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Chemical Structure| 109-04-6
Chemical Structure| 109-04-6
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Product Details of [ 109-04-6 ]

CAS No. :109-04-6 MDL No. :MFCD00006219
Formula : C5H4BrN Boiling Point : -
Linear Structure Formula :- InChI Key :IMRWILPUOVGIMU-UHFFFAOYSA-N
M.W :158.00 Pubchem ID :7973
Synonyms :

Calculated chemistry of [ 109-04-6 ]

Physicochemical Properties

Num. heavy atoms : 7
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 31.94
TPSA : 12.89 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.26 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.62
Log Po/w (XLOGP3) : 1.42
Log Po/w (WLOGP) : 1.84
Log Po/w (MLOGP) : 1.24
Log Po/w (SILICOS-IT) : 2.18
Consensus Log Po/w : 1.66

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.35
Solubility : 0.708 mg/ml ; 0.00448 mol/l
Class : Soluble
Log S (Ali) : -1.3
Solubility : 8.0 mg/ml ; 0.0506 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.86
Solubility : 0.217 mg/ml ; 0.00137 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.61

Safety of [ 109-04-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 109-04-6 ]

* 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.

  • Upstream synthesis route of [ 109-04-6 ]
  • Downstream synthetic route of [ 109-04-6 ]

