* 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.
Stage #1: With caesium carbonate In 2-pyrrolidone at 130℃; for 2 h; Sealed vessel Stage #2: With methanol In 2-pyrrolidone; dichloromethane at 20℃; Filtering through Celite pad
General procedure: A flame-dried resealable 2-5 mL Pyrex reaction vessel was charged with the solid reactant(s): (hetero)aryl nitriles 1 (1.0 mmol) and Cs2CO3 (1.5 mmol). The reaction vessel was capped with a rubber septum, and pyrrolidinone (2 mL per mmol [0.5 M]) was added through the septum. The septum was replaced with a teflon screwcap. The reaction vessel was sealed and heated at 130 °C for 2 h. The resulting suspension was cooled to room temperature and filtered through a pad of celite eluting with CH2Cl2/MeOH (7:3), and the inorganic salts were removed. The filtrate was concentrated and purification of the residue by silica gel column chromatography gave the desired product.
Reference：
[1] Tetrahedron Letters, 2012, vol. 53, # 23, p. 2860 - 2863
[2] Catalysis Science and Technology, 2015, vol. 5, # 5, p. 2865 - 2868
2
[ 368-83-2 ]
[ 1801-10-1 ]
Yield
Reaction Conditions
Operation in experiment
87%
With [(η(5)-C5Me5)Ir(III)(H2O)3](OTf)2 In water at 110℃; for 12 h; Schlenk technique
To a stirred solution of 3-trifluoromethylbenzaldehyde oxime (94.6 mg, 0.5 mmol), [Cp * Ir (H20) 3] [0Tf] 2 (5.0 mg, 0.0075 mmol, ) And water (lml) were added sequentially to a 25 ml Schlenk reaction flask. The reaction mixture was allowed to react at 110 ° C for 12 hours, then cooled to room temperature. The water was removed by rotary evaporation, and the product was isolated by column chromatography. Yield: 87percent. (S, 1H, ArH), 8.17 (d, J = 7.8Hz, 1 H, (1H, ArH), 7. 90 (d, J = 7.8Hz, 1 H, ArH), 7.71 (t, J = 7.8Hz, 1Hz, ArH), 7.64 (br s, (Q, JCF = 31.8Hz), 127.7 (q, JCF = 2 (125MHz, DMSO-d6)? 166.3, 135.2, 131.4, 129.5, 129.1 (Q, Jc F = 2.8. 8), 124.0 (q, JcF = 2.8? Z)
Reference：
[1] Patent: CN104418682, 2016, B, . Location in patent: Paragraph 0090-0093
[2] Catalysis Science and Technology, 2014, vol. 4, # 4, p. 988 - 996
3
[ 2338-76-3 ]
[ 1801-10-1 ]
Yield
Reaction Conditions
Operation in experiment
94%
With ammonium hydroxide; 2% Ru/C In tetrahydrofuran at 30℃; for 25 h;
In an air atmosphere,0.01 g (5percent Qmmol Ru) Ru / C catalyst was added to the reaction flask,Then, 2 mL of 30percent aqueous ammonia solution (II-2)10 mL of THF,Then, 156yL (lmmOl) of trifluoromethylphenylacetonitrile (1-2) was added to the reaction flask under agitation,The temperature is maintained at around 30 ° C,The reaction was stirred for 25 hours,The reaction was monitored and the starting material (1-2) was essentially complete. After filtration, the residue was washed twice with dichloromethane. The filtrate was combined with dichloromethane / water (30 mL / 30 mL). The organic phase was dried, concentrated and thin-layer chromatographed (ethyl acetate / petroleum ether = 1/5) to obtain 0.178 g of m-trifluoromethylbenzamide represented by the formula (III-5) as a yellow solid in 94percent yield with a purity of 98percent.
Reference：
[1] Patent: CN104710259, 2016, B, . Location in patent: Paragraph 0066-0069
[2] Catalysis Science and Technology, 2017, vol. 7, # 17, p. 3747 - 3757
4
[ 454-89-7 ]
[ 1801-10-1 ]
Yield
Reaction Conditions
Operation in experiment
75%
Stage #1: With hydroxylamine hydrochloride; sodium carbonate In water at 20℃; for 0.5 h; Schlenk technique Stage #2: With [(η(5)-C5Me5)Ir(III)(H2O)3](OTf)2 In water at 110℃; for 12 h;
3-Trifluoromethylbenzaldehyde (87.1 mg, 0.5 mmol),Hydroxylamine hydrochloride (34.7 mg, 0.5 mmol)Sodium carbonate (26.5 mg, 0.25 mmol)And water (1 ml) were sequentially added to a 25 ml Schlenk reaction flask,After half an hour of room temperature reaction,[Cp * Ir (H2O) 3] [OTf] 2 (10.2 mg, 0.0150 mmol, 3 molpercent) was addedThe reaction mixture was reacted at 110 ° CAfter hours,Cooled to room temperature,Rotary evaporation to remove water,Column to give the title compound,Yield: 75percent.
