* 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 bromine In acetic acid; ethyl acetate at 100℃; for 8 h; Stage #2: With sodium hydrogencarbonate In water at 0 - 20℃;
EXAMPLE 29A 4-Bromo-1-phenyl-1H-pyrazole To 1-phenylpyrazole (Aldrich, 1 g, 6.94 mmol) in 10 mL acetic acid was added 1.1 g of Br2 (Fisher, 6.94 mmol) in 10 mL acetic acid. This mixture was warmed to 100° C. in a pressure tube for 8 h. The material was cooled to ambient temperature, poured into ice and H2O in a 500 mL beaker and excess saturated, aqueous NaHCO3 was added until all the acetic acid had been quenched. EtOAc (50 mL) was added and the layers were separated. The aqueous layer was extracted 2*15 mL EtOAc and the combined organics were dried over Na2SO4 and concentrated under reduced pressure to give a crude solid. Purification via flash column chromatography (SiO2, 50percent hexanes-EtOAc) gave 1.5 g of the title compound (6.72 mmol, 97percent yield). MS (DCI/NH3) m/z 223, 225 (M+H)+.
97%
With bromine In acetic acid at 100℃; for 8 h;
Example 257A 4-Bromo-1-phenyl-1H-pyrazole A solution of bromine (1.1 g, 6.94 mmol) in acetic acid (10 mL) was added to a mixture of 1-phenylpyrazole (Aldrich, 1 g, 6.94 mmol) in acetic acid (10 mL). This mixture was warmed to 100° C. in a pressure tube for 8 h. The material was cooled to ambient temperature, poured into ice and H2O neutralized with excess saturated, aqueous NaHCO3. Ethyl acetate (50 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2*15 mL) and the combined organic extract was dried over Na2SO4 and concentrated under reduced pressure to give a crude solid. Purification by column chromatography (SiO2, 50percent hexanes-EtOAc) provided the title compound (1.5 g, 6.72 mmol, 97percent yield). MS (DCl/NH3) m/z 223, 225 (M+H)+.
Reference：
[1] Chemistry - A European Journal, 2015, vol. 21, # 34, p. 11976 - 11979
[2] Patent: US2005/65178, 2005, A1, . Location in patent: Page/Page column 31
[3] Patent: US2005/101602, 2005, A1, . Location in patent: Page/Page column 68
[4] RSC Advances, 2016, vol. 6, # 93, p. 90031 - 90034
[5] Tetrahedron Letters, 2007, vol. 48, # 26, p. 4595 - 4599
[6] Organic Letters, 2015, vol. 17, # 12, p. 2886 - 2889
[7] Journal of Medicinal Chemistry, 2016, vol. 59, # 10, p. 4711 - 4723
[8] Gazzetta Chimica Italiana, 1889, vol. 19, p. 131[9] Chemische Berichte, 1890, vol. 23, p. 1452
2
[ 2075-45-8 ]
[ 591-50-4 ]
[ 15115-52-3 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 6, p. 2067 - 2070
Reference：
[1] Gazzetta Chimica Italiana, 1889, vol. 19, p. 131[2] Chemische Berichte, 1890, vol. 23, p. 1452
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[ 59360-06-4 ]
[ 100-63-0 ]
[ 15115-52-3 ]
Reference：
[1] Chemische Berichte, 1904, vol. 37, p. 4641
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[ 20638-31-7 ]
[ 15115-52-3 ]
Reference：
[1] Chemische Berichte, 1890, vol. 23, p. 1452
9
[ 58668-67-0 ]
[ 100-63-0 ]
[ 15115-52-3 ]
Reference：
[1] Chemische Berichte, 1904, vol. 37, p. 4641
[2] Chemische Berichte, 1904, vol. 37, p. 4641
10
[ 59360-06-4 ]
[ 64-19-7 ]
[ 100-63-0 ]
[ 15115-52-3 ]
Reference：
[1] Chemische Berichte, 1904, vol. 37, p. 4641
11
[ 19263-02-6 ]
[ 64-17-5 ]
[ 100-63-0 ]
[ 15115-52-3 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1901, vol. 133, p. 539
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[ 56-23-5 ]
[ 1134-50-5 ]
[ 7726-95-6 ]
[ 15115-52-3 ]
Reference：
[1] Journal of the Chemical Society, 1958, p. 2435
13
[ 15115-52-3 ]
[ 73183-34-3 ]
[ 1002334-12-4 ]
Yield
Reaction Conditions
Operation in experiment
50%
With potassium acetate In dimethyl sulfoxide at 20 - 80℃;
To a solution of compound 4-bromo-l -phenyl- lH-pyrazo Ie (0.5 g, 2.3 mmol) in DMSO (50 mL) was added KOAc (0.66 g, 6.8 mmol), bis(pinacolato)diboron (0.63 g, 2.5 mmol) and .yen.dCb(dpp{) (0.076g, 0.11 mmol) at room temperature. The reaction mixture was stirred overnight at 8O0C. The result mixture was diluted with EA, washed with brine, dried over Na2SO4, concentrated, purified by chromatography (EA:PE=1: 12) to give l-phenyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH- pyrazole (0.3 g, 50percent) as light yellow solid
EXAMPLE 29A 4-Bromo-1-phenyl-1H-pyrazole To 1-phenylpyrazole (Aldrich, 1 g, 6.94 mmol) in 10 mL acetic acid was added 1.1 g of Br2 (Fisher, 6.94 mmol) in 10 mL acetic acid. This mixture was warmed to 100 C. in a pressure tube for 8 h. The material was cooled to ambient temperature, poured into ice and H2O in a 500 mL beaker and excess saturated, aqueous NaHCO3 was added until all the acetic acid had been quenched. EtOAc (50 mL) was added and the layers were separated. The aqueous layer was extracted 2*15 mL EtOAc and the combined organics were dried over Na2SO4 and concentrated under reduced pressure to give a crude solid. Purification via flash column chromatography (SiO2, 50% hexanes-EtOAc) gave 1.5 g of the title compound (6.72 mmol, 97% yield). MS (DCI/NH3) m/z 223, 225 (M+H)+.
