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CAS No. : | 2412-58-0 | MDL No. : | MFCD00047648 |
Formula : | C10H11N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JZZLDIIDMFCOGF-UHFFFAOYSA-N |
M.W : | 145.20 | Pubchem ID : | 231502 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.3 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 50.89 |
TPSA : | 12.36 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.02 cm/s |
Log Po/w (iLOGP) : | 2.07 |
Log Po/w (XLOGP3) : | 1.64 |
Log Po/w (WLOGP) : | 1.67 |
Log Po/w (MLOGP) : | 2.01 |
Log Po/w (SILICOS-IT) : | 3.58 |
Consensus Log Po/w : | 2.2 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.18 |
Solubility : | 0.966 mg/ml ; 0.00665 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.51 |
Solubility : | 4.46 mg/ml ; 0.0307 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.62 |
Solubility : | 0.0344 mg/ml ; 0.000237 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.42 |
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 |
---|---|---|
92% | With C21H21ClIrNO2; hydrogen In 2,2,2-trifluoroethanol at 20℃; for 17h; | |
89% | With C21H21ClIrNO2 In tetrahydrofuran; 2,2,2-trifluoroethanol for 20h; Inert atmosphere; | |
89% | With C21H21ClIrNO2 In 2,2,2-trifluoroethanol for 20h; Reflux; |
81% | With diphenyldisulfane In tetralin at 200℃; for 20h; | |
With palladium | ||
With nickel | ||
With selenium | ||
With palladium on activated charcoal; tetralin at 250℃; | ||
With sulfur |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Sodium borohydride (2.12 g, 56 mmol) was slowly added at 0 0C to a solution of l-methyl-3,4-dihydroisoquinoline (4.1 g, 28 mmol) prepared in Step 2 in methanol (100ml). The reaction mixture was stirred overnight at room temperature. IN hydrochloric acid was added to the reaction mixture, which was then concentrated under reduced pressure. The resulting residue was alkalized with potassium hydroxide and then extracted with dichloromethane. The separated organic layer was washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate and then EPO <DP n="18"/>concentrated under reduced pressure to give the titled compound (3.8 g, 92 %) as brown oil. The product was used in subsequent steps without further purification. | |
With Streptomyces sp. GF3587 imine reductase; NADPH; In aq. phosphate buffer; dimethyl sulfoxide; at 20℃;pH 7.5;Enzymatic reaction;Kinetics; | General procedure: The activities of the purified IREDs were determined from a liquid-phase spectrophotometric assay (Tecan infinite M200 pro, Maennedorf, Swiss) monitoring the change of NADPH concentration at 340nm (=6.22mM-1cm-1). Reaction mixtures contained buffer (100mM, sodium phosphate pH 7.5 for the reduction or glycine-NaOH pH 10.5 for the oxidation), 0.2mM NADPH or 0.2mM NADP+ for the reduction or oxidation, respectively, in the presence of 5% (v/v) DMSO as cosolvent, and the substrate at the desired concentration. The reaction was started by adding the purified enzyme to the mixture. The reactions were performed at room temperature. One unit is defined as the amount of protein that oxidizes 1mumolNADPH/min. Controls were done using the same reaction composition but by substitution of enzyme or substrate with buffer. The reported activities are the mean of three purifications (from independent cultivations), each measured in triplicates. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With PPA at 130 - 200℃; for 3.5h; | Procedure for preparationof 1-methyl-3,4-dihydroisoquinoline (9) To a round-bottomed flask were added N-phenethylacetamide (8) (1.30g, 8 mmol) and PPA 115% (6.90 g). The round-bottomed flask was capped with arubber septum and the mixture was stirred at 130 °C for 30 min and then at 200°C for 3 h. After that, the reaction mixture was cooled to room temperature andadded to a beaker containing crushed ice (30 g). Then, a 25% (w/v) aqueoussolution of NH4OH was added to the mixture until pH 9. The mixture wasextracted with dichloromethane (3 x 30 mL) and washed with a saturated aqueoussolution of NaCl (3 x 20 mL). The organic phase was dried over MgSO4.After filtration, the solvent was evaporated under reduced pressure, affordingdesired product 9 |
100% | With polyphosphoric acid at 130 - 200℃; for 3.5h; | 1-Methyl-3,4-dihydroisoquinoline (29)26 To a round-bottomed flask were added N-phenethylacetamide (28; 2.45 g, 15 mmol) and polyphosphoric acid (PPA; 12.95 g). The reaction mixture was maintained under magnetic stirring and anhydrous conditions at 130 °C for 30 min and at 200 °C for 3 h. Afterwards, thereaction mixture was cooled to r.t. and poured into a beaker containing crushed ice (40 g). Then, 28-30% (w/v) aq NH4OH was added tothe mixture until pH 9 and extracted with CH2Cl2 (3 × 50 mL). The combined organic phases were washed with brine (3 × 50 mL) and dried (MgSO4). After filtration, the solvent was evaporated under reduced pressure to afford the desired product 29; yield: 2.18 g (quant); brownish liquid; Rf = 0.22 (EtOAc/MeOH 20:1). IR (ATR): 2940, 2843, 1628, 1487, 1280, 762 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.44 (dd, J = 7.4, 1.4 Hz, 1 H), 7.35-7.24 (m, 2 H), 7.15 (dd, J = 7.2, 0.9 Hz, 1 H), 3.64 (tq, J = 7.5, 1.5 Hz, 2 H), 2.67 (t, J = 7.5 Hz, 2 H), 2.37 (t, J = 1.5 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 164.0, 137.0, 130.3, 129.1, 127.0, 126.5,125.0, 46.4, 25.6, 22.8. MS (EI): m/z (%) = 144 (100.0), 130 (4.3), 115 (22.9), 103 (16.6), 91 (4.8). |
