* 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.
Reference：
[1] Advanced Synthesis and Catalysis, 2018, vol. 360, # 21, p. 4153 - 4160
3
[ 352-34-1 ]
[ 141-97-9 ]
[ 587-88-2 ]
Reference：
[1] Chemical Communications, 2013, vol. 49, # 60, p. 6767 - 6769
4
[ 352-34-1 ]
[ 201230-82-2 ]
[ 25569-77-1 ]
Reference：
[1] Chemical Communications, 2012, vol. 48, # 9, p. 1320 - 1322
5
[ 352-34-1 ]
[ 371-42-6 ]
Reference：
[1] Chinese Journal of Chemistry, 2010, vol. 28, # 8, p. 1441 - 1443
[2] Organic Letters, 2009, vol. 11, # 22, p. 5250 - 5253
6
[ 616-45-5 ]
[ 352-34-1 ]
[ 54660-08-1 ]
Yield
Reaction Conditions
Operation in experiment
85%
With copper(I) oxide; potassium phosphate; tetra-n-propylammonium bromide In water at 130℃; for 24 h;
The N-nucleophile (2.21 mmol), Cu2O (Sigma-Aldrich, 99.99percent purity, 0.147-0.294 mmol), K3PO4(2.94 mmol), the aryl halide (1.47 mmol), phase transfer catalyst (0.147-0.294 mmol) and water(0.40 mL) were added to a reaction vial and a screw cap was fitted to it. The reaction mixture wasstirred under air in a closed system at 130°C for 24 h, then the heterogeneous mixture was cooledto RT and diluted with dichloromethane. The resulting solution was directly filtered through apad of Celite. The combined organic extracts were dried with anhydrous Na2SO4 and the solventwas removed under reduced pressure. The crude product was purified by silica-gel columnchromatography to afford the N-arylated product. The identity and purity of all products wasconfirmed by 1H and 13C NMR spectroscopic analysis.
82%
With cobalt(II) oxalate dihydrate; caesium carbonate; N,N`-dimethylethylenediamine In water at 120℃; for 24 h; Green chemistry
General procedure: A mixture of cobalt(II) oxalate dihydrate(Sigma-Aldrich, 0.294 mmol), Cs2CO3 (2.94 mmol), pyrrolidinoneor aliphatic amide (1.47 mmol), DMEDA (0.588 mmol),distilled H2O (0.3 mL) and aryl halide (2.205 mmol) were addedto an 8.0-mL reaction vial fitted with a Teflon-sealed screw cap.The reaction mixture was stirred under air in a closed system at120 °C and 130 °C, respectively for 24 h. The heterogeneousmixture was subsequently cooled to r.t. and diluted withCH2Cl2. The combined organic extracts were dried over anhydNa2SO4, filtered and the solvent was removed under reducedpressure. The crude product was loaded into the column usingminimal amounts of CH2Cl2 and was purified by silica gel column chromatography to afford the N-arylated product. Theidentity and purity of products were confirmed by 1H NMR and13C NMR spectroscopic analysis.
Reference：
[1] Tetrahedron Letters, 2011, vol. 52, # 11, p. 1169 - 1172
[2] Synlett, 2015, vol. 26, # 12, p. 1697 - 1701
[3] Advanced Synthesis and Catalysis, 2018, vol. 360, # 11, p. 2178 - 2182
7
[ 352-34-1 ]
[ 802294-64-0 ]
[ 459-31-4 ]
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 70, p. 17697 - 17700
8
[ 462-06-6 ]
[ 108-95-2 ]
[ 352-34-1 ]
[ 1121-86-4 ]
[ 348-52-7 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1987, p. 1167 - 1174
9
[ 462-06-6 ]
[ 352-34-1 ]
[ 348-52-7 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1986, p. 1003 - 1006[2] Zhurnal Organicheskoi Khimii, 1986, vol. 22, # 6, p. 1117 - 1120
[3] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1987, vol. 36, # 11, p. 2424 - 2426[4] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1987, # 11, p. 2609 - 2611
[5] Journal of Organic Chemistry USSR (English Translation), 1986, p. 1003 - 1006[6] Zhurnal Organicheskoi Khimii, 1986, vol. 22, # 6, p. 1117 - 1120
[7] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3548 - 3553
[8] Journal of applied chemistry of the USSR, 1984, vol. 57, # 1 pt 2, p. 121 - 123
[9] Synthesis, 2008, # 5, p. 690 - 692
10
[ 462-06-6 ]
[ 108-95-2 ]
[ 352-34-1 ]
[ 1121-86-4 ]
[ 348-52-7 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1987, p. 1167 - 1174
With 1H-imidazole; palladium diacetate; triethylamine; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane; magnesium chloride In tetrahydrofuran at 90℃; for 0.5 h; Microwave irradiation
To a stirred mixture of aryl or heteroaryl halide(Br, I) (0.5 mmol), potassium mono ethyl malonate (0.75 mmol) in THF (10 mL) taken in a 30 mL microwave vial, was added Pd(OAc)2(5 molpercent), Xantphos (5 mol percent), MgCl2 (0.75), Et3N ( 0.75mmol), imidazole (1 mmol) followed by Co2(CO)8 (0.15mmol). The vial was sealed immediately and microwave irradiated at 90°C for 30min. The reaction mixture was concentrated and diluted with ethyl acetate and water. The ethyl acetate layer was separated, dried over sodium sulphate and concentrated. The crude product obtained was purified by column chromatography to get the pure compound.
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2006, vol. 49, # 9, p. 817 - 827
[2] Patent: WO2012/35421, 2012, A2, . Location in patent: Page/Page column 293
15
[ 352-34-1 ]
[ 52692-09-8 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1927, vol. 36, p. 375,376[2] Chem. Zentralbl., 1927, vol. 98, # I, p. 886
16
[ 352-34-1 ]
[ 364-75-0 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1927, vol. 36, p. 375,376[2] Chem. Zentralbl., 1927, vol. 98, # I, p. 886
[3] Bl. Acad. Belg., vol. <5> 12, p. 824,829
17
[ 371-41-5 ]
[ 352-34-1 ]
[ 330-93-8 ]
Reference：
[1] Catalysis Science and Technology, 2016, vol. 6, # 6, p. 1701 - 1709
[2] Angewandte Chemie - International Edition, 2018, vol. 57, # 14, p. 3752 - 3757[3] Angew. Chem., 2018, vol. 130, p. 3814 - 3819,6
18
[ 352-34-1 ]
[ 330-93-8 ]
Reference：
[1] Angewandte Chemie - International Edition, 2010, vol. 49, # 12, p. 2185 - 2189
19
[ 3054-95-3 ]
[ 352-34-1 ]
[ 7116-38-3 ]
Reference：
[1] Synlett, 2003, # 8, p. 1133 - 1136
20
[ 352-34-1 ]
[ 79-10-7 ]
[ 459-32-5 ]
Yield
Reaction Conditions
Operation in experiment
97%
Stage #1: With lithium tert-butoxide In water at 20℃; for 0.166667 h; Inert atmosphere; Green chemistry Stage #2: With bis-(1-methylimidazole)palladium(II) dichloride In water at 100℃; for 12 h; Green chemistry
General procedure: Under a N2 atmosphere, LiOtBu or KOtBu (3.0 mmol), H2O (2.0 mL) and acrylic acid (1.2 mmol) were added into a Schlenk reaction tube and the mixture was stirred at room temperature for 10 minutes. Then an aryl halide 2 (1.0 mmol) and Pd(II)–Im complex 1 (1.0 molpercent) were added. The mixture was stirred at 100 °C for 12 h. After cooling to room temperature, the reaction mixture was acidified by HCl (4 M) to pH 1 and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel to afford the pure product 5.
