* 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.
With ytterbium(III) triflate In 1,3,5-trimethyl-benzene at 165℃; for 6 h; Inert atmosphere
General procedure: A mixture of 2-aminobenzamide (1, 4.0 mmol), carboxamide (2, 6.0 mmol), Yb(OTf)3 (0.20 mmol,5.0 molpercent), and mesitylene (5.0 mL) was placed in a 20-mL Pyrex flask equipped with a magnetic stirring bar and a reflux condenser under a flow of argon. The reaction was carried out at 120-165 oC (bath temp.) for 6 h with stirring. Then, the reaction mixture was cooled to room temperature, and analyzed by GLC, GC-MS (EI), and LC-MS (ESI). After evaporation of mesitylene under vacuum,the products (3) were isolated by recrystallization from MeOH/hexane and/or medium pressure column chromatography on silica gel (eluent: EtOAc/hexane = 50/50 ~ EtOAc 100percent. For 3j, eluent:MeOH/CHCl3 = 50/50). 1H NMR spectra were recorded at 400 MHz, and 13C NMR spectra wererecorded at 100 MHz in DMSO-d6. The analytical and spectral data of 3a-e,38 3f,39 3g,40 3h,41 and3j,42 were consistent with those reported previously. The product, 3i, was characterized below.
2-amino-4-mthylbenzamide (4.93 g, 32.8 mmol) obtained in above was added with formic acid (30 mL, 787.9 mmol), followed by stirring for 6 hours at 100°C. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and washed with water. The filtered solid was dried with warm wind in an oven (40°C) for 6 hours or more to obtain the title compound (4.79 g, 91percent). 1H-NMR Spectrum (300 MHz, DMSO-rftf): δ 8.06 (s, 1H), 8.00 (d, 1H), 7.47 (s, 1H), 7.34 (d, 1H), 2.45 (s, 3H) MS(ESI+, m/z): 161 [M+H]+
91%
at 100℃; for 6 h;
2-amino-4-methylbenzamide (4.93 g, 32.8 mmol) obtained in <Step 1> above was added with formic acid (30 mL, 787.9 mmol), followed by stirring for 6 hours at 100° C. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and washed with water. The filtered solid was dried with warm wind in an oven (40° C.) for 6 hours or more to obtain the title compound (4.79 g, 91percent). 1H-NMR Spectrum (300 MHz, DMSO-d6): δ 8.06 (s, 1H), 8.00 (d, 1H), 7.47 (s, 1H), 7.34 (d, 1H), 2.45 (s, 3H) MS (ESI+, m/z): 161 [M+H]+
84%
at 100℃; for 6 h;
A mixture of 2-amino-4-methylbenzamide (20 g, 133 mmol) and formic acid (120 ml, 3129 mmol) was heated to 100 0C for 6 h. The reaction was cooled to RT and the volatiles were removed under reduced pressure. The residue was then washed carefully with aqueous saturated sodium bicarbonate and then with water. The tan solid was then dried in a vacuum oven at 45 0C overnight to give 7-methylquinazolin-4(3H)-one (18.00 g, 84percent yield). MS (ESI, pos. ion) m/z: 161 [M+H]+
at 130℃; for 2 h; Inert atmosphere; Microwave irradiation
2-amino-4-methylbenzamide (75 mg, 0.5 mmol), [Cp * Ir (2,2'-bpyO) (H2O)](5.4 mg, 0.005 mmol, 1 molpercent),Cesium carbonate (49 mg, 0.15 mmol, 0.3 equiv.) And methanol (0.5 ml) were sequentially added to a dried 5 mL microwave reaction tube.The tube was nitrogen protected and placed in a single mode pressure microwave synthesizer (Discover CEM, USA). After the reaction mixture was reacted at 130 ° C for 2 hours, it was cooled to room temperature. Rotary evaporation to remove the solvent,Then, column chromatography (developing solvent: petroleum ether / ethyl acetate)The pure target compound was obtained in a yield of 87percent
Reference:
[1] Organic Letters, 2016, vol. 18, # 11, p. 2580 - 2583
[2] Patent: CN107337646, 2017, A, . Location in patent: Paragraph 0040; 0041; 0042; 0043
4
[ 39549-79-6 ]
[ 144-62-7 ]
[ 75844-40-5 ]
Reference:
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 8, p. 1337 - 1342
5
[ 39549-79-6 ]
[ 122-51-0 ]
[ 75844-40-5 ]
Yield
Reaction Conditions
Operation in experiment
1.1 g
at 110℃; for 4 h; Sealed tube
A suspension of 2-amino-4-methylbenzamide (1.2 g, 8.0 mmol) in CH(OEt)3 (10 mL) was heated in a sealed tube at 110° C. for 4 h. Then the reaction was quenched with aq. NaHCO3 solution at rt and the precipitate obtained was filtered and dried. The solid mass was purified by column chromatography to afford 1.1 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 12.14 (br s, 1H), 8.05 (s, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.34 (d, J=7.8 Hz, 1H), 2.45 (s, 3H).
