* 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 palladium dichloride; silver(l) oxide In ethanol at 70℃; for 24 h;
General procedure: b.Cyanation of aryl bromides. To a solution of arylbromide (0.5 mmol) in EtOH (5.0 mL) was added NCTS (272 mg, 1.0 mmol), PdCl2 (13.3 mg, 0.075 mmol), and Ag2O (57.75 mg, 0.5 mmol). The mixture was stirred at 70 for 24 hunder air atmosphere. Then the reaction mixture was cooled to room temperature and filtered through a pad of celite (1.0 g) and rinsed with CH2Cl2 (10.0 mL). The resulting organic solution was concentrated under reduced pressure and further purified by flash chromatography (SiO2,petroleum ether/EtOAc gradient), yielding the corresponding aryl nitriles.
Reference：
[1] Tetrahedron Letters, 2016, vol. 57, # 11, p. 1205 - 1209
[2] Advanced Synthesis and Catalysis, 2015, vol. 357, # 16-17, p. 3419 - 3423
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 28, p. 10999 - 11005
7
[ 5798-75-4 ]
[ 7153-22-2 ]
Reference：
[1] Chemical Science, 2017, vol. 8, # 12, p. 8094 - 8105
8
[ 5798-75-4 ]
[ 7153-22-2 ]
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 18, p. 3056 - 3059
9
[ 5798-75-4 ]
[ 75-16-1 ]
[ 2077-19-2 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: at -40 - 0℃; Stage #2: With water; ammonium chloride In tetrahydrofuran; toluene
Example 2: Synthesis of 1-bromo-4-(1-methoxy-1-methyl-ethyl)-benzene:A mixture of 6.87 g of ethyl 4-bromobenzoate (10) was allowed to react with 64 mL(1.4 M in toluene) of methyl magnesium bromide in THF at -4O0C for 1 hour, and the reaction mixture was gradually warmed to O0C. The reaction was quenched with saturated aqueous ammonium chloride solution and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with brine, was dried over magnesium sulfate, was filtered, and the solvent was removed in vacuo. Purification by silica gel chromatography (50:1 to 10:1 EPO <DP n="23"/>hexanes-ethyl acetate) afforded 6.44 g (99percent yield) of 2-(4-bromophenyl)propan-2-o1 ; MS (AP/CI) observed: 199.1 (M+H - H2O)+, 100percent; 213.1 , 215.1 (M-H)", 60percent, 80percent. 2-(4- Bromophenyl)propan-2-o1 (1.77 g) and iodomethane (1.16 g) in THF (100 mL) were treated with sodium hydride, 60percent in mineral oil (328 mg). After stirring for 24 h at room temperature, the reaction mixture was quenched with dilute aqueous hydrochloric acid, was extracted with ethyl acetate, and the organic layer was washed with brine, was dried over magnesium sulfate, was filtered, and the solvent was removed in vacuo. The resultant oil was purified by silica gel chromatography (200:1 hexanes-ethylacetate) to afford 0.5 g of 1-bromo-4-(1- methoxy-1-methyl-ethyl)-benzene; 13C NMR (400 MHz, CDCI3) δ 145.35, 131.53, 127.91 , 121.00, 50.90, 28.60.
Reference：
[1] Journal of the American Chemical Society, 1957, vol. 79, p. 1906,1909
11
[ 5798-75-4 ]
[ 1667-12-5 ]
Reference：
[1] Archives of Pharmacal Research, 2010, vol. 33, # 12, p. 1919 - 1926
[2] Archives of Pharmacal Research, 2010, vol. 33, # 12, p. 1919 - 1926
12
[ 5798-75-4 ]
[ 51934-41-9 ]
Yield
Reaction Conditions
Operation in experiment
91%
With copper(I) oxide; <i>L</i>-proline; potassium iodide In ethanol at 110℃; for 30 h; Schlenk technique; Inert atmosphere; Sealed tube
General procedure: A Schlenk tube was charged with Cu2O (7.2 mg, 10 molpercent), l-proline (11.5 mg, 20 molpercent), aryl (or heteroaryl) bromide (1 or 3,0.50 mmol), potassium iodide (KI) (249 mg, 0.75 mmol), and EtOH(1.5 mL) under nitrogen atmosphere. The Schlenk tube was sealedwith a teflon valve, and then the reaction mixture was stirred at110C for a period (the reaction progress was monitored by GCanalysis). After the reaction was completed, GC yield of high volatileproduct was determined using an appropriate internal standard(chlorobenzene or 1-chloro-4-methylbenzene) or the solvent wasremoved under reduced pressure. The residue obtained was puri-fied via silica gel chromatography (eluent: petroleum ether/ethylacetate = 10/1) to afford aryl iodides 2a–2o or heteroaryl iodides4a–4g.
