C(5), C(6), C(7)), 28.5 (CMe3), 32.4 (C(4)), 51.5 (NCH2Ph), 59.0 (C(3)), 59.2 (C(alpha)), 71.6 (C(2)), 82.8 (CMe3), 126.2, 126.8, 127.4, 128.5, 128.6, 128.7 (o,m,p-Ph), 144.0, 143.2 (i-Ph), 174.9 (C(1)); m/z (ESI+) 426 ([M+H]+, 100%); HRMS (ESI+) C27H40NO3+ ([M+H]+) requires 426.3003; found 426.2996. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: (R)-N-benzyl-1-phenylethylamine; (S)-4-chloro-α-hydroxy-benzeneacetic acid In isopropyl alcohol Stage #2: at 65℃; for 0.5h; | 3.4. Preparation of the More Soluble Salt (R)-(-)-4-ClMA·(S)-(-)-BPA General procedure: The more soluble salt (R)-(-)-4-ClMA·(S)-(-)-BPA was synthesized by optical purity(R)-(-)-4-ClMA and (S)-(-)-BPA. (R)-(+)-BPA (1.1 g, 5.0 mmol) was added dropwise to a solution of(R)-(-)-4-ClMA (0.935 g, 5.0 mmol) in 6 mL 2-propanol, and the white crystals appeared. The slurrywas heated to 65 °C, the solid was dissolved completely. The solution was kept at 65 °C for 0.5 h,then cooled slowly to 20 °C. The crystals were collected by filtration and washed with 2-propanol(0.75 mL 2) twice to give 1.72 g enantiopure (R)-(-)-4-ClMA(S)-(-)BPA with a yield of 86.3%.Its melting point was 138.1 °C; specific rotation [α]22D = 51.1 (c = 1, methanol), 1HNMR (400 MHz,DMSO) δ: 1.36-1.38 (d, 3H, CH3), 2.50 (s, 2H, CH2), 3.92-3.94 (m, 1H, CH), 4.84 (s, 1H, CH), 7.21-7.43 (m,14H, C6H4 + C6H5 + C6H5). Elemental analysis: Calculated for C23H24ClNO3 (FW397.88) C: 69.43,H: 6.04, N: 3.52; Found C: 69.39, H: 6.25; N: 3.42. The more soluble salt (S)-(+)-4-ClMA·(R)-(+)-BPA,the enantiomer of (R)-(-)-4-ClMA(S)-(-)-BPA, was prepared in a similar way, its melting point was131.2 °C, and specific rotation [α]22D = +51.4 (c = 1, methanol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | n-BuLi (2.5 M in hexanes, 16.5 mL, 41.3 mmol) was added dropwise to a stirred solution of (R)-N-benzyl-N-(alpha-methylbenzyl)amine (>98% ee, 8.92 mL, 42.7 mmol) in THF (90 mL) at -78 C. The resultant solution was stirred at -78 C for 30 min, then a solution of 10 (5.90 g, 26.7 mmol, >95:5 dr [(E):(Z) ratio]) in THF (80 mL) at -78 C was added dropwise via cannula. The resultant solution was stirred at -78 C for 2 h, then satd aq NH4Cl (40 mL) was added.The resultant mixture was allowed to warm to rt over 15 min then concentrated in vacuo. The residue was partitioned between CH2Cl2 (50 mL) and 10% aq citric acid (50 mL). The aqueous layer was extracted with CH2Cl2 (2 x 30 mL) and the combined organic extracts were washed sequentially with satd aq NaHCO3 (50 mL) and brine (50 mL), then dried and concentrated in vacuo. Purification via flash column chromatography (eluent 30-40 C petroleum ether/EtOAc, 8:1/2:1) gave 11 as a yellow oil (10.8 g, 94%, >95:5 dr); [alpha]25D 3.2 (c 1.0 in CHCl3); numax 1656; deltaH (400 MHz, CDCl3) 1.33 (3H, d, J 5.8, C(alpha)Me), 2.53 (1H, dd, J 15.8, 3.7, C(2)HA), 2.85-2.89 (1H, m,C(2)HB), 3.01 (3H, s, NMe), 3.35 (3H, s, C(3')OMe), 3.77 (2H, app s, NCH2Ph), 3.83 (3H, s, NOMe), 4.04 (1H, q, J 5.8, C(alpha)H), 4.59 (1H, dd, J 9.6, 3.7, C(3)H), 6.78 (1H, dd, J 8.1, 2.8, C(4')H), 7.01-7.04 (2H, m, C(2')H, C(6')H), 7.15-7.48 (11H, m, C(5')H, Ph); deltaC (100 MHz, CDCl3) 15.8 (C(alpha)Me), 32.0 (NMe), 34.8 (C(2)), 51.0 (NCH2Ph), 55.3 (NOMe), 57.0 (C(alpha)), 58.9 (C(3)), 61.0 (C(3')OMe), 112.3 (C(4')), 114.2 (C(2')),120.6 (C(6')), 126.6, 126.8 (p-Ph), 128.0, 128.1, 128.2, 128.2 (o,m-Ph), 129.2 (C(5')), 142.1, 144.4, 144.6 (C(1'), i-Ph), 159.6 (C(3')), 172.6(C(1)); m/z (ESI) 455 ([M + Na]+, 30%), 329 ([M-C8H8], 100%); HRMS (ESI) C27H33N2O3 ([M + H]+) requires 433.2486; found 433.2489. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water In water at 100℃; for 24h; | 4.4. Synthesis of (1R,2R,4S)-1-methyl-2-(R)-N-benzyl (α-methyl-benzyl) amino -4-isopropenyl-cyclohexanol 2b and (1R,2R,4S)-1-methyl -2-(R)-N-methy (α-methyl-benzyl) amino-4-isopropenyl-cyclohexanol 3b General procedure: The 1:1 cis and trans limonene oxide (2.4 mmol), water (0.55 ml) and secondary amine 2a or 3a (5 mmol) were placed in a flask under magnetic stirring at 100 °C. After 24 h, the product reaction was obtained by column chromatography using as eluent hexane ether 8: 2 -aminoalcohol 2b was obtained in a yield of 50%, and β-aminoalcohol 3b with a yield of 60%. |
[ 5933-40-4 ]
(R)-N-Methyl-1-phenylethanamine
Similarity: 0.97
[ 1096105-18-8 ]
(R)-N-Methyl-1-phenylethanamine hydrochloride
Similarity: 0.94
[ 163831-65-0 ]
(R)-N-Benzyl-1-(naphthalen-1-yl)ethanamine hydrochloride
Similarity: 0.91
[ 5933-40-4 ]
(R)-N-Methyl-1-phenylethanamine
Similarity: 0.97
[ 1096105-18-8 ]
(R)-N-Methyl-1-phenylethanamine hydrochloride
Similarity: 0.94
[ 163831-65-0 ]
(R)-N-Benzyl-1-(naphthalen-1-yl)ethanamine hydrochloride
Similarity: 0.91
[ 56862-34-1 ]
N-(1-Phenylethyl)prop-2-yn-1-amine
Similarity: 0.91
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :