* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With caesium carbonate In N,N-dimethyl-formamide; toluene at 140℃; for 1 h; Irradiation
To a mixture of 4,6-dichloro-5-methylpyrimidine (available from Sigma- Aldrich No.595446) (0.50 g, 3.07 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.18 g, 0.15 mmol) in toluene (6 ml) and DMF (1 ml) was added cesium carbonate (3 g, 9.20 mmol), followed by methylboronic acid (0.20 g, 3.37 mmol). The resulting reaction mixture was heated at 140 0C under microwave irradiation (2 cycles x 30 min), allowed to cool down to room temperature and filtered. Solvents were removed under reduced pressure. The residue was taken-up in EtOAc and washed with a saturated NaHCO3 aqueous solution and brine. The organic phase was separated, dried (Na2SO4), filtered and concentrated to afford the title compound D8 (0.18 g, 1.26 mmol, 41percent yield). UPLC: rt = 0.53 min, peak observed: 143 <n="22"/>(M+1-HC1, 100percent) and 445 (M+1-HC1, 33percent). C6H7ClN2 requires 142. 1H NMR (400 MHz, CDCl3) δ(ppm): 8.70 (s, 1 H), 2.57 (s, 3 H), 2.39 (s, 3 H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 8, p. 2586 - 2590
6
[ 5470-18-8 ]
[ 13061-96-6 ]
[ 18699-87-1 ]
Yield
Reaction Conditions
Operation in experiment
55%
With potassium carbonate In 1,4-dioxane for 24 h; Heating / reflux
A mixture of 2-chloro-3-nitropyridine (1.6g, 10.09mmol), Pallac tetrakis(triphenylphosphine) (1170mg, 1.01 mmol), methylboronic acid (665mg, mmol ) and potassium carbonate (4180mg, 30.3 mmol) was refluxed in dioxane 1 days. The reaction was cooled to room temperature, and then filtered. The filtrate concentrated and the residue was purified by flash column chromatography (? EtOAc/Hexanes) to afford 760mg (55percent) of 2-methyl-3-nitropyridine. 1H NMR (CDC 8.71 (tetra, 1.7Hz, 5.0Hz, 1H), 8.26 (tetra, 1.7Hz, 8.3Hz, 1H)1 7.34 (dd, 5.( 8.3Hz, 1 H), 2.85 (s, 3H). MS m/z 139.1(M+H)+.
With potassium phosphate In water; toluene at 100℃;
INTERMEDIATE 31Methyl 2-chloro-5-methylnicotinate; To a solution of methyl 5-bromo-2-chloronicotinate (1.05g, 4.19mmol), K3PO4 (2.95g, 13.90mmol), methylboronic acid (0.32g, 5.26mmol) and tricyclohexylphosphine (0.11g, 0.39mmol) in toluene/water (16ml/0.8ml) under nitrogen atmosphere was added Pd(OAc)2 (0.04g, 0.18mmol). The mixture was heated at 1000C overnight under nitrogen atmosphere. The reaction mixture was then cooled to room temperature and concentrated in vacuum. Ethyl acetate was added to the residue and this organic layer was washed with water, brine, dried over MgSO4, filtered and the solvent evaporated under vacuum to yield the desired product as a yellow oil. Yield=87percent LRMS: m/z 186 (M+1 )+ Retention time: 4.84min
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; for 18 h;
A suspension of 4,6-dichloropyridin-2-amine (1.63 g, 10 mmol), methylboronic acid (0.6 g, 10 mmol), Cs2C03 (9.75 g, 30 mmol), and Pd(dppf)Cl2 (400 mg) in dioxane/water (4: 1, 50 mL) was stirred for 18 hours at 100 °C. The reaction was diluted with water and extracted with EtOAc (50 mLx3). The combined organic layer was washed with water and brine. The resulting solution was concentrated under reduced pressure and the residue was purified via prep-HPLC to afford 4-chloro-6-methylpyridin-2-amine (100 mg) as brown solid. MS ESI calcd. For C6H7C1N2 [M + H]+ 143, found 143.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In N,N-dimethyl-formamide at 100℃; for 2 h;
A solution of ethyl 5-bromopyrazolo[1,5-ajpyridine-3-carboxylate (1.0 g, 3.73 mmol),methylboronic acid (448 mg, 7.46 mmol), Pd(dppf)C12 (545 mg, 0.746 mmol) and C52CO3(2.42 g, 7.46 mmol) was dissolved in DMF (5.0 mL), then the mixture was stirred at 100 °Cfor two hours. It was concentrated, and purified by silica gel chromatography with PE:EA=5: 1to obtain the desired compound as an orange solid (589 mg, 77percent). ESI MS m/z = 204.5[M+Hj.
Reference：
[1] Green Chemistry, 2017, vol. 19, # 21, p. 5046 - 5053
13
[ 22353-40-8 ]
[ 13061-96-6 ]
[ 51984-62-4 ]
Yield
Reaction Conditions
Operation in experiment
344 mg
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In 1,4-dioxane at 100℃; for 6 h;
Cesium carbonate (338 mg), methylboronic acid (47 mg), and tetrakis(triphenylphosphine)palladium (60 mg) were added to a 1,4-dioxane (3 ml) solution containing 2,3-dichloro-5-nitropyridine (100 mg), followed by stirring at 100°C for 6 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and 3-chloro-2-methyl-5-nitropyridine (344 mg) was thus obtained.
With pyridine; copper diacetate In 1,4-dioxane for 6 h; Reflux
Intermediate 1: N-Methyl-4-(trifluoromethyl) aniline To a mixture of 4-trifluoromethylaniline (196 mg, 1.2 mmol), copper acetate (550 mg, 3.0 mmol) and pyridine (0.34 mL, 4.2 mmol) in dioxane (6 mL) was added methylboronic acid (181 mg, 3.0 mmol, Aldrich, Catalog number: 165335). The mixture was heated with stirring under reflux for 6 hours. The resulting mixture was filtered. The filtrate was concentrated under vacuum and purified by column chromatography to afford N-methyl-4-(trifluoromethyl)-aniline (150 mg, 70 percent). MS obsd. (ESI+) [(M+H)+]: 176
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 20, p. 3302 - 3310
22
[ 76-09-5 ]
[ 13061-96-6 ]
[ 94242-85-0 ]
Reference：
[1] Chemical Communications, 2012, vol. 48, # 9, p. 1230 - 1232
[2] Journal of the American Chemical Society, 2000, vol. 122, # 23, p. 5455 - 5463
Under nitrogen protection, In a reactor equipped with a reflux water separation device(S)-(+)-2-(diphenylhydroxymethyl)pyrrolidine (2.53 kg, 10 moles) and methylboronic acid (779 g, 13 moles) were added to 7.1 g of n-heptane, Slowly stirring, As the water is constantly being separated, The solution gradually becomes clear, Then adjust the stirring speed to the normal state, When there is no more water, Stop stirring, Slow down to 40 deg C, After standing overnight, Diatomaceous earth temperature filtration, The filtrate was once again cooled to -10 ° C, Stirring for 1.5 hours to complete precipitation, After filtration, 40 deg C in a double cone and dried in vacuo for 8 hours to give 2.30 kg of S-MeCBS, Yield 83percent The product is a white solid, GC: 98.2percent, water content: 0.31percent
Reference：
[1] Patent: CN106478703, 2017, A, . Location in patent: Paragraph 0015; 0016
26
[ 22348-32-9 ]
[ 13061-96-6 ]
[ 112022-81-8 ]
Reference：
[1] Helvetica Chimica Acta, 2001, vol. 84, # 2, p. 431 - 472
[2] Synthesis, 2003, # 12, p. 1851 - 1855
[3] Journal of the Chemical Society. Perkin Transactions 2, 2000, # 1, p. 69 - 76
[4] Angewandte Chemie, International Edition, 1998, vol. 37, p. 1987 - 2014[5] Angewandte Chemie, 1998, vol. 110, p. 2092 - 2118
[6] Chemical Communications, 2010, vol. 46, # 45, p. 8624 - 8626
[7] Organic Letters, 2017, vol. 19, # 16, p. 4355 - 4358
With cesium fluoride In 1,4-dioxane at 20 - 80℃; for 3 h;
Step 4; Preparation of Methyl 2-amino-5-methyl-4-trifluoromethylbenzoate; Add cesium fluoride (184.3 g, 1.21 mol), methyl boronic acid (63.7 g, 1.05 mol, 3 molequiv.) andbis(diphenylphosphinoferrocene)palladium(II) chloride (27.83 g, 35.1 mmol)to a solution of methyl 2-amino-5-iodo-4-trifluoromethylbenzoate (121 g, 351 mmol) inanhydrous 1,4-dioxane (2.5 L) at room temperature under an atmosphere of nitrogen andheat the mixture at 80 °C for 3 h. Allow the mixture to cool to room temperature thenpartition between ethyl acetate (2.5 L) and water (2.5 L) and filter through a pad ofCelite.(R). to remove the fine black suspension. Extract the aqueous phase with ethylacetate (2 x 100 mL) and wash the combined organic extracts with brine (1 L). Dry overanhydrous magnesium sulfate, filter and remove the solvent under reduced pressure at 45°C to give a red oil. Purify the residue by column chromatography on silica gel, elutingwith isohexane/ethyl acetate (9:1), to give the title compound as a pale yellow crystallinesolid (75.25 g, 92percent).