Reference：
[1] Catalysis Today, 2016, vol. 274, p. 129 - 132
[2] Chemical Communications, 2012, vol. 48, # 33, p. 3993 - 3995
[3] Angewandte Chemie - International Edition, 2015, vol. 54, # 1, p. 263 - 266[4] Angew. Chem., 2015, vol. 127, # 01, p. 265 - 268,4
[5] Catalysis Science and Technology, 2017, vol. 7, # 10, p. 2110 - 2117
13
[ 5798-75-4 ]
[ 10602-00-3 ]
Reference：
[1] Macromolecules, 2005, vol. 38, # 18, p. 7645 - 7652
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7186 - 7194
14
[ 5798-75-4 ]
[ 141-52-6 ]
[ 23676-09-7 ]
Reference：
[1] European Journal of Organic Chemistry, 2015, vol. 2015, # 21, p. 4744 - 4755
15
[ 13675-18-8 ]
[ 5798-75-4 ]
[ 4334-88-7 ]
Reference：
[1] Chemical Science, 2016, vol. 7, # 6, p. 3676 - 3680
[2] Organic Process Research and Development, 2017, vol. 21, # 11, p. 1859 - 1863
16
[ 5798-75-4 ]
[ 10602-03-6 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1999, vol. 47, # 3, p. 398 - 404
[2] Journal of Polymer Science, Part A: Polymer Chemistry, 2011, vol. 49, # 1, p. 211 - 224
[3] Tetrahedron Letters, 2015, vol. 56, # 51, p. 7105 - 7107
[4] European Journal of Organic Chemistry, 2016, vol. 2016, # 18, p. 3056 - 3059
[5] Journal of the Brazilian Chemical Society, 2018, vol. 29, # 1, p. 109 - 124
[6] Molecular Crystals and Liquid Crystals, 2017, vol. 647, # 1, p. 395 - 404
General procedure: Hydrazides (30-58) were synthesized by one pot conventionalmethod24 Benzoic acid or its derivative (10 mmol) was dissolvedin ethanol (20 mL). Sulfuric acid (3 N, 2 mL) was added and thereaction contents were refluxed for six hours. The reaction wasmonitored with TLC. After the completion of the reaction, the reactionmixture was neutralized by adding solid NaHCO3, and filteredto remove excess of NaHCO3. In the neutralized reaction mixture which contains ethyl ester, hydrazine monohydrate (1.5 mL,3 mmol) was added and refluxed for 3-6 h to complete the reaction.Ethanol and unreacted hydrazine were removed by distillationupto 1/3 volume. The reaction contents were cooled, filteredand recrystallized from methanol to obtain the desired hydrazidecrystals (see Supporting information).
96%
With hydrazine; In ethanol; at 78℃; for 5h;
(i) Synthesis of 4-bromobenzoylhydrazine A synthesis scheme of 4-bromobenzoylhydrazine is shown in (B-1). 25 g (0.19 mol) of ethyl-4-bromobenzoate was put into a 200 mL three-neck flask, 50 mL of ethanol was added thereto, and the mixture was stirred. After that, 20 mL of hydrazine monohydrate was added, the mixture was stirred at 78 C. for 5 hours, and the contents of the flask were reacted together. After the reaction, water was added to the reactive mixture, and suction filtration was performed on a precipitated solid. The obtained solid was washed and collected by suction filtration, so that 24 g of a white solid, which was the object of the synthesis, was obtained at a yield of 96%.
96%
With hydrazine hydrate; In ethanol; water;
(1) Synthesis of 4-Bromobenzoylhydrazine Into a 200 mL three-neck flask was put 25 g (0.19 mol) of ethyl-4-bromobenzoate, 50 mL of ethanol was added thereto, and the mixture was stirred. After that, 20 mL of hydrazine monohydrate was added to the mixture, and then the mixture was stirred while being heated at 78 C. for 5 hours to be reacted. After the reaction, water was added to the reaction mixture, and a precipitated solid was collected by suction filtration. The obtained solid was washed with water and collected by suction filtration, whereby 24 g of a white solid of 4-bromobenzoylhydrazine, which was the object of the synthesis, was obtained in a yield of 96% (synthesis scheme (a-1)).
96%
With hydrazine; In ethanol; at 78℃; for 5h;
(Synthesis Example 1); In this example, a synthesis method of4-(9H-carbazol-9-yl)-4'-(4,5-diphenyl-4H-l,2,4-triazol-3-yl)triphenylamine (abbreviation: YGATAZl) represented by a structural formula (200) is described. [0247](200) [0248]; [Step 1: Synthesis of 3-(4-Bromophenyl)-4,5-diphenyl-4H-l,2,4-triazole]; (1) Synthesis of 4-Bromobenzoylhydrazine; Into a 200 mL three-neck flask was put 25 g (0.19 mol) of ethyl-4-bromobenzoate, 50 mL of ethanol was added thereto, and the mixture was stirred. After that, 20 mL of hydrazine monohydrate was added to the mixture, and then the mixture was stirred while being heated at 78 0C for 5 hours to be reacted. After the reaction, water was added to the reaction mixture, and a precipitated solid was collected by suction filtration. The obtained solid was washed with water and collected by suction filtration, whereby 24 g of a white solid of 4-bromobenzoylhydrazine, which was the object of the synthesis, was obtained in a yield of 96 % (synthesis scheme (a-1)).
85%
With hydrazine; In ethanol; water; at 80℃; for 4.5h;
A synthetic scheme of 4-bromobenzoylhydrazine is shown in (B-1). In a 300 mL three-necked flask were placed 25 g (0.10 mol) of 4-bromoethyl benzoate and 40 mL of ethanol, and the mixture was stirred. After that, to this mixture was added 13 mL (0.67 mol) of hydrazine monohydrate. This solution was stirred at 80 C. for 4.5 hours under a stream of nitrogen. After a predetermined time, water was added to this solution, and the precipitated solid was collected by suction filtration. The obtained solid was washed with ethanol, and 19 g of a white powder, which was a target substance, was obtained at a yield of 85%.
82%
With hydrazine; In ethanol; for 12h;Reflux;
4-bromobenzoate (1.5 g, 6.52 mmol) and NH2NH2 (3.5 mL) were dissolved in ethanol (50 mL), followed by reaction under reflux for 12 hours. After completion of the reaction was confirmed by TLC, extraction was carried out with water (100 mL) and ethyl acetate (200 mL). The organic layer was washed with brine and distilled under reduced pressure. The resulting solids were washed with hexane, filtered and dried under vacuum to afford the title compound 4-bromobenzohydrazide (19b). Yield: 82%.1H NMR (CDCl3, 400 MHz): 9.75 (s, 1H), 7.87 (d, 2H, J=8.0 Hz), 7.69 (d, 2H, J=8.0 Hz), and 4.26 (bs, 2H).
