| 86% |
Stage #1: carbon disulfide; benzylamine With triethylamine In dichloromethane at 0℃; for 1h;
Stage #2: With trichloromethyl chloroformate In dichloromethane at 20℃; for 4h; |
|
| 86% |
Stage #1: carbon disulfide; benzylamine With triethylamine In ethanol at 20℃;
Stage #2: With dmap; di-<i>tert</i>-butyl dicarbonate In ethanol at 20℃; for 0.25h; Further stages.; |
|
| 86% |
With tert.-butylhydroperoxide; dmap In methanol; water at 0℃; |
3 Preparation of benzyl isothiocyanate
Dissolve benzylamine (54mg, 0.5mmol) in 5mL methanol at 0°C,Then add 4-dimethylaminopyridine (6mg, 0.05mmol),Carbon disulfide (133mg, 1.75mmol) and tert-butyl hydroperoxide (96mg, 0.75mol, 70% in H2O).The reaction continued to stir at 0°C. When TLC indicated that the conversion of the starting material was completed, the solvent was distilled off under reduced pressure.Water was added to the crude reaction system and extracted with petroleum ether.The obtained crude product was purified by column chromatography with 1:20 ethyl acetate/petroleum ether,The target molecule (64mg, 86% yield) can be obtained. The primary amine, alkali catalyst,The molar ratio of carbon disulfide to oxidant is 1:0.1:3.5:1.5. |
| 84% |
With S,S'-bis(1-phenyl-1H-tetrazol-5-yl) dithiocarbonate; triethylamine In acetonitrile for 0.333333h; |
|
| 75% |
With dicyclohexyl-carbodiimide In dichloromethane at -10 - 20℃; for 8h; |
|
| 73% |
Stage #1: carbon disulfide; benzylamine With triethylamine In tetrahydrofuran at 0 - 20℃; for 1.75h;
Stage #2: With p-toluenesulfonyl chloride In tetrahydrofuran at 0 - 20℃; for 1h; |
|
| 67% |
Stage #1: carbon disulfide; benzylamine In diethyl ether for 0.25h; Cooling with ice;
Stage #2: With dicyclohexyl-carbodiimide In diethyl ether at 20℃; for 24h; |
|
| 63% |
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate In N,N-dimethyl-formamide for 0.5h; Ambient temperature; |
|
| 61% |
With tert.-butylhydroperoxide; dmap; tetra-(n-butyl)ammonium iodide In methanol; water at 0℃; |
General procedure for the synthesis of isothiocyanates
General procedure: To a solution of amine (0.5 mmol) in MeOH (2.5 mL) at 0 °C was added Bu4NI (18 mg, 0.05 mmol), DMAP (6 mg, 0.05 mmol) sequentially. The solution was stirred at 0 °C for 10 min. After that, 70% aq. TBHP (96 mg, 0.75 mmol), CS2 (133 mg, 1.75 mmol) was added. The solution was stirred at 0 °C for 6-18 h. Upon consumption of the amine, 50 mL EtOAc was added, the organic phase was washed with H2O (10 mL) and dried with Na2SO4. After concentration of the organic phase under reduced pressure, the residue was purified by column chromatography on silica gel using EtOAc/ PE = 1:20 to give the desired product. |
| 60% |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 72h; |
|
| 47% |
With sodium hydroxide; diethyl chlorophosphate In toluene for 3h; Reflux; |
|
| 45% |
Stage #1: carbon disulfide; benzylamine In water; ethyl acetate at 30℃; for 1h;
Stage #2: With copper(ll) sulfate pentahydrate In water; ethyl acetate at 30℃; for 1h; |
|
| 34% |
Stage #1: carbon disulfide; benzylamine With triethylamine In tetrahydrofuran for 0.5h; Cooling with ice;
Stage #2: With dihydrogen peroxide In tetrahydrofuran; water at 20℃; Cooling with ice; |
|
| 23% |
With sodium hydroxide In acetonitrile at 20℃; for 9h; Green chemistry; |
General procedure of isothiocyanate synthesis
General procedure: To an 8mL vial were added CH3CN (1.5 mL), powder sodium hydroxide (40.0 mg, 1 mmol), primary amines (0.5 mmol) and carbon disulfide (114.2 mg, 1.5 mmol) subsequently. The mixture was allowed to stir for 9 h at room temperature and slightly yellow solids were observed to precipitate at the bottom of the reaction vials. Then the reaction mixture was centrifuged for 3 min at 6000 rmp. The upper clear solution was collected and concentrated by rotavap. Flash chromatography on silica gel (eluent: petroleum ether) provided the desired isothiocyanates. The supplemental materials contain experimental details and spectroscopic characterization data of 2a - 2o (Figures S1-S5). |
