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CAS No. : | 1985-12-2 | MDL No. : | MFCD00004808 |
Formula : | C7H4BrNS | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XQACWEBGSZBLRG-UHFFFAOYSA-N |
M.W : | 214.08 | Pubchem ID : | 16133 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 48.83 |
TPSA : | 44.45 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -4.74 cm/s |
Log Po/w (iLOGP) : | 2.45 |
Log Po/w (XLOGP3) : | 4.03 |
Log Po/w (WLOGP) : | 3.18 |
Log Po/w (MLOGP) : | 3.97 |
Log Po/w (SILICOS-IT) : | 4.14 |
Consensus Log Po/w : | 3.56 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.08 |
Solubility : | 0.0176 mg/ml ; 0.0000824 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -4.67 |
Solubility : | 0.00461 mg/ml ; 0.0000215 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -3.45 |
Solubility : | 0.0754 mg/ml ; 0.000352 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 2.12 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P260-P261-P264-P270-P271-P280-P285-P301+P312-P301+P330+P331-P303+P361+P353-P304+P340-P304+P341-P305+P351+P338-P310-P312-P321-P330-P342+P311-P363-P405-P501 | UN#: | 1759 |
Hazard Statements: | H302-H314-H332-H334 | Packing Group: | Ⅲ |
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 chlorobenzene | ||
In chlorobenzene for 8h; Reflux; | 3.3. General Procedure for the Synthesis of Aryl-isothiocyanates (3a-d) General procedure: The aryl-thioureas (7 mmol) was submitted under 8 h of reflux in chlorobenzene as solvent. The solution was then distilled under reduced pressure for chlorobenzene removal.The aryl-isothiocyanates (3a-d) were used immediately in the subsequent step as crude products [49]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | at 20℃; | |
With ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia | ||
With ammonia In ethanol Yield given; | ||
With ammonia; water In tetrahydrofuran at 20℃; for 0.166667h; | 16 Referential Example 16 N-(4-Bromophenyl)thiourea (33) 4-Bromophenylisothiocyanate (21.4 g) was dissolved in tetrahydrofuran (50 mL), and concentrated aqueous ammonia (28%) (13.7 mL) was added dropwise to the solution, followed by stirring at room temperature for 10 minutes. The solvent was concentrated under reduced pressure, and the crystals were recovered through filtration by use of water, followed by recrystallization from ethanol, to thereby yield the title compound (16.4 g). 1H-NMR(400MHz,DMSO-d6+D2O)δ:7.43(2H,dt,J=2.4,8.8Hz), 7.49(2H,dt, J=2.4,8.8Hz). FAB-MS m/z:233(M+H)+. |
With ammonia In water at 20℃; for 0.333333h; Cooling with ice; | ||
With ammonium hydroxide In water; ethyl acetate at 20℃; | ||
With ammonia In tetrahydrofuran at 25℃; | 31.2 Step 2: (4-Bromophenyl)-thiourea In a 500 mL round-bottomed flask, l-bromo-4-isothiocyanatobenzene (1.5 g, 7.01 mmol) was combined with 0.4M ammonia in THF (52.5 mL, 21.0 mmol, Eq: 3) to give a yellow solution. The reaction was stirred at 25 °C overnight. The crude reaction mixture was concentrated in vacuo to afford the desired product as a light brown solid. (M+H)+ = 230.9/233.0 (m/e). | |
With ammonium hydroxide In dichloromethane at 0℃; for 3h; | ||
With ammonium hydroxide In tetrahydrofuran at 20℃; for 0.833333h; | Synthesis of 1-(4-bromophenyl)-1H-tetrazol-5-amine (4) Intermediate 2 was dissolved in THF (20 mL) and 25% aqueous ammonia (7.1 mL) was added. The mixture was stirred at room temperature for 50 min and monitored by TLC. The reaction was terminated and the solvent was removed under reduced pressure to give a yellow solid 3. | |
With ammonia In tetrahydrofuran at 25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfur; triethylamine In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(i) H2, Raney-Ni, (ii) /BRN= 878549/; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With dmap In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With aluminium trichloride In nitromethane at 0 - 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | for 2h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In acetic acid for 16h; Reflux; | |
With acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.8% | In dichloromethane for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In ethanol for 3h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium ethanolate In 1,4-dioxane; ethanol for 44h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In 1,4-dioxane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With agar at 20℃; for 0.133333h; | |
89.5% | microwave irradiation; | |
88.7% | at 20℃; for 0.133333h; |
88% | In ethanol for 0.0833333h; Reflux; | 4.1.2. General procedure for the synthesis of 1-[(3-chlorophenyl)carbonyl]-4-substituted-thiosemicarbazides (1-11) General procedure: A solution of 0.01 mol of 3-chlorobenzoic acid hydrazide and equimolar amount of appropriate isothiocyanate in 25 ml of anhydrous EtOH was heated under reflux for 2 min (for compounds 2, 6, 8-10) or for 5 min (in the case of compounds 1, 3-5, 7, 11). Next, the solution was cooled and the solid formed was filtered off, washed with diethyl ether, dried, and crystallized from EtOH. |
85% | In ethanol for 0.0833333h; Reflux; | 3.1.1. General Procedure for the Synthesis of Thiosemicarbazide Derivatives (1-18) General procedure: A solution of 0.01 mol of 3-chlorobenzhydrazide or 4-chlorobenzhydrazide and equimolar amount of appropriate aryl isothiocyanate in 25 mL of anhydrous ethanol (EtOH) was heated under reflux for 5 min. Next, the solution was cooled and the solid formed was filtered off, washed with diethyl ether and crystallized from EtOH. Information on already known compounds may be retrieved in the Chemical Abstract Service database (CAS numbers are given below). |
In ethanol for 0.0833333h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium hydroxide In N,N-dimethyl-formamide at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In pyridine at 100℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Multistep reaction.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: rac-Ala-OH; 4-Bromophenyl isothiocyanate With sodium hydroxide microwave irradiation; Stage #2: With sodium hydrogen sulfate for 0.0333333h; microwave irradiation; | |
85% | Stage #1: rac-Ala-OH; 4-Bromophenyl isothiocyanate With potassium hydroxide In ethanol; water for 3h; Reflux; Stage #2: With hydrogenchloride In ethanol; water for 2h; Reflux; | 4.1.2 Synthesis of 3-(4-bromophenyl)-5-methyl-2-thioxoimidazolidin-4-one (3) To a solution of KOH (11mmol, 0.61 g) in water (50 mL) and ethanol (25 mL), D/L alanine 1 (0.89 g, 10mmol) was added and dissolved. Then 4-bromophenylisothiocyanate 2 (2.35 g, 11mmol) was added and the reaction mixture was heated under reflux for 3h, thereafter 10 ml conc. HCl was added and the reflux was continued for another 2h. The precipitated solid was filtered off, dried and recrystallized from ethanol to give the pure compound 3. Physical, analytical and spectral data are listed below. Yellowish solid; Yield, 85%; m.p. 208-210°C; IR (KBr) 3166 (NH), 3001 (CH aromatic), 2936, 2903, 2821 (CH aliphatic), 1753 (C=O), 1589, 1527 (C=C aromatic) cm-1; 1H NMR (CDCl3) δ 1.61 (d, 3H, J=7.2, CH3), 4.37 (q, 1H, J=7.2, -CH), 7.24 (d, 2H, J=8.4, phenyl H), 7.65 (d, 2H, J=8.4, phenyl H), 7.87 (s, 1H, NH, D2O exchangeable); 13C NMR (CDCl3) δ 17.03, 55.50, 123.40, 129.85, 131.54, 132.41, 173.72, 183.01; EIMS (m/z) (%) 284 (M+, 83.31%), 285.95 (M+2, 86.47%), 86 (100%).. Anal. Calcd for C10H9BrN2OS: C, 42.12; H, 3.18; N, 9.82. Found: C, 42.23; H, 3.16; N, 9.97. |