82%
With ethanol; hydrazine; for 12h;Heating / reflux;
Step 2: Preparation of 4-bromobenzohydrazide (19b)4-bromobenzoate (1.5 g, 6.52 mmol) and NH2NH2 (3.5 mL) were dissolved in ethanol (50 mL), followed by reaction under reflux for 12 hours. After completion of the reaction was confirmed by TLC, extraction was earned out with water (100 mL) and ethyl acetate (200 mL). The organic layer was washed with brine and distilled under reduced pressure. The resulting solids were washed with hexane, filtered and dried under vacuum to afford the title compound 4-bromobenzohydrazide (19b). Yield: 82%.1H NMR(CDCl3, 400MHz): 9.75(s, IH), 7.87(d, 2H, J=8.0Hz), 7.69(d, 2H, J=8.0Hz), and 4.26(bs, 2H).
With hydrazine hydrate;Reflux;
General procedure: The 0.015 mol of ethyl aromatic esters (8a-s) and 0.02 mol of hydrazine hydrate were dissolved in absolute ethanol or methanol (20 mL) to reflux the reaction mixture for 3-6 h for complete hydrazinolysis of ethyl aromatic esters. The product obtained was isolated after cooling as a white or yellow solid and recrystallized from ethanol or methanol.
With hydrazine hydrate; In ethanol;Reflux;
General procedure: Then, the corresponding ester was refluxed with 85% hydrazine monohydrate in ethanol to get hydrazide 1.
With hydrazine hydrate; In ethanol;Reflux;
General procedure: To a stirred solution of ethyl benzoate (3 mmol) derivatives in ethanol was added hydrazine-hydrate (5.44 mmol) and refluxed for 6-12 h. The reaction mixture was diluted with ethyl acetate followed by water. The organic layer was dried over sodium sulphate, filtered and evaporated to obtain the respective benzohydrazide derivatives (4a-m)15,16. The yields of the products varied from 80-85 %.
With hydrazine hydrate; In ethanol; for 8h;Reflux;
General procedure: Benzoic acids a-j(8.12 mmol) was dissolved in ethanol (15 mL) and added catalytic qty of conc.H2SO4and heated to reflux for 10 h. Ethanol was evaporated and the obtained residue was diluted with ethylacetate (25 mL). The organic layer was washed with aqueous saturated NaHCO3(3 X 15 mL) followed by water (2 X 15 mL) and brine solution (20 mL). The organic layer was separated, dried over sodium sulphate, filtered and evaporated to obtain respective ethyl benzoates.To the above prepared respective ethyl benzoates (6.65 mmol) in ethanol was added hydrazine-hydrate (40.0 mmol) and refluxed for 8 h. Ethanol was evaporated from the reaction mixture and the precipitated solids were slurred with petether (5 times) and filtered at the pump and dried to obtain benzohydrazides7a-7j.
With hydrazine hydrate; In ethanol; for 6h;Reflux;
General procedure: The substituted ethyl benzoates (16-30) (0.01 mol)dissolved in dry ethanol (25 mL), hydrazine hydrate (99%,0.01 mol) was added and the mixture was reuxed for 6 h.The reaction mixture was cooled and the solid obtained wasltered and recrystallized from dilute ethanol or from water.Details of these compounds are available in SupplementaryInformation.
With hydrazine hydrate; In ethanol; for 5h;Reflux;
General procedure: 5mL of hydrazine monohydrate (80%) was added to a solution of intermediate 3 (5mmol) in ethanol (5mL). The reaction mixture was maintained under reflux for 5h. was then concentrated under reduced pressure and the resulting solid was collected by filtration, washed with cold water and dried to give the desired intermediate 4 as a white solid.
With hydrazine hydrate; In ethanol; for 48h;Reflux;
General procedure: A mixture of an ester 24-28 (15 mmol each) and hydrazine hydrate(15 mmol) were refluxed in ethanol (30 mL), for 48 h. Reaction was monitored through TLC. After completion of reaction the excess of solvent was distilled out. The resulting precipitates were then filtered and thoroughly washed with solvent.
A suspension of NaH (1.3 g, 52.4 mmol) in THF (50 mL) was refluxed at 75C, and ethyl 4- bromobenzoate (10.0 g, 42.8 mmol) was added, followed by the slow addition of CH3CN (5.3 g, 128 mmol) (H2 evolution). The reaction mixture was then refluxed for 16 h and cooled to rt. The excess base was quenched by adding water (10 mL), after which the organic solvent was removed under reduced pressure, and the resulting aqueous mixture was washed with EtOAc. Acidification of the aqueous solution using acetic acid caused the formation of a precipitate, which was collected by filtration. After drying under mechanical vacuum, Example 230 was obtained as a solid (9.4 g, 98%). ES-MS: did not ionize, LCMS RT (min) 2.65.
With sodium hydride; In toluene; at 90℃; for 7h;Inert atmosphere;
General procedure: A dry and nitrogen-flushed 150 mL three-neck flask equipped with a magnetic stirring bar was charged with a solution of sodium hydride (60%) (3.8 g, 1.5 equiv) and ethyl benzoate (9.2 mL, 64 mmol) in dry toluene (100 mL). The reaction mixture was stirred at 90 C, and acetonitrile (8.0 mL) was dropped with stirring in 1 h, thereafter, the solvent was stirred at 90 C for 6 h. Then saturated NH4Cl (10 mL) and 70 mL of water were added at 0 C to quench the reaction. The suspension was extracted with ethyl acetate (3×100 mL), the solvent was evaporated and the crude mixture was recrystallized to yield 6.0 g (41 mmol, 64%) of the desired product as a yellow solid.