Stage #1: at 80℃; for 2 h; Sealed tube; Green chemistry Stage #2: at 80℃; for 1 h; Sealed tube; Green chemistry
General procedure: A sealed tube equipped with a magnetic stirring bar was charged with styrene 1 (1.0mmol), NBS (2.0 mmol) and water (2.0mL) at room temperature. The resulting mixture was heated to 80 °C for 2h. After disappearance of the reactant (monitored by TLC), reaction mixture was cooled to room temperature. To this reaction mixture molecular iodine (2.2 mmol) and 30percent aq. ammonia solution or n-butylamine (10 mmol) were added and it was heated to 80 °C for 1h. After completion of the reaction (monitored by TLC), saturated Na2S2O3 solution (10 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (2×10 mL). The organic layer was washed with brine solution (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue obtained was purified by column chromatography on 60–120 mesh silica gel using ethyl acetate: n-hexane (1:2) as the eluent to obtain the corresponding aromatic amide 2.
Reference：
[1] Tetrahedron Letters, 2018, vol. 59, # 29, p. 2820 - 2823
[2] Organic and Biomolecular Chemistry, 2017, vol. 15, # 46, p. 9889 - 9894
6
[ 2251-65-2 ]
[ 1801-10-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 2008, vol. 51, # 8, p. 2400 - 2411
[2] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 14, p. 3263 - 3270
[3] Organic Letters, 2017, vol. 19, # 13, p. 3596 - 3599
7
[ 401-78-5 ]
[ 77287-34-4 ]
[ 1801-10-1 ]
Reference：
[1] Journal of Organic Chemistry, 2002, vol. 67, # 2, p. 594 - 597
8
[ 129946-88-9 ]
[ 1801-10-1 ]
Reference：
[1] Chemical Communications, 2011, vol. 47, # 14, p. 4300 - 4302
9
[ 401-78-5 ]
[ 201230-82-2 ]
[ 77287-34-4 ]
[ 1801-10-1 ]
Reference：
[1] Journal of Organic Chemistry, 2002, vol. 67, # 2, p. 594 - 597
10
[ 401-78-5 ]
[ 201230-82-2 ]
[ 1801-10-1 ]
Reference：
[1] Journal of Organic Chemistry, 2001, vol. 66, # 12, p. 4311 - 4315
[2] ChemCatChem, 2017, vol. 9, # 22, p. 4206 - 4211
11
[ 201230-82-2 ]
[ 402-43-7 ]
[ 77287-34-4 ]
[ 1801-10-1 ]
[ 1533-01-3 ]
Reference：
[1] Journal of Organic Chemistry, 2001, vol. 66, # 12, p. 4311 - 4315
12
[ 2740-83-2 ]
[ 1801-10-1 ]
Reference：
[1] Chemistry - A European Journal, 2018, vol. 24, # 5, p. 1067 - 1071
General procedure: To a stirred solution of appropriate benzamide 4a-e (1.0 eq) in toluene (10 vol), chlorocabonylsulphenyl chloride (1.2 eq) was added at room temperature and then heated to reflux for 8 h during which time HCl gas was evolved. TLC analysis (30% EA in pet ether) showed completion of the reaction. The solution was allowed to cool to room temperature and solvent was removed in vacuo. The residue was triturated with mixture of solvents (n-pentane: diethyl ether, 1:1) at below 0 C and the solids were filtered and dried to give the compounds 5a-e in good yields.
70%
In toluene; for 6h;
General procedure: Substituted benzamide (10mmol) was dissolved in toluene 80mL, after chlorocarbonylmethanesulfonyl chloride (1.57g, 12mmol), and refluxed for 6 hours to complete the reaction.Spin solvent, adding n-pentane: diethyl ether = 1: 1 ultrasound, freezing was allowed to stand, filtered, and the filtrate was recrystallized, to give the product cake were combined.5- (3-trifluoromethylphenyl) -1,3,4-oxathiazol-2-one (17.1), an off-white solid with a yield of 70%.
93.14 g (0.377 mol, 86.2%)
In ethyl acetate;
EXAMPLE 4 Preparation of 5-(alpha,alpha,alpha-Trifluoro-m-Tolyl)-1,3,4-Oxathiazol-2-One. alpha,alpha,alpha-Trifluoro-m-toluamide (82.7 g, 0.437 mol) and chlorocarbonylsulfenyl chloride (86 g, 0.667 mol, 53% excess) were reacted under the conditions of Example 2 for 0.5 hours. The light yellow residue was dissolved in ethyl acetate and cooled to -78. The white precipitate was filtered and washed with hexane to yield 93.14 g (0.377 mol, 86.2%) of white solid, m.p. 85-86.5. Anal. Calc'd. for C9 H4 F3 NO2 S: C, 43.73; H, 1.63. Found: C, 43.66; H, 1.58.