65% | Stage #1: rac-Ala-OH; 4-Bromophenyl isothiocyanate With triethylamine In 1,4-dioxane; water at 0℃; Stage #2: With hydrogenchloride In 1,4-dioxane; water at 0 - 50℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In pyridine at 45℃; for 3h; | 1.M Ethyl S-arnino-l-methyl-lH-imidazole^-carboxylate (3.50 g, 20.69 mmol) and 4- bromophenyl isothiocyanate (4.43 g, 20.69 mmol) are added to pyridine (12 mL). The solution is heated at 45 0C for 3 h.~ Most of the solvent is removed under vacuum and the resulting solid is dissolved in CH2Cl2 (300 mL). The CH2Cl2 solution is washed with water (30 mL x 2), brine (30 mL * 2), dried over MgSO4, and concentrated in vacuo. The resulting yellow solid is treated with 1 % NaOH aqueous solution (125 mL) and heated at 90 0C for 18 h. The reaction mixture is filtered and the filtrate adjusted pH to 3 by the addition of concentrated HCl. Most of the water is removed under reduced pressure. The resulting solid is collected by filtration, the solid is azeotroped with toluene (30 mL * 3) to give the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD) 8.10 (IH, s), 7.65 (2H, d), 7.14 (2H, d), 3.85 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | 2-Amino-4-(trifluoromethyl)phenol (250 mg, 1.41 mmol) and 1-bromo-4-isothio-cyanatobenzene (302 mg, 1.41 mmol) were stirred in ethyl alcohol at ambient temperature for 18 h. The flask was charged with 1-[3-(dimethylamino)propyl]-3-ethylcarhodiimide hydrochloride (EDCI) (405 mg, 2.12 mmol), and the mixture was stirred for 2 h before being heated at reflux overnight. The reaction was allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 2 N aqueous hydrochloric acid solution and water, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 85:15 hexanes/ethyl acetate to provide the title compound (315 mg, 62%). LC-MS m/z 357.1 (MH+), retention time 4.20 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 6-amino-2,4-xylenol; 4-Bromophenyl isothiocyanate In tetrahydrofuran at 20℃; for 3h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 40℃; for 16h; | 69.A EXAMPLE 69; N-[4-(4-amino-2-methylthieno[3,2-c]pyridin-3-yl)phenyl]-N'-(5,7-dimethyl-1.3-benzoxazol-2-yl)urea; EXAMPLE 69A; N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea A mixture of 1-bromo-4-isothiocyanatobenzene (63.92 g, 0.298 mol) and THF (1200 mL) was treated with 2-amino-4,6-dimethylphenol (41.8 g, 0.304 mol), stirred at room temperature for 3 hours, treated with EDCI (68.46 g, 0.358 mol), warmed to 40 C. for 16 hours, cooled to room temperature, and filtered. The filtrate was concentrated at 50 C. to a final volume of about 300 mL, treated with acetonitrile (800 mL), concentrated to a volume of about 200 mL, treated with acetonitrile (800 mL), and again concentrated to a volume of about 200 mL. The mixture was treated with acetonitrile (800 mL), cooled to room temperature, and filtered. The filter cake was washed with acetonitrile (100 mL) and dried to constant weight in a vacuum oven at 45 C. over 24 hours to provide 85.8 g (85%) of 5,7-dimethyl-1,3-benzoxazol-2-amine. A mixture of 5,7-dimethyl-1,3-benzoxazol-2-amine (76.4 g, 0.230 mol), 4,4,4?,4?,5,5,5?,5?-octamethyl-2,2?-bi-1,3,2-dioxaborolane (73.9 g, 0.292 mol), potassium acetate (71.5 g, 0.730 mol), and DMF (760 mL) was cycled three times through vacuum degassing and nitrogen purging, treated with Pd(dppf)Cl2.CH2Cl2 (19.9 g, 0.024 mol), sealed, cycled three times through vacuum degassing and N2 purging, heated to 80 C. for 5 hours, and distilled on high vacuum (0.2 mm Hg) at 40 C. to 80 C. to remove DMF. The residue was treated with CH2Cl2 (1300 mL), stirred for 10 minutes, and filtered. The filter cake was washed with CH2Cl2 (300 mL) and the filtrate was concentrated to a volume of about 800 mL. The solution was treated with SiO2 (509 g), stirred for 10 minutes, poured onto a bed of SiO2 (790 g) in a 4 L coarse glass fritted funnel. The SiO2 was washed with 16 L of 15% ethyl acetate and the solution was concentarated at 50 C. The concentrate was treated with heptane (800 mL), concentrated, treated with heptane (900 mL), stirred at 50 C. for 30 minutes, cooled to room temperature over 2 hours, and filtered. The filter cake was washed with 100 mL heptane and dried to constant weight in a vacuum oven at 45 C. over 24 hours to provide 68.3 g (77%) of the desired product. The final product was determined to be 98.2% potency (vs. analytical standard) by HPLC. Rt=6.5 min. HPLC conditions: Zorbax SB-c8 Rapid Resolution (4.6 mm?75 mm, 3.5 um); flow 1.5 mL/min; 5:95 to 95:5 acetonitrile:water (0.1% H3PO4) over 7 minutes. |
85% | Stage #1: 6-amino-2,4-xylenol; 4-Bromophenyl isothiocyanate In tetrahydrofuran at 20℃; for 3h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 40℃; for 16h; | 69.A 5,7-dimethyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine [0459] A mixture of 1-bromo-4-isothiocyanatobenzene (63.92 g, 0.298 mol) and THF (1200 mL) was treated with 2-amino-4,6-dimethylphenol (41.8 g, 0.304 mol), stirred at room temperature for 3 hours, treated with EDCI (68.46 g, 0.358 mol), warmed to 40° C. for 16 hours, cooled to room temperature, and filtered. The filtrate was concentrated at 50° C. to a final volume of about 300 mL, treated with acetonitrile (800 mL), concentrated to a volume of about 200 mL, treated with acetonitrile (800 mL), and again concentrated to a volume of about 200 mL. The mixture was treated with acetonitrile (800 mL), cooled to room temperature, and filtered. The filter cake was washed with acetonitrile (100 mL) and dried to constant weight in a vacuum oven at 45° C. over 24 hours to provide 85.8 g (85%) of 5,7-dimethyl-1,3-benzoxazol-2-amine. A mixture of 5,7-dimethyl-1,3-benzoxazol-2-amine (76.4 g, 0.230 mol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (73.9 g, 0.292 mol), potassium acetate (71.5 g, 0.730 mol), and DMF (760 mL) was cycled three times through vacuum degassing and nitrogen purging, treated with Pd(dppf)Cl2.CH2Cl2 (19.9 g, 0.024 mol), sealed, cycled three times through vacuum degassing and N2 purging, heated to 80° C. for 5 hours, and distilled on high vacuum (0.2 mm Hg) at 40° C. to 80° C. to remove DMF. The residue was treated with CH2Cl2 (1300 mL), stirred for 10 minutes, and filtered. The filter cake was washed with CH2Cl2 (300 mL) and the filtrate was concentrated to a volume of about 800 mL. The solution was treated with SiO2 (509 g), stirred for 10 minutes, poured onto a bed of SiO2 (790 g) in a 4 L coarse glass fritted funnel. The SiO2 was washed with 16 L of 15% ethyl acetate and the solution was concentarated at 50° C. The concentrate was treated with heptane (800 mL), concentrated, treated with heptane (900 mL), stirred at 50° C. for 30 minutes, cooled to room temperature over 2 hours, and filtered. The filter cake was washed with 100 mL heptane and dried to constant weight in a vacuum oven at 45° C. over 24 hours to provide 68.3 g (77%) of the desired product. The final product was determined to be 98.2% potency (vs. analytical standard) by HPLC. Rt=6.5 min. HPLC conditions: Zorbax SB-C8 Rapid Resolution (4.6 mm×75 mm, 3.5 um); flow 1.5 mL/min; 5:95 to 95:5 acetonitrile:water (0.1% H3PO4) over 7 minutes. |
