* 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.
0535] Preparation of 1-(o-tolyl)-1H-pyrazole [0536] Operating protocol A (82 C., 70 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 383 ?l of 2-iodotoluene (3 mmoles), 136 mg of pyrazole (2 mmoles) and 1.2 ml of acetonitrile. [0537] The degree of transformation and selectivity for 1-(o-tolyl)-1H-pyrazole were 100percent. [0538] The residue obtained was purified by silica gel chromatography (eluent: hexane/dichloromethane, 100/0 to 0/100). [0539] 297 mg of a pale yellow oil was obtained, corresponding to a yield of 94percent by weight. [0540] The compound obtained had the following formula: [CHEMMOL-00045]
87%
With 2,2'-biimidazole; copper(II) acetate monohydrate; caesium carbonate In dimethyl sulfoxide at 80℃; for 48 h;
(1) The o-iodobenzene 0.218g (1.0mmol), pyrazole 0.069g (1.0mmol), Cu (OAc)2·H2O 0.030g (0.15mmol), 2,2- biimidazole 0.022g (0.15mmol), cesium carbonate 0.652g (2mmol), DMSO (2mL) was added the reaction tube with a piston, was heated to 80 deg.] C with stirring for 48 hours reaction.(2) TLC until the reaction was complete the reaction was followed ends.After the reaction was cooled to room temperature, diluted with water, extracted with ethyl acetate 3-4 was added, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product.After the end of (3) to obtain the crude product was purified by column chromatography (petroleum ether / ethyl acetate elution) to give the desired product 4 (87percent yield).
83%
With (N,N'-bis(salicylidenate)cyclohexane-1,2-diamine)copper(II); sodium hydroxide In dimethyl sulfoxide at 100℃; for 12 h; Sealed tube
General procedure: Complex 2 (0.05 mmol) was added to a 5 mL of a sealed tube containing the aryl iodide or bromide (0.5 mmol), 1H-pyrazole (0.75 mmol), NaOH (1 mmol), and DMSO (1 mL). The mixture was stirred at 100 °C for 12 h. After being cooled to room temperature, the mixture was quenched with 10 mL H2O and extracted with EtOAc(3 × 20 mL). The combined EtOAc extracts were dried with anhydrous Na2SO4, filtered and the solvent was removed under reduced pressure.The residue was purified by flash column chromatography on silicagel with PE/EtOAc (from 10:1 to 5:1) as the eluent to afford the pure products. All N-aryl pyrazoles reported here are known products and were characterised by 1H NMR, and GC-MS.
65%
With copper(l) iodide; tetrabutylammomium bromide; N-(2-aminoethyl)-N'-{2-[(2-aminoethyl)amino]ethyl}ethane-1,2-diamine In water at 125℃; for 12 h;
General procedure: Iodobenzene (1.0 mmol), imidazole (1.5 mmol), TEPA (2.0 mmol), TBAB (0.3 mmol), CuI (0.1 mmol), and 3 mL H2O were added to a 10 mL flask, which was subsequently capped with a rubber balloon. The mixture was stirred in a preheated oil bath at 125 °C for 12 h. After cooling the mixture to the room temperature, 5 mL water was added and the product was extracted by ethyl acetate (10 mL×3). The combined organic layer was washed by brine (15 mL), dried over anhydrous MgSO4, and evaporated under the reduced pressure. Further purification by silica gel column chromatography (6:1 petroleum ether/ethyl acetate) give the 1-phenyl-1H-imidazole.
40%
With copper diacetate; sodium hydroxide; 3-(diphenylphosphino)propionic acid In 1,4-dioxane at 100℃; for 24 h; Sealed tube
General procedure: Cu(OAc)2 (0.03mmol), L2 (0.06mmol), aryl idione or bromide (0.5mmol), 1H-pyrazole (0.75mmol), NaOH (1mmol), and 1,4-dioxane (1mL) was added into a 5mL tube, then sealed. The mixture was stirred at 100°C for certain time. After cooling to room temperature, the mixture was quenched with 10mL H2O and extracted with EtOAc (3×20mL). The combined EtOAc extracts were dried with anhydrous Na2SO4 and filtrated and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel with PE/EtOAc, as the eluent, to afford the desired products.