|
With iodine und nachfolgendes Behandeln mit Natriumaethylat, dann mit Jod in Alkohol; |
|
|
With dicyclohexyl-carbodiimide In diethyl ether at -10 - 20℃; |
|
|
With ammonium hydroxide; lead(II) nitrate |
|
|
Stage #1: carbon disulfide With sodium hydroxide at 4℃;
Stage #2: benzylamine for 2h; Heating;
Stage #3: With chloroformic acid ethyl ester for 0.5h; |
|
|
With dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 3h; |
|
|
Stage #1: carbon disulfide; benzylamine With triethylamine In tetrahydrofuran at 20℃; for 1.5h; Inert atmosphere; Cooling with ice;
Stage #2: With p-toluenesulfonyl chloride In tetrahydrofuran at 20℃; Cooling with ice; |
|
|
Stage #1: carbon disulfide; benzylamine With triethylamine In dichloromethane at 0 - 20℃; for 1h;
Stage #2: With p-toluenesulfonyl chloride In dichloromethane at 0℃; for 3h; |
|
|
Stage #1: carbon disulfide; benzylamine With sodium hydrogencarbonate In N,N-dimethyl-formamide at 20℃; for 1h;
Stage #2: With cobalt(II) sulfate monohydrate In N,N-dimethyl-formamide at 20℃; for 1h; |
General Procedure for the synthesis of 1-benzylthiourea
To a stirred solution of DMF (4-5 ml), Benzyl amine (2 mmol, 254 mg) was added in slowly and followed by carbon disulphide (20 mmol (10 eq), 1520 mg) and sodium bicarbonate (2 mmol (1 eq), 168 mg) were added at room temperature. The whole reaction mixture stirred for one hour (until get the yellow color solid) at room temperature. Thiocarbomate formation was monitored by TLC. To this, CoSO4xH2O (25 mol%, 121 mg) and sodium bicarbonate (2 mmol (1 eq), 168 mg) were added slowly for 5 min and the reaction mixture stirred for 1 h. During this period, a block color precipitate was observed and settles at bottom of round bottom flask. The progress of the reaction was investigated by TLC (5% ethylacetate in hexane). After 1 h, ammonia solution (2 ml) was added slowly. Then the whole reaction mixture stirred for 1 h at room temperature. After finish the reaction, the reaction mixture was transferred into centrifuged tubes and the mixture was centrifuged for 10 min by using centrifugation machine. Block color solid was settled in the bottom of centrifuged tubes. The clear solution was concentrated by using rotary evaporator and the crude mixture was purified by silica gel (60-120 mesh) column chromatography using 20% Ethylacetate in Hexane as eluent to afford a 1-Benzyl thiourea as white solid. |
|
Stage #1: carbon disulfide; benzylamine With sodium hydrogencarbonate In ethyl acetate at 20℃; for 1h;
Stage #2: With copper(II) acetate monohydrate; sodium hydrogencarbonate at 20℃; for 2h; |
Representative experimental procedure for the synthesis of phenyl cyanamide
General procedure: To a stirred solution of ethyl acetate (4-5 mL), aniline (2 mmol, 186 mg) was added in slowly and followed by carbon disulfide [20 mmol (10 eq.), 1520 mg or 1.21 mL] and sodium bicarbonate [2 mmol (1 eq.), 168 mg] were added at room temperature. The whole reaction mixture stirred for 1 h (until get the yellow color solid) at room temperature. Thiocarbomate formation was monitored by TLC. To this, Cu(OAc)2 · H2O (50 mol%, 199 mg) was added slowly followed by sodium bicarbonate [2 mmol (1 eq.), 168 mg] was added slowly for 10 min and the reaction mixture was stirred for 1 h. During this period, a black color precipitate (CuS) was observed and settles at bottom of round bottom flask. The progress of the reaction was investigated by TLC (5% ethyl acetate in hexane). After completion of the reaction, the reaction mixture was transferred into centrifuged tubes and the mixture was centrifuged for 10 min using centrifugation machine. Black color solid was removed from the centrifuged tubes. To that clear solution, ammonia sol (2 mL) was added slowly, and the reaction mixture stirred for 1 h. Later, Cu(OAc)2 · H2O (50 mol%, 199 mg) and sodium bicarbonate [2 mmol (1 eq.), 168 mg] were added to that previous solution. The whole reaction mixture stirred for 2 h at room temperature. During this period black color precipitate (CuS) was observed, and it was removed by centrifugation. The clear solution was concentrated using rotary evaporator and the crude mixture was purified by silica gel (60-120 mesh) column chromatography using ethyl acetate in hexane as eluent to obtain a phenyl cyanamide as gummy. |