Reference：
[1] Journal of Chemical Research, 2013, vol. 37, # 5, p. 294 - 297
[2] Synlett, 2006, # 18, p. 2959 - 2964
[3] Journal of Organic Chemistry, 2004, vol. 69, # 23, p. 8105 - 8107
[4] Reactive and Functional Polymers, 2011, vol. 71, # 7, p. 756 - 765
21
[ 108-31-6 ]
[ 352-34-1 ]
[ 459-32-5 ]
Reference：
[1] Catalysis Science and Technology, 2017, vol. 7, # 17, p. 3692 - 3697
With pyridine; cesium fluoride In dimethyl sulfoxide at 105℃; for 2 h; Inert atmosphere; Schlenk technique
General procedure: An oven-dried Schlenk tube, containing a Teflon-coated magnetic stir bar was charged with CsF (228 mg, 1.5 mmol, 3 equiv) and bispinacolatodiboron (254 mg, 1 mmol, 2 equiv). Under an argon atmosphere, freshly distilled DMSO (0.4 mL), the appropriate aryl iodide (0.5mmol), and pyridine (0.4 to 1 equiv) were added successively. The reaction mixture was heated to 105 °C and stirred for 2 h under argon.
81 %Chromat.
With copper(II) ferrite; potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 12 h; 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 (5molpercent 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.
Reference：
[1] Synthesis (Germany), 2017, vol. 49, # 21, p. 4759 - 4768
[2] Journal of the American Chemical Society, 2017, vol. 139, # 2, p. 607 - 610
[3] Chemical Science, 2016, vol. 7, # 6, p. 3676 - 3680
[4] Catalysis Communications, 2016, vol. 85, p. 61 - 65
28
[ 352-34-1 ]
[ 78782-17-9 ]
[ 214360-58-4 ]
Yield
Reaction Conditions
Operation in experiment
63%
With sodium t-butanolate In tetrahydrofuran; toluene at 80℃; for 6 h; Sealed tube
Fluoro-4-iodobenzene (44 mg, 0.20 mmol), 1,1-diboxomethane (107 mg, 0.40 mmol)And sodium tert-butoxide base (38 mg, 0.40 mmol) was placed in a 4 mL vial.Toluene / tetrahydrofuran (2.0 mL, 1: 1 mixed solution) was then added.This vial was sealed for 6 hours at 80 ° C sealed with a PTFE / silicone coated capThe reaction proceeded. The reaction solution was then filtered through celite using dichloromethane,This organic material was concentrated under reduced pressure. The subsequent productsIn condition Φ 2.0 cm x 8 cm After silica gel column chromatography, n-hexane: diethyl ether,15: 1 eluent.The results showed that 2- (4-Fluorophenyl) -4,4,5,5, -tetramethyl-1,3,2-dioxaborolaneA boronated compound was produced. (28 mg, 63percent yield);
Reference：
[1] Journal of the American Chemical Society, 2017, vol. 139, # 2, p. 975 - 984
[2] Patent: KR2018/12458, 2018, A, . Location in patent: Paragraph 0049; 0050; 0055
29
[ 352-34-1 ]
[ 73183-34-3 ]
[ 99770-93-1 ]
[ 24388-23-6 ]
[ 214360-58-4 ]
Reference：
[1] European Journal of Organic Chemistry, 2013, # 28, p. 6263 - 6266
at 20℃; for 16 h; Schlenk technique; Sealed tube; Inert atmosphere
General procedure: The syntheses of alkyne-substituted aromatic amines (15–18) followed the general Scheme 1. A 50 mL Schlenk flask was charged with aryl iodide (2mmol, 1.0 eq.), bis-(triphenylphosphine) palladium dichloride (70mg, 0.05 eq.), cuprous iodide (10mg, 0.05 eq.), triphenylphosphine (13mg, 0.025 eq.), and a stir bar and sealed with rubber septum [33]. The flask was evacuated and refilled three times with Argon. Ethynylaniline (1.1 eq.) was added to 10mL of distilled dry iPr2NH and degassed together in a separated round bottom flask for 15min and then transferred to the Schlenk flask through cannula. The mixture was stirred for 16hat room temperature (65°C in the case of aryl bromide). After completion of the reaction, the mixture was diluted with ethyl acetate (50mL) and the slurry was filtered through a pad of Celite in a sintered glass funnel (medium frit). The tan solids were additionally washed with ethyl acetate until the filtrate was nearly colorless. The filtrate was washed with H2O and brine and dried over magnesium sulfate. The combined organic fraction filtrates were concentrated in vacuum, yielding a black solid. The residue was further purified by flash column chromatography on silica gel using ethyl acetate/hexane mixture as eluent.
Reference：
[1] European Journal of Medicinal Chemistry, 2016, vol. 118, p. 266 - 275
With tetrabutyl ammonium fluoride;palladium bis[bis(diphenylphosphino)ferrocene] dichloride; In tetrahydrofuran; at 65℃;Inert atmosphere;
Step 1 : Synthesis of 4-bromo-4'-fluoro- 1,1 '-biphenylTo THF (90 mL) degassed by purging argon was added 4- flouroiodobenzene (4.5g, 20.2 mmol), 4-bromophenylboronic acid (4g, 20.2 mmol), and tetrabutylammonium flouride (1M in THF, 40.5 mL, 40.5 mmol), and the mixture was degassed again. Pd(dppf)Cl2 (732 mg, 1 mmol) was added and the mixture was degassed again for 15 minutes. The reaction mixture was heated at 65°C in an oil bath overnight. TLC (heptane eluent) showed the reaction was complete. The reaction mixture was diluted with ethyl acetate and extracted with brine. The organic layer was dried (sodium sulfate) and concentrated to yield the crude product. Purification by column chromatography (60-120 mesh silica, heptane eluent) yielded 3.2 g of 4- bromo-4'-fluoro- 1 , 1 '-biphenyl.