Reference：
[1] European Journal of Organic Chemistry, 2004, # 4, p. 695 - 709
[2] Patent: US2003/236413, 2003, A1, . Location in patent: Page 21
[3] Patent: CN104447557, 2017, B, . Location in patent: Paragraph 0050; 0051; 0052; 0053; 0054; 0055
[4] Journal of Chemical Research, 2013, vol. 37, # 10, p. 636 - 637
[5] Synlett, 2006, # 13, p. 2124 - 2126
[6] Tetrahedron Letters, 2009, vol. 50, # 42, p. 5868 - 5871
[7] Tetrahedron, 2013, vol. 69, # 30, p. 6230 - 6233
[8] Chinese Chemical Letters, 2014, vol. 25, # 5, p. 775 - 778
[9] Synlett, 2012, vol. 23, # 19, p. 2763 - 2767
2
[ 615-37-2 ]
[ 95-52-3 ]
Reference：
[1] Journal of the American Chemical Society, 2012, vol. 134, # 26, p. 10795 - 10798
3
[ 615-37-2 ]
[ 4387-36-4 ]
Reference：
[1] Patent: US4124631, 1978, A,
4
[ 615-37-2 ]
[ 26260-02-6 ]
Reference：
[1] Helvetica Chimica Acta, 1925, vol. 8, p. 441
[2] Journal of the Chemical Society, 1958, p. 1375,1378
5
[ 615-37-2 ]
[ 7745-92-8 ]
[ 5326-38-5 ]
[ 6277-17-4 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1988, p. 1281 - 1286
6
[ 615-37-2 ]
[ 609-67-6 ]
Reference：
[1] Patent: CN107987057, 2018, A,
7
[ 615-37-2 ]
[ 5159-41-1 ]
Reference：
[1] Journal of the Chemical Society, 1958, p. 1375,1378
8
[ 615-37-2 ]
[ 40400-13-3 ]
Yield
Reaction Conditions
Operation in experiment
69%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethaneReflux
A mixture of l-iodo-2-methylbenzene (0.5 g, 2.3 mmol), N-bromosuccinimide (0.7 g, 3.7 mmol) and 2,2'-azobisisobutyronitrile (0.02 g, 0.1 mmol) in tetrachloromethane (10 mL) was heated at reflux until the reaction was completed (tic control). After cooled down to the ambient temperature the reaction mixture was quenched with water and water layer was extracted with dichloromethane. Combined organic phases were washed with sodium hydrocarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; hexane/ethyl acetate 9: 1) to give l-(bromomethyl)-2-iodobenzene (0.5 g) as yellowish oil; yield 69percent.
Reference：
[1] Patent: WO2017/68064, 2017, A1, . Location in patent: Page/Page column 188; 189
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1985, p. 1583 - 1588
[3] Journal of the Chemical Society, 1941, p. 487,489
[4] American Chemical Journal, 1882, vol. 4, p. 101
[5] Journal of the Chemical Society, 1958, p. 1375,1378
[6] Canadian Journal of Chemistry, 1988, vol. 66, p. 2256 - 2258
[7] Advanced Synthesis and Catalysis, 2004, vol. 346, # 7, p. 767 - 776
[8] Angewandte Chemie - International Edition, 2012, vol. 51, # 16, p. 3826 - 3831
9
[ 128-08-5 ]
[ 615-37-2 ]
[ 40400-13-3 ]
Reference：
[1] Patent: US5180741, 1993, A,
10
[ 615-37-2 ]
[ 40400-15-5 ]
Reference：
[1] Journal of the Chemical Society, 1941, p. 487,489
11
[ 615-37-2 ]
[ 116632-39-4 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1912, vol. 31, p. 271
12
[ 615-37-2 ]
[ 7745-92-8 ]
[ 5326-38-5 ]
[ 6277-17-4 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1988, p. 1281 - 1286
13
[ 615-37-2 ]
[ 5326-38-5 ]
Reference：
[1] Chemische Berichte, 1897, vol. 30, p. 3000
[2] Justus Liebigs Annalen der Chemie, 1871, vol. 158, p. 347
[3] Chemische Berichte, 1897, vol. 30, p. 3000
[4] Journal of the Chemical Society, 1929, p. 2742
[5] Journal of the American Chemical Society, 1919, vol. 41, p. 2041
14
[ 615-37-2 ]
[ 7664-93-9 ]
[ 5326-38-5 ]
Reference：
[1] Journal of the Chemical Society, 1929, p. 2742
[2] Journal of the American Chemical Society, 1919, vol. 41, p. 2041
15
[ 615-37-2 ]
[ 90794-29-9 ]
Reference：
[1] Journal of the Chemical Society, 1941, p. 487,489
16
[ 615-37-2 ]
[ 39959-51-8 ]
Reference：
[1] American Chemical Journal, 1882, vol. 4, p. 101
17
[ 615-37-2 ]
[ 62-53-3 ]
[ 1205-39-6 ]
Yield
Reaction Conditions
Operation in experiment
70%
With potassium hydroxide In dimethyl sulfoxide at 120℃; for 16 h; Inert atmosphere
To a mixture of 0.05 g catalyst and aryl iodide (1.0 mmol) in9.0 cm3 DMSO, amine (1.2 mmol) and KOH (1.5 mmol)was added and the mixture was vigorously stirred at 120 Cfor appropriate time under a dry nitrogen atmosphere. Afterthe completion of the reaction, the catalyst was filtered offand washed with water followed by acetone and dried inoven. The filtrate was extracted with ethyl acetate(3 9 20 cm3) and the combined organic layers were driedwith anhydrous Na2SO4 by vacuum. The filtrate was concentratedby vacuum and the resulting residue was purifiedby column chromatography on silica gel to provide thedesired product. All the products are known and the spectroscopicdata (FT-IR and NMR) and melting points wereconsistent with those reported in the literature [26].
63%
With potassium hydroxide In dimethyl sulfoxide at 140℃; for 22 h; Inert atmosphere
General procedure: In an oven dried 100 mL RB flask, polymer supported Cu(II)catalyst (50 mg, 0.0098 mmol), aryl halide (1 mmol), aromatic amines (1.2 mmol), KOH (1 mmol), and 10 ml DMSO were stirred under nitrogen atmosphere, at 140 °C. The reaction mixtures were collected at different time intervals and identified by GCMS and quantified by GC. After the completion of the reaction, the catalyst was filtered off and washed with water followed by acetone and dried in oven. The filtrate was extracted with ethyl acetate(3 x 20 mL) and the combined organic layers were dried with anhydrous Na2SO4 by vacuum. The filtrate was concentrated by vacuum and the resulting residue was purified by column chromatography on silica gel to provide the desired product.