85.8 g (85%) | In tetrahydrofuran; acetonitrile | 69.A N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea EXAMPLE 69A N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N'-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea A mixture of 1-bromo-4-isothiocyanatobenzene (63.92 g, 0.298 mol) and THF (1200 mL) was treated with 2-amino-4,6-dimethylphenol (41.8 g, 0.304 mol), stirred at room temperature for 3 hours, treated with EDCI (68.46 g, 0.358 mol), warmed to 40° C. for 16 hours, cooled to room temperature, and filtered. The filtrate was concentrated at 50° C. to a final volume of about 300 mL, treated with acetonitrile (800 mL), concentrated to a volume of about 200 mL, treated with acetonitrile (800 mL), and again concentrated to a volume of about 200 mL. The mixture was treated with acetonitrile (800 mL), cooled to room temperature, and filtered. The filter cake was washed with acetonitrile (100 mL) and dried to constant weight in a vacuum oven at 45° C. over 24 hours to provide 85.8 g (85%) of 5,7-dimethyl-1,3-benzoxazol-2-amine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine;copper(I) chloride; In methanol; acetonitrile; | B. 2-(4-bromoanilino)-1,3-benzoxazole-5-carbonitrile To a mixture of <strong>[14543-43-2]3-amino-4-hydroxybenzonitrile</strong> (1.84 g, 0.0137 mol) in acetonitrile (140 mL) was added 4-bromophenyl isothiocyanate (2.93 g, 0.0137 mol) at room temperature. The mixture was stirred for 16 hours at room temperature. Cuprous chloride (1.36 g, 0.0137 mol) and triethylamine (1.9 mL, 0.0137 mol) were added to the reaction mixture. The mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure, and the solid was suspended in methanol. The mixture was filtered through celite pad using methanol. The brownish filtrate was left at 4 for three days. The precipitate was filtered and washed with methanol to yield 2-(4-bromoanilino)-1,3-benzoxazole-5-carbonitrile (2.4 g, 0.0076 mol). RP-HPLC (Delta Pak C18, 5 mum, 300 A, 15 cm; 5%-95% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 11.1 min. MS: MH: 313 | |
With triethylamine;copper(l) chloride; In acetonitrile; at 20℃; for 32h; | [0974] To a mixture of <strong>[14543-43-2]3-amino-4-hydroxybenzonitrile</strong> (1.84 g, 0.0137 mol) in acetonitrile (140 mL) was added 4-bromophenyl isothiocyanate (2.93 g, 0.0137 mol) at room temperature. The mixture was stirred for 16 hours at room temperature. Cuprous chloride (1.36 g, 0.0137 mol) and triethylamine (1.9 mL, 0.0137 mol) were added to the reaction mixture. The mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure, and the solid was suspended in methanol. The mixture was filtered through celite pad using methanol. The brownish filtrate was left at 40 for three days. The precipitate was filtered and washed with methanol to yield 2-(4-bromoanilino)-1,3-benzoxazole-5-carbonitrile (2.4 g, 0.0076 mol). RP-HPLC (Delta Pak C18, 5 mum, 300A, 15 cm; 5%-95% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 11.1 min. MS: MH-: 313 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
140% | With triethylamine; In tetrahydrofuran; methanol; | EXAMPLE 1 N2-(4-Bromophenyl)-5-trifluoromethyl-1,3-benzoxazol-2-amine 4-Bromophenyl isothiocyanate (1.667 g, 7.785 mmol) was added to a solution of <strong>[454-81-9]2-amino-4-trifluoromethylphenol</strong> (1.379 g, 7.785 mmol) in tetrahydrofuran (THF) (100 mL) and the reaction was stirred at room temperature for about 16 hours then at about 50 C. for about another 5 hours. Copper (I) chloride (0.771 g, 7.785 mmol) and triethylamine (1.08 mL, 7.785 mmol) were added, and the mixture was stirred at room temperature for about 72 hours and then at about 50 C. for about another 18 hours. Additional copper (I) chloride (0.385 g) was added and the reaction was stirred at about 60 C. for about another 2 hours. The reaction was concentrated under reduced pressure, dissolved in methanol (200 mL), filtered through a pad of diatomaceous earth and the solvent removed in vacuo to afford N2-(4-bromophenyl)-5-trifluoromethyl-1,3-benzoxazol-2-amine as a brown solid (3.90 g, 140% of theory); RP-HPLC Rt 17.627 min, 77% purity (5% to 85% acetonitrile/0.1 M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; lambda=254 nm; Waters Deltapak C18, 300 A, 5 mum, 150*3.9 mm column); and m/z 354.9 and 356.9 (M-H)-. |
140% | With triethylamine; In tetrahydrofuran; methanol; | EXAMPLE 1 N2-(4-Bromophenyl)-5-trifluoromethyl-1,3-benzoxazol-2-amine 4-Bromophenyl isothiocyanate (1.667 g, 7.785 mmol) was added to a solution of <strong>[454-81-9]2-amino-4-trifluoromethylphenol</strong> (1.379 g, 7.785 mmol) in tetrahydrofuran (THF) (100 mL) and the reaction was stirred at room temperature for about 16 hours then at about 50 C. for about another 5 hours. Copper (I) chloride (0.771 g, 7.785 mmol) and triethylamine (1.08 mL, 7.785 mmol) were added, and the mixture was stirred at room temperature for about 72 hours and then at about 50 C. for about another 18 hours. Additional copper (I) chloride (0.385 g) was added and the reaction was stirred at about 60 C. for about another 2 hours. The reaction was concentrated under reduced pressure, dissolved in methanol (200 mL), filtered through a pad of diatomaceous earth and the solvent removed in vacuo to afford N2-(4-bromophenyl)-5-trifluoromethyl-1,3-benzoxazol-2-amine as a brown solid (3.90 g, 140% of theory); RP-HPLC Rt 17.627 min, 77% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; lambda=254 nm; Waters Deltapak C18, 300 A, 5 mum, 150*3.9 mm column); and m/z 354.9 and 356.9 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine In tetrahydrofuran | 4 N2-(4-Bromophenyl)-7-isopropyl-1,3-benzoxazol-2-amine EXAMPLE 4 N2-(4-Bromophenyl)-7-isopropyl-1,3-benzoxazol-2-amine 4-Bromophenyl isothiocyanate (0.50 g, 2.34 mmol) was added to a solution of 2-amino-6-isopropylphenol (0.354 g, 2.34 mmol) in tetrahydrofuran (35 mL) and the reaction was stirred at room temperature for about 3 hours. Anhydrous copper (II) sulfate (3.361 g, 21.06 mmol), silica gel (3.361 g), and triethylamine (0.33 mL, 2.34 mmol) were added, and the mixture was stirred at room temperature for about 18 hours. The reaction was filtered through a pad of diatomaceous earth, the diatomaceous earth was washed with diethyl ether (3*50 mL), and the combined filtrate was concentrated under reduced pressure and the resulting brown solid was purified by column chromatography through a silica pad using neat ethyl acetate as the eluent to afford N2-(4-bromophenyl)-7-isopropyl-1,3-benzoxazol-2-amine as a light brown solid (0.70 g, 91%); RP-HPLC Rt 18.066 min, 86% purity (5% to 85% acetonitrile/0.1 M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150*3.9 mm column); 1H NMR (400 MHz, d6-DMSO) 1.34 (6H, d, J 6.9 Hz), 3.25 (1H, hept, J 6.9 Hz), 7.02 (1H, d, J 7.3 Hz), 7.16 (1H, t, J 7.7 Hz), 7.29 (1H, dd, J 7.7 and 1.1 Hz), 7.55 (2H, dd, J 6.9 and 2.1 Hz), 7.74 (2H, dd, J 6.9 and 2.1 Hz) and 10.807 (1H, s). |
