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CAS No. : | 1196-38-9 | MDL No. : | MFCD00853963 |
Formula : | C9H9NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YWPMKTWUFVOFPL-UHFFFAOYSA-N |
M.W : | 147.17 | Pubchem ID : | 150896 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 46.21 |
TPSA : | 29.1 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) : | -6.32 cm/s |
Log Po/w (iLOGP) : | 1.5 |
Log Po/w (XLOGP3) : | 1.23 |
Log Po/w (WLOGP) : | 0.59 |
Log Po/w (MLOGP) : | 1.45 |
Log Po/w (SILICOS-IT) : | 2.14 |
Consensus Log Po/w : | 1.38 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.93 |
Solubility : | 1.73 mg/ml ; 0.0117 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.44 |
Solubility : | 5.36 mg/ml ; 0.0364 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.15 |
Solubility : | 0.105 mg/ml ; 0.000714 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.28 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium aluminium tetrahydride; diethyl ether | ||
With lithium aluminium tetrahydride In tetrahydrofuran for 12h; Inert atmosphere; Reflux; | ||
With lithium aluminium tetrahydride In tetrahydrofuran for 12h; Inert atmosphere; Reflux; |
With lithium aluminium tetrahydride In tetrahydrofuran for 12h; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium hydroxide In lithium hydroxide monohydrate at 90℃; for 24h; | |
82% | With 9H-fluoren-9-imine; oxygen In toluene for 24h; Reflux; | |
82% | With tert.-butylhydroperoxide; N,N,N-tributyl-1-butanaminium iodide In lithium hydroxide monohydrate at 85℃; for 8h; Green chemistry; | General procedure for the allylic/benzylic oxidation and oxidation of benzylamines General procedure: Water (1.0 mL), substrate (1 mmol), TBAI (0.25 equiv.) and TBHP (5 equiv.) were added to a 20-mL test tube and the mixture was stirred at 85 °C for 8 h. After completion of the reaction, ethyl acetate (5 mL) was added for quenching. The aqueous layer was extracted with ethyl acetate (3 * 10 mL), the combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude product mixture was purified by flash column chromatography (EtOAc/Hexanes gradient). |
77% | With lithium hydroxide monohydrate; oxygen at 100℃; for 24h; Green chemistry; | |
75% | With tert.-butylhydroperoxide; triethylamine; 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride In lithium hydroxide monohydrate; acetonitrile at 80℃; for 15h; | |
71% | With lithium hydroxide monohydrate; potassium bromide at 20℃; for 2h; | |
61% | With tert.-butylhydroperoxide In 1,4-dioxane; decane at 20℃; for 24h; Irradiation; | |
45% | With iodosylbenzene In dichloromethane for 72h; Ambient temperature; | |
With sodium hydroxide; iodosylbenzene | ||
Multi-step reaction with 2 steps 1: oxygen; catalase; E. coli xanthine dehydrogenase; monoamine oxidase variant D9 / acetonitrile; aq. phosphate buffer / 2 h / 20 °C / pH 7.4 / Enzymatic reaction 2: dihydrogen peroxide; copper (I) iodide / lithium hydroxide monohydrate / 37 °C | ||
Multi-step reaction with 2 steps 1: NBS / dichloromethane / 2.33 h / Cooling with ice 2: sodium chlorine monoxide; phosphoric acid monosodium salt; 2-Methyl-1-butene / tetrahydrofuran; lithium hydroxide monohydrate | ||
Multi-step reaction with 4 steps 1.1: sodium hydroxide; NBS / dichloromethane / 20 °C 2.1: toluene / Heating 3.1: potassium permanganate / propan-2-one / 3 h / 60 °C 4.1: potassium hydroxide / isopropanol; toluene / 2 h / Reflux 4.2: pH 5 | ||
Multi-step reaction with 3 steps 1.1: hydrogenchloride; NaNO2 / lithium hydroxide monohydrate / 0.17 h / Cooling with ice 1.2: 0.5 h / Cooling 2.1: potassium carbonate; oxygen; 18-crown-6 ether; eosin Y disodium salt / N,N-dimethyl acetamide / 36 h / 20 °C / 760.05 Torr / Irradiation 3.1: boron trifluoride diethyl ether complex; lithium hydroxide monohydrate / 8 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium hydroxide; dihydrogen peroxide In methanol; water for 0.5h; Ambient temperature; | |
85% | With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol for 30h; Heating; further halogens as catalysts and other reagentsunder phase transfer conditions; | |
85% | With potassium <i>tert</i>-butylate; iodine In <i>tert</i>-butyl alcohol for 30h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With phosphorus pentoxide; trichlorophosphate; for 2h; | 4A (4 g, 0.02 mol) was refluxed in a mixture of phosphorous pentoxide(5 g) and phosphorous oxy chloride (25 mL) for 2 h. The reaction mixture was concentrated in vacuo to an oil, carefully quenched with wet ice followed by neutralization with sodium bicarbonate and extracted with diethyl ether. The combined organics were washed with water (2 x 50 mL), brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography (0- 100% EtOAc in hexane) to yield 4B (1.1 g, 38%). 1H NMR (400 MHz, CD3OD) delta ppm 2.97 (t, J=6.59 Hz, 2 H) 3.44 - 3.53 (t, J=6.52 Hz, 2 H) 7.26 - 7.30 (m, J=7.91 Hz, 1 H) 7.31 - 7.38 (m, 1 H) 7.43 - 7.52 (m, 1 H) 7.92 (dd, J=7.69, 1.10 Hz, 1 H) |
38% | With phosphorus pentoxide; trichlorophosphate; for 2h;Heating / reflux; | Intermediate IB:; [00189] Intermediate IA (4 g, 0.02 mol) was refluxed in a mixture of phosphorous pentoxide (5 g) and phosphorous oxychloride (25 mL) for 2 h. The reaction mixture was concentrated in vacuo to an oil, carefully quenched with wet ice followed by neutralization with sodium bicarbonate and extracted with diethyl ether. The combined organics were washed with water (2x50 mL), brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography (0-100% EtOAc in hexane) to yield Intermediate IB (1.1 g, 38%). |
9.1% | With polyphosphoric acid; at 115 - 120℃; for 6h; | Phenethyl-carbamic acid ethyl ester (I-23a: 9g, 46.875mmol) and poly phosphoric acid (187.5g) were taken in a flask and the flask was heated to 120C for 4 hours. The reaction was monitored by TLC (30% ethylacetate in hexane). The reaction mixture was partitioned between chilled water and ethylacetate. The resulting mixture was stirred at 115C for 2 hours to afford the crude product. Purification by column chromatography on silica gel (60% ethylacetate in hexane) afforded 0.090g of the product (9.1% yield). NMR (CDC13, 300 MHz): delta 8.16-7.92 (m, 1H), 7.56-6.80 (m, 4H), 3.70- 3.46 (m, 2H), 2.96 (t, 2H)LCMS purity: 100%, m/z = 148.0 (M+l) |
9.1% | With polyphosphoric acid; at 120℃; for 4h; | Step 2: Preparation of Intermediate 3,4-Dihydro-2H-isoquinolin-1-one (I-23b) Phenethyl-carbamic acid ethyl ester (I-23a: 9 g, 46.875 mmol) and poly phosphoric acid (187.5 g) were taken in a flask and the flask was heated to 120 C. for 4 hours. The reaction was monitored by TLC (30% ethylacetate in hexane). The reaction mixture was partitioned between chilled water and ethylacetate. The resulting mixture was stirred at 115 C. for 2 hours to afford the crude product. Purification by column chromatography on silica gel (60% ethylacetate in hexane) afforded 0.090 g of the product (9.1% yield). 1H NMR (CDCl3, 300 MHz): delta 8.16-7.92 (m, 1H), 7.56-6.80 (m, 4H), 3.70-3.46 (m, 2H), 2.96 (t, 2H) LCMS purity: 100%, m/z=148.0 (M+1) |
With PPA; at 140 - 160℃; for 2.5h; | A suspension of ethyl phenethyl carbamate (77.2 g, 40 mmol) in polyphosphoric acid (300 mL) was heated to 140-160 C and stirred for 2.5h. The reaction mixture was cooled to RT, carefully poured into ice-H2O and stirred for Ih. The aqueous solution was extracted with EtOAc (3x300 mL). The combined organic phases were washed with H2O, 5% K2CO3 and brine, dried (Na2SO4), filtered and concentrated to a crude solid which was purified by flash chromatography to afford 3,4-dihydro-2H-isoquinolin-1-one (24 g). | |
With PPA; at 140 - 160℃; for 2.5h; | A suspension of ethyl phenethylcarbamate (77.2 g, 40 mmol) in polyphosphoric acid (300 mL) was heated to 140-160 C. and stirred for 2.5 h. The reaction mixture was cooled to RT, carefully poured into ice-H2O and stirred for 1 h. The aqueous solution was extracted with EtOAc (3*300 mL). The combined organic phases were washed with H2O, 5% K2CO3 and brine, dried (Na2SO4), concentrated in vacuo and purified by flash chromatography to afford 3,4-dihydro-2H-isoquinolin-1-one (24 g). 1H NMR (400 MHz, DMSO-d6) delta 7.91 (brs, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.33-7.25 (m, 2H), 3.37-3.32 (m, 2H), 2.87 (t, J=6.6 Hz, 2H). | |
24 g | With polyphosphoric acid; at 140 - 160℃; for 2.5h; | A suspension of ethyl phenethylcarbamate (77.2 g, 40 mmol) in polyphosphoric acid (300 mL) was heated to 140- 160 C and stirred for 2.5h. The reaction mixture was cooled to RT, carefully poured into ice-H20 and stirred for lh. The aqueous solution was extracted with EtOAc (3x300 mL). The combined organic phases were washed with H20, 5% K2C03 and brine, dried (Na2SC>4), concentrated in vacuo and purified by flash chromatography to afford 3,4-dihydro-2H-isoquinolin-l-one (24 g). FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-i/6) delta 7.91 (brs, 1H), 7.83 (d, J= 7.5 Hz, 1H,), 7.43 (t, J = 7.5 Hz, 1H), 7.33-7.25 (m, 2H), 3.37-3.32 (m, 2H), 2.87 (t, J = 6.6 Hz, 2H). |
3 g | With polyphosphoric acid; at 120℃; for 16h;Inert atmosphere; | A 100 mL three necked round bottom flask was charged with ethyl phenethylcarbamate (5.0 g) and polyphosphoric acid (25 mL) under nitrogen atmosphere. After being heated at 120C for 16 hours, the reaction mixture was cooled to room temperature and diluted with ice-cold water (100 mL). The aqueous phase was extracted with dichloromethane (3 x 50 mL), and the combined organic layer was washed with brine (50 mL), dried over anhydrous Na2S04 and concentrated under vaccum. The resulting crude was purified by column chromatography using MeOH / CHCI3 (0.1 : 9.9) as eluent to afford 3,4- dihydroisoquinolin-l(2H)-one (3 g) as yellow gummy liquid. lH NMR (DMSO - d6): delta 2.86-2.89 (t, 2H), 3.35-3.37 (t, 2H), 7.27-7.34 (m, 2H), 7.43-7.47 (m, 1H), 7.81-7.83 (d, 1H), 7.92 (bs, 1H). MS: 148.1 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With sodium hydroxide In water; benzene for 24h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With tetrabutylammomium bromide In sodium hydroxide; benzene at 65℃; for 5.5h; Irradiation; | |
41 mg | With sodium carbonate; bis(dibenzylideneacetone)-palladium(0); catacxium A In toluene at 80℃; Inert atmosphere; Sealed chamber; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium hydride In benzene Reflux; | |
62% | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In benzene for 1h; Inert atmosphere; Reflux; Stage #2: 4-chlorobutyl bromide In benzene for 72h; Inert atmosphere; Reflux; | |