62%
With potassium hydroxide In dimethyl sulfoxide at 140℃; for 16 h; Inert atmosphere
General procedure: In an oven dried 100 mL round bottom flask, Cu-grafted cat-alyst (0.05 g), aryl halide (1 mmol), aromatic amines (1.2 mmol),KOH (1 mmol), and 10 mL DMSO were stirred under nitrogen atmo-sphere, at 140C. The reaction mixtures were collected at differenttime intervals and identified by GC–MS and quantified by GC.After the completion of the reaction, the catalyst was filtered offand washed with water followed by acetone and dried in oven.The filtrate was extracted with ethyl acetate (3 × 20 mL) and thecombined organic layers were dried with anhydrous Na2SO4byvacuum. The filtrate was concentrated by vacuum and the result-ing residue was purified by column chromatography on silica gelto provide the desired product.
62%
With C104H96N16O8Pd2(4+)*4NO3(1-); sodium t-butanolate In toluene at 110℃; for 18 h;
General procedure: In a 50 mL round bottom flask, the mixture of iodobenzene (2 mmol), amine (2.4 mmol), t-BuONa (3 mmol), and 1 as catalyst (0.05 mol percent) was taken in toluene (10 mL). The reaction mixture was then heated to 110°C and continued for 12–18 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction the aqueous reaction mixture was extracted with ethyl acetate, washed with brine, dried over MgSO4, concentrated, and purified by column chromatography on silica gel which afforded corresponding coupling products (yield 75–96percent).
Reference：
[1] Organometallics, 2012, vol. 31, # 21, p. 7336 - 7338
[2] Applied Organometallic Chemistry, 2014, vol. 28, # 2, p. 81 - 85
[3] Monatshefte fuer Chemie, 2015, vol. 146, # 8, p. 1329 - 1334
[4] Journal of Organometallic Chemistry, 2012, vol. 696, # 26, p. 4264 - 4274
[5] Journal of Molecular Catalysis A: Chemical, 2014, vol. 387, p. 7 - 19
[6] Tetrahedron Letters, 2016, vol. 57, # 14, p. 1532 - 1536
[7] Asian Journal of Chemistry, 2015, vol. 27, # 3, p. 1075 - 1078
[8] Angewandte Chemie - International Edition, 2016, vol. 55, # 42, p. 13219 - 13223[9] Angew. Chem., 2016, vol. 128, # 42, p. 13413 - 13417,5
[10] ACS Catalysis, 2014, vol. 4, # 6, p. 1725 - 1734
18
[ 615-37-2 ]
[ 7745-92-8 ]
[ 5326-38-5 ]
[ 6277-17-4 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1988, p. 1281 - 1286
19
[ 615-37-2 ]
[ 115290-81-8 ]
[ 82248-59-7 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: With potassium carbonate In toluene at 148℃; for 21 h; Heating / reflux Stage #2: With hydrogenchloride In water Stage #3: With sodium hydroxide In water
(R)-N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride:; A 3 -necked 100 ml glass reactor was flushed for 15 min with N2 and subsequently charged with 15 g (90.8 mmol) of the above mentioned (3R)-methyl-3-hydroxy-3- phenylpropylamine (>99 percent ee, chiral HPLC), potassium phosphate (28.9 g, 136.2 mmol) and 1.73 g copper(I)iodide (9.8 mmol, 10 mol-percent). 60 ml of toluene was added to the mixture and the suspension was stirred for 5 min. 12.8 ml (100 mmol) of 2-iodotoluene was added and the reaction mixture was heated to reflux for 24 h. After cooling to room temperature, the suspension was filtered and the filter cake was washed with 60 ml of toluene. 75 ml of water was added to the filtrate and the mixture was stirred for 10 min at room temperature. The aqueous phase was brought to pH 1-2 with 30 percent HCl and the phases were separated. 60 ml of toluene was added to the aqueous phase and aqueous NaOH was added until pH 12-14 of the aqueous phase was reached. After stirring for EPO <DP n="16"/>10 min the phases were separated. The organic phase was evaporated under reduced pressure yielding 25 g of an oil.The oil was redissolved in 80 ml of toluene, warmed to 80 °C and 36 g of a 10 percent HCl- ethyl acetate solution was added dropwise to the solution. During cooling of the solution a white solid precipitated. After 5 h at room temperature, the suspension was filtered and the residue was dried in vacuum at about 50 °C to yield 22 g (75.4 mmol, 83 percent) of (R)- N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride.The (R)-N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride salt was placed in a 100 ml reaction vessel and 55 ml of isopropanol was added. Upon heating to reflux temperature all solids were dissolved. Slow cooling to room temperature gave 18.1 g (82 percent) of colorless (R)-N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride (>99 percent ee, HPLC).