93.14 g (0.377 mol, 86.2%)
In ethyl acetate;
EXAMPLE 4 Preparation of 5-(alpha,alpha,alpha-Trifluoro-m-Tolyl)-1,3,4-Oxathiazol-2-One. alpha,alpha,alpha-Trifluoro-m-toluamide (82.7 g, 0.437 mol) and chlorocarbonylsulfenyl chloride (86 g, 0.667 mol, 53% excess) were reacted under the conditions of Example 2 for 0.5 hours. The light yellow residue was dissolved in ethyl acetate and cooled to -78. The white precipitate was filtered and washed with hexane to yield 93.14 g (0.377 mol, 86.2%) of white solid, m.p. 85-86.5. Anal. Calc'd. for C9 H4 F3 NO2 S: C, 4.373; H, 1.63. Found: C, 43.66; H, 1.58.
EXAMPLE 7 Preparation of 3-(trifluoromethyl)-benzoic Acid Amide The process is carried out analogously to example 3, but adding 0.431 g of 4-dimethylamino-pyridine and 7.11 g of tributylamine. The yield of title compound is 96% by weight.
bis(triphenylphosphine)palladium(II) dichloride[ No CAS ]
diethylene glycol dibutylether[ No CAS ]
[ 401-78-5 ]
[ 60-29-7 ]
[ 1801-10-1 ]
Yield
Reaction Conditions
Operation in experiment
With formamide; triphenylphosphine; In water;
EXAMPLE 1 Preparation of 3-(trifluoromethyl)-benzoic Acid Amide 0.491 g of bis(triphenylphosphine)-palladium(II)chloride, 0.371 g of triphenylphosphine and 2.6 g of imidazole are placed in a 200 ml glass autoclave, and then 8.01 g of 3-(trifluoromethyl)bromobenzene, 25 ml of formamide and 810.3 mg of diethylene glycol dibutylether are added as an internal gas chromatography (GC) standard. The autoclave is closed, flushed with nitrogen three times and then 5 bars carbon monoxide are applied. The reaction mixture is heated to 120 C. and stirred for 14 hours. The mixture is then cooled and the content determined by GC (0.8 ml of reaction mixture mixed with 5 ml of water, then 2 ml of diethylether added, and GC determination effected with the organic phase). The yield of title compound is 82% by weight. 1H-NMR: 5.6-6.4 (br, d NH2), 7.61 (t, Ph-H), 7.80 (d, Ph-H), 8.01 (d, Ph-H), 8.11 (s, Ph-H).
A. N-[Dichlorophosphinyl]-<strong>[1801-10-1]3-trifluoromethylbenzamide</strong> A suspension of 15 g (0.08 mole) of <strong>[1801-10-1]3-trifluoromethylbenzamide</strong>, 16.5 g (0.08 mole) of phosphorus pentachloride and 150 ml of AR carbon tetrachloride was heated at 65-70 until the HCl gas evolution nearly stops, ca. 30 min. The solution was cooled to 30 and 3.8 g (0.08 mole) of 97% formic acid added dropwise. Stirring was continued for 30 min., then the precipitate was collected, washed with AR carbon tetrachloride and air-dried to give 14 g, m.p. softens 112, melts 114-116.
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 3h;Heating / reflux;
Example 71 and 72: Synthesis of N-(4-Chloro-l-oxo-l,2-dihydro-phthalazin-6-yl)-3- trifluoromethyl-benzamide and N^l-Chloro^-oxo-S^-dihydro-phthalazin--ylJ-S- trifiuoromethyl-benzamide; <n="76"/>A mixture 6-Bromo-4-chloro-2H-phthalazin-l-one and 7-Bromo-4-chloro-2H- phthalazin-1-one (150mg, 0.58 mmol), 3-Trifluoromethyl-benzamide (120mg, 0.64 mmol), Pd2(dba)3 (53mg, 0.054 mmol), xantphos (lOlmg, 0.174 mmol) and cesium carbonate (472mg, 1.45 mmol) in dioxane (1OmL) was heated at reflux for 3h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with NaHCO3 (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/Hexanes) yielded the title compounds. N-(4-Chloro-l- oxo-l,2-dihydro-phthalazin-6-yl)-3-trifluoromethyl-benzamide: 1H-NMR (DMSO-J6) delta: 12.80 (s, IH), 11.05 (s, IH), 8.59 (s, IH), 8.34 (m, 4H), 8.02 (d, IH), 7.82 (t, IH); m/z (M+l) = 368.06; and N-(I -Chloro^-oxo-S^-dihydro-phthalazin--y^-S-trifluoromethyl- benzamide: 1H-NMR (DMSO-^5) delta: 12.80 (s, IH), 11.05 (s, IH), 8.80 (d, IH), 8.42 (dd, IH), 8.36 (s, IH), 8.32 (d, IH), 8.03 (d, IH), 8.01 (d, IH), 7.82 (t, IH); m/z (M+l) = 367.99.