With potassium carbonate In 1,4-dioxane at 110℃; for 72 h; Inert atmosphere
An oven-dried resealable Schlenk tube was charged with ethyl 5,6-dibromonicotinate (preparation 47b, 1.09 g, 3.5 mmol), methylboronic acid (0.24 g, 4.0 mmol), potassium carbonate (1.46 g, 10.6 mmol) and 1,4-dioxane (27 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and then tetrakis(triphenylphosphine)palladium(0) (0.41 g, 0.35 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated in an oil bath to 110 °C. After 3 days, the mixture was cooled, filtered through Celite.(R). and the filtrate was evaporated. Purification of the residue by flash chromatography (97:3 to 9:1 hexanes/ethyl acetate) gave the title compound (0.41 g, 45percent) as a solid. LRMS (m/z): 244/246 (M+1)+. 1H-NMR δ (CDCl3): 1.41 (t, J=9.0Hz, 3H), 2.74 (s, 3H), 4.41 (q, J=9.0Hz, 2H), 8.40 (d, J=3.0Hz, 1H), 9.01 (d, J=3.0Hz, 1H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,4-dioxane; water at 105℃; for 16 h; Inert atmosphere
To a mixture of 6-bromo-3,4-dihydro-2H-isoquinolin-1-one (19.0 g, 82.4 mmol),CH3B(OH)2 (20.8 g, 329 mmol) and Na2CO3 (18.4 g, 165 mmol) in 1,4-dioxane (200 mL)and water (10.0 mL) is added [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (2.46 g, 3.29 mmol) under a nitrogen atmosphere and the mixture is stirred at 105 °C for 16 hours under a nitrogen atmosphere. The suspension is filtered through a pad of diatomaceous earth and the filter cake is washed with DCM (3 x250 mL). The combined filtrates are washed with water (100 mL) and brine (80 mL), dried over Na2SO4, and the solvent isevaporated under reduced pressure. The crude product is purified by silica gel flash chromatography, eluting with a gradient of 0percent to 50percent EtOAc in PE to give the title compound (13.0 g, 95.2percent) as a yellow solid. ES/MS (m/z): 162.0 (M+H), ‘H NIVIR (400MHz, CDC13) 7.94 (d, J=8.0 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 7.02 (s, 1H), 6.89 (br s, 1H),3.55 (dt, J=2.9, 6.6 Hz, 2H), 2.94 (t, J=6.5 Hz, 2H), 2.37 (s, 3H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; for 24h;Heating / reflux;
A mixture of 2-chloro-3-nitropyridine (1.6g, 10.09mmol), Pallac tetrakis(triphenylphosphine) (1170mg, 1.01 mmol), methylboronic acid (665mg, mmol ) and potassium carbonate (4180mg, 30.3 mmol) was refluxed in dioxane 1 days. The reaction was cooled to room temperature, and then filtered. The filtrate concentrated and the residue was purified by flash column chromatography (? EtOAc/Hexanes) to afford 760mg (55%) of 2-methyl-3-nitropyridine. 1H NMR (CDC 8.71 (tetra, 1.7Hz, 5.0Hz, 1H), 8.26 (tetra, 1.7Hz, 8.3Hz, 1H)1 7.34 (dd, 5.( 8.3Hz, 1 H), 2.85 (s, 3H). MS m/z 139.1(M+H)+.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 110℃; for 16h;Product distribution / selectivity;
Heat a mixture of 2-chloro-3-nitro-pyridine (1a-1, 7.9 g, 49.8 mmol), methylboronic acid (1.10 equiv. 54.8 mmol, 3.30 g), K2CO3 (3.0 equiv, 150 mmol, 20.7 g) and Pd(PPh3)4 (1.2 g, 1.2 mmol) to 110 C. in dioxane (250 mL) for 16 h. Allow the reaction to cool to rt, concentrate to a dark oil and flash chromatograph on SiO2 (heptane/Et2O 3:1, dilute the oil with limited quantities of CH2Cl2 to apply to the column) to give compound 2a-1 (Niu, C.; Li, J.; Doyle, T. W.; Chen, S-H. Tetrahedron, 1998, 6311-6318).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; for 48h;Heating / reflux;
Preparation 1.; 2-(4-fluorophenoxymethyl)-3-nitropyridine; Step 1: 2-methyl-3-nitropyridine; A solution of 2-chloro-3-nitropyridine (20 g, 0.126 mol), methyl boronic acid (8.3g, 0.139 mol), tetrakis(triphenylphosphine)palladium (0) (14.58 g, 0.013 mol) andpotassium carbonate (52.3 g, 0.378 mol) in anhydrous 1,4-dioxane (100 ml) wasrefluxed for 2 days. The reaction mixture was cooled to room temperature, filtered, andconcentrated under reduced pressure. The resulting residue was purified with silica gelcolumn chromatography (ethyl acetate/n-hexane=l/3, v/v) to give 14 g of the titledcompound as brown oil.lH-NMR(400MHz, CDC1) 5 8.74(d, 1H), 8.27(d, 1H), 7.34(t, 1H), 2.88(s, 3H)
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; for 48h;Heating / reflux;
Preparation 1. (4-fluorophenyl)-(3-nitropyridin-2-ylmethyl)carbamic acid tert-butylester; Step 1: 2-methyl-3-nitropyridine; A solution of 2-chloro-3-nitropyridine (20 g, 0.126 mol), methylboronic acid (8.3g, 0.139 mol), tetrakis(triphenylphosphine)palladium (0) (14.58 g, 0.013 mol), andpotassium carbonate (52.3 g, 0.378 mol) in 1,4-dioxane (100 ml) was refluxed for 2days. The reaction mixture was cooled to room temperature and then filtered. Thefiltrate was concentrated under reduced pressure. The resulting residue was purifiedwith silica gel column chromatography (ethyl acetate/n-hexane=l/3, v/v) to give 14 gof the titled compound as brown oil.lH-NMR(400MHz, CDCy 5 8.74(d, 1H), 8.27(d, 1H), 7.34(t, 1H), 2.88(s, 3H)
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 100℃; for 48h;Inert atmosphere;
2-Methyl-3-nitropyridine; 2-Chloro-3-nitropyridine (20 g, 126.18 mmol), methane boronic acid (9.8 g, 164 mmol), tetrakis(triphenylphosphine)palladium (11.66 g, 10 mmol) and potassium carbonate (51.48 g, 378.6 mmol) were all mixed in 1-4 dioxane (500 mL), degasified and heated to 100 C. for 48 h under N2. Work up was carried out by allowing the reaction mass to cool to ambient temperature and quenched with water and extracted with ethyl acetate. The aqueous layer was back extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a solid. The solid was further purified by silica gel column chromatography using 6% of ethyl acetate in hexane as eluent to give 2-methyl-3-nitropyridine as an off white solid: 1H-NMR (CDCl3) delta: 2.9 (s, 3H), 7.4 (m, 1H), 8.3 (d, 1H), 8.7 (d, 1H).
With potassium phosphate; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In water; toluene; at 115℃; for 1h;
Methyl 3-amino-6-bromopyrazine-2-carboxylate (2 g, 8.62 mmol), Pd2(OAc)3 (0.2 g, 0.89 mmol) and Xantphos (0.79 g, 1 .37 mmol) were placed in a closed vessel with toluene (30 mL) and water (1 mL). Methylboronic acid (0.78 g, 13.1 mmol) and potassium phosphate tribasic (3.42 g, 16.1 mmol) were added and the reaction mixture was heated to 1 15 C for 1 h. The reaction mixture was allowed to reach RT, and then it was filtrate on Celite and washed with DCM. The filtrate was concentrate under vacuum and purified through FC on S1O2 column (DCM: EtOAc from 98:2 to 85: 15) affording methyl 3-amino-6-methylpyrazine-2-carboxylate (p125, 870 mg, y= 60 % yield) as a beige solid. MS (mlz): 168.0 [MH]+
With potassium phosphate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In water; toluene; for 24h;Heating / reflux;
5. Reactions which are covered by Scheme 12; Example 5.1: Preparation of 3-amino-6-methyl-pyrazine-2-carboxylic acid methyl ester; 3-Amino-6-bromo-pyrazme-2-carboxylic acid methyl ester (1.0 g) (made according to J. Org. Chem. (1988), 59(9), 2052-5), palladium(II) acetate (0.101 g), and 2'-dicyclohexylphosphino-2,6-dimethoxy-l,l'-biphenyl ("S-Phos") were placed in a flask with toluene (15 ml) and water (3 drops). Methyl boronic acid (0.394 g) and potassium phosphate (1.71 g) were added and the reaction mixture was heated to reflux for 24 hours. After allowing the reaction mixture to cool to ambient temperature, the mixture , was diluted with aqueous hydrochloric acid (IM) and extracted with ethyl acetate. The combined organic extracts were concentrated and the residue was purified by column chromatography on silica gel (eluent: diethyl ether) to give 3-amino-6-methyl-pyrazine- 2-carboxylic acid methyl ester as a yellow solid (0.114 g). 1H-NMR (400 MHz, CDCl3): 2.40 (s, 3H), 3.92 (s, 3H), 6.21 (bs, 2H), 8.03 (s, IH) ppm.
With potassium phosphate; water;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In toluene; for 24h;Heating / reflux;
Example 12.2: Preparation of 3-amino-6-methylpyrazine-2-carboxylic acid methyl ester; 3-Amino-6-bromopyrazine-2-carboxylic acid methyl ester (1.0 g), palladium acetate (0.101 g), and S-Phos (2'-dicyclohexylphosphino-2,6-dimethoxy-l,l'-biphenyl) were placed in a flask, with toluene (15 mL) and water (3 drops). Methyl boronic acid (0.394 g) and potassium phosphate (1.71 g) were added and the reaction mixture was refluxed for 24 hours. After allowing the reaction mixture to cool, the mixture was diluted with aqueous hydrochloric acid (IM) and extracted with ethyl acetate. The solvent was evaporated and the residue was purified by column chromatography on silica gel (eluent: diethyl ether) to give 3-amino-6-methylpyrazine-2-carboxylic acid methyl ester as a yellow solid (0.1 14 g).1H NMR (CDCl3): 2.40 (s, 3H), 3.92 (s, 3H), 6.21 (bs, 2H), 8.03 (s, IH) ppm.
With p-benzoquinone; silver(l) oxide;palladium diacetate; In tert-Amyl alcohol; at 100℃; for 6h;Product distribution / selectivity;
Substrate 14 was reacted with methylboronic acid following General Procedure 3. Column chromatography gave 16 as a pale yellow liquid (13.0 mg, 48%). The analysis data are supplied in Example 14 above.; Alkylation of sp2 and sp3 hvdridized C-H Bonds with Boronic Acids In a 20 mL tube, the substrate (0.2 mmol, 1 equiv), Pd(OAc)2 (4.5 mg, 0.02 mmol, 10 mol%), boronic acid (0.6 mmol, 3 equiv), Ag2O (46.3 mg, 0.2 mmol, 1 equiv) and <n="64"/>benzoquinone (10.8 mg, 0.1 mmol, 0.5 equiv) were dissolved in 1 mL of tert-Amyl alcohol under atmospheric air. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 100 0C for 6 hours. The reaction mixture was filtered through a pad of Celite, and the Celite was washed with 20 mL OfCH2Cl2. The filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel (hexane: ether = 10: 1) to give the alkylated product.