|
Stage #1: carbon disulfide; benzylamine With triethylamine In ethanol at 20℃; for 3h;
Stage #2: With dmap; di-<i>tert</i>-butyl dicarbonate In ethanol at 20℃; for 0.5h; |
4.2. General procedure for the synthesis of compounds(2a-k)
General procedure: One pot method was adopted for synthesis of 2a-k. Firstly, in a50 ml round-bottom flask, appropriate primary amine 1a-k(3.125 mmol), triethylamine (6.25 mmol) and CS2 (6.25 mmol) weredissolved in ethanol (15 mL). The reaction mixture was stirred for3 h at room temperature. Upon completion of the reaction, di-tertbutyldecarbonate (8.5 mmol), dissolved in absolute ethanol, wasadded followed by the immediate addition of a catalytic amount of4-dimethylaminopyridine (0.425 mmol). After the reaction mixturewas kept for further 30 min at room temperature, the solvent wasdistilled off under reduced pressure, and the residue was purifiedby column chromatography (petroleum ether/ethyl acetate= 4:1)to afford the corresponding 2a-k in 48-66% yield. |
|
Stage #1: carbon disulfide; benzylamine With triethylamine In tetrahydrofuran for 1h; Cooling with ice;
Stage #2: With p-toluenesulfonyl chloride In tetrahydrofuran for 1h; Cooling with ice; |
1 Preparation of benzyl isothiocyanate
Dissolve 8 mmol of benzylamine in 15 ml of anhydrous tetrahydrofuran solvent, add 5 ml (36 mmol) of triethylamine, place in an ice bath, add 2 ml (33 mmol) of carbon disulfide for 1 hour, and then add 2 g (10.5 mmol) of p-toluenesulfonyl chloride (PTSC) In the flask, withdraw the ice bath again, stop the reaction after one hour of reaction, add 20ml of 0.5mol/L dilute hydrochloric acid to acidify, extract three times with 60ml of anhydrous ether, and separate the organic phase and add anhydrous sulfuric acid after liquid separation After the sodium is dried, add the sample silica gel and spin dry to the column, use petroleum ether flash column chromatography (developing agent: petroleum ether Rf value 0.4-0.6. pyridine ring thioisocyanate, developing agent: ethyl acetate; petroleum ether = 1; 5, Rf value is 0.4-0.5) to obtain a transparent oily liquid (yield 75-80%). |
|
Stage #1: carbon disulfide; benzylamine With triethylamine In tetrahydrofuran at 20℃; for 3h;
Stage #2: With dmap; di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran at 20℃; for 0.3h; |
4.2. General procedure for the synthesis of intermediate compounds(2a-g)
General procedure: The substituted phenyl isothiocyanate 2a-g were synthesized byone-pot reaction. In a 25 mL round-bottom flask, availablesubstituted aniline 1a-g (4 mmol) was dissolved in THF (8 mL), CS2(40 mmol) and Et3N (4 mmol) were added in turn. While reactingfor 3 h at room temperature and monitoring via TLC until thecomplete conversion to dithiocarbamic acid salt, the system wascooled in an ice bath, then (Boc)2O (4 mmol, dissolved in 1 mL THF)and DMAP (0.04 mmol, dissolved in 0.5 mL THF) were addedimmediately, followed by stirring for another 0.3 h. The systemwasconcentrated under reduced pressure and purified by columnchromatography to provide phenyl isothiocyanate 2a-g with45e70% yield. |
|
Stage #1: carbon disulfide; benzylamine With triethylamine In tetrahydrofuran at 0 - 20℃; for 1.5h;
Stage #2: With p-toluenesulfonyl chloride at 0 - 20℃; for 1h; |
5.1.1. General synthetic procedure of target compounds 5a-s