With ammonium hydroxide; In dichloromethane; at 0 - 20℃; for 3.5h;
General procedure: The reaction of substituted benzoic acid M4 (10 mmol) with oxalyl chloride (2.52 g, 20 mmol) gavesubstituted benzoyl chloride. A solution of the substituted benzoyl chloridewas added dropwise to the solution of ammonium hydroxide (5 mL) indichloromethane (10 mL) at 0 oC. Then the reaction mixture wasstirred for 3.5 h at room temperature. Dichloromethane (10 mL) was added to themixture and the mixture was washed with water, a solution of sodium hydroxide(1 M), a solution of diluted hydrochloric acid (1 M) and brine, dried oversodiumsulfate and ltered. The solvent was evaporated under reduced pressure toget crude products. The crude products were recrystallized with dichloromethaneto give the pure compounds M5, whichwere used directly for preparation of isocyanates M6. The key intermediates isocyanates M6wereprepared by the usual method. Substituted benzamides M5 (5mmol), and to this 10mmol of oxalyl chloride was addeddropwisefor 10 min at ice-bath. After addition, the resulting clearsolution was heatedat about 75 oC for 6-8 h, and then the excessive oxalyl chloride wasremoved under reduced pressure to givea clear solution of substituted benzoylisocyanate M6, which was usedfor thenext step reaction without further purication.
Example 332 Production of N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)pyridin-3-yl]-<strong>[1801-10-1]3-(trifluoromethyl)benzamide</strong> To a solution of N-{6-[(5-bromopyridin-3-yl)oxy]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide (200 mg, 0.53 mmol), <strong>[1801-10-1]3-(trifluoromethyl)benzamide</strong> (160 mg, 0.91 mmol), trans-1,2-diaminocyclohexane (15 mg, 0.13 mmol) and potassium carbonate (220 mg, 1.6 mmol) in 1,4-dioxane (3.0 mL) was added copper (I) iodide (25 mg, 0.13 mmol) under argon atmosphere, and the mixture was stirred at 110 C. for 60 hr. The reaction mixture was cooled, and diluted with 20% tetrahydrofuran/ethyl acetate. The mixture was washed with water, 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=60/40?100/0) and precipitated from ethyl acetate/hexane to give the title compound (110 mg, 42%) as a white powder. 1H-NMR (DMSO-d6, 300 MHz) delta 0.72-0.86 (4H, m), 1.84-1.98 (1H, m), 7.17 (1H, d, J=9.6 Hz), 7.81 (1H, t, J=7.8 Hz), 7.96-8.04 (2H, m), 8.10 (1H, d, J=9.6 Hz), 8.20 (1H, t, J=2.4 Hz), 8.23-8.35 (2H, m), 8.38 (1H, d, J=2.4 Hz), 8.85 (1H, d, J=2.4 Hz), 10.83 (1H, s), 11.10 (1H, s).
With racemic-2-(di-tert-butylphosphino)-1,1?-binaphthyl; sodium t-butanolate;palladium diacetate; In toluene; at 85℃; for 17h;
Example 254-Methyl-2- [4 '-trifluoromethyl-5-(3-trifluoromethyl-benzoylamino)-biphenyl-3-yl] - pentanoic acidA mixture of compound 5a (40 mg, 0.078 mmol), 3-trifluoromethyl-benzamide (25 mg, 0.132 mmol), Pd(OAc)2 (6.6 mg, 0.029 mmol), racemic-2-(di-t-butylphosphino)- l,l '-binaphthyl (35 mg, 0.088 mmol), and NaOt-Bu (11.3 mg, 0.12 mmol) in toluene (1.5 mL) was heated to 85 0C for 17 h. After cooling to room temperature, the solution was <n="129"/>partitioned between EtOAc and H2O. The organic layer was dried (Na2SO4), concentrated and purified by column chromatography to give an ester intermediate.