With cesium fluoride;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 20 - 80℃; for 3h;
Step 4; Preparation of Methyl 2-amino-5-methyl-4-trifluoromethylbenzoate; Add cesium fluoride (184.3 g, 1.21 mol), methyl boronic acid (63.7 g, 1.05 mol, 3 molequiv.) andbis(diphenylphosphinoferrocene)palladium(II) chloride (27.83 g, 35.1 mmol)to a solution of <strong>[872624-52-7]methyl 2-amino-5-iodo-4-trifluoromethylbenzoate</strong> (121 g, 351 mmol) inanhydrous 1,4-dioxane (2.5 L) at room temperature under an atmosphere of nitrogen andheat the mixture at 80 C for 3 h. Allow the mixture to cool to room temperature thenpartition between ethyl acetate (2.5 L) and water (2.5 L) and filter through a pad ofCelite to remove the fine black suspension. Extract the aqueous phase with ethylacetate (2 x 100 mL) and wash the combined organic extracts with brine (1 L). Dry overanhydrous magnesium sulfate, filter and remove the solvent under reduced pressure at 45C to give a red oil. Purify the residue by column chromatography on silica gel, elutingwith isohexane/ethyl acetate (9:1), to give the title compound as a pale yellow crystallinesolid (75.25 g, 92%).
Method 2 A mixture of 2-chloro-3-nitropyridine 1 (793 mg, 5.0 mmol), methylboronic acid (329 mg, 5.5 mmol), Pd(PPh3)4 (578 mg, 0.5 mmol) and K2 CO3 (2.073 g, 15.0 mmol) in dioxane (25 mL) was refluxed for 2 days. It was then cooled to room temperature and filtered. The solvent was removed and the residue was isolated by flash chromatography (50% ethyl acetate in hexanes) to provide 623 mg (90%) of 2-methyl-3-nitropyridine 3. 1 H NMR (CDCI3) delta 2.88 (s, 3H), 7.36 (dd, 1H, J=4.8 & 8.4 Hz), 8.28 (dd, 1H, J=1.2 & 8.1 Hz), 8.73 (dd, 1H, J=1.2 & 4.8 Hz).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 130℃; for 0.5h;Microwave;
Three reaction vials are prepared. 214 mg of 3-Bromo-thieno[2,3-b]pyridine (1.0 mmol) and 180 mg of Methylboronic acid (3.0 mmol) are put in the each vial with 4 ml of DME/water/EtOH=7/3/l. 1.5 ml of 2 M Na2CO3 aq. (3.0 mmol) is added and N2 gas is bubbled in for 15 min. 58 mg of Pd(PPh3)4 (0.05 mmol) is added and each vials are sealed. These vials are heated at 13O0C for 30 min in the microwave. All reaction EPO <DP n="69"/>mixtures are combined and water and CH2Cl2 are added. The CH2Cl2 layer are separated and dried over Na2SO4 and evaporated. The crude products are applied onto a silica-gel chromatography column (Hexane:AcOEt=5:l) to give 120 mg of the title compound. Yield 27%. mass spectrum (m/e):150(M+l); IH-NMR(CDCl3): 8.61(dd, IH, J=5.0Hz, 1.4Hz), 8.01(dd, IH, J=8.3Hz, 1.4Hz), 7.35(dd, IH, J=8.3Hz, 5.0Hz), 7.19(d, IH, J=I.3Hz), 2.46(d, 3H, J=I.3Hz).
tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water;Heating / reflux;
642 mg of 3-Bromo-thieno[2,3-c]pyridine (3.0 mmol), 540 mg of methylboronic acid (9.0 mmol) are placed into flask with 10 ml of DME / water / EtOH = 7:3:1. The air is replaced with N2 gas and 174 mg of Pd(PPh3)4 (0.15 mmol) is added. The reaction mixture is stirred under reflux for overnight. To the reaction mixture is added water and EPO <DP n="98"/>CH2Cl2. The separated CH2Cl2 layer is washed by brine, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=20:4:l) to give 131 mg of the title compound. Yield 29%. mass spectrum (m/e):150(M+l); IH-NMR(CDCl3): 9.16(d, IH, J=0.8Hz), 8.56(d, IH, J=5.2Hz), 7.64(dd,lH, J=5.2Hz, 0.8Hz), 7.37(d, IH, J=1.2Hz), 2.50(d, 3H, J=1.2Hz) ppm.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 4h;
2, 6-Dichloro-5 -fluoropyridine-3 -carbonitrile (250 mg, 1.31 mmol), methylboronic acid (78 mg, 1.31 mmol), PdC12(dppf) (48 mg, 0.07 mmol) and sodium carbonate (416 mg, 3.93 mmol) were suspended in 2:1 DMF / H20 (6 ml) and the mixture was stirred at 80 C for 4 hours. The reaction was filtered through Celite and washed with EtOAc (20 ml). To the filtrate was added water (30 ml). The organics were separated and the aqueous phase extracted with EtOAc (3 x 30 ml). The combined organics were washed with brine (30 ml), dried over MgSO4, filtered and concentrated in vacuo. The residue was then purified via flash column chromatography (gradient of 0 - 100% EtOAc in heptane followed by 0-100% MeOH in EtOAc). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a white solid (24 mg, 11%).1H NIVIR (250 MHz, Chloroform-d) 7.65 (s, 1H), 2.60 (s, 3H). LCMS Method 2 - Tr = 0.99 mm (ES+) (M+H)+ 143.5
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; N,N-dimethyl-formamide; at 80℃; for 3h;
Step A:; To a mixture of compound U-I (10 g, 52.6 mmol), MeB(OH)2 (3.16 g, 52.6 mmol), Na2CO3 (16.8 g, 158 mmol), and PdCl2dppf (1.9 g, 2.64 mmol) were added dropwise H2O (40 mL) and DMF (80 mL). The reaction mixture was heated to 80 0C for 3 hours, then filtered through a thin layer of Celite and washed with ethyl acetate (200 mL). The filtrate was partitioned between H2O (200 mL) and ethyl acetate (400 mL); the organic layer was separated and the aqueous layer were extracted with ethyl acetate EPO <DP n="82"/>(3 X 100 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered, concentrated. The resulting residue was purified by chromatography to afford product U-2 (m/z (ES) (MH-H)+= 171 ).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 3h;
A mixture of <strong>[82671-02-1]2,6-dichloro-5-fluoropyridine-3-carbonitrile</strong> (5 g, 26.18 mmol), methylboronic acid (1.58 g, 26.36 mmol), Na2CO3 (8.33 g, 78.54 mmol), and Pd(dppf)Cl2-CH2C12 (95 8mg, 1.31 mmol) in DMF (40 mL) and water (20 mL) was stirred for 3 h at 80C. After cooling to room temperature, the reaction mixture was diluted with 50 mL of water. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:5 EtOAc/pet. ether) afforded 2-chloro-5-fluoro-6-methylnicotinonitrile as a pink solid. MS: (ESI, m/z): 171 [M+H]t
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In monoethylene glycol diethyl ether; water;Heating / reflux;
The procedure described by Lisowski et al. (see J. Org. Chem., 2000, 65: 4193) was followed. Intermediate 79 (1.12 g, 3.28 mmol) and tetrakis(triphenylphosphine)palladium (190 mg, 0.16 mmol) were taken up in 100 mL of ethylene glycol dimethyl ether in a 500 mL round-bottom flask. This solution was purged three times by opening to vacuum followed by backfilling with nitrogen. Methylboronic acid (390 mg, 6.6 mmol) was added, followed by a solution of sodium bicarbonate (0.55 g, 6.6 mmol) in 100 mL of water, and the evacuation/nitrogen backfill procedure was repeated once more. The mixture was heated at reflux temperature and monitored for product appearance/starting material disappearance by LC-MS analysis. After 1.5 hours, an additional 190 mg (0.16 mmol) of the palladium catalyst was added and the reaction allowed to be heated at reflux temperature overnight. The organic solvent was removed and the remaining aqueous mixture was partitioned between 100 mL each of 2 M hydrochloric acid and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the crude product, which was purified by flash chromatography over silica gel (0-6% ethyl acetate in dichloromethane) to give intermediate 80 of sufficient purity (the product contained about 20% of the deiodinated side-product, 7-(trifluoromethyl)isatin). 1H NMR (400 MHz, DMSO-d6) delta 3.33 (s, 3H), 7.62 (s, 1H), 7.68 (s, 1H), 11.35 (s, 1H).
With potassium phosphate;palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100.0℃;
INTERMEDIATE 31Methyl 2-chloro-5-methylnicotinate; To a solution of methyl 5-bromo-2-chloronicotinate (1.05g, 4.19mmol), K3PO4 (2.95g, 13.90mmol), methylboronic acid (0.32g, 5.26mmol) and tricyclohexylphosphine (0.11g, 0.39mmol) in toluene/water (16ml/0.8ml) under nitrogen atmosphere was added Pd(OAc)2 (0.04g, 0.18mmol). The mixture was heated at 1000C overnight under nitrogen atmosphere. The reaction mixture was then cooled to room temperature and concentrated in vacuum. Ethyl acetate was added to the residue and this organic layer was washed with water, brine, dried over MgSO4, filtered and the solvent evaporated under vacuum to yield the desired product as a yellow oil. Yield=87% LRMS: m/z 186 (M+1 )+ Retention time: 4.84min
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; toluene; at 140℃; for 1h;Irradiation;
To a mixture of 4,6-dichloro-5-methylpyrimidine (available from Sigma- Aldrich No.595446) (0.50 g, 3.07 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.18 g, 0.15 mmol) in toluene (6 ml) and DMF (1 ml) was added cesium carbonate (3 g, 9.20 mmol), followed by methylboronic acid (0.20 g, 3.37 mmol). The resulting reaction mixture was heated at 140 0C under microwave irradiation (2 cycles x 30 min), allowed to cool down to room temperature and filtered. Solvents were removed under reduced pressure. The residue was taken-up in EtOAc and washed with a saturated NaHCO3 aqueous solution and brine. The organic phase was separated, dried (Na2SO4), filtered and concentrated to afford the title compound D8 (0.18 g, 1.26 mmol, 41% yield). UPLC: rt = 0.53 min, peak observed: 143 <n="22"/>(M+1-HC1, 100%) and 445 (M+1-HC1, 33%). C6H7ClN2 requires 142. 1H NMR (400 MHz, CDCl3) delta(ppm): 8.70 (s, 1 H), 2.57 (s, 3 H), 2.39 (s, 3 H).