Reference:
[1] Journal of the Chemical Society, 1948, p. 1759,1765
7
[ 26830-95-5 ]
[ 39549-79-6 ]
[ 26830-96-6 ]
Reference:
[1] Justus Liebigs Annalen der Chemie, 1941, vol. 546, p. 277,291
[2] Journal of the Chemical Society, 1929, p. 2557
[3] Justus Liebigs Annalen der Chemie, 1941, vol. 546, p. 277,291
8
[ 39549-79-6 ]
[ 2305-36-4 ]
Reference:
[1] Chemische Berichte, 1888, vol. 21, p. 1539[2] Journal fuer Praktische Chemie (Leipzig), 1889, vol. <2> 40, p. 15
9
[ 26830-96-6 ]
[ 39549-79-6 ]
Yield
Reaction Conditions
Operation in experiment
53%
With sulfuric acid In water at 120℃; for 0.333333 h;
Concentrated sulfuric acid (3 mL) was carefully added to a suspension of 2- amino-4-methylbenzonitrile (800 mg, 6.1 mmol) in H2O (1 mL). The solution was then placed into an oil bath, pre-heated to 120 0C, the reaction stirred for 20 min and then immediately cooled in an ice bath. The solution was made basic via the addition of 5 percent NaOH and the resulting solid collected via vacuum filtration. 484.4 mg (53 percent) of the title compound as a light brown solid were obtained. 1H NMR (DMSO-dβ) δ 7.63 (br s, 1 H), 7.42 (d, 1 H), 6.95 (br s, 1 H), 6.55 (br s, 2 H), 6.45 - 6.48 (m, 1 H), 6.29 (ddd, 1 H), 2.16 (s, 3 H). MS (ES) 134 (M - 16).
43%
With potassium hydroxide In ethanol for 8 h; Reflux
2-amino-4-methylbenzonitrile (10 g, 75.7 mmol) was dissolved in ethanol, added with potassium hydroxide (21.2 g, 378 mmol), followed by refluxing for 8 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and dissolved in ethyl acetate. The organic layer formed was washed with a saturated aqueous solution of sodium bicarbonate and brine. The obtained organic layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from ethanol to obtain the title compound (4.9 g, 43percent). 1H-NMR Spectrum (300 MHz, DMSO- 6): δ 7.40 (d, 1H), 6.52 (s, 2H), 6.45 (s, 1H), 6.28 (d, lH), 2.14 (s, 3H)
43%
With potassium hydroxide In ethanol for 8 h; Reflux
2-amino-4-methylbenzonitrile (10 g, 75.7 mmol) was dissolved in ethanol, added with potassium hydroxide (21.2 g, 378 mmol), followed by refluxing for 8 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and dissolved in ethyl acetate. The organic layer formed was washed with a saturated aqueous solution of sodium bicarbonate and brine. The obtained organic layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from ethanol to obtain the title compound (4.9 g, 43percent). 1H-NMR Spectrum (300 MHz, DMSO-d6): δ 7.40 (d, 1H), 6.52 (s, 2H), 6.45 (s, 1H), 6.28 (d, 1H), 2.14 (s, 3H)
Reference:
[1] Journal of the American Chemical Society, 2008, vol. 130, # 47, p. 15786 - 15787
[2] Journal of Organic Chemistry, 2006, vol. 71, # 1, p. 382 - 385
[3] Patent: WO2006/74223, 2006, A2, . Location in patent: Page/Page column 51
[4] Patent: WO2013/100632, 2013, A1, . Location in patent: Page/Page column 49; 50
[5] Patent: US2014/371219, 2014, A1, . Location in patent: Paragraph 0342; 0343
[6] Journal fuer Praktische Chemie (Leipzig), 1889, vol. <2> 40, p. 12
10
[ 2305-36-4 ]
[ 39549-79-6 ]
Yield
Reaction Conditions
Operation in experiment
69%
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 3 h; Inert atmosphere Stage #2: With ammonium hydroxide In water; N,N-dimethyl-formamide for 16 h;
Compound 22 (3.00 g, 19.8 mmol) in dry DMF (100 mL) under Ar was treated with EDC.HCl (4.17 g, 21.8 mmol) and HOBt (3.33 g, 21.8 mmol) for 3 h, after which aq. NH3 (35percent, 20 mL) was added and the mixture was stirred for 16 h. The evaporation residue, in EtOAc, was washed twice with water and with brine. Drying and evaporation gave 25 (2.04 g, 69percent) as an off-white solid: mp 151-153 °C (lit. [62] mp 148 °C); 1H NMR ((CD3)2SO) δ 2.22 (3 H, s, Me), 6.35 (1 H, dd, J = 8.0, 1.2, 5-H), 6.52 (1 H, d, J = 0.5 Hz, 3-H), 6.57 (2 H, s, NH2), 6.95 (1 H, brs, CONHH), 7.48 (1 H, d, J = 8.0 Hz, 6-H), 7.65 (1 H, brs, CONHH); 13C NMR ((CD3)2SO) (HSQC/HMBC) δ 21.03 (Me), 111.14 (1-C), 115.61 (5-C), 116.44 (3-C), 128.77 (6-C), 141.55 (2-C), 150.31 (4-C), 171.19 (C=O).
64%
With N-hydroxybenzotriazole ammonium salt; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 1 h;
To a stirred solution of 2-amino-4-methyl-benzoic acid (300 mg, 1.99 mmol) in THF (6 mL),EDC.HCl (569 mg, 2.98 mmol), HOBt·NH3 (447 mg, 2.98 mmol) and DIPEA (1.06 mL, 5.96mmol) were added at RT and stirred for 1 h (TLC indicated complete consumption of startingmaterial). The reaction mixture was diluted with water (30 mL), extracted with EtOAc (3 x25 mL). The combined organic extracts were dried over Na2S04, concentrated under reducedpressure to give the crude compound which was purified by flash column chromatography(100-200 silica gel, 5 g, 50percent EtOAc-Hexane) to afford 2-amino-4-methyl-benzamide (190mg, 64percent) as a white solid 1H NMR [300 MHz, DMSO-d6]: J 7.62 (brs, 1H), 7.42 (d, J = 8.1 Hz, 1H), 6.93 (brs, 1H),6.54-6.46 (m, 3H), 6.30- 6.27 (m, 1H), 2.15 (s, 3H).