With racemic-2-(di-tert-butylphosphino)-1,1?-binaphthyl; sodium t-butanolate;palladium diacetate; In toluene; at 85℃; for 17h;
A mixture of compound 1g (40 mg, 0.078 mmol), 3-trifluoromethyl-benzamide (25 mg, 0.132 mmol), Pd(OAc)2 (6.6 mg, 0.029 mmol), racemic-2-(di-t-butylphosphino)-1,1'-binaphthyl (35 mg, 0.088 mmol), and NaOt-Bu (11.3 mg, 0.12 mmol) in toluene (1.5 mL) was heated to 85 C. for 17 h. After cooling to room temperature, the solution was partitioned between EtOAc and H2O. The organic layer was dried (Na2SO4), concentrated and purified by column chromatography to give an ester intermediate.The above obtained ester intermediate was stirred with a solution of 1 N LiOH aqueous solution and MeOH (1 to 1 v/v) at room temperature to give the title compound; 1H NMR (400 MHz, MeOD) delta 0.97 (dd, J=6.60, 2.20 Hz, 6 H), 1.56 (dt, J=13.39, 6.63 Hz, 1 H), 1.75 (ddd, J=13.69, 7.21, 6.97 Hz, 1 H), 2.02 (dt, J=13.69, 7.70 Hz, 1 H), 3.77 (t, J=7.70 Hz, 1 H), 7.45 (s, 1 H), 7.71-7.79 (m, 4 H), 7.81-7.92 (m, 3 H), 8.05 (s, 1 H), 8.24 (d, J=7.82 Hz, 1 H), 8.30 (s, 1 H); Calcd for C27H23F6NO3 (M+H) 524.16, Found 524.
With caesium carbonate;copper(l) iodide; N,N`-dimethylethylenediamine; In toluene; at 110℃; for 20h;
(a) 3-(5-r(4-Chlorophenyl)(methyl)aminolpicolinoyl)-5-r3-(trifluoromethyl)- benzamidolbenzoic acid methyl ester; A mixture of 3-{5-[(4-chlorophenyl)(methyl)amino]picolinoyl}-5-iodobenzoic acid methyl ester (150 mg, 0.296 mmol, see Example 2:1 , step (b)), 3-(trifluoromethyl)- benzamide (70 mg, 0.37 mmol), N1,N2-dimethylethane-1 ,2-diamine (9.7 mul_, 0.09 mmol), CuI (8.6 mg, 0.045 mmol), Cs2CO3 (195 mg, 0.6 mmol) and toluene (3 mL) was stirred at 110 C for 20 h. The mixture was cooled to rt and filtered through Celite and the filtrate was concentrated. The residue was purified by chromatography to give the sub-title compound. Yield 135 mg (80%).
General procedure: A flame-dried resealable 2-5 mL Pyrex reaction vessel was charged with the solid reactant(s): (hetero)aryl nitriles 1 (1.0 mmol) and Cs2CO3 (1.5 mmol). The reaction vessel was capped with a rubber septum, and pyrrolidinone (2 mL per mmol [0.5 M]) was added through the septum. The septum was replaced with a teflon screwcap. The reaction vessel was sealed and heated at 130 C for 2 h. The resulting suspension was cooled to room temperature and filtered through a pad of celite eluting with CH2Cl2/MeOH (7:3), and the inorganic salts were removed. The filtrate was concentrated and purification of the residue by silica gel column chromatography gave the desired product.
With Lawessons reagent; In tetrahydrofuran; for 4h;Reflux;
General procedure: To a solution of benzamide 11a-u (1 equiv) in THF (30mL) was added Lawesson?s reagent (0.6 equiv), and the mixture was heated to reflux for 4 hrs. The reaction mixture was concentrated invacuo,then diluted with ethyl acetate (30 ml), and washed with 1N NaHCO3 (3× 20 mL) and brine (2 × 20 mL). The organic layer was dried over anhydrous sodium sulfate,filtered and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using a mixture of dichloromethane/methanol(100:1, v/v) as eluent to afford a yellow solid product.A solution of the obtained solid 12a-u (1 equiv) and ethyl 2-chloroacetoacetate (1.2 equiv) in ethanol (25 ml) was heated to reflux for 6 h, then the mixture was allowed to stand at 0 C for 10 hrs, and a white needle crystal was precipitate out.The reaction mixture was filtered and the filter cake was washed with 10 mL of ethanol, dried in vacuum to give the desired product.