With pyridine; copper diacetate; In 1,4-dioxane; for 6h;Reflux;
Intermediate 1: N-Methyl-4-(trifluoromethyl) aniline To a mixture of 4-trifluoromethylaniline (196 mg, 1.2 mmol), copper acetate (550 mg, 3.0 mmol) and pyridine (0.34 mL, 4.2 mmol) in dioxane (6 mL) was added methylboronic acid (181 mg, 3.0 mmol, Aldrich, Catalog number: 165335). The mixture was heated with stirring under reflux for 6 hours. The resulting mixture was filtered. The filtrate was concentrated under vacuum and purified by column chromatography to afford N-methyl-4-(trifluoromethyl)-aniline (150 mg, 70 %). MS obsd. (ESI+) [(M+H)+]: 176
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 110℃; for 72h;Inert atmosphere;
An oven-dried resealable Schlenk tube was charged with ethyl 5,6-dibromonicotinate (preparation 47b, 1.09 g, 3.5 mmol), methylboronic acid (0.24 g, 4.0 mmol), potassium carbonate (1.46 g, 10.6 mmol) and 1,4-dioxane (27 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and then tetrakis(triphenylphosphine)palladium(0) (0.41 g, 0.35 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated in an oil bath to 110 C. After 3 days, the mixture was cooled, filtered through Celite and the filtrate was evaporated. Purification of the residue by flash chromatography (97:3 to 9:1 hexanes/ethyl acetate) gave the title compound (0.41 g, 45%) as a solid. LRMS (m/z): 244/246 (M+1)+. 1H-NMR delta (CDCl3): 1.41 (t, J=9.0Hz, 3H), 2.74 (s, 3H), 4.41 (q, J=9.0Hz, 2H), 8.40 (d, J=3.0Hz, 1H), 9.01 (d, J=3.0Hz, 1H).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; for 4.0h;Reflux;
Compound 535b (180 mg, 1.05 mmol), methylboronicacid (200 mg), Pd(PPh3)4 (100 mg), and potassium carbon-ate (500 mg) were dissolved in dioxane (10 mE) and water (3 mE) and stirred at reflux for 4 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Colunm chromatography (2:1 ethyl acetate/hexanes)provided the desired product (70 mg). [M+H]151.1
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 130.0℃; for 15.0h;Inert atmosphere;
To a solution of 4.0 g of <strong>[1689-89-0]4-hydroxy-3-iodo-5-nitrobenzonitrile</strong> in 240 ml dimethylformamide was added 4.13 g of methyl boronic acid, and 8.99 g of cesium carbonate. The mixture was then degassed by bubbling argon gas through it for 30 min. Tris(dibenzylidineacetone)dipalladium (1.38 g) was added, and the mixture was then heated to 130C for 15 h. Analysis of the crude mixture via LC/MS showed complete formation of the desired product with ca. 14% reduction of the iodide. The mixture was cooled to room temperature, diluted with water (300 ml) and acetic acid (-50 ml), and then extracted with ethyl acetate (5 x 300 ml). The organic layers were dark red-brown to light green-yellow in succession. The combined organic layers were extracted with water (2 x 300 ml) and then 2M sodium hydroxide (3 x 300 ml). The aqueous layers were red to yellow in succession. The combined aqueous layers (containing the phenol), were made slightly acidic by addition of 100 ml of acetic acid and then extracted with ethyl acetate (3 x 300 ml). These organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via flash chromatography (R/= 0.17 in 2/1 hexanes/ethyl acetate) on a Biotage Horizon, 65i column, eluting with 1 column volume of 5% ethyl acetate in <n="71"/>hexanes, followed by a linear gradient from 5 to 80% of ethyl acetate in hexanes over 10 column volumes to provide 1.01 g (41%) of the title compound. The base-extracted organic layer was concentrated in vacuo and purified via flash chromatography on a Biotage Horizon in the same way to provide an additional 305 mg (12%) of the title compound. Mass spectrum (ESI) 177.0 (M-I). 1H NMR (500 MHz, CDCl3): delta 11.23 (s, IH), 8.33 (s, IH), 7.68 (s, IH), 2.39 (s, 3H).
With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 50℃;Reflux; Inert atmosphere;
Intermediate 413-Bromo-5-chloro-2-methylpyridine; 2,3-Dibromo-5-chloropyridine (1.3 g, 4.70 mmol), methylboronic acid (0.30 g, 5.01 mmol), bis(triphenylphosphine)palladium(II) chloride (0.50 g, 0.70 mmol) and dioxane (10 mL) were added. K2CO3 (2 M aq. solution, 7.0 mL, 14.0 mmol) was added and the reaction was put under N2 (g) atmosphere. The reaction was heated to reflux for 5 h. The reaction was stirred at 50 C. overnight and then heated to reflux for additionally 1 h. Methylboronic acid (0.14 g, 2.35 mmol) was added and the reaction was refluxed for 4 h and the allowed to cool down to r.t. The mixture is was filtered through a silica plug. EtOAc and water were added and the phases were separated. The organic phase was washed two more times with water. The organic phase was dried with MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (12 g SiO2, 0-20% MeOH containing 0.1 M NH3 in DCM). The fractions containing pure product were pooled and concentrated, yielding the title compound (123 mg, 13% yield): 1H NMR (DMSO-d6) delta ppm 2.56 (s, 3H), 8.29 (d, 1H), 8.52 (d, 1H); MS (CI) m/z 206 [M+H]+.
With pyridine; copper diacetate; In 1,4-dioxane; at 20℃; for 48h;Reflux;
A mixture of <strong>[45762-41-2]2-ethyl-4-bromoaniline</strong> (2.84 mL, 20 mmol), copper(II) acetate (3.0 g, 50 mmol) and pyridine (5.66 mL, 70 mmol) in 1,4-dioxane (240 mL) were stirred at room temperature for 15 min. Methylboronic acid (3.0 g, 50 mmol) was added and the resulting mixture was heated to reflux for 48 h. The mixture was cooled to room temperature, filtered through Celite and concentrated in vacuo. Purification by silica chromatography (eluent, 10% EtOAc : iso-hexane) gave the desired compound
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 18h;
A suspension of 4,6-dichloropyridin-2-amine (1.63 g, 10 mmol), methylboronic acid (0.6 g, 10 mmol), Cs2C03 (9.75 g, 30 mmol), and Pd(dppf)Cl2 (400 mg) in dioxane/water (4: 1, 50 mL) was stirred for 18 hours at 100 C. The reaction was diluted with water and extracted with EtOAc (50 mLx3). The combined organic layer was washed with water and brine. The resulting solution was concentrated under reduced pressure and the residue was purified via prep-HPLC to afford 4-chloro-6-methylpyridin-2-amine (100 mg) as brown solid. MS ESI calcd. For C6H7C1N2 [M + H]+ 143, found 143.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere;
12113] A mixture of 500 mg of methyl 4-bromobenzo[b] thiophene-2-carboxylate, 161 mg of methylboronic acid,g of potassium phosphate, 151 mg ofa [1,1?-bis(diphe- nylphosphino)ferrocene]palladium (II) dichloride dichloromethane adduct, 6 ml of 1,4-dioxane, and 0.1 ml of waterstirred for 3 hours at 100 C. under a nitrogen atmosphere. Afier being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform and water were added to the residues, and insoluble matter was separated by filtration. Tbe filtrate was extracted using chloroform, and the organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The residues were subjected to silica gel colunm chromatography, thereby obtaining 340 mg of methyl 4-methylbenzo[b]thiophene-2- carboxylate (hereinafier, described as a ?compound 22 ofpresent invention?).12114] Compound 22 of the Present InventionMe12115] ?H-NMR (CDC13) oe: 8.17-8.16 (m, 1H), 7.71-7.69(m, 1H), 7.37-7.35 (m, 1H), 7.20-7.18 (m, 1H), 3.95 (s, 3H),2.64 (s, 3H).
340 mg
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere;
A mixture of 500 mg of <strong>[360575-29-7]methyl 4-bromobenzo[b]thiophene-2-carboxylate</strong>, 161 mg of methylboronic acid, 1.17g of potassium phosphate, 151 mg of a [1,1?-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethaneadduct, and 6 ml of 1,4-dioxane, and 0.1 ml of water was stirred for 3 hours at 100C under a nitrogen atmosphere. Afterbeing cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Chloroform andwater were added to the residues, and insoluble matter was separated by filtration. The filtrate was extracted usingchloroform, and the organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentratedunder reduced pressure. The residues were subjected to silica gel column chromatography, thereby obtaining 340 mgof methyl 4-methylbenzo[b]thiophene-2-carboxylate.
5-chloro-6-methylnicotinic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
420 mg
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 75℃;
A mixture of methyl 5 6-dichloronicotinate (D1 2 g) methylboronic acid (0.581 g) K2CO3(2.68 g) and Pd (PPh3)4(0.561 g) in 1 4-dioxane (100 mL) was stirred at 75 overnight. The resulting mixture was filtered and the filtrate was concentrated in vacuo to give the crude product which was further purified by column chromatography (eluting with EAPE50to 100) to give the title compound (420 mg) as a yellow solid. MS (ESI) C8H8ClNO2requires 185 found 186 [M+H]+.
420 mg
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 75℃;
Description 124Methyl 5-chloro-6-methylnicotinate (D124)NCI0To a solution of <strong>[56055-54-0]methyl 5,6-dichloronicotinate</strong> (D123, 2 g), methylboronic acid (0.581 g), K2C03 (2.68 g) and Pd(PPh3)4 (0.561 g) in 1,4-dioxane (100 mL) was stirred at 75C overnight. The reaction was filtered and the filtrate concentrated under vacuum to give the residue, which waspurified by column chromatography (silica gel, petroleum ether/EtOAc = 1:1) to afford the titlecompound (420 mg) as yellow solid. MS (ESI): C8H8C1NO2 requires 185; found 186 [M+H].
420 mg
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 75℃;
Take <strong>[56055-54-0]5,6-dichloronicotinic acid methyl ester</strong> (D1, 2g), methyl boronic acid (0.158 g), K2CO3(2.68 g) and Pd(PPh3)4 (0.561 g), of 1,4-dioxane (100 mL) was dissolved at 75 C at over night. The filtrate was concentrated in vacuo to give the crude product which was further purified by column chromatography (usingEpsilonAlpha: PE = 50% to 100%) to give the title compound (420 mg) as a yellow solid.