94% | With 1-butyl-3-methylpyrrolidinium triflate; trichlorophosphate at 95 - 100℃; for 1h; Inert atmosphere; | 1-Methyl-3,4-dihydroisoquinoline 2c General procedure: General procedure for the preparation of 3,4-dihydroisoquinolines 2 in ILs. A mixture of N-acyl-2-arylethylamine 1 (1 mmol), POCl3 (2.5 or 9 mmol) and 2 g of the corresponding IL (Table 1) was heated with a backflow condenser and protection from moisture at 95-100 °C at stirring until the full consumption of 1 (TLC control). Then the reaction mixture was cooled to 20 °C, diluted with water (3 ml) and NaOH aqueous solution was added dropwise to pH 10. The liberated 3,4-dihydroisoquinoline was extracted with diethyl ether (5 × 3 ml), the ether solution was washed with water (2 × 3 ml), dried with MgSO4 and the solvent was evaporated. The residue was purified by flash chromatography through a short column with SiO2 or by crystallization. |
92% | With polyphosphoric acid at 180 - 200℃; | |
80% | With PPA at 180℃; for 3h; | |
75% | With phosphorus pentoxide; trichlorophosphate In toluene for 0.1h; Microwave irradiation; | |
72% | With phosphoric acid at 180℃; for 4h; | |
72% | With 2-chloropyridine; trifluoromethylsulfonic anhydride In dichloromethane at -78 - 45℃; for 49h; Inert atmosphere; | |
69.9% | With phosphorus pentoxide In tetralin for 0.5h; Heating; | |
67% | With PPA In toluene for 10h; Reflux; | |
64% | With phosphorus pentoxide; trichlorophosphate In 5,5-dimethyl-1,3-cyclohexadiene at 160℃; for 4h; | 4.2 Preparation of 2a Compound 5 (21.8 g, 134 mmol) was mixed with phosphorus(V) oxychloride (47.0 ml, 502 mmol) and phosphorus(V) oxide (23.8 g, 168 mmol). The resulting mixture was refluxed in dry xylene (400 ml) for 4 h (Scheme 4). The cooled mixture was slowly hydrolyzed with warm water, until the addition of more water did not heat the reaction mixture. The aqueous phase was separated, concentrated HCl (25 ml) was added and the mixture was extracted with toluene (3 × 50 ml). The combined organic extracts were added to the separated organic phase, which was then extracted with 3.6% (w/w) HCl (1 × 110 ml). The extract was added to the previously separated water phase and the organic phase was discarded. The aqueous solution was cooled in an ice bath, alkalized by an addition of 400 ml concentrated solution of sodium hydroxide, allowed to cool down slightly and extracted with toluene (5 × 60 ml) and diethyl ether (4 × 30 ml). The extracts were combined and dried over anhydrous sodium sulfate. The dried extract was evaporated on a rotary evaporator, affording a reddish-brown oily substance which was then distilled in vacuo. The fraction of 95-97 °C (4 Torr) contained the desired 2a (slightly yellowish oil). Yield: 12.5 g (64%), purity: 99% (GC). 1H NMR (400.00 MHz, CDCl3, 303.2 K): δ 2.374 (3H, t, J = 1.5 Hz, 1-CH3), 2.689 (2H, m, H-4), 3.652 (2H, tq, J = 7.5, 1.5 Hz, H-3), 7.163 (1H, m, H-5),7.275 (1H, m, H-7), 7.323 (1H, ddd, J = 7.4, 7.4, 1.4 Hz, H-6), 7.462 (1H, dd, J = 7.6, 1.4 Hz, H-8). 13C NMR (100.58 MHz, CDCl3, 303.2 K): δ 23.17 (1-CH3), 25.96 (C-4), 46.85 (C-3), 125.19 (C-8), 126.78 (C-7), 127.32 (C-5), 129.49 (C-8a), 130.45 (C-6), 137.32 (C-4a), 164.14 (C-1). Mass calcd: 145.09; measured: 145.16. |
54% | With phosphorus pentoxide; trichlorophosphate In o-xylene for 20h; Reflux; | |
49% | With phosphorus pentoxide In 5,5-dimethyl-1,3-cyclohexadiene at 160℃; for 6h; Inert atmosphere; | |
49% | With phosphorus pentoxide In 5,5-dimethyl-1,3-cyclohexadiene at 160℃; for 6h; Inert atmosphere; | |
38% | Stage #1: methyl-N-(benzyl-methyl)-formamide for 3h; Heating / reflux; Stage #2: With potassium hydroxide In water at 0℃; | 7.2 A mixture of JV-(2-phenylethyl)-acetamide (12 g, 73.5 mmol) prepared in Step 1 and polyphosphoric acid (200ml) was refluxed for 3 hours. The reaction mixture was cooled to room temperature, poured into ice water, alkalized with 2N potassium hydroxide solution, and then extracted with ethyl acetate. The separated organic layer was washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/methanol=10/l, v/v) to give the titled compound (4.1 g, 38 %) as brown oil. The product was used in the subsequent step without further purification. |
36% | With phosphorus pentoxide; trichlorophosphate In toluene Heating; | |
30% | Stage #1: methyl-N-(benzyl-methyl)-formamide With phosphoric acid at 140 - 240℃; for 1.5h; Stage #2: With ammonia; sodium hydroxide In water | |
26% | With triphenyl phosphite; bromine; triethylamine In dichloromethane at -60 - 20℃; | |
With phosphorus pentoxide; xylene; trichlorophosphate | ||
With phosphorus pentaoxide | ||
With phosphorus pentaoxide; toluene | ||
With zinc(II) chloride at 240℃; | ||
With PPA at 200℃; | ||
With tetralin; phosphorus pentoxide | ||
by Bischler-Napieralsky cyclisation; | ||
With polyphosphoric acid (83percent P2O5) at 145℃; | ||
With PPA | ||
Multi-step reaction with 3 steps 1: CH2Cl2 / 0.5 h / Ambient temperature 2: FeCl3 / CH2Cl2 / -10 deg C to rt 3: conc. H2SO4 / methanol / Heating | ||
16 g | With PPA at 130 - 200℃; for 3.5h; | |
With 2-chloropyridine; trifluoromethylsulfonic anhydride In dichloromethane at -78℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With peracetic acid In ethanol; benzene at 25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With triethylamine In benzene for 12h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 1h; Inert atmosphere; | |
69% | With pyridine for 3h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With N,N-dimethylammonium chloride In acetic acid at 60 - 80℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.9% | In diethyl ether; ethanol for 16h; Ambient temperature; | |
89.4% | In ethanol for 0.5h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With diethylamine In acetic acid at 60 - 100℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With triethylamine In dichloromethane at 0℃; for 0.666667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium hydroxide; sodium chloride; nitric acid In conc. nitric acid | 3 (10-3) (10-3) 1.0 g of 1-methyl-3,4-dihydroisoquinoline was dissolved in 7.0 ml of conc. nitric acid at 0° C., and 14.0 ml of fuming nitric acid was added dropwise to the solution. The solution was stirred for one hour at the same temperature, and overnight at room temperature. The reaction mixture was poured into ice, neutralized with aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate. The desiccant was separated by filtration, and the filtrate was purified by silica gel column chromatography to obtain 1.08 g of 1-methyl-7-nitro-3,4-dihydroisoquinoline, which was white crystal (yield: 82%). |