With sodium hydride 1.) DMF, 15 min, 2.) DMF,, RT, 0.5 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sulfuric acid; nitric acid at 0℃; for 0.5h; | |
93% | With sulfuric acid; nitric acid at 0℃; for 1.5h; | |
76% | With potassium nitrate In sulfuric acid | 1.c c c 7-nitro-1,2,3,4-tetrahydroisoquinolin-1-one To a cold solution consisting of potassium nitrate (8.2 g, 81.6 mmol) in sulfuric acid (40 mL) was added 1,2,3,4-tetrahydroisoquinolin-1-one (10 g, 68mmol) dropwise over a period of five minutes. The reaction mixture was stirred overnight at room temperature and then poured into ice. The solution was filtered. After washing with water several times, the solid was dried to yield the title compound (9.85 g, 76%). |
76% | With nitric acid at -5 - 20℃; | |
68% | With sulfuric acid; potassium nitrate at 0℃; for 2h; | 1.1.1 1.1,Preparation of 7-nitro-3,4-dihydroisoquinoline-1(2H)-one Potassium nitrate (3.71 g, 36.7 mmol) was added to concentrated sulfuric acid (27 mL).3,4-Dihydroisoquinoline-1(2H)-one (4.50 g, 30.6 mmol) was added at 0 ° C for 2 hours.The reaction solution was poured into ice water, suction filtered, and the obtained solid was washed with water and dried.The title compound (4.00 g, yield 68.0%) was obtained. |
61.2% | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sulfuric acid; potassium nitrate at 0 - 20℃; for 3h; Stage #2: With water at 20℃; | 24.1 NO3 (348mg, 3.7414mmol) was added to a solution of 3,4-dihydro-2H- isoquinolin-l-one (I-23b: 500mg, 3.4013mmol) in concentrated H2S04 (10.2mL) at 0°C and the resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (80% ethylacetate in hexane). The reaction mixture was quenched in chilled water and extracted with ethylacetate. The organic layer was washed with brine solution, dried over Na2S04 and concentrated. The concentrate was crystallized from diethyl ether to afford 400mg of the product (61.2% yield).1H NMR (DMSO-D6, 300 MHz): δ 8.60-8.48 (m, IH), 8.40-8.24 (m, 2H), 7.63 (d, IH), 3.52-3.40 (m, 2H), 3.05 (t, 2H) |
61.2% | With sulfuric acid; potassium nitrate at 0 - 20℃; | 24.1 Preparation of Intermediate 7-Nitro-3,4-dihydro-2H-isoquinolin-1-one (I-24a) Step 1: Preparation of Intermediate 7-Nitro-3,4-dihydro-2H-isoquinolin-1-one (I-24a) KNO3 (348 mg, 3.7414 mmol) was added to a solution of 3,4-dihydro-2H-isoquinolin-1-one (I-23b: 500 mg, 3.4013 mmol) in concentrated H2SO4 (10.2 mL) at 0° C. and the resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (80% ethylacetate in hexane). The reaction mixture was quenched in chilled water and extracted with ethylacetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. The concentrate was crystallized from diethyl ether to afford 400 mg of the product (61.2% yield). 1H NMR (DMSO-D6, 300 MHz): δ 8.60-8.48 (m, 1H), 8.40-8.24 (m, 2H), 7.63 (d, 1H), 3.52-3.40 (m, 2H), 3.05 (t, 2H) |
55% | With sulfuric acid; nitric acid at 0 - 20℃; for 2.5h; | 4.C 4B (1. Ig, 7.48mmol) was added portionwise to a mixture of sulfuric acid (1 mL) and fuming nitric acid (5 mL) at 0 0C with stirring. The reaction was allowed to warm to ambient temperature and stirred for 2.5 h before pouring onto ice. The precipitate collected by filtration and dried in vacuo to yield 770 mg of 4C (770 mg, 55% yield) as white solid. 1H NMR (400 MHz, CD3OD) δ ppm 2.81 (t, J=6.59 Hz, 2 H) 3.42 (t J=6.52 Hz, 2 H) 6.84 (dd, J=8.13, 2.42 Hz, 1 H) 7.02 (d, J=7.91 Hz, 1 H) 7.26 (d, J=2.64 Hz, 1 H). |
55% | With sulfuric acid; nitric acid at 0 - 20℃; for 2.5h; | Intermediate 1C:; [00190] Intermediate IB (1. Ig, 7.48mmol) was added portionwsie to a mixture of sulfuric acid (1 mL) and fuming nitric acid (5 mL) at 0 0C with stirring. Reaction was allowed to warm to ambient temperature and stirred for 2.5 h before pouring onto ice. The precipitate was collected by filtration and dried in vacuo to yield Intermediate 1C (770 mg, 55% yield) as a white solid. |
55% | With sulfuric acid; nitric acid at 0 - 20℃; for 2.5h; | |
55% | With sulfuric acid; nitric acid at 0 - 20℃; | |
With sulfuric acid; nitric acid at 0℃; | ||
Multi-step reaction with 2 steps 1: fuming HNO3 / 1 h / 0 °C 2: 86 percent / conc. HCl / methanol / 0.08 h / Heating | ||
With sulfuric acid; nitric acid for 2h; | A34 To an ice-salt bath cooled mixture of cone. HNO3 and cone. H2SO4 (200 mL, 1 :1) was added 4-dihydro-2H-isoquinolin-1-one (15 g, 0.102 mol) dropwise over 15 min. After stirring for 2h, the resulting mixture was poured into ice-Η2O and stirred for 30 min. The EPO precipitate was filtered, washed with H2O, and dried in air to afford 7-nitro-3,4-dihydro-2H- isoquinolin-1-one (13 g). | |
With sulfuric acid; nitric acid for 2.25h; | B.29 To an ice-salt bath cooled mixture of conc. HNO3 and conc. H2SO4 (200 mL, 1:1) was added 4-dihydro-2H-isoquinolin-1-one (15 g, 0.102 mol) dropwise over 15 min. After stirring for 2 h, the resulting mixture was poured into ice-H2O and stirred for 30 min. The precipitate was filtered, washed with H2O, and dried in air to afford 7-nitro-3,4-dihydro-2H-isoquinolin-1-one (13 g). 1H NMR (300 MHz, DMSO-d6) δ 8.53 (d, J=2.4 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 8.29 (d, J=2.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 3.44-3.39 (m, 2H), 3.04 (t, J=6.6 Hz, 2H). | |
With sulfuric acid; potassium nitrate at 0℃; | ||
13 g | With sulfuric acid; nitric acid for 2h; Cooling with ice; | B29 To an ice-salt bath cooled mixture of cone. HNO3 and cone. H2SO4 (200 mL, 1 : 1) was added 4-dihydro-2H-isoquinolin-l-one (15 g, 0.102 mol) dropwise over 15 min. After stirring for 2h, the resulting mixture was poured into ice-H20 and stirred for 30 min. The precipitate was filtered, washed with H20, and dried in air to afford 7-nitro- 3,4-dihydro-2H-isoquinolin-l-one (13 g). FontWeight="Bold" FontSize="10" H NMR (300 MHz, DMSO-i/6) δ 8.53 (d, J = 2.4 Hz, IH,), 8.31 (d, J =2.4 Hz, IH), 8.29 (d, J =2.4 Hz, IH), 7.62 (d, J =8.4 Hz, IH), 3.44-3.39 (m, 2H), 3.04 (t, J= 6.6 Hz, 2H). |
800 mg | With sulfuric acid; nitric acid In water at 20℃; for 0.75h; | 91 7-nitro-3,4-dihydro-2H-isoquinolin-1-one Raw material 3,4-dihydro-2H-isoquinolin-1-one (1.47g, 9.99mmoL) with sulfuric acid (20ml) were dissolved, under ice-cooling conditions dropwise fuming nitric acid (2ml).Stirred for 45 minutes at room temperature, the reaction solution was poured into a large amount of ice water.Aqueous solution was extracted with ethyl acetate, the ethyl acetate layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a yellow oil which was purified by flash column chromatography (petroleum ether: ethyl acetate = 3: 1) to give the intermediate 15 (800mg). |
With sulfuric acid; nitric acid at 0 - 25℃; for 1h; | 1 Step 1 : To a mixture of fuming HNO3 (300 mL) and cone. H2SO4 (1.2 L) was added compound B1-1 (230 g, 1.563 mol, 1 equiv) in portions at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. TLC (100% EA) confirmed compound B1-1 was consumed. The reaction mixture was poured into ice water (10 L) and the solid was collected by filtration to afford 7- nitro-3,4-dihydroisoquinolin-1 (2H)-one (B1-2) (360g, crude) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) d = 8.53 (d, J=2.6 Hz, 1 H), 8.30 (dd, J=2.6, 8.3 Hz, 2H), 7.62 (d, J=8.4 Hz, 1 H), 3.45 - 3.41 (m, 2H), 3.05 (t, J=6.5 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 83% 2: 8% 3: 8% | With sodium periodate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; acetic acid In water; acetonitrile for 20h; | |
1: 36% 2: 8% 3: 11% | With 1-(tert-butylperoxy)-1,2-benziodoxol-3(1H)-one In benzene for 120h; Ambient temperature; | |
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; laccasefrom Trametes versicolor; oxygen In water at 30℃; for 168h; Enzymatic reaction; |
1: 11 %Spectr. 2: 40 %Spectr. 3: 12 %Spectr. | With C47H15F20N5Zn; oxygen for 1h; Irradiation; Green chemistry; | Oxidation of Amines 1 Catalyzed by a Photocatalyst (Equations 6 and 7, Tables 7-10); General Procedure 4 General procedure: Fluorinated chlorins were prepared and metalated according to reported methods, to provide catalysts 4 and 5.22 Amine 1 (0.5 mmol) and photocatalyst 4 or 5 (0.001 mmol) were added to BTF (1.0 mL) in a two-necked Pyrex glass vessel. O2 gas was introduced into the vessel by connecting an O2 balloon, and the reaction mixture was stirred and irradiated using a Xe lamp through Pyrex (hν >300 nm) for 1 h. After extraction of the reaction mixture with Et2O, the organic layer was concentrated under reduced pressure. The yield of the product was confirmed by 1H NMR by using 1,3,5-trioxane as the internal standard. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 85% 2: 7% | With sodium hydroxide In water; <i>tert</i>-butyl alcohol for 24h; Reflux; | |
27% | With sodium hypochlorite; racemic (salen)Mn(III) In dichloromethane at 0℃; for 4h; | |
1: 13 %Spectr. 2: 36 %Spectr. | With C47H15F20N5Zn; oxygen for 1.5h; Irradiation; Green chemistry; | Oxidation of Amines 1 Catalyzed by a Photocatalyst (Equations 6 and 7, Tables 7-10); General Procedure 4 General procedure: Fluorinated chlorins were prepared and metalated according to reported methods, to provide catalysts 4 and 5.22 Amine 1 (0.5 mmol) and photocatalyst 4 or 5 (0.001 mmol) were added to BTF (1.0 mL) in a two-necked Pyrex glass vessel. O2 gas was introduced into the vessel by connecting an O2 balloon, and the reaction mixture was stirred and irradiated using a Xe lamp through Pyrex (hν >300 nm) for 1 h. After extraction of the reaction mixture with Et2O, the organic layer was concentrated under reduced pressure. The yield of the product was confirmed by 1H NMR by using 1,3,5-trioxane as the internal standard. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With trifluorormethanesulfonic acid at 0 - 70℃; for 24h; | 18 4.1.18 3,4-Dihydroisoquinolin-1(2H)-one (24) To a solution of phenethylamine (3mL, 24mmol) and Et3N (3.6mL, 26.4mmol) in DMF (50mL) was added methyl chloroformate (2.0mL, 26.4mmol) at 0°C. The reaction mixture was stirred 1hat room temperature and diluted with EtOAc (100mL). The solution was washed three times with water (3×30mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using hexanes/ EtOAc (1:1 to 0:1) to afford the carbamate intermediate (3.72g, 86%) as a colorless liquid. CAS: 26011-68-7. The obtained carbamate (3g, 16.7mmol) was dissolved in trifluoromethanesulfonic acid (30mL) at 0°C and the mixture was stirred for 24hat 70°C. The mixture was then poured into crushed ice and extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using hexanes/EtOAc (1:1) to afford 24 (2.34g, 95%) as a yellow oil. CAS: 1196-38-9. |