With [(eta.(5)-pentamethylcyclopentadienyl)Ir(H2O)3](OTf)2; In water; at 110℃; for 12h;Schlenk technique;
To a stirred solution of 3-trifluoromethylbenzaldehyde oxime (94.6 mg, 0.5 mmol), [Cp * Ir (H20) 3] [0Tf] 2 (5.0 mg, 0.0075 mmol, ) And water (lml) were added sequentially to a 25 ml Schlenk reaction flask. The reaction mixture was allowed to react at 110 C for 12 hours, then cooled to room temperature. The water was removed by rotary evaporation, and the product was isolated by column chromatography. Yield: 87%. (S, 1H, ArH), 8.17 (d, J = 7.8Hz, 1 H, (1H, ArH), 7. 90 (d, J = 7.8Hz, 1 H, ArH), 7.71 (t, J = 7.8Hz, 1Hz, ArH), 7.64 (br s, (Q, JCF = 31.8Hz), 127.7 (q, JCF = 2 (125MHz, DMSO-d6)? 166.3, 135.2, 131.4, 129.5, 129.1 (Q, Jc F = 2.8. 8), 124.0 (q, JcF = 2.8? Z)
N-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-(trifluoromethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 75: N-[[3-[4-amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4- d]pyrimidin-3-yl]phenyl]methyl]-<strong>[1801-10-1]3-(trifluoromethyl)benzamide</strong> N-[[3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-3- (trifluoromethyl)benzamide Under N2, a stirred solution of sodium hydride (60% dispersed in mineral oil) (54 mg, 1.35 mmol) in THF (6 mL) was cooled to 0 C using an ice bath before <strong>[1801-10-1]3-(trifluoromethyl)benzamide</strong> (153 mg, 0.81 mmol) was added. The resulting solution was stirred at this temperature for 1 h30 before 2-[3- (bromomethyl)phenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (200 mg, 0.67 mmol) was added and the solution allowed to warm to room temperature and was stirred overnight. The solution was diluted with EtOAc (20 mL) and quenched with a saturated ammonium chloride solution (20 mL) before being partitioned. The aqueous layer was washed with EtOAc (3 × 10 mL) before the combined organics were washed with water (30 mL) and brine (30 mL). The combined organics were dried (Na2SO4), filtered and concentrated to dryness in vacuo to afford crude N-[[3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-<strong>[1801-10-1]3-(trifluoromethyl)benzamide</strong> (400 mg, 0.56 mmol, 84% yield) as a clear oil that crystallised upon standing. UPLC-MS (ES+, Short acidic): 1.99 min, m/z 406 [M+H]+
N-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-(trifluoromethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydride; at 0 - 20℃;Inert atmosphere;
Example 20: N-[[4-[4-Amino-1-[(3R)-1-prop-2-enoyl-3-piperidyl]pyrazolo[3,4- d]pyrimidin-3-yl]phenyl]methyl]-<strong>[1801-10-1]3-(trifluoromethyl)benzamide</strong> N-[[4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-(trifluoromethyl)- benzamide To a solution of <strong>[1801-10-1]3-(trifluoromethyl)benzamide</strong> (330.0 mg, 1.74 mmol) and 4- bromomethylphenylboronic acid pinacol ester (431.9 mg, 1.45 mmol), cooled to 0 C under a nitrogen atmosphere, was added sodium hydride (87.2 mg, 2.18 mmol). The reaction mixture was stirred at this temperature for 1 h, then allowed to return to room temperature and stirred overnight. The reaction mixture was then diluted with EtOAc (20 mL) and quenched with a saturated aqueous solution of NH4Cl (20 mL) and partitioned. The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed successively with water (2 10 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude N-[[4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl]-<strong>[1801-10-1]3-(trifluoromethyl)benzamide</strong> (644.0 mg, 0.79 mmol, 55% yield) as an off-white solid. UPLC-MS (ES+, Short acidic): 1.99 min, m/z 406.0 [M+H]+
3-Trifluoromethylbenzaldehyde (87.1 mg, 0.5 mmol),Hydroxylamine hydrochloride (34.7 mg, 0.5 mmol)Sodium carbonate (26.5 mg, 0.25 mmol)And water (1 ml) were sequentially added to a 25 ml Schlenk reaction flask,After half an hour of room temperature reaction,[Cp * Ir (H2O) 3] [OTf] 2 (10.2 mg, 0.0150 mmol, 3 mol%) was addedThe reaction mixture was reacted at 110 CAfter hours,Cooled to room temperature,Rotary evaporation to remove water,Column to give the title compound,Yield: 75%.
General procedure: The reaction of substituted benzoic acid M4 (10 mmol) with oxalyl chloride (2.52 g, 20 mmol) gavesubstituted benzoyl chloride. A solution of the substituted benzoyl chloridewas added dropwise to the solution of ammonium hydroxide (5 mL) indichloromethane (10 mL) at 0 oC. Then the reaction mixture wasstirred for 3.5 h at room temperature. Dichloromethane (10 mL) was added to themixture and the mixture was washed with water, a solution of sodium hydroxide(1 M), a solution of diluted hydrochloric acid (1 M) and brine, dried oversodiumsulfate and ltered. The solvent was evaporated under reduced pressure toget crude products. The crude products were recrystallized with dichloromethaneto give the pure compounds M5, whichwere used directly for preparation of isocyanates M6. The key intermediates isocyanates M6wereprepared by the usual method. Substituted benzamides M5 (5mmol), and to this 10mmol of oxalyl chloride was addeddropwisefor 10 min at ice-bath. After addition, the resulting clearsolution was heatedat about 75 oC for 6-8 h, and then the excessive oxalyl chloride wasremoved under reduced pressure to givea clear solution of substituted benzoylisocyanate M6, which was usedfor thenext step reaction without further purication.