60%
With ammonia; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In methanol; N,N-dimethyl-formamide at 20℃; for 24 h; Inert atmosphere
Accordingtoaliteratureprocedure,3toasolutionof2-amino-3-methylbenzoicacid(151mg,1.00mmol,1.0eq)indegassedDMF(2.00mL)wereaddedHOBt(162mg,1.20mmol,1.2eq.),EDCI.HCl(230mg,1.20mmol,1.2eq.),N,N-diisopropylethylamine(350μL,2.00mmol,2.0eq),and7MNH3/MeOH(429μL,1.50mmol,1.5eq.).Thesolutionwasstirredatroomtemperaturefor24hoursthenpouredoverwaterandtheaqueouslayerextractedwithEtOAc(320mL),thecombinedorganiclayerswashedwithbrine(25mL),driedwithNa2SO4andconcentratedinvacuo.TheresiduewaspurifiedbyFCC(gradient50percentEtOAc/hexanes to 80percent EtOAc/hexanes) to give 2-amino-3-methylbenzamide (90.0 mg,0.599mmol,60percent)asawhiteamorphoussolid;mp:144–146°C,lit.144–145°C.
Reference:
[1] European Journal of Medicinal Chemistry, 2016, vol. 118, p. 316 - 327
[2] Patent: WO2018/125961, 2018, A1, . Location in patent: Page/Page column 53; 54
[3] Synthesis (Germany), 2017, vol. 49, # 1, p. 135 - 144
11
[ 26830-95-5 ]
[ 39549-79-6 ]
Reference:
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1987, vol. 26, # 1-12, p. 602 - 604
[2] Journal fuer Praktische Chemie (Leipzig), 1889, vol. <2> 40, p. 12
12
[ 65078-05-9 ]
[ 39549-79-6 ]
Yield
Reaction Conditions
Operation in experiment
1.2 g
With iron; ammonium chloride In ethanol; water for 2 h; Reflux
General procedure: To a solution of 5-nitro-N-(3-(trifluoromethyl)phenyl)isoquinolin-1-amine (1.0 g, 3.0 mmol) in a mixture of EtOH:H2O (8:2, 10 mL) were added iron powder (1.26 g, 4.8 mmol), and NH4Cl (1.6 g, 30.0 mmol). The reaction mass was heated at reflux for 2 h and filtered. The filtrate was concentrated and the residue was purified by column chromatography to afford 0.800 g of the title product. 1H NMR (300 MHz, DMSO-d6): δ 9.18 (s, 1H), 8.35 (s, 1H), 8.20 (d, J=7.8 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.42-7.24 (m, 3H), 6.86 (d, J=7.5 Hz, 1H), 5.84 (s, 2H). The title compound was prepared following the procedure described in Step 3 of Intermediate-i using 4-methyl- 2-nitrobenzamide (1.60 g, 8.88 mmol), iron powder (2.97 g,53.33 mmol), and NH4C1 (2.85 g, 53.33 mmol) in EtOH (8 mE) and water (2 mE) to afford 1.2 g of the title product. 1HNMR (300 MHz, DMSO-d5): ö 7.62 (br s, 1H), 7.42 (d, J=7.8 Hz, 1H), 6.93 (br s, 1H), 6.53 (s, 2H), 6.46 (s, 1H), 6.29 (d, J=7.8 Hz, 1H), 2.15 (s, 3H).
Reference:
[1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 4, p. 549 - 551
[2] Patent: US2013/210844, 2013, A1, . Location in patent: Paragraph 0263; 0269; 0436; 0437
Reference:
[1] Journal of Organic Chemistry, 2010, vol. 75, # 10, p. 3311 - 3316
17
[ 50424-81-2 ]
[ 39549-79-6 ]
Reference:
[1] Patent: US2013/210844, 2013, A1,
18
[ 26830-95-5 ]
[ 39549-79-6 ]
[ 26830-96-6 ]
Reference:
[1] Justus Liebigs Annalen der Chemie, 1941, vol. 546, p. 277,291
[2] Journal of the Chemical Society, 1929, p. 2557
[3] Justus Liebigs Annalen der Chemie, 1941, vol. 546, p. 277,291
19
[ 24920-35-2 ]
[ 39549-79-6 ]
Reference:
[1] Journal of the Chemical Society, 1929, p. 2557
2-amino-4-mthylbenzamide (4.93 g, 32.8 mmol) obtained in above was added with formic acid (30 mL, 787.9 mmol), followed by stirring for 6 hours at 100°C. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and washed with water. The filtered solid was dried with warm wind in an oven (40°C) for 6 hours or more to obtain the title compound (4.79 g, 91percent). 1H-NMR Spectrum (300 MHz, DMSO-rftf): delta 8.06 (s, 1H), 8.00 (d, 1H), 7.47 (s, 1H), 7.34 (d, 1H), 2.45 (s, 3H) MS(ESI+, m/z): 161 [M+H]+
91%
at 100℃; for 6h;
<strong>[39549-79-6]2-amino-4-methylbenzamide</strong> (4.93 g, 32.8 mmol) obtained in <Step 1> above was added with formic acid (30 mL, 787.9 mmol), followed by stirring for 6 hours at 100° C. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and washed with water. The filtered solid was dried with warm wind in an oven (40° C.) for 6 hours or more to obtain the title compound (4.79 g, 91percent). 1H-NMR Spectrum (300 MHz, DMSO-d6): delta 8.06 (s, 1H), 8.00 (d, 1H), 7.47 (s, 1H), 7.34 (d, 1H), 2.45 (s, 3H) MS (ESI+, m/z): 161 [M+H]+
84%
at 100℃; for 6h;
A mixture of <strong>[39549-79-6]2-amino-4-methylbenzamide</strong> (20 g, 133 mmol) and formic acid (120 ml, 3129 mmol) was heated to 100 0C for 6 h. The reaction was cooled to RT and the volatiles were removed under reduced pressure. The residue was then washed carefully with aqueous saturated sodium bicarbonate and then with water. The tan solid was then dried in a vacuum oven at 45 0C overnight to give 7-methylquinazolin-4(3H)-one (18.00 g, 84percent yield). MS (ESI, pos. ion) m/z: 161 [M+H]+
Example 332; Preparation of 7-methyIquinazolin-4(3H)-oneA mixture of <strong>[39549-79-6]2-amino-4-methylbenzamide</strong> (20 g, 133 mmol)and formic acid (120 ml, 3129 mmol) was heated to 100 0C. After 6 hours, the reaction was cooled down to to RT and the volatiles were removed under reduced pressure. The residue was then washed carefully with aqueous saturated sodium bicarbonate and then with water. The tan solid <n="118"/>was then dried in a vacuum oven at 45 0C overnight to give 7-methylquinazolin-4(3H)- one. MS (M+H)+ 161.