With sodium hydroxide; n-butyllithium; IPr2NH; In tetrahydrofuran; water; ethyl acetate;
Preparation 1 PNU-244019 2-fluoro-5-iodobenzoic acid To a -78 C. solution of iPr2NH (16.80 mL, 0.12 mol) in 200 mL freshly distilled THF is added n-butyllithium (68 mL, 0.11 mol) dropwise, maintaining the temperature of the reaction below -65 C. The reaction is stirred for 10 minutes, then 1-fluoro-4-iodobenzene (11.50 mL, 0.10 mol) as a solution in 10 mL THF is added over 20 minutes. The reaction is stirred at -78 C. for 90 minutes, then cannulated rapidly into diethyl ether (180 mnL) and dry ice (approximately 75 g). The reaction is stirred at room temperature overnight. To the ether solution is added 1N NaOH (100 mL) and water (200 mL) and the solution placed in a separatory funnel. The aqueous layer is removed. The organic layer is washed with H2O (2*100 mL). All the aqueous portions are combined, chilled in ice/H2O, and acidified to pH 2 with 6N HCl. This solution is then extracted with diethyl ether (2*200 mL). The ether portions are combined, dried over Na2SO4, filtered, and concentrated to give a pale yellow solid. The solid is dissolved in a minimal amount of EtOAc on the steam bath, and hexanes are added to affect recrystallization. After standing in the freezer overnight, the product is obtained as a crystalline white solid (15.44 g, 0.058 mol, 58%). Physical characteristics are as follows: m.p. 157-159 C.; 1H NMR (300 MHz, CDCl3) delta 8.34, 7.88, 6.97; IR (drift) 3098, 3079, 3051, 3017, 3007, 2998, 2981, 2971, 2881, 2817, 1708, 1681, 1300, 1236, 824 cm-1; Anal. Calcd for C7H4FIO2: C, 31.61; H, 1.52; Found: C, 31.70; H, 1.59.
With sodium hydroxide; n-butyllithium; IPr2NH; In tetrahydrofuran; diethyl ether; water; ethyl acetate;
Preparation 1 2-fluoro-5-iodobenzoic acid To a -78 C.solution of iPr2NH (16.80 mL) in 200 mL freshly distilled THF is added n-butyllithium (68 mL) dropwise, maintaining the temperature of the reaction below -65 C. The reaction is stirred for 10 minutes, then 1-fluoro-4-iodobenzene (11.50 mL) as a solution in 10 mL THF is added over 20 minutes. The reaction is stirred at -78 C. or 90 minutes, then cannulated rapidly into diethyl ether (180 mL) and dry ice (approximately 75 g). The reaction is stirred at room temperature overnight. To the ether solution is added 1N NaOH (100 mL) and water (200 mL) and the solution placed in a separatory funnel. The aqueous layer is removed. The organic layer is washed with H2O (2*100 mL). All the aqueous portions are combined, chilled in ice/H2O, and acidified to pH 2 with 6N HCl. This solution is then extracted with diethyl ether (2*200 mL). The ether portions are combined, dried over Na2SO4, filtered, and concentrated to give a pale yellow solid. The solid is dissolved in a minimal amount of EtOAc on the steam bath, and hexanes are added to affect recrystallization. After standing in the freezer overnight, the product is obtained as a crystalline white solid (15.44 g, 58%). Physical characteristics are as follows: m.p. 157-159 C.; 1H NMR (300 MHz, CDCl3) delta 8.34, 7.88, 6.97; IR (drift) 3098, 3079, 3051, 3017, 3007, 2998, 2981, 2971, 2881, 2817, 1708, 1681, 1300, 1236, 824 cm-1; Anal. Calcd for C7H4FIO2: C, 31.61; H, 1.52; Found: C, 31.70; H, 1.59.
With n-butyllithium; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; hydrogenchloride; hexane;
PREPARATION 7 2-Fluoro-5-iodobenzoic acid To an argon-covered, stirred solution of 16.8 mL of diisopropylethylamine in 200 mL of THF, cooled at -78 C., is added dropwise 67 mL of a 1.6 M solution of butyllithium in hexane. The solution is allowed to warm to 0 C. and then recooled to -78 C. To this solution is added dropwise 11.5 mL of 4-fluoroiodobenzene in 10 mL of THF. The solution is stirred for 90 min at -78 C, then cannulated rapidly onto a Dry Ice-ether slurry. The mixture is allowed to warm to room temperature, then extracted with 300 mL of 0.3 M NaOH. The aqueous phase is chilled in ice and acidified with 40 mL of 6N HCl. The precipitate is extracted with two portions of ether, and the organic phase dried (MgSO4) and concentrated under reduced pressure. Recrystallization of the residue with ethyl acetate-hexane provides 19.57 g of the title compound as white needles. A second crop of 3.78 g is obtained by recrystallization of the mother liquor residue. Physical properties as follows: 1H NMR (CDCl3) delta 6.97, 7.88, 8.33 ppm. Anal found: C, 31.57; H, 1.59.
With n-butyllithium; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; hydrogenchloride; hexane;
Preparation 28 2-Fluoro-5-iodobenzoic acid To an argon-covered, stirred solution of 16.8 mL of diisopropylethylamine in 200 mL of THF, cooled at -78 C., is added dropwise 67 mL of a 1.6 M solution of butyllithium in hexane. The solution is allowed to warm to 0C and then recooled to -78 C. To this solution is added dropwise 11.5 mL of 4-fluoroiodobenzene in 10 mL of THF. The solution is stirred for 90 min at -78 C., then cannulated rapidly onto a Dry Ice-ether slurry. The mixture is allowed to warm to room temperature, then extracted with 300 mL of 0.3 M NaOH. The aqueous phase is chilled in ice and acidified with 40 mL of 6N HCl. The precipitate is extracted with two portions of ether, and the organic phase dried (MgSO4) and concentrated under reduced pressure. Recrystallization of the residue with ethyl acetate-hexane provides 19.57 g of the title compound as white needles. A second crop of 3.78 g is obtained by recrystallization of the mother liquor residue. Physical properties as follows: 1H NMR (CDCl3) delta6.97, 7.88, 8.33 ppm. Anal found: C, 31.57; H, 1.59.