97%
With bromine; In acetic acid; at 100℃; for 8h;
Example 257A 4-Bromo-1-phenyl-1H-pyrazole A solution of bromine (1.1 g, 6.94 mmol) in acetic acid (10 mL) was added to a mixture of 1-phenylpyrazole (Aldrich, 1 g, 6.94 mmol) in acetic acid (10 mL). This mixture was warmed to 100 C. in a pressure tube for 8 h. The material was cooled to ambient temperature, poured into ice and H2O neutralized with excess saturated, aqueous NaHCO3. Ethyl acetate (50 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2*15 mL) and the combined organic extract was dried over Na2SO4 and concentrated under reduced pressure to give a crude solid. Purification by column chromatography (SiO2, 50% hexanes-EtOAc) provided the title compound (1.5 g, 6.72 mmol, 97% yield). MS (DCl/NH3) m/z 223, 225 (M+H)+.
5-(1-phenyl-1H-pyrazol-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5%
With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 20 - 85℃; for 42h;
EXAMPLE 29B 5-(1-Phenyl-1H-pyrazol-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic Acid Tert-Butyl Ester To the product of Example 6C (0.5 g, 2.4 mmol) in 15 mL toluene in a pressure tube was added the product of 29A (0.68 g, 3.06 mmol), tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3, Strem, 43 mg, 0.047 mmol), racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP, Strem, 59 mg, 0.094 mmol), and tert-BuONa (0.362 g, 3.8 mmol). This mixture was warmed to 85 C. and stirred for 18 h. At this point, the reaction was incomplete, so additional Pd2(dba)3 (43 mg, 0.047 mmol) and BINAP (59 mg, 0.094 mmol) were added and the mixture stirred for an additional 24 h. The reaction was cooled to ambient temperature, filtered through Celite diatomaceous earth, concentrated under reduced pressure and purified via flash column chromatography (SiO2, 50% hexanes-EtOAc) to give the title compound (40 mg, 0.113 mmol, 5% yield). MS (DCI/NH3) m/z 355 (M+H)+.
5%
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 85℃; for 42h;
Example 257B 5-(1-Phenyl-1H-pyrazol-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic Acid tert-butyl Ester To the product of Example 6C (0.5 g, 2.4 mmol) in 15 mL toluene in a pressure tube was added the product of Example 257A (0.68 g, 3.06 mmol), tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3, Strem, 43 mg, 0.047 mmol), racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP, Strem, 59 mg, 0.094 mmol), and tert-BuONa (0.362 g, 3.8 mmol). This mixture was warmed to 85 C. and stirred for 18 h. At this point, the reaction was incomplete, so additional Pd2(dba)3 (43 mg, 0.047 mmol) and BINAP (59 mg, 0.094 mmol) were added and the mixture stirred for an additional 24 h. The reaction was cooled to ambient temperature, filtered through Celite diatomaceous earth, concentrated under reduced pressure and purified via flash column chromatography (SiO2, 50% hexanes-EtOAc) to give the title compound (40 mg, 0.113 mmol, 5% yield). MS (DCl/NH3) m/z 355 (M+H)+.