57% | With sulfuric acid; potassium nitrate at -5 - 60℃; | |
With potassium nitrate In sulfuric acid | 35.a (a) (a) 1-Methyl-7-nitro-3,4-dihydroisoquinoline 1-Methyl-3,4-dihydroisoquinoline (4.25 g, 29.3 mmol) was dissolved in ice cold concentrated sulfuric acid (15 ml) and to this was added potassium nitrate (3.25 g, 32.2 mmol) portionwise with cooling. The mixture was stirred overnight, poured over ice, basified with concentrated ammonium hydroxide, and the precipitated solid was collected, washed with water and dried: 4.47 g (80%), MS (M+H)+ 191, 1 H NMR (D2 O), 8.30 (d, 1H), 8.22 (dd, 1H), 7.39 (d, 1H), 3.80-3.62 (m, 2H), 2.92-2.70 (m, 2H), 2.48 (broad s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 96 percent / benzene / 2 h / Heating 2: 80 percent / PPA / 3 h / 180 °C | ||
Multi-step reaction with 2 steps 1: toluene / 70 - 80 °C 2: polyphosphoric acid (83percent P2O5) / 145 °C | ||
Multi-step reaction with 4 steps 1: 5 N NaOH / CH2Cl2 / 5 °C 2: CH2Cl2 / 0.5 h / Ambient temperature 3: FeCl3 / CH2Cl2 / -10 deg C to rt 4: conc. H2SO4 / methanol / Heating |
Multi-step reaction with 2 steps 2: zinc chloride / 240 °C | ||
Multi-step reaction with 2 steps 1: pyridine 2: polyphosphoric acid / 200 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 - 40 °C 2: trichlorophosphate; phosphorus pentoxide / 5,5-dimethyl-1,3-cyclohexadiene / 4 h / 160 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0.75 h / 25 - 45 °C 2: phosphorus pentoxide / 5,5-dimethyl-1,3-cyclohexadiene / 6 h / 160 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0.75 h / 25 - 45 °C 2: phosphorus pentoxide / 5,5-dimethyl-1,3-cyclohexadiene / 6 h / 160 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 - 23 °C 2: polyphosphoric acid / 180 - 200 °C | ||
Multi-step reaction with 2 steps 1: pyridine / 2 h / 90 °C 2: PPA / 3.5 h / 130 - 200 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 1.5 h / 0 °C 2: phosphoric acid / 1.5 h / 140 - 240 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 12 h / 0 - 30 °C 2: phosphoric acid / 4 h / 180 °C | ||
Multi-step reaction with 2 steps 1: pyridine / 2 h / 90 °C 2: polyphosphoric acid / 3.5 h / 130 - 200 °C | ||
Multi-step reaction with 2 steps 1: pyridine / 2 h / 90 °C 2: phosphorus pentoxide; trichlorophosphate / o-xylene / 20 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: CH2Cl2 / 16 h / Ambient temperature 2: 36 percent / xylene / 8 h / Heating 3: 85 percent / hydrogen / 10percent Pt/C / acetic acid / 4 h / Ambient temperature; atmospheric pressure |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With silver hexafluoroantimonate; C31H36ClN2O2RhS; hydrogen In dichloromethane; water at 20℃; for 1h; Autoclave; optical yield given as %ee; enantioselective reaction; | |
87% | With D-glucose; (S)-imine reductase from Streptomyces sp. GF3546; NADPH In aq. phosphate buffer; N,N-dimethyl-formamide at 30℃; for 6h; Enzymatic reaction; enantioselective reaction; | |
84% | With bis(1,5-cyclooctadiene)diiridium(I) dichloride; (11bS)-N,N-bis((S)-1-(naphthalen-2-yl)ethyl)dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-amine; hydrogen; potassium iodide In tert-butyl methyl ether at 20℃; Autoclave; stereoselective reaction; |
72% | With D-glucose; BmGDH; imine reductase from Stackebrandtia nassauensis; NADP In aq. phosphate buffer; dimethyl sulfoxide at 30℃; for 4h; Enzymatic reaction; enantioselective reaction; | |
99 % ee | With glucose dehydrogenase; D-glucose; S-selective imine reductase from Streptomyces aurantiacus; NADPH In aq. buffer at 20℃; for 20h; Enzymatic reaction; stereoselective reaction; | |
99 % ee | With glucose dehydrogenase; D-glucose; C23H30N4O17P3(1+) In aq. phosphate buffer; dimethyl sulfoxide at 30℃; for 6h; Enzymatic reaction; enantioselective reaction; | |
99 % ee | With glucose dehydrogenase; D-glucopyransoe; imine reductase from Paenibacillus elgii B69 (GI 498183793) In aq. buffer at 25℃; enantioselective reaction; | |
Multi-step reaction with 2 steps 1: borane-ammonia complex 2: LG-I-D11 / Resolution of racemate; Enzymatic reaction |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With silver hexafluoroantimonate; C10H14*C21H21ClN2O2RuS; hydrogen In dichloromethane; water at 20℃; for 10h; Autoclave; optical yield given as %ee; enantioselective reaction; | ||
With formic acid; RuCl(η6-p-cymene)((1S,2S)-N-p-toluenesulfonyl-1,2-diphenylethylenediamine); triethylamine In acetonitrile at 30℃; for 0.833333h; Optical yield = 86 %ee; enantioselective reaction; | 4.3 General protocol for reactions carried out in round-bottom flasks General procedure: A solution of substrate 2a in acetonitrile (LC-MS grade) was prepared, so that its concentration was 150 mg/ml. A solution of catalyst 1a was prepared by dissolving 5.4 mg of 1a in 1 ml acetonitrile. A round-bottom flask was equipped with a magnetic stirrer and a septum with a needle, and pre-heated on a water bath. The initial volume of acetonitrile was transferred into the flask, the hydrogenation mixture (HM) consisting of formic acid (FA) and triethylamine (TEA) was added, followed by the solution of the catalyst. Active catalytic species 1b was allowed to form by stirring the mixture for 5 min. After that, the solution of 2a (S) was added. Standard reaction conditions: 0.11 mmol 2a; 2a/1a (S/C) ratio 100; HM/S ratio 8.83; FA/TEA ratio 2.5, total reaction mixture volume 1500 μl, concentration 7% (see Section 2.1), temperature 30 °C. All ratios are molar. Samples were taken in the following way: the calculated amount of the reaction mixture containing approximately 2 mg total of 2b and 3 was transferred into a vial containing saturated aqueous solution of sodium carbonate (1 ml). The mixture was shaken well and extracted with diethyl ether (3 × 1 ml). The extract was dried over anhydrous magnesium sulfate and stripped in a stream of argon to dryness. The residue was dissolved in acetonitrile (700 μl) and analyzed on GC for conversion. After that, triethylamine (20 μl) and (-)-menthyl chloroformate 6 (10 μl) were added to the sample, affording a pair of diastereomeric carbamates 7a, 7b. The mixture was analyzed on GC for enantioselectivity (Scheme 5). | |