In dichloromethane;Inert atmosphere; Schlenk technique; Reflux;
General procedure: The appropriate amide 32a-p, benzhydrazide (40a), or p-toluenesulfonylhydrazide (43a) (1.0 mmol, 1.0 equiv) was placed in a SchlenkKjeldahl reaction flask and the flask was evacuated/argon re-filledthree times. Subsequently, anhyd CH2Cl2 (25 mL) was added and themixture was stirred at r.t. for 10 min before dropwise addition of oxalylchloride (3.0 mmol, 3.0 equiv) followed. The reaction mixturewas then stirred at reflux for 2.5-3.0 h before cooling to r.t. and thesolvent was evaporated in vacuo. Subsequently, the appropriate nucleophile32, 34, 36, 38, 40, 42, 43, or 45 (1.1-1.25 mmol, 1.1-1.25equiv) was rapidly added and the flask was evacuated/argon re-filledbefore anhyd toluene (12 mL) was added. The reaction mixture wasthen stirred at reflux for 2.5-3 h before cooling to r.t. and concentrationto about 1/3 of the initial volume on rotavapor. Hexane was addedto the residue and the obtained precipitate (often sonicated) wascollected by filtration under reduced pressure to yield the crudeproduct. When necessary, the isolated material was purified either bycrystallization from MeOH or flash chromatography on silica gel withhexane-EtOAc as the eluent.
(E)-methyl 3-(3-bromopyridin-4-yl)acrylate[ No CAS ]
(E)-methyl 3-(3-(3-(trifluoromethyl)benzamido)pyridin-4-yl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11%
With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; potassium phosphate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃;Inert atmosphere;
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (E)-methyl 3-(3-bromopyridin-4-yl)acrylate (500 mg, 2.07 mmol, 1.00 equiv) in toluene (30 mL), <strong>[1801-10-1]3-(trifluoromethyl)benzamide</strong> (784 mg, 4.15 mmol, 2.00 equiv), Pd2(dba)3.CHCl3 (107 mg, 0.05 equiv), XantPhos (122 mg, 0.21 mmol, 0.10 equiv) and K3PO4 (1.32 g, 6.22 mmol, 3.00 equiv). The resulting mixture was stirred overnight at 100 C. The reaction was cooled to room temperature, concentrated under vacuum. The residue was diluted with 100 mL of water, extracted with 3×100 mL of ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). The collected fraction was concentrated under vacuum to give (E)-methyl 3-(3-(3-(trifluoromethyl)benzamido)pyridin-4-yl)acrylate (80 mg, 11%) as a yellow solid. MS: (ES, m/z): 351[M+H]+.
tert-butyl 4-(10-bromo-2-oxo-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate[ No CAS ]
tert-butyl 4-(2-oxo-10-[3-(trifluoromethyl)benzoyl]amino}-1,2-dihydropyrimido[1,2-b]indazol-4-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
With potassium phosphate; t-BuBrettPhos; [(2-di-tert-butylphosphino-3,6-dimethoxy-2?,4?,6?-triisopropyl-1,1?-biphenyl)-2-(2?-amino-1,1?-biphenyl)]palladium(II) methanesulfonate; at 110℃; for 16h;Inert atmosphere;
Under argon, tert-butyl 4-(10-bromo-2-oxo-l,2-dihydropyrimido[l,2-b]indazol-4-yl)piperidine-l- carboxylate (200 mg, 447 muiotaetaomicron), 3-(trifluoromefhyl)benzamide (211 mg, 1.12 mmol), Tripotassium phosphate (133 mg, 626 muiotaetaomicron), tBuBrettPhos (13.0 mg, 26.8 muiotaetaomicron), and tBuBrettPhos Pd G3 (22.9 mg, 26.8 muiotaetaomicron) were dissolved in degassed l-Methoxy-2-propanol (5.0 ml, 52 mmol). The mixture was stirred at 110 C for 16 h and then purified via reverse phase chromatography (Method: Reprosil C18; 10 muiotaeta; 125x30 mm / flow: 50 ml/min / solvents: A = water (0,01% formic acid), B = Acetonitrile / gradient 0.00-4.25 min = 20%B, 4.50min = 30%B, 19.00-22.50min = 100%B, 22.75-25.00min = 20%B) which afforded the product after drying in vacuo. The obtained amout was 73.0 mg (95 % purity, 29 % of theory). LC-MS (Method 1): Rt = 1.28 min; MS (ESIpos): m/z = 556 [M+H]+
N-(2-acetylphenyl)-3-(trifluoromethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In toluene; at 110℃; for 24h;Schlenk technique; Inert atmosphere; Molecular sieve;Catalytic behavior;
General procedure: The following compounds were synthesized based upon reported literatureprocedure2 under our optimized cross-coupling conditions. An oven-dried round-bottom flaskwith a Teflon stir bar was charged with amide (2.0 equiv, 1.00 mmol), CuI (20 mol%, 0.10mmol), base (2 equiv, 1.00 mmol), and 200 mg activated 4 A molecular sieves. The roundbottomflask was sealed with a rubber septum, evacuated and refilled with nitrogen (thissequence was performed three times). Under nitrogen, 2?-bromoacetophenone (1.0 equiv, 0.50 mmol), N, N?- dimethylethylenediamine (40 mol%, 0.2 mmol), and toluene (3 mL) were eachadded via syringe. The round-bottom flask was then placed in a preheated oil bath at 110 C. Thereaction was heated with stirring for 24 h until TLC showed completion of the reaction. Thecrude of reaction obtained was cooled to room temperature. Toluene was removed under vacuothen water (5 mL) was added to the reaction mixture. The biphasic mixture was extracted withethyl acetate (3x15 mL). The organic extracts were collected, dried over anhydrous sodiumsulfate, filtered, and concentrated in vacuo to remove solvent. The product was purified bycolumn chromatography on silica gel (100-200 mesh) with EtOAc/hexane system, to afford thecorresponding N-ketoarylamides.