[ 109-04-6 ] Synthesis Path-Upstream   1~153

  • 1
  • [ 109-04-6 ]
  • [ 81290-20-2 ]
  • [ 368-48-9 ]
YieldReaction ConditionsOperation in experiment
79%
Stage #1: With silver fluoride In N,N-dimethyl-formamide at 20℃; for 0.333333 h;
Stage #2: With copper In N,N-dimethyl-formamide for 4 h;
Stage #3: at 90℃; for 5 h;
General procedure: To a well stirred mixture of AgF (1.27 g, 10 mmol) in 10 ml of DMF, Me3SiCF3 (1.7 g, 12 mmol) was added at room temperature. The mixture was stirred for 20 min and copper powder (1.0 g, 15 mmol) was added. After stirring for 4 h, the formation of CuCF3 was complete. The corresponding halogen containing compound (9 mmol) (in the case of 2,6-dibromopyridine, 4.5 mmol) was added and the reaction mixture was stirred under conditions surveyed in Table 1. The reaction was terminated unless signals of CuCF3 were no longer detected in the 19F NMR spectra. The mixture was filtered from the solid precipitate and poured into 50 ml of water. The organic layer was extracted with diethyl ether and dried over MgSO4. Ether was evaporated and the remainder was distilled under reduced pressure or crystallized.
Reference: [1] Journal of Fluorine Chemistry, 2012, vol. 133, p. 67 - 71
  • 2
  • [ 109-04-6 ]
  • [ 129946-88-9 ]
  • [ 368-48-9 ]
YieldReaction ConditionsOperation in experiment
96% With copper In N,N-dimethyl-formamide at 0 - 80℃; for 4 h; Inert atmosphere 2-bromopyridine (1.58 g, 0.01 mol) was added to a 100 ml three-necked flask under N2 protection.25 ml of DMF, Cu powder (1.92 g, 0.03 mol), stirring was started, and the ice water bath was cooled to 0-5 °C. add Umemoto reagent (8.76g, 0.02mol).After stirring for 1 h in an ice water bath, the mixture was further heated to 80 ° C for 3 h.The reaction solution was subjected to 19F NMR analysis using OTf as an internal standard, and the yield was 96percent.
Reference: [1] Patent: CN108239021, 2018, A, . Location in patent: Paragraph 0060-0062
  • 3
  • [ 109-04-6 ]
  • [ 431-47-0 ]
  • [ 368-48-9 ]
Reference: [1] Journal of Fluorine Chemistry, 2007, vol. 128, # 10, p. 1318 - 1325
  • 4
  • [ 109-04-6 ]
  • [ 88986-32-7 ]
  • [ 368-48-9 ]
Reference: [1] Journal of the Chemical Society, Chemical Communications, 1993, # 18, p. 1389 - 1391
  • 5
  • [ 109-04-6 ]
  • [ 77152-08-0 ]
  • [ 368-48-9 ]
Reference: [1] Journal of Organic Chemistry, 2013, vol. 78, # 22, p. 11126 - 11146
[2] Organic Letters, 2015, vol. 17, # 2, p. 298 - 301
  • 6
  • [ 109-04-6 ]
  • [ 368-48-9 ]
Reference: [1] Journal of Fluorine Chemistry, 1996, vol. 78, # 2, p. 177 - 181
  • 7
  • [ 109-04-6 ]
  • [ 368-48-9 ]
Reference: [1] Journal of Organic Chemistry, 2017, vol. 82, # 15, p. 7708 - 7719
  • 8
  • [ 109-04-6 ]
  • [ 2923-18-4 ]
  • [ 368-48-9 ]
Reference: [1] Chemistry Letters, 1981, p. 1719 - 1720
  • 9
  • [ 109-04-6 ]
  • [ 368-48-9 ]
Reference: [1] Organic Letters, 2014, vol. 16, # 6, p. 1744 - 1747
  • 10
  • [ 109-04-6 ]
  • [ 75-46-7 ]
  • [ 368-48-9 ]
Reference: [1] Journal of the American Chemical Society, 2011, vol. 133, # 51, p. 20901 - 20913
  • 11
  • [ 109-04-6 ]
  • [ 75-63-8 ]
  • [ 368-48-9 ]
Reference: [1] Journal of the Chemical Society, Chemical Communications, 1992, # 1, p. 53 - 54
  • 12
  • [ 109-04-6 ]
  • [ 4392-87-4 ]
Reference: [1] Journal of the Chemical Society, 1938, p. 1662,1669
  • 13
  • [ 109-04-6 ]
  • [ 5029-67-4 ]
YieldReaction ConditionsOperation in experiment
92% With copper(l) iodide; sodium iodide; N,N`-dimethylethylenediamine In 1,4-dioxane at 110℃; for 18 h; Inert atmosphere; Schlenk technique Aromatic Finkelstein Reaction; General ProcedureThe reaction was carried out under argon using standard Schlenktechniques due to the moisture and oxygen sensitivity of the copper(I) iodide. A two-neck pear-shaped flask equipped with a refluxcondenser was charged with the (het)aryl bromide starting material,NaI (2 equiv per bromine to exchange), and CuI (5 molpercent per bromineto exchange). N,N′-Dimethylethylenediamine (L1) or N,N′-dimethyl-1,2-cyclohexanediamine (L2) (10 molpercent per bromine toexchange) and anhydrous 1,4-dioxane (0.5 mL per 1 mmol NaI)were added. The resulting suspension was heated to 110 °C for 18h. After cooling to r.t., the mixture was poured into aq 25percent NH3 solution.The blue solution was diluted to a doubled volume with H2Oand was extracted three times with CH2Cl2. In the case of the 2,2′-bipyridines, the combined organic phases were additionally washedwith aq EDTA solution. Otherwise, the combined organic phaseswere solely washed with brine and dried with MgSO4. The solventwas removed under reduced pressure to give the desired product inpure form. If needed, the crude product can be purified by columnchromatography or recrystallization.
88 %Chromat. With copper(I) oxide; <i>L</i>-proline; potassium iodide In ethanol at 110℃; for 30 h; Schlenk technique; Inert atmosphere; Sealed tube General procedure: A Schlenk tube was charged with Cu2O (7.2 mg, 10 molpercent), l-proline (11.5 mg, 20 molpercent), aryl (or heteroaryl) bromide (1 or 3,0.50 mmol), potassium iodide (KI) (249 mg, 0.75 mmol), and EtOH(1.5 mL) under nitrogen atmosphere. The Schlenk tube was sealedwith a teflon valve, and then the reaction mixture was stirred at110C for a period (the reaction progress was monitored by GCanalysis). After the reaction was completed, GC yield of high volatileproduct was determined using an appropriate internal standard(chlorobenzene or 1-chloro-4-methylbenzene) or the solvent wasremoved under reduced pressure. The residue obtained was puri-fied via silica gel chromatography (eluent: petroleum ether/ethylacetate = 10/1) to afford aryl iodides 2a–2o or heteroaryl iodides4a–4g.
Reference: [1] Tetrahedron Letters, 1999, vol. 40, # 23, p. 4339 - 4342
[2] Tetrahedron, 2000, vol. 56, # 10, p. 1349 - 1360
[3] Synthesis (Germany), 2014, vol. 46, # 8, p. 1085 - 1090
[4] Phosphorus and Sulfur and the Related Elements, 1984, vol. 21, p. 197 - 204
[5] Chemistry - A European Journal, 2010, vol. 16, # 41, p. 12425 - 12433
[6] European Journal of Organic Chemistry, 2002, # 24, p. 4181 - 4184
[7] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297
[8] Tetrahedron Letters, 1990, vol. 31, # 47, p. 6757 - 6758
[9] Tetrahedron Letters, 1990, vol. 31, # 47, p. 6757 - 6758
[10] Journal of the Chemical Society, 1951, p. 83,86
[11] Journal of Organic Chemistry, 2005, vol. 70, # 17, p. 6904 - 6906
[12] Journal of the Chemical Society. Perkin Transactions 2, 2001, # 9, p. 1620 - 1630
[13] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 15, p. 1781 - 1782
[14] Patent: US2013/109876, 2013, A1, . Location in patent: Page/Page column 5
[15] Journal of Organic Chemistry, 1955, vol. 20, p. 118,128
[16] European Journal of Organic Chemistry, 2014, vol. 2014, # 27, p. 5986 - 5997
[17] Catalysis Today, 2016, vol. 274, p. 129 - 132
[18] Catalysis Science and Technology, 2017, vol. 7, # 10, p. 2110 - 2117
  • 14
  • [ 109-04-6 ]
  • [ 10034-85-2 ]
  • [ 5029-67-4 ]
Reference: [1] Patent: US6358971, 2002, B1,
  • 15
  • [ 109-04-6 ]
  • [ 677-22-5 ]
  • [ 5944-41-2 ]
Reference: [1] Journal of Organic Chemistry, 1987, vol. 52, # 17, p. 3847 - 3850
[2] Patent: WO2008/24953, 2008, A2, . Location in patent: Page/Page column 62
[3] Patent: WO2008/24953, 2008, A2, . Location in patent: Page/Page column 62
  • 16
  • [ 13534-89-9 ]
  • [ 74-88-4 ]
  • [ 109-04-6 ]
  • [ 3430-17-9 ]
Reference: [1] Green Chemistry, 2011, vol. 13, # 5, p. 1110 - 1113
[2] Green Chemistry, 2011, vol. 13, # 5, p. 1110 - 1113
  • 17
  • [ 109-04-6 ]
  • [ 74-88-4 ]
  • [ 3430-17-9 ]
Reference: [1] Journal of Chemical Research, Miniprint, 1982, # 10, p. 2863 - 2878
  • 18
  • [ 13534-89-9 ]
  • [ 109-04-6 ]
  • [ 58530-53-3 ]
Reference: [1] Tetrahedron, 1985, vol. 41, # 16, p. 3433 - 3440
  • 19
  • [ 109-04-6 ]
  • [ 100523-96-4 ]
Reference: [1] Journal of the American Chemical Society, 2012, vol. 134, # 5, p. 2653 - 2671
  • 20
  • [ 109-04-6 ]
  • [ 100523-96-4 ]
  • [ 73290-22-9 ]
  • [ 1353056-31-1 ]
  • [ 234111-08-1 ]
  • [ 265981-13-3 ]
Reference: [1] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297
  • 21
  • [ 109-04-6 ]
  • [ 100523-96-4 ]
  • [ 1353056-31-1 ]
  • [ 234111-08-1 ]
  • [ 265981-13-3 ]
Reference: [1] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297
  • 22
  • [ 109-04-6 ]
  • [ 624-28-2 ]
  • [ 75806-85-8 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1932, vol. 51, p. 940,949
  • 23
  • [ 109-04-6 ]
  • [ 253-72-5 ]
Reference: [1] Synthesis, 1999, # 2, p. 306 - 311
  • 24
  • [ 109-04-6 ]
  • [ 13534-89-9 ]
Reference: [1] Journal of Organic Chemistry, 2006, vol. 71, # 5, p. 2188 - 2191
  • 25
  • [ 109-04-6 ]
  • [ 4930-98-7 ]
YieldReaction ConditionsOperation in experiment
58% With hydrazine hydrate In ethanol; water 2-hydrazopyridine
A mixture of hydrazine hydrate (600 ml) and 2-bromopyridine (250 g, 1.6 mol) with ethanol (500 ml) is refluxed for 30 h and then evaporated in vacuum.
Water (1500 ml) is added and the mixture is extracted with ether (4x400 ml).
The combined organic extract is dried over Na2SO4 and the solvent is evaporated in vacuum, yielding the desired product as an oil (100 g, 58percent).
Reference: [1] Heterocycles, 2000, vol. 53, # 2, p. 265 - 270
[2] Patent: EP2743266, 2014, A2, . Location in patent: Page/Page column
[3] European Journal of Medicinal Chemistry, 1998, vol. 33, # 3, p. 189 - 199
[4] Organic and Biomolecular Chemistry, 2018, vol. 16, # 9, p. 1457 - 1460
[5] Organic letters, 2001, vol. 3, # 9, p. 1351 - 1354
[6] Journal of the Chemical Society, 1949, p. 2546,2549