84 % ee | With [(1S,2S)-N-(p-toluensulfonyl)-1,2-diphenylethanediamine](p-cymene)ruthenium (I); formic acid; N-ethyl-N,N-diisopropylamine In [D3]acetonitrile |
84 % ee | With [(1S,2S)-N-(p-toluensulfonyl)-1,2-diphenylethanediamine](p-cymene)ruthenium (I); formic acid; triethylamine In [D3]acetonitrile | |
60 % ee | With streptavidin-[Cp*Ir(biotinyl-NH(1,4-C6H4)SO2NCH2CH2NH2)Cl] complex; C28H42IrN5O4S2; sodium formate In aq. buffer at 37℃; Enzymatic reaction; enantioselective reaction; | |
70 % ee | With bis(1,5-cyclooctadiene)iridium(I) tetrakis[3,5-bis(trifluoromethyl)phenyl]borate; hydrogen; iodine; (Ra)-4-(piperidino)dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepine In tetrahydrofuran at 25℃; for 12h; enantioselective reaction; | |
25 % ee | With (2S,3R)-2-amino-3-hydroxybutanamide; streptavidin biotin-wild type; C42H64Cl4Ir2N6O4S2 In dimethyl sulfoxide at 30 - 50℃; for 18h; Overall yield = 100 %; enantioselective reaction; | |
With [RuCl(TsDPEN)(hexamethylbenzene)]; formic acid; triethylamine In acetonitrile for 1.16667h; Optical yield = 85 %ee; | 4.2. Standard hydrogenation procedure General procedure: The asymmetric transfer hydrogenation reactions were performed according to a previously reported procedure. A round bottom flask was equipped with a magnetic stirrer bar and was pre-heated on a water bath (30 C). Stock solutions of the substrates and catalyst were prepared. The amounts of reaction components were calculated in order to fulfill the following ratios: S/Cratio = 100, HCOOH/triethylamine ratio = 2.5, concentration = 7.0%(defined as: (mass of substrate + mass of catalyst + mass of formic acid + mass of triethylamine)/mass of solvent), hydrogenation mixture/substrate ratio = 8.83, total volume of reaction mixture = 2 mL (all ratios are molar). The components were transferred into the flask in the following order: acetonitrile, formic acid, triethylamine, solution of the catalyst. After five minutes, the calculated amount of the substrate solution containing 0.15 mmol of substrate was added into the reaction mixture. The samples were taken in defined time intervals. The samples were treated with a saturated solution of sodium carbonate (1 mL) and extracted three times with diethyl ether (3 1 mL). The extract was dried over sodium sulfate, filtered,and stripped in a stream of argon. The residue was dissolved in 600 μL of acetonitrile and analyzed via GC. After the addition of 20 μL triethylamine and 10 μL of ()-(R)-menthyl chloroformate,the enantioselectivity could be determined. | |
71 % ee | With (R)-imine reductase from Streptomyces sp GF3587 for 24h; enantioselective reaction; | |
81 % ee | With glucose-6-phosphate dehydrogenase; glucose-6-phosphate; oxidoreductase from Bacillus cereus BAG3X2; NADPH In N,N-dimethyl-formamide at 30℃; Enzymatic reaction; enantioselective reaction; | |
81 % ee | With formic acid; pentamethylcyclopentadienyl*RhCl[(S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine]; triethylamine In methanol; water at 40℃; for 0.1h; Overall yield = 96 %; Overall yield = 141 mg; enantioselective reaction; | |
87 % ee | With [(1S,2S)-N-(p-toluensulfonyl)-1,2-diphenylethanediamine](p-cymene)ruthenium (I); hydrogen; trifluoroacetic acid In methanol at 40℃; for 6h; Autoclave; Sealed tube; | |
80 % ee | With formic acid; bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; biphenyl; triethylamine; N-[(1S,2S)-2-amino-1,2-diphenylethyl]-4-methylbenzenesulfonamide In dichloromethane at 20℃; Inert atmosphere; enantioselective reaction; | |
82 % ee | With formic acid; Noyori's catalyst; triethylamine In acetonitrile at 30℃; | General procedure for asymmetric transfer hydrogenation General procedure: The formic acid-triethylamine azeotropic mixture (218 μL; 6.3 eq of formic acid with respect to the imine) was charged into a round-bottom flask (10 mL), followed by the catalyst (0.01 eq) dissolved in acetonitrile (1 mL). The resulting mixture was stirred for 10 min to activate the catalyst. The imine (0.42 mmol) dissolved in acetonitrile (1 mL) was introduced at once and the mixture was stirred at 30 °C. The samples of the reaction mixture (60 μL) were collected at 10, 20, 30, 40, 50, 90, 120 and 180 min. (0014) Each sample was quenched by using saturated solution of Na2CO3 (1 mL) and extracted with diethyl ether (3 × 1 mL). Combined extracts were dried over anhydrous sodium sulfate and the solvent was stripped off in a stream of nitrogen. The dry sample was dissolved in acetonitrile (1 mL) and analyzed. |
13 % ee | With glucose dehydrogenase; D-glucose; streptavidin K121R mutant; C33H40ClIrN5O4S; nicotinamide adenine dinucleotide phosphate In aq. buffer at 37℃; for 24h; | |
20 % ee | With glucose dehydrogenase; D-glucose; streptavidin S112T mutant; C33H40ClIrN5O4S; nicotinamide adenine dinucleotide phosphate In aq. buffer at 37℃; for 24h; | |
63 % ee | With glucose dehydrogenase; D-glucopyransoe; imine reductase from Streptomyces sp. RGF3587 (GI 460838084) In aq. buffer at 25℃; | |
25 % ee | With Tyr-Gly-Phe; C42H64Cl4Ir2N6O4S2; streptavidin K121A mutant In aq. buffer at 37℃; for 24h; Enzymatic reaction; enantioselective reaction; | |
11 % ee | With C42H64Cl4Ir2N6O4S2; SGF; streptavidin WT mutant In aq. buffer at 37℃; for 24h; Enzymatic reaction; enantioselective reaction; | |