General procedure: CS2 (2.3 mL, 30 mmol) was added dropwise to the mixture ofmethylamine derivative (30 mmol) and triethylamine (12 mL) inTHF (25 mL) at 0 C within 30 min. After stirring for 1 h at roomtemperature, the mixture was then cooled down to 0 C and thetoluene sulfonyl chloride (6 g, 31.5 mmol) were added in. Afterstirring for another 1 h at room temperature, the mixture wasdiluted with 5% HCl (100 mL) and petroleum ether, sequentiallywashed with water, saturated NaHCO3 solution and brine, driedwith anhydrous Na2SO4 and evaporated in vacuo to obtain compound1. HCl (10.5 mL) was added to the mixture of benzene orbenzene derivatives (6.65 mmol) and paraformaldehyde(11.97 mmol), and then stirred for 10 h at 60 C. After cooling downto room temperature, the mixture was then dispersed with waterand ethyl acetate, and sequentially washed with water, 5% HCl,saturated NaHCO3 solution and brine, dried with anhydrousNa2SO4. The solvent was then removed by evaporation to givecompound 2. Methyl 2-amino-4-hydroxybenzoate (0.01 mol) andisothiocyanate derivatives (0.01 mol) was heated in the presence oftriethylamine and ethanol at reflux temperature for 4 h. Aftercooling down to room temperature, the mixturewas filtered to giveintermediate 3, which was subsequently reacted with intermediate2 (0.01 mmol) in the presence of K2CO3 and 1,4-dioxane underreflux for 10 h. Then, the mixture was cooled down to room temperature,dissolved with ethyl acetate, sequentially washed withwater, 5% HCl, saturated NaHCO3 solution and brine, dried withanhydrous Na2SO4. Removal of the solvent gave a residue, whichwas then recrystallized in ethanol to obtain intermediate 4. Finally,the target compounds 5a-s were prepared by alkylating intermediate4 (5 mmol) with 2-dimethylaminoethyl chloride hydrochloride,2-diethylaminoethyl chloride hydrochloride or 3-dimethylaminopropyl chloride hydrochloride (6 mmol) in thepresence of 1, 4-dioxane and K2CO3, respectively. Spectra of thetarget compounds were shown in the Supplementary Material. |
|
Stage #1: carbon disulfide; benzylamine With triethylamine In tetrahydrofuran at 0 - 20℃; for 1.5h;
Stage #2: With p-toluenesulfonyl chloride In tetrahydrofuran at 0 - 20℃; |
5.1.1 General procedure for the synthesis of compounds 5a-q
General procedure: 2-furanethylamine, benzylamine, 2-thiophenemethylamine or cyclohexanol methylamine (10mmol) and triethylamine (12mL) dissolved in THF (25mL), CS2 (1.53mL, 20mmol) was added dropwise to the mixture at 0°C within 30min. After stirring at room temperature for 1h, the mixture was cooled down to 0°C and then add the toluene sulfonyl chloride (4g, 21.0mmol). After stirring at room temperature for 30-60min, the reaction was terminated by adding 5% HCl (100mL) and then extracted with petroleum ether (200mL), washed sequentially with water, saturated NaHCO3 solution and brine, dried with anhydrous Na2SO4 and evaporated in vacuo to give isothiocyanatomethyl derivatives 1a-d. Intermediates 1a-d (20mmol) reacted with methyl 2-amino-5-hydroxybenzoate (2.7g, 20mmol) in triethylamine (12mL) and ethyl alcohol (12mL) at reflux temperature for 4h. By reaction the precipitate formed, which was collected, washed with ethyl alcohol, and dried to give 2-thioxo-2,3-dihydroquinazolin-4(1H)-one derivatives 2a-d. Intermediates 2a-d reacted with benzyl bromide, 3-fluorobenzyl bromide, 4-fluorobenzyl bromide or 2-methoxybenzyl bromide and K2CO3 (3.0g) in dioxane (8mL) and DMF (2mL) at 90°C for 3h to obtain 2-(benzylthio)-6-hydroxyquinazolin-4(3H)-one derivatives 3a-i. Intermediates 3a-i (5mmol) reacted with 1,2-dibromoethane (10mmol), 1,3-dibromopropane (10mmol) or 1,4-dibromobutane (10mmol) in K2CO3 (3.0g), dioxane (8mL) and DMF (2mL) at 90°C for 3h to prepare bromides 4a-k. Intermediates 4a-k (5mmol) reacted with 4-hydroxypiperidine (10mmol), 4-methylpiperazine (10mmol), or amino-4-hydroxypyrimidine (10mmol) in K2CO3 (3.0g), dioxane (8mL) and DMF (2mL) at 90°C for 3h to prepare the target compounds 5a-q, respectively. |
|
Stage #1: carbon disulfide; benzylamine With triethylamine In tetrahydrofuran at 0 - 20℃; for 1.5h;
Stage #2: With p-toluenesulfonyl chloride In tetrahydrofuran at 0 - 20℃; |
5.1.1 General procedure for the synthesis of compounds 5a-q