With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; tricyclohexylphosphine; In 1,4-dioxane; at 110℃;
A mixture of K2CO3(1.342 g) tricyclohexylphosphine (0.272 g) Pd2(dba)3(0.444 g) methylboronic acid (0.291 g) and methyl 5 6-dichloronicotinate (D1 1 g) in 1 4-dioxane (20 mL) was heated to 110overnight. Cold water (30 mL) was added and the aqueous layer was extracted with DCM (2×100 mL) . The combined organic layers were dried over Na2SO4 filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (eluting with EAPE 0to 50) to give the title compound (1 g) as a yellow oil. MS (ESI) C9H11NO2requires 165 found 166 [M+H]+.
1 g
With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; tricyclohexylphosphine; In 1,4-dioxane; at 110℃;
A mixture of K2C03 (1.342 g), tricyclohexylphosphine (0.272 g), Pd2(dba)3 (0.444 g),methylboronic acid (0.291 g) and <strong>[56055-54-0]methyl 5,6-dichloronicotinate</strong> (Dl, 1 g) in 1,4-dioxane (20 mL) was heated to 110C overnight. Cold water (30 mL) was added and the aqueous layer was extracted with DCM (2x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (eluting with EA:PE = 0% to 50%) to give the title compound (1 g) as yellow oil. MS (ESI): C9H11N02 requires165; found 166 [M+H].
1 g
With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; tricyclohexylphosphine; In 1,4-dioxane; at 110℃;
Take K2CO3 (1.342 g), Tricyclohexylphosphine (0.272 g),Pd2 (dba) 3 (0.444 g),Methyl boronic acid(0.291 g) and <strong>[56055-54-0]methyl 5,6-dichloronicotinate</strong> (D1, 1 g)Of the 1,4-dioxane(20 mL)The mixture was heated to 110 C overnight.Add cold water (30 mL),The aqueous layer was extracted using DCM (2 x l00 mL).The combined organic layers were dehydrated by Na2S04,Filtration, and vacuum concentration.The resulting residue was purified by column chromatography (using EpsilonAlpha: PE = G% to 5G%) to give the title compound (1 g) as a yellow oil.
With potassium phosphate; In 1,4-dioxane; at 110℃; for 2h;Inert atmosphere;
A solution of PdCl2(dppf)-DCM adduct (0.922 g, 1.129 mmol), methylboronic acid (2.70 g, 45.2 mmol), 4-bromo-3-chloroanisole (6.39 ml, 45.2 mmol), and potassium phosphate (28.8 g, 135 mmol) in 150 mL dioxane and 50 mL water was heated to 110 C. for 2 hours. The reaction mixture was then diluted with heptane, the organics dried over MgSO4 and concentrated to afford 2-chloro-4-methoxy-1-methylbenzene. m/z (ESI) 141.0 (M-CH3)+.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; at 90℃; for 5h;Inert atmosphere;
A mixture of bromide 1 (1.0 g, 4.78 mmol), methyl boronic acid (860 mg, 14.3 mmol), Pd(dppf)2Cl2 (194 mg, 0.239 mmol), and K2CO3 (1.32 g, 9.56 mmol) in dioxane (20 mL) was degassed and stirred at 90 C. for 5 h under nitrogen. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (EtOAc/petroleum ether=1/4) to give the desired product (636 mg, 4.39 mmol, 91.8%) as a white solid.
With norborn-2-ene; P(p-CH3OC6H4)3; palladium diacetate; caesium carbonate; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;
General procedure: Table 2, example 4 PdOAc2 (3.4 mg, 0.015 mmol), cesium carbonate (293 mg, 0.900 mmol), and tris(4-methoxyphenyl)phosphine (12 mg, 0.033 mmol) were combined in dioxane (2 mL) and stirred for 15 min at room temperature under an atmosphere of nitrogen. Then 6-chloro-3-iodo-2-methylpyridine (76 mg, 0.30 mmol), O-benzoyl morpholine (69 mg, 0.330 mmol), methylboronic acid(20 mg, 0.33 mmol), and bicyclo[2.2.1]hept-2-ene (28 mg,0.30 mmol) were added as a solution in dioxane (2 mL) to the previously prepared solution of catalyst and base. The reaction was sealed and heated to 100C for 18 h. The reaction mixturewas cooled to room temperature and filtered through a pad of celite eluting with ethyl acetate. The eluent was concentrated and the residue was puried by silica gel chromatography (ISCO 24 gsilica cartridge; 0-30% ethyl acetate in hexanes) to provide4-(6-chloro-2,3-dimethylpyridin-4-yl)morpholine (41 mg, 60%yield) as a colorless oil
With norborn-2-ene; P(p-CH3OC6H4)3; palladium diacetate; caesium carbonate; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;
General procedure: Table 2, example 4 PdOAc2 (3.4 mg, 0.015 mmol), cesium carbonate (293 mg, 0.900 mmol), and tris(4-methoxyphenyl)phosphine (12 mg, 0.033 mmol) were combined in dioxane (2 mL) and stirred for 15 min at room temperature under an atmosphere of nitrogen. Then 6-chloro-3-iodo-2-methylpyridine (76 mg, 0.30 mmol), O-benzoyl morpholine (69 mg, 0.330 mmol), methylboronic acid(20 mg, 0.33 mmol), and bicyclo[2.2.1]hept-2-ene (28 mg,0.30 mmol) were added as a solution in dioxane (2 mL) to the previously prepared solution of catalyst and base. The reaction was sealed and heated to 100C for 18 h. The reaction mixturewas cooled to room temperature and filtered through a pad of celite eluting with ethyl acetate. The eluent was concentrated and the residue was puried by silica gel chromatography (ISCO 24 gsilica cartridge; 0-30% ethyl acetate in hexanes) to provide4-(6-chloro-2,3-dimethylpyridin-4-yl)morpholine (41 mg, 60%yield) as a colorless oil
With norborn-2-ene; P(p-CH3OC6H4)3; palladium diacetate; caesium carbonate; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;
General procedure: Table 2, example 4 PdOAc2 (3.4 mg, 0.015 mmol), cesium carbonate (293 mg, 0.900 mmol), and tris(4-methoxyphenyl)phosphine (12 mg, 0.033 mmol) were combined in dioxane (2 mL) and stirred for 15 min at room temperature under an atmosphere of nitrogen. Then 6-chloro-3-iodo-2-methylpyridine (76 mg, 0.30 mmol), O-benzoyl morpholine (69 mg, 0.330 mmol), methylboronic acid(20 mg, 0.33 mmol), and bicyclo[2.2.1]hept-2-ene (28 mg,0.30 mmol) were added as a solution in dioxane (2 mL) to the previously prepared solution of catalyst and base. The reaction was sealed and heated to 100C for 18 h. The reaction mixturewas cooled to room temperature and filtered through a pad of celite eluting with ethyl acetate. The eluent was concentrated and the residue was puried by silica gel chromatography (ISCO 24 gsilica cartridge; 0-30% ethyl acetate in hexanes) to provide4-(6-chloro-2,3-dimethylpyridin-4-yl)morpholine (41 mg, 60%yield) as a colorless oil
With norborn-2-ene; P(p-CH3OC6H4)3; palladium diacetate; caesium carbonate; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;
General procedure: Table 2, example 4 PdOAc2 (3.4 mg, 0.015 mmol), cesium carbonate (293 mg, 0.900 mmol), and tris(4-methoxyphenyl)phosphine (12 mg, 0.033 mmol) were combined in dioxane (2 mL) and stirred for 15 min at room temperature under an atmosphere of nitrogen. Then 6-chloro-3-iodo-2-methylpyridine (76 mg, 0.30 mmol), O-benzoyl morpholine (69 mg, 0.330 mmol), methylboronic acid(20 mg, 0.33 mmol), and bicyclo[2.2.1]hept-2-ene (28 mg,0.30 mmol) were added as a solution in dioxane (2 mL) to the previously prepared solution of catalyst and base. The reaction was sealed and heated to 100C for 18 h. The reaction mixturewas cooled to room temperature and filtered through a pad of celite eluting with ethyl acetate. The eluent was concentrated and the residue was puried by silica gel chromatography (ISCO 24 gsilica cartridge; 0-30% ethyl acetate in hexanes) to provide4-(6-chloro-2,3-dimethylpyridin-4-yl)morpholine (41 mg, 60%yield) as a colorless oil
With norborn-2-ene; P(p-CH3OC6H4)3; palladium diacetate; caesium carbonate; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;
General procedure: Table 2, example 4 PdOAc2 (3.4 mg, 0.015 mmol), cesium carbonate (293 mg, 0.900 mmol), and tris(4-methoxyphenyl)phosphine (12 mg, 0.033 mmol) were combined in dioxane (2 mL) and stirred for 15 min at room temperature under an atmosphere of nitrogen. Then 6-chloro-3-iodo-2-methylpyridine (76 mg, 0.30 mmol), O-benzoyl morpholine (69 mg, 0.330 mmol), methylboronic acid(20 mg, 0.33 mmol), and bicyclo[2.2.1]hept-2-ene (28 mg,0.30 mmol) were added as a solution in dioxane (2 mL) to the previously prepared solution of catalyst and base. The reaction was sealed and heated to 100C for 18 h. The reaction mixturewas cooled to room temperature and filtered through a pad of celite eluting with ethyl acetate. The eluent was concentrated and the residue was puried by silica gel chromatography (ISCO 24 gsilica cartridge; 0-30% ethyl acetate in hexanes) to provide4-(6-chloro-2,3-dimethylpyridin-4-yl)morpholine (41 mg, 60%yield) as a colorless oil.
With norborn-2-ene; P(p-CH3OC6H4)3; palladium diacetate; caesium carbonate; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;
General procedure: Table 2, example 4 PdOAc2 (3.4 mg, 0.015 mmol), cesium carbonate (293 mg, 0.900 mmol), and tris(4-methoxyphenyl)phosphine (12 mg, 0.033 mmol) were combined in dioxane (2 mL) and stirred for 15 min at room temperature under an atmosphere of nitrogen. Then 6-chloro-3-iodo-2-methylpyridine (76 mg, 0.30 mmol), O-benzoyl morpholine (69 mg, 0.330 mmol), methylboronic acid(20 mg, 0.33 mmol), and bicyclo[2.2.1]hept-2-ene (28 mg,0.30 mmol) were added as a solution in dioxane (2 mL) to the previously prepared solution of catalyst and base. The reaction was sealed and heated to 100C for 18 h. The reaction mixturewas cooled to room temperature and filtered through a pad of celite eluting with ethyl acetate. The eluent was concentrated and the residue was puried by silica gel chromatography (ISCO 24 gsilica cartridge; 0-30% ethyl acetate in hexanes) to provide4-(6-chloro-2,3-dimethylpyridin-4-yl)morpholine (41 mg, 60%yield) as a colorless oil.