35 % ee | With tris(2,2'-bipyridyl)ruthenium dichloride; ascorbic acid In aq. phosphate buffer at 20℃; for 20h; Irradiation; Enzymatic reaction; Overall yield = > 95 %Spectr.; enantioselective reaction; | |
49 % ee | With sterptovidin; [Cp*Ir(biot-p-L)Cl] In dimethyl sulfoxide at 25℃; for 16h; Enzymatic reaction; enantioselective reaction; | |
41 % ee | With Cp*Ir(biot-p-L)Cl; MASMTGGQQMGRDQAGITGTWYNQLGSTFIVTAGADGALTGTYESAVGNAESRYVLTGRYDSAPATDGSGTALGWTVAWKNNYRNAHSATTWSGQYVGGAEARINTQWLLTRGTTEANAWASTLVGHDTFTKVKPSAASIDAAKKAGVNNGNPLDAVQQGSGGGNGGGNGGGNGGGNIDGRGGGNASMTGGQQMGRDQAGITGTWYNQLGSTFIVTAGADGALTGTYVTARGNAESRYVLTGRYDSAPATDGSGTALGWTVAWKNNYRNAHSATTWSGQYVGGAEARINTQWLLTRGTTEANAWASTLVGCDTFTKVKPSAASIDAAKKAGVNNGNPLDAVQQ In dimethyl sulfoxide at 25℃; for 24h; Sealed tube; | |
89 % ee | With Cp*Ir(biot-p-L)Cl; MASMTGGQQMGRDQAGITGTWYNQLGSTFIVTAGADGALTGTYESAVGNAESRYVLTGRYDSAPATDGSGTALGWTVAWKNNYRNAHSATTWSGQYVGGAEARINTQWLLTSGTTEANAWASTLVGHDTFTKVKPSAASIDAAKKAGVNNGNPLDAVQQGSGGGNGGGNGGGNGGGNIDGRGGGNASMTGGQQMGRDQAGITGTWYNQLGSTFIVTAGADGALTGTYVTARGNAESRYVLTGRYDSAPATDGSGTALGWTVAWKNNYRNAHSATTWSGQYVGGAEARINTQWLLTRGTTEANAWKSTLVGCDTFTKVKPSAASIDAAKKAGVNNGNPLDAVQQ In dimethyl sulfoxide at 50℃; for 48h; Sealed tube; | |
63 % ee | With imine reductases expressed in the cyanobacterium Synechocystis sp. PCC 6803 at 30℃; for 24h; Irradiation; Enzymatic reaction; enantioselective reaction; | |
80 % ee | With formic acid; C32H31ClN2O3RuS; triethylamine In dichloromethane at 20℃; for 24h; Inert atmosphere; Schlenk technique; Overall yield = 87 percent; Overall yield = 64 mg; enantioselective reaction; | |
80 % ee | With formic acid; C32H31ClN2O3RuS; triethylamine In dichloromethane for 24h; Schlenk technique; Inert atmosphere; | General Procedure 5: Reduction of cyclic imines General procedure: To a Schlenk tube charged with the catalyst (5 mmol) was added formic acid/triethylamine 5:2 (0.25 mL) and left to stir for 15 min under a N2 atmosphere. A solution of the imine (0.5 mmol) in DCM (0.25 mL) was added to the mixture and left to stir at rt overnight. The reaction was quenched with sat. NaHC03 (5 mL) and extracted with EtOAc (3 x 5 mL). The organic layers were combined, dried over MgSO4, filtered and the solvent removed under reduced pressure. The product was purified by column chromatography gradient elution 0-60% EtOAc in Pet. Ether. Referring first to Table 1 , there is shown the results for asymmetric transfer hydrogenations using General Procedure 1 for the reduction of ketones using Catalysts 1 to 4 according to the invention. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With N-chloro-succinimide In tetrachloromethane at 0℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 52% 2: 32% | With N-chloro-succinimide In tetrachloromethane at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane at 20℃; for 1.16667h; Inert atmosphere; | 4.2. Typical procedure for the reaction of cyclic imines 1 with TMSCF2SO2Ph (2) General procedure: Under a nitrogen atmosphere, into a CH2Cl2 (8 mL) solution of cyclic imine 1a (96 mg, 0.5 mmol) was added MeOTf (0.068 mL, 0.6 mmol) dropwise in 10 min. After the reaction mixture was stirred for 1 h at ambient temperature, the solvent CH2Cl2 was gently evaporated and dry DMF (3 mL) and KF (87 mg, 1.5 mmol) were added. Then a DMF (2 mL) solution of TMSCF2SO2Ph (2) (264 mg, 1.0 mmol) was added to the reaction system dropwise in 10 min. After stirring at ambient temperature for 30 min, the reaction mixture was quenched with a saturated NaHCO3 aqueous solution (20 mL) and extracted with ethyl acetate (3×15 mL). The combined organic phase was washed with saturated NaHCO3 solution (15 mL), and dried by anhydrous Na2SO4. After the removal of the solvent under reduced pressure, the residue was purified by flash column chromatography (petroleum ether/ethyl acetate, 3:1) to give 3a as a pale yellow solid (187 mg, 94%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With D-glucose; glucose dehydrogenase from Bacillus subtilis; imine reductase from Streptomyces viridochromogenes; nicotinamide adenine dinucleotide phosphate In methanol; aq. phosphate buffer; water; methyl cyclohexane at 30℃; for 6h; Enzymatic reaction; enantioselective reaction; | |
73% | With D-glucose; NADP; sodium hydroxide In methanol at 30℃; for 24h; Microbiological reaction; enantioselective reaction; | Procedure for the Asymmetric Biocatalytic Reduction of 1-Methyl-3,4-dihydroisoquinoline (1) Thebiotransformations on a preparative scale (40 mL) were performed in a pH stat apparatus flask with 20,50 and 100 mM concentration of 1-methyl-3,4-dihydroisoquinoline (1), 2, 5 and 10 mg mL-1 oflyophilized whole-cell catalyst (added from 4, 10 and 20 mg mL-1 of cell suspension in KPi buffer (pH 7,50 mM)), 120 mM (in case of 20, 50 mM 1) or 240 mM (in case of 100 mM 1) of D-glucose, 0.1 mM ofNADP+ and 1% (in case of 50 mM 1) or 2% (in case of 20, 100 mM 1) of MeOH as cosolvent. The flaskwas equipped with the titration head and pH electrode of a pH stat apparatus and stirred at 30 °C. Byaddition of aqueous NaOH solution, the pH was kept stable at 7. The reaction was stopped by adding 2mL of 32% NaOH solution and 30 mL of CH2Cl2. Phase separation was promoted by centrifugation. Theorganic phase was dried over magnesium sulfate. In all biotransformations conversion and enantiomericexcess was determined by analyzing the organic phase by means of a LC2000 high performance liquidchromatography (HPLC) system from Jasco (Easton, USA) with HPLC column Chiralpak IC from Daicel(supercritical CO2:EtOH (Et2NH) = 80:20 (0.02), 1 mL min-1, 20 °C, 12 MPa, 213 nm). For isolation ofthe product, the organic phase was washed with HCl (2M, 3 x 10 mL). The pH of the resulting aqueousphase was adjusted to pH 13 and the aqueous phase was extracted with CH2Cl2 (3 x 30 mL).Subsequently, the