86% | With PPA | 1.b b b 1,2,3,4-tetrahydroisoquinolin-1-one To a solution of polyphosphoric acid (200 mL) at 140° C. N-methoxycarbonyl-phenethylamine (28 g, 0.16 mol) was added portionwise over a 5 hour period. The reaction solution was poured into cold water (400 mL) and extracted with methylene chloride (5*200 mL). The organic layers were combined, dried with anhydrous magnesium sulfate, filtered and concentrated to give the title compound (17.96 g, 86% yield). |
37.5% | With PPA at 145℃; for 0.333333h; | VIII.1 Example VIII: Synthesis of 4-(l-methoxy-cyclohexyl)-2-methyl-l,2,3,4-tetrahydro- isoquinoline; Stepl: Synthesis of 3,4-dihydro-2if-isoquinolin-l-one; To Phenethylcarbamic acid methyl ester (3 g, 16.76 mmol) was added polyphosphoric acid (16.8 g) and stirred at 145 0C for 20 min. The reaction mixture was quenched with water and extracted with DCM (3x50 mL). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude material which was purified by column chromatography (silica gel, 60:40, EtOAc : Pet ether), to yield the title compound (925mg, 37.5%). ESIMS (m/z): 147.3 (M+l) |
36% | With phosphorus pentoxide; trichlorophosphate | |
With polyphosphoric acid at 160℃; for 16h; | ||
With trifluorormethanesulfonic acid; trifluoroacetic acid at 70℃; Inert atmosphere; | ||
With trifluorormethanesulfonic acid at 80℃; for 12h; | ||
With trifluorormethanesulfonic acid at 20 - 70℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ethanol; palladium at 55℃; Hydrogenation; | ||
With 1,4-dioxane; palladium at 55℃; Hydrogenation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With lithium aluminium deuteride In tetrahydrofuran for 20h; Reflux; | |
85% | With lithium aluminium deuteride In tetrahydrofuran | |
52% | With lithium aluminium deuteride In tetrahydrofuran for 19h; Heating; |
With lithium aluminium deuteride | ||
With lithium aluminium deuteride In tetrahydrofuran for 20h; Inert atmosphere; Reflux; | ||
With lithium aluminium deuteride In tetrahydrofuran at 0℃; for 20h; Reflux; | ||
With LiDH4 In tetrahydrofuran at 0 - 65℃; Inert atmosphere; | ||
With lithium aluminium deuteride In tetrahydrofuran at 0℃; for 20h; Inert atmosphere; Reflux; | ||
With lithium aluminium deuteride In tetrahydrofuran at 0 - 80℃; for 0.5h; Inert atmosphere; | 1 Step 1: A stirred solution of 3.4-dihydroisoquinolin- 1 (2H)-one (300 mg, 2.04 mmol) in L1AID4 (171 mg, 4.08 mmol) was added THF (10 mL) at 0 °C. The resulting mixture was stirred at 80 °C for 0.5 h under N2. The mixture was quenched by water (5 drops), and the mixture was dried over anhydrous Na2S04, filtered, and the filtrate was concentrated under reduced pressure to give 1.2.3.4-tetrahydroisoquinoline- 1.1 -cri as an oil, which was used in the next step without further purification. MS: 136 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With zirconium chloride In dichloromethane at 10 - 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With tetraphosphorus decasulfide In dichloromethane for 5h; Inert atmosphere; Reflux; | |
0.47 g | With Lawessons reagent In tetrahydrofuran at 50℃; for 60h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With trichlorophosphate In toluene for 4h; Heating; | |
24% | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With trichlorophosphate In tetrahydrofuran at 60℃; for 0.666667h; Inert atmosphere; Stage #2: 2-carbomethoxyaniline In tetrahydrofuran at 75℃; for 113h; Inert atmosphere; Stage #3: With ammonium hydroxide In tetrahydrofuran; water at 20℃; for 0.5h; | 1.5 4.1.5. 5H-Isoquinolino[1,2-b]quinazolin-8(6H)-one 3,4-Dihydroisoquinolin-1(2H)-one (190 mg, 1.28 mmol, 1.0 equiv) was dissolved in dry THF (15 mL) and POCl3 (0.15 mL, 1.54 mmol, 1.2 equiv) added at 60 °C. The mixture was stirred under Ar atmosphere for 40 min. Methyl 2-aminobenzoate (340 mg, 2.25 mmol, 1.8 equiv) was dissolved in dry THF (3 mL) and added dropwise to the reaction mixture over 5 min. The temperature was increased to 75 °C and the solution stirred for 113 h. The solution was cooled to rt and 25% NH3 solution (6 mL) was added until the aqueous phase reached pH=9. The yellow mixture was stirred vigorously for 30 min. The mixture was extracted with CH2Cl2 (4*50 mL), washed with brine and the combined organic layers were dried over Na2SO4. Evaporation of solvent yielded 0.38 g of crude product. Parts of the crude product (220 mg) were purified by column chromatography (SiO2, 30*2 cm, petrolether/ethyl acetate 2:1, F 8-15) to yield off-white crystals (84.7 mg, 0.302 mmol, 24%). Rf=0.50 (SiO2, petrolether/ethyl acetate 2:1). Mp=158.0-158.7 °C. 1H NMR (400 MHz, CDCl3, 300 K): δ=8.56-8.41 (m, 1H, Ar-HD-ring), 8.42-8.24 (m, 1H, Ar-HA-ring), 7.86-7.63 (m, 2H, Ar-HA-ring), 7.54-7.41 (m, 3H, Ar-HD-ring (2H) and Ar-HA-ring (1H)), 7.33-7.25 (m, 1H, Ar-HD-ring), 4.47-4.37 (m, 2H, NCH2CH2), 3.11 (t, J=6.4 Hz, 2H, NCH2CH2) ppm. 13C{1H} NMR (101 MHz, CDCl3, 300 K): δ=161.85 (s, C=O), 149.51 (s, Cquart.), 147.97 (s, C=N), 137.19 (s, Cquart.), 134.35 (Ar-CA-ring), 131.84 (Ar-CA-ring), 129.74 (s, Cquart.), 128.18 (Ar-CD-ring), 127.77 (2 Ar-CA-ring), 127.64 (Ar-CD-ring), 127.01 (Ar-CD-ring), 126.66 (Ar-CD-ring), 120.91 (s, Cquart.), 39.76 (s, NCH2CH2), 27.63 (s, NCH2CH2) ppm. IR: ν=3070w, 3031w, 2928w, 2901w, 2850w, 2359w, 2120w, 1921w, 1668s, 1608m, 1589s, 1557s, 1470s, 1457s, 1395s, 1334s, 1308m, 1265m, 1253m, 1173m, 1149s, 1108m, 1065w, 1030w, 1013w, 980m, 958w, 947m, 905m, 876m, 840m, 795w, 760s, 737s, 705s, 691s, 669m cm-1. HPLC: Synergi 4U fusion-RP (15*0.46 cm), water/methanol (30-95%), 1.00 mL/min, 20 °C, tR=9.917 min, purity>99.99%. Mass: calcd for [M+H]+ (C16H13N2O) requires m/z: 249.10; found: 249.05. Spectral data is in accordance with literature data. 24 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With hydrogen; acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chlorosulfonic acid at 80℃; for 4h; | 11 1-oxo-1 ,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride: 3,4-dihydroisoquinolin-1(2H)-one (300 mg, 2.0 mmol) was dissolved in sulfurochloridic acid (3 mL). The solution was heated at 80°C for 4 hrs and cooled to room temperature. The mixture was poured onto ice in a separatory funnel and extracted with methylene chloride (10 mL x 3). The combined organic phase was washed with water, brine, and dried over Na2504. Concentration provided a white solid, which was used directly in the next step. Calculated for C9H8C1NO3S, 244.99; observed MS (ESI) (mlz) 246.0 (M+1). | |
With chlorosulfonic acid at 0 - 60℃; regioselective reaction; | 20 4.1.20 N-cyclopentyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (28) To chlorosulfonic acid (25mL) cooled to 0°C was added portion wise compound 24 (2g, 13.6mmol). After complete addition, the yellow solution was allowed to warm up to room temperature, then heated at 60°C for 16h. The reaction mixture was then cooled down to room temperature and poured dropwise into crushed ice. The light yellow precipitate was filtered, washed with water and cold Et2O and dried in vacuo to afford the desired sulfonyl chloride intermediate 26. To a solution of compound 26 (1g, 4.07mmol) in CH2Cl2 (10mL) were added cyclopentylamine (400μL, 4.07mmol) and Et3N (624μL, 4.48mmol). The mixture was stirred 2hat room temperature and quenched with 1M HCl. The precipitate was filtered and washed with water and cold Et2O. The solid was dried in vacuo to afford 28 (971mg, 81%) as a light yellow solid. 1H NMR (400MHz, DMSO-d6) δ 8.27 (d, J=2.1Hz, 1H), 8.19 (s, 1H), 7.87 (dd, J=7.9, 2.1Hz, 1H), 7.75 (d, J=6.9Hz, 1H), 7.53 (d, J=8.0Hz, 1H), 3.46-3.39 (m, 2H), 3.06-2.96 (m, 2H), 1.64-1.49 (m, 4H), 1.44-1.23 (m, 4H). 13C NMR (101MHz, DMSO-d6) δ 163.7, 144.0, 140.7, 130.4, 129.7, 129.1, 125.7, 54.9, 39.2, 32.9, 28.0, 23.2. HRMS (ESI): m/z [M+H]+ calcd for C14H19N2O3S: 295.1116, found: 295.1110. | |
With chlorosulfonic acid at 0 - 50℃; for 17.5h; | M6.A To Chlorosulfonic acid (30 mL) is added 3,4-Dihydro-2H-isoquinolin-1-one (5 g, 34 mmol) at 0°C. After stirring at rt during 1h, the mixture is heated at 500C during 16h, then it is poured carefully into an ice bath and stirred at O0C during 30min. The precipitate is filtered and dried in oven at 60°C to give the title compound. MS: 246 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 96 percent / Et3N / CH2Cl2 / 0.5 h 2: polyphosphoric acid / 2 h / 140 - 160 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 3 h / 0 °C 2: polyphosphoric acid / 3 h / 140 °C | ||
Multi-step reaction with 2 steps 1: tetrahydrofuran / 12 h / 0 - 25 °C / Inert atmosphere 2: trifluorormethanesulfonic acid / 50 °C / Inert atmosphere |
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 24 h / 0 - 20 °C / Inert atmosphere 2: polyphosphoric acid / 16 h / 160 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / N,N-dimethyl-formamide / 1 h / 0 - 25 °C 2: trifluorormethanesulfonic acid; trifluoroacetic acid / 70 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: sodium carbonate / ethyl acetate; water / 2 h / 0 - 20 °C 2: polyphosphoric acid / 2.5 h / 140 - 160 °C | ||
Multi-step reaction with 2 steps 1: sodium carbonate / chloroform / 0 - 20 °C 2: polyphosphoric acid / 4 h / 120 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 48 h / 20 °C 2: trifluorormethanesulfonic acid / -15 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 48 h / 20 °C 2: trifluorormethanesulfonic acid; trifluoroacetic acid / -15 - 6 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 48 h / 20 °C 2: trifluorormethanesulfonic acid; trifluoroacetic acid / -15 - 6 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: triethylamine / diethyl ether / 2 h / 20 °C 2: phosphorus pentoxide; trichlorophosphate / 2 h / Reflux | ||
Multi-step reaction with 2 steps 1: diethyl ether / 6 h / 0 °C 2: polyphosphoric acid | ||
Multi-step reaction with 2 steps 1: triethylamine / diethyl ether / 10 - 20 °C / Inert atmosphere 2: phosphorus pentoxide; trichlorophosphate / 2 h / Inert atmosphere; Reflux | ||
Multi-step reaction with 2 steps 1: tetrahydrofuran / 2 h / 20 °C 2: trifluorormethanesulfonic acid / dichloromethane / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: triethylamine / N,N-dimethyl-formamide / 1 h / 0 - 20 °C 2: trifluorormethanesulfonic acid / 24 h / 0 - 70 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 1 h / 0 - 20 °C 2: trifluorormethanesulfonic acid / 16 h / 70 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 1 h / 0 - 25 °C 2: trifluorormethanesulfonic acid / 16 h / 20 - 70 °C | ||