With N,N,N,N,-tetramethylethylenediamine; hydrogen;(9-methylfluoren-9-yl)dicyclohexylphosphine; palladium diacetate; In toluene; at 115℃; under 18751.9 Torr; for 20h;Autoclave;Product distribution / selectivity;
(ii) Reductive carbonylation of ethyl 4-bromobenzoate using different phosphonium salts 0.0025 mmol Pd(OAc)2, 0.0075 mmol ligand (phosphonium salts) and 0.385 mmol TMEDA were diluted in toluene to a total volume of 10 ml. 0.5 mmol of ethyl 4-bromobenzoate was introduced directly in the autoclaves, and then 1 ml of the catalyst solution was added to the autoclave. After purging with synthesis gas (CO/H2 1:1), the pressure was set to 25 bar CO/H2 and the autoclave was stirred while warming up to 115C. The reactions were hold at 115C for 20h. After cooling down and releasing the pressure the raw mixtures were filtered through a short path of Al2O3 and the conversion was determined via GC.
With N,N,N,N,-tetramethylethylenediamine; hydrogen;9-(octadecylfluoren-9-yl)dicyclohexylphosphine; palladium diacetate; In toluene; at 115℃; under 18751.9 Torr; for 20h;Autoclave;Product distribution / selectivity;
(ii) Reductive carbonylation of ethyl 4-bromobenzoate using different phosphonium salts 0.0025 mmol Pd(OAc)2, 0.0075 mmol ligand (phosphonium salts) and 0.385 mmol TMEDA were diluted in toluene to a total volume of 10 ml. 0.5 mmol of ethyl 4-bromobenzoate was introduced directly in the autoclaves, and then 1 ml of the catalyst solution was added to the autoclave. After purging with synthesis gas (CO/H2 1:1), the pressure was set to 25 bar CO/H2 and the autoclave was stirred while warming up to 115C. The reactions were hold at 115C for 20h. After cooling down and releasing the pressure the raw mixtures were filtered through a short path of Al2O3 and the conversion was determined via GC.
With N,N,N,N,-tetramethylethylenediamine; hydrogen;9-(methylfluoren-9-yl)diisopropylphosphine; palladium diacetate; In toluene; at 115℃; under 18751.9 Torr; for 20h;Autoclave;Product distribution / selectivity;
(ii) Reductive carbonylation of ethyl 4-bromobenzoate using different phosphonium salts 0.0025 mmol Pd(OAc)2, 0.0075 mmol ligand (phosphonium salts) and 0.385 mmol TMEDA were diluted in toluene to a total volume of 10 ml. 0.5 mmol of ethyl 4-bromobenzoate was introduced directly in the autoclaves, and then 1 ml of the catalyst solution was added to the autoclave. After purging with synthesis gas (CO/H2 1:1), the pressure was set to 25 bar CO/H2 and the autoclave was stirred while warming up to 115C. The reactions were hold at 115C for 20h. After cooling down and releasing the pressure the raw mixtures were filtered through a short path of Al2O3 and the conversion was determined via GC.
With N,N,N,N,-tetramethylethylenediamine; hydrogen;9-(ethylfluoren-9-yl)diisopropylphosphine; palladium diacetate; In toluene; at 115℃; under 18751.9 Torr; for 20h;Autoclave;Product distribution / selectivity;
(ii) Reductive carbonylation of ethyl 4-bromobenzoate using different phosphonium salts 0.0025 mmol Pd(OAc)2, 0.0075 mmol ligand (phosphonium salts) and 0.385 mmol TMEDA were diluted in toluene to a total volume of 10 ml. 0.5 mmol of ethyl 4-bromobenzoate was introduced directly in the autoclaves, and then 1 ml of the catalyst solution was added to the autoclave. After purging with synthesis gas (CO/H2 1:1), the pressure was set to 25 bar CO/H2 and the autoclave was stirred while warming up to 115C. The reactions were hold at 115C for 20h. After cooling down and releasing the pressure the raw mixtures were filtered through a short path of Al2O3 and the conversion was determined via GC.
With N,N,N,N,-tetramethylethylenediamine; hydrogen;9-(ethylfluoren-9-yl)dicyclohexylphosphine; palladium diacetate; In toluene; at 115℃; under 18751.9 Torr; for 20h;Autoclave;Product distribution / selectivity;
(ii) Reductive carbonylation of ethyl 4-bromobenzoate using different phosphonium salts 0.0025 mmol Pd(OAc)2, 0.0075 mmol ligand (phosphonium salts) and 0.385 mmol TMEDA were diluted in toluene to a total volume of 10 ml. 0.5 mmol of ethyl 4-bromobenzoate was introduced directly in the autoclaves, and then 1 ml of the catalyst solution was added to the autoclave. After purging with synthesis gas (CO/H2 1:1), the pressure was set to 25 bar CO/H2 and the autoclave was stirred while warming up to 115C. The reactions were hold at 115C for 20h. After cooling down and releasing the pressure the raw mixtures were filtered through a short path of Al2O3 and the conversion was determined via GC.
With N,N,N,N,-tetramethylethylenediamine; hydrogen;9-iPrFluPCy2; palladium diacetate; In toluene; at 115℃; under 18751.9 Torr; for 20h;Autoclave;Product distribution / selectivity;
(ii) Reductive carbonylation of ethyl 4-bromobenzoate using different phosphonium salts 0.0025 mmol Pd(OAc)2, 0.0075 mmol ligand (phosphonium salts) and 0.385 mmol TMEDA were diluted in toluene to a total volume of 10 ml. 0.5 mmol of ethyl 4-bromobenzoate was introduced directly in the autoclaves, and then 1 ml of the catalyst solution was added to the autoclave. After purging with synthesis gas (CO/H2 1:1), the pressure was set to 25 bar CO/H2 and the autoclave was stirred while warming up to 115C. The reactions were hold at 115C for 20h. After cooling down and releasing the pressure the raw mixtures were filtered through a short path of Al2O3 and the conversion was determined via GC.