94%
Stage #1: With potassium carbonate In toluene at 148℃; for 21 h; Heating / reflux Stage #2: With hydrogenchloride In water Stage #3: With sodium hydroxide In water
(R)-N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride:; A 3 -necked 100 ml glass reactor was flushed for 15 min with N2 and subsequently charged with 15 g (90.8 mmol) of the above mentioned (3R)-methyl-3-hydroxy-3- phenylpropylamine (>99 percent ee, chiral HPLC), potassium phosphate (28.9 g, 136.2 mmol) and 1.73 g copper(I)iodide (9.8 mmol, 10 mol-percent). 60 ml of toluene was added to the mixture and the suspension was stirred for 5 min. 12.8 ml (100 mmol) of 2-iodotoluene was added and the reaction mixture was heated to reflux for 24 h. After cooling to room temperature, the suspension was filtered and the filter cake was washed with 60 ml of toluene. 75 ml of water was added to the filtrate and the mixture was stirred for 10 min at room temperature. The aqueous phase was brought to pH 1-2 with 30 percent HCl and the phases were separated. 60 ml of toluene was added to the aqueous phase and aqueous NaOH was added until pH 12-14 of the aqueous phase was reached. After stirring for EPO <DP n="16"/>10 min the phases were separated. The organic phase was evaporated under reduced pressure yielding 25 g of an oil.The oil was redissolved in 80 ml of toluene, warmed to 80 °C and 36 g of a 10 percent HCl- ethyl acetate solution was added dropwise to the solution. During cooling of the solution a white solid precipitated. After 5 h at room temperature, the suspension was filtered and the residue was dried in vacuum at about 50 °C to yield 22 g (75.4 mmol, 83 percent) of (R)- N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride.The (R)-N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride salt was placed in a 100 ml reaction vessel and 55 ml of isopropanol was added. Upon heating to reflux temperature all solids were dissolved. Slow cooling to room temperature gave 18.1 g (82 percent) of colorless (R)-N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride (>99 percent ee, HPLC).
82%
Stage #1: With potassium phosphate In toluene for 24 h; Heating / reflux Stage #2: With hydrogenchloride In water Stage #3: With sodium hydroxide In water
(R)-N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride:; A 3 -necked 100 ml glass reactor was flushed for 15 min with N2 and subsequently charged with 15 g (90.8 mmol) of the above mentioned (3R)-methyl-3-hydroxy-3- phenylpropylamine (>99 percent ee, chiral HPLC), potassium phosphate (28.9 g, 136.2 mmol) and 1.73 g copper(I)iodide (9.8 mmol, 10 mol-percent). 60 ml of toluene was added to the mixture and the suspension was stirred for 5 min. 12.8 ml (100 mmol) of 2-iodotoluene was added and the reaction mixture was heated to reflux for 24 h. After cooling to room temperature, the suspension was filtered and the filter cake was washed with 60 ml of toluene. 75 ml of water was added to the filtrate and the mixture was stirred for 10 min at room temperature. The aqueous phase was brought to pH 1-2 with 30 percent HCl and the phases were separated. 60 ml of toluene was added to the aqueous phase and aqueous NaOH was added until pH 12-14 of the aqueous phase was reached. After stirring for EPO <DP n="16"/>10 min the phases were separated. The organic phase was evaporated under reduced pressure yielding 25 g of an oil.The oil was redissolved in 80 ml of toluene, warmed to 80 °C and 36 g of a 10 percent HCl- ethyl acetate solution was added dropwise to the solution. During cooling of the solution a white solid precipitated. After 5 h at room temperature, the suspension was filtered and the residue was dried in vacuum at about 50 °C to yield 22 g (75.4 mmol, 83 percent) of (R)- N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride.The (R)-N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride salt was placed in a 100 ml reaction vessel and 55 ml of isopropanol was added. Upon heating to reflux temperature all solids were dissolved. Slow cooling to room temperature gave 18.1 g (82 percent) of colorless (R)-N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride (>99 percent ee, HPLC).
[00430] In a reaction tube under nitrogen, a mixture of PdCl2(dppf)CH2Cl2 (22 mg; 0.027 mmol) and triethylamine (0.36 ml; 2.58 mmol) in dioxane (4 ml; dried over 4 ? sieves) was sealed and stirred at 80 C. overnight (18 h). After cooling to room temperature, HB(pin) (0.19 ml; 1.31 mmol) and 2-iodotoluene (188 mg; 0.862 mmol) were added and the reaction mixture was stirred at 80 C. GC analysis after 18 h showed a peak at 6.45 mins which was identified by GC/MS as the desired borate compound.
With potassium acetate; In N,N-dimethyl acetamide; at 130℃; for 3h;Schlenk technique; Inert atmosphere;
General procedure: MCM-41-3N-Pd(0) (21mg, 0.01mmol), KOAc (1.5mmol) and aryl iodide 1 (1.0mmol) (if solid) were placed in an oven-dried 20mL Schlenk tube, the reaction vessel was evacuated and filled with argon for three times. Then aryl iodide 1 (1.0mmol) (if liquid), diphenylphosphine (1.2mmol) and DMAc (1mL) were added with a syringe under a counter flow of argon. The reaction mixture was stirred at 130C for 3h. After completion of the reaction, the mixture was cooled to room temperature and diluted with CH2Cl2 (20mL) and filtered. The MCM-41-3N-Pd(0) catalyst was washed with distilled water (2×5mL) and ethanol (2×5mL), and reused in the next run. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel to provide the product 2.