organic phases were dried over magnesium sulfate and the solvent was evaporated invacuo. (R)-1-Methyl-1,2,3,4-tetrahydroisoquinoline ((R)-2):(R)-1-Methyl-1,2,3,4-tetrahydroisoquinoline ((R)-2) was obtained as a brown oil. 1H-NMR (500 MHz, CDCl3): δ (ppm) = 7.11-7.17 (m, 3 H), 7.07-7.09 (m, 1 H), 4.11 (q, J = 6.7 Hz, 1H), 3.26 (dt, J = 5.2, 12.5 Hz, 1 H), 3.02 (ddd, J = 4.7, 8.8, 12.5 Hz, 1 H), 2.84-2.91 (m, 1 H), 2.71-2.76(m, 1 H), 1.82 (s, 1 H), 1.46 (d, J = 6.7 Hz, 3 H). NMR data are in accordance with literature data (ref.6d).HPLC analysis with chiral stationary phase: rt = 15.8 min (HPLC column Chiralpak IC (Daicel),supercritical CO2:EtOH (Et2NH) = 80:20 (0.02), 1 mL min-1, 20 °C, 12 MPa, 213 nm).Determination of absolute configuration: nD25 +73 (c 1.1; CHCl3). Optical rotation is in accordance with literature data (ref. 11). According to the ired.biocatnet database (ired.biocatnet.de) the iminereductase from Streptomyces viridochromogenes is indicated to be R-enantioselective.Isolated yield: 85.6 mg, 73% (in case of 20 mM 1), 169.8 mg, 58% (in case of 50 mM 1), 339.6 mg, 58%(in case of 100 mM 1). |
99 % ee | With [N-[(1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN][(1,2,3,4,5,6-η)-1,2,3,4,5,6-hexamethylbenzene](1,1,1-trifluoromethanesulfonato-κO)-ruthenium; hydrogen at 25℃; Autoclave; Inert atmosphere; Ionic liquid; enantioselective reaction; |
With glucose dehydrogenase; D-glucose; streptavidin K121R mutant; C33H40ClIrN5O4S; nicotinamide adenine dinucleotide phosphate; monoamine oxidase In aq. buffer at 37℃; for 24h; | ||
93 % ee | With Cp*Ir(biot-p-L)Cl; MASMTGGQQMGRDQAGITGTWYNQLGSTFIVTAGADGALTGTYESAVGNAESRYVLTGRYDSAPATDGSGTALGWTVAWKNNYRNAHSATTWSGQYVGGAEARINTQWLLTSGTTEANAWASTLVGHDTFTKVKPSAASIDAAKKAGVNNGNPLDAVQQGSGGGNGGGNGGGNGGGNIDGRGGGNASMTGGQQMGRDQAGITGTWYAQLGDTFIVTAGADGALTGTYVTARGNAESRYVLTGRYDSAPATDGSGTALGWTVAWKNNYRNAHSATTWSGQYVGGAEARINTQWLLTRGTTEANAWKSTLVGCATFTKVKPSAASIDAAKKAGVNNGNPLDAVQQ In dimethyl sulfoxide at 50℃; for 48h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; chloroform at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With zinc(II) chloride In dimethyl sulfoxide at 80℃; for 1h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With (R)-3,3′-di-9-phenanthrenyl-1,1′-bi-2-naphthol; diethylzinc In toluene at -78℃; for 12h; Inert atmosphere; Sealed tube; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With zinc(II) chloride In dimethyl sulfoxide at 80℃; for 1h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With (R)-3,3′-di-9-phenanthrenyl-1,1′-bi-2-naphthol; diethylzinc In toluene at -78℃; for 12h; Inert atmosphere; Sealed tube; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With ammonium hydroxide; hydroxylamine-O-sulfonic acid In methanol at -20 - 20℃; for 48h; Inert atmosphere; | 2.4 6.2.4 1-methyl-1,2,3,7b-tetrahydro-1,1a-diazacyclopropa[α]naphthalene (compound 5) A solution of NH4OH (0.35) in MeOH (0.85mL) was cooled to -20°C, and hydroxylamine-O-sulfonic acid (0.290g, 2.57mmol) was added portionwise to the mixture. After stirring the suspension for about 30min at -20°C, a solution of 1-methyl-3,4-dihydroisoquinoline (0.330g, 2.27mmol) in MeOH (0.85mL) was added dropwise. The reaction mixture was gradually warmed to room temperature and stirred for 2 days. The reaction mixture was then filtered, and the filtrate was concentrated. The crude red oil was purified directly by silica gel chromatography (50% EtOAc/hexanes) to yield diaziridine 5 as a dark yellow solid (231mg, 1.44mmol, 63% yield). 1H NMR (300MHz, CDCl3) δ 7.57-7.54 (m, 1H, ArH), 7.29-7.23 (m, 2H, ArH), 7.12-7.09 (m, 1H, ArH), 3.57-3.51 (ddd, J=6.5, 6.9, and 1.5Hz, 1H, ArCH2CH2N), 3.05-2.94 (td, J=13.8 and 6.0Hz, 1H, ArCH2CH2N), 2.85-2.75 (td, J=12.9 and 3.9Hz, 1H, ArCH2CH2N), 2.47-2.41 (dd, J=15.0 and 3.3Hz, 1H, ArCH2CH2N), 1.95 (br s, 1H, NH), 1.87 (s, 3H, ArCHCH3). 13C NMR (300MHz, CDCl3) δ 135.2, 134.4, 128.1, 127.6, 127.3, 126.3, 54.1, 46.2, 25.1, 24.2. IR (neat) 3218, 3068, 2987, 2944, 2919, 2857, 1497, 1458, 1439, 1381, 1345, 1313, 1271, 1229, 1189, 1149, 1114, 1076, 1064, 1047, 1028, 980, 907, 785, 766, 749, 724, 634cm-1. LRMS (APCl+) mass calcd for C10H13N2+ (MH+) requires m/z 161.11, found m/z 161.44. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 1-methyl-3,4,dihydroisoquinoline; p-methoxybenzylnitrile With manganese; chloro-trimethyl-silane; bis(cyclopentadienyl)titanium(IV) diphenoxide; triethylamine hydrochloride In tetrahydrofuran at 60℃; for 24h; Schlenk technique; Inert atmosphere; Stage #2: With hydrogenchloride; water In tetrahydrofuran; diethyl ether; dichloromethane Cooling; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 1-methyl-3,4,dihydroisoquinoline; p-chlorobenzyl cyanide With manganese; chloro-trimethyl-silane; bis(cyclopentadienyl)titanium(IV) diphenoxide; triethylamine hydrochloride In tetrahydrofuran at 60℃; for 24h; Schlenk technique; Inert atmosphere; Stage #2: With hydrogenchloride; water In tetrahydrofuran; diethyl ether; dichloromethane Cooling; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: 1-methyl-3,4,dihydroisoquinoline; 4-fluorophenylacetonitrile With manganese; chloro-trimethyl-silane; bis(cyclopentadienyl)titanium(IV) diphenoxide; triethylamine hydrochloride In tetrahydrofuran at 60℃; for 24h; Schlenk technique; Inert atmosphere; Stage #2: With hydrogenchloride; water In tetrahydrofuran; diethyl ether; dichloromethane Cooling; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: 1-methyl-3,4,dihydroisoquinoline; benzonitrile With manganese; chloro-trimethyl-silane; bis(cyclopentadienyl)titanium(IV) diphenoxide; triethylamine hydrochloride In tetrahydrofuran at 60℃; for 24h; Schlenk technique; Inert atmosphere; Stage #2: With hydrogenchloride; water In tetrahydrofuran; diethyl ether; dichloromethane Cooling; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: 4-Cyanochlorobenzene; 