General procedure: 2-furanethylamine, benzylamine, 2-thiophenemethylamine or cyclohexanol methylamine (10mmol) and triethylamine (12mL) dissolved in THF (25mL), CS2 (1.53mL, 20mmol) was added dropwise to the mixture at 0°C within 30min. After stirring at room temperature for 1h, the mixture was cooled down to 0°C and then add the toluene sulfonyl chloride (4g, 21.0mmol). After stirring at room temperature for 30-60min, the reaction was terminated by adding 5% HCl (100mL) and then extracted with petroleum ether (200mL), washed sequentially with water, saturated NaHCO3 solution and brine, dried with anhydrous Na2SO4 and evaporated in vacuo to give isothiocyanatomethyl derivatives 1a-d. Intermediates 1a-d (20mmol) reacted with methyl 2-amino-5-hydroxybenzoate (2.7g, 20mmol) in triethylamine (12mL) and ethyl alcohol (12mL) at reflux temperature for 4h. By reaction the precipitate formed, which was collected, washed with ethyl alcohol, and dried to give 2-thioxo-2,3-dihydroquinazolin-4(1H)-one derivatives 2a-d. Intermediates 2a-d reacted with benzyl bromide, 3-fluorobenzyl bromide, 4-fluorobenzyl bromide or 2-methoxybenzyl bromide and K2CO3 (3.0g) in dioxane (8mL) and DMF (2mL) at 90°C for 3h to obtain 2-(benzylthio)-6-hydroxyquinazolin-4(3H)-one derivatives 3a-i. Intermediates 3a-i (5mmol) reacted with 1,2-dibromoethane (10mmol), 1,3-dibromopropane (10mmol) or 1,4-dibromobutane (10mmol) in K2CO3 (3.0g), dioxane (8mL) and DMF (2mL) at 90°C for 3h to prepare bromides 4a-k. Intermediates 4a-k (5mmol) reacted with 4-hydroxypiperidine (10mmol), 4-methylpiperazine (10mmol), or amino-4-hydroxypyrimidine (10mmol) in K2CO3 (3.0g), dioxane (8mL) and DMF (2mL) at 90°C for 3h to prepare the target compounds 5a-q, respectively. |
| 95 % |
In methanol at 20℃; Electrochemical reaction; |
|
|
Stage #1: carbon disulfide; benzylamine With trimethylamine In water; ethyl acetate at 20℃;
Stage #2: With copper(ll) sulfate pentahydrate In water; ethyl acetate at 20℃; |
General Procedure for phenyl isothiocyanate
General procedure: To a stirred solution of EtOAc/H2O ((2:1) (4-5 ml)),aniline (2 mmol, 186 mg) was added in slowly andfollowed by carbon disulphide (20 mmol (10 eq), 1520 mg) and trimethylamine (2 mmol (1 eq), 202 mg) were added at room temperature. The whole reaction mixture stirred for one hour (until get the yellow color solid) at room temperature. Thiocarbomate formation was monitored by TLC. To this, CuSO4.5H2O (50 mol %, 125 mg) was added slowly for 5 min and the reaction mixture stirred for 1h. During this period, a black color precipitate was observed and settles at bottom of round bottom flask. The progress of the reaction was investigated by TLC (5% ethylacetate in hexane). After finishing the reaction, the reaction mixture was transferred into centrifuged tubes and the mixture was centrifuged for 10 min by using centrifugation machine. Black color solid was settled in the bottom of centrifuged tubes. The resulted clear solution was washed with ethyl acetate (10 ml) and water (7 ml) for 3 times. And organic layer was concentrated by using rotary evaporator and the crude mixture was purified by silica gel (60-120 mesh) column chromatography using 2% Ethylacetate in Hexane as eluent to obtain a Phenyl isothiocyanate as a target product, which was characterized by 1H NMR and IR spectroscopy analysis. |
| 89 % |
With cobalt(II) oxide In Petroleum ether at 25℃; |
8 Embodiment 8 prepares benzyl isothiocyanate (Ih)
Weigh benzylamine (10.7g) and dissolve in petroleum ether,Then drop in petroleum etherCarbon disulfide (46g),Carbon disulfide is added in about 30 minutes; then cobalt oxide(20.1g) was ground into a powder with an average particle size of 100-200um and added to petroleum ether dripped with carbon disulfide,After vigorously stirring to form a suspension, continue to stir and react at 25°C for 24h;Stop heating and stirring, filter to remove solids and leave the filtrate,Finally, after the filtrate was distilled to remove the solvent, rectification under reduced pressure (66mmHg),The distillate products at 100-103°C were collected to obtain Ih (13.3g, 89%). |
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