With caesium carbonate;copper(I) oxide; trans-N,N'-bis(pyridin-2-ylmethylene)cyclohexane-1,2-diamine; at 82℃; for 70h;Conversion of starting material;
0535] Preparation of 1-(o-tolyl)-1H-pyrazole [0536] Operating protocol A (82 C., 70 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 383 ?l of 2-iodotoluene (3 mmoles), 136 mg of pyrazole (2 mmoles) and 1.2 ml of acetonitrile. [0537] The degree of transformation and selectivity for 1-(o-tolyl)-1H-pyrazole were 100%. [0538] The residue obtained was purified by silica gel chromatography (eluent: hexane/dichloromethane, 100/0 to 0/100). [0539] 297 mg of a pale yellow oil was obtained, corresponding to a yield of 94% by weight. [0540] The compound obtained had the following formula: [CHEMMOL-00045]
87%
With 2,2'-biimidazole; copper(II) acetate monohydrate; caesium carbonate; In dimethyl sulfoxide; at 80℃; for 48h;
(1) The o-iodobenzene 0.218g (1.0mmol), pyrazole 0.069g (1.0mmol), Cu (OAc)2·H2O 0.030g (0.15mmol), 2,2- biimidazole 0.022g (0.15mmol), cesium carbonate 0.652g (2mmol), DMSO (2mL) was added the reaction tube with a piston, was heated to 80 deg.] C with stirring for 48 hours reaction.(2) TLC until the reaction was complete the reaction was followed ends.After the reaction was cooled to room temperature, diluted with water, extracted with ethyl acetate 3-4 was added, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product.After the end of (3) to obtain the crude product was purified by column chromatography (petroleum ether / ethyl acetate elution) to give the desired product 4 (87% yield).
83%
With (N,N'-bis(salicylidenate)cyclohexane-1,2-diamine)copper(II); sodium hydroxide; In dimethyl sulfoxide; at 100℃; for 12h;Sealed tube;
General procedure: Complex 2 (0.05 mmol) was added to a 5 mL of a sealed tube containing the aryl iodide or bromide (0.5 mmol), 1H-pyrazole (0.75 mmol), NaOH (1 mmol), and DMSO (1 mL). The mixture was stirred at 100 C for 12 h. After being cooled to room temperature, the mixture was quenched with 10 mL H2O and extracted with EtOAc(3 × 20 mL). The combined EtOAc extracts were dried with anhydrous Na2SO4, filtered and the solvent was removed under reduced pressure.The residue was purified by flash column chromatography on silicagel with PE/EtOAc (from 10:1 to 5:1) as the eluent to afford the pure products. All N-aryl pyrazoles reported here are known products and were characterised by 1H NMR, and GC-MS.
65%
With copper(l) iodide; tetrabutylammomium bromide; N-(2-aminoethyl)-N'-{2-[(2-aminoethyl)amino]ethyl}ethane-1,2-diamine; In water; at 125℃; for 12h;
General procedure: Iodobenzene (1.0 mmol), imidazole (1.5 mmol), TEPA (2.0 mmol), TBAB (0.3 mmol), CuI (0.1 mmol), and 3 mL H2O were added to a 10 mL flask, which was subsequently capped with a rubber balloon. The mixture was stirred in a preheated oil bath at 125 C for 12 h. After cooling the mixture to the room temperature, 5 mL water was added and the product was extracted by ethyl acetate (10 mL×3). The combined organic layer was washed by brine (15 mL), dried over anhydrous MgSO4, and evaporated under the reduced pressure. Further purification by silica gel column chromatography (6:1 petroleum ether/ethyl acetate) give the 1-phenyl-1H-imidazole.
40%
With copper diacetate; sodium hydroxide; 3-(diphenylphosphino)propionic acid; In 1,4-dioxane; at 100℃; for 24h;Sealed tube;
General procedure: Cu(OAc)2 (0.03mmol), L2 (0.06mmol), aryl idione or bromide (0.5mmol), 1H-pyrazole (0.75mmol), NaOH (1mmol), and 1,4-dioxane (1mL) was added into a 5mL tube, then sealed. The mixture was stirred at 100C for certain time. After cooling to room temperature, the mixture was quenched with 10mL H2O and extracted with EtOAc (3×20mL). The combined EtOAc extracts were dried with anhydrous Na2SO4 and filtrated and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel with PE/EtOAc, as the eluent, to afford the desired products.
2-Iodotoluene (0.217 g, 1.00 mmol), (CyPF-r-Bu)PdCl2 (7.30 mg, 1.00 x 10'2 mmol), and LiNH2 (0.230 g, 10.0 mmol) in 20.0 mL DME gave 86.8 mg (81%) of o-toluidine as a colorless liquid.
79%
2-Iodotoluene (0.217 g, 1.00 mmol), (CyPF-J-Bu)PdCl2 (7.30 mg, 1.00 x 10"2 mmol), and NaOtBu (0.192 g, 2.00 mmol) in 20.0 mL DME gave 84.7 mg (79%) of o-toluidine as a colorless liquid.