With N,N,N,N,-tetramethylethylenediamine; hydrogen;(1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl)dicyclhexylphosphine; palladium diacetate; In toluene; at 115℃; under 18751.9 Torr; for 20h;Autoclave;Product distribution / selectivity;
(ii) Reductive carbonylation of ethyl 4-bromobenzoate using different phosphonium salts 0.0025 mmol Pd(OAc)2, 0.0075 mmol ligand (phosphonium salts) and 0.385 mmol TMEDA were diluted in toluene to a total volume of 10 ml. 0.5 mmol of ethyl 4-bromobenzoate was introduced directly in the autoclaves, and then 1 ml of the catalyst solution was added to the autoclave. After purging with synthesis gas (CO/H2 1:1), the pressure was set to 25 bar CO/H2 and the autoclave was stirred while warming up to 115C. The reactions were hold at 115C for 20h. After cooling down and releasing the pressure the raw mixtures were filtered through a short path of Al2O3 and the conversion was determined via GC.
With N,N,N,N,-tetramethylethylenediamine; hydrogen;EtFluP(nButBu); palladium diacetate; In toluene; at 115℃; under 18751.9 Torr; for 20h;Autoclave;Product distribution / selectivity;
(ii) Reductive carbonylation of ethyl 4-bromobenzoate using different phosphonium salts 0.0025 mmol Pd(OAc)2, 0.0075 mmol ligand (phosphonium salts) and 0.385 mmol TMEDA were diluted in toluene to a total volume of 10 ml. 0.5 mmol of ethyl 4-bromobenzoate was introduced directly in the autoclaves, and then 1 ml of the catalyst solution was added to the autoclave. After purging with synthesis gas (CO/H2 1:1), the pressure was set to 25 bar CO/H2 and the autoclave was stirred while warming up to 115C. The reactions were hold at 115C for 20h. After cooling down and releasing the pressure the raw mixtures were filtered through a short path of Al2O3 and the conversion was determined via GC.
With N,N,N,N,-tetramethylethylenediamine; hydrogen;palladium diacetate; (1-methyl-9-ethyl-fluorenyl-9-yl)dicyclohexylphosphine; In toluene; at 115℃; under 18751.9 Torr; for 20h;Autoclave;Product distribution / selectivity;
(ii) Reductive carbonylation of ethyl 4-bromobenzoate using different phosphonium salts 0.0025 mmol Pd(OAc)2, 0.0075 mmol ligand (phosphonium salts) and 0.385 mmol TMEDA were diluted in toluene to a total volume of 10 ml. 0.5 mmol of ethyl 4-bromobenzoate was introduced directly in the autoclaves, and then 1 ml of the catalyst solution was added to the autoclave. After purging with synthesis gas (CO/H2 1:1), the pressure was set to 25 bar CO/H2 and the autoclave was stirred while warming up to 115C. The reactions were hold at 115C for 20h. After cooling down and releasing the pressure the raw mixtures were filtered through a short path of Al2O3 and the conversion was determined via GC.
A suspension of NaH (1.3 g, 52.4 mmol) in THF (150 mL) was refluxed at 65C, and ethyl 4-bromobenzoate 10.0 g, 43.7 mmol) was added, followed by the slow addition of CH3CN (5.4 g, 130.9 mmol) (H2 evolution). The reaction mixture was then refluxed for 4 h, cooled to rt, and 6- fluoro-2H-3,1-benzoxazine-2,4(1 H)-dione (7.9 g, 43.7 mmol) was added. The reaction mixture was refluxed for 16 h (precipitate appears) and then cooled to rt. Water (1 L) was added, and the pH was adjusted to ~ 6 using HCI (1 N solution in water). After stirring for 30 min, the solid was collected by filtration and rinsed with water. Example 93 was obtained as a solid (10 g, 70%) after drying under mechanical vacuum at 40C. 1H NMR (400 MHz, DMSO-Of6) 12.95 (s, 1 H), 7.86 (m, 2H), 7.75 (m, 5H); ES-MS m/z 343.2 [M+H]+, LCMS RT (min) 2.74.
With copper(l) iodide; caesium carbonate; dimethylbiguanide; In N,N-dimethyl-formamide; at 20 - 110℃; for 20.1667h;
General procedure: A 25 mL flask with a magnetic stirring bar was charged with CuI(9.6 mg, 0.05 mmol), metformin (0.1 mmol), Cs2CO3 (652 mg,2.0 mmol), imidazole (1.0 mmol), an aryl halide (1.1 mmol), andDMF (5 mL). The mixture was stirred for 10 min at room temperature,and then heated to 110?C for the appropriate amount of time(see Table 2). The progress of the reaction was monitored by TLC.After completion of the reaction, the mixture was extracted with EtOAc (5 1 mL) and the organic phase separated and evaporated. Further purification by column chromatography gave the desired coupled product.
Example 2: Synthesis of 1-bromo-4-(1-methoxy-1-methyl-ethyl)-benzene:A mixture of 6.87 g of ethyl 4-bromobenzoate (10) was allowed to react with 64 mL(1.4 M in toluene) of methyl magnesium bromide in THF at -4O0C for 1 hour, and the reaction mixture was gradually warmed to O0C. The reaction was quenched with saturated aqueous ammonium chloride solution and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with brine, was dried over magnesium sulfate, was filtered, and the solvent was removed in vacuo. Purification by silica gel chromatography (50:1 to 10:1 EPO <DP n="23"/>hexanes-ethyl acetate) afforded 6.44 g (99% yield) of 2-(4-bromophenyl)propan-2-o1 ; MS (AP/CI) observed: 199.1 (M+H - H2O)+, 100%; 213.1 , 215.1 (M-H)", 60%, 80%. 2-(4- Bromophenyl)propan-2-o1 (1.77 g) and iodomethane (1.16 g) in THF (100 mL) were treated with sodium hydride, 60% in mineral oil (328 mg). After stirring for 24 h at room temperature, the reaction mixture was quenched with dilute aqueous hydrochloric acid, was extracted with ethyl acetate, and the organic layer was washed with brine, was dried over magnesium sulfate, was filtered, and the solvent was removed in vacuo. The resultant oil was purified by silica gel chromatography (200:1 hexanes-ethylacetate) to afford 0.5 g of 1-bromo-4-(1- methoxy-1-methyl-ethyl)-benzene; 13C NMR (400 MHz, CDCI3) delta 145.35, 131.53, 127.91 , 121.00, 50.90, 28.60.