[7] Journal of the American Chemical Society, 1948, vol. 70, p. 1381,1384
[8] Farmaco, Edizione Scientifica, 1985, vol. 40, # 9, p. 645 - 654
[9] Patent: WO2017/46318, 2017, A1, . Location in patent: Page/Page column 41
  • 26
  • [ 109-04-6 ]
  • [ 67-64-1 ]
  • [ 37988-38-8 ]
Reference: [1] Tetrahedron Letters, 1999, vol. 40, # 23, p. 4339 - 4342
[2] Tetrahedron, 2000, vol. 56, # 10, p. 1349 - 1360
[3] Journal of the Chemical Society, Dalton Transactions: Inorganic Chemistry (1972-1999), 1992, # 12, p. 1949 - 1956
  • 27
  • [ 109-04-6 ]
  • [ 75-05-8 ]
  • [ 2739-97-1 ]
Reference: [1] Synlett, 2000, # 10, p. 1488 - 1490
  • 28
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  • [ 928664-98-6 ]
  • [ 2739-97-1 ]
Reference: [1] Journal of the American Chemical Society, 2011, vol. 133, # 18, p. 6948 - 6951
  • 29
  • [ 109-04-6 ]
  • [ 75-05-8 ]
  • [ 504-29-0 ]
  • [ 2739-97-1 ]
Reference: [1] Journal of Organic Chemistry, 1983, vol. 48, # 14, p. 2392 - 2399
  • 30
  • [ 109-04-6 ]
  • [ 881183-42-2 ]
  • [ 2859-68-9 ]
Reference: [1] Tetrahedron, 2001, vol. 57, # 15, p. 3125 - 3130
  • 31
  • [ 109-04-6 ]
  • [ 274-87-3 ]
Reference: [1] Dalton Transactions, 2016, vol. 45, # 25, p. 10209 - 10221
[2] Inorganic Chemistry, 2015, vol. 54, # 4, p. 1572 - 1587
[3] Organic and Biomolecular Chemistry, 2014, vol. 12, # 31, p. 5954 - 5963
[4] Journal of the American Chemical Society, 1953, vol. 75, p. 5298
[5] Patent: WO2018/160845, 2018, A1, . Location in patent: Paragraph 0246
  • 32
  • [ 109-04-6 ]
  • [ 4648-54-8 ]
  • [ 274-87-3 ]
Reference: [1] Synthesis, 2008, # 24, p. 4002 - 4006
  • 33
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  • [ 17945-79-8 ]
Reference: [1] Patent: WO2014/144836, 2014, A2,
  • 34
  • [ 109-04-6 ]
  • [ 35905-85-2 ]
Reference: [1] Synthetic Communications, 1993, vol. 23, # 19, p. 2727 - 2730
[2] Tetrahedron Letters, 1991, vol. 32, # 37, p. 4883 - 4884
  • 35
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  • [ 124-38-9 ]
  • [ 35905-85-2 ]
Reference: [1] Synthetic Communications, 1993, vol. 23, # 19, p. 2727 - 2730
  • 36
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  • [ 13472-80-5 ]
Reference: [1] Roczniki Chemii, 1938, vol. 18, p. 96,100[2] Chem. Zentralbl., 1939, vol. 110, # II, p. 643
  • 37
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  • [ 10034-85-2 ]
  • [ 13472-80-5 ]
Reference: [1] Roczniki Chemii, 1938, vol. 18, p. 96,100[2] Chem. Zentralbl., 1939, vol. 110, # II, p. 643
  • 38
  • [ 109-04-6 ]
  • [ 214360-73-3 ]
  • [ 18471-73-3 ]
YieldReaction ConditionsOperation in experiment
79% With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2 h; Step 4 [Show Image] 2-bromopyridine 5 (14.53 g, 92.0 mmol) and 4-aminophenylboronic acid pinacol ester (30.20 g, 138.0 mmol) were dissolved in dimethylformamide (200 ml). To the solution were added tetrakis triphenyl phosphine palladium (7.44 g, 6.4 mmol) and 2 M potassium carbonate solution (230 ml, 460 mmol) and the mixture was stirred for 2 hours at 100°C. The reactant was poured into water and filtered and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and then saturated saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography. To the obtained solid were added ethyl acetate and hexane and the deposited solid was collected with filtration to give the desired substituted aniline 6 (12.35 g, yield 79 percent). 1H-NMR (DMSO-d6) δppm: 5.42 (s, 2H), 6.63 (m, 2H), 7.14 (m, 1H), 7,69-7.75 (m, 2H), 7.79 (m, 2H), 8.51 (m, 1H).
79% With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2 h; 2-bromopyridine 5 (14.53 g, 92.0 mmol) and 4-aminophenylboronic acid pinacol ester (30.20 g, 138.0 mmol) were dissolved in dimethylformamide (200 ml). To the solution were added tetrakis triphenyl phosphine palladium (7.44 g, 6.4 mmol) and 2 M potassium carbonate solution (230 ml, 460 mmol) and the mixture was stirred for 2 hours at 100° C. The reactant was poured into water and filtered and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and then saturated saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography. To the obtained solid were added ethyl acetate and hexane and the deposited solid was collected with filtration to give the desired substituted aniline 6 (12.35 g, yield 79percent).1H-NMR (DMSO-d6) δ ppm: 5.42 (s, 2H), 6.63 (m, 2H), 7.14 (m, 1H), 7.69-7.75 (m, 2H), 7.79 (m, 2H), 8.51 (m, 1H).
Reference: [1] Patent: EP2280000, 2011, A1, . Location in patent: Page/Page column 32
[2] Patent: US2011/28468, 2011, A1, . Location in patent: Page/Page column 20
[3] MedChemComm, 2017, vol. 8, # 1, p. 176 - 183
[4] Patent: WO2006/55951, 2006, A2, . Location in patent: Page/Page column 33
  • 39
  • [ 109-04-6 ]
  • [ 540-37-4 ]
  • [ 18471-73-3 ]
Reference: [1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 2, p. 286 - 297
  • 40
  • [ 109-04-6 ]
  • [ 71597-85-8 ]
  • [ 51035-40-6 ]
YieldReaction ConditionsOperation in experiment
0.431 g With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 80℃; Inert atmosphere A mixture of sodium carbonate (2.364 g), tetrakis(triphenylphosphine)palladium(0) (0.644 g), 2-bromopyridine (1.76 g), 4-hydroxyphenylboronic acid (2 g), 1,2-dimethoxyethane (50 mL) and water (10 mL) was stirred overnight at 80°C under nitrogen atmosphere.
To the reaction mixture was added silica gel, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.431 g).
MS (API+): [M+H]+172.1.
Reference: [1] Dalton Transactions, 2012, vol. 41, # 35, p. 10514 - 10517
[2] Organometallics, 2015, vol. 34, # 11, p. 2683 - 2694
[3] Patent: EP2873669, 2015, A1, . Location in patent: Paragraph 0487; 0488
[4] Angewandte Chemie - International Edition, 2018, vol. 57, # 34, p. 11045 - 11049[5] Angew. Chem., 2018, vol. 130, # 34, p. 11211 - 11215,5
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  • [ 51035-40-6 ]
Reference: [1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1990, vol. 26, # 9, p. 1022 - 1025[2] Khimiya Geterotsiklicheskikh Soedinenii, 1990, vol. 26, # 9, p. 1226 - 1229
  • 42
  • [ 109-04-6 ]
  • [ 87199-17-5 ]
  • [ 127406-56-8 ]
YieldReaction ConditionsOperation in experiment
80% With palladium diacetate; triphenylphosphine; potassium hydroxide In tetrahydrofuran; methanol at 60℃; for 24 h; Inert atmosphere; Schlenk technique General procedure: The brominated derivative (2-bromopyridine for 13a and 1-bromo-4-nitrobenzene for 14a) 1.1 equiv.of 4-formylphenyl boronic acid, Pd(OAc)2 2 mol percent and PPh3 4 mol percent were added to a Schlenk flask.Then, under an inert atmosphere methanol/THF 1:1 (2mL/mmol) and 2 equiv. of KOH were added. Thesystem was stirred for 24 h at 60 °C [21]. Compounds were purified by column chromatography(cyclohexane/EtOAc, 9:1) in yields of 80percent (13a) and 75percent (14a).
Reference: [1] European Journal of Organic Chemistry, 2008, # 12, p. 2049 - 2055
[2] Angewandte Chemie - International Edition, 2015, vol. 54, # 47, p. 14103 - 14107[3] Angew. Chem., 2015, vol. 127, # 47, p. 14309 - 14313,5
[4] Organic and Biomolecular Chemistry, 2013, vol. 11, # 39, p. 6806 - 6813
[5] European Journal of Organic Chemistry, 2014, vol. 2014, # 27, p. 5901 - 5905
[6] Organic Letters, 2004, vol. 6, # 19, p. 3337 - 3340
[7] Molecules, 2015, vol. 20, # 5, p. 9229 - 9241
[8] Organic Process Research and Development, 2002, vol. 6, # 3, p. 323 - 328
[9] Organometallics, 2015, vol. 34, # 11, p. 2683 - 2694
[10] Inorganica Chimica Acta, 2016, vol. 440, p. 102 - 106
[11] Journal of Organic Chemistry, 2006, vol. 71, # 26, p. 9589 - 9594
[12] Organic Letters, 2014, vol. 16, # 7, p. 2022 - 2025
[13] Organic Letters, 2014, vol. 16, # 7, p. 2046 - 2049
[14] Journal of Organic Chemistry, 2014, vol. 79, # 10, p. 4414 - 4422
[15] Organic Letters, 2014, vol. 16, # 12, p. 3328 - 3331
[16] Organic Letters, 2014, vol. 16, # 20, p. 5466 - 5469
[17] Angewandte Chemie - International Edition, 2015, vol. 54, # 15, p. 4508 - 4511[18] Angew. Chem., 2015, vol. 127, # 15, p. 4591 - 4594,4
[19] Journal of Organic Chemistry, 2015, vol. 80, # 8, p. 4116 - 4122
[20] Angewandte Chemie - International Edition, 2015, vol. 54, # 40, p. 11677 - 11680[21] Angew. Chem., 2015, vol. 127, # 40, p. 11843 - 11846,4
[22] Journal of the American Chemical Society, 2015, vol. 137, # 42, p. 13448 - 13451
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  • [ 24856-58-4 ]
  • [ 127406-56-8 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2 h;
Stage #2: at 50℃; for 2.5 h;
While regulating the temperature at from 30 to 35° C., iodine (0.2 g) and then, over a period of approximately one hour, a solution of 4-bromobenzaldehyde dimethyl acetal (93 g, 0.394 mol) in tetrahydrofuran (80 g) are added to a suspension of magnesium (9.6 g, 0.394 mol) in tetrahydrofuran (68 g) maintained at 30° C. with agitation under an inert atmosphere. The reaction mixture is maintained at 35° C. with agitation for one hour. Toluene (88 g) is added to the reaction mixture. [00039] Coupling Reaction: Preparation of 4-(2'-pyridyl)benzaldehyde [00040] Anhydrous zinc chloride (13.6 g 0.1 mol) and then 2-bromopyridine (52.8 g, 0.334 mol) are added, with agitation under an inert atmosphere, to a solution constituted by toluene (156 g) and tetrahydrofuran (132 g). Palladium tetrakistriphenylphosphine (0.204 g, 0.178 mmol) and then, over a period of two hours, the Grignard solution are added to the suspension maintained at 50° C. with agitation and under an inert atmosphere. The reaction mixture is maintained at 50° C. for approximately 30 minutes and then cooled to 25° C. [00041] A solution constituted by water (300 g) and 30percent hydrochloric acid (70 g) is added to the reaction mixture over a period of approximately 30 minutes. The mixture is maintained under agitation at 25° C.-30° C. for one hour and then the phases are separated. 30percent ammonia is added to the aqueous phase up to a pH of 8, and then toluene (90 g) is added. The phases are separated, the organic phase is evaporated under vacuum to yield a residue constituted by 4-(2'-pyridyl)benzaldehyde (61.1 g, 0.334 mol; yield in moles relative to the 2-bromopyridine added: 100percent; turnover of the catalyst (Pd) 1876). [00042] IR: 1695.7 cm-1 (aldehyde CO stretching); M.P.: 52°-53° C.; 1H-NMR (300 MHz, CDCl3): ppm 10.2 (1H, s); 8.8 (1H,dt, J=4.8 Hz, J=1.4 Hz); 8.25 (2H, part B of an AB system, J=7.0 Hz); 8.15 (2H, part A of an AB system, J=7.0 Hz); 7.8 (2H, AB system, J=8.6 Hz, J=1.4 Hz); 7.35 (1H,m). [00043] The product as identified by comparison with an authentic sample prepared in accordance with Example 37b described in patent WO97/40029.