With norborn-2-ene; P(p-CH3OC6H4)3; palladium diacetate; caesium carbonate; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;
General procedure: Table 2, example 4 PdOAc2 (3.4 mg, 0.015 mmol), cesium carbonate (293 mg, 0.900 mmol), and tris(4-methoxyphenyl)phosphine (12 mg, 0.033 mmol) were combined in dioxane (2 mL) and stirred for 15 min at room temperature under an atmosphere of nitrogen. Then <strong>[249291-79-0]6-chloro-3-iodo-2-methylpyridine</strong> (76 mg, 0.30 mmol), O-benzoyl morpholine (69 mg, 0.330 mmol), methylboronic acid(20 mg, 0.33 mmol), and bicyclo[2.2.1]hept-2-ene (28 mg,0.30 mmol) were added as a solution in dioxane (2 mL) to the previously prepared solution of catalyst and base. The reaction was sealed and heated to 100C for 18 h. The reaction mixturewas cooled to room temperature and filtered through a pad of celite eluting with ethyl acetate. The eluent was concentrated and the residue was puried by silica gel chromatography (ISCO 24 gsilica cartridge; 0-30% ethyl acetate in hexanes) to provide4-(6-chloro-2,3-dimethylpyridin-4-yl)morpholine (41 mg, 60%yield) as a colorless oil
With norborn-2-ene; P(p-CH3OC6H4)3; palladium diacetate; caesium carbonate; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;
General procedure: Table 2, example 4 PdOAc2 (3.4 mg, 0.015 mmol), cesium carbonate (293 mg, 0.900 mmol), and tris(4-methoxyphenyl)phosphine (12 mg, 0.033 mmol) were combined in dioxane (2 mL) and stirred for 15 min at room temperature under an atmosphere of nitrogen. Then <strong>[249291-79-0]6-chloro-3-iodo-2-methylpyridine</strong> (76 mg, 0.30 mmol), O-benzoyl morpholine (69 mg, 0.330 mmol), methylboronic acid(20 mg, 0.33 mmol), and bicyclo[2.2.1]hept-2-ene (28 mg,0.30 mmol) were added as a solution in dioxane (2 mL) to the previously prepared solution of catalyst and base. The reaction was sealed and heated to 100C for 18 h. The reaction mixturewas cooled to room temperature and filtered through a pad of celite eluting with ethyl acetate. The eluent was concentrated and the residue was puried by silica gel chromatography (ISCO 24 gsilica cartridge; 0-30% ethyl acetate in hexanes) to provide4-(6-chloro-2,3-dimethylpyridin-4-yl)morpholine (41 mg, 60%yield) as a colorless oil
4-(6-chloro-2,3-dimethylpyridin-4-yl)morpholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With norborn-2-ene; P(p-CH3OC6H4)3; palladium diacetate; caesium carbonate; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;
Table 2, example 4 PdOAc2 (3.4 mg, 0.015 mmol), cesium carbonate (293 mg, 0.900 mmol), and tris(4-methoxyphenyl)phosphine (12 mg, 0.033 mmol) were combined in dioxane (2 mL) and stirred for 15 min at room temperature under an atmosphere of nitrogen. Then <strong>[249291-79-0]6-chloro-3-iodo-2-methylpyridine</strong> (76 mg, 0.30 mmol), O-benzoyl morpholine (69 mg, 0.330 mmol), methylboronic acid(20 mg, 0.33 mmol), and bicyclo[2.2.1]hept-2-ene (28 mg,0.30 mmol) were added as a solution in dioxane (2 mL) to the previously prepared solution of catalyst and base. The reaction was sealed and heated to 100C for 18 h. The reaction mixturewas cooled to room temperature and filtered through a pad of celite eluting with ethyl acetate. The eluent was concentrated and the residue was puried by silica gel chromatography (ISCO 24 gsilica cartridge; 0-30% ethyl acetate in hexanes) to provide4-(6-chloro-2,3-dimethylpyridin-4-yl)morpholine (41 mg, 60%yield) as a colorless oil. 1H NMR (600 MHz, CDCl 3 ) d : 6.72 (s, 1H), 3.85 (m, 4H), 2.94 (m,4H), 2.44 (s, 3H), 2.14 (s, 3H).13C NMR (150 MHz, CDCl 3 ) d : 160.4,158.6, 148.4, 123.2, 111.4, 66.9, 51.4, 23.0, 14.4. LCMS (M+1):227.12.
With norborn-2-ene; P(p-CH3OC6H4)3; palladium diacetate; caesium carbonate; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;
General procedure: Table 2, example 4 PdOAc2 (3.4 mg, 0.015 mmol), cesium carbonate (293 mg, 0.900 mmol), and tris(4-methoxyphenyl)phosphine (12 mg, 0.033 mmol) were combined in dioxane (2 mL) and stirred for 15 min at room temperature under an atmosphere of nitrogen. Then <strong>[249291-79-0]6-chloro-3-iodo-2-methylpyridine</strong> (76 mg, 0.30 mmol), O-benzoyl morpholine (69 mg, 0.330 mmol), methylboronic acid(20 mg, 0.33 mmol), and bicyclo[2.2.1]hept-2-ene (28 mg,0.30 mmol) were added as a solution in dioxane (2 mL) to the previously prepared solution of catalyst and base. The reaction was sealed and heated to 100C for 18 h. The reaction mixturewas cooled to room temperature and filtered through a pad of celite eluting with ethyl acetate. The eluent was concentrated and the residue was puried by silica gel chromatography (ISCO 24 gsilica cartridge; 0-30% ethyl acetate in hexanes) to provide4-(6-chloro-2,3-dimethylpyridin-4-yl)morpholine (41 mg, 60%yield) as a colorless oil.
With norborn-2-ene; P(p-CH3OC6H4)3; palladium diacetate; caesium carbonate; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;
General procedure: Table 2, example 4 PdOAc2 (3.4 mg, 0.015 mmol), cesium carbonate (293 mg, 0.900 mmol), and tris(4-methoxyphenyl)phosphine (12 mg, 0.033 mmol) were combined in dioxane (2 mL) and stirred for 15 min at room temperature under an atmosphere of nitrogen. Then 6-chloro-3-iodo-2-methylpyridine (76 mg, 0.30 mmol), O-benzoyl morpholine (69 mg, 0.330 mmol), methylboronic acid(20 mg, 0.33 mmol), and bicyclo[2.2.1]hept-2-ene (28 mg,0.30 mmol) were added as a solution in dioxane (2 mL) to the previously prepared solution of catalyst and base. The reaction was sealed and heated to 100C for 18 h. The reaction mixturewas cooled to room temperature and filtered through a pad of celite eluting with ethyl acetate. The eluent was concentrated and the residue was puried by silica gel chromatography (ISCO 24 gsilica cartridge; 0-30% ethyl acetate in hexanes) to provide4-(6-chloro-2,3-dimethylpyridin-4-yl)morpholine (41 mg, 60%yield) as a colorless oil
With norborn-2-ene; P(p-CH3OC6H4)3; palladium diacetate; caesium carbonate; In 1,4-dioxane; at 100℃; for 18.0h;Inert atmosphere;
General procedure: Table 2, example 4 PdOAc2 (3.4 mg, 0.015 mmol), cesium carbonate (293 mg, 0.900 mmol), and tris(4-methoxyphenyl)phosphine (12 mg, 0.033 mmol) were combined in dioxane (2 mL) and stirred for 15 min at room temperature under an atmosphere of nitrogen. Then 6-chloro-3-iodo-2-methylpyridine (76 mg, 0.30 mmol), O-benzoyl morpholine (69 mg, 0.330 mmol), methylboronic acid(20 mg, 0.33 mmol), and bicyclo[2.2.1]hept-2-ene (28 mg,0.30 mmol) were added as a solution in dioxane (2 mL) to the previously prepared solution of catalyst and base. The reaction was sealed and heated to 100C for 18 h. The reaction mixturewas cooled to room temperature and filtered through a pad of celite eluting with ethyl acetate. The eluent was concentrated and the residue was puried by silica gel chromatography (ISCO 24 gsilica cartridge; 0-30% ethyl acetate in hexanes) to provide4-(6-chloro-2,3-dimethylpyridin-4-yl)morpholine (41 mg, 60%yield) as a colorless oil
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;
A solution of ethyl 5-bromopyrazolo[1,5-ajpyridine-3-carboxylate (1.0 g, 3.73 mmol),methylboronic acid (448 mg, 7.46 mmol), Pd(dppf)C12 (545 mg, 0.746 mmol) and C52CO3(2.42 g, 7.46 mmol) was dissolved in DMF (5.0 mL), then the mixture was stirred at 100 Cfor two hours. It was concentrated, and purified by silica gel chromatography with PE:EA=5: 1to obtain the desired compound as an orange solid (589 mg, 77%). ESI MS m/z = 204.5[M+Hj.