91% | With triethylamine In tetrahydrofuran | 4 N2-(4-Bromophenyl)-7-isopropyl-1,3-benzoxazol-2-amine EXAMPLE 4 N2-(4-Bromophenyl)-7-isopropyl-1,3-benzoxazol-2-amine 4-Bromophenyl isothiocyanate (0.50 g, 2.34 mmol) was added to a solution of 2-amino-6-isopropylphenol (0.354 g, 2.34 mmol) in tetrahydrofuran (35 mL) and the reaction was stirred at room temperature for about 3 hours. Anhydrous copper (II) sulfate (3.361 g, 21.06 mmol), silica gel (3.361 g), and triethylamine (0.33 mL, 2.34 mmol) were added, and the mixture was stirred at room temperature for about 18 hours. The reaction was filtered through a pad of diatomaceous earth, the diatomaceous earth was washed with diethyl ether (3*50 mL), and the combined filtrate was concentrated under reduced pressure and the resulting brown solid was purified by column chromatography through a silica pad using neat ethyl acetate as the eluent to afford N2-(4-bromophenyl)-7-isopropyl-1,3-benzoxazol-2-amine as a light brown solid (0.70 g, 91%); RP-HPLC Rt 18.066 min, 86% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150*3.9 mm column); 1H NMR (400 MHz, d6-DMSO) 1.34 (6H, d, J 6.9 Hz), 3.25 (1 H, hept, J 6.9 Hz), 7.02 (1H, d, J 7.3Hz), 7.16 (1H, t, J 7.7 Hz), 7.29 (1H, dd, J 7.7 and 1.1 Hz), 7.55 (2H, dd, J 6.9 and 2.1 Hz), 7.74 (2H, dd, J 6.9 and 2.1 Hz) and 10.807 (1H, s). |
91% | With triethylamine In tetrahydrofuran; ethyl acetate | B B. B. N2-(4-Bromophenyl)-7-isopropyl-1,3-benzoxazol-2-amine A solution of 2-amino-6-isopropylphenol (0.354 g, 2.34 mmol) and 4-bromophenylisothiocyanate (0.500 g, 2.34 mmol) in tetrahydrofuran (35 mL) was stirred at room temperature for 3 h. Anhydrous copper (II) sulfate (3.361 g, 21.06 mmol), silica gel (3.361 g), and triethylamine (0.236 g, 0.33 mL, 2.34 mmol) were added, and the mixture stirred at room temperature for 18 h. The reaction mixture was filtered through a pad of Celite and the washed with diethyl ether (3*50 mL). The filtrate was concentrated to afford a brown solid. The solid material was applied to silica gel and passed through a pad a silica gel along with ethyl acetate (3*50mL). The filtrate was concentrated to afford N2-(4-bromophenyl)-7-isopropyl-1,3-benzoxazol-2-amine (0.702 g, 91%). RP-HPLC Rt 18.066 min, 86% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; k 254 nm; Deltapak C18, 300 Å, 5 μm, 150*3.9 mm column); m/z 333 (MH+). |
91% | With triethylamine In tetrahydrofuran; ethyl acetate | B B. B. N2-(4-Bromophenyl)-7-isopropyl-1,3-benzoxazol-2-amine A solution of 2-amino-6-isopropylphenol (0.354 g, 2.34 mmol) and 4-bromophenylisothiocyanate (0.500 g, 2.34 mmol) in tetrahydrofuran (35 mL) was stirred at room temperature for 3 h. Anhydrous copper (II) sulfate (3.361 g, 21.06 mmol), silica gel (3.361 g), and triethylamine (0.236 g, 0.33 mL, 2.34 mmol) were added, and the mixture stirred at room temperature for 18 h. The reaction mixture was filtered through a pad of Celite and the washed with diethyl ether (3*50 mL). The filtrate was concentrated to afford a brown solid. The solid material was applied to silica gel and passed through a pad a silica gel along with ethyl acetate (3*50 mL). The filtrate was concentrated to afford N2-(4-bromophenyl)-7-isopropyl-1,3-benzoxazol-2-amine (0.702 g, 91%). RP-HPLC Rt 18.066 min, 86% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150*3.9 mm column); m/z 333 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With triethylamine; In methanol; n-heptane; dichloromethane; ethyl acetate; acetonitrile; | EXAMPLE 2 N2-(4-Bromophenyl)-5-methyl-1,3-benzoxazol-2-amine 4-Bromophenyl isothiocyanate (2.0 g, 9.34 mmol) was added to a solution of 2-amino-4-methylphenol (1.15 g, 9.34 mmol) in acetonitrile (100 mL) and the reaction was stirred at room temperature for about 16 hours. The formation of the intermediate N-(4-bromophenyl)-N'-(2-hydroxy-5-methylphenyl)thiourea was complete, as analyzed by RP-HPLC Rt 13.010 min, 98% purity (5% to 85% acetonitrile/0.1 M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; lambda=254 nm; Deltapak C18, 300 A, 5 mum, 150*3.9 mm column). <strong>[7758-89-6]Copper (I) chloride</strong> (0.925 g, 9.34 mmol) and triethylamine (1.29 mL, 9.34 mmol) were added, and the mixture was stirred at room temperature for about 6 days. The reaction was concentrated under reduced pressure, dissolved in methanol (200 mL), filtered through a pad of diatomaceous earth and the solvent removed in vacuo to afford a brown solid. The solid was dissolved in dichloromethane (200 mL), washed with water (2*200 mL), dried over anhydrous sodium sulfate and absorbed onto silica (10 mL). The product was purified by chromatography through a silica pad using 10% ethyl acetate in n-heptane as the eluent to afford N2-(4-bromophenyl)-5-methyl-1,3-benzoxazol-2-amine as a yellow solid (0.30 g, 11%); RP-HPLC Rt 16.451 min, 95% purity (5% to 85% acetonitrile/0.1 M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; lambda=254 nm; Deltapak C18, 300 A, 5 mum, 150*3.9 mm column); and m/z 302.9 and 304.9 (MH+). |
11% | With triethylamine; In methanol; n-heptane; dichloromethane; ethyl acetate; acetonitrile; | EXAMPLE 2 N2-(4-Bromophenyl)-5-methyl-1,3-benzoxazol-2-amine 4-Bromophenyl isothiocyanate (2.0 g, 9.34 mmol) was added to a solution of 2-amino-4-methylphenol (1.15 g, 9.34 mmol) in acetonitrile (100 mL) and the reaction was stirred at room temperature for about 16 hours. The formation of the intermediate N-(4-bromophenyl)-N'-(2-hydroxy-5-methylphenyl)thiourea was complete, as analyzed by RP-HPLC Rt 13.010 min, 98% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; lambda=254 nm; Deltapak C18, 300 A, 5 mum, 150*3.9 mm column). <strong>[7758-89-6]Copper (I) chloride</strong> (0.925 g, 9.34 mmol) and triethylamine (1.29 mL, 9.34 mmol) were added, and the mixture was stirred at room temperature for about 6 days. The reaction was concentrated under reduced pressure, dissolved in methanol (200 mL), filtered through a pad of diatomaceous earth and the solvent removed in vacuo to afford a brown solid. The solid was dissolved in dichloromethane (200 mL), washed with water (2*200 mL), dried over anhydrous sodium sulfate and absorbed onto silica (10 mL). The product was purified by chromatography through a silica pad using 10% ethyl acetate in n-heptane as the eluent to afford N2-(4-bromophenyl)-5-methyl-1,3-benzoxazol-2-amine as a yellow solid (0.30 g, 11%); RP-HPLC Rt 16.451 min, 95% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; lambda=254 nm; Deltapak C18, 300 A, 5 mum, 150*3.9 mm column); and m/z 302.9 and 304.9 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine In tetrahydrofuran; acetonitrile | 3 N2-(4-Bromophenyl)-5-methyl-1,3-benzoxazol-2-amine EXAMPLE 3 N2-(4-Bromophenyl)-5-methyl-1,3-benzoxazol-2-amine 4-Bromophenyl isothiocyanate (2.0 g, 9.34 mmol) was added to a solution of 2-amino-4-methylphenol (1.15 g, 9.34 mmol) in tetrahydrofuran (100 mL) and the reaction was stirred at room temperature for about 16 hours. The formation of the intermediate N-(4-bromophenyl)-N'-(2-hydroxy-5-methylphenyl)thiourea was complete, as analyzed by RP-HPLC Rt 12.973 min, 88% purity (5% to 85% acetonitrile/0.1 M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150*3.9 mm column). Anhydrous copper (II) sulfate (14.06 g, 88.10 mmol), silica gel (14.06 g), and triethylamine (1.3 mL, 9.34 mmol) were added, and the mixture was stirred at room temperature for about another 72 hours. The reaction was filtered through a pad of diatomaceous earth washed with diethyl ether (3*100 mL) and the combined filtrate was concentrated under reduced pressure to afford N2-(4-bromophenyl)-5-methyl-1,3-benzoxazol-2-amine as a brown solid (2.70 g, 95%); RP-HPLC Rt 16.433 min, 99% purity (5% to 85% acetonitrile/0.1 M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150*3.9 mm column); and 1H NMR (400 MHz, d6-DMSO) 2.37 (3H, s), 6.94 (1H, d, J 8.1 Hz), 7.27 (1H, s), 7.36 (1H, d, J 8.1 Hz), 7.54 (2H, d, J 8.4 Hz), 7.72 (2H, d, J (8.4 Hz), and 10.72 (1H, s). |
95% | With triethylamine In tetrahydrofuran; acetonitrile | 3 N2-(4-Bromophenyl)-5-methyl-1,3-benzoxazol-2-amine EXAMPLE 3 N2-(4-Bromophenyl)-5-methyl-1,3-benzoxazol-2-amine 4-Bromophenyl isothiocyanate (2.0 g, 9.34 mmol) was added to a solution of 2-amino-4-methylphenol (1.15 g, 9.34 mmol) in tetrahydrofuran (100 mL) and the reaction was stirred at room temperature for about 16 hours. The formation of the intermediate N-(4-bromophenyl)-N'-(2-hydroxy-5-methylphenyl)thiourea was complete, as analyzed by RP-HPLC Rt 12.973 min, 88% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150*3.9 mm column). Anhydrous copper (II) sulfate (14.06 g, 88.10 mmol), silica gel (14.06 g), and triethylamine (1.3 mL, 9.34 mmol) were added, and the mixture was stirred at room temperature for about another 72 hours. The reaction was filtered through a pad of diatomaceous earth washed with diethyl ether (3*100 mL) and the combined filtrate was concentrated under reduced pressure to afford N2-(4-bromophenyl)-5-methyl-1,3-benzoxazol-2-amine as a brown solid (2.70 g, 95%); RP-HPLC Rt 16.433 min, 99% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150*3.9 mm column); and 1H NMR (400 MHz, d6-DMSO) 2.37 (3H, s), 6.94 (1H, d, J 8.1 Hz), 7.27 (1H, s), 7.36 (1H, d, J 8.1 Hz), 7.54 (2H, d, J 8.4 Hz), 7.72 (2H, d, J 8.4 Hz), and 10.72 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In methanol; acetonitrile; | EXAMPLE 5 N2-(4-Bromophenyl)-5-cyano-1,3-benzoxazol-2-amine 4-Bromophenyl isothiocyanate (2.93 g, 0.0137 mol) was added to a solution of <strong>[14543-43-2]3-amino-4-hydroxybenzonitrile</strong> (1.84 g, 0.0137 mol) in acetonitrile (140 mL) at room temperature. The mixture was stirred for about 16 hours prior to the addition of copper (I) chloride (1.36 g, 0.0137 mol) and triethylamine (1.9 mL, 0.0137 mol). The mixture was stirred for about another 16 hours and the solvent was removed under reduced pressure. The solid was dissolved in methanol (100 mL), filtered through a pad of diatomaceous earth, and washed with additional methanol (2*50 mL). The brownish filtrate was left to stand at about 4 C. for about 3 days and the resulting precipitate was collected by filtration to afford N2-(4-bromophenyl)-5-cyano-1,3-benzoxazol-2-amine (2.4 g, 0.0076 mol, 55%); RP-HPLC Rt 11.1 min, 92% purity (Delta Pak C18, 5 mum, 300 A, 15 cm; 5%-95% acetonitrile-0.1 M ammonium acetate over 10 min, 1 mL/min); and 1H NMR (400 MHz, d6-DMSO) 7.59 (3H, m), 7.72 (3H, m), 7.97 (1H, s), and 11.12 (1H, s). | |
With triethylamine; In methanol; acetonitrile; | EXAMPLE 5 N2-(4-Bromophenyl)-5-cyano-1,3-benzoxazol-2-amine 4-Bromophenyl isothiocyanate (2.93 g, 0.0137 mol) was added to a solution of <strong>[14543-43-2]3-amino-4-hydroxybenzonitrile</strong> (1.84 g, 0.0137 mol) in acetonitrile (140 mL) at room temperature. The mixture was stirred for about 16 hours prior to the addition of copper (I) chloride (1.36 g, 0.0137 mol) and triethylamine (1.9 mL, 0.0137 mol). The mixture was stirred for about another 16 hours and the solvent was removed under reduced pressure. The solid was dissolved in methanol (100 mL), filtered through a pad of diatomaceous earth, and washed with additional methanol (2*50 mL). The brownish filtrate was left to stand at about 4 C. for about 3 days and the resulting precipitate was collected by filtration to afford N2-(4-bromophenyl)-5-cyano-1,3-benzoxazol-2-amine (2.4 g, 0.0076 mol, 55%); RP-HPLC Rt 11.1 min, 92% purity (Delta Pak C18, 5 mum, 300 A, 15 cm; 5%-95% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min); and 1H NMR (400 MHz, d6-DMSO) 7.59 (3H, m), 7.72 (3H, m), 7.97 (1H, s), and 11.12 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; n-heptane; ethyl acetate; | EXAMPLE 6 N2-(4-Bromophenyl)-5-(trifluoromethoxy)-1,3-benzoxazol-2-amine 4-Bromophenyl isothiocyanate (1.00 g, 0.0047 mol) was added to a solution of <strong>[461699-34-3]2-amino-4-(trifluoromethoxy)phenol</strong> (0.90 g, 0.0047 mol) in tetrahydrofuran (60 mL) at room temperature. The mixture was stirred for about 16 hours prior to the addition of anhydrous copper (II) sulfate (7.10 g, 0.0443 mol), triethylamine (0.67 mL, 0.0047 mol) and silica gel (8.50 g). The mixture was stirred for about another 4 hours and the solvent was then removed under reduced pressure. The residue was purified by column chromatography through a silica pad using 25% ethyl acetate in n-heptane as the eluent. The resulting orange solid was further purified by chromatography over silica gel; using a 0% to 25% ethyl acetate in n-heptane gradient as the eluent. The solid was triturated with n-heptane to give N2-(4-bromophenyl)-5-(trifluoromethoxy)-1,3-benzoxazol-2-amine (0.90 g, 0.0024 mol, 51%); RP-HPLC Rt 12.2 min, 99% purity (DeltaPak C18, 5 mum, 300 A, 15 cm; 5%-95% acetonitrile-0.1 M ammonium acetate over 10 min, 1 mL/min); and m/z 373 and 375 (MH+). | |