Multi-step reaction with 2 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 12 h / Reflux 2: trifluorormethanesulfonic acid / 12 h / 80 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 1 h / 0 - 20 °C 2: trifluorormethanesulfonic acid / 16 h / 20 - 70 °C | ||
Multi-step reaction with 2 steps 1.1: triethylamine / 0.25 h / 0 - 5 °C 1.2: 4.5 h / 0 - 30 °C 2.1: polyphosphoric acid / 2 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 95 percent / fuming HNO3, conc. H2SO4 / 0.5 h / 0 °C 2: 93 percent / H2 / 10percent Pd/C / methanol 3: 1) NaNO2, 3 N HCl, 2) KI / 1) H2O, 0 degC, 1.5 h, 2) warm to room temp., 4 h | ||
Multi-step reaction with 3 steps 1: fuming HNO3 / 1 h / 0 °C 2: 93 percent / H2 / 10percent Pd/C / methanol 3: 1) NaNO2, 3 N HCl, 2) KI / 1) H2O, 0 degC, 1.5 h, 2) warm to room temp., 4 h | ||
Multi-step reaction with 4 steps 1: fuming HNO3 / 1 h / 0 °C 2: 86 percent / conc. HCl / methanol / 0.08 h / Heating 3: 93 percent / H2 / 10percent Pd/C / methanol 4: 1) NaNO2, 3 N HCl, 2) KI / 1) H2O, 0 degC, 1.5 h, 2) warm to room temp., 4 h |
Multi-step reaction with 3 steps 1.1: potassium nitrate; sulfuric acid / 3 h / 0 - 20 °C 1.2: 20 °C 2.1: hydrogen / palladium 10% on activated carbon / methanol / 3.5 h / 20 °C / Inert atmosphere 3.1: hydrogenchloride; sodium nitrite / water / 0.25 h / 0 °C 3.2: 20 °C | ||
Multi-step reaction with 3 steps 1.1: potassium nitrate; sulfuric acid / 0 - 20 °C 2.1: hydrogen; palladium 10% on activated carbon / methanol / 3.5 h / 20 °C 3.1: hydrogenchloride; sodium nitrite / water / 0.25 h / 0 °C 3.2: 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In toluene for 1h; Heating / reflux; Stage #2: ethyl iodoacetae In toluene at 20℃; for 12h; Heating / reflux; | 18 To a solution of 3,4-dihydro-2//-isoquinolin-l-one (0.250 g, 1.70 mmol) in toluene (5 ml_) was added sodium hydride (60% in mineral oil, 0.049 g, 2.04 mmol) and the resulting suspension was heated at about reflux for about 1 h. The reaction mixture was cooled at room temperature and ethyl 2-iodoacetate (0.364 g, 1.70 mmol) was added dropwise and the mixture was again heated at about reflux for about 12 h. The reaction mixture was cooled at room temperature and filtered, rinsed with toluene. The filtrate was concentrated in vacuo to provide (l-oxo-3,4-dihydro-l//- isoquinolin-2-yl)-acetic acid ethyl ester as a peach oil (0.336 g, 1.44 mmol). The crude material was used in subsequent reactions without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: 3,4-dihydroisoquinoline With sodium chlorite; sodium dihydrogenphosphate In tetrahydrofuran; water at 20℃; Stage #2: With sodium hyposulfite In tetrahydrofuran; water; ethyl acetate at 20℃; | |
With copper(l) iodide; dihydrogen peroxide In water at 37℃; | ||
With sodium hypochlorite; sodium dihydrogenphosphate; 2-Methyl-1-butene In tetrahydrofuran; water |
With E coli xanthine dehydrogenase; oxygen In aq. buffer at 37℃; Enzymatic reaction; | ||
Multi-step reaction with 3 steps 1.1: toluene / Heating 2.1: potassium permanganate / acetone / 3 h / 60 °C 3.1: potassium hydroxide / isopropyl alcohol; toluene / 2 h / Reflux 3.2: pH 5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31.7% | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sec.-butyllithium In tetrahydrofuran at -78℃; for 2h; Stage #2: cyclohexanone In tetrahydrofuran at -78℃; for 2h; Stage #3: With water; ammonium chloride In tetrahydrofuran | VIII.2 Step 2: Synthesis of 4-(l-hydroxy-cyclohexyl)-3,4-dihydro-2H-isoquinolin-l-one; To a stirred solution of 3,4-dihydro-2H-isoquinolin-l-one (1.80 g, 12.24 mmol) in tetrahydrofuran (25 mL) was added 5-BuLi (24.5 mL, 36.73 mmol) at -78 ° C and stirring was continued for 2 h. Cyclohexanone (3.79 mL, 36.73 mmol) was added and stirring was continued for 2 h at -78 0C. Reaction mixture was then quenched with saturated ammonium chloride solution (20 mL) and extracted with EtOAc (4x25 mL). Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude material which was purified by column chromatography (silica gel, 3.5:97.5, MeOH : CHCl3) to yield the title compound (950 mg, 31.7%) as viscous liquid. ESIMS (m/z): 268.5 (M+Na), 246.0 (M+l) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In benzene for 1h; Inert atmosphere; Reflux; Stage #2: 1-(3-chloropropyl)-4-(2,3-dichlorophenyl)piperazine In benzene at 90℃; for 72h; Inert atmosphere; | |
With sodium hydride In benzene Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In benzene for 1h; Inert atmosphere; Reflux; Stage #2: 1-(3-Chloropropyl)-4-(p-methoxyphenyl)piperazine In benzene at 90℃; for 72h; Inert atmosphere; | |
With sodium hydride In benzene Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium hydride In benzene Reflux; | |
75% | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In benzene for 1h; Inert atmosphere; Reflux; Stage #2: 1-bromo-5-chloropentane In benzene for 72h; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In benzene for 1h; Inert atmosphere; Reflux; Stage #2: 1-(3-chloropropyl)-4-[3-(trifluoromethyl)phenyl]piperazine In benzene at 90℃; for 72h; Inert atmosphere; | |
With sodium hydride In benzene Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In benzene for 1h; Inert atmosphere; Reflux; Stage #2: 2-[4-(3-chloropropyl)piperazin-1-yl]quinoline In benzene at 90℃; for 72h; Inert atmosphere; | |
With sodium hydride In benzene Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In benzene for 1h; Inert atmosphere; Reflux; Stage #2: 1-(2-methoxyphenyl)-4-(3-chloropropyl)piperazine In benzene at 90℃; for 72h; Inert atmosphere; | |
With sodium hydride In benzene Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 75% 2: 10% | Stage #1: inden-1-one With hydrogenchloride; sodium azide In water at 0℃; for 0.5h; Stage #2: With potassium carbonate In water Cooling with ice; | |
With hydrogenchloride; sodium azide In water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With tri-n-propylamine; tetraethylammonium chloride In diethylene glycol dimethyl ether at 140℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; cesium acetate In methanol at 20℃; for 16h; | |
91% | With cesium acetate; C24H39Br2Rh; potassium carbonate In 1,2-dichloro-ethane at 20℃; for 16h; Sealed tube; | |
90% | With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; cesium pivalate In 2,2,2-trifluoroethanol at 23℃; for 18h; regioselective reaction; | General Procedure for Ethylene (2) Insertion General procedure: To a vial, equipped with a magnetic stir bar and rubber septum,was added O-pivaloyl benzhydroxamic acid (1, 1.00 mmol, 1.0equiv), [Cp*RhCl2]2 (0.025 mmol, 2.5 mol%), and CsOPiv (2.00mmol, 2.0 equiv). The vial was purged with ethylene (2) underdynamic vacuum for 10 s. Then trifluoroethanol (5.0 mL, 0.2 M)was added, and the reaction mixture was sparged with ethylene(2) for 2 min. The vial was stirred under a balloon of ethylene(2; atmospheric pressure) at room temperature for 16-20 h.After 16-20 h, the reaction was filtered using EtOAc, and the filtratewas concentrated under reduced pressure. The cruderesidue was purified via flash column chromatography to afforddihydroisoquinolones 3. |
88% | With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; cesium acetate In methanol at 60℃; for 16h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In toluene; mineral oil at 0℃; Stage #2: 3-[6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl]propan-1-ol methanesulphonate In toluene; mineral oil at 0℃; Reflux; | 5.7. General procedure for the synthesis of amide (15a,b) General procedure: To a solution of 10 (0.1g, 0.72 mmol) in dry toluene (5 mL), NaH 60% dispersion in mineral oil (0.07 g, 1.8 mmol) was added at 0 °C cautiously. Then, a solution of appropriate methansulphonate derivative 9ab (1.15 mmol) in dry toluene (5 mL) was added in a dropwise manner. The resulting mixture was heated under stirring to reflux overnight. Then water was added to the reaction mixture which was extracted with AcOEt (3 × 5 mL). The collected organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude residue was purified by column chromatography with CH2Cl2/MeOH (95:5) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In toluene; mineral oil at 0℃; Stage #2: 3-(4-cyclohexylpiperazin-1-yl)propan-1-ol methanesulphonate In toluene; mineral oil at 0℃; Reflux; | 5.7. General procedure for the synthesis of amide (15a,b) General procedure: To a solution of 10 (0.1g, 0.72 mmol) in dry toluene (5 mL), NaH 60% dispersion in mineral oil (0.07 g, 1.8 mmol) was added at 0 °C cautiously. Then, a solution of appropriate methansulphonate derivative 9ab (1.15 mmol) in dry toluene (5 mL) was added in a dropwise manner. The resulting mixture was heated under stirring to reflux overnight. Then water was added to the reaction mixture which was extracted with AcOEt (3 × 5 mL). The collected organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude residue was purified by column chromatography with CH2Cl2/MeOH (95:5) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: 2-(2-azidoethyl)benzamide With triphenylphosphine In tetrahydrofuran at 20℃; for 1h; Stage #2: With water In tetrahydrofuran for 24h; Reflux; | |
92% | With tri-n-butyl-tin hydride In toluene for 24h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Sodium Hydride (31 .8 mg, 0.796 mmol) was added to DMF (1 mL), followed by 3,4-dihydro-1 (2H)- isoquinolinone (107 mg, 0.730 mmol). The resulting suspension was stirred at r.t. for 5 min, then 4,6- dichloro-2-(2-pyridinyl)pyrimidine (150 mg, 0.664 mmol) was added and resulting mixture was stirred at r.t. for 45 min.The mixture was partitioned between EtOAc and water then the aqueous layer extracted with DCM three times. The organic layers were combined, filtered throught a phase separator and volatiles removed under reduced pressure to afford 212 mg of a white-brown powder.The crude material was purified by column chromatography, eluting with a 0 to 100% EtOAc in cyclohexane, to give the title compound, 121 mg (54%) as an off white powder.LCMS (Method A) Rt 1 .05 min, MH+=337.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With trifluorormethanesulfonic acid at 50℃; Inert atmosphere; | |