With potassium carbonate;copper(l) iodide; trans-N,N'-dimethylcyclohexane-1,2-diamine; In N,N-dimethyl-formamide; at 140℃; for 0.333333h;Microwave irradiation;
1-(4-Fluorophenyl)-1 H-indazol-4-amine <n="63"/>A mixture of 1 /-/-indazol-4-amine (750mg, 5.64mmol), copper (I) iodide (247mg, 1.3mmol), potassium carbonate (1.56g, 11.28mmol), frans-/V,W-dimethyl-1 ,2-cyclohexanediamine (0.321g, 2.26mmol) and 4-fluoro-1-iodobenzene (0.78ml, 6.77mmol) in dry DMF (2ml) was heated in a microwave reactor at 14O0C for 20 minutes (potassium carbonate was placed in the tube first and care was taken to avoid any particles of potassium carbonate being left on the side of the tube above the level of the liquid (in order to avoid any superheating). Three identical reactions plus two using 500mg input of 1 /-/-indazol-4- amine were then combined and partitioned between water and dichloromethane. The organic layer was evaporated and the residue purified by silica gel chromatography using the Flashmaster Il (2 x 10Og cartridges) eluting with a 0 to 50% dichloromethane : ethyl acetate gradient over 60 minutes to give the title compound (4.73g). LCMS: tRET = 3.19 min; MH+ = 228
With potassium phosphate;copper(l) iodide; cis-N,N'-dimethyl-1,2-diaminocyclohexane; In 1,4-dioxane; at 110℃; for 24.0h;Heating / reflux;
The 1-(4-fluorophenyl)-2-piperazinone used in the above procedure was prepared as follows:A mixture of 2-piperazinone (1.5 g, 15.0 mmol), 1-fluoro-4-iodobenzene (3.5 ml, 30.0 mmol), copper(l) iodide (0.57 g, 3.0 mmol), N,N'-dimethyl-1 ,2-cyclohexanediamine (0.95 ml, 6.0 mmol) and potassium phosphate (9.5 g, 44.9 mmol) in 1 ,4-dioxane (20 ml) was heated at reflux (1 10 0C) under argon for 24 hours. The mixture was allowed to cool to room temperature and then diluted with methanol, and filtered through a pad of celite, washing with methanol. The filtrate was evaporated in vacuo and the resulting residue was dissolved in dichloromethane and 0.88 aqueous ammonia solution (~5ml) in water (~30ml). The mixture was then extracted into dichloromethane (x3), and the combined organic extracts were washed with water (x1 ) and dried over magnesium sulphate. The solvent was evaporated in vacuo and the crude product was purified further by column chromatography on flash-silica gel, eluting with 0-10percent methanol in dichloromethane. The relevant fractions were combined and the solvent was evaporated in vacuo. The residue was purified by SCX, eluting first with methanol and then with 2M ammonia in methanol. The basic fractions were combined and the solvent was evaporated in vacuo to give crude product which was purified again by flash-silica gel column chromatography, eluting with 20percent 2M ammonia in methanol in dichloromethane, to give 1-(4-fluorophenyl)-2- piperazinone (560 mg) as a colourless solid. LC/MS [M+H]+ = 195.
With potassium carbonate;copper(l) iodide; trans-N,N'-dimethylcyclohexane-1,2-diamine; In N,N-dimethyl-formamide; at 120℃; for 3h;Sealed tube; Inert atmosphere;
A mixture of lH-<strong>[192945-49-6]indazole-4-carboxylic acid methyl ester</strong> (5.0 g, 28 mmol), copper iodide (5.7 g, 3.0 mmol), potassium carbonate (4.15 g, 30.0 mmol) and 4- fluoroiodobenzene (3.47 g, 30.0 mmol) is charged in a sealed tube at room temperature. The tube is evacuated, back-filled with argon and dimethylformamide (20 mL) is added followed by rac-trans-N,N'-dimethylcyclohexane-l,2-diamine (0.93 g, 6.5 mmol). The solution is stirred at 120C for 3 hours, then cooled to room temperature and diluted with water (50 mL) and ethyl acetate (80 mL). The organic layer is separated, washed with brine (30 mL), and dried over sodium sulfate. The crude product is filtered, concentrated and purified by silica gel chromatography eluting with a gradient of 0-30% ethyl acetate in hexanes to afford l-(4-fluoro- phenyl)-lH-<strong>[192945-49-6]indazole-4-carboxylic acid methyl ester</strong>.
With potassium carbonate;trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; at 20 - 120℃;Inert atmosphere; sealed tube;
A mixture of lH-<strong>[192945-49-6]indazole-4-carboxylic acid methyl ester</strong> (5.0 g, 28 mmol), copper(I) iodide (5.7 g, 3.0 mmol), potassium carbonate (4.15 g, 30.0 mmol) and A- fluoroiodobenzene (3.47 g, 30.0 mmol) was charged in a sealed tube at room temperature. The tube was evacuated, back-filled with argon and dimethylformamide (20 mL) was added followed by rac-trans-N,N'-dimethylcyclohexane-l,2-diamine (0.93 g, 6.5 mmol). The solution was stirred at 120 0C for 3 hours. The solution was cooled to room temperature and diluted with water (50 mL) and ethyl acetate (80 mL). The organic layer was separated, washed with brine (30 mL), and dried over sodium sulfate. The crude product was filtered, concentrated and purified by silica gel chromatography eluting with a gradient of 0-30% ethyl acetate in hexanes to afford l-(4-fluoro-phenyl)-lH-indazole-4- carboxylic acid methyl ester.
With potassium carbonate;trans-N,N'-dimethyl-1,2-cyclohexyldiamine; In N,N-dimethyl-formamide; at 20 - 120℃;Inert atmosphere; sealed tube;
A mixture of <strong>[885518-49-0]6-bromo-4-indazolecarboxylic acid methyl ester</strong> (2.0 g, 7.8 mmol), copper(I) iodide (0.4 g, 0.2 mmol), potassium carbonate (1.2 g, 8.5 mmol) and 4- fluoroiodobenzene (1.8 g, 8.5 mmol) was charged in a sealed tube at room temperature. The tube was evacuated and back-filled with argon, and DMF (10 mL) and x&c-trans- N,N'-dimethylcyclohexane-l,2-diamine (0.20 g, 1.4 mmol) was added. The solution was stirred at 120 0C for 3 hours, cooled to room temperature, and diluted with water (30 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with brine (10 mL) and dried over sodium sulfate. The solvent was removed in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0-30% ethyl acetate in hexanes to afford 6-bromo-l-(4-fluoro-phenyl)-lH-indazole-4-carboxylic acid methyl ester.