With triethylamine; In tetrahydrofuran; n-heptane; ethyl acetate; | EXAMPLE 6 N2-(4-Bromophenyl)-5-(trifluoromethoxy)-1,3-benzoxazol-2-amine 4-Bromophenyl isothiocyanate (1.00 g, 0.0047 mol) was added to a solution of <strong>[461699-34-3]2-amino-4-(trifluoromethoxy)phenol</strong> (0.90 g, 0.0047 mol) in tetrahydrofuran (60 mL) at room temperature. The mixture was stirred for about 16 hours prior to the addition of anhydrous copper (II) sulfate (7.10 g, 0.0443 mol), triethylamine (0.67 mL, 0.0047 mol) and silica gel (8.50 g). The mixture was stirred for about another 4 hours and the solvent was then removed under reduced pressure. The residue was purified by column chromatography through a silica pad using 25% ethyl acetate in n-heptane as the eluent. The resulting orange solid was further purified by chromatography over silica gel; using a 0% to 25% ethyl acetate in n-heptane gradient as the eluent. The solid was triturated with n-heptane to give N2-(4-bromophenyl)-5-(trifluoromethoxy)-1,3-benzoxazol-2-amine (0.90 g, 0.0024 mol, 51%); RP-HPLC Rt 12.2 min, 99% purity (DeltaPak C18, 5 mum, 300 A, 15 cm; 5%-95% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min); and m/z 373 and 375 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine In tetrahydrofuran | 8 N2-(4-Bromophenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine EXAMPLE 8 N2-(4-Bromophenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine 2-Amino-4,6-dimethylphenol (0.214 g, 1.00 mmol) was added to a solution of 4-bromophenyl isothiocyanate (0.137 g, 1.00 mmol) in tetrahydrofuran (15 mL) and the reaction was stirred at room temperature for about 12 hours. Anhydrous copper (II) sulfate (1.50 g, 9.43 mmol), silica gel (1.50 g), and triethylamine (0.14 mL, 1.00 mmol) were added, and the mixture was stirred at room temperature for about another 16 hours. The reaction was filtered through a pad of diatomaceous earth, washed with additional tetrahydrofuran (2*20 mL), and the combined filtrate was concentrated under reduced pressure to afford N2-(4-bromophenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine as a brown pink solid (0.30 g, 90%); RP-HPLC Rt 17.395 min, 95% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150*3.9 mm column); 1H NMR (400 MHz, d6-DMSO) 2.33 (3H, s), 2.38 (3H, s), 6.79 (1H, s), 7.09 (1H, s), 7.54 (2H, dd, J 11.7 and 2.9 Hz), 7.72 (2H, dd, J 11.7 and 2.9 Hz) and 10.77 (1H, s). |
89% | With triethylamine In tetrahydrofuran | 8.9 EXAMPLE 8.9 EXAMPLE 8.9 2-Amino-4,6-dimethylphenol (0.160 g, 1.17 mmol) anhydrous copper (II) sulfate (0.21 g, 1.29 mmol) and triethylamine (0.164 mL, 1.17 mmol) were added to a solution of 4-bromophenyl isothiocyanate (0.250 g, 1.17 mmol), in tetrahydrofuran (20 mL) and the reaction was stirred at room temperature for about 24 hours. The reaction was filtered through a pad of diatomaceous earth, washed with ethyl acetate (2*20 mL), and the combined filtrate was concentrated under reduced pressure to afford N2-(4-bromophenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine as a brown pink solid (0.33 g, 89%); RP-HPLC Rt 17.294 min, 93% purity (5% to 85% acetonitrile/0.1 M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150*3.9 mm column). |
89% | With triethylamine In tetrahydrofuran | 8.9 EXAMPLE 8.9. EXAMPLE 8.9. 2-Amino-4,6-dimethylphenol (0.160 g, 1.17 mmol) anhydrous copper (II) sulfate (0.21 g, 1.29 mmol) and triethylamine (0.164 mL, 1.17 mmol) were added to a solution of 4-bromophenyl isothiocyanate (0.250 g, 1.17 mmol), in tetrahydrofuran (20 mL) and the reaction was stirred at room temperature for about 24 hours. The reaction was filtered through a pad of diatomaceous earth, washed with ethyl acetate (2*20 mL), and the combined filtrate was concentrated under reduced pressure to afford N2-(4-bromophenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine as a brown pink solid (0.33 g, 89%); RP-HPLC Rt 17.294 min, 93% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150*3.9 mm column). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With triethylamine In tetrahydrofuran; n-heptane; ethyl acetate | C C. C. N2-(4-bromophenyl)-5-methyl-1,3-benzoxazol-2-amine 2-Amino-4-methylphenol (1.15 g, 9.34 mmol) was added to a solution of 4-bromophenyl isothiocyanate (2.00 g, 9.34 mmol) in tetrahydrofuran (35 mL) and the reaction was stirred at room temperature for 16 h. Anhydrous copper (II) sulfate (14.06 g, 88.10 mmol), silica gel (14.06 g), and triethylamine (1.3 mL, 9.34 mmol) were added, and the mixture was stirred at room temperature for 24 h. The reaction was concentrated under reduced pressure and then added to a silica pad and purified using 1:5 ethyl acetate:heptane (2 L) followed by diethyl ether as the eluent to afford N2-(4-bromophenyl)-5-methyl-1,3-benzoxazol-2-amine as a light brown solid (2.30 g, 81%); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine;copper(I) chloride; In methanol; acetonitrile; | B. 2-(4-bromoanilino)-1,3-benzoxazole-5-carbonitrile To a mixture of <strong>[14543-43-2]3-amino-4-hydroxybenzonitrile</strong> (1.84 g, 0.0137 mol) in acetonitrile (140 mL) was added 4-bromophenyl isothiocyanate (2.93 g, 0.0137 mol) at room temperature. The mixture was stirred for 16 hours at room temperature. Cuprous chloride (1.36 g, 0.0137 mol) and triethylamine (1.9 mL, 0.0137 mol) were added to the reaction mixture. The mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure, and the solid was suspended in methanol. The mixture was filtered through celite pad using methanol. The brownish filtrate was left at 4 for three days. The precipitate was filtered and washed with methanol to yield 2-(4-bromoanilino)-1,3-benzoxazole-5-carbonitrile (2.4 g, 0.0076 mol). RP-HPLC (Delta Pak C18, 5 mum, 300 A, 15 cm; 5%-95% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 11.1 min. MS: MIT: 313 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; n-heptane; ethyl acetate; | C. N2-(4-bromophenyl)-5-(trifluoromethoxy)-1,3-benzoxazol-2-amine To a mixture of <strong>[461699-34-3]2-amino-4-(trifluoromethoxy)phenol</strong> (0.9 g, 0.0047 mol) in tetrahydrofuran (60 mL) was added 4-bromophenyl isothiocyanate (1 g, 0.0047 mol) at room temperature. The mixture was stirred for 16 hours at room temperature. Anhydrous copper sulfate (7.1 g, 0.0443mol, 9.43 eq.), triethylamine (0.67 mL, 0.0047 mol, 1 eq.), and silica gel (8.5 g) were added to the reaction mixture. The mixture was stirred for 4 hours at room temperature. The solvent was removed under reduced pressure. The mixture was filtered through silica gel pad using 25% ethyl acetate/n-heptane as a mobile phase to give orange colored solid. The solid was purified by flash column chromatography on silica using 0%-25% ethyl acetate/n-heptane as a mobile phase. The solvent was removed, and the residue was triturated with n-heptane to give N2-(4-bromophenyl)-5-(trifluoromethoxy)-1,3-benzoxazol-2-amine (0.9 g, 0.0024 mol). RP-HPLC (Delta Pak C18, 5 mum, 300 A, 15 cm; 5%-95% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 12.2 min. MS: MH+: 373 | |
With triethylamine; In tetrahydrofuran; n-heptane; ethyl acetate; | C. N2-(4-bromophenyl)-5-(trifluoromethoxy)-1,3-benzoxazol-2-amine To a mixture of <strong>[461699-34-3]2-amino-4-(trifluoromethoxy)phenol</strong> (0.9 g, 0.0047 mol) in tetrahydrofuran (60 mL) was added 4-bromophenyl isothiocyanate (1 g, 0.0047 mol) at room temperature. The mixture was stirred for 16 hours at room temperature. Anhydrous copper sulfate (7.1 g, 0.0443 mol, 9.43 eq.), triethylamine (0.67 mL, 0.0047 mol, 1 eq.), and silica gel (8.5 g) were added to the reaction mixture. The mixture was stirred for 4 hours at room temperature. The solvent was removed under reduced pressure. The mixture was filtered through silica gel pad using 25% ethyl acetate/n-heptane as a mobile phase to give orange colored solid. The solid was purified by flash column chromatography on silica using 0%-25% ethyl acetate/n-heptane as a mobile phase. The solvent was removed, and the residue was triturated with n-heptane to give N2-(4-bromophenyl)-5-(trifluoromethoxy)-1,3-benzoxazol-2-amine (0.9 g, 0.0024 mol). RP-HPLC (Delta Pak C18, 5 mum, 300 A, 15 cm; 5%-95% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 12.2 min. MS: MH+: 373. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