Example 2; Preparation of N-Methyl-3-f2-methylphenoxyVbenzenepropanamine hydrochloride; A 100ml flask was flushed for 15 min with N2 and subsequently charged with 1O g (60.5 mmol) N-methyl-3-hydroxy-3-phenylpropylamine, 15,3 g (72 mmol) potassium phosphate and 1.14 g copper iodide (6.0 mmol, 10 mol-%). 40 ml of toluene followed by 7.7 ml (60 mmol) of 2-iodotoluene were added to the mixture and the suspension was heated to reflux for 20 h. After cooling to room temperature, the suspension was filtered and the residue was washed with 20 ml of toluene. 30 ml of water was added to the filtrate and the mixture was stirred for 15 min at room temperature. The phases were separated and 30 ml of water was added to the toluene phase. The aqueous phase was brought to pH 1 with 30 % HCl. The phases were stirred and separated. The aqueous phase was brought to pH 12 with aqueous NaOH followed by addition of 30 ml toluene. The mixture was heated to 50 C and the phases were separated. The toluene phase was evaporated giving 7.4 g of an oil. EPO <DP n="17"/>5,8 g of the residue was dissolved in 18ml of toluene, warmed to 80 0C and 11,1 g of 7.7 % HCl-ethyl acetate solution was added dropwise to the solution. After 15 min stirring at reflux temperature the solution was cooled to 0 0C with a rate of 10-15 C/h. The precipitate was collected and dried under reduced pressure at 40 C over night. Yield 5.0 g (17.1 mmol, 75 %).The crystals obtained in the before mentioned crystallization were combined with 17 ml of toluene and heated to reflux, causing all solids to dissolve. Upon cooling to room temperature, 4,3 g (86 %) of N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride was collected after filtration and drying at about 50 C under reduced pressure.; Example 4; Preparation of N-Methyl-3 -(2-methylphenoxyVbenzenepropanamine hydrochloride; A 100 ml flask was flushed for 15 min with N2 and subsequently charged with 1O g (60.5 mmol) N-methyl-3-hydroxy-3-phenylpropylarnine, 15,3 g (72 mmol) potassium phosphate and 604 mg copper(I)chloride (6.0 mmol, 10 mol-%). 40 ml of toluene followed by 8.4 ml (66 mmol) of 2-iodotoluene was added to the mixture and the suspension was heated to reflux for 26 h. After cooling to room temperature, the suspension was filtered and the residue washed with 20 ml of toluene. 30 ml of water was added to the filtrate and the mixture was stirred for 15 min at room temperature. The phases were separated and 30 ml of water was added to the toluene phase. The aqueous phase was brought to pH 1 with 30 % HCl. The mixture was stirred and the phases were separated. The aqueous phase was brought to pH 12 with aqueous NaOH followed by addition of 30ml toluene. The mixture was heated to 50 C and the phases were separated. The toluene phase was evaporated giving 7.4 g of an oil.5,8 g of the residue was dissolved in 18ml of toluene, warmed to 80 0C and 11,1 g of 7.7 % HCl-ethyl acetate solution was added dropwise to the solution. After 15 min stirring at reflux temperature the solution was cooled to 0 C with a rate of 10-15 C/h. The precipitate was collected and dried under reduced pressure at 40 C over night. Yield 5.0 g (17.1 mmol, 75 %).The crystals obtained in the before mentioned crystallization were combined with 17 ml of toluene and heated to reflux, causing all solids to dissolve. Upon cooling to room EPO <DP n="19"/>temperature, 4,3 g (86 %) of N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride was collected after filtration and drying at about 50 C under reduced pressure.
85%
Example 3; Preparation of N-Methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride; A 10 ml flask was subsequently filled with I g (6.1 mmol) N-methyl-3-hydroxy-3- phenylpropylamine, 2.6 g (12.2 mmol) potassium phosphate and 0.11 g copper iodide (0.6 mmol, 10 mol-%) under a flow of nitrogen. 15 ml of acetonitrile and 1.17 g 2- iodotoluene (9.2 mmol) were added to the mixture and the suspension was heated to reflux temperature. After heating for about 3O h the mixture was cooled to room temperature. The mixture was filtrated and the residue washed with 15 ml acetonitrile. The organic phase was evaporated and redissolved in 30 ml toluene. 15 ml water was added and the aqueous phase was brought to pH 1 with 30 % aq. HCl. The phases were separated and the aqueous phase was brought to pH 12 with aqueous KOH. 10 ml of toluene was added and the mixture was stirred for 15 min, after which the phases were separated. The combined toluene phases were evaporated giving 1.6 g of an oil.The oil was dissolved in 5 ml of toluene and heated to reflux temperature. 1,85 g of 12 %-HCl-ethyl acetate was added and the solution was cooled to room temperature. After filtration and drying of the residue under reduced pressure at 50 C 1.3 g EPO <DP n="18"/>(4.5 mmol, 71 %) of N-methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride was collected.Recrystallization of the received solids from 4 ml of MEBK gave 1.1 g (85 %) of N- methyl-3-(2-methylphenoxy)-benzenepropanamine hydrochloride after drying under reduced pressure at 50 C.
A mixture of N-methyl-3-hydroxy-3-phenylpropylamine (0.3 g, 1.8 mmol), 2-iodotoluene (0.59 g, 2.7 mmol), cupric sulfate (0.06 g), cesium carbonate (0.65 g, 2.0 mmol) and xylenes (0.5 mL) was stirred under nitrogen at 130-140 C. until reaction completion as determined by 1H NMR. The reaction mixture was cooled to room temperature and filtered, washed with toluene. The filtrate was washed with 5% aqueous ammonia solution and water. The organic layer was evaporated to dryness and the residue dissolved in ethyl acetate (5 mL). A 20% HCl solution in isopropanol (0.5 g) was added and the resulting suspension stirred at 0-5 C., filtered, and washed with more ethyl acetate to give 0.22 g of N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine hydrochloride (Tomoxetine hydrochloride) as an off-white solid. 1H NMR spectrum of the product is identical to that of Example 5.