99%
Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5 h;
Stage #2: at 70℃; for 3.5 h;
2-bromopyridine (7.90 g, 0.050 mol) and palladium tetrakistriphenylphosphine (0.029 g, 0.025 mmol) and then, at a temperature of 70° C. and over a total of 3 hours, a solution of the Grignard reagent of 4-bromobenzaldehyde dimethyl acetal (53 g of solution, containing 0.062 mol), prepared analogously to Example 9, are added to a mixture of ZnCl2 (0.72 g, 0.0053 mol) in tetrahydrofuran (12.4 g) maintained under agitation under an inert atmosphere. The reaction mixture is maintained at 70° C. for 30 minutes and then cooled to 25° C. [00082] A solution constituted by water (28 g) and 30percent hydrochloric acid (10 g) is added to the reaction mixture and the mixture is maintained under agitation for 2 hours at 25° C. Toluene (30 g) and 30percent ammonia (9.7 g), are added and the phases are separated to give a solution of 4-(2'-pyridyl)benzaldehyde (53.5 g, HPLC strength 17percent, equal to 9.09 g, 0.049 mol; yield in moles relative to the 2-bromopyridine added: 99percent, turnover of catalyst (Pd): 1960).
96.4%
Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5 h;
Stage #2: at 50℃; for 3.5 h;
A chip of iodine (50 mg) and p-bromobenzaldehyde dimethyl acetal (6.8 g, 98percent, 0.029 mol) are added to a suspension of magnesium filings (7.0 g, 0.287 mol) in tetrahydrofuran (109 g) maintained at 30° C. with agitation under an inert atmosphere: after a few minutes, the reaction is triggered and the internal temperature reaches 35° C. At the end of the exothermic reaction, a solution of p-bromobenzaldehyde dimethyl acetal (62.4 g, 98percent, 0.262 mol) in tetrahydrofuran (64.3 g) is added over a period of 1.5 hours while regulating the temperature at from 30 to 35° C. The reaction mixture is maintained under agitation at 30° C. for one hour. [00066] Coupling Reaction: Preparation of 4-(2'-pyridyl)benzaldehyde [00067] 2-bromopyridine (38.92 g, 0.246 mol) and palladium tetrakistriphenylphosphine (0.135 g, 0.117 mmol) are added to a mixture of ZnCl2 (3.08 g, 0.0226 mol) in tetrahydrofuran (59.6 g) maintained at 50° C. with agitation under an inert atmosphere. The Grignard solution (249.5 g of solution, equal to 0.291 mol) is added dropwise over a total of 3 hours to the resulting suspension, which is still maintained at 50° C. with agitation under an inert atmosphere. The reaction mixture is maintained at 50° C. for 30 minutes and then cooled to 18° C. [00068] A solution constituted by water (126 g) and 30percent hydrochloric acid (40 g) is added to the reaction mixture, keeping the temperature of the mixture below 35° C. After 30 minutes' agitation at 25° C., toluene (44 g) is added and the phases are separated. Toluene (87 g) and 30percent ammonia (42 g) are added to the aqueous phase, and the phases are separated to yield, as the organic phase, a solution of 4-(2'-pyridyl)benzaldehyde (210.8 g, HPLC strength 20.6percent, equal to 43.42 g, 0.237 mol; yield in moles relative to the 2-bromopyridine added: 96.4percent, turnover of catalyst (Pd): 2028).
96%
Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2 h;
Stage #2: at 50℃; for 3.5 h;
2-bromopyridine (8.07 g, 0.051 mol) and palladium tetrakistriphenylphosphine (0.032 g, 0.028 mmol) and then, over a total of 3 hours, a solution of the Grignard reagent of 4-bromobenzaldehyde dimethyl acetal (50 g of solution, equal to 0.058 mol), prepared analogously to Example 9, are added to a mixture of ZnCl2 (7.12 g, 0.052 mol) in tetrahydrofuran (24.2 g) maintained at 50° C. with agitation under an inert atmosphere. The reaction mixture is maintained at 50° C. for 30 minutes and then cooled to 25° C. [00076] A solution constituted by water (30 g) and 30percent hydrochloric acid (9 g) is added to the reaction mixture and the mixture is maintained under agitation for 2 hours at 25° C. A portion of the solvent (30 g) is evaporated under vacuum and replaced by an equal amount of toluene and then the phases are separated. Toluene (30 g) and 30percent ammonia (14 g) are added to the aqueous phase. The phases are separated to give a solution of 4-(2'-pyridyl)benzaldehyde (53.74 g, HPLC strength 16.66percent, equal to 8.95 g, 0.0489 mol; yield in moles relative to the 2-bromopyridine added: 96percent; turnover of the catalyst (Pd): 1920).
93%
Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2 h;
Stage #2: at 50℃; for 2.5 h;
Example 1 was repeated using anhydrous zinc bromide (22.5 g, 0.10 mol) instead of zinc chloride. The yield in moles of 4-(2'-pyridyl)benzaldehyde relative to the 2-bromopyridine added was 93percent, the turnover of the catalyst (Pd) 1744.
93%
Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2 h;
Stage #2: at 50℃; for 2.5 h;
Example 1 was repeated using a different amount of zinc chloride (2.28 g, 0.0167 mol). The yield in moles of 4-(2'-pyridyl)benzaldehyde relative to the 2-bromopyridine added was 93percent, the turnover of the catalyst (Pd) 1744.
91%
Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2 h;
Stage #2: at 50℃; for 2.5 h;
Example 1 was repeated using palladium acetate (0.040 g, 0.178 mmol) and triphenylphosphine (0.186 g, 0.712 mmol) instead of palladium tetrakistriphenylphosphine. The yield in moles of 4-(2'-pyridyl)benzaldehyde relative to the 2-bromopyridine added was 91percent the turnover of the catalyst (Pd) 1707.
89%
Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5 h;
Stage #2: at 50℃; for 6.5 h;
A solution of the Grignard reagent of 4-bromobenzaldehyde dimethyl acetal (63 g of solution, containing 0.074 mol), prepared analogously to Example 9, is added dropwise over a total of 6 hours to a solution of 2-bromopyridine (7.95 g, 0.050 mol), ZnCl2 (0.0071 g, 0.052 mmol) and palladium tetrakistriphenylphosphine (0.032 g, 0.028 mmol) in tetrahydrofuran (23.6 g) maintained at 50° C. with agitation under an inert atmosphere. The reaction mixture is maintained at 50° C. for 30 minutes and then cooled to 25° C. [00079] A solution constituted by water (28 g) and 30percent hydrochloric acid (9 g) is added to the reaction mixture and the mixture is maintained under agitation for 2 hours at 25° C. 30 g of solvent are evaporated under vacuum and replaced by an equal amount of toluene and then the phases are separated. Toluene (30 g) and 30percent ammonia (12 g) are added to the aqueous phase. After filtering over a panel of Celite the solid at the interphase and washing the panel with toluene, the phases are separated to give a solution of 4-(2'-pyridyl)benzaldehyde (73.53 g, HPLC strength 11.1percent, equal to 8.16 g, 0.0446 mol; yield in moles relative to the 2-bromopyridine added 89percent; turnover of catalyst (Pd): 1620; turnover of Zn: 890).
88%
Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2 h;
Stage #2: at 50℃; for 2.5 h;
Example 1 was repeated using palladium acetate (0.04 g, 0.178 mmol) and triphenylphosphine (0.186 g, 0.712 mmol) instead of palladium tetrakistriphenylphosphine and a different amount of anhydrous zinc chloride (18.2 g, 0.133 mol). The yield in moles of 4-(2'-pyridyl)benzaldehyde relative to the 2-bromopyridine added was 88percent, the turnover of the catalyst (Pd) 1650.
81.2%
Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5 h;
Stage #2: at 50℃; for 3.5 h;
Example 9 is repeated using a different amount of ZnCl2 (0.1 g, 0.73 mmol), to give a molar yield of 4-(2'-pyridyl)benzaldehyde relative to the 2-bromopyridine added of 81.2percent, turnover of the catalyst (Pd) equal to 1700.
3.8%
Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2.5 h;
Stage #2: at 50℃; for 4 h;
A solution of the Grignard reagent of 4-bromobenzaldehyde dimethyl acetal (51.4 g of solution, equal to 0.060 mol), prepared analogously to Example 9, is added dropwise over a total of 3 hours to a solution of 2-bromopyridine (8.04 g, 0.0509 mol) and palladium tetrakistriphenylphosphine (0.29 g, 0.25 mmol) in tetrahydrofuran (24 g) maintained at 50° C. with agitation under an inert atmosphere. The reaction mixture is maintained at 50° C. for one hour and then cooled to 25° C. [00073] A yield of 4-(2-pyridyl)benzaldehyde solution of 3.8percent relative to the 2-bromopyridine added is obtained, turnover of the catalyst (Pd) 76.
1%
Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2 h;
Stage #2: at 50℃; for 2.5 h;
Example 1 was repeated without the addition of the catalytic amount of zinc chloride. The yield in moles of 4-(2'-pyridyl)benzaldehyde relative to the 2-bromopyridine added was 1percent, the turnover of the catalyst (Pd) 18.