With (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; potassium carbonate;copper(l) iodide; In toluene;Reflux;
Preparation 116A: Ethyl l-(4-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-4- carboxylateF^>N'^CO2B (1 16A) [00329] To a solution of ethyl 3-(trifluoromethyl)-lH-pyrazole-4-carboxylate (100 mg, 0.480 mmol) in toluene (0.5 mL) was added (lR,2R)-Nl,N2-dimethylcyclohexane-l,2- diamine (13.67 mg, 0.096 mmol), 1 -fluoro-4-iodobenzene (0.166 mL, 1.441 mmol), potassium carbonate (139 mg, 1.009 mmol), and copper(I) iodide (9.00 mg, 0.047 mmol). This reaction was heated to reflux overnight. The next day, the reaction was complete by HPLC so it was filtered through a frit with EtOAc and purified on a Sitheta2 column using 25-100% EtOAc hexanes gradient to give white crystalline ethyl l-(4-fluorophenyl)-3- (trifluoromethyl)-lH-pyrazole-4-carboxylate (140 mg, 0.463 mmol, 96 % yield). The structure was assigned by small molecule X-ray crystallography. 1H NMR (400 MHz, CDCl3) delta ppm 8.35 (1 H, s), 7.62 (2 H, m), 7.14 (2 H, m), 4.25 (2 H, q), 1.37 (3 H, t).
With tris-(dibenzylideneacetone)dipalladium(0); (R)-(-)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine; potassium tert-butylate; lithium chloride; In toluene; at 130℃; for 3h;Inert atmosphere;
General procedure: A flame-dried resealable Schlenk tube was charged with Pd2(dba)3 (0.025 mmol, 2.5 mol %), Josiphos (0.05 mmol, 5 mol %), the solid reactant(s) (1.0 mmol of the <strong>[53406-38-5]1-aminoindole</strong>, 2.0 mmol of the aryl halide), LiCl (2.0 mmol) and KOtBu (1.4 mmol). The Schlenk tube was capped with a rubber septum, evacuated, and backfilled with argon; this evacuation/backfill sequence was repeated one additional time. The liquid reactant(s) and toluene (2 mL/mmol) were added through the septum. The septum was replaced with a teflon screwcap. The Schlenk tube was sealed, and the mixture was stirred at 130 C for 3 h. The resulting suspension was cooled to room temperature and filtered through a pad of celite eluting with ethyl acetate, and the inorganic salts were removed. The filtrate was concentrated and purification of the residue by silica gel column chromatography gave the desired product. All the compounds gave satisfactory spectroscopic data. Data for the selected compounds are given below:Compound 3a: Yield: 94%; TLC : Rf 0.39 (c-hexane/AcOEt 8:2). IR (neat): 3306, 1604, 1508, 1446, 1359, 1246, 1220, 1112, 1063, 832, 754 cm-1; 1H NMR (CDCl3, 300 MHz) : delta 7.55 (dd, 1H, J = 6.5, 2.3 Hz), 7.25-6.95 (m, 4H), 6.65 (d, 2H, J = 8.9 Hz), 6.42 (d, 1H, J = 3.3 Hz), 6.37 (d, 2H, J = 8.9 Hz), 6.32 (s, 1H), 3.62 (s, 3H).13C NMR (75 MHz, CDCl3) delta 154.5, 141.0, 135.9, 128.7, 126.6, 122.3, 121.1, 120.3, 114.7 (2C), 114.2 (2C), 109.5, 100.6, 55.6. m/z MS (ES+) 239.0 (M+H+).Compound 3i: Yield: 63%; TLC : Rf 0.40 (c-hexane/AcOEt 8:2). IR (neat): 3326, 1521, 1466, 1236, 1220, 1125, 1103, 832, 754 cm-1; 1H NMR (CDCl3, 300 MHz) : delta 7.79-7.61 (m, 1H), 7.33-7.10 (m, 4H), 6.99-6.83 (m, 2H), 6.55 (dd, 1H, J = 3.3, 0.7 Hz), 6.54, (br s, 1H), 6.46 (dd, 2H, J = 9.0, 4.4 Hz). 13C NMR (75 MHz, CDCl3) delta 159.4 (d, 1C, JC-F = 237.0 Hz), 143.4, 135.6, 128.5, 126.7, 122.5, 121.2, 120.4, 116.0 (d, 2C, JC-F = 23.5 Hz), 114.0 (d, 2C, JC-F = 8.3 Hz), 109.3, 100.9. m/z MS (ES+) 227.0 (M+H+).
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; potassium carbonate;copper(l) iodide; In N,N-dimethyl-formamide; at 135℃; for 1.5h;
Example 4: Synthesis of l-(4-Fluorophenyl)-lH-pyrrolo[2,3-c]pyridine-4- carboxylic acid (4); A solution of the 4-bomo-6-azaindole (250 mg, 1.3 mmol) (for a synthesis see: Prokopov, A. A.; Yakhontov, L. N. Khim. Geterotsikl. Soedin. 1979, 15, 86; Chem. Heterocycl. Compd. (Engl. Transl.) 1979, 15, 76.), Cul (48 mg, 0.25 mmol), K2C03 (350.0 mmol, 2.54 mmol), iran5-N,N'-dimethyl-cyclohexane-l,2-diamine (50.0 lL, 0.32 mmol) and 4-fluoroiodobenzene (174.0 lL, 1.51 mmol) in DMF (5 mL) is warmed at 135C. After 1.5 hours, the reaction is diluted first with saturated aqueous ammonium chloride (15 mL) and then saturated aqueous sodium bicarbonate (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers are washed with brine (3 x 15 mL), dried over magnesium sulfate, filtered and concentrated. The residue is purified by silica gel chromatography using dichloromethane-hexanes (1 : 1) to load the sample and then eluting with EtOAc-hexanes (5:95) to afford partially purified 4-bromo-l-(4-fluorophenyl)-lH-pyrrolo[2,3-c]pyridine which is used without further purification.
With potassium carbonate;copper(l) iodide; cis-N,N'-dimethyl-1,2-diaminocyclohexane; In N,N-dimethyl-formamide; at 130.0℃; for 1.0h;microwave irradiation;
J-3 (1.50 g, 8.56 mmol) and K2CO3 (1.50 g, 10.9 mmol) in methanol (20 mL) is warmed at reflux for 5 minutes. The mixture is filtered and concentrated to provide J-4. J-4 (1.10 g, 8.26 mmol), Oil (980.0 mg, 5.15 mmol), K2CO3 (2.75 g, 19.9 mmol), N,N- dimethyl-l,2-diaminocyclohexane (150.0 muL, 0.95 mmol) and 4-fluoroiodobenzene (2.40 g, 10.8 mmol) in DMF (13 mL) is warmed at 130C in a microwave reactor. After 1 hour, the reaction is diluted with saturated aqueous NH4C1 (50 mL) and then NaHCO3 is added and the mixture is extracted with EtOAc (3 x 50 mL). The combined organic layers are washed with saturated aqueous NH4C1 (3 x 40 mL), dried over magnesium sulfate, filtered and concentrated. The residue is purified by silica gel chromatography eluting with a gradient of 0-50% EtOAc in hexanes and crystallized from ether-hexanes to provide J-6.