7-methylbenzo[d][1,2,3]triazin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
A suspension of 2-amino-5-methylbenzamide (404 mg, 2.7 mmol) in HCl (2N, 5 mL) at 0 C was treated with NaNO2 (208 mg, 3.0 mmol). The mixture was stirred for 1 h, then made basic with Na2CO3 (20 % soln). The resulting solid was collected via vacuum filtration to provide 249 mg (57 %) of the title compound as a brown solid. 1H EPO <DP n="53"/>NMR (DMSO-J6) delta 8.11 (d, 1 H), 7.96 - 8.00 (m, 1 H), 7.73 (ddd, 1 H), 2.56 (s, 3 H). MS (ES) 160 (M - H), 162 (M + H).
General procedure: A solution of anthranilamide (30 mmol) in 1N HCl (120 mL) was stirred at 0 C for 20 min. Then, sodium nitrite (60 mmol) dissolved in deionized water (100 mL) was added dropwise to the above solution for 40 min. After another 2 h of stirringat 0 C, 30% NaOH solution was added slowly to adjustp H value to 8.0. The reaction mixture was allowed to stir vigorously for 15 min. The precipitated product was filtered, washed with deionized water (200 mL), and dried to afford compounds 10 in yields of 40-92%.
5-(4-fluorophenyl)-1,3-dioxolane-2,4-dione[ No CAS ]
[ 1241915-26-3 ]
Yield
Reaction Conditions
Operation in experiment
91%
With hydrogenchloride; sodium methylate; In tetrahydrofuran; methanol;
Step A:To a solution of <strong>[39549-79-6]2-amino-4-methylbenzamide</strong> (3 g, 20.0 mmol) in THF (40 mL) was added 5-(4-fluorophenyl)-1,3-dioxolane-2,4-dione from Example 16 (4.7 g, 24 mmol) and the solution was stirred for 2 hrs at 50° C. Sodium methoxide in MeOH (25percent, 5.2 mL, 24 mmol) was then added and the solution was stirred at 50° C. overnight.The reaction mixture solution was concentrated, 2N HCl was added and the mixture was filtered.The collected solid was dried to give 2-((4-fluorophenyl)(hydroxy)methyl)-7-methylquinazolin-4-ol (5.14 g, 91percent) which was used without further purification. LC-MS (ESI) m/z 285 (M+H)+.
00319] Step A: To a solution of <strong>[39549-79-6]2-amino-4-methylbenzamide</strong> (3 g, 20.0 mmol) in THF (40 mL) was added 5-(4-fluorophenyl)-l,3-dioxolane-2,4-dione from Example 16 (4.7 g, 24 mmol) and the solution was stirred for 2 h at 50 0C. Sodium methoxide in MeOH (25percent, 5.2 mL, 24 mmol) was then added and the solution was stirred at 50 0C overnight. The reaction mixture solution was concentrated, 2N HCl was added and the mixture was filtered. The collected solid was dried to give 2-((4- fluorophenyl)(hydroxy)methyl)-7-methylquinazolin-4-ol (5.14 g, 91percent) which was used without further purification. LC-MS (ESI) m/z 285 (M + H)+.
With triethylamine; In 1,2-dichloro-ethane; at 20℃;
00325] Step B: To a solution of 2-(2,2-difluoro-2-(4-fluorophenyl)acetamido)-4- methylbenzamide (5.85 g, 0.0181 mol) in DCE (120 mL) were added TEA (91.5 mL, 0.724 mol) and chlorotrimethylsilane (34.4 mL, 0.272 mol) at rt. The reaction mixuture was stirred at 85 0C overnight. After cooling to rt, the solid was filtered and the filtrate was concentrated to dryness. The residue was taken in a mixture of EtOAc/THF (1: 1) and washed with water and brine. Pure product was obtained after crystallization from hot EtOAc (2.02 g, 37percent); LC-MS (ESI) m/z 305 (M+H)+.