77%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;
A solution of ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (1.0 g, 3.73 mmol), methylboronic acid (448 mg, 7.46 mmol), Pd(dppf)Cl2 (545 mg, 0.746 mmol) and Cs2CO3 (2.42 g, 7.46 mmol) was dissolved in DMF (5.0 mL), then the mixture was stirred at 100C for two hours. It was concentrated, and purified by silica gel chromatography with PE:EA=5:1 to obtain the desired compound as an orange solid (589 mg, 77%). ESI MS m/z = 204.5 [M+H]+.
methyl (1S,8R)-12-bromo-15-oxatetracyclo[6. 6.1.02,7. 09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate[ No CAS ]
[ 35277-02-2 ]
methyl (1R,8S)-12-[(4-fluoro-1H-pyrazol-1-yl)methyl]-15-oxatetracyclo[6.6.1.02,7.09,14]pentadeca-2,4,6,9,11,13-hexaene-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34.9 mg
Step 1: A stirred suspension of methyl (1S,8R)-12-bromo-15-oxatetracyclo-[6.6.1 .02?7.09?4jpentadeca-2,4,6,9, 11,1 3-hexaene-4-carboxylate (NT-3a1; 480,00 mg: 1.45mmol: 1.00 eq.), methylboronic acid (173.53 mg; 2.90 mmol; 2.00 eq.), cesium carbonate (1 180.65 mg; 3.62 mmol; 2.50 eq.) and 1,1 -bis(diphenylphosphino)ferrocenej dichloro palladium(II) (106.06 mg; 0.14 mmol; 0.10 eq.) in 1,4-dioxane (57.98 ml) and methanol (16.10 ml) was heated to 80 C. After 1 h the reacting mixture was cooled to RT, filtered withadditional MeOH and concentrated. The brown residue was purified by column chromatography (40 G ISCO Gold) eluting with 1 0/b EtOAc in heptane to provide the desired methyl (1 R,8S)- 12-methyl-i 5-oxatetracyclo[6.6. 1. 02?7.09?4jpentadeca-2.4,6,9, 11,13- hexaene-4-carboxylate contaminated by inseparable methyl (1 R.8 S) 15 -oxatetracyclo[6.6,1 ,02?7,09?4lpentadeca-2,4,6,9, 11,1 3-hexaene-4-carboxylate (320 mg), Step 2: To a stirred suspension of methyl (1R,8S)-12-methyl-15-oxatetracyclo- [6.6.1 .02?7.09?4jpentadeca-2,4,6,9, 11,1 3-hexaene-4-carboxylate and methyl (1 R,8S) 15- oxatetracyclo [6.6.1.027. 14j pentadeca-2,4,6,9, 11,1 3-hexaene-4-carboxylate (320.00 mg; 1.20 mmol; 1.00 eq.), and N-bromosuccinimide (224.58 mg; 1.26 mmol; 1.05 eq.) in carbon tetrachloride (12.02 ml) was added AIBN (9.87 mg; 0.06 mmol; 0.05 eq.). The resultingmixture was heated to 75 C. After 3 h the reacting mixture was cooled to RT diluted with DCM, washed with sat. NaHCO3, dried over MgSO4, filtered and concentrated. The crude material was purified by column chromatography (12 G ISCO Gold) eluting with 10% EtOAc in heptane to provide methyl (1S,8R)-12-(bromomethyl)-15-oxatetracyclo- [6.6.1.027. ue 14j pentadeca-2,4,6,9, 11,1 3-hexaene-4-carboxylate contaminated by inseparablemethyl (1 S,SR)-i 2-(dibromomethyl)- 1 5-oxatetracyclo[6. 6.1 .02?7.09?4jpentadeca-2,4,6,9,11,1 3-hexaene-4-carboxylate (273 mg).
Under nitrogen protection, In a reaction flask equipped with a reflux water separation device, (R)-(+)-2-(diphenylhydroxymethyl)pyrrolidine (253 g, 1.0 mol) and methylboronic acid (87 g, 1.45 mol) were added to 750 ml of n-hexane, Slowly stirring, As the water is constantly being separated, The solution gradually becomes clear, Then adjust the stirring speed to the normal state, When there is no more water, Stop stirring, Slow down to 30 deg C, After standing overnight, Diatomaceous earth temperature filtration, The filtrate was once again cooled to -10 C, Stirring for 2 hours to complete precipitation, After filtering, The oven was vacuum dried at 45 C for 4 hours to give 225 g of R-MeCBS, Yield 81% The product is a white solid, GC: 98.1%, water content: 0.27%
In n-heptane; at 40℃;Inert atmosphere; Reflux; Large scale;
Under nitrogen protection, In a reactor equipped with a reflux water separation device(S)-(+)-2-(diphenylhydroxymethyl)pyrrolidine (2.53 kg, 10 moles) and methylboronic acid (779 g, 13 moles) were added to 7.1 g of n-heptane, Slowly stirring, As the water is constantly being separated, The solution gradually becomes clear, Then adjust the stirring speed to the normal state, When there is no more water, Stop stirring, Slow down to 40 deg C, After standing overnight, Diatomaceous earth temperature filtration, The filtrate was once again cooled to -10 C, Stirring for 1.5 hours to complete precipitation, After filtration, 40 deg C in a double cone and dried in vacuo for 8 hours to give 2.30 kg of S-MeCBS, Yield 83% The product is a white solid, GC: 98.2%, water content: 0.31%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; at 80℃;
Step 2: 5-methyl-2-(trifluoromethoxy) aniline 5-bromo-2-(trifluoromethoxy) aniline (1.14g, 4.46mmol) obtained from the last step, methyl boronic acid (0.72g, 12mmol), potassium carbonate (1.66g, 12mmmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (0.29g, 0.4mmol) and 1,4-dioxane (25mL) were added to a 100mL reaction flask. The reaction mixture was heated up to 80 C and stirred overnight. After completion of the reaction, the reaction solution was concentrated and dissolved in ethyl acetate. The organic phase was washed with saturated ammonium chloride and saturated brine, dried, concentrated and purified by column chromatography (ethyl acetate/petroleum ether=1:15) to obtain the title compound (yellow oil, 0.61g, 72%). (MS: [M+1] 192.1)
With potassium phosphate; tricyclohexylphosphine tetrafluoroborate; palladium diacetate; In 1,4-dioxane; water; at 110℃; for 12h;Inert atmosphere;
To a 1000-mL round-bottom flask was placed a solution of <strong>[103273-01-4]2-bromo-4-tert-butylaniline</strong> (9.2 g,40.33 mmol) in dioxane/water (500 mL) then Pd(OAc)2 (900 mg,4.01 mmol),PCy3.HBF4 (2.95 g,8.01 mmol),methylboronic acid (3.6 g,60.14 mmol),and K3P04 (26 g,122.64 mmol) were added under nitrogen. The reaction was stirred for 12 h at 110C then quenched by the addition of water and extracted with DCM. Theorganic extracts were combined and concentrated under reduced pressure. The residue was purified by column chromatography eluting with EtOAc/petroleum ether (1:80) affording 5.7 g (87%) of the title compound as a dark red oil. Mass Spectrum (LCMS,ESI pos): Calcd. for C,,H,8N: 164.1 (M+H); Found: 164.1.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 18.0h;Inert atmosphere; Schlenk technique;
2-bromo-4-chlorobenzo [d] thiazole (1.99 g, 8 mmol) was added to a 250 mL Schlenk flask which was well-methylboronic acid (484 mg, 8.08 mmol), 2M Na2CO3 aqueous solution (10 mL, 20 mmol), anhydrous ethanol (20 mL)Anhydrous toluene (20 mL) and Pd (PPh3) 4 (279 mg, 0.24 mmol) were added. After degassing, it was substituted with Ar and stirred vigorously at 80 C for 18 hours.After a certain period of time, the mixture was cooled to room temperature and the organic layer was separated. The water layer was washed with dichloromethane (20 mL x 2).The organic layer was collected, passed through a silica gel pad, and concentrated.The crude product was purified by column chromatography (n-hexane / ethyl acetate = 100/1) to obtain 4-chloro-2-methylbenzo [d] thiazole. Yield 1.41 g (96%).
96%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; for 18.0h;Reflux; Schlenk technique;
Well dried and Ar-substituted 250 mL Schlenk flask2-bromo-4-chlorobenzo [d] thiazole (1.99 g, 8 mmol), onic (484 mg, 8.08 mmol), 2M Na2CO3 aqueous solution (10 mL, 20 mmol),Anhydrous ethanol (20 mL),Anhydrous toluene (20 mL),Pd (PPh3) 4 (279 mg, 0.24 mmol) was added thereto.After degassing, it was substituted with Ar and stirred vigorously at 80 C for 18 hours.After a certain period of time, the mixture was cooled to room temperature and the organic layer was separated.The water layer was washed with dichloromethane (20 mL x 2).The organic layer was collected, passed through a silica gel pad, and concentrated.Crude product was purified by column chromatography(n-hexane / ethyl acetate = 100/1)To give 4-chloro-2-methylbenzo [d] thiazole. Yield 1.41 g (96%).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 120℃; for 12h;Inert atmosphere;
[1042] a mixture of compound 163c (2 g, 8.58 mmol), meb(oh)2 (2.05 g, 34.3 mmol), pd(pph3)4 (793 mg, 687 umol), K2CO3 (2.37 g, 17.2 mmol) in dioxane (50 ml) and H2O (10 ml) was degassed and purged with n2 for 3 times, and then the mixture was stirred at 120 C for 12 hour under N2 atmosphere. The reaction mixture was extracted with ethyl acetate 50 ml (50 ml x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 100: 1 to 80: 1). Compound 408a (1.4 g, yield: 97.0%) was obtained as a yellow solid. 1H NMR (400mhz, CDCl3) delta 7.87 - 7.73 (m, 1h), 4.27 (q, j = 7.1 hz, 2h), 3.91 -3.75 (m, 3h), 2.51 - 2.40 (m, 3h), 1.33 (t, j = 7.1 hz, 3h).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 105℃; for 16.0h;Inert atmosphere;
To a mixture of 6-bromo-3,4-dihydro-2H-isoquinolin-1-one (19.0 g, 82.4 mmol),CH3B(OH)2 (20.8 g, 329 mmol) and Na2CO3 (18.4 g, 165 mmol) in 1,4-dioxane (200 mL)and water (10.0 mL) is added [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (2.46 g, 3.29 mmol) under a nitrogen atmosphere and the mixture is stirred at 105 C for 16 hours under a nitrogen atmosphere. The suspension is filtered through a pad of diatomaceous earth and the filter cake is washed with DCM (3 x250 mL). The combined filtrates are washed with water (100 mL) and brine (80 mL), dried over Na2SO4, and the solvent isevaporated under reduced pressure. The crude product is purified by silica gel flash chromatography, eluting with a gradient of 0% to 50% EtOAc in PE to give the title compound (13.0 g, 95.2%) as a yellow solid. ES/MS (m/z): 162.0 (M+H), ?H NIVIR (400MHz, CDC13) 7.94 (d, J=8.0 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 7.02 (s, 1H), 6.89 (br s, 1H),3.55 (dt, J=2.9, 6.6 Hz, 2H), 2.94 (t, J=6.5 Hz, 2H), 2.37 (s, 3H).