Reference: [1] Patent: US6765097, 2004, B1, . Location in patent: Page column 7-8
[2] Patent: US6765097, 2004, B1, . Location in patent: Page column 11
[3] Patent: US6765097, 2004, B1, . Location in patent: Page column 9-10
[4] Patent: US6765097, 2004, B1, . Location in patent: Page column 10-11
[5] Patent: US6765097, 2004, B1, . Location in patent: Page column 8
[6] Patent: US6765097, 2004, B1, . Location in patent: Page column 8
[7] Patent: US6765097, 2004, B1, . Location in patent: Page column 8
[8] Patent: US6765097, 2004, B1, . Location in patent: Page column 11
[9] Patent: US6765097, 2004, B1, . Location in patent: Page column 8
[10] Patent: US6765097, 2004, B1, . Location in patent: Page column 10
[11] Patent: US6765097, 2004, B1, . Location in patent: Page column 10
[12] Patent: US6765097, 2004, B1, . Location in patent: Page column 8
[13] Journal of Medicinal Chemistry, 1998, vol. 41, # 18, p. 3387 - 3401
[14] Patent: US5849911, 1998, A,
  • 44
  • [ 109-04-6 ]
  • [ 105114-53-2 ]
  • [ 127406-56-8 ]
YieldReaction ConditionsOperation in experiment
2%
Stage #1: With iodine; magnesium In tetrahydrofuran at 30 - 35℃; for 2 h;
Stage #2: at 50℃; for 2.5 h;
Stage #3: Acidic aqueous solution
Example 7 was repeated without the addition of the catalytic amount of zinc chloride. The yield in moles of 4-(2'-pyridyl)benzaldehyde relative to the 2-bromopyridine added was 2percent, turnover of the catalyst (Pd) 37.
Reference: [1] Patent: US6765097, 2004, B1, . Location in patent: Page column 9
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Reference: [1] Journal of Organic Chemistry, 2012, vol. 77, # 9, p. 4402 - 4413
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[2] Synthetic Communications, 2001, vol. 31, # 6, p. 869 - 875
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[4] Organic Letters, 2018, vol. 20, # 18, p. 5533 - 5536
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Reference: [1] Australian Journal of Chemistry, 1997, vol. 50, # 2, p. 109 - 114
  • 50
  • [ 109-04-6 ]
  • [ 30418-59-8 ]
  • [ 15889-32-4 ]
YieldReaction ConditionsOperation in experiment
42% With potassium carbonate In 1,2-dimethoxyethane; water at 80℃; REFERENCE EXAMPLE 31; 2-(3-Aminophenyl)pyridine; To a suspension of 2-bromopyridine (0.5 g, 3.2 mmol), 3-aminophenylboronic acid (0.49 g, 3.2 mmol), anhydrous K2CO3 (0.87 g, 6.3 mmol) and Pd(PPh3J4 (0.36 g, 0.32 mmol) in 1 ,2-dimethoxyethane (50 mL) under argon, water (0.66 mL) was added. The mixture was heated under argon at 80 °C overnight. It was allowed to cool and water and EtOAc were added. The phases were separated and the aqueous phase was reextracted with EtOAc. The combined organic phases were dried over Na2SO4 and the solvent was evaporated. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 0.22 g of the title compound (yield: 42percent). LC-MS (method 1): tR = 1.46 min; m/z = 171.2 [M+H]+.
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[2] Journal of Medicinal Chemistry, 2000, vol. 43, # 6, p. 1123 - 1134
[3] Patent: WO2007/339, 2007, A1, . Location in patent: Page/Page column 52
[4] Tetrahedron, 2006, vol. 62, # 49, p. 11483 - 11498
[5] Patent: US2006/94644, 2006, A1, . Location in patent: Page/Page column 23
[6] Patent: WO2007/130743, 2007, A2, . Location in patent: Page/Page column 64
[7] Patent: WO2005/40152, 2005, A1, . Location in patent: Page/Page column 56
[8] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 23, p. 7268 - 7271
  • 51
  • [ 109-04-6 ]
  • [ 15889-32-4 ]
YieldReaction ConditionsOperation in experiment
37% With sodium carbonate In 1,2-dimethoxyethane; water for 5 h; Reflux (i)
3-(Pyridin-2-yl)aniline
3.72 g (20.0 mmol) of 3-aminophenyl boronic acid* hemisulphate salt, 3.16 g (20.0 mmol) of 2-bromopyridine, 1.16 g (1.0 mmol) of tetrakis(triphenyl phosphine)palladium(0), and 11.2 g (106 mmol) of sodium carbonate were heated under reflux for 5 hours in a mixed solvent of 100 mL of DME and 34 mL of water.
After completion of the reaction, extraction with ethyl acetate, and drying over anhydrous sodium sulfate were carried out.
The solvent was distilled off under reduced pressure.
The resulting crude product was separated and purified using silica gel column chromatography to give 1.27 g of 3-(pyridin-2-yl)aniline (yield: 37percent).
1H-NMR (CDCl3) δ: 3.76 (2H, br), 6.65-6.78 (1H, m), 7.10-7.40 (4H, m), 7.60-7.78 (2H, m), 8.60-8.70 (1H, m).
Reference: [1] Patent: EP2272822, 2011, A1, . Location in patent: Page/Page column 53
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Reference: [1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 2, p. 286 - 297
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Reference: [1] Patent: US6335343, 2002, B1, . Location in patent: Page column 51
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[2] Dalton Transactions, 2011, vol. 40, # 45, p. 12060 - 12062
[3] Chemistry - A European Journal, 2005, vol. 11, # 6, p. 1911 - 1923
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[2] Chemical Communications, 2012, vol. 48, # 8, p. 1120 - 1122
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[4] Chemistry - A European Journal, 2017, vol. 23, # 50, p. 12162 - 12170
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[2] Dalton Transactions, 2013, vol. 42, # 18, p. 6478 - 6488
[3] Journal of the American Chemical Society, 2017, vol. 139, # 23, p. 7745 - 7748
[4] ACS Chemical Neuroscience, 2017, vol. 8, # 4, p. 723 - 730
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Reference: [1] Journal of the Chemical Society, 1938, p. 1662,1669
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[2] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 9, p. 2467 - 2469
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[2] Inorganic Chemistry, 2013, vol. 52, # 9, p. 5570 - 5580
[3] Patent: KR2015/142709, 2015, A,
  • 64
  • [ 109-04-6 ]
  • [ 14047-29-1 ]
  • [ 4385-62-0 ]
YieldReaction ConditionsOperation in experiment
91% With potassium carbonate In water; acetonitrile for 24 h; Reflux; Inert atmosphere Example 155 A4-(pyridin-2-yl)benzoic acid; To a solution of 4-boronobenzoic acid (1.66 g, 10 mmol) and 2-bromopyridine (1.72 g, 11 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.5 g, 40 mmol), bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.37 mmol) were added. The mixture was degassed and purged withed nitrogen. The mixture was stirred under reflux for 24 h. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH=4 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 1.81 g of white solid of 4-(pyridin-2-yl)benzoic acid. Yield: 91percent. LC-MS (ESI) m/z: 200 (M+1)+.
85%
Stage #1: With sodium carbonate In water; acetonitrile at 90℃;
4-pyridin-2-ylbenzoic acid
To a solution of 4-(dihydroxyboryl)benzoic acid (1.03 g, 6.21 mmol) and 2-bromopyridine (0.59 mL, 6.21 mmol) in ACN (20 mL) was added sodium carbonate (0.396 g, 3.74 mmol) in water (20 mL).
The reaction mixture was degassed with argon and then tetrakis(triphenylphosphine)palladium (0.108 g, 0.09 mmol) was added.
The reaction mixture was allowed to stir at 90° C. overnight and then filtered.
The solution was concentrated to remove ACN and the aqueous solution was washed with DCM.
The aqueous solution was acidified with 1N HCl and the resulting white precipitate was filtered and dried to give 4-pyridin-2-ylbenzoic acid (1.06 g, 85percent). LCMS: (FA) ES+200.1.
84% With sodium carbonate In acetonitrile at 90℃; for 20 h; Example 107 10-(4-PYRIDIN-2-YLBENZOYL)-N-(PYRIDIN-3-YLMETHYL)-10,11-DIHYDRO-5H-PYRROLO[2,1-C][1,4]BENZODIAZEPINE-3-CARBOXAMIDE Step A. 4-Pyridin-2-ylbenzoic acid; To a suspension of 4-carboxybenzeneboronic acid (0.660 g, 3.98 mmol) and 2-bromopyridine (0.38 mL, 3.98 mmol) in dry acetonitrile (20 mL) was added 0.4 M aqueous sodium carbonate (20 mL) and mixture purged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.240 g) was then added and the reaction mixture heated to 90° C. for 20 hours. The hot mixture was filtered through celite and concentrated in vacuo to remove acetonitrile. The resulting aqueous suspension was diluted with water (20 mL), washed with dichloromethane (2.x.40 mL), and then acidified to pH 6 by the addition of concentrated hydrochloric acid. The resulting white suspension was diluted with water (20 mL), filtered and the solid product dried in vacuo at 50° C. overnight to give the title compound (0.662 g, 84percent) as a white solid, m.p. 232-234° C. MS [(+)ESI, m/z]: 200 [M+H]+ MS [(-)ESI, m/z]: 198 [M-H]- Anal. Calcd for C12H9NO2: C, 72.35; H, 4.55; N, 7.03. Found: C, 72.04; H, 4.38; N, 6.89.
75% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In water; acetonitrile at 90℃; for 48 h; Inert atmosphere 5.1.4
4-Pyridin-2-ylbenzoic acid (5a)
Pd(PPh3)4 (0.6 g, 0.5 mmol) was added to a degassed solution of 4-Carboxyphenyl-boronic acid (2a) (2.0 g, 12 mmol), 2-bromopyridine (1. 58 g, 10 mmol) and Cs2CO3 (13.0 g, 30 mmol) in 50 ml acetonitrile and 50 ml water.
The reaction mixture was heated at 90 °C in an oil bath and stirred under nitrogen for 48 h.The hot suspension was filtered and the filtrate distilled by rotary evaporation to remove acetonitrile.
Water was added and the mixture was exacted with ethyl acetate (3 * 30 ml).
The aqueous layer was acidified with conc. HCl and exacted with ethyl acetate three times.
The combined organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated by rotary evaporation to give the crude product, which was isolated by flash chromatography on silica gel to obtain the targeted compound (1.5 g, 75percent), mp.: 238-240 °C.
The intermediates 4-pyridin-3-ylbenzoic acid (5b), 4-(4- methylpyridin-2-yl)benzoic acid (5c), 4-(6-methylpyridin-3 -yl)benzoic acid (5d), 4-(2-thienyl)benzoic acid (5e) and 4-(1,3-thiazol-2-yl)benzoic acid (5f) were prepared by commercially available materials 3-bromo-pyridine, 2-bromo-4-methylpyridine, 5-bromo-2-methylpyridine, 2-bromothiophene and 2-bromo-1,3-thiazole respectively using the general procedure described above.