Step A: To a mixture of <strong>[39549-79-6]2-amino-4-methylbenzamide</strong> (804 mg, 5.36 mmol) and sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate from Example 2 Step B (1.25 g, 5.89 mmol) was added trimethylsilyl polyphosphate (ca. 10 mL) and the mixture was heated at 130° C. in a sand bath overnight. The mixture was allowed to cool to rt, and then water (75 mL) and EtOAc (75 mL) were added and the mixture was stirred at rt for 1 h. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-60percent EtOAc/hexanes to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methylquinazolin-4-ol (1.09 g, 66percent). LCMS (ESI) m/z 306 (M+H)+.
A suspension of <strong>[39549-79-6]2-amino-4-methylbenzamide</strong> (1.2 g, 8.0 mmol) in CH(OEt)3 (10 mL) was heated in a sealed tube at 110° C. for 4 h. Then the reaction was quenched with aq. NaHCO3 solution at rt and the precipitate obtained was filtered and dried. The solid mass was purified by column chromatography to afford 1.1 g of the title product. 1H NMR (300 MHz, DMSO-d6): delta 12.14 (br s, 1H), 8.05 (s, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.34 (d, J=7.8 Hz, 1H), 2.45 (s, 3H).
With ytterbium(III) triflate; In 1,3,5-trimethyl-benzene; at 165℃; for 6h;Inert atmosphere;
General procedure: A mixture of 2-aminobenzamide (1, 4.0 mmol), carboxamide (2, 6.0 mmol), Yb(OTf)3 (0.20 mmol,5.0 molpercent), and mesitylene (5.0 mL) was placed in a 20-mL Pyrex flask equipped with a magnetic stirring bar and a reflux condenser under a flow of argon. The reaction was carried out at 120-165 oC (bath temp.) for 6 h with stirring. Then, the reaction mixture was cooled to room temperature, and analyzed by GLC, GC-MS (EI), and LC-MS (ESI). After evaporation of mesitylene under vacuum,the products (3) were isolated by recrystallization from MeOH/hexane and/or medium pressure column chromatography on silica gel (eluent: EtOAc/hexane = 50/50 ~ EtOAc 100percent. For 3j, eluent:MeOH/CHCl3 = 50/50). 1H NMR spectra were recorded at 400 MHz, and 13C NMR spectra wererecorded at 100 MHz in DMSO-d6. The analytical and spectral data of 3a-e,38 3f,39 3g,40 3h,41 and3j,42 were consistent with those reported previously. The product, 3i, was characterized below.
2-(4-pentynyl)-7-methyl-4(3H)-quinazolinone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: To a solution of 5-hexynoic acid (3.0 mmol) in dryCH2Cl2 (5 mL) was added EDCI (3.1 mmol) and HOBt(3.1 mmol). The resulting mixture was stirred at rt for 2 h. Then substituted or unsubstituted 2-aminobenzamide (3.0 mmol) wasadded, and the reaction mixture was stirred at rt for 12 h whilebeing monitored by TLC. After the addition of H2O (10 mL) themixture was extracted with ethyl acetate (3 × 20 mL). Theorganic layers were combined and concentrated under vacuumto give the amide intermediate.
2-(3-butynyl)-7-methyl-4(3H)-quinazolinone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: To a solution of 5-hexynoic acid (3.0 mmol) in dryCH2Cl2 (5 mL) was added EDCI (3.1 mmol) and HOBt(3.1 mmol). The resulting mixture was stirred at rt for 2 h. Then substituted or unsubstituted 2-aminobenzamide (3.0 mmol) wasadded, and the reaction mixture was stirred at rt for 12 h whilebeing monitored by TLC. After the addition of H2O (10 mL) themixture was extracted with ethyl acetate (3 × 20 mL). Theorganic layers were combined and concentrated under vacuumto give the amide intermediate.
7-methyl-2-(naphthalen-1-yl)quinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃;
General procedure: Sodium hydrogen sulfite (4 mmol) was added to a solution of anthranilamide 1 (2 mmol) and benzaldehyde 2 (2 mmol) in N,N- dimethylacetamide (5 mL). The mixture was heated under continuous stirring at 150 o C for 2-3 h and poured into ice water. The precipitate was then filtered, washed with water followed byethanol, and dried to yield the 2-arylquinazolinones 3-31.#10;#10;
7-methyl-2-(o-tolyl)quinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
With sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃;
General procedure: Sodium hydrogen sulfite (4 mmol) was added to a solution of anthranilamide 1 (2 mmol) and benzaldehyde 2 (2 mmol) in N,N- dimethylacetamide (5 mL). The mixture was heated under continuous stirring at 150 o C for 2-3 h and poured into ice water. The precipitate was then filtered, washed with water followed byethanol, and dried to yield the 2-arylquinazolinones 3-31.#10;#10;
7-methyl-2-(m-tolyl)quinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃;
General procedure: Sodium hydrogen sulfite (4 mmol) was added to a solution of anthranilamide 1 (2 mmol) and benzaldehyde 2 (2 mmol) in N,N- dimethylacetamide (5 mL). The mixture was heated under continuous stirring at 150 o C for 2-3 h and poured into ice water. The precipitate was then filtered, washed with water followed byethanol, and dried to yield the 2-arylquinazolinones 3-31.#10;#10;