Methylmagnesiura bromide solution (1.4M in 75:25 toluene:THF, 20 mL, 28mmol) was added slowly to ethyl 4-bromobenzoate (2-1, 2.52g, 1 l.Ommol) in THF (1OmL) at -30 0C. After 2hr, the mixture was quenched with ammonium chloride and extracted with ether. The organic layer was washed with 1:1 brine: water, dried over magnesium sulfate, filtered and concentrated to give the title compound as a pale yellow oil (J. Am. Chem. Soc. 1971, 93, 6877).
Methylmagnesium bromide solution (1.4M in 75:25 toluene:THF, 20 rnL, 27.5mmol) was added slowly to ethyl 4-bromobenzoate (2.5 g, 11 mmol) in THF (1OmL) at - 300C. After 2hr, quenched with ammonium chloride and extracted with ether. The organic layer was washed with 1 : 1 brine :water, dried over magnesium sulfate, filtered, and concentrated to give 1-1 as a pale yellow oil. MS: 119.1 (M- 17).
In tetrahydrofuran; at -30 - 25℃; for 16h;
To a mixture of A-37 (2.14 mL, 13.10 mmol) in THF (80 mL) was added MeMgBr (3 M, 26.20 mL, 6.00 eq) dropwise at -30C. The reaction mixture was allowed to warm to room temperature and stirred at 25C for 16 hours. The reaction was quenched with sat.NH4Cl (200 mL), extracted with EtOAc (200 mL x 2), and the combined organic layers were washed with I_0 (200mL x 2), brine (100 mL), dried over Na2S04, filtered and concentrated to give A-38 (2.80 g, crude) as an oil. 1H NMR (400MHz DMSO-d6) _ = 7.50 - 7.44 (m, 2H), 7.44 - 7.38 (m, 2H), 5.10 (s, 1H), 1.40 (s, 6H).
With nitric acid; sodium hydrogencarbonate; In water; ethyl acetate;
Step A Ethyl 4-Bromo-3-nitrobenzoate At 0 C., to a stirred solution comaining 35 mL of concentrated nitric acid was added 3.5 g (15.3 mmol) of ethyl 4-bromobenzoate. After 30 min at 0 C., the reaction mixture was treated with ice and ethyl acetate was added. The phases were separated, and the organic phase was treated with 5% NaHCO3, water, and brine, and dried over anhydrous Na2 SO4. Evaporation of volatiles gave 3.68 g (88%) of a white solid, homogeneous by TLC (4/1 hexane/EtOAc); mass spectrum (EI) m/e 273, 275 (M+). 200 MHz 1 H NMR (CDCl3) delta1.41 (t,J=7.2 Hz, 3 H), 4.42 (q, J=7.2 Hz, 2 H), 7.83 (d, J=8.3 Hz, 1 H), 8.07 (dd, J=1.9, 8.3 Hz, 2H), 8.44 (dd, J=1.9 Hz, 1 H)
With copper(II) ferrite; potassium tert-butylate; In N,N-dimethyl-formamide; at 155℃; for 24h;Inert atmosphere;
General procedure: To a solution of N-heterocycle (1 equiv), bromobenzene (1.02 equiv) and tBuOK (2 equiv) in dry DMF, CuFe2O4 (10 mol %) was added and heated at reflux for 24 h under N2 atmosphere. After cooling to room temperature, the mixture was diluted with ethyl acetate and the catalyst was separated by a magnetic separator. The catalyst was washed with ethyl acetate. The combined ethyl acetate layer was washed with water (twice), dried over anhydrous Na2SO4, and concentrated to yield the crude product, which was further purified by silica gel column chromatography using petroleum ether/ethyl acetate to yield N-arylated product.