Example 7; A mixture of N-methyl-3-hydroxy-3-phenylpropylamine (0.3 g, 1.8 mmol), 2- iodotoluene (0.59 g, 2.7 mmol), cupric sulfate (0.06 g), cesium carbonate (0.65 g, 2.0 mmol) and xylenes (0.5 ml_) was stirred under nitrogen at 130- 1400C until reaction completion as determined by 1H NMR. The reaction mixture was cooled to room temperature and filtered, washed with toluene. The filtrate was washed with 5% aqueous ammonia solution and water. The organic layer was evaporated to dryness and the residue dissolved in ethyl acetate (5 ml_). A 20% HCI solution in isopropanol (0.5 g) was added and the resulting suspension stirred at 0-50C, filtered, and washed with more ethyl acetate to give 0.22 g of N-methyl-3-(2-methylphenoxy)-3- phenylpropylamine hydrochloride (Tomoxetine hydrochloride) as an off- EPO <DP n="23"/>white solid. 1H NMR spectrum of the product is identical to that of Example 5.
With [(1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)Cu(O-tBu)]; In benzene; at 50℃;Sealed tube;
A vial was charged with 270 mg (1.20 mmol) of2-iodotoluene or 4-iodotoluene and 105 mg (0.12 mmol) of[(SIMes)2Cu][Cu(CF3)2] in 5.4 mL of DMI/benzene (1.5:7.5)with 90.0 muL (0.95 mmol) of fluorobenzene, as internal standard. After the solution was allowed to stir for five minutes,0.6 mL aliquots were taken and transferred into 5 mL air-tightampules. The ampules were sealed and placed in an oil bath at50 C. The reactions were removed from the oil bath at varioustime intervals and quenched with 0.6 mL of methanol in air.Each aliquot was monitored by 19F NMR spectroscopy for formation of the respective 2-trifluoromethyltoluene or 4-trifluoromethyltoluene product.
General procedure: For the generation of (phen)CuCF3 insitu, a vial was charged with 28.4 mg (0.28 mmol) of CuCl,32.3 mg (0.28 mmol) of KO-t-Bu, and 51.5 mg (0.28 mmol) of1,10-phenanthroline. To the vial, 5.4 mL of DMF was added.The solution was stirred for 0.5 h before the addition of0.042 mL (0.28 mmol) of Me3SiCF3. The solution was stirredfor an additional hour before the introduction of 52.1 mg(0.23 mmol) of 2-iodotoluene or 4-iodotoluene and 90.0 muL(0.95 mmol) of fluorobenzene, as internal standard. After thesolution was allowed to stir for five minutes, 0.60 mL aliquotswere taken and transferred into 5 mL air-tight ampules. Theampules were sealed and placed in an oil bath at 50 C. Thereactions were removed from the oil bath at various time intervals and quenched with 0.6 mL of methanol in air. Each aliquotwas monitored by 19F NMR spectroscopy for formation of therespective 2-trifluoromethyltoluene or 4-trifluoromethyltolueneproduct
With copper(II) ferrite; potassium tert-butylate; In N,N-dimethyl-formamide; at 20℃; for 12h;Green chemistry;
General procedure: 4-Iodoanisole (0.813 mmol, 200 mg), bis(pinacolato)diboron (1.219 mmol, 309 mg) were dissolved in 3 mL of dmf followed by copper ferrite nanoparticles (5mol% with respect to 4-iodoanisole) and potassiumtert-butoxide (1.219 mmol, 137 mg) were added to a 10 mLcapped vial and stirred at RT for time indicated. After stirring, the mixture was diluted with diethyl ether and filtered through celite bed. The filtrate was extracted with water (3 times) and the organic phase was dried over anhydrous MgSO4. The crude product was subjected to analyze by GC-MS. The conversion yield is accurately measured based on the consumption of 4-iodoanisole and the side product formed due to protodeiodination.
With palladium; potassium hydroxide; In water; at 100℃; for 1h;Sealed tube; Green chemistry;
derivativesIn a typical synthesis, sealed tube of 10 mL capacity wascharged with aryl halide (1.0 mmol), (2-phenoxyphenyl) boronicacid (1.2 mmol)/(3-(dimethylamino)phenyl) boronic acid, KOH(2.0 mmol), Pd nanoplates solution (50 L, 0.0005 mmol) in aque-ous medium. The reaction mixture was heated at 100C for 1 h andthen allowed to cool at room temperature. Conversion of aryl halideand the formation of product were monitored by gas chromatog-raphy. The product was extracted with ethyl acetate (3 × 5 mL);died over Na2SO4and the solvent was evaporated under vacuum.The obtained crude product was then purified by column chro-matography using silica gel, (100-200 mesh size) with petroleumether/ethyl acetate (PE-EtOAc, 95:05) as eluent to give pure prod-uct. All products are confirmed by GC-MS (Shimadzu GC-MS QP2010). The representative products were characterized by1H NMRand13C NMR (Bruker UXNMR/XWIN-NMR (300 MHz) or Inova Var-ian VXR Unity (400, 500 MHz) instruments. Chemical shifts () arereported in ppm downfield from an internal TMS standard. Highresolution MS (HR-MS) data were recorded on a QSTAR XL HybridMS-MS mass spectrometer.