98% | With trifluorormethanesulfonic acid In chloroform at 50℃; | General procedure: Given the success of the Friedel-Crafts acylations, it was sought to determine if similar reactions could be accomplished with urea or carbamide substrates. The carbamides are even less reactive electrophiles (compared to the amide group) because the urea carbonyl group interacts with two adjacent nitrogen centers. However, it has now been found that nitro-substituted aryl groups do indeed activate carbamides for electrophilic aromatic substitution. Intermolecular reactions of carbamides 24 and 26 provided 3,4-dihydro-1(2H)-isoquinolinones (29-30) in good yields (Table 2). In the case of carbamide 24, the product 3,4-dihydro-1(2H)-isoquinolinone (29) was formed in 98%, while the L-phenylalanol-derived carbamide (26) gave product (30) in 80% yield. Interestingly, reaction of urea 25 (under the same reactions conditions) does not give cyclized product 29, but the starting material was recovered. This demonstrates the importance of the nitro-substituent in the activation of the carbamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With trifluorormethanesulfonic acid In dichloromethane at 0℃; for 1h; Inert atmosphere; | |
Multi-step reaction with 2 steps 1: triethylamine / diethyl ether / 24 h / 20 °C 2: trifluorormethanesulfonic acid / -15 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: triethylamine / diethyl ether / 24 h / 20 °C 2: trifluorormethanesulfonic acid; trifluoroacetic acid / -15 - 37 °C / Inert atmosphere |
Multi-step reaction with 2 steps 1: triethylamine / diethyl ether / 24 h / 20 °C 2: trifluorormethanesulfonic acid; trifluoroacetic acid / -15 - 37 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: triethylamine / diethyl ether / 48 h / 20 °C 2: trifluorormethanesulfonic acid; trifluoroacetic acid / -15 - 6 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: triethylamine / diethyl ether / 48 h / 20 °C 2: trifluorormethanesulfonic acid; trifluoroacetic acid / -15 - 6 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: sodium hydride / mineral oil; diethyl ether / 21 h / 20 °C 2: trifluorormethanesulfonic acid / 0 - 50 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1: triethylamine / diethyl ether / 24 h / 20 °C 2: trifluorormethanesulfonic acid; trifluoroacetic acid / -15 - 37 °C / Inert atmosphere 3: triethylamine / dichloromethane / 48 h / 20 °C 4: trifluorormethanesulfonic acid / -15 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1: triethylamine / diethyl ether / 24 h / 20 °C 2: trifluorormethanesulfonic acid; trifluoroacetic acid / -15 - 37 °C / Inert atmosphere 3: triethylamine / dichloromethane / 48 h / 20 °C 4: trifluorormethanesulfonic acid; trifluoroacetic acid / -15 - 6 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1: triethylamine / diethyl ether / 24 h / 20 °C 2: trifluorormethanesulfonic acid; trifluoroacetic acid / -15 - 37 °C / Inert atmosphere 3: triethylamine / dichloromethane / 48 h / 20 °C 4: trifluorormethanesulfonic acid; trifluoroacetic acid / -15 - 6 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1: triethylamine / diethyl ether / 24 h / 20 °C 2: trifluoroacetic acid / -15 - 37 °C / Inert atmosphere 3: triethylamine / dichloromethane / 48 h / 20 °C 4: trifluorormethanesulfonic acid / -15 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1: triethylamine / diethyl ether / 24 h / 20 °C 2: trifluoroacetic acid / -15 - 37 °C / Inert atmosphere 3: triethylamine / dichloromethane / 48 h / 20 °C 4: trifluorormethanesulfonic acid; trifluoroacetic acid / -15 - 6 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1: triethylamine / diethyl ether / 24 h / 20 °C 2: trifluoroacetic acid / -15 - 37 °C / Inert atmosphere 3: triethylamine / dichloromethane / 48 h / 20 °C 4: trifluorormethanesulfonic acid; trifluoroacetic acid / -15 - 6 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With copper(l) iodide; 2,2,6,6-tetramethylheptane-3,5-dione In toluene at 130℃; for 24h; Schlenk technique; Inert atmosphere; Sealed tube; | |
With potassium phosphate; copper(l) iodide; 2,2,6,6-tetramethylheptane-3,5-dione In toluene at 130℃; for 24h; Inert atmosphere; Schlenk technique; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With trifluorormethanesulfonic acid In dichloromethane at 50℃; for 12h; | General procedure: Additional intramolecular reactions of carbamides are shown in Table 4. Reactions were carried out in dichloromethane for 12 hours at 50° C. using 16 equivalent of CF3SO3H. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.9% | With sodium hydroxide In tetrahydrofuran at 20℃; for 3h; | 17 Preparation 17 Methyl 3-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propanoate Dissolve 3,4-dihydroisoquinolin-l(2H)-one (500 mg, 3.40 mmol) in THF (20 mL) and add sodium hydroxide (274.5 mg, 6.79 mmol) followed by methyl acrylate (438.7 mg, 5.10 mmol) in THF (1 mL). Stir the mixture at ambient temperature for 3 hours; quench with water (20 mL); and then dilute with EtOAc (100 mL). Wash the resulting mixture with brine; dry the organic phase over Na2S04; filter; and concentrate the filtrate under reduced pressure to provide the title compound as a yellow oil (530 mg, 66.9%). MS (m/z): 234(M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | at 200℃; for 1h; Microwave irradiation; | 7.3.1. General synthetic procedure (I) for compounds 6, 7, 8, 33,34 and 35 General procedure: The respective lactame or benzolactame and 6-benzyloxyisatoic anhydride 5 were placed in a 10 mL crimp-sealed thick-walled glass tube equipped with a pressure sensor and a magnetic stirrer.The sealed reaction tube was placed inside the cavity of a CEM Discover focused microwave synthesis system, operated at 200°C(temperature monitored by a built-in infrared sensor), power 200 W, for 1 h. The residue was purified by column chromatography using dichloromethane/methanol (20:1) as eluent system toafford the title compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trichlorophosphate In benzene at 120℃; for 2h; Inert atmosphere; | 2 Step 2: A 100 mL three necked round bottom flask was charged with 3,4-dihydroisoquinolin- l(2H)-one (900 mg), benzene (10 mL) and phosphorusoxychloride (4.5 mL) under nitrogen atmosphere. The reaction mixture was heated to 120°C for 2 hours. The reaction mixture was cooled to room temperature and solvents were removed under reduced pressure. The resulting oil was neutralized with saturated aHC03 solution and pH was adjusted to 8-9. The aqueous layer was diluted with dichloromethane (100 mL) and further extracted with dichloromethane (2 x 50 mL). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2S04. Evaporation of solvents under reduced pressure gave crude l-chloro-3,4-dihydroisoquinoline (600 mg) as yellow liquid, which was used further without any purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With trifluorormethanesulfonic acid In dichloromethane at 0 - 20℃; for 0.5h; Inert atmosphere; | |
With trifluorormethanesulfonic acid; trifluoroacetic acid at -15 - 6℃; Inert atmosphere; | ||
With trifluorormethanesulfonic acid In dichloromethane at 0 - 20℃; Inert atmosphere; | III. Cyclization reactions A typical procedure: Synthesis of isoindolin-1-one (2a) General procedure: To a solution of methyl 2-((benzylcarbamoyl)oxy)benzoate (282 mg, 0.988 mmol) in drydichloromethane (4.94 mL, 0.2 M), trifluoromethanesulfonic acid (0.88 mL, 10 eq) was added at 0 C.The mixture was stirred at 20 C under argon atmosphere for 1 hr. Then the mixture was quenched with20 mL of ice water and the whole was extracted with dichloromethane (50 mL x 2). The organic layerwas dried over sodium sulfate and the solvent was evaporated to give a crude oil mixture. The crudeproduct was purified by column chromatography (eluent: ethyl acetate: chloroform = 1 : 2) to affordisoindolin-1-one (74.1 mg, 0.557 mmol, 56% yield) as colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 1h; Inert atmosphere; Stage #2: 4-bromomethylphenylboronic acid pinacol ester In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Inert atmosphere; | 87 [00596] 2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,4-dihydroisoquinolin-1-one 3,4-Dihydro-1 (2/-/)-isoquinolinone (89.2 mg, 0.61 mmol) was added to a stirring solution of sodium hydride (40.4 mg, 1 .01 mmol) in DMF (5 ml_) under nitrogen at 0 °C. The reaction mixture was stirred for 1 h at this temperature before 4-bromomethylphenylboronic acid pinacol ester (150.0 mg, 0.51 mmol) was added. The reaction mixture was allowed to warm to rt overnight. The reaction mixture was quenched with water (10 ml_) and extracted into DCM (3 x 10 ml_). The organics were combined, dried over Na2S04, filtered and concentrated in vacuo to afford 2-[[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl]-3,4-dihydroisoquinolin-1 -one (21 1 .0 mg, 0.58 mmol, 1 15% yield) as a cream solid. UPLC-MS (ES+, Short acidic): 1 .97 min, m/z 364.0 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With hydrogenchloride; sodium azide In water at 20℃; | |
15% | With sodium azide; methanesulfonic acid In dichloromethane at 0 - 20℃; | 3.A Step A: 3,4-Dihydroisoquinolin-1(2H)-one To a solution of 2,3-dihydro-1H-inden-1-one (30 g, 227 mmol) in DCM (300 mL) was added methanesulfonic acid (300 mL) and the solution was cooled to about 0 °C. Sodium azide (30 g, 461 mmol) was added to the solution in portions at about 0 °C and the reaction mixture was stilTed overnight at rt. The reaction mixture was neutralized with 20% aqueous NaOH and extracted with DCM (2 x 1 L). The organic phase was dried with anhydrous Na2SO4 and concentrated to give a residue, which was purified by column chromatography on silica gel to provide 3,4- dihydroisoquinolin-](2H)-one (5 g, 15%): ‘H NMR (MeOD) 3 7.93-7.91 (m, 1H), 7.49-7.45 (m, 1H), 7.36-7.45 (m, 1H), 7.28-7.26 (d, 1H), 3.50-3.46 (t, 2H), 2.97-2.94 (t, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With copper(l) iodide; potassium carbonate; In dimethyl sulfoxide; at 160℃; for 4h;Inert atmosphere; | A mixture of 3,4-dihydroisoquinolin-1(2H)-one (3.5 g, 13.6 mmol), <strong>[69321-60-4]1,3-dibromo-2-methylbenzene</strong> (17.5 g, 70.5 mmol) and K2C03 (9.85 g, 71.3 mmol) in DMSO (40 mL) was purged with N2, treated with CuT (1.75 g, 9 mmol) and heated to about 160 C for about 4 h. The reaction mixture was diluted with DCM and filtered through Celite. The filtrate was washed with 5% ammonia hydroxide, dried and concentrated. The residue was purified by column chromatography on silica gel to provide 2-(3- bromo-2-methylphenyl)-3,4-dihydroisoquinolin-](2H)-one (6 g, 80%): ?H NMR (CDC13) 3 8.16-8.14 (d, 1H), 7.56-7.54 (d, 2H), 7.49-7.41 (t, 1H), 7.26 (d, 1H), 7.25-7.18 (d, 1H), 7. 