1-methyl-3,4,dihydroisoquinoline With manganese; chloro-trimethyl-silane; bis(cyclopentadienyl)titanium(IV) diphenoxide; triethylamine hydrochloride In tetrahydrofuran at 60℃; for 24h; Schlenk technique; Inert atmosphere; Stage #2: With hydrogenchloride; water In tetrahydrofuran; diethyl ether; dichloromethane Cooling; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: 1-methyl-3,4,dihydroisoquinoline; 1-Cyanonaphthalene With manganese; chloro-trimethyl-silane; bis(cyclopentadienyl)titanium(IV) diphenoxide; triethylamine hydrochloride In tetrahydrofuran at 60℃; for 24h; Schlenk technique; Inert atmosphere; Stage #2: With hydrogenchloride; water In tetrahydrofuran; diethyl ether; dichloromethane Cooling; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: 1-methyl-3,4,dihydroisoquinoline; propyl cyanide With manganese; chloro-trimethyl-silane; bis(cyclopentadienyl)titanium(IV) diphenoxide; triethylamine hydrochloride In tetrahydrofuran at 60℃; for 24h; Schlenk technique; Inert atmosphere; Stage #2: With hydrogenchloride; water In tetrahydrofuran; diethyl ether; dichloromethane Cooling; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: 1-methyl-3,4,dihydroisoquinoline; cyclopropropanecarbonitrile With manganese; chloro-trimethyl-silane; bis(cyclopentadienyl)titanium(IV) diphenoxide; triethylamine hydrochloride In tetrahydrofuran at 60℃; for 24h; Schlenk technique; Inert atmosphere; Stage #2: With hydrogenchloride; water In tetrahydrofuran; diethyl ether; dichloromethane Cooling; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In toluene at 120℃; for 20h; | General procedure for the DIA reaction General procedure: To a solution of imine (1 mmol) and acid (1.2 mmol) in dry toluene (10 mL) was added sequentially DIPEA (1.85 mmol) andthen T3P (1.5 mmol, 50% in THF). The resulting solution was heatedat 90°C or 120°C in a sealable tube for the specified time, before cooling to RT and pouring into satd aq NaHCO3 (20 mL). The aqueous layer was extracted with DCM (330 mL), concentrated in vacuo and purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In pyridine at 60℃; for 3h; | 1-[1-Methylene-3,4-dihydroisoquinolin-2(1H)-yl]ethanone (23)27 To a round-bottomed flask were added 1-methyl-3,4-dihydroisoquinoline (29; 1.45 g, 10 mmol) and a mixture of pyridine and Ac2O (1:1,10 mL). The reaction mixture was maintained under magnetic stirring and anhydrous conditions at 60 °C for 3 h. Afterwards, the reaction was cooled to r.t. and CH2Cl2 (50 mL) was added. The mixture was washed with 10% (w/v) aq NaHCO3 (50 mL), sat. aq CuSO4 (50 mL), and distilled H2O (50 mL). The organic phase was dried (MgSO4), filtered, and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using EtOAc as eluent, affording the desired product 23; yield: 1.48 g (79%); brownish solid; mp 64-66 °C; 39 Rf = 0.63 (EtOAc). IR (KBr): 3109, 3055, 2940, 2928, 1632, 1425, 1395, 899 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.63 (d, J = 7.2 Hz, 1 H), 7.27-7.12 (m, 3H), 5.75 (s, 1 H), 5.06 (s, 1 H), 3.98 (t, J = 6.0 Hz, 2 H), 2.90 (t, J = 6.0 Hz,2 H), 2.22 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 169.3, 143.4, 134.9, 131.5, 129.1, 128.6, 126.4, 123.9, 106.1, 41.5, 28.7, 22.3. MS (EI): m/z (%) = 187 (41.2), 172 (0.4), 159 (13.2), 144 (100.0), 130(7.3), 115 (36.5). |
74% | With pyridine at 60℃; for 3h; | Procedurefor preparation of 1-(1-methylene-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (4) To a round-bottomed flask were added 1-methyl-3,4-dihydroisoquinoline (9) (1.12 g, 6 mmol) and a mixture of pyridine andacetic anhydride (1:1) (6 mL). The round-bottomed flask was capped with a rubber septum and the mixture was stirred at 60 °C for 3 h. Then, the reaction mixture wascooled to room temperature and diluted with dichloromethane(15 mL). The mixture was washed with distilled water (15 mL), with a 10% (w/v) aqueoussolution of NaHCO3 (2 x 30 mL) and with distilled water (15 mL). Theorganic phase was dried over MgSO4. The residue was purified by column chromatography on silica gel usingethyl acetate as eluent, affording desired product 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With bis(η3-allyl-μ-chloropalladium(II)); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In dimethyl sulfoxide at 60℃; for 1h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With bis(η3-allyl-μ-chloropalladium(II)); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In dimethyl sulfoxide at 60℃; for 1h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: phenethylamine; acetyl chloride With triethylamine In dichloromethane at 20℃; for 2h; Inert atmosphere; Stage #2: With trichlorophosphate In para-xylene at 20℃; for 16h; Inert atmosphere; | |
0.81 g | Stage #1: phenethylamine; acetyl chloride With triethylamine In dichloromethane at 0 - 20℃; for 19.5h; Schlenk technique; Stage #2: at 180℃; for 16h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 1-methyl-3,4,dihydroisoquinoline With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: phenylpropynoic acid methyl ester In tetrahydrofuran; hexane at -78 - 20℃; for 1.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: 1-methyl-3,4,dihydroisoquinoline With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: methyl non-2-ynoate In tetrahydrofuran; hexane at -78 - 20℃; for 1.