With copper(l) iodide; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; at 140℃; for 3h;
A flask was charged with 2-iodotoluene (0.964mL, 7.57 mmol), <strong>[5932-27-4]ethyl-1H-pyrazole-3-carboxylate</strong> (1.00 g,7.14 mmol), Cul (272 mg, 1.43 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.451 mL, 2.86 mmol), and K2CO3 (3.15 g, 22.8 mmol). The reaction mixture was then heated to 140° C. for 3 h. The reaction was then partitioned between CH2C12 and saturated aqueous NH4C1 and separated.The organic layer was washed with water, dried over Na2SO4, filtered and concentrated. The crude was purified via flash chromatography on silica gel (90:10-70:30 hexanes:methyl tert-butyl ether) to give the product (238 mg, 1.03mmol, 14percent) as a colorless oil.
2-(2'-methylbiphenyl-2-yl)-1-methyl-1H-benzoimidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With [ruthenium(II)(eta6-1-methyl-4-isopropyl-benzene)(chloride)(mu-chloride)]2; potassium carbonate; triphenylphosphine; In benzene; at 150℃; for 24h;Sealed tube;
General procedure: In a 30-mL sealed tube, <strong>[2622-63-1]1-methyl-2-phenylbenzimidazole</strong> (1, 0.25mmol), [RuCl2(p-cymene)]2 (0.0125 mmol), Ph3P (0.075 mmol),K2CO3 (0.50 mmol), and iodoarene (0.25 mmol) were combined inanhydrous benzene (2 mL) under air. The mixture was then stirredat 150 °C for 24 h. The mixture was cooled to r.t., diluted with EtOAc, and filtered through a small pad of Celite. The filtrate was concentrated in vacuo and purified by flash chromatography (silicagel, EtOAc?hexane) to give the analytically pure 2-(biphenyl-2-yl)benzimidazoles.
1,10-phenanthroline trifluoroacetic acid cuprous (I)[ No CAS ]
[ 13630-19-8 ]
Yield
Reaction Conditions
Operation in experiment
70%Spectr.
With sodium fluoride; In N,N-dimethyl-formamide; at 140℃; for 8h;
In a nitrogen atmosphere, A polytetrafluoroethylene magnet was placed in a reactor, Followed by addition of 0.20 mmol of Example 1. 1,10-phenanthroline trifluoroacetic acid cuprous (I) complex (phen-CuO2CCF3), 0.20 mmol o-iodotoluene and 0.60 mmol NaF, Finally add 5 mL of N, N-dimethylformamide solvent, After stirring for 8 h at 140 C in a closed system, Cooled to room temperature, Extracted with ether three times, Each time 10 mL, The extract was concentrated on silica gel column chromatography, Eluting with n-pentane as the eluent, To give 2-trifluoromethyltoluene (nuclear magnetic yield 70%).
With palladium diacetate; caesium carbonate; In toluene; at 80℃; for 12h;Sealed tube; Inert atmosphere;
General procedure: In a sealed vial, under nitrogen, p-methylbenzoyldiphenylphosphine (61 Cs2CO3 mg, 0.20 mmol, 1.0 equiv), Pd(OAc)2 (1.4 mg, 0.006 mmol), aryl iodides (0.21mmol, 1.05 equiv), (72 mg, 0.22 mmol, 1.1 equiv) and toluene (0.5 mL) were mixed and stirred at 80 oC for 12 h. When reaction completed, the reaction mixture was directly purified by flash column chromatography on silica gel to give pure product.
(2-(benzo[d]oxazol-2-yl)-3-methylphenyl)(4-fluorophenyl)-methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With norborn-2-ene; trifuran-2-yl-phosphane; potassium carbonate; copper(I) bromide; palladium dichloride; In acetonitrile; at 100℃;Schlenk technique; Inert atmosphere;
In a dry 25 mL Schlenk reaction tube, 65 mg of o-methyl iodobenzene, 236 mg of <strong>[25569-77-1]4-fluorobenzoic anhydride</strong>, 71 mg of benzoxazole, 5.3 mg of palladium chloride,14 mg of tris(2-furyl)phosphine, 43 mg of copper bromide, 56 mg of norbornene, 124 mg of potassium carbonate, and 3 mL of acetonitrile.Under nitrogen atmosphere, stirring was performed at 100C for 16 hours.After the reaction was completed, the mixture was cooled to room temperature and insoluble material was removed by filtration and passed through a silica gel column (volume ratio of ethyl acetate to petroleum ether was 1:10) to obtain 159 mg of a product in a yield of 48%. The reaction process was as follows:
N-methyl-2-phenyl-2-trifluoromethylbenzimidazoline[ No CAS ]
[ 13630-19-8 ]
Yield
Reaction Conditions
Operation in experiment
41%
With potassium carbonate; copper(l) chloride; at 60℃; for 48h;Inert atmosphere;
General procedure: Under a nitrogen atmosphere, a mixture of iodoarene 1a (0.10 mmol), 5a (0.20 mmol, 2.0 equiv), copper(I) chloride (0.30 mmol, 3.0 equiv), and potassium carbonate (0.40 mmol, 4.0 equiv) in propionitrile (1.0 mL) was stirred at 60 C for 2 d, and the reaction was monitored by TLC. After completion of the reaction, supernatant of the reaction mixture was purified by preparative TLC to give trifluorotoluene 2a (88%).
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