2-(3-methoxyphenyl)-7-methylquinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃;
General procedure: Sodium hydrogen sulfite (4 mmol) was added to a solution of anthranilamide 1 (2 mmol) and benzaldehyde 2 (2 mmol) in N,N- dimethylacetamide (5 mL). The mixture was heated under continuous stirring at 150 o C for 2-3 h and poured into ice water. The precipitate was then filtered, washed with water followed byethanol, and dried to yield the 2-arylquinazolinones 3-31.#10;#10;
7-methyl-2-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃;
General procedure: Sodium hydrogen sulfite (4 mmol) was added to a solution of anthranilamide 1 (2 mmol) and benzaldehyde 2 (2 mmol) in N,N- dimethylacetamide (5 mL). The mixture was heated under continuous stirring at 150 o C for 2-3 h and poured into ice water. The precipitate was then filtered, washed with water followed byethanol, and dried to yield the 2-arylquinazolinones 3-31.#10;#10;
7-methyl-2-(3-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃;
General procedure: Sodium hydrogen sulfite (4 mmol) was added to a solution of anthranilamide 1 (2 mmol) and benzaldehyde 2 (2 mmol) in N,N- dimethylacetamide (5 mL). The mixture was heated under continuous stirring at 150 o C for 2-3 h and poured into ice water. The precipitate was then filtered, washed with water followed byethanol, and dried to yield the 2-arylquinazolinones 3-31.#10;#10;
7-methyl-2-(2-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃;
General procedure: Sodium hydrogen sulfite (4 mmol) was added to a solution of anthranilamide 1 (2 mmol) and benzaldehyde 2 (2 mmol) in N,N- dimethylacetamide (5 mL). The mixture was heated under continuous stirring at 150 o C for 2-3 h and poured into ice water. The precipitate was then filtered, washed with water followed byethanol, and dried to yield the 2-arylquinazolinones 3-31.#10;#10;
2-(2-fluorophenyl)-7-methylquinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃;
General procedure: Sodium hydrogen sulfite (4 mmol) was added to a solution of anthranilamide 1 (2 mmol) and benzaldehyde 2 (2 mmol) in N,N- dimethylacetamide (5 mL). The mixture was heated under continuous stirring at 150 o C for 2-3 h and poured into ice water. The precipitate was then filtered, washed with water followed byethanol, and dried to yield the 2-arylquinazolinones 3-31.#10;#10;
2-(3-fluorophenyl)-7-methylquinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃;
General procedure: Sodium hydrogen sulfite (4 mmol) was added to a solution of anthranilamide 1 (2 mmol) and benzaldehyde 2 (2 mmol) in N,N- dimethylacetamide (5 mL). The mixture was heated under continuous stirring at 150 o C for 2-3 h and poured into ice water. The precipitate was then filtered, washed with water followed byethanol, and dried to yield the 2-arylquinazolinones 3-31.#10;#10;
2-(2-(dimethylamino)phenyl)-7-methylquinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃;
General procedure: Sodium hydrogen sulfite (4 mmol) was added to a solution of anthranilamide 1 (2 mmol) and benzaldehyde 2 (2 mmol) in N,N- dimethylacetamide (5 mL). The mixture was heated under continuous stirring at 150 o C for 2-3 h and poured into ice water. The precipitate was then filtered, washed with water followed byethanol, and dried to yield the 2-arylquinazolinones 3-31.#10;#10;
With dihydrogen peroxide; In water; at 120℃; for 20h;Sealed tube;
General procedure: A 15 mL tube was added 2-aminobenzamide (1 mmol), benzyl amine (1.5 mmol), and a stir bar. Then H2O2 (30 wt% in H2O, 5 equiv.) was added by a syringe at room temperature under open air. The tube was closed and kept at 120C for 20 h. The conversion and yield were determined by GC and GC-MS using hexadecane (0.1 mmol) as the internal standard.
With dihydrogen peroxide; In water; at 120℃; for 20h;Sealed tube;
General procedure: A 15 mL tube was added 2-aminobenzamide (1 mmol), benzyl amine (1.5 mmol), and a stir bar. Then H2O2 (30 wtpercent in H2O, 5 equiv.) was added by a syringe at room temperature under open air. The tube was closed and kept at 120°C for 20 h. The conversion and yield were determined by GC and GC?MS using hexadecane (0.1 mmol) as the internal standard.
Compound 22 (3.00 g, 19.8 mmol) in dry DMF (100 mL) under Ar was treated with EDC.HCl (4.17 g, 21.8 mmol) and HOBt (3.33 g, 21.8 mmol) for 3 h, after which aq. NH3 (35%, 20 mL) was added and the mixture was stirred for 16 h. The evaporation residue, in EtOAc, was washed twice with water and with brine. Drying and evaporation gave 25 (2.04 g, 69%) as an off-white solid: mp 151-153 C (lit. [62] mp 148 C); 1H NMR ((CD3)2SO) delta 2.22 (3 H, s, Me), 6.35 (1 H, dd, J = 8.0, 1.2, 5-H), 6.52 (1 H, d, J = 0.5 Hz, 3-H), 6.57 (2 H, s, NH2), 6.95 (1 H, brs, CONHH), 7.48 (1 H, d, J = 8.0 Hz, 6-H), 7.65 (1 H, brs, CONHH); 13C NMR ((CD3)2SO) (HSQC/HMBC) delta 21.03 (Me), 111.14 (1-C), 115.61 (5-C), 116.44 (3-C), 128.77 (6-C), 141.55 (2-C), 150.31 (4-C), 171.19 (C=O).