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.5 h / -78 °C 1.2: 1.25 h / -78 - 20 °C 2.1: silver trifluoroacetate / toluene / 15 h / 110 °C / Sealed tube |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 2h; chemoselective reaction; | General Procedure for the Preparation of 3. General procedure: To a solutionof DHIQ 1a (100 mg, 0.571 mmol, 1.0 equiv) in CH3CN (1.0 mL) was added alkyl or benzyl halides (2.85 mmol, 5.0 equiv) followed by DIPEA (0.11 mL,0.628 mmol, 1.1 equiv) at rt. The reaction mixture was stirred at rt. for 2 to 5 h and then the solvent was evaporated under reduced pressure. The crude mixture was quenched with 0.5 M HCl (aq) and extracted with DCM (3 X25 mL). The combined organic layers were dried over anhydrous Na2SO4 and the solvent was removed under vacuum. The crude mixture was purified on silica gel column chromatography using DCM/MeOH (9/1) as an eluent toafford 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With trifluoroacetic acid In dichloromethane at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With triethylamine In toluene at 0 - 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With methanol; o-phenylenebis(diphenylphosphine); iron(II) chloride In tetrahydrofuran at 80℃; for 15h; Schlenk technique; | 1-Allyl-1-methyl-1,2,3,4-tetrahydroisoquinoline (3aa); Typical Procedure General procedure: To a small reaction vessel, FeCl2 (1.6 mg, 0.0125 mmol, 2.5 mol%), 1,2-bis(diphenylphosphanyl)benzene (5.6 mg, 0.0125 mmol) and anhyd THF (1 mL) were added in turn. The resulting mixture were sealed and stirred for 0.5 h at rt to afford a homogeneous and green solution, which was then ready to serve as a catalyst. To a Schlenk reaction tube containing MeOH (80 mg, 2.5 mmol) and THF (1 mL) were added the catalyst solution prepared above, 1-methyl-3,4-dihydroisoquinoline (1a; 73 mg, 0.5 mmol), and potassium allyltrifluoroborate (2a; 89 mg, 0.6 mmol). The reaction vessel was then sealed and the contents were stirred at 80 °C for 15 h. After cooling to rt, the mixture was diluted with CH2Cl2 followed by filtration on a short Celite column. The filtrates were concentrated to afford the crude product, which was purified by flash chromatography (PE:EtOAc:Et3N 80:1:0.5); slightly yellow oil; yield: 82 mg (0.44 mmol, 88%). 1H NMR (600 MHz, CDCl3): = 7.21 (dd, J = 7.8, 1.5 Hz, 1H), 7.19-7.15 (m, 1H), 7.11 (td, J = 7.3, 1.5 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 5.63 (dddd, J = 16.7, 10.2, 8.3, 6.4 Hz, 1H), 5.15-5.07 (m, 2 H), 3.14 (dt, J = 13.0, 5.4 Hz, 1H), 3.11-3.06 (m, 1H), 2.77-2.70 (m, 3 H), 2.39 (dd, J = 14.0, 8.3 Hz, 1H), 2.20 (br s, 1H), 1.43 (s, 3 H). 13C NMR (151 MHz, CDCl3): = 142.9, 134.9, 134.3, 129.2, 126.0, 125.9, 125.7, 118.6, 54.9, 46.9, 38.7, 30.6, 29.4. HRMS (ESI): m/z calcd for [C13H17NNa]+ [M + Na]+: 210.1253; found: 210.1266. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With methanol; sodium borodeuteride at 20℃; for 15h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium phosphate; palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In neat (no solvent) at 120℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With potassium phosphate; palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In neat (no solvent) at 120℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With Cs2CO3 In dichloromethane at 20℃; for 12h; | 2. General procedure for synthesis of 1,2,4-oxadiazolo[5,4-a]isoquinoline compounds General procedure: Cs2CO3 (0.22 mmol) was added to a solution of oxime chlorides 1 (0.22 mmol), cyclic imines 2 (0.2 mmol) in CH2Cl2 (1 mL). The solution was stirred at rt for 12 h. After completion, product 3 was obtained by flash chromatographyon silica gel (petroleum ether/ethyl acetate = 15:1 to 10:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With Cs2CO3 In dichloromethane at 20℃; for 12h; | 2. General procedure for synthesis of 1,2,4-oxadiazolo[5,4-a]isoquinoline compounds General procedure: Cs2CO3 (0.22 mmol) was added to a solution of oxime chlorides 1 (0.22 mmol), cyclic imines 2 (0.2 mmol) in CH2Cl2 (1 mL). The solution was stirred at rt for 12 h. After completion, product 3 was obtained by flash chromatographyon silica gel (petroleum ether/ethyl acetate = 15:1 to 10:1). |
Tags: 2412-58-0 synthesis path| 2412-58-0 SDS| 2412-58-0 COA| 2412-58-0 purity| 2412-58-0 application| 2412-58-0 NMR| 2412-58-0 COA| 2412-58-0 structure
[ 41173-70-0 ]
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Precautionary Statements-General | |
Code | Phrase |
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Code | Phrase |
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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 |
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P240 | Ground/bond container and receiving equipment. |
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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. |
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P282 | Wear cold insulating gloves/face shield/eye protection. |
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Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
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P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
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P332 | IF SKIN irritation occurs: |
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P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
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P350 | Gently wash with plenty of soap and water. |
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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. |
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P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
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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: |
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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. |
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P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
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P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
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P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
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Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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