With copper(l) iodide; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In 1,4-dioxane;Inert atmosphere; Reflux;
Synthesis of 6-bro -l-(4-fluorophenyl)-lH-pyrrolo[3, 2-b]pyridineTo a solution of 6-bromo-lH-pyrrolo[3, 2-b]pyridine (100 mg, 0.51 mmol), 1- fluoro-4-iodobenzene (225 mg, 1.02 mmol) and Cs2C03 (496 mg, 1.52 mmol) in dioxane (2 mL) was allowed to stir at room temperature, the Cul (cat) and (IS, 2S)-N,N'-dimethylcyclohexane-l, 2-diamine (cat) were added under N2, and then the mixture was allowed to stir at reflux for overnight. After the reaction mixture was cooled to room temperature and filtrated, the filtrate was concentrated, the resulting residue was purified using prep-TLC (PE : EtOAc = 1 : 1) to provide 6-bromo-l-(4-fluorophenyl)-lH-pyrrolo[3, 2-b]pyridine (80 mg, yield: 50.2%>). 'Eta- NMR (CDCI3, 400 MHz) delta 8.54 (s, 1H), 7.65 (s, 1H), 7.90-7.94 (m, 3H), 7.78-7.80 (m, 1H), 7.65-7.67 (m, 1H), 7.54-7.57 (m, 1H).
50.2%
With copper(l) iodide; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In 1,4-dioxane;Inert atmosphere; Reflux;
Synthesis of 6-bro -l-(4-fluorophenyl)-lH-pyrrolo[3, 2-bJpyridine To a solution of 6-bromo-lH-pyrrolo[3, 2-b]pyridine (100 mg, 0.51 mmol), 1- fluoro-4-iodobenzene (225 mg, 1.02 mmol) and CS2CO3 (496 mg, 1.52 mmol) in dioxane (2 mL) was allowed to stir at room temperature, the Cul (cat) and (I S, 2S)-N,N'-dimethylcyclohexane-l, 2-diamine (cat) were added under N¾ and then the mixture was allowed to stir at reflux for overnight. After the reaction mixture was cooled to room temperature and filtrated, the filtrate was concentrated, the resulting residue was purified using prep-TLC (PE : EtOAc = 1 : 1) to provide 6-bromo-l-(4-fluorophenyl)-lH-pyrrolo[3, 2-b]pyridine (80 mg, yield: 50.2%). 1H- MR (CDCI3, 400 MHz) delta 8.54 (s, 1H), 7.65 (s, 1H), 7.90-7.94 (m, 3H), 7.78-7.80 (m, 1H), 7.65-7.67 (m, 1H), 7.54-7.57 (m, 1H). (M+H)+: 291 / 293.
With caesium carbonate; ethyl 2-oxocyclohexane carboxylate; copper(I) bromide; In dimethyl sulfoxide; at 60℃; for 18h;Sealed tube;
General procedure: 2-Hydroxynicotinic acid methyl ester (CAS number 10128-91-3) (100-200 mg scale), the corresponding aryl iodide (0.95 equiv), CuBr (10 mol%), 2-ethylester cyclohexanone (20 mol%) and Cs2CO3 (2.2 equiv) were suspended in DMSO (anhydrous, 2-3 mL) in a sealed tube. The reaction was complete after about 18 h heating at 60 C. The mixture was diluted in EtOAc and washed with brine. The aqueous phase was re-extracted once with EtOAc. The combined organic phases were dried over anhydrous MgSO4, and the solids filtered off. The solvent was removed in vacuo and the resulting crude material purified by column chromatography over lica gel, EtOH/CH2Cl2. The products were isolated in good yields (53-58%).
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 85℃; for 18h;
The title compound was synthesized as per 4-(4-bromophenoxy)-l -(oxetan-3 - .- yl)piperidine by utilizing (R)-l-methylpyrrolidin-3-ol (500 mg, 4.94 mmol), 4- fluoro-l-iodobenznene (1.21 g, 5.44 mmol), NaH (55-60% in mineral oil, 247 mg, 6.17 mmol) and anh DMF (10 mL) at 85C for 18 h. After work up and purification the title compound was isolated as a white solid (115 mg, 7.6%). ? NMR (400 MHz, CDCl3) delta 7.47 - 7.56 (m, 2 H), 6.59 - 6.66 (m, 2 H), 4.74-4.78 (m, 1 H), 2.74 - 2.87 (m, 3 H), 2.41 - 2.47 (m, 1 H), 2.39 (s, 3 H), 2.30 (d, J=7.8 Hz, 1 H), 1.92 - 2.01 (m, 1 H); MS ESI 303.9 [M + Hf, calcd for[0, 1Eta14GammaNu04+Eta]+ 304
(3aS,6aR,9aR,9bS,E)-3-(4-fluorobenzylidene)-6,9-dimethylenedecahydroazuleno[4,5-b]furan-2(9bH)-one[ No CAS ]
(3aS,6aR,9aR,9bS,Z)-3-(4-fluorobenzylidene)-6,9-dimethylenedecahydroazuleno[4,5-b]furan-2(9bH)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%; 8%
With palladium diacetate; triethylamine; In N,N-dimethyl-formamide; at 80℃; for 20.0h;
General procedure: A mixture of compound 2 (500 mg, 1.38 mmol), triethylamine (0.6 mL, 4.14 mmol), and 1-chloro-4-iodobenzene (1.55 mmol) in DMF (3.45 mL) was treated with palladium(II) acetate (15.5 mg, 0.04 mmol) and then heated at 80 ºC under air. After 20 h, the resulting solution was allowed to cool to room temperature, water (7 mL) was added, and the resultant mixture was extracted with ether (7 mL × 5). The organics was dried over Na2SO4 and concentrated under reduced pressure to give a crude residue, which was purified by silica gel column chromatography to afford the product.#10;
(3aR,5S,8aR,9aR,E)-3-(4-fluorobenzylidene)-5,8a-dimethyl-3,3a,6,7,8,8a,9,9a-octahydronaphtho[2,3-b]furan-2(5H)-one[ No CAS ]
(5S,8aR,9aS)-3-(4-fluorobenzyl)-5,8a-dimethyl-6,7,8,8a,9,9a-hexahydronaphtho[2,3-b]furan-2(5H)-one[ No CAS ]
(5S,8aR,9aS)-3,5,8a-trimethyl-6,7,8,8a,9,9a-hexahydronaphtho[2,3-b]furan-2(5H)-one[ No CAS ]
(2S,3S,3a'R,5R,5'S,8aS,8a'R,9aR,9a'R)-3-(4-fluorophenyl)-5,5',8a,8a'-tetramethyl-3,3a',5,5',6,6',7,7',8,8a,8',8a',9,9a,9',9a'-hexadecahydro-1H,2'H-spiro[anthracene-2,3'-naphtho[2,3-b]furan]-2'-one[ No CAS ]
With copper(l) iodide; potassium carbonate; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; In toluene; at 110℃; for 2h;
To a solution of 1-fluoro-4-iodo-benzene (1.47 g, 6.6 mmol, 1.3 eq) and <strong>[5932-27-4]ethyl 1H-pyrazole-3-carboxylate</strong> (0.71 g, 5.1 mmol, 1 eq) in 15 mL of toluene was added CuI (0.19 g, 1.0 mmol, 0.2 eq), trans-N,-N-dimethylcyclohexane 1,2-diamine (0.4 mL, 2.5 mmol, 0.2 eq), and potassium carbonate (1.4 g, 10 mmol, 2 eq). The reaction mixture was heated at 110° C. for 2 d then filtered and concentrated. The residue was purified by silica gel column chromatography (hex:EtoAc 4:1) to afford ethyl 1-(4-fluorophenyl)pyrazole-3-carboxylate (0.92 g, 3.9 mmol, 77percent).