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; at 100.0℃; for 6.0h;
Cesium carbonate (338 mg), methylboronic acid (47 mg), and tetrakis(triphenylphosphine)palladium (60 mg) were added to a 1,4-dioxane (3 ml) solution containing 2,3-dichloro-5-nitropyridine (100 mg), followed by stirring at 100C for 6 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and 3-chloro-2-methyl-5-nitropyridine (344 mg) was thus obtained.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; toluene; at 100℃;Inert atmosphere;
Methyl boronic acid (2.30 g, 38.4 mmol), c2 (7.95 g, 30.7 mmol) and K2CO3(8.48 G, 61.4 mmol) dissolved in toluene (150 ml) and water (30 ml) in. The mixture through the degassing by bubbling by nitrogen for 30 minutes, and add four trityl phosphorus palladium Pd (PPh3)4(1.78G,1 . 53 mmol). The mixture is then maintained at 100 C lower overnight. After the completion of the reaction, the mixture is cooled to room temperature, toluene extraction, and for brine and washed. The organic solution is filtered and evaporation. The crude product by column chromatography, using ethyl acetate in heptane gradient mixture (20% to 65%) purification. The white powder product by the heptane recrystallized three times, to get to the colorless crystal e2. In a 1 L three-opening in the bottle, adding hydration iridous chloride (14.1 g, 40 mmol) and compound e2 (33.02 g, 170 mmol), then add 300 mL2 - ethoxy ethanol and 100 ml of water, the mixture at reflux overnight under a nitrogen atmosphere. After the reaction, cooling to room temperature, the methanol precipitation and filtration and washing, drying to obtain intermediate A2 (24.00 g, yield 90%).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere;
1-Bromo-3-chloro-2-(trifluoromethyl)benzene (1.0 g, 3.85 mmol),Methylboronic acid (231 mg, 3.85 mmol) andK2CO3 (1.6 g, 11.58 mmol) was dispersed in 1,4-dioxane/water (16 mL / 4 mL).After replacing the nitrogen, Pd(dppf)Cl2 (145 mg, 0.2 mmol) was added.After replacing the nitrogen three times, the reaction was warmed to 90 C and allowed to react overnight.The reaction system was used directly for the next reaction.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere;
1-Bromo-3-chloro-2-methoxybenzene (1.0 g, 4.52 mmol),Methylboronic acid (270 mg, 4.52 mmol) and K2CO3 (1.9 g, 13.56 mmol) were dispersed inIn 1,4-dioxane/water (16 mL/4 mL),After replacing the nitrogen, Pd(dppf)Cl2 (145 mg, 0.2 mmol) was added.After replacing the nitrogen three times, the reaction was warmed to 90 C and allowed to react overnight.The reaction system was used directly for the next reaction.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In N,N-dimethyl-formamide; at 120℃;
A mixture of <strong>[953039-63-9]8-bromo-2-chloro-6-fluoroquinazoline</strong> (500 mg, 1.91 mmol, 1 equiv), methylboronic acid (114.5 mg, 1.91 mmol, 1 equiv), K2CO3 (528.6 mg, 3.82 mmol, 2 equiv), Pd(dppf)Cl2 (139.9 mg, 0.19 mmol, 0.1 equiv) in 20 mL of DMF was stirred overnight at 120C. The reaction was then quenched by the addition of 50 mL of water, extracted with ethyl acetate (2x20 mL) and the combined organic layers concentrated. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1 :3) to afford the desired product as a yellow solid in 53% yield.
53%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In N,N-dimethyl-formamide; at 120℃;
A mixture of <strong>[953039-63-9]8-bromo-2-chloro-6-fluoroquinazoline</strong> (500 mg, 1.91 mmol, 1 equiv), methylboronic acid (114.5 mg, 1.91 mmol, 1 equiv), K2C03 (528.6 mg, 3.82 mmol, 2 equiv), Pd(dppf)Cl2 (139.9 mg, 0.19 mmol, 0.1 equiv) in 20 mL of DMF was stirred overnight at l20C. The reaction was then quenched by the addition of 50 mL of water, extracted with ethyl acetate (2x20 mL) and the combined organic layers concentrated. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1 :3) to afford the desired product as a yellow solid in 53% yield.
With pyridine; copper diacetate; In 1,4-dioxane; at 15 - 100℃; under 775.743 Torr; for 16h;
Cu(OAc)2 (303 mg, 1.67 mmol, 1 eq) was added to a solution of the compound (1154) 88-lc (116 mg, 0.668 mmol, 0.4 eq) and pyridine (185 mg, 2.34 mmol, 0.19 mL, 1.40 eq) in dioxane (6 mL). The reaction mixture was stirred at 15C for 15 min. The compound 88- lb (100 mg, 1.67 mmol, 1 eq) was added and the reaction was heated to 100C and stirred at 100C under 02 (15 Psi) for 16 h. LCMS showed no desired MS was detected. TLC indicated the compound 88- lc was remained and one new spot was formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography. XH NMR confirmed that the product was 88-la (35 mg, 0.187 mmol, 11.2% yield). XH NMR (400MHz, CDC13) delta 7.93 (d, J = 5.60 Hz, 1H), 6.62 (d, J=2.00 Hz, 1H), 6.39 (dd, J= 2.20, 5.60 Hz, 1H), 4.32 (br s, 1H), 2.87 (d, J= 5.20 Hz, 3H).
With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100℃; for 10h;Inert atmosphere;
Example 66A 3-methylisonicotinonitrile To a mixture of 3-chloroisonicotinonitrile (50 g) in toluene (1.5 L) was added K3PO4 (306 g), and the mixture was stirred for 10 minutes at 25 C. Methylboronic acid (32.4 g) and tricyclohexylphosphine (10.12 g) were added. After 5 minutes, 150 mL of water was added, and the mixture was stirred for 5 minutes at 25 C. Diacetoxypalladium (2.431 g) was added under a nitrogen atmosphere. The resulting mixture was stirred for 10 hours at 100 C. Eleven additional reactions were set up as described above. After cooling to 20 C., all twelve reaction mixtures were combined. 5 L of water was added to the mixture, and the layers were separated. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography using 1-20% ethyl acetate in heptanes as the eluent to provide the title compound. 1H NMR (400 MHz, chloroform-d) delta ppm 8.68 (s, 1H), 8.60 (d, 1H), 7.46 (d, 1H), 2.56 (s, 3H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 95℃;Inert atmosphere;
A flask charged with 8-bromo-9H-purin-6-ylamine (500 mg, 2.3 mmol), methylboronic (200 mg, 3.5mmol), Pd(dppf)Cl2 (84 mg, 0.115 mmol) and K2C03 (938 mg, 0.9 mmol) in dioxane/H20 (50 mL/l0 mL) was degassed and filled with N2. The mixture was stirred at 95 C overnight. Solvent was removed and the residue was purified with prep-TLC (DCM/MeOH = 10/1) to give 8-methyl-9H-purin-6-ylamine (150 mg, yield: 43 %) as yellow solid. MS: m/z 150.0 (M+H+).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; toluene; at 60℃; for 168h;
Into a 250-mL 3 -necked round-bottom flask, was placed 2,5-dibromo-3- fluoropyridine (5 g, 19.62 mmol, 1.00 equiv), methylboronic acid (8.3 g, 138.66 mmol, 7.00 equiv), potassium carbonate (10.96 g, 79.30 mmol, 4.00 equiv), toluene (150 mL), water (15 mL), and Pd(PPli3)4 (3.4 g, 2.94 mmol, 0.15 equiv). The resulting solution was stirred for 7 days at 60 C. The resulting mixture was concentrated under vacuum to give crude 26-1 in toluene (150 mL).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;
A mixture of <strong>[76537-18-3]3-bromo-5-chloro-pyrazin-2-amine</strong> (31 g, 148.72 mmol), Pd(dppf)Cl2 (16.32 g, 22.31 mmol), methylboronic acid (13.35 g, 223.09 mmol) and CS2CO3 (96.91 g, 297.45 mmol) in Water (30 mL) and l,4-Dioxane (300 mL) was stirred at 90 C for 16 hours. After cooling to room temperature, the mixture was concentrated to give a residue. To the residue was added water (100 mL), extracted with EtOAc (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 20% to 40% to 60% to 80%) to give the product (13 g, 90.548 mmol, 61% yield) as a solid. 'H NMR(DMSO -ck, 400MHz) dH= 7.83 (s, 1H), 6.40 (s, 2H), 2.26 (s, 3H).
Ir(acac){κ2-C,N-[C6MeH3-py]{κ2-C,N-[C6H4-py][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Ca. 60%
General procedure: 2-(2-bromophenyl)pyridine (312 muL, 1.83 mmol) was added to [IrCl(cyclooctene)2]2 (1) (400 mg, 0.446 mmol), in 10 mL of 2-ethoxyethanol. The mixture was stirred overnight at reflux (135 C.) leading a yellow suspension, which was dried under vacuum and the residue treated with 3*5 mL of diethylether to afford 581 mg of an insoluble yellow powder. HR-MS (MALDI-TOF; DMSO): m/z calcd. for [C22H14Br2IrN2] 658.9, found: 658.4. Calcd. for [C22H15BrIrN2]: 579.0, found: 579.1. Calcd. for [C22H16IrN2]. Acetylacetone (67.4 muL, 0.666 mmol) and KOH (44.0 mg, 0.666 mmol) in 2 mL of methanol was added to the yellow powder (439.5 mg, 0.317 mmol) in 15 mL of THF. The mixture was stirred at 60 C., for 90 min, in a closed system. Then, the solvent was removed under vacuum and the residue was treated with 15 mL of CH2Cl2. The resulting suspension was filtered over Celite to afford a yellow solution, which was concentrated almost to dryness under vacuum. The addition of 5 mL pentane led to a yellow solid, which was washed with 2*4 mL pentane and dried under vacuum. The solid (a mixture of compounds 5, 6, and 7) was purified by silica column chromatography using toluene-pentane-ethyl acetate (1-3-1) as eluents. Yield: 180.6 mg (42%). The desired tris-heteroleptic compound 6 is obtained with 82% selectivity. Anal. Calcd for C27H22BrIrN2O2: C, 47.79; H, 3.27; N, 4.13. Found: C, 47.78; H, 3.66; N, 4.16. Suzuki-Miyaura cross-coupling reactions were performed in toluene, at 90 C. Under these conditions, the treatment of a mixture of compounds 5, 6, and 7 with 4.0 mol of RB(OH)2 and 4.0 mol of K3PO4, in the presence of Pd(PPh3)4 (10 mol %), for 24 hr quantitatively gives the corresponding tris-heteroleptic complexes Ir(acac) {kappa2-C,N-[C6RH3-py]{kappa2-C,N-[C6H4-py] (R=Me (8), Ph (9)), which were isolated after column chromatography as pure yellow solids in about 75% yield (about 60% with regard to the starting dimer (1) which a person of skill would not expect, particularly for a one-pot procedure. Compounds (8) and (9) were characterized by X-ray diffraction analysis. FIG. 5 shows the geometry around the iridium is octahedral with the pyridyl groups situated mutually trans. In the perpendicular plane, the metalated carbon atoms of the phenyl groups lie trans to the acac-oxygen atoms.
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