64%
With N-hydroxybenzotriazole ammonium salt; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h;
To a stirred solution of 2-amino-4-methyl-benzoic acid (300 mg, 1.99 mmol) in THF (6 mL),EDC.HCl (569 mg, 2.98 mmol), HOBt·NH3 (447 mg, 2.98 mmol) and DIPEA (1.06 mL, 5.96mmol) were added at RT and stirred for 1 h (TLC indicated complete consumption of startingmaterial). The reaction mixture was diluted with water (30 mL), extracted with EtOAc (3 x25 mL). The combined organic extracts were dried over Na2S04, concentrated under reducedpressure to give the crude compound which was purified by flash column chromatography(100-200 silica gel, 5 g, 50% EtOAc-Hexane) to afford 2-amino-4-methyl-benzamide (190mg, 64%) as a white solid 1H NMR [300 MHz, DMSO-d6]: J 7.62 (brs, 1H), 7.42 (d, J = 8.1 Hz, 1H), 6.93 (brs, 1H),6.54-6.46 (m, 3H), 6.30- 6.27 (m, 1H), 2.15 (s, 3H).
60%
With ammonia; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In methanol; N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere;
Accordingtoaliteratureprocedure,3toasolutionof2-amino-3-methylbenzoicacid(151mg,1.00mmol,1.0eq)indegassedDMF(2.00mL)wereaddedHOBt(162mg,1.20mmol,1.2eq.),EDCI.HCl(230mg,1.20mmol,1.2eq.),N,N-diisopropylethylamine(350muL,2.00mmol,2.0eq),and7MNH3/MeOH(429muL,1.50mmol,1.5eq.).Thesolutionwasstirredatroomtemperaturefor24hoursthenpouredoverwaterandtheaqueouslayerextractedwithEtOAc(320mL),thecombinedorganiclayerswashedwithbrine(25mL),driedwithNa2SO4andconcentratedinvacuo.TheresiduewaspurifiedbyFCC(gradient50%EtOAc/hexanes to 80% EtOAc/hexanes) to give 2-amino-3-methylbenzamide (90.0 mg,0.599mmol,60%)asawhiteamorphoussolid;mp:144-146C,lit.144-145C.
With [Cp*Ir(2,2'-bpyO)(H2O)]; caesium carbonate; at 130℃; for 2h;Inert atmosphere; Microwave irradiation;
<strong>[39549-79-6]2-amino-4-methylbenzamide</strong> (75 mg, 0.5 mmol), [Cp * Ir (2,2'-bpyO) (H2O)](5.4 mg, 0.005 mmol, 1 molpercent),Cesium carbonate (49 mg, 0.15 mmol, 0.3 equiv.) And methanol (0.5 ml) were sequentially added to a dried 5 mL microwave reaction tube.The tube was nitrogen protected and placed in a single mode pressure microwave synthesizer (Discover CEM, USA). After the reaction mixture was reacted at 130 ° C for 2 hours, it was cooled to room temperature. Rotary evaporation to remove the solvent,Then, column chromatography (developing solvent: petroleum ether / ethyl acetate)The pure target compound was obtained in a yield of 87percent
With oxygen; In dimethyl sulfoxide; N,N-dimethyl-formamide; at 120℃; for 5h;
General procedure: In a typical experiment, a solution of phenylacetic acid (0.3mmol, 40.8mg) in DMF (0.5mL) was added to a 10mL vial with the VNU-21 catalyst (5.5mg, 5mol%). The mixture was stirred at 120C for 4h under an oxygen atmosphere. After that, the catalyst was removed by filtration. A solution of 2-aminobenzamide (0.2mmol, 27.2mg) in DMSO (0.5mL) was then added to the reactor. The mixture was additionally stirred at 120C for 5h under oxygen. The GC yield of benzaldehyde and 2-phenylquinazolin-2(3H)-one were monitored by withdrawing samples from the reaction mixture, quenching with brine (1mL), extracting with ethyl acetate (3×1mL), drying over anhydrous Na2SO4, and analyzing by GC regarding diphenyl ether as internal standard. After the completion of the second step, the reaction mixture was cooled to room temperature. Resulting solution was quenched with brine (5mL), extracted by ethyl acetate (3×5mL), dried over anhydrous Na2SO4 prior to the removal of solvent under vacuum. The crude product was purified by silica gel column chromatography using hexane and ethyl acetate (1:1, v/v) as eluent. The structure of 2-phenylquinazolin-4(3H)-one was verified by GC-MS, 1H NMR and 13C NMR. For the leaching test, after the first 4h reaction time, the catalyst was removed by filtration. The solution phase was transferred to a new and clean reactor. New phenylacetic acid was added, and the resulting mixture was subsequently stirred for additional 4h at 120C under an oxygen atmosphere. The yield of benzaldehyde was monitored by GC.
7-methyl-2-(nitromethyl)quinazolin-4(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
In water; at 70℃; for 2h;
General procedure: 2-Aminobenzamides (1 mmol) and 1,1-dichloro-2-nitroethene (1.2 mmol) were added to 5 mL of water in a 25 mL round-bottom flask. Then stirred at corresponding temperature and corresponding reaction time, after completion, the product precipitated from the reaction mixture and can be easily separated by filtration, then give the pure products.
2-(4-chlorobutanamido)-4-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With triethylamine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;
General procedure: Asolutionoftheappropriatesubstituted2-aminobenzamide(1.0eq)inTHF(2.5mLpermmolsubstrate)wascooledto0°Candtriethylamine(2.0eq)thentheappropriateacidchloride(1.2eq)inTHF(2mLpermmolsubstrate)wereaddedtothestirredsolution.ThereactionwasstirredatroomtemperatureuntilcompletionasindicatedbyTLC,whenthemixturewasdilutedwithEtOAcandquenchedwithNaHSO4(20mL).TheaqueousphasewasextractedwithEtOAc(320mL),combinedorganicphasesdriedoverMgSO4,excesssolventremovedinvacuoandtheresiduepurifiedbyFCC.