15-7.13 (d, 1H), 3.98- 3.92 (m, 1H), 3.76-3.70 (m, 1H), 3.30-3.22 (m, 1H), 3.13-3.07(m, 1H) 2.36 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 1,2-bis(dicyclohexylphosphonium)ethane bis(tetrafluoroborate); palladium diacetate; potassium carbonate In N,N-dimethyl-formamide at 80℃; for 18h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With copper(l) iodide; potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h; Sealed tube; | 4 Synthesis of 2-(3-chlorophenyl)-3,4-dihydroisoquinolin-1(2H)-one Example 4 Synthesis of 2-(3-chlorophenyl)-3,4-dihydroisoquinolin-1(2H)-one In a pressure tube was charged with 3,4-dihydroisoquinolin-1(2H)-one (150 mg, 1.0 mmol), 1-chloro-3-iodobenzene (0.25 mL, 2.0 mmol), CuI (38.1 mg, 0.2 mmol), K2CO3 (152 mg, 1.1 mmol) and N,N-dimethylformamide (2 mL). The mixture was stirred at 80° C. for 24 hours, The reaction mixture was diluted with ethyl acetate and washed with HCl (2N), NH3 (10%) twice, and brine. The organic phase was concentrated, and the residue was purified on silica gel (24 g), eluted with a gradient of ethyl acetate and hexanes from 1:9 to 3:7 to give 2-(3-chlorophenyl)-3,4-dihydroisoquinolin-1(2H)-one compound as a white solid (200 mg, 76%). 1H NMR (300 MHz, CDCl3): δ 8.11-8.06 (m, 1H), 7.45-7.12 (m, 7H), 3.92 (t, J=6.4 Hz, 2H), 3.08 (t, J=6.4 Hz, 2H); Calculated for C15H12ClNO, 257.06; observed MS (ESI) (m/z) 258.1 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 47 %Spectr. 2: 13 %Spectr. | With C47H15F20N5Zn; oxygen for 0.5h; Irradiation; Green chemistry; | Oxidation of Amines 1 Catalyzed by a Photocatalyst (Equations 6 and 7, Tables 7-10); General Procedure 4 General procedure: Fluorinated chlorins were prepared and metalated according to reported methods, to provide catalysts 4 and 5.22 Amine 1 (0.5 mmol) and photocatalyst 4 or 5 (0.001 mmol) were added to BTF (1.0 mL) in a two-necked Pyrex glass vessel. O2 gas was introduced into the vessel by connecting an O2 balloon, and the reaction mixture was stirred and irradiated using a Xe lamp through Pyrex (hν >300 nm) for 1 h. After extraction of the reaction mixture with Et2O, the organic layer was concentrated under reduced pressure. The yield of the product was confirmed by 1H NMR by using 1,3,5-trioxane as the internal standard. |
With silver carbonate In toluene at 90℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With palladium diacetate; triethylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; hydrazine In tetrahydrofuran; 1,4-dioxane at 100℃; Flow reactor; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 80℃; for 1h; Reflux; | |
Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: methyl iodide In tetrahydrofuran for 16h; Reflux; | 48.1 2-methyl-3,4-dihydroisoquinolin-1 (211)-one Sodium hydride (408 tug, 10.2 mmol) was added slowly to a stirring solution of 3,4- dihydroisoquinolin-1(211)-one (1.00 g, 6.80 mmol) in THF (30 mL) at 0 °C. The mixturestirred for 0.5 h before methyl iodide (1.45 mg, 10.2 mmol) was added and the mixture was heated to reflux for 16 hours. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product (1.2 g) as a yellow oil that required no further purification. | |
7.5 g | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydroxide In N,N-dimethyl-formamide for 0.5h; Cooling with ice; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; | 101 2-methyl-3,4-dihydroisoquinoline-1(2H)-one The starting material 3,4-dihydro-isoquinoline -1 (2H) -one (8g, 54.36mmoL) with DMF (100ml) was dissolved, with ice-cooling, was added sodium hydroxide (60%, 3.0g), the resulting mixture was after stirring for 30 minutes, iodomethane (15g, 105.68mmoL).The reaction was stirred overnight at room temperature, poured into ice water, and ethyl acetate (500ml × 3), washed ethyl acetate layer was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a yellow oil, fast column chromatography (petroleum ether: ethyl acetate = 1: 1) to give the intermediate 23 (7.5g, yellow oil). |
Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; Sealed tube; Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil at 20 - 80℃; for 1h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With trichlorophosphate In tetrahydrofuran at 60℃; for 1.5h; Inert atmosphere; Stage #2: Methyl N-methylanthranilate In tetrahydrofuran at 75℃; for 41h; Inert atmosphere; Further stages; | 1.3 4.1.3. 2-[2-(Methylamino)benzoyl]-3,4-dihydroisoquinolin-1(2H)-one (4b). 3,4-Dihydroisoquinolin-1(2H)-one (170 mg, 1.18 mmol, 1.0 equiv) was dissolved in dry THF (12 mL) and POCl3 (0.18 mL, 1.75 mmol, 1.5 equiv) added at 60 °C. The mixture was stirred under Ar atmosphere for 90 min. Methyl 2-(methylamino)benzoate (300 mg, 1.79 mmol, 1.5 equiv) was dissolved in dry THF (3.5 mL) and added dropwise to the reaction mixture over 5 min. The temperature was increased to 75 °C and the solution stirred for 41 h. The solution was cooled to rt and 2M HCl and CH2Cl2 were added until the aqueous phase reached pH=2. The organic layer was separated and the aqueous layer was basified using 2M NaOH to pH=9. By this a color change from colorless to yellow was observed. The water phase was extracted three times with CH2Cl2 (3*50 mL) and dried over Na2SO4. The solvent was evaporated. The formed crystals were filtered off and washed three times with petrol ether until the organic phase remained colorless. This yielded light-yellowish crystals (71.7 mg, 0.26 mmol, 22%). Rf=0.23-0.72 (tailing) (SiO2, methanol/dichloromethane/NH3 (25% aq-solution) 10:1:0.1%). Mp=136.5-137.0 °C. 1H NMR (400 MHz, CDCl3, 300 K): δ=8.13 (dd, J=7.8, 1.4 Hz, 1H, C(NH)-CHA-ring), 7.52 (td, J=7.5, 1.4 Hz, 1H, Ar-HD-ring), 7.43 (dd, J=8.0, 1.6 Hz, 1H, Ar-HD-ring), 7.39-7.35 (m, 2H, Ar-HA-ring), 7.32-7.27 (m, 2H, NH and Ar-HD-ring), 6.73 (dd, J=8.5, 1.0 Hz, 1H, Cquart.-CHA-ring), 6.55 (ddd, J=8.1, 7.1, 1.1 Hz, 1H, Ar-HD-ring), 4.01-3.98 (m, 2H, NCH2CH2), 3.18 (t, J=6.2 Hz, 2H, NCH2CH2), 2.94 (d, J=4.6 Hz, 3H, CH3) ppm. 13C{1H} NMR (101 MHz, CDCl3, 300 K): δ=176.61 (s, C=O), 165.51 (s, C=O), 151.37 (s, Cquart.), 139.92 (s, Cquart.), 134.87 (s, Ar-CA-ring), 133.32 (s, Ar-CD-ring), 132.64 (Ar-CD-ring), 129.76 (s, C(NH)-CHA-ring), 128.69 (s, Cquart.), 127.63 (s, Ar-CD-ring), 127.44 (s, Ar-CA-ring), 115.21 (s, Cquart.), 114.64 (s, Ar-CD-ring), 111.41 (s, Ar-CA-ring), 45.11 (s, NCH2CH2), 29.82 (s, CH3), 28.65 (s, NCH2CH2) ppm. IR: ν=3370m, 2898w, 2822w, 2372w, 2350w, 1688s, 1640s, 1603m, 1569m, 1516m, 1470m, 1422m, 1374m, 1335m, 1303s, 1265s, 1223s, 1176m, 1140s, 1089m, 1043m, 1006m, 960m, 905m, 848m, 797m, 786m, 742s, 716m, 691m, 653m cm-1. HPLC: Synergi 4U fusion-RP (15*0.46 cm), water/methanol (10-80%), 0.1% formic acid, 1.00 mL/min, 20 °C, tR=4.916 min, purity>99.99%. Mass: calcd for [M+H]+ (C17H17N2O2) requires m/z: 281.13 (open), 263.12 (closed); found: 263.15. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-[2-(methylamino)benzoyl]-3,4-dihydroisoquinolin-1(2H)-one With potassium hydroxide In isopropyl alcohol; toluene for 2h; Reflux; Stage #2: In water | 3.3 Procedure and experimental data for stability testing General procedure: For stability tests compounds 2b and 4b (15 μmol) were dissolved in dry toluene (3.0 mL) and the additive (10.0 eq. HCl, 10.0 eq KOH or 10.0 eq water) was added. For the DABCO experiment, benz-DHED 4b was dissolved in toluene, 13.0 eq diazabicyclooctane (DABCO) and after 10 min of stirring 10.0 eq. HCl were added. The reaction mixture was heated for 2 ;h to 115 °C oil bath temperature. Removal of the solvent yielded the products which were directly measured in NMR and LCMS. Only for the additive KOH an extraction protocol (acidified water to pH 5 (10 mL), CH2Cl2 (3*10 mL)) was performed. Reaction products were analyzed by LCMS as fast and simple detection method and 1H-NMR spectroscopy. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium hydroxide In tetrahydrofuran; methanol at 80℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: methyl (2S)-2-amino-3-phenylpropanoate hydrochloride; 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide; acetonitrile at 20℃; for 2h; Stage #2: 3,4-dihydroisoquinolin-1(2H)-one With triethylamine In N,N-dimethyl-formamide; acetonitrile at 20℃; for 24h; | 4.2.1 (S)-Methyl 2-(3-benzylureido)-3-phenylpropanoate (I-1a) General procedure: To a solution of N,N'-carbonyldiimidazole (CDI, 1.64g, 10.1mmol) in DMF (8mL) and acetonitrile (40mL) was added l-phenylalanine methyl ester hydrochloride (2.0g, 9.3mmol) in portions. The solution was stirred at room temperature for 2h. Benzylamine (1g, 9.3mmol) was then added, followed by the addition of triethylamine (1.72mL, 18.6mmol), and the aggregation system began to become clear. The reaction mixture was stirred at room temperature for 24h until completion as monitored by TLC, and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50mL) and washed with brine (50mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was recrystallized from ethyl acetate to afford the product I-1a as a white solid (1.22g, 43% yield); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 6h; Inert atmosphere; | |
95% | With dmap In tetrahydrofuran at 20℃; for 12h; | |
Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In tetrahydrofuran at 0℃; for 1h; Stage #2: di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran at 20℃; for 12h; |