2-(4'-fluorobiphenyl-2-yl)-1-methyl-1H-benzoimidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
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.
tert-butyl 2-(4-fluorophenyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With potassium phosphate; copper(l) iodide; (S,S)-1,2-diaminocyclohexane; In tetrahydrofuran; at 120℃; for 16h;Inert atmosphere; Sealed tube;
To a 500 mL pressure vessel were added tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate (9.0 g, 43.01 mmol) and 1 -fluoro-4-iodobcnzenc (11.46 g, 51.61 mmol) in anhydrous THF (117 mL). Nitrogen gas was bubbled through the mixture for 5 minutes. Potassium phosphate (18.26 g, 86.02 mmol), Cul (1.64 g, 8.6 mmol) and (1S,2S)-(+)-1,2-diaminocyclohexane (0.982 g, 8.6 mmol) were then added. The reaction vessel was sealed and the mixture stirred at 120 C for 16 hours. The reaction mixture was removed from heating and filtered while still hot. The filtrate was allowed to cool, diluted with ethyl acetate (250 mL) and washed with concentrated ammonium hydroxide (2 X 100mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated and the resulting residue was purified by FCC (15% ethyl acetate/hexanes) to afford the title compound (7.4 g, 57%).
With sodium carbonate; In N,N-dimethyl-formamide; at 150℃; for 24h;
Chemical compound4-fluorophenol (2mmol)With the compound 4-fluoroiodobenzene (6mmol)Dissolve in N, N-dimethylformamide (20mL) solution,After adding sodium carbonate, it was stirred at 150 C for 24h.The formed compound was extracted with ethyl acetate and washed with saturated brine to obtain compound 1a
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; diisopropylamine; triphenylphosphine; at 20℃; for 16h;Schlenk technique; Sealed tube; Inert atmosphere;
General procedure: The syntheses of alkyne-substituted aromatic amines (15-18) followed the general Scheme 1. A 50 mL Schlenk flask was charged with aryl iodide (2mmol, 1.0 eq.), bis-(triphenylphosphine) palladium dichloride (70mg, 0.05 eq.), cuprous iodide (10mg, 0.05 eq.), triphenylphosphine (13mg, 0.025 eq.), and a stir bar and sealed with rubber septum [33]. The flask was evacuated and refilled three times with Argon. Ethynylaniline (1.1 eq.) was added to 10mL of distilled dry iPr2NH and degassed together in a separated round bottom flask for 15min and then transferred to the Schlenk flask through cannula. The mixture was stirred for 16hat room temperature (65C in the case of aryl bromide). After completion of the reaction, the mixture was diluted with ethyl acetate (50mL) and the slurry was filtered through a pad of Celite in a sintered glass funnel (medium frit). The tan solids were additionally washed with ethyl acetate until the filtrate was nearly colorless. The filtrate was washed with H2O and brine and dried over magnesium sulfate. The combined organic fraction filtrates were concentrated in vacuum, yielding a black solid. The residue was further purified by flash column chromatography on silica gel using ethyl acetate/hexane mixture as eluent.
5-chloro-1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; 2-(2-methyl-1-oxopropyl)cyclohexanone; caesium carbonate; In N,N-dimethyl acetamide; at 100℃;Inert atmosphere;
A suspension of 5-chloro-lH-pyrazolo[3,4-c]pyridine (100 mg, 0.651 mmol), 4- fluoro-l-iodobenzene (225 mg, 1.01 mmol), 2-isobutyrylcyclohexanone (50 mg, 0.297 mmol), copper(I) iodide (25 mg, 0.131 mmol) and cesium carbonate (400 mg, 1.23 mmol) in 5 mL of DMA was deoxygenated by bubbling nitrogen for 15 min. Next, the reaction mixture was warmed to 100C and stirred overnight. The reaction mixture was then cooled and diluted with DCM, washed with 1 N aqueous NaOH and water, dried (Na2S04) and concentrated to dryness. The solid residue was suspended in ether, stirred for 30 min, and filtered to collect the desired intermediate, 5-chloro-l-(4-fluorophenyl)-lH-pyrazolo[3,4-c]pyridine: MS (EI) calc'd for Ci2H8ClFN3 [M+H]+ 248, found 248; 1H NMR (600 MHz, OMSO-d6) delta 9.07 (s, 1 H), 8.48 (s, 1 H), 8.01 (s, 1 H), 7.86 (dd, J= 7.1, 5.0 Hz, 2 H), 7.43 (t, J= 8.8 Hz, 2 H)
tert-butyl 4-(4-fluorophenyl)-3,3-dimethylpiperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With bis(tri-t-butylphosphine)palladium(0); sodium t-butanolate; In toluene; at 110℃; for 2h;Inert atmosphere;
Step 1 : tert-butyl 4-(4-fluorophenyl)-3,3-dimethyl-piperazine-l-carboxylate [00400] A32-1 (200.0 mg, 0.933 mmol, 1.00 eq), A32-2 (310.8 mg, 1.40 mmol, 0. 16 mL, (1153) 1.50 eq), f-BuONa (179.4 mg, 1.87 mmol, 2.00 eq) and bis(tri-tertbutylphosphine) Palladium(O) (47.69 mg, 0.093 mmol, 0. 10 eq) were taken up into toluene (6.00 mL). The reaction mixture was stirred at 1 10 C for 2 hour under N2. LCMS and TLC (Petroleum ether: Ethyl acetate=10/l) showed desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated to give a crude product. The residue was purified by Prep- TLC (Petroleum ether: Ethyl acetate= 10/1) to give the A32-3 (260.0 mg, 0.776 mmol, 83. 1 1% yield, 92% purity) as a yellow oil. LCMS (ESI): RT =0.630 min, mass calcd. for C17H25FN2O2 308.19, m/z found 308.9 [M+H]+
5-bromo-2-fluoro-3-(4-fluorophenyl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 0.75h;Sealed tube;