In N,N-dimethyl-formamide; at 80℃; for 24h;Inert atmosphere; Sealed vial;
General procedure: Carboxylic acid (0.5 mmol) and MImC (2a, 1.0 mmol) were placed in a dry 20 mL vial with a Teflon tape-coated thread. A magnetic stirbar was added, followed by dry MeCN (1.0 mL), and the vial was quickly sealed with a plastic cap (gas is evolved during the course of the reaction. All experiments should be performed behind a blast shield if a sealed container is used.). The reaction mixture was then stirred at 23 C for 15 min and then heated to 80 C using a heating block for 24 h. The mixture was cooled to room temperature and then the vial was carefully opened (CAUTION: vial under pressure.). The volatiles were removed in vacuo, the resulting residue was dissolved in diethyl ether (20 mL), and then washed with 1 M HCl (10 mL). The aqueous layer was back-extracted with diethyl ether (20 mL) and the organic fractions were combined, washed with a saturated solution of NaHCO3 and then brine, dried over MgSO4, and concentrated in vacuo to afford the desired ester.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 140℃; for 0.333333h;Sealed tube;
INTERMEDIATE 116: ethyl 4-(5-((((R)-2-((R)-1-(N- (benzyloxy)formamido)propy moyl)furan-2-yl)benzoate Step 1 : ethyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate Ethyl 4-bromobenzoate (0.356 mL, 2.183 mmol), bis(pinacolato)diboron (0.665 g, 2.62 mmol), potassium acetate (0.857 g, 8.73 mmol), PdCI2(dppf)-CH2CI2 (0.089 g, 0.109 mmol) in 1 ,4-dioxane (20 mL) was placed in a microwave vial. The vial was sealed and heated to 140 C for 20 min in iwave. The reaction was diluted with EtOAc (100 mL) and brine (100 mL) and passed through a pad of celite. The organic phase was passed through a phase separator and the organic phase was concentrated. Purification by Si (0-100% EtOAc/Hex) afforded the title compound as a yellow oil. (876 mg, 67 % yield). MS (m/z) 277.2 (M+H)+
General procedure: To a well stirred mixture of AgF (0.51 g, 4 mmol) in 5 ml of propionitrile Me3SiCF3 (0.57 g, 4 mmol) was added at room temperature. The mixture was stirred for 20 min and copper powder (0.51 g, 8 mmol) was added. After stirring for 4 h, the formation of ?CuCF3? was complete. The corresponding halogen containing aromatic derivative (4 mmol) was added and the reaction mixture was stirred for up to 6 h at ambient temperature and for additional 12 h at 75-80 C. The reaction was terminated after signals of CuCF3 were no longer detected in the 19F NMR spectra. The mixture was filtered from precipitates and 15 ml of diethyl ether were added. The mixture was washed with water and dried over MgSO4. The solvent was evaporated and the remainder was crystallized or distilled from the organic phase under reduced pressure.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 6h;Inert atmosphere;
General procedure: A round-bottomed flask was charged with Pd2(dba)3 (5 mol percent ), ligand (10 molpercent), aryl halide (1mmol), appropriate isoquinolinamine (1 mmol), base (1.5 mmol) and dry solvent (5 mL). Theflask was flushed with argon for 5 min. The mixture was heated at reflux under magnetic stirring.After cooling down to room temperature, the reaction mixture was concentrated and the residuewas purified by flash column chromatography on silica gel.
General procedure: Under Ar atmosphere in a dry Schlenk tube, a mixture of NaH (6.0 mmol) and trifluoroacetate (6.0 mmol) was stirred in THF (5 mL) at room temperature for 10 min. To this mixture enolizable ketones (5.0 mmol) in THF (5 mL) was added dropwise at 0 C under Ar atmosphere. After stirring for 2-6 h at reaction temperature, the reaction solution was cooled to 0 C again and quenched with 6 mL of 1 mol/L HCl. After stirring for additional 15 min, the mixture was neutralized with saturated NaHCO3 solution. After usual workup, the residue was purified by chromatography on silica gel to afford the trifluoromethyl alkyl ketone products.
Preparation Example 9 Under an argon gas atmosphere, n-butyllithium (1.63 M n-hexane solution, 2.41 mL) was added to a THF (3.0 mL) solution of <strong>[514797-99-0]3-chloro-5-fluoropyridine</strong> (517 mg) under cooling at -78 in a dry ice/acetone bath, followed by stirring for 0.5 hours, and then zinc chloride (0.5 M THF solution, 7.86 mL) was added thereto, followed by stirring again for 0.5 hours at the same temperature. After the temperature was elevated to room temperature, a THF (3.0 mL) solution of ethyl 4-bromobenzoate (300 mg) and tetrakis(triphenylphosphine)palladium (303 mg) were added thereto, followed by stirring under heating for 16 hours at an oil temperature of 60 C., and cooling to room temperature. 1 M hydrochloric acid was added to the reaction liquid, followed by diluting with ethyl acetate, washing with saturated brine, drying, and then concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining ethyl 4-(3-chloro-5-fluoropyridin-4-yl)benzoate (194 mg).
ethyl 4-(3,5-difluoropyridin-4-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80 mg; 83 mg
Preparation Example 8 Lithium diisopropylamide (2.0 M heptane/THF/ethylbenzene solution, 5.57 mL) was added to a THF (7.5 mL) solution of <strong>[71902-33-5]3,5-difluoropyridine</strong> (1.26 g) under an argon gas atmosphere at -78° C. with dry ice/acetone, followed by stirring for 0.5 hours, and then zinc chloride (1.55 g) was added thereto, followed by stirring again for 0.5 hours at the same temperature. After the temperature was elevated to room temperature, a N-methylpyrrolidin-2-one (NMP) (7.5 mL) solution of ethyl 4-bromobenzoate (0.50 g) and tetrakis(triphenylphosphine)palladium (0.50 g) were added thereto, followed by stirring under heating for 8 hours at an oil temperature of 100° C., and cooling to room temperature. 1 M hydrochloric acid was added to the reaction liquid, and then the generated solid was collected by filtration, thereby obtaining 4-(3,5-difluoropyridin-4-yl)benzoic acid (Preparation Example 8-1, 80 mg). The filtrate was diluted with ethyl acetate and then washed with saturated brine, followed by drying and then concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining ethyl 4-(3,5-difluoropyridin-4-yl)benzoate (Preparation Example 8-2, 83 mg).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos; In toluene; at 100℃;
A. solution of the compound 4 (1.0 g, 4.4 mmoi). ethyl 4-bromobenzoar.e (943 nig, 4.4 mmol), Pd2(dba)3 (202 mg, 0.22 mmol), Ruphos (103 mg, 0.22 nunol) arid Cs2CO3 (2.9 g, 8.8 inmol) in toluene (25 in) was stirred at 100C overnight. The mixture was concentrated and purified by silica gel column with EA:PE = 1:5 to affbrd compound 5 (1.0 g, 59%) as a light yellow solid.