With dmap In tetrahydrofuran at 20℃; for 12h; | General Procedure for the Synthesis of 6 or 7 General procedure: To a solution of compound 14 or 15 (2.0 mmol) in dry THF (10 mL) was added DMAP (0.2 mmol) and Boc2O (5.0 mmol). After being stirred at room temperature for 12 h, the mixture was quenched with NH4Cl and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over MgSO4, filtrated and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA = 5:1) to give the desired product 16 or 17. The compound 16 or 17 (0.5 mmol) was dissolved in dry THF (3 mL) under Ar atmosphere. Then DIBAL-H (1 M, 1.5 equiv) was dropped slowly. After being stirred at -78 °C for 2 h, the mixture was quenched with EtOAc and potassium sodium tartrate, and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over MgSO4, filtrated and concentrated, then obtained the crude product 6 or 7 to be used without purification because of its unstablity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With trichlorophosphate In 1,2-dichloro-ethane at 90℃; for 12h; Inert atmosphere; | 2.2 Typical procedure exemplified by the synthesis of2-(2-chloro-5-nitrophenyl)-7,8-dihydropyrrolo[1,2-a]pyrimidin-4(6H)-one (Table 1, Entry 1, 3aa) General procedure: A mixture of (ethyl 3-amino-3-(2-chloro-5-nitrophenyl)acrylate (200 mg, 0.739 mmol) (2a), 1,2-dichloroethane (5 mL),pyrrolidin-2-one (1a) (62.9 mg, 0.739 mmol), POCl3 (0.2 mL,1.5 mmol) was taken in a round bottom flask and stirredat 90C for 12 h under nitrogen. After completion of thereaction, as monitored by the LCMS, the reaction mixturewas cooled to room temperature. It was quenched with 10%sodium bicarbonate solution and extracted with ethyl acetate(3 × 25 mL). The combined organic layers were washedwith brine, dried over sodium sulphate, and concentrated ona rotary evaporator. The crude product was purified by ISCOchromatography on silica gel to give the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With dichloro bis(acetonitrile) palladium(II); copper(l) chloride In 1,2-dimethoxyethane at 60℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.25h; Inert atmosphere; Stage #2: 1-bromo-hexane In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 1-bromoacetone In N,N-dimethyl-formamide at 20 - 50℃; for 29h; | T-22 Example T-22: N-alkylation (addition of an amide to an α-halo-ketone) To a solution of 3,4-dihydroisoquinolin-1(2H)-one (200 mg, 1.36 mmol) in DMF (5 mL) was added sodium hydride (0.07 g, 2.72 mmol). The reaction was stirred at ambient temperature for 1 h.1- bromopropan-2-one (0.28 g, 2.04 mmol) was added to the reaction mixture. The reaction was stirred at ambient temperature for 24 h. TLC and LC-MS showed only a small amount of the desired product. The reaction mixture was heated to 50 °C and stirred at that temperature for an additional 5 h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5 g | With potassium <i>tert</i>-butylate; tetrabutylammomium bromide In tetrahydrofuran; N,N-dimethyl-formamide at 70℃; | 194.A Example 194. Synthesis of 2-(2-(4-(3-chlorophenoxy)piperidin-1-yl)ethyl)-3,4- dihydroisoquinolin-1(2H)-one A. To a solution of 3,4-dihydroisoquinolin-1(2H)-one (5.00 g, 33.97 mmol), t-Bu-OK (5.72 g, 50.96 mmol) and TBAB (5.48 g, 16.99 mmol) in THF / DMF (30 / 5 mL) was added 2-bromo-1,1- dimethoxyethane (11.48 g, 67.94 mmol). The reaction mixture was heated to 70 °C and stirred at that temperature overnight. TLC showed 20% of the starting material was still remained.2-bromo-1,1- dimethoxyethane (3.0 g) was added to the mixture. The reaction was stirred for another 6 h at 70 °C. TLC showed about 10~20% of starting material was still remained. The reaction mixture was treated with H2O (30 mL). The aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil was purified by column chromatography (hexanes:EtOAc=6:1) to provide the desired product (5.00 g) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.76 g | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane for 24h; Reflux; Inert atmosphere; | 35 Reference Example 35 A mixture of 1,2,3,4-tetrahydroisoquinolin-1-one (1.0 g), 1,4-dioxane (10.0 mL), methyl 6-chloronicotinate (1.39 g), Pd2(dba)3 (0.124 g), xantphos (0.197 g), and Cs2CO (2.88 g) was stirred for 1 day under heating to reflux under nitrogen atmosphere. After cooled to room temperature, water was added to the reaction solution and the mixture was extracted with AcOEt. The organic layer was dried over anhydrous Na2SO , and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane/AcOEt) to give methyl 6-( 1 -oxo- 1,2,3 ,4-tetrahydroisoquinolin-2-yl)pyridine-3-carboxylate (1.76 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.08 g | With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In toluene; at 90℃; for 24h;Inert atmosphere; | A mixture of 1,2,3,4-tetrahydroisoquinolin-1-one (0.509 g), <strong>[35387-92-9]methyl <strong>[35387-92-9]4-iodo-3-methoxybenzoate</strong></strong> (1.01 g), CuT (66.0 mg), DMEDA (74.0 1iL), K3P04 (1.47 g), and toluene (5.0 mL) was stirred at 90C for 1 day under nitrogen atmosphere. The reaction solution was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Haxane/AcOEt) to give methyl3-methoxy-4-( 1 -oxo- 1,2,3 ,4-tetrahydroisoquinoline-2-yl)benzoate (1.08 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.5h; Stage #2: 2-(trimethylsilyl)ethyl (S)-(3-(4-(chloromethyl)phenoxy)-3-(thiophen-2-yl)propyl)(methyl)carbamate With tetra-(n-butyl)ammonium iodide In N,N-dimethyl-formamide; mineral oil at 10 - 20℃; for 16h; | 50.a a) 2-(Trimethylsilyl)ethyl (S)-methyl(3-(4-((1 -oxo-3,4-dihydroisoquinolin-2(1 H)-yl) methyl)phenoxy)-3-(thiophen-2-yl)propyl)carbamate: To a solution of 3,4- dihydroisoquinolin-1 (2H)-one (63 mg, 0.43 mmol) in DMF (3 mL) cooled at 0 °C, NaH (60% suspension in mineral oil, 25 mg, 0.64 mmol) was added and the mixture was stirred at rt for 30 min. The reaction mixture was cooled again at 0 °C and a solution of 2-(trimethylsilyl)ethyl (S)-(3-(4-(chloromethyl)phenoxy)-3-(thiophen-2-yl)propyl)(methyl) carbamate (283 mg, 0.64 mmol) and TBAI (16 mg, 0.04 mmol) in DMF (2 mL) was added. The reaction mixture was stirred at rt for 16 h, water was added and extracted with EtOAc. The organic layer was dried with Na2S04, filtered and concentrated under vacuum afford the title compound that was used in the next step without further purification. HPLC (Method B): Ret, 6.51 min; ESI+-MS m/z, 573.2 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine In 1,4-dioxane at 130℃; for 20h; Inert atmosphere; | 32.b b) tert-Butyl methyl(3-((3-(1 -oxo-3,4-dihydroisoquinolin-2(1 H)-yl)benzyl)oxy)-3- (thiophen-2-yl)propyl)carbamate: A mixture of Cul (37 mg, 0.19 mmol) and N1 ,N2- dimethylethane-1 ,2-diamine (17 mg, 0.19 mmol) in dioxane (0.5 mL) was stirred at rt for 20 min. A solution of the compound obtained in step a) (150 mg, 0.34 mmol), 3,4- dihydroisoquinolin-1 (2H)-one (55 mg, 0.37 mmol) and K3PO4 (145 mg, 0.68 mmol) were added and the mixture was heated at 130 °C under Ar atmosphere for 20 h. The reaction mixture was cooled to rt and the solvent was removed under vacuum. Purification by flash chromatography, silica gel, gradient Hex to 100% EtOAc afforded the title compound (150 mg, 87% yield). HPLC (Method B): Ret, 6.12 min; ESI+-MS m/z, 529.2 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Inert atmosphere; Stage #2: (3S)-methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(2-iodo-4-methylpentanamido)propanoate In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h; Inert atmosphere; | 3.6 Step 6: (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)pentanamido)propanoic acid To a solution of 3,4-dihydroisoquinolin-1(2H)-one (135 mg, 0.92 mmol) in DMF (10 mL) was added NaH (60% in oil, 37 mg, 0.92 mmol) and the solution was stirred at room temperature for 0.5 hours under N2 atmosphere. Then a solution of (3S)-methyl 3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(2-iodo-4-methylpentanamido) propanoate (233 mg, 0.46 mmol) in DMF (2 mL) was added dropwise at room temperature and the reaction mixture was stirred at room temperature for another 1 hour. The reaction mixture was quenched with a HCl (1 M) solution. The solvent was removed in vacuo and the residue was purified by Preparative-HPLC A (30˜70% MeCN) to give the product (3S)-3-(5-(2,6-dimethylphenyl)pyridin-3-yl)-3-(4-methyl-2-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)pentanamido)propanoic acid (52.7 mg) as a white solid. Compound Z LC/MS A: 100% purity, UV=214 nm, Rt=1.67 min, ESI 514 (M+H)+ 1H NMR (500 MHz, MeOD) δ 8.59-8.56 (m, 1H), 8.25-8.18 (m, 1H), 7.97-7.84 (m, 1H), 7.73-7.58 (m, 1H), 7.49 (q, J=7.7 Hz, 1H), 7.40-7.00 (m, 5H), 5.49-5.32 (m, 2H), 3.76-3.42 (m, 2H), 3.17-2.78 (m, 4H), 2.01-1.95 (m, 5H), 1.87-1.66 (m, 3H), 1.65-1.43 (m, 1H), 1.07-0.89 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: p-toluenesulfonyl chloride In tetrahydrofuran at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: benzyl bromide In tetrahydrofuran; mineral oil at 0 - 23℃; for 15h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dichloro-ethane at 20℃; for 24h; | General procedures for the one-pot synthesis of 1:15 synthesis of 2-(diphenylmethylene)-2,5,6,7,8,9-hexahydro-3H-imidazo[1,2-a]azepin-3-one (1a) General procedure: Methyl trifluoromethanesulfonate (67 μL, 0.61 mmol) was added to astirred solution of 4a-O (103 mg, 0.91 mmol) in 1,2-dichloroethane (3.0 mL) at rt, and the resultingmixture was stirred at rt for 24 h. Tetramethylammonium acetate (81 mg, 0.61 mmol) was then added tothe mixture at rt, and the obtained mixture was stirred at rt for 20 min. Acetic acid (349 μL, 6.10 mmol)and glycinate 3 (815 mg, 3.05 mmol) were then added to the mixture at rt, and the mixture thus obtainedwas stirred under reflux conditions for 24 h. The rest of the procedure was the same as that describedabove, and it yielded 1a (100 mg, 52%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.22% | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; Stage #2: C14H15FO3 In tetrahydrofuran at -78 - 30℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.11% | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; Stage #2: C14H15ClO3 In tetrahydrofuran at -78 - 30℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.73% | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; Stage #2: C15H15NO3 In tetrahydrofuran at -78 - 30℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 80℃; for 12h; Inert atmosphere; | Step 1 - Methyl 2-(( 1 R.4R)-4-((bcnzylov)mcthyl)cvclohcyl)-6-( l-oxo-3.4- dihvdroisoquinolin -2( 1 H)-yl)benzo|dlthiazole-5-carboxylate To a solution of methyl 2-[4-(benzyloxymethyl)cyclohexyl]-6-bromo-l,3-benzothiazole- 5-carboxylate (500 mg, 1.05 mmol, synthesized via Steps 1-3 of Intermediate BAW) and 3,4-dihydro-2H- isoquinolin-l-one (162 mg, 1.11 mmol, CAS 1196-38-9) in dioxane (5 mL) was added Pd2(dba)3 (96.5 mg, 105 umol), CS2CO3 (686 mg, 2.11 mmol) and Xantphos (121 mg, 210 umol). The mixture was stirred at 80 °C for 12 hours. On completion, the reaction mixture was fdtered and the fdtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, DCM/MeOH=100/l to 20/1) to give the title compound (360 mg, 58% yield) as a brown solid. NMR (400 MHz, CDCI3) d 8.52 (s, 1H), 8.03 (dd, J= 1.2, 8.0 Hz, 1H), 7.73 (s, 1H), 7.42 - 7.37 (m, 1H), 7.27 (s, 2H), 7.24 - 7.16 (m, 5H), 4.45 (s, 2H), 4.03 - 3.94 (m, 1H), 3.92 - 3.80 (m, 1H), 3.74 (s, 3H), 3.28 (d, J = 6.4 Hz, 3H), 3.10 (d, J= 2.4, 6.8 Hz, 1H), 3.06 - 2.93 (m, 1H), 2.26 - 2.16 (m, 2H), 2.00 - 1.90 (m, 2H), 1.75 - 1.66 (m, 1H), 1.65 - 1.53 (m, 2H), 1.16 - 1.05 (m, 2H); LC-MS (ESI+) m/z 541.