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 20 - 80℃;
To a solution of compound 4-bromo-l -phenyl- lH-pyrazo Ie (0.5 g, 2.3 mmol) in DMSO (50 mL) was added KOAc (0.66 g, 6.8 mmol), bis(pinacolato)diboron (0.63 g, 2.5 mmol) and ¥dCb(dpp{) (0.076g, 0.11 mmol) at room temperature. The reaction mixture was stirred overnight at 8O0C. The result mixture was diluted with EA, washed with brine, dried over Na2SO4, concentrated, purified by chromatography (EA:PE=1: 12) to give l-phenyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH- pyrazole (0.3 g, 50%) as light yellow solid
With PEPPSI-iPr; potassium carbonate; In methanol; toluene; at 80℃; for 0.166667h;Microwave irradiation;
Example 12 Preparation of 1-phenyl-4-(thiophen-2-yl)-1H-pyrazole (Formula Ib-i) <strong>[15115-52-3]4-Bromo-1-phenyl-1H-pyrazole</strong> (150 mg, 0.672 mmol), thiophen-2-ylboronic acid (296 mg, 2.31 mmol), PEPPSI-iPr (13.6 mg, 0.062 mmol), and K2CO3 (480 mg, 3.48 mmol) were combined in toluene-methanol (1:1) (2 ml). The reaction mixture was heated under microwave at 80 C. for 10 minutes. The reaction mixture was then filtered and washed with toluene-methanol (5 ml), and the filtrate was concentrated. The crude mixture was then column purified using 15-20% ethyl acetate/hexane to yield 1-phenyl-4-(thiophen-2-yl)-1H-pyrazole (42 mg, yield 27%). The HPLC purity of the final product was 99.32%. LC-MS [M+H] 227 (C13H10N2S+H expected 227.06). The 1H-NMR spectra was in accordance with the chemical structure.
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In methanol; toluene; at 80℃; for 1h;
Example 14 Preparation of 4-(furan-2-yl)-1-phenyl-1H-pyrazole (Formula Ib-iii) <strong>[15115-52-3]4-bromo-1-phenyl-1H-pyrazole</strong> (140 mg, 0.627 mmol), furan-2-ylboronic acid (88.2 mg, 0.941 mmol), Pd(PPh3)4 (70 mg, 0.062 mmol), and Cs2CO3 (400 mg, 1.254 mmol) were combined in toluene-methanol (1:1) (2 ml). The reaction mixture was heated under microwave at 80 C. for 60 minutes. The reaction mixture was then filtered and washed with toluene-ethanol (5 ml), and the filtrate was concentrated. The crude product was column purified using 15-20% ethyl acetate/hexanes, and was then further purified by preparative HPLC to yield the desired 4-(furan-2-yl)-1-phenyl-1H-pyrazole (22 mg, 0.10 mmol 16.7%). The HPLC purity of the final product was 99.72%. LC-MS [M+H] 211 (C13H10N2O+H expected 211.08). The 1H-NMR spectra was in accordance with the chemical structure.
2-(difluoromethoxy)-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline[ No CAS ]
2-(difluoromethoxy)-7-methyl-5-(1-phenyl-1H-pyrazol-4-yl)quinoxaline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18.4%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In N,N-dimethyl-formamide; at 90℃; for 0.5h;Inert atmosphere; Microbiological reaction; Sealed tube;
Intermediate I-1 (15 mg, 0.045 mmol) and <strong>[15115-52-3]4-bromo-1-phenyl-1H-pyrazole</strong> (14.93 mg, 0.067 mmol) were dissolved in DMF (446 muL). PdCl2(dppf)-CH2Cl2 (2.187 mg, 2.68 mumol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 26.8 muL, 0.054 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90 C in the microwave for 30 minutes. The reaction mixture was diluted with DMF, filtered, and purified by preparative HPLC (Method D, 40 to 75% B in 20 minutes) to give Example 2 (3.0 mg, 0.00823 mmol, 18.4%): 1H NMR (500MHz, METHANOL-d4) delta 8.89 (s, 1H), 8.61 (s, 1H), 8.34 (s, 1H), 7.86-7.75 (m, 3H), 7.70-7.56 (m, 2H), 7.55-7.48 (m, 2H), 7.40-7.33 (m, 1H), 2.62 (s, 3H); LC-MS: Method H, RT = 1.18 min, MS (ESI) m/z: 352.9 (M+H)+ Analytical HPLC Method B: 96.6% purity.
tert-butyl 4-(1-phenyl-1H-pyrazol-4-yl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos; In toluene; at 90℃; for 16h;Sealed tube; Inert atmosphere;
A solution of 4-bromo-l -phenyl- l/7-pyrazole (500 mg, 2.24 mmol, 1.00 eq.), tert- butyl piperazine- l-carboxylate (419 mg, 2.25 mmol, 1.00 eq.), NaOtBu (324 mg, 1.50 eq.), DavePhos (45 mg, 0.05 eq.), and Pd2(dba)3 (105 mg, 0.11 mmol, 0.05 eq.) in toluene (10 mL) was stirred in a 30-mL sealed tube under N2 for 16 h at 90 C in an oil bath. The resulting solution was extracted with 2x30 mL EtOAc, and the organic layers were combined and concentrated in vacuo. The residue was purified by silica gel column chromatography using EtOAc / petroleum ether (1/1) to afford 600 mg (82 %) of the title compound as an off-white solid. LC-MS: (ES, m/z): 329.1
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