tert-butyl 5-(4-(ethoxycarbonyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃; for 24h;
A 100-mE round-bottom flask was charged with ethyl 4-bromobenzoate (500 mg, 2.18 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (226 mg, 0.22 mmol), 2,2?-bis(diphenylphosphino)-l , 1 ?-binaphthyl (261 mg, 0.44 mmol), cesium carbonate (2.14 g, 6.57 mmol), toluene (20 mE) and tert-butyl 2,5-diazabicyclo[2.2. 1]hep- tane-2-carboxylate (521 mg, 2.61 mmol). The resulting solution was stirred for 24 hat 1100 C. The reaction was cooled to room temperature and quenched by the addition of water (20 mE). The resulting solution was extracted with of dichloromethane (4x20 mE). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative thin layer chromatography eluting with ethyl acetate/petroleum ether (1:10 to 1:1, v/v). The collected fractions were combined and concentrated under vacuum to afford tert-butyl 5-(4-(ethoxycarbonyl)phenyl)-2,5-diaza-bicyclo[2.2. 1 ]heptane-2-carboxylate as a yellow oil (700 mg, 92%). ECMS:(ESI) mlz 347 [M+H].
ethyl 4-(9-(β-naphthalen)-10-anthryl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With palladium diacetate; potassium carbonate; triphenylphosphine; In 1,2-dimethoxyethane;Inert atmosphere; Reflux;
To a 150 mL reaction flask was charged 2.26 g of 9- (beta-naphthalene) -10-anthraceneboronic acid, 1.13 g of ethyl 4-bromobenzoate, 0.056 g of palladium acetate, 0.26 g of triphenylphosphine, 2.5 mL of 2 mol / L potassium carbonate, and then the reaction flask was evacuated and filled with nitrogen three times, adding ethylene glycol dimethyl ether, reflux. After the completion of the reaction, water was added to the reaction system and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, suction filtered and spin-dried. The product was chromatographed on silica gel (200 300 mesh), petroleum ether and ethyl acetate Separation and purification by column gave ethyl 4- (9- (beta-naphthalene) -10-anthryl) benzoate (2.01 g, 89%).
With bis(benzonitrile)palladium(II) dichloride; 1,8-diazabicyclo[5.4.0]undec-7-ene; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 80℃; for 24h;Inert atmosphere;
General procedure: Pd(PhCN)2Cl2 (1.9 mg, 5.00 mumol, 1 mol%), Xantphos 1.9 mg, 10.0 mumol, 2 mol%), bromoarene (0.500 mmol), 123)(226 mg, 1.00 mmol, 2.0 eq), and toluene (1.0 mL) were addedto a 10 mL test tube with a septum containing a magnetic stirring bar. The tube was evacuated and backfilled with Ar three times. DBU (150 muL, 1.00 mmol, 2.0 eq) was added to the mixture using a syringe through the septum. The tube was screw-capped and warmed to 80C in an oil bath. The mixture was stirred for 24 h. After cooling to r.t., the mixture was quenched with aq. citric acid (10% (w/v)), diluted with CH2Cl2and H2O, extracted with CH2Cl2 from aqueous layer, washed with H2O, aq. Na2CO3 (0.5 M), and brine, dried over Na2SO4,filtered, and concentrated. The obtained residue was purified by preparative TLC (SiO2, hexane-EtOAc 30 : 1) to afford the desired ester.
ethyl 4-[6-(dimethylamino)pyridazin-3-yl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With bis(bipyridine)nickel(II) bromide; tetrabutylammomium bromide; In ethylene dibromide; N,N-dimethyl-formamide; at 20.0℃;Inert atmosphere; Electrochemical reaction;
General procedure: To an undivided electrochemical cell, fitted with an iron/nickel (64/36) rod as the anode and surroundedby a nickel foam as the cathode, were added DMF (50 mL), tetrabutylammonium bromide (1.2 mmol, 400mg), and 1,2-dibromoethane (2.5 mmol, 215 muL). The mixture was electrolyzed under argon at a constantcurrent intensity of 0.2 A at room temperature for 15 min. The current was then stopped, and the NiBr2bpycomplex (0.4 mmol, 150 mg), 3-amino- or 3-alkoxy/aryloxy-6-chloropyridazine (4 mmol), and aromatic orheteroaromatic halides (8 mmol) were sequentially added. The solution was electrolyzed at 0.2 A at roomtemperature until one of the starting materials was totally consumed. A saturated aqueous solution of EDTAsodium salt (100 mL) was added to the mixture, and the solution was extracted with dichloromethanecontaining 2-5% methanol (3 × 100 mL). The combined organic layers were dried over MgSO4, filtered,and evaporated under vacuum. The crude product was purified by flash chromatography on silica, elutedwith a gradient of solvents (pentane/acetone). For some polar cross-coupling compounds, a mixture ofacetone/methanol (95/5) was necessary.
ethyl 4-(6-ethoxypyridazin-3-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With bis(bipyridine)nickel(II) bromide; tetrabutylammomium bromide; In ethylene dibromide; N,N-dimethyl-formamide; at 20.0℃;Inert atmosphere; Electrochemical reaction;
General procedure: To an undivided electrochemical cell, fitted with an iron/nickel (64/36) rod as the anode and surroundedby a nickel foam as the cathode, were added DMF (50 mL), tetrabutylammonium bromide (1.2 mmol, 400mg), and 1,2-dibromoethane (2.5 mmol, 215 muL). The mixture was electrolyzed under argon at a constantcurrent intensity of 0.2 A at room temperature for 15 min. The current was then stopped, and the NiBr2bpycomplex (0.4 mmol, 150 mg), 3-amino- or 3-alkoxy/aryloxy-6-chloropyridazine (4 mmol), and aromatic orheteroaromatic halides (8 mmol) were sequentially added. The solution was electrolyzed at 0.2 A at roomtemperature until one of the starting materials was totally consumed. A saturated aqueous solution of EDTAsodium salt (100 mL) was added to the mixture, and the solution was extracted with dichloromethanecontaining 2-5% methanol (3 × 100 mL). The combined organic layers were dried over MgSO4, filtered,and evaporated under vacuum. The crude product was purified by flash chromatography on silica, elutedwith a gradient of solvents (pentane/acetone). For some polar cross-coupling compounds, a mixture ofacetone/methanol (95/5) was necessary.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