Reference: [1] Patent: US2009/197863, 2009, A1, . Location in patent: Page/Page column 73
[2] Patent: US2008/171754, 2008, A1, . Location in patent: Page/Page column 94-95
[3] Patent: US2006/287522, 2006, A1, . Location in patent: Page/Page column 52
[4] European Journal of Medicinal Chemistry, 2015, vol. 101, p. 780 - 789
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[9] Patent: CN104262238, 2016, B, . Location in patent: Paragraph 0046; 0047; 0048
  • 65
  • [ 110-85-0 ]
  • [ 109-04-6 ]
  • [ 34803-66-2 ]
YieldReaction ConditionsOperation in experiment
54% at 150℃; for 0.333333 h; Microwave irradiation Step l0.1 g (0.63 mmol) of 2-bromopyridine and 0.065 g (0.75 mmol) of piperazine was reacted at 150°C for 20 mins in a dried 5 mL microwave reactor provided with nitrogen gas. After cooling to room temperature, the reaction mixture was filtered using a cellite with in concurrence with washing with ethyl acetate, and distilled under a reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane:methanol=4: l) to obtain l-(pyridin-2-yl)piperazine (yield: 54percent).
36% With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene for 18 h; Heating / reflux To a 5ml round bottom flask equipped with magnetic stirrer, condenser, and argon inlet, 2-bromopyridine (320mg, 2.0 mmole), piperazine (520mg, 6.0 mmole), Pd2(dba)3 (46mg, 0.050mmole), BINAP (31mg, O.lOmmole), NaO-?- Bu (277mg, 2.8mmole) were added. The reaction mixture was purged with argon for 10 minutes. Toluene (2.0ml) was added. The reaction mixture was heated to reflux for 18hrs. The reaction was partitioned with EtOAc, and filtered through Celite. The solvent was then removed under vacuum. The desired product EPO <DP n="39"/>(74mg, 36percent yield) was isolated via column chromatography with CH2Cl2/MeOH saturated with NH3 (9/1) as eluent. 1H -NMR(400 MHz, CDCl3): δ 3.30-3.09 (m, 4H), 3.51-3.59 (m, 4H), 6.64-6.71 (m, 2H), 7.50-7.55 (m,lH), 8.22-8.27 (m, IH).
Reference: [1] Patent: WO2008/153325, 2008, A1, . Location in patent: Page/Page column 43
[2] Patent: WO2006/47415, 2006, A2, . Location in patent: Page/Page column 37-38
[3] Journal of the American Chemical Society, 1949, vol. 71, p. 2731,2732
[4] Journal of Organic Chemistry, 1953, vol. 18, p. 1484,1487
[5] Patent: WO2008/62276, 2008, A2, . Location in patent: Page/Page column 50
  • 66
  • [ 109-04-6 ]
  • [ 34803-66-2 ]
Reference: [1] Journal of Organic Chemistry, 1953, vol. 18, p. 1484,1487
[2] Patent: WO2011/28947, 2011, A2,
  • 67
  • [ 1121-60-4 ]
  • [ 109-04-6 ]
  • [ 35047-29-1 ]
YieldReaction ConditionsOperation in experiment
70%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.25 h;
Stage #2: at -78 - 20℃; for 2.5 h;
Stage #3: With water; ammonium chloride In tetrahydrofuran; hexane
Example 26Preparation of Compounds 174 and 175Step A - Synthesis of Di-(Pyridin-2-yl)-MethanolTo a -78 °C solution of 2-bromoρyridine (3.0 g, 19.0 mmol) in 60 mL THF was added w-BuLi (2.5 M in hexane, 7.6 mL, 19.0 mmol). The resulting reaction was allowed to stir at - 78 °C for about 15 minutes, then 2-pyridine carboxaldehyde (2.17 mL, 22.8 mmol) was added dropwise at -78 °C. The resulting reaction mixture was allowed to stir for 30 minutes at -78 0C, then for 2 hours at room temperature after which time the reaction was quenched with saturated aqueous NH4Cl solution. After diluting the reaction mixture with ethyl acetate, the organic layer was separated and the aqueous layer was back extracted twice with ethyl acetate. The combined organic fractions were washed with brine, dried (magnesium sulfate), filtered, and concentrated in vacuo to provide di-pyridin-2-yl-methanol in 70percent yield as a yellow oil.
Reference: [1] Synlett, 2006, # 16, p. 2553 - 2558
[2] Synlett, 2008, # 9, p. 1418 - 1422
[3] Patent: WO2008/130581, 2008, A1, . Location in patent: Page/Page column 181
[4] Journal of Organic Chemistry, 1993, vol. 58, # 16, p. 4382 - 4388
  • 68
  • [ 109-04-6 ]
  • [ 6148-64-7 ]
  • [ 82102-37-2 ]
  • [ 26510-52-1 ]
Reference: [1] Angewandte Chemie - International Edition, 2013, vol. 52, # 37, p. 9763 - 9766[2] Angew. Chem., 2013, vol. 125, # 37, p. 9945 - 9948
  • 69
  • [ 109-04-6 ]
  • [ 49669-22-9 ]
Reference: [1] Journal of the Chemical Society, 1938, p. 1662,1669
[2] Patent: CN107935919, 2018, A, . Location in patent: Paragraph 0049; 0051
  • 70
  • [ 109-04-6 ]
  • [ 153025-65-1 ]
  • [ 49669-22-9 ]
Reference: [1] Journal of Organic Chemistry, 1995, vol. 60, # 6, p. 1755 - 1762
[2] Journal of Organic Chemistry, 1995, vol. 60, # 6, p. 1755 - 1762
  • 71
  • [ 109-04-6 ]
  • [ 140-29-4 ]
  • [ 5005-36-7 ]
Reference: [1] Tetrahedron, 2002, vol. 58, # 24, p. 4931 - 4935
[2] Journal of Heterocyclic Chemistry, 2002, vol. 39, # 4, p. 773 - 782
[3] Heterocycles, 1991, vol. 32, # 10, p. 1947 - 1953
[4] Journal of Organic Chemistry, 1983, vol. 48, # 14, p. 2392 - 2399
[5] Journal of Organic Chemistry, 1983, vol. 48, # 14, p. 2392 - 2399
[6] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 11, p. 3067 - 3071
[7] Journal of Medicinal Chemistry, 1996, vol. 39, # 6, p. 1201 - 1209
[8] European Journal of Medicinal Chemistry, 2006, vol. 41, # 1, p. 125 - 134
[9] Patent: US3984557, 1976, A,
[10] European Journal of Medicinal Chemistry, 2009, vol. 44, # 4, p. 1710 - 1717
[11] Patent: US6407120, 2002, B1, . Location in patent: Page column 25
[12] European Journal of Medicinal Chemistry, 2009, vol. 44, # 11, p. 4702 - 4715
[13] European Journal of Medicinal Chemistry, 2011, vol. 46, # 1, p. 142 - 149
[14] Organic Letters, 2014, vol. 16, # 7, p. 2050 - 2053
[15] European Journal of Medicinal Chemistry, 2014, vol. 90, p. 21 - 32
[16] European Journal of Medicinal Chemistry, 2015, vol. 98, p. 221 - 236
  • 72
  • [ 109-04-6 ]
  • [ 140-29-4 ]
  • [ 91-02-1 ]
  • [ 5005-36-7 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1987, vol. 24, p. 1061 - 1065
[2] Journal of Heterocyclic Chemistry, 1987, vol. 24, p. 1061 - 1065
  • 73
  • [ 109-04-6 ]
  • [ 5570-19-4 ]
  • [ 4253-81-0 ]
YieldReaction ConditionsOperation in experiment
66% With palladium diacetate; potassium carbonate; triphenylphosphine In ethanol; water; N,N-dimethyl-formamide at 70℃; Inert atmosphere To a suspension of K2CO3 (4.65 g, 33.6 mmol), Pd(OAc)2 (0.189 g,0.840 mmol), and PPh3 (0.882 g, 3.36 mmol) in 170 mL of DME/EtOH/H2O = 4/1/1 was added2-nitrophenylboronic acid (3) (3.37 g, 20.2 mmol) and 2-bromopyridine (1.60 mL, 16.8 mmol). Afterstirring at 70 °C overnight, the reaction mixture was concentrated under reduced pressure. To the residuewere added water (100 mL) and Et2O (100 mL), and the aqueous layer was extracted with Et2O (50 mL ×2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and evaporated.The residue was purified by silica gel chromatography (hexane/EtOAc = 6/1) to afford2-(2-nitrophenyl)pyridine (4) (2.23 g, 66percent) as white solid. Spectroscopic data were in agreement withthose previously reported:12Rf = 0.28 (hexane/EtOAc = 2/1); 1H NMR (400 MHz, CDCl3): δ 8.66 (d, J =5.0 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.81 (dd, J = 7.7, 7.7 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.63 (dd, J= 7.7, 7.7 Hz, 1H), 7.55 (dd, J = 7.7, 7.2 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.32 (dd, J = 7.7, 5.0 Hz, 1H).
18%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 0.5 h; microwave
Stage #2: With sodium hydrogen sulfate In water; N,N-dimethyl-formamide
2-bromopyridine (0.25 g, 1.58 mmol) and 2-nitrophenylboronic acid (0.48 g,2.85 mmol) were suspended in DMF (8.0 mL) in a microwave vial. Nitrogen was bubbled through the solution for 5 min. Pd (l,l '-Bis(diphenylphosphino)feiτocene i.e., dppf) catalyst (0.10 g, 0.13 mmol) and potassium carbonate (0.44 g, 3.16 mmol) were added and the vial was sealed. The mixture was heated in the microwave to 140 °C for 30 min. The vial was cooled to room temperature, and the mixture was neutralized with 1 N sodium hydrogen sulfate (3.16 mL). Ethyl acetate (100 mL) and water (100 mL) were added. The organic layer was separated and washed with brine (30 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (10-50percent ethyl acetate/pentane) to give 2-(2-nitrophenyl)pyridine as a brown oil (58 mg, 18percent).
Reference: [1] Heterocycles, 2014, vol. 8, # 2, p. 1539 - 1551
[2] Patent: WO2009/58348, 2009, A1, . Location in patent: Page/Page column 83
[3] Patent: CN108530490, 2018, A, . Location in patent: Paragraph 0086; 0087; 0088; 0089
  • 74
  • [ 109-04-6 ]
  • [ 577-19-5 ]
  • [ 4253-81-0 ]
YieldReaction ConditionsOperation in experiment
22%
Stage #1: With copper In dimethyl sulfoxide at 120℃; for 2 h;
Stage #2: With ammonia In water; dimethyl sulfoxide for 0.5 h;
A solution of 2-nitrobromobenzene (2.02 g), 2-bromopyridine (0.80 g), copper powder (1.29 g), and palladium dichloride (0.049 g) in 15 mL of DMSO was heated at 120° C. under N2 for 2 hours. Once cooled, the mixture was diluted with 100 mL of 10percent aqueous ammonia and stirred for 30 min. This mixture was filtered, and the filtrate was extracted several times with CHCl3. The combined extracts were dried (Na2SO4) and evaporated. The crude product was purified by chromatography on silica gel with 20percent EtOAc/hexanes to yield 0.12 g (22percent) of 2-(2-Nitrophenyl)pyridine. [This compound was reported by Molina, Pedro; Lorenzo, Angeles; Aller, Enrique; Tetrahedron; 1992, 48, (22), 4601-4616.]
Reference: [1] Patent: US6884801, 2005, B1, . Location in patent: Page/Page column 31-32
  • 75
  • [ 109-04-6 ]
  • [ 552-16-9 ]
  • [ 4253-81-0 ]
Reference: [1] Journal of the American Chemical Society, 2007, vol. 129, # 15, p. 4824 - 4833
  • 76
  • [ 109-04-6 ]
  • [ 104-88-1 ]
  • [ 27652-89-7 ]
Reference: [1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 43, p. 10681 - 10690
  • 77
  • [ 109-04-6 ]
  • [ 4411-83-0 ]
Reference: [1] Journal of the Chemical Society, 1938, p. 1662,1669
  • 78
  • [ 109-04-6 ]
  • [ 1079-66-9 ]
  • [ 37943-90-1 ]
Reference: [1] Journal of the American Chemical Society, 1984, vol. 106, # 5, p. 1323 - 1332
[2] Phosphorus and Sulfur and the Related Elements, 1983, vol. 15, p. 165 - 176
[3] European Journal of Organic Chemistry, 2000, # 14, p. 2601 - 2604
  • 79
  • [ 109-04-6 ]
  • [ 829-85-6 ]
  • [ 37943-90-1 ]
  • [ 64741-30-6 ]
Reference: [1] Chemistry - A European Journal, 2012, vol. 18, # 31, p. 9622 - 9627
  • 80
  • [ 109-04-6 ]
  • [ 829-85-6 ]
  • [ 37943-90-1 ]
Reference: [1] Dalton Transactions, 2018, vol. 47, # 31, p. 10439 - 10442
  • 81
  • [ 109-04-6 ]
  • [ 603-35-0 ]
  • [ 37943-90-1 ]
Reference: [1] Journal of the Chemical Society - Dalton Transactions, 1998, # 22, p. 3771 - 3776
  • 82
  • [ 109-04-6 ]
  • [ 5419-55-6 ]
  • [ 197958-29-5 ]
YieldReaction ConditionsOperation in experiment
81%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane; toluene at -30℃; for 3 h; Inert atmosphere
Stage #2: With hydrogenchloride In tetrahydrofuran; hexane; water; toluene at 20℃; for 1 h; Inert atmosphere
1.58 g (10 mmol) of compound V-1 and 3.76 g (20 mmol) of B(i-PrO)3 were dissolved in 14 mL of dry toluene and 7 mL of THF, stirred and cooled to -30°C under a nitrogen atmosphere, and then slowly dried with a syringe. A solution of 6.25 mL (10 mmol) of 1.6 M n-BuLi in n-hexane was added dropwise. After completion of the addition, the reaction mixture was stirred at this temperature for 3 hours and then at room temperature for a further 3 hours, and the reaction was completed by TLC. To the reaction mixture was slowly added 1 mL of concentrated hydrochloric acid, stirred at room temperature for 1 hour, and poured into 200 mL of ice water.Where, pH=8 was adjusted with saturated NaHCO 3 solution, stirred, extracted with 50 mL×3 CH 2 Cl 2 , the combined extracts were washed with 100 mL 5percent brine and dried over anhydrous sodium sulfate. The desiccant was filtered off with suction, the filtrate was evaporated to dryness on a rotary evaporator and the residue was purified using silica gel column chromatography to afford compound VI-I, 1.00 g (81percent yield).
81%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane; toluene at -30 - 20℃; for 6 h;
Stage #2: With hydrogenchloride In tetrahydrofuran; hexane; toluene at 20℃; for 1 h;
1.58 g (10 mmol) of compound V-1 and 3.76 g(20mmol) B(i-PrO)3 dissolved in 14mL dry toluene and 7mLIn THF,Stir and cool to -30 ° C under nitrogen.Then slowly add 6.25 mL (10 mmol) with a syringe.1.6 M n-BuLi in n-hexane solution.After the addition is completed,The reaction compound was stirred at this temperature for 3 hours.Then stir at room temperature for another 3 hours.TLC tracking revealed that the reaction was complete.Slowly add 1 mL of concentrated hydrochloric acid to the reaction mixture.Stir at room temperature for 1 hour, then pour into 200 mL of ice water.Adjust pH=8 with saturated NaHCO3 solution, stir,Extract with 50 mL×3 CH 2 Cl 2 and combine the extract phases.Wash with 100 mL of 5percent brine and dry over anhydrous sodium sulfate.The desiccant was removed by suction filtration, and the filtrate was evaporated to dryness on a rotary evaporator.The residue was purified using silica gel column chromatography.Compound VI-I, 1.00 g (yield 81percent) was obtained. ESI-MS, m/z = 24 ([M+H]+).
81% With n-butyllithium In tetrahydrofuran; hexane; toluene at -30 - 20℃; for 6 h; Inert atmosphere 1.58g (10mmol)Compounds V-1 and 3 · 76 g (20 mmol) of iridium (i-Pr0) 3 were dissolved in 14 mL of dry toluene and 7 mL of THF.After stirring, it was cooled to -30 ° C under a nitrogen atmosphere, and then 6.25 mL (10 mmol) of a 1.6 Μ n-BuLi n-hexane solution was slowly added dropwise with a syringe. After completion of the dropwise addition, the reaction mixture was stirred at this temperature for 3 hours, and then stirred at room temperature for further 3 hours, and the reaction was confirmed by TLC.[0031] slowly adding 1 mL of concentrated hydrochloric acid to the reaction mixture,Stir at room temperature for 1 hour, then pour into 200 mL of ice water.The mixture was stirred with a saturated NaHCO3 solution, and then stirred and extracted with 50 mL of EtOAc. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the residue was purified by silica gel column chromatography to afford compound VI-I, 1.00 g yield: 81percent) SI-MS, m/z = 124 ([M +H]+).
73%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.5 h;
Stage #2: at -78 - 20℃;
Sub 1-1-1 (1) (3.2g, 20mmol) was dissolved in anhydrous Ether, lowering the temperature of the reaction to -78 , n-BuLi (2.5M inhexane) (1.4g, 22mmol) was slowly added dropwise, and I then, the reaction is stirred for 30 minutes. After lowering the temperature of the reaction back to -78 dropwise Triisopropyl borate (5.64g, 30mmol). Stirring at room temperature, diluted with water and it binds the 2N HCl. After completion of reaction, the organic layer was dried and extracted with water and ethyl acetate and recrystallized with MgSO4 and silicagel column The concentrated organics to give 1.8g Sub 1-1 (1). (Yield: 73percent)