N-(1-(dimethylamino)ethylidene)-3-(trifluoromethyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
In toluene;Reflux;
General procedure: The starting amides (30.0 mmol) were suspended in toluene (40 mL) and 1.5 equivalents of N,N-dimethylacetamide dimethylacetal (45.0 mmol) were added. The reaction mixture was refluxed for 2-10 h. The reaction mixture was then cooled. Generally, the corresponding products deposited upon cooling and were thus collected via vacuum filtration and washed with diethyl ether to remove any impurities. In other cases, the volatile components were removed under reduced pressure and the products were obtained and purified with column chromatography, using various mixtures of ethyl acetate/petroleum ether as the eluent.
With ammonium hydroxide; ruthenium-carbon composite; In tetrahydrofuran; at 30℃; for 25h;
In an air atmosphere,0.01 g (5% Qmmol Ru) Ru / C catalyst was added to the reaction flask,Then, 2 mL of 30% aqueous ammonia solution (II-2)10 mL of THF,Then, 156yL (lmmOl) of trifluoromethylphenylacetonitrile (1-2) was added to the reaction flask under agitation,The temperature is maintained at around 30 C,The reaction was stirred for 25 hours,The reaction was monitored and the starting material (1-2) was essentially complete. After filtration, the residue was washed twice with dichloromethane. The filtrate was combined with dichloromethane / water (30 mL / 30 mL). The organic phase was dried, concentrated and thin-layer chromatographed (ethyl acetate / petroleum ether = 1/5) to obtain 0.178 g of m-trifluoromethylbenzamide represented by the formula (III-5) as a yellow solid in 94% yield with a purity of 98%.
3-nitro-N-[3-(trifluoromethyl)benzoyl]carbamoyl}benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
325 mg
In toluene;Schlenk technique; Inert atmosphere; Reflux;
General procedure: The appropriate amide 32a-p, benzhydrazide (40a), or p-toluenesulfonylhydrazide (43a) (1.0 mmol, 1.0 equiv) was placed in a SchlenkKjeldahl reaction flask and the flask was evacuated/argon re-filledthree times. Subsequently, anhyd CH2Cl2 (25 mL) was added and themixture was stirred at r.t. for 10 min before dropwise addition of oxalylchloride (3.0 mmol, 3.0 equiv) followed. The reaction mixturewas then stirred at reflux for 2.5-3.0 h before cooling to r.t. and thesolvent was evaporated in vacuo. Subsequently, the appropriate nucleophile32, 34, 36, 38, 40, 42, 43, or 45 (1.1-1.25 mmol, 1.1-1.25equiv) was rapidly added and the flask was evacuated/argon re-filledbefore anhyd toluene (12 mL) was added. The reaction mixture was then stirred at reflux for 2.5-3 h before cooling to r.t. and concentrationto about 1/3 of the initial volume on rotavapor. Hexane was addedto the residue and the obtained precipitate (often sonicated) wascollected by filtration under reduced pressure to yield the crudeproduct. When necessary, the isolated material was purified either bycrystallization from MeOH or flash chromatography on silica gel withhexane-EtOAc as the eluent.
General procedure: A mixture of the amide (1, 1 mmol), alcohol (15 mL), and pulverized potassium bisulfate (1.1 g, 8 mmol) was refluxed for the specified time. The alcohol was removed in vacuo and the residue was triturated with hexanes (or other appropriate solvent such as DCM or ethyl acetate to dissolve the product). Removal of hexanes in vacuo provided the following pure products
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