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.01% | Stage #1: methyl 2-hydroxy-2-(4-methoxyphenyl)acetate With phosphorus tribromide In dichloromethane at 0℃; for 1h; Inert atmosphere; Stage #2: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In tetrahydrofuran; mineral oil at 20℃; | 10.B B. Synthesis of methyl-2-(4-methoxyphenyl)-2-(1-oxo-3,4-dihydroisoquinolin-2-yl)acetate Step 1: In a flame dried flask under argon containing a solution of methyl-2-hydroxy-2-(4- methoxyphenyl)acetate (2.95 g, 15.04 mmol) in anhydrous dichloromethane (50.12 mL) was added phosphorous tribromide (0.99 mL, 10.52 mmol) at 0 °C. The reaction stirred at 0 °C for one hour. Afterwards, the reaction was diluted with water and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was taken up in 5 mL anhydrous tetrahydrofuran and added to the second step. Step 2: 3,4-Dihydro-2H-isoquinoli-1-one (2.21 g, 15.04 mmol) in 30 mL anhydrous tetrahydrofuran at 0 °C was added sodium hydride (60% in mineral oil) (721.71 mg, 18.04 mmol). After stirring for 30 minutes, the brominated product from Step 1 was added slowly. The reaction continued to stir at room temperature overnight or until complete by TLC or LC-MS. Upon completion, the reaction was diluted with aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed once with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified via silica gel column chromatography using hexanes and ethyl acetate to yield methyl-2-(4-methoxyphenyl)-2- (1-oxo-3,4-dihydroisoquinolin-2-yl)acetate (2.74 g, 8.42 mmol, 56.01% yield) as a pale-yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18.6% | Stage #1: 3,4-dihydroisoquinolin-1(2H)-one With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.5h; Stage #2: bromo-phenyl-acetic acid methyl ester In N,N-dimethyl-formamide; mineral oil at 20℃; | 11.B B. Synthesis of methyl-2-(1-oxo-3,4-dihydroisoquinolin-2-yl)-2-phenyl-acetate To a solution of 3,4-dihydro-2H-isoquinolin-1-one (209 mg, 1.42 mmol) in DMF (10 mL) was added sodium hydride (60% in mineral oil) (62.49 mg, 1.56 mmol). The mixture stirred for 30 minutes before the addition of methyl-2-bromo-2-phenyl-acetate (357.84 mg, 1.56 mmol). The reaction stirred at room temperature until complete by TLC or LC-MS. Upon completion, the reaction was quenched with an aqueous solution of ammonium chloride. This mixture was extracted three times with ethyl acetate. The combined organic layers were washed once with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified via silica gel column chromatography using hexanes and ethyl acetate to yield methyl-2- (1-oxo-3,4-dihydroisoquinolin-2-yl)-2-phenyl-acetate (78 mg, 0.264 mmol, 18.60% yield) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95 %Spectr. | With sodium t-butanolate; hydroxylamine-O-sulfonic acid In N,N-dimethyl-formamide at 0 - 23℃; | 3. General Procedure A: Lactam N-Amination General procedure: To a 100 mL round bottom flask, lactam 3,4-dihydro-2(1H)-quinolinone (180 mg, 1.23 mmol, 1equiv) was dissolved in 5 mL of anhydrous N,N-dimethylformaldehyde (DMF). In a separate 20mL vial, sodium tert-butoxide (540 mg, 5.658 mmol, 4.3 equiv) was dissolved in DMF (5 mL).After all solids were dissolved, both solutions were cooled to 0 C. The solution of sodium tertbutoxidewas added to the lactam solution dropwise over 5 min and the reaction was allowed tostir at 0 C for 5 min. Hydroxylamine-O-sulfonic acid (278 mg, 2.46 mmol, 2 equiv) was added asa white solid to the flask at 0 C. After the reaction was warmed to 23 C, the reaction was allowedto stir until completion by HPLC (usually 30 min). Additional portions of sodium tert-butoxide (2equiv increments) and HOSA (1 equiv increments) were added as needed to push the reaction tocompletion. After the reaction was was complete, it was quenched with a 1:1 solution of sat.Na2SO3 (aq) : water (5 mL) at 0 C and extracted with i-PrOAc (3 x 20 mL). The combined organiclayers were dried over magnesium sulfate and filtered through a fritted funnel. The mother liquorwas concentrated in vacuo. Then the crude material was telescoped directly into the next triazolecondensation step.For the reaction of lactam 2a (150 mg, 1.019 mmol, 1 equiv) to N-amino lactam 3a, isolation canbe achieved using by flash column chromatography (silica gel, 0-5% MeOH in CH2Cl2) to give awhite solid (106 mg, 0.653 mmol, 65% yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With 2-chloroanthracene-9,10-dione; cobalt(II) diacetate tetrahydrate; butane-2,3-dione dioxime In 1,2-dichloro-ethane at 20 - 30℃; for 36h; Irradiation; Schlenk technique; Sealed tube; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | Stage #1: 2-(chloromethyl)-5-(thiophen-2-yl)-1,3,4-oxadiazole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 3,4-dihydroisoquinolin-1(2H)-one In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h; | 39.c c) 2-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one To a solution of 2-(chloromethyl)-5-(thiophen-2-yl)-1,3,4-oxadiazole (250 mg, 1.25 mmol) in DMF (15 mL) was added NaH (74.8 mg, 1.87 mmol, 60% in oil) at 0° C. and the resulting mixture was stirred at this temperature for 30 minutes, 3,4-dihydroisoquinolin-1(2H)-one (250 mg, 1.25 mmol) was added. The reaction mixture was warmed up to RT and stirred for an hour. The resulting mixture was mixed with EA (100 mL) and brine (100 mL). The organic layer was separated, dried over anhydrous Na2SO4 and filtered in vacuum. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (system: Waters 2767/2545/2489/Qda, Column name: Inertsil ODS-3 10 um 20*250 nm, Mobile Phase A: 0.1% FA in water, Mobile Phase B: CH3CN. Wavelength: 254 nm/214 nm. Flow: 20 mL/min: Column temp: RT) to afford the titled compound (43.1 mg, yield: 11%). LC-MS (ESI): m/z 312.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=4.9 Hz, 1H), 7.77-7.85 (m, 2H), 7.54-7.64 (m, 2H), 7.17-7.36 (m, 1H), 5.02 (s, 2H), 3.75 (t, J=6.5 Hz, 2H), 3.07 (t, J=6.4 Hz, 2H). |
11% | Stage #1: 2-(chloromethyl)-5-(thiophen-2-yl)-1,3,4-oxadiazole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 3,4-dihydroisoquinolin-1(2H)-one In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h; | 39.c c) 2-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one To a solution of 2-(chloromethyl)-5-(thiophen-2-yl)-1,3,4-oxadiazole (250 mg, 1.25 mmol) in DMF (15 mL) was added NaH (74.8 mg, 1.87 mmol, 60% in oil) at 0° C. and the resulting mixture was stirred at this temperature for 30 minutes, 3,4-dihydroisoquinolin-1(2H)-one (250 mg, 1.25 mmol) was added. The reaction mixture was warmed up to RT and stirred for an hour. The resulting mixture was mixed with EA (100 mL) and brine (100 mL). The organic layer was separated, dried over anhydrous Na2SO4 and filtered in vacuum. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (system: Waters 2767/2545/2489/Qda, Column name: Inertsil ODS-3 10 um 20*250 nm, Mobile Phase A: 0.1% FA in water, Mobile Phase B: CH3CN. Wavelength: 254 nm/214 nm. Flow: 20 mL/min: Column temp: RT) to afford the titled compound (43.1 mg, yield: 11%). LC-MS (ESI): m/z 312.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=4.9 Hz, 1H), 7.77-7.85 (m, 2H), 7.54-7.64 (m, 2H), 7.17-7.36 (m, 1H), 5.02 (s, 2H), 3.75 (t, J=6.5 Hz, 2H), 3.07 (t, J=6.4 Hz, 2H). |
11% | Stage #1: 2-(chloromethyl)-5-(thiophen-2-yl)-1,3,4-oxadiazole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 3,4-dihydroisoquinolin-1(2H)-one In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h; | 39.c c) 2-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one To a solution of 2-(chloromethyl)-5-(thiophen-2-yl)-1,3,4-oxadiazole (250 mg, 1.25 mmol) in DMF (15 mL) was added NaH (74.8 mg, 1.87 mmol, 60% in oil) at 0° C. and the resulting mixture was stirred at this temperature for 30 minutes, 3,4-dihydroisoquinolin-1(2H)-one (250 mg, 1.25 mmol) was added. The reaction mixture was warmed up to RT and stirred for an hour. The resulting mixture was mixed with EA (100 mL) and brine (100 mL). The organic layer was separated, dried over anhydrous Na2SO4 and filtered in vacuum. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (system: Waters 2767/2545/2489/Qda, Column name: Inertsil ODS-3 10 um 20*250 nm, Mobile Phase A: 0.1% FA in water, Mobile Phase B: CH3CN. Wavelength: 254 nm/214 nm. Flow: 20 mL/min: Column temp: RT) to afford the titled compound (43.1 mg, yield: 11%). LC-MS (ESI): m/z 312.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=4.9 Hz, 1H), 7.77-7.85 (m, 2H), 7.54-7.64 (m, 2H), 7.17-7.36 (m, 1H), 5.02 (s, 2H), 3.75 (t, J=6.5 Hz, 2H), 3.07 (t, J=6.4 Hz, 2H). |
39.c c) c) 2-((5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one To a solution of 2-(chloromethyl)-5-(thiophen-2-yl)-1,3,4-oxadiazole (250 mg, 1.25 mmol) in DMF (15 mL) was added NaH (74.8 mg, 1.87 mmol, 60% in oil) at 0° C. and the resulting mixture was stirred at this temperature for 30 minutes, 3,4-dihydroisoquinolin-1(2H)-one (250 mg, 1.25 mmol) was added. The reaction mixture was warmed up to RT and stirred for an hour. The resulting mixture was mixed with EA (100 mL) and brine (100 mL). The organic layer was separated, dried over anhydrous Na2SO4 and filtered in vacuum. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (system: Waters 2767/2545/2489/Qda, Column name: Inertsil ODS-3 10 um 20*250 nm, Mobile Phase A: 0.1% FA in water, Mobile Phase B: CH3CN. Wavelength: 254 nm/214 nm. Flow: 20 mL/min: Column temp: RT) to afford the titled compound (43.1 mg, yield: 11%). LC-MS (ESI): m/z 312.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=4.9 Hz, 1H), 7.77-7.85 (m, 2H), 7.54-7.64 (m, 2H), 7.17-7.36 (m, 1H), 5.02 (s, 2H), 3.75 (t, J=6.5 Hz, 2H), 3.07 (t, J=6.4 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With sodium chlorate In lithium hydroxide monohydrate; acetonitrile at 60℃; for 1.5h; Green chemistry; | General procedure for the oxidation of tertiary amines to corresponding amides: General procedure: A solution of (4-nitrophenyl) morpholine (1.04 g, 5 mmol) in CH3CN (10mL) was added into a 100mL three-port roundbottomflask, and it was stirred under CO2 atmosphere at 50°C. Then a solution of sodium chlorite (morethan 80%, 1.69 g, 15mmol) in 5 mL water was added in 20 min. TLC and HPLC showed that the reactionwas completed in 2.5 h. The reaction was quenched with aqueous saturated sodium sulfite. The mixture wasextracted by DCM (3×30 mL). The combined organic solution was dried over anhydrous sodium sulphate.Removal of all volatiles heft a residue, which was purified by flash chromatography on silica gel(hexane/EtOAc, from 5:1 to 3:1) to give 1.05g (95% yield) of 2a as a light-yellow solid. |
Tags: 1196-38-9 synthesis path| 1196-38-9 SDS| 1196-38-9 COA| 1196-38-9 purity| 1196-38-9 application| 1196-38-9 NMR| 1196-38-9 COA| 1196-38-9 structure
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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.
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