Reference: [1] Patent: CN107903250, 2018, A, . Location in patent: Paragraph 0025; 0029; 0030; 0031
[2] Patent: CN108047215, 2018, A, . Location in patent: Paragraph 0032; 0036-0038
[3] Patent: CN108047214, 2018, A, . Location in patent: Paragraph 0024; 0025; 0029; 0031
[4] Patent: KR2015/121394, 2015, A, . Location in patent: Paragraph 0154-0157
  • 83
  • [ 109-04-6 ]
  • [ 121-43-7 ]
  • [ 197958-29-5 ]
YieldReaction ConditionsOperation in experiment
66.8%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere
Stage #2: at 20℃; for 2 h; Inert atmosphere
30 g (0.19 mol) of 2-bromopyridine and 250 mL of tetrahydrofuran were placed in a 500 mL round-bottomed flask, stirred under nitrogen for 30 minutes, and cooled to -78 ° C. 1.6 mol of n-butyllithium 142.41 mL (0.23 mol) was slowly added dropwise. After stirring at the same temperature for 1 hour, 29.64 mL (0.27 mol) of trimethyl borate was slowly added dropwise. The temperature was raised to room temperature and stirred for 2 hours. After completion of the reaction, the reaction was terminated with 2 molar hydrochloric acid aqueous solution and extraction. The organic layer was concentrated under reduced pressure, recrystallized with hexane, and dried to obtain 15.6 g (66.8percent) of a compound represented by the formula 1-d
Reference: [1] Patent: KR101897045, 2018, B1, . Location in patent: Paragraph 0145; 0166-0169
  • 84
  • [ 109-04-6 ]
  • [ 197958-29-5 ]
Reference: [1] Synthetic Communications, 2003, vol. 33, # 5, p. 795 - 800
  • 85
  • [ 109-04-6 ]
  • [ 201230-82-2 ]
  • [ 141-43-5 ]
  • [ 16347-06-1 ]
Reference: [1] Organic Letters, 2014, vol. 16, # 16, p. 4296 - 4299
  • 86
  • [ 109-04-6 ]
  • [ 25487-66-5 ]
  • [ 4467-07-6 ]
YieldReaction ConditionsOperation in experiment
85% With potassium carbonate In water; acetonitrile at 100℃; for 24 h; Inert atmosphere Example 161 A3-(pyridin-2-yl)benzoic acid; To a solution of 3-boronobenzoic acid (1.66 g, 10 mmol) and 2-bromopyridine (1.72 g, 11 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.5 g, 40 mmol), Bis(triphenylphosphine)palladium(II)chloride (400 mg, 0.37 mmol) was added. The mixture was degassed and purged withed nitrogen. The mixture was stirred at 100° C. for 24 h. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH=3 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 1.69 g of white solid of 3-(pyridin-2-yl)benzoic acid. Yield: 85percent. LC-MS (ESI) m/z: 200 (M+1)+.
Reference: [1] Patent: US2009/197863, 2009, A1, . Location in patent: Page/Page column 75
  • 87
  • [ 109-04-6 ]
  • [ 269409-73-6 ]
  • [ 4467-07-6 ]
YieldReaction ConditionsOperation in experiment
75% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In water; N,N-dimethyl-formamide at 110℃; Inert atmosphere To a degassed souton of DMF:H20 (10:1 raUo) (0.3 M), under an atmosphere of nitrogen, was added the pnaco ester (1 mmo), 2-bromopyrdne or 2-choropyrmdne (1 .5 eq.), and Cs2CO3 (4.4 eq.). The whoe mxture was degassed once agan and then Pd(PPh3)4 (5mopercent) was added. The resutng souton was heated to 110°C overnght. The sovent was removed in vacuo to give a dark gummy residue, which was taken up nto EtOAc and H20, then acdfied with 2 M HC to pH 2. The organic ayer was separated and the aqueous ayer was further extracted with EtOAc (2x). The combined organic ayers were dried over MgSO4 and concentrated in vacuo to gve a back ofly residue. The residue was dry oaded ontosWca ge in vacuo then purfied by flash coumn chromatography, eutng with 10-30percent EtOAc/petroeum benzne and 1percent acetic acid to afford the tWe compound.The foHowng compounds were made by Suzuk CoupUng F:P1B1Off white soUd (75percent yed). 1H NMR (400 MHz,DMSO) 6 8.71 8.68 (m, 1 H), 8.67 (s, 1 H), 8.29 (d,J = 7.8 Hz, 1 H), 8.01 (t, J = 8.4 Hz, 2H), 7.91 (td, J =7.8, 1.8 Hz, 1 H), 7.61 (t, J = 7.7 Hz, 1 H), 7.42 7.37(m, 1H). LCMS B rt3.17, m/z200.1 [M + H].
Reference: [1] Patent: WO2016/198507, 2016, A1, . Location in patent: Page/Page column 40; 50
  • 88
  • [ 109-04-6 ]
  • [ 4467-07-6 ]
Reference: [1] Inorganic Chemistry Communications, 2013, vol. 32, p. 78 - 81
[2] Patent: WO2014/100734, 2014, A1,
[3] Organic Letters, 2015, vol. 17, # 6, p. 1513 - 1516
[4] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 2, p. 162 - 166
  • 89
  • [ 109-04-6 ]
  • [ 75-77-4 ]
  • [ 13737-04-7 ]
Reference: [1] Inorganic Chemistry, 2017, vol. 56, # 10, p. 5930 - 5940
[2] Chemistry - A European Journal, 2010, vol. 16, # 41, p. 12425 - 12433
[3] Journal of Organometallic Chemistry, 1991, vol. 406, # 3, p. 283 - 298
[4] C. A., 1954, p. 2783
[5] , Gmelin Handbook: Si: MVol.C, 30, page 94 - 96,
[6] Australian Journal of Chemistry, 2013, vol. 66, # 2, p. 199 - 207
  • 90
  • [ 109-04-6 ]
  • [ 38427-94-0 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1994, vol. 131, # 4, p. 429 - 433
  • 91
  • [ 109-04-6 ]
  • [ 5794-88-7 ]
  • [ 1563-56-0 ]
YieldReaction ConditionsOperation in experiment
89.3%
Stage #1: at -40℃; for 1.5 h;
Stage #2: at 0℃; for 2 h;
To a -40°C solution of 2.5 M n-butyllithium in hexane (400 mL, 1000 mmol, 4 eq) and diethyl ether (1 L) was added 2-bromopyridine (173.93 g, 1101 mmol, 4.4 eq) over approximately 30 min. The reaction was stirred for 1 h at -40°C, and then treated with 5-bromoanthranilic acid (54.14 g, 250.6 mmol, 1 eq) in THF (1 L). The reaction was warmed to 0°C and stirred 2 h at 0°C, then quenched with chlorotrimethylsilane (625 mL, 4924 mmol, 20 eq). The reaction was stirred 30 min at ambient temperature, then cooled to 0°C and quenched with 3N HCI (625 mL). The aqueous layer was separated, and the organic layer was extracted once with 3N HCl. The combined aqueous layers were neutralized with solid sodium hydroxide pellets, with cooling via ice bath. The resulting mixture was extracted with diethyl ether (3 .x. 1 L). The combined ether layers were dried over sodium sulfate, filtered and concentrated to a black oil, which was subsequently purified by flash chromatography (1 L silica gel, 20-30percent ethyl acetate/hexane) to give the required compound as a brown solid (62 g, 224 mmol, 89.3percent).
62.7%
Stage #1: With n-butyllithium In tetrahydrofuran at -40℃;
Stage #2: at -40 - 0℃; for 2 h;
Stage #3: With chloro-trimethyl-silane In tetrahydrofuran at 20℃; for 0.5 h;
To a -40 °C solution of 2.5 M n-BuLi (18 mL) in THF (300 mL) is added 2- bromopyridine (5.0 g, 32 mmol) over 15 min. The reaction is stirred for 1 h at -40 °C, and then treated with 2-Amino-5-bromo-benzoic acid (6.9 g, 32 mmol) in THF (300 mL). The reaction is warmed to 0 °C and stirred for 2 h then quenched with TMSC1 (3.4 g, 32 mmol). The reaction is stirred at room temperature for 30 min then cooled to 0 °C and quenched with 3M HCl (20 mL). The aqueous layer is separated and the organic layer is extracted with 3M HCl. The organic layer is basified with solid NaOH, the resulting mixture is extracted with EtOAc, and the organic layer is dried over Na2S04, filtered and concentrated. The residue is purified by column chromatography on silica gel to give the desired product as a yellow solid. Yield: 5.50 g (62.7percent) HPLC-MS: M+H=277/279; tRet =3.16 min; AM6
62.7%
Stage #1: With n-butyllithium In tetrahydrofuran at -40℃; for 1.25 h;
Stage #2: at 0℃; for 2 h;
To a -40° C. solution of 2.5 M n-BuLi (18 mL) in THF (300 mL) is added 2-bromopyridine (5.0 g, 32 mmol) over 15 min. The reaction is stirred for 1 h at -40° C., and then treated with 2-Amino-5-bromo-benzoic acid (6.9 g, 32 mmol) in THF (300 mL). The reaction is warmed to 0° C. and stirred for 2 h then quenched with TMSCl (3.4 g, 32 mmol). The reaction is stirred at room temperature for 30 min then cooled to 0° C. and quenched with 3M HCl (20 mL). The aqueous layer is separated and the organic layer is extracted with 3M HCl. The organic layer is basified with solid NaOH, the resulting mixture is extracted with EtOAc, and the organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography on silica gel to give the desired product as a yellow solid. Yield: 5.50 g (62.7percent) HPLC-MS: M+H=277/279; tRet=3.16 min; AM6
50.7%
Stage #1: With n-butyllithium In tetrahydrofuran at -40℃; for 1 h; Inert atmosphere
Stage #2: at 0 - 10℃; for 3 h; Inert atmosphere
Add tetrahydrofuran (44 mL) to the reaction flask, protect with nitrogen, add n-butyl lithium (51 mL) at -40 ° C, control the internal temperature not to exceed -20 ° C, lower the temperature to -40 ° C, and slowly add 2-bromopyridine ( 15.8g), the reaction was incubated for 1 hour, the temperature was controlled below -40 ° C, and a solution of 2-amino-5-bromo-benzoic acid (6.7 g) dissolved in (44 mL) tetrahydrofuran was added dropwise.After the dropwise addition, the temperature was naturally raised to about 0 ° C for 3 hours.The internal temperature was kept below 10 °C, and a saturated ammonium chloride solution (11 mL) was slowly added dropwise to terminate the reaction. Water (50 mL) was added thereto, and the mixture was partitioned. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50mL) The organic layers were combined and washed with saturated aqueous sodium chloride (40 mL×2).Drying over anhydrous sodium sulfate, filtration, and concentrated under reduced pressure to give an oily substance, purified by column chromatography (eluent PE: EA = 3:1 to 1:1, volume ratio), and the positive component was collected and concentrated to give a solid product ( 4.37 g, yield 50.7percent).