In a sealed tube, p-dioxane(15 mL) was degassed for 15 min followed by the addition of <strong>[501435-91-2]5-bromo-2-fluoropyridine-3-boronic acid</strong> (4; 1.14 g, 5.18 mmol), 1-fluoro-4-iodobenzene (520muL, 4.5 mmol), Pd(PPh3)4 (260 mg, 0.23 mmol) and then a solution of Na2CO3 (1.9 g,18 mmol) in 10 mL of water, which had been previously degassed for 5 min. The tubewas sealed and heated at 90 C for 45 min. Workup as described above for 5a(dry-packed column, gradient elution with 0 - 0.5 % ethyl acetate in hexanes) gave 5b(450 mg, 37 %) as a white solid. 1H NMR (400 MHz, chloroform-d) delta 8.24 (s, 1H),7.95 (dd, J = 8.6, 1.9 Hz, 1H), 7.56 - 7.49 (m, 2H), 7.18 (t, J = 8.4 Hz, 2H). MSTOFES+: m/z 270.0, 272.0 (M+H)+
3-(4-fluorophenyl)-6-methoxy-2-(4-methoxyphenyl)benzofuran[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
General procedure: To a solution of the 2-Iodo-5-methoxyphenol (1mmol, 252mg) and the 4-Ethynylanisole (1.2 equiv., 166mg) in dry THF (1.6mL, 0.6M of the Iodophenol), at 0C under N2, was added CH3MgBr (THF solution, 2.3M, 2 equiv., 0.792mL) dropwise. The mixture was allowed to warm to room temperature, and Pd(Ph3P)2Cl (3mol%, 21.3mg) was added before the mixture was heated to 65C for 2h under N2. The reaction mixture was then cooled to room temperature and the THF was removed under reduced pressure. DMSO (2mL) was added to the residue followed by addition of 2-Fluoro-4-iodopyridine (1.2 equiv., 269.7mg) and the mixture was heated to 80C for 4h under N2. The mixture was cooled to room temperature and diluted with EtOAc, washed with H2O and brine. The organic phase was dried over Na2SO4, concentrated and purified on silica followed by preparative HPLC (25?100% B over 25min).
With bis(eta3-allyl-mu-chloropalladium(II)); silver trifluoromethanesulfonate; In 1,2-dichloro-ethane; at 80℃; under 3040.2 Torr; for 24h;Inert atmosphere; Sealed tube; Glovebox; Schlenk technique; Green chemistry;
General procedure: Under an inert nitrogen atmosphere, silver triflate (386 mg,1.5 mmol) was transferred to a Teflon sealed thick-walled 50 ml glass reaction vessel equipped with a stir bar, followed by aryl iodide (1.0 mmol), arene (2.0 mmol), DCE (4 ml) and then a freshly prepared stock solution of [Pd(allyl)Cl]2 (0.2 mg, 5 × 10?4 mmol). The vessel was closed, removed from the glovebox, evacuated and backfilled with carbon monoxide three times, and finally pressurized with 4 atm carbon monoxide. After heating at 100 °C for 24 h with stirring, the reaction was cooled to room temperature and carbon monoxide was released. The reaction mixture was filtered through Celite, eluting with dichloromethane. Saturated NaHCO3 was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were concentrated in vacuo and the residue was purified by column chromatography (silica gel, gradient hexane/ethyl acetate 0 to 20percent) to afford the pure ketone product.
tert-butyl 3-(4-iodophenoxy)-3-methylazetidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.2%
To a solution of tert-butyl 3-hydroxy3-methyl-azetidine- 1-carboxylate (0.52 g) in DMF (6.0 mL) was added sodium hydride (0.13 g) at 0 C. After stirring at the same temperature for 30 minutes, l-fluoro-4-iodo-benzene (0.32 mL) was added into the mixture, which was stirred at room temperature for 30 minutes and then stirred at 85 C for 19 hours. After cooling, water and EtOAc were added carefully. The bilayer was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified with OH-type silica gel column chromatography (12- 100% EtOAc in n-hexane) to give the title compound (24 mg, 2.2% yield) as pale yellow oil. NMR (400 MHz, CHLOROFORM-d) delta ppm 1.44 (s, 9 H), 1.64 (s, 3 H), 3.92 (d, J=8.9 Hz, 2 H), 4.17 (d, J=8.9 Hz, 2 H), 6.48 (d, J=8.6 Hz, 2 H), 7.55 (d, J=8.6 Hz, 2 H).
methyl 1-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
560 mg
With potassium phosphate; copper(l) iodide; trans-N,N'-dimethylcyclohexane-1,2-diamine; In toluene; at 110℃; for 6h;
To a suspension of methyl lH-pyrrolo[2,3-b]pyridine-5-carboxylate (500.0 mg, 2.84 mmol, CAS RN 849067-96-5) in toluene (15 mL) was added 4-fluoroiodobenzene (0.69 g, 3.12 mmol, CAS RN 352-34-1), trans 1, 2 N, N-dimethyl cyclohexane diamine (121.11 mg, 0.850 mmol, CAS RN 67579-81-1), K3P04 (1.81 g, 8.51 mmol, CAS RN 7778-53-2) and Cul (54.05 mg, 0.280 mmol, CAS RN 7681-65-4) successively. The reaction mixture was heated to 110 C and the reaction was stirred for 6 h. LC-MS of the crude reaction mixture showed the formation of desired mass along with traces of unreacted SM. The reaction mixture was diluted with DCM (50 mL), filtered through the bed of celite and concentrated to dryness. The crude thus obtained was purified by combiflash column using 10% EtOAc in n-hexane as eluent to provide an off-white solid (560 mg, 2.07 mmol). lH NMR (400 MHz, DMSO- 6) delta 8.87 (d, J= 2.2 Hz, 1H), 8.66 (d, J= 2.1 Hz, 1H), 8.05 (d, J = 3.7 Hz, 1H), 7.95 - 7.86 (m, 2H), 7.43 (t, J= 8.8 Hz, 2H), 6.89 (d, J= 3.7 Hz, 1H), 3.90 (s, 3H). MS (ESI): m/z = 271.2 [M+H]+.
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Material Science
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110K+ Compounds
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