An ambient solution of <strong>[17672-22-9]2-amino-6-methylphenol</strong> (0.74 g, 6.0 mmol) and A- bromophenyl isothiocyanate (1.28 g, 6.0 mmol) in tetrahydrofuran (20 mL) was stirred for 16 h. The reaction was cooled (0 0C), and LiOHH2O (0.521 g, 12.41 mmol) was added, followed by the dropwise addition of 30percent H2O2 (3.41 mL, 31.0 mmol) over 15 minutes. The reaction was warmed to room temperature and stirred for 16h. The reaction was then quenched by the addition of 20percent aqueous sodium sulfite solution (50 mL) and ethyl acetate <n="47"/>(75 niL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2 x 75 mL). The combined organics were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 25percent ethyl acetate in hexane, to give the title compound. MS (ESI) m/z 303 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol for 4h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | In diethyl ether; at 20℃; for 24.0h; | General procedure: A mixture of 4-pyridine acetic acid hydrazide (0.01 mol) and appropriate isothiocyanate (0.01 mol) in anhydrous diethyl ether (10 mL) was kept at room temperature for 24 h. The product was filtered off and crystallized from ethanol. (Supplementary Material includes experimental data of all compounds). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With lithium perchlorate; triethylamine In acetonitrile for 2.5h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
for 1h;Inert atmosphere; Heating; | General experimental procedure: o-iodoaniline (1.0 mmol) and phenyl isothiocyanate (1.2 mmol) was mixtured and stirred for 1 h at room temperature (Method A), or o-iodoaniline (1.0 mmol) and phenyl isothiocyanate (1.2 equiv) was mixtured and stirred for 1 h at melting point temperature of phenyl isothiocyanate (Method B), or o-halobenzothioureas (1.0 mmol) (Method C), then anhydrous DMSO (5 ml) and base (3.0 mmol) was added, the stirring continued for about 5-10 h at 130 C (TLC monitor). After the reaction was completed, the reaction mixture was cooled to room temperature and ice-water was added, then the mixture was extracted with EtOAc. The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum and then the residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate (5:1 to 7:1)) on silica gel to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.2% | Preparation of intermediate 3A:N-(4-bromophenyl)-4-fluorobenzothiazol-2-ylamine<strong>[65896-11-9]2-Bromo-6-fluoroaniline</strong> (500 mg, 2.63 mmol) and potassium carbonate (5726 mg, 5.26 mmol) were placed in a flask, to which was added 10 mL of DMSO. l-Bromo-4-thiocyanato-benzene (845 mg, 3.95 mmol) was added under nitrogen protection and resulting mixture was stirred at room temperature for 30 min. Cuprous iodide (50 mg, 0.263 mmol) was added and then heated to 120 C under nitrogen protection, and reacted overnight. The mixture was cooled to room temperature, poured into water to give a precipitate, which was filtered to give 383 mg of compound 3 A, which was used directly in the next step without further purification. Yield: 45.2%.MS (ESI, m/z): [M+H]+: 324.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | Stage #1: 5,6-dihydro-<6H>-cyclopenta-<b>-thiophene-4-one; 4-Bromophenyl isothiocyanate With lithium hexamethyldisilazane In tetrahydrofuran at 20℃; for 8h; Stage #2: With hydrazine hydrate; acetic acid In tetrahydrofuran for 24h; Reflux; | 20 Example 20 (4-bromophenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)amine A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-Bromo-4-isothiocyanato-benzene (1.5 g, 7.2 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (4-Bromo-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine as brown solid in 32% yield. [0229] MS (ESI) m/z: 332.0 (M+H)+. 1H NMR (CDCl3): 7.36-7.32 (m, 3H), 7.19 (d, 1H), 6.89 (d, 2H), 3.46 (s, 2H). |
32% | Stage #1: 5,6-dihydro-<6H>-cyclopenta-<b>-thiophene-4-one; 4-Bromophenyl isothiocyanate With lithium hexamethyldisilazane In tetrahydrofuran at 20℃; for 8h; Stage #2: With hydrazine hydrate; acetic acid In tetrahydrofuran; water for 24h; Reflux; | 20 Example 20(4-bromo-phenyl) - (4,7-dihydro-1-thia-4,5-diazo-cyclopentadienyl [a] cyclopentan-6-yl) amine 5,6-dihydro-cyclopenta [b] thiophen-4-one (1.0 g, 7.4 mmol) in THF (2.0 mL) and 1-bromo-4-isothiocyanato-benzene 1.5 g, 7.2 mmol) was added dropwise at room temperature to a solution of lithium hexamethyldisilane (7.0 mL, 7.2 mmol). The reaction mixture was stirred for 8 hours. Aqueous monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture and heated at reflux temperature for 24 hours. The product mixture was added to water (30 mL) and extracted with ethyl acetate. Purification by gravity column chromatography (50% EtOAc in hexanes) afforded the title product as a brown solid (4-bromo-phenyl) - (4,7-dihydro-1, Cyclopentadiene [a] cyclopentan-6-yl) -amine in 32% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In ethanol for 0.5h; Reflux; | General procedure for the synthesis of 2-(imidazo[1,2-a]pyridin-2-ylcarbonyl)-N-substitutedhydrazinecarbothioamide (4a-j) General procedure: First 0.075 mol of 3, 0.075 mol of appropriate alkyl/aryl isothiocyanate, and 40 mL of absolute ethanol werereuxed 30 min. The solid formed was ltered and recrystallized from ethanol (96%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With pyridine for 0.5h; Reflux; | 4.1.6. General method for the preparation of compounds 7a-d General procedure: An equimolar mixture (0.01 mol) of 4-amino-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol (2) and the appropriate aryl isothiocyanate was heated under reflux in pyridine (10 mL) for 30 min. The reaction mixture was poured onto ice cold water. The obtained solid was filtered, washed with water, dried and crystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With pyridine Reflux; | 4.1.6. General method for the preparation of compounds 8a-d General procedure: An equimolar mixture (0.01 mol) of 4-amino-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol (2) and the appropriate aryl isothiocyanate was heated under reflux in pyridine (10 mL) for 2-3 h until the complete evolution of H2S (detected by lead acetate paper). The reaction mixture was poured onto ice cold water. The obtained solid was filtered, washed with water, dried and crystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With caesium carbonate; In toluene; at 110.0℃; for 12h; | General procedure: A mixture of the oxime acetate (0.5 mmol), the isothiocyanate (0.5 mmol), Cs2CO3(0.25 mmol), toluene (3 mL) and the MCM-41-2NCuI complex (222 mg, 20 mol%) was stirred at 110 C in air for 12 h. The reaction mixture was cooled to room temperature and quenched with H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The MCM-41-2N-CuI catalyst was recovered by filtration, washed with distilled water (2 × 5 mL), DMF (2 × 5 mL) and EtOH (2 × 5 mL) and could be reused in the next run. The combined organic layers were dried over MgSO4and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (hexane/ethyl acetate) on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol;Reflux; Inert atmosphere; | General procedure: To the stirred solution of compound 1 (0.22 g, 2 mmol) in 3 mL absolute ethanol, 2 mmol of aryl isothiocyanate was added and refluxed for 13-16 h under the atmosphere of nitrogen. The solvent was removed by rotary evaporation and the crude product was washed with cold ethanol, dried, and recrystallized from ethanol to afford compounds 2a-i. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | To a solution of 1-acetylpiperidin-4-one (15.0 g, 106.3 mmol) in anhydrous THF (100 mE)was added 1-BuOK (14.3 g, 127.5 rnmol) portionwise. The mixture was allowed to stir for 3 hbefore a solution of 1-bromo-4-isothiocyanatobenzene (27.3 g, 127.5 mmol) in aithydrousTHF (100 mL) was added dropwise at 40 C. The mixture stirred for an additional 2 h at this temperature. Then Mel (45.3 g, 318.8 mmol) was added dropwise and the reaction was stirred for another I h. After cooling to room temperature, the mixture was poured into water (200 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gelchromatography (petroleum ether/EtOAc = 1/1) to afford the title compound (24.3 g, 62%) as a yellow solid. LCMS MJZ (M+H) 371 (Br85. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With triethylamine In ethanol for 3h; Reflux; | 8 General experimental procedure for the syntheses of thiazolederivatives 1-24 General procedure: Benzohydrazide derivative/phenyl hydrazine/benzophenonehydrazone (1 mmol), phenyl isothiocyanate derivative (1 mmol)were taken in ethanol (10 mL) into a 100 mL round-bottomed flaskand refluxed for half an hour. Than phenacyl bromide derivatives(1 mmol) and trimethylamine (1 mmol) were added into abovemixture and further refluxed for 3 h. TLC was taken in order tocheck the reaction progress. Precipitates were formed which werefiltered and washed with cold ethanol (10 mL) to afford pure productsin high yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine In ethanol for 3h; Reflux; | 6 General experimental procedure for the syntheses of thiazolederivatives 1-24 General procedure: Benzohydrazide derivative/phenyl hydrazine/benzophenonehydrazone (1 mmol), phenyl isothiocyanate derivative (1 mmol)were taken in ethanol (10 mL) into a 100 mL round-bottomed flaskand refluxed for half an hour. Than phenacyl bromide derivatives(1 mmol) and trimethylamine (1 mmol) were added into abovemixture and further refluxed for 3 h. TLC was taken in order tocheck the reaction progress. Precipitates were formed which werefiltered and washed with cold ethanol (10 mL) to afford pure productsin high yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine In ethanol for 3h; Reflux; | 7 General experimental procedure for the syntheses of thiazolederivatives 1-24 General procedure: Benzohydrazide derivative/phenyl hydrazine/benzophenonehydrazone (1 mmol), phenyl isothiocyanate derivative (1 mmol)were taken in ethanol (10 mL) into a 100 mL round-bottomed flaskand refluxed for half an hour. Than phenacyl bromide derivatives(1 mmol) and trimethylamine (1 mmol) were added into abovemixture and further refluxed for 3 h. TLC was taken in order tocheck the reaction progress. Precipitates were formed which werefiltered and washed with cold ethanol (10 mL) to afford pure productsin high yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine In acetone Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In acetonitrile for 6h; Reflux; | 3.1.2. General Procedure for the Preparation of Palmitic Acid Thiosemicarbazide (1-10) General procedure: Palmitohydrazide (A 0.01 mol, 2.7 g) and 0.01 mol of appropriate isothiocyanate were refluxedin acetonitrile for 6 h. The product was filtered and dried. The solid residue was purified by columnchromatography (chloroform:methanol 9.5:0.5 vol.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetone; at 20 - 80℃; for 6.5h; | General procedure: Compounds 10-14 were reported in the previous study.[20] Compound 15-23 were synthesized and characterized for thefirst time in this study according to the following method. <strong>[144-82-1]Sulfamethizole</strong>(0.00105 mol) was solved in acetone, at 80C. Then,a solution of the suitable isothiocyanate (0.00105 mol) in dryacetone was added to two parts, over 30 min. After 6 h the reactionwas finalized by TLC control and left overnight. The precipitatewas filtered off, dried and purified with ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.4% | With triethylamine; In toluene; at 75 - 80℃; for 5h; | General procedure: To the stirred reaction mixture of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo-[4,3-a]pyrazine hydrochloride(11) (300 mg, 1.32 mmol), TEA (0.55 mL, 3.95 mmol)and toluene (10 mL), substituted cyanates 12(a-e)/isocyanates12(f-j) (1.32 mmol) were added at ambient temperature.The reaction mass was agitated at 75-80 C until thecompletion of the reaction that was monitored by TLC. Thereaction mass was allowed to cool at ambient temperatureand it was washed sequentially with 3% aqueous HCl(5.0 mL) and then water (5.0 mL). The organic fraction wasconcentrated under vacuum at 50-55 C to obtain crudeproduct. It was purified by column chromatography using10-50% of EtOAc:hexane mixture as a mobile phase. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In acetonitrile at 20℃; for 12h; | 2.1.2. General procedure for the synthesis of 3-(4-methoxyphenyl)thiourea derivatives (1-9) General procedure: A solution of commercially available (4-methoxyphenyl)aniline (0.003 mol, 0.40 g) in anhydrous acetonitrile (6 ml) was treated with a corresponding isothiocyanate (0.003 mol). The mixture was stirred at room temperature for 12 h. After that, the solvent was evaporated. The solid residue was crystallized from acetonitrile or purified by column chromatography (chloroform: methanol;9.5:0.5 vol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol Reflux; | 3.1.1. General Procedure for Synthesis of the Thiosemicarbazides General procedure: A solution of appropriate fluorobenzoic hydrazide (0.01 mol) and an equimolaramount of aryl or alkyl isothiocyanate (0.01 mol) in anhydrous ethanol (25 mL) washeated under reflux for 10-40 min. After cooling, the solid formed was filtered off, dried,and crystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With methyllithium lithium bromide In tetrahydrofuran; diethyl ether at -78℃; for 0.0833333h; Inert atmosphere; Schlenk technique; |
Tags: 1985-12-2 synthesis path| 1985-12-2 SDS| 1985-12-2 COA| 1985-12-2 purity| 1985-12-2 application| 1985-12-2 NMR| 1985-12-2 COA| 1985-12-2 structure
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