Reference: [1] Patent: EP1183243, 2006, B1, . Location in patent: Page/Page column 11
[2] Patent: WO2014/154762, 2014, A1, . Location in patent: Page/Page column 62
[3] Patent: US2014/296230, 2014, A1, . Location in patent: Paragraph 0303-0306
[4] Patent: CN108264499, 2018, A, . Location in patent: Paragraph 0050-0051; 0075; 0076; 0077-0079
  • 92
  • [ 109-04-6 ]
  • [ 1461-22-9 ]
  • [ 17997-47-6 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With n-butyllithium In tetrahydrofuran at -70℃; for 0.5 h; Inert atmosphere
Stage #2: at -70℃; for 2 h;
To a solution of 2-bromopyridine (XCVI) (10 g, 63 mmol, 1.00 eq) in THF (150 mL) was added n-BuLi (25.3 mL, 63 mmol, 1.00 eq) and the mixture was stirred at −70° C. for 30 min under nitrogen atmosphere. Then n-Bu3SnCl (21.7 g, 67 mmol, 1.06 eq) was added and the mixture was stirred at the same temperature for another 2 h. Saturated ammonium chloride solution (150 mL) was added to the solution and extracted with ethyl acetate (150 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford the crude 2-(tributylstannyl)pyridine (XCVII) (25.9 g, 63 mmol, 100percent yield) as a yellow oil. The crude product was used without further purification.
100%
Stage #1: With n-butyllithium In tetrahydrofuran at -70℃; for 0.5 h; Inert atmosphere
Stage #2: at -70℃; for 2 h;
Step 1
To a solution of 2-bromopyridine (LVIII) (10 g, 63 mmol, 1.00 eq) in THF (150 mL) was added n-BuLi (25.3 mL, 63 mmol, 1.00 eq) and the mixture was stirred at -70° C. for 30 min under nitrogen atmosphere.
Then n-Bu3SnCl (21.7 g, 67 mmol, 1.06 eq) was added and the mixture was stirred at the same temperature for another 2 h.
Saturated ammonium chloride solution (150 mL) was added to the solution and extracted with EtOAc (150 mL*3).
The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford the crude 2-(tributylstannyl)pyridine (LIX) (25.9 g, 63 mmol, 100percent yield) as a yellow oil.
The crude product was used without further purification.
98%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Inert atmosphere
Stage #2: at -78 - 20℃; for 3.5 h;
2-bromopyridine (3.3 g, 21.0 mmol) was placed in a reaction flask. To ensure a nitrogen atmosphere in the reaction flask, the gas in the reaction flask was drawn out and the reaction flask was refilled with nitrogen gas in a rapid manner three times. To the reaction flask, 30 ml of anhydrous tetrahydrofuran was added, and then 9 ml of an n-butyllithium solution (23.0 mmol, 2.5 M in n-hexane) was slowly added at −78° C. to obtain a mixture. The mixture was kept at −78° C. and stirred for 60 minutes. At this moment, the color of the mixture changed from clear dark brown to cloudy yellowish green. Next, tributyltin chloride (6.3 ml, 23.0 mmol) was slowly added to the mixture at −78° C. for reaction for 3 hours. Thereafter, the temperature of the mixture was raised to 20° C., and the mixture was continuously stirred for 30 minutes to allow the color of the mixture to change to clear yellow. Then, a saturated ammonium chloride (NH4Cl) aqueous solution was slowly added to the mixture to terminate the reaction. The solvents in the mixture were drawn out of the reaction flask, and the residue in the reaction flask was washed several times with ethyl acetate and with a saturated sodium chloride aqueous solution to collect an organic layer. The organic layer was dehydrated using sodium sulfate (Na2SO4) to obtain a dark brown liquid (7.53 g, 98percent yield). (0070) The spectrum analysis for the dark brown liquid is: 1H NMR (400 MHz, CDCl3): δ 8.66 (d, J=1.2 Hz, 1H), 7.49 (m, 1H), 7.40 (d, J=1.2 Hz, 1H), 7.097.13 (m, 1H), 1.57 (m, 6H), 1.301.35 (m, 6H), 1.101.14 (m, 6H), 0.88 (t, J=7.2 Hz, 9H). The dark brown liquid was confirmed to be Compound L3-2 having a chemical structure represented by
94%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Inert atmosphere
Stage #2: at -78 - 20℃; for 2 h;
Example 32; 2-tributylstannylpyridine (18); Butyllithium (2.5 M in hexane, 6.33 mmol) is added to a solution of 2-bromopyridine (1 g, 6.33 mmol) in THF (12 mL) freshly distilled and degassed at -78° C. The reddish solution is stirred for 30 minutes at -78° C. Tributyltin chloride (1.7 mL, 6.33 mmol) is then added and the solution is stirred for 1 hour -78° C. and for 1 hour at room temperature. The mixture is treated with a NH4Cl saturated solution and extracted with diethylic ether. The organic phase is washed with a NaCl saturated solution, dried over MgSO4 and concentrated under reduced pressure. The residue is submitted to aluminium column chromatography (hexane/AcOET: 20/1), thus providing a pure product with a yield of 94percent.1H RMN (CDCl3) δ (ppm): 8.73 (ddd, J=4.9, 1.9, 1.0, 1H, H6), 7.48 (dt, J=7.4, 1.8, 1H, H5), 7.39 (dt, J=7.4, 1.6, 1H, H3), 7.10 (ddd, J=6.9, 4.9, 1.7, 1H, H4), 1.70-1.05 (m, 18H, CH2), 0.85 (t, 9H, J=7.3, CH3).
93%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 2 h;
Stage #2: at -78 - 20℃; for 12.5 h;
1.5 mL (15.57 mmol) of 2-bromopyridine was dissolved in 15 mL of THF in a 2-necked round-bottom flask, and the temperature of the flask was cooled down to about -78° C. 11.67 mL (18.69 mmol) of n-BuLi (1.6 M in hexane) was slowly added thereto and stirred at the same temperature for about 2 hours. After adding 4.65 mL (17.13 mmol) of tributyltin chloride, the resulting reaction mixture was stirred at about -78° C. for about 30 minutes and then at room temperature for about 12 hours, followed by adding a saturated aqueous NH4C1 solution, and extraction with diethyl ether. The resulting organic layer was separated and then dried with anhydrous MgS04, followed by evaporation under reduced pressure to remove the solvent, drying, and separation by column chromatography (hexane: ethyl acetate=9:l by v/v) to obtain 3.23 g of Intermediate 139-(1) as transparent oil (Yield: 93percent).
92%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; Inert atmosphere
Stage #2: at -78 - 20℃; for 3 h;
Following a modified procedure of Bianchini et al. [22] 2-bromopyridine (4.86 mL, 50.0 mmol, 1.00 eq) was dissolved under argon in Et2Odry(50 mL), added dropwise with ca. 1 mL/min to a solution of nBuLi (1.6 M in n-hexane, 31.3 mL, 50.0 mmol, 1.00 eq)in Et2Odry(25 mL) at–78C and the resulting reaction mixture was stirred for 1 h at -78C. Then tributyltinchloride (12.00 mL, 17.90 g,55.00 mmol, 1.10 eq) dissolved in THFdry(10 mL) was added dropwise at -78C and the reaction mixture was stirred 1 h at -78C followed by another 2 h stirring at room temperature. The reaction was stopped by the addition of NH4Cl (aq., sat., 30 mL). Subsequently the reaction mixture was washed with additional NH4Cl(aq., sat., 1 × 50 mL) and the aqueous phase was extracted with Et2O (3 × 30 mL). The combined organic phases were successively washed successively washed with H2O (30 mL) and brine (30 mL), dried over Na2SO4 and the solvent was removed in vacuum. Further drying under high vacuum gave the product (16.84 g, 92percent) as orange oil, which was used without further purification.
80%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2.8 h;
Stage #2: at -78 - 20℃; for 12 h;
a)
5-Bromo-2-pyridin-2-ylpyrimidine
14.6 ml (150 mmol) of 2-bromopyridine are dissolved in 700 ml of dry THF and cooled to -78° C.
At this temperature, 66.0 ml (165 mmol/2.5 M in hexane) of n-BuLi are added over the course of about 20 min., and the mixture is subsequently stirred at -78° C. for a further 2.5 h. 44.8 ml (165 mmol) of tributyltin chloride are added as rapidly as possible at this temperature, and the reaction is slowly allowed to come to room temperature (about 18 h).
150 ml of NH4Cl solution are subsequently added to the reaction mixture, which is then extracted with ethyl acetate.
The organic phase is dried over MgSO4, and the solvents are removed in vacuo. Yield: 44 g of 2-(tributyltin)pyridine, 80percent of theory.
80% With magnesium; ethylene dibromide In tetrahydrofuran at 35℃; for 1 h; Sonication; Inert atmosphere General procedure: A mixture of magnesium turnings (0.036g, 1.5mmol), bromobenzene (0.15g, 1mmol), tri-n-butyltin chloride (0.49g, 1.5mmol) and 1,2-dibromoethane (0.094g, 0.5mmol) as initiator in dry THF (5mL) was sonicated for 1h in an ultrasonic cleaning bath at around 35°C, with monitoring of the reaction by TLC. Once the reaction finished, aqueous saturated NH4Cl solution (40mL) was added and extracted with ethyl acetate (3×20mL). The combined extracts were washed with brine (60mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the product was isolated by column chromatography with silica gel doped with 10percent of KF to retain tri-n-butyltin halides formed during the reaction. 4 (0.286, 0.78mmol, 78percent) eluted with 98:2 (hexane/diethyl ether).
80%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h; Inert atmosphere
Stage #2: at 20℃; for 2 h; Inert atmosphere
Product 6a (1 g, 6.33 mmol) was charged into a flask, evacuated and put under argon. Freshly distilled THF (12 mL) was added a syringe under stirring, and the solution was cooled to -78°C in a dry ice/acetone bath. n-BuLi (2.5 M, 3.6 mL, 7.8 mmol) was added dropwise from a syringe, and the reaction mixture was stirred for 30 min under continued cooling. Then chlorotributyltin (1.7 mL, 6.33 mmol) was added dropwise from a syringe. After 1h, the mixture was allowed to warm slowly to room temperature and stirred for another 1 hour, then quenched with saturated NH4Cl, extracted with diethyl ether. The organic layer was washed with brine, dried with anhydrous MgSO4, concentrated and purified by Al2O3 column chromatography to obtain 1.86 g of product 7a (yield: 80percent). The synthesis route of (Entity 7b) was similar to 7a, and the delicate difference was replacing of 5a with 5b as the starting material.
59.53%
Stage #1: With n-butyllithium In tetrahydrofuran at -78 - 20℃; for 1 h; Inert atmosphere
Stage #2: at -78 - 20℃;
The compound 2-bromopyridine (2.09 g, 13.33 mmol) was dissolved in dry THF (10 mL)The resulting colorless reaction mixture was evacuated (nitrogen) three times,After stirring at -78 ° C for 30 minutes,Then n-butyllithium (2.4 M, 6 mL, 14.4 mmol) was added slowly,The reaction was moved to room temperature and stirred for 30 minutes,The reaction mixture was then moved to -78 ° C,And tributyltin chloride (3.67 g, 13.33 mmol) was slowly added thereto.The resulting mixture was stirred at -78 ° C for 1 hour, then shifted to room temperature and stirred overnight. It was then diluted with water (200 mL) and the resulting mixture was extracted with EtOAc (100 mLx3). The combined organic phases were washed with water (100 mLx2) And brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by a silica gel column (PE / EtOAc (v / v) = 10/1) to give the title compound as a pale yellow oil , 59.53percent).
34%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; Inert atmosphere
Stage #2: at -78 - -20℃; for 5 h;
Example 109 B2-(tributylstannyl)pyridine; 2-bromopyridine (14.9 g, 93.1 mmol) in anhydrous THF (700 mL) was cooled to -78° C. under a stream of nitrogen gas, n-BuLi in hexane (54 mL) were added thereto and the mixture was stirred for 30 min. Tributyltin chloride (29 mL, 108 mmol) was added and the mixture was stirred, at -78° C. for 2 hours and afterwards at -20° C. for 3 hours. It was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried and the solvent was evaporated. The residue was purified by chromatography (petroleum ether/ethyl acetate=9/1) to give 2-(tributylstannyl)pyridine (12 g, yield 34percent) as a yellow liquid, LC-MS (ESI) m/z: 370 (M+1)+.

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  • 93
  • [ 109-04-6 ]
  • [ 56-35-9 ]
  • [ 17997-47-6 ]
YieldReaction ConditionsOperation in experiment
83% With magnesium; ethylene dibromide In tetrahydrofuran at 35℃; for 1 h; Sonication; Inert atmosphere General procedure: A mixture of magnesium turnings (0.027g, 1.1mmol), bromobenzene (0.15g, 1mmol), bis(tri-n-butyltin) oxide (0.60g, 1mmol) and 1,2-dibromoethane (0.094g, 0.5mmol) as initiator in dry THF (5mL) was sonicated for 1h in an ultrasonic cleaning bath at around 35°C, with monitoring of the reaction by TLC. Once the reaction finished, aqueous saturated NH4Cl solution (40mL) was added and extracted with ethyl acetate (3×20mL). The combined extracts were washed with brine (60mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was purified by column chromatography with silica gel doped with 10percent of KF to retain the tri-n-butyltin bromide formed during the reaction.
Reference: [1] Journal of Organometallic Chemistry, 2013, vol. 741-742, # 1, p. 24 - 32
  • 94
  • [ 109-04-6 ]
  • [ 813-19-4 ]