With ytterbium(III) triflate; In 1,3,5-trimethyl-benzene; at 60℃; for 24h;Inert atmosphere;
General procedure: 2-aminobenzamide (1, 1.0 mmol), 1,3-diketone (2, 1.5 mmol), Yb(OTf)3 (0.050 mmol, 5.0 molpercent),and mesitylene (2.0 mL) was placed in a 20-mL Pyrex flask equipped with a magnetic stirring bar and a reflux condenser under a flow of argon. The reaction was carried out at 60°C (bath temp.) for 24 h with stirring. The reaction mixture was then cooled to room temperature and analyzed by GLCand GC-MS. The product 3 was isolated by medium-pressure column chromatography on silica gel(eluent: EtOAc/hexane = 30/70 ~ EtOAc 100percent. For 3j, eluent: MeOH/CHCl3 = 30/70 ~ 50/50) andrecrystallization from MeOH/hexane. The products 3l and 3m were isolated by recrystallizationfrom EtOAc/hexane. 1H NMR spectra were recorded at 400 MHz, and 13C NMR spectra wererecorded at 100 MHz in DMSO-d6 (For 3j, in a mixture of DMSO-d6 and methanol-d4). Elemental analyses were performed at the Microanalytical Center of Kyoto University. The analytical and spectral data of 3a,10 3b-c,11 3d,12 3e,13 3f,14 3g-h,10 and 3j-l,7 are fully consistent with those reported previously. The products 3i,15 and 3m16 were characterized below.
With triethylamine; copper(l) chloride; at 20℃; for 12h;
In air, <strong>[39549-79-6]2-amino-4-methylbenzamide</strong> (75.1 mg, 0.5 mmol), benzeneboronic acid(91.4 mg, 0.75 mmol), cuprous chloride (7.4 mg, 0.075 mmol), triethylamine (35 uL, 0.25 mmol). Reaction at room temperature12h; after the reaction, filtration, the solvent was removed by rotary evaporation, column chromatography (using 200-300 mesh size silica gel and silica gel to be pure Mass ratio of 100: 1, the eluent as a mixture of petroleum ether and ethyl acetate, the mixture of petroleum ether: ethyl acetate Volume ratio of 3: 1) to give 4-methyl-2- (phenylamino) benzamide (86.5 mg, 77percent) as a white solid.
7-methyl-2-phenethylquinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; In toluene; at 120℃; for 12h;Inert atmosphere;
Under nitrogen atmosphere, <strong>[39549-79-6]2-amino-4-methylbenzamide</strong> (150 mg, 1 mmol), [Cp*IrCl2]2 (8 mg, 0.01 mmol, 1 molpercent), toluene (1.0 mL), cinnamaldehyde (132 mg, 1 mmol)Add to a 25 mL Schlenk reaction flask.The mixture was reacted at 120°C for 12 hours and then cooled to room temperature.The solvent was removed in vacuo under reduced pressure and then purified by column chromatography (developer: ethyl acetate/petroleum ether) to give the pure target compound, yield: 80percent.
4-(2-carbamoyl-5-methylanilino)-4-oxobutanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With acetic acid; at 20℃; for 2h;
To a stirred solution of 2-amino-4-methyl-benzamide (190 mg, 1.27 mmol) in AcOH (5 mL),succinic anhydride (151 mg, 1.52 mmol) was added at RT and stirred for 2 h (TLC indicatedcomplete consumption of starting material). The reaction mixture was diluted with water (20mL), solid was precipitated out, filtered and dried under vacuum to get the required 4-(2-carbamoyl-5-methyl-anilino)-4-oxo-butanoic acid (250 mg, 89percent) which was used for nextstep without further purification.1H NMR [300 MHz, DMSO-d6]: J 12.37 (brs, 1H), 11.88 (s, 1H), 8.33 (s, 1H), 8.20 (s, 1H),7.70 (d, J = 8.1 Hz, 1H), 7.64 (s, 1H), 6.91 (d, J = 7.8 Hz, 1H), 2.53-2.50 (m, 4H), 2.31 (s,3H).LCMS: m/z: 273.50 [M+Nat.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 120℃; under 7500.75 Torr; for 20h;Inert atmosphere; Autoclave;
General procedure: A 12mL vial was charged with MCM-41-2P-Pd(OAc)2 (2mol%), 2-aminobenzamide (1mmol), aryl iodide (1mmol) (if solid) and a stirring bar. Then, DMF (2mL), aryl iodide (1mmol) (if liquid) and DBU (2mmol) were injected by syringe under an argon atmosphere. The vial was placed in an alloy plate, which was transferred into a 300mL Parr Instruments 4560 series autoclave under an argon atmosphere. After flushing the autoclave three times with CO, a pressure of 10bar CO was fixed at ambient temperature. The autoclave was heated for 20hat 120C. After completion of the reaction, the autoclave was cooled to room temperature and the pressure was released carefully. The reaction mixture was diluted with ethyl acetate (10mL) and filtered. The palladium catalyst was washed with distilled water (2×5mL) and acetone (2×5mL), and reused in the next run. The filtrate was concentrated in vacuo and the pure product was isolated by either washed with water, ethyl acetate and finally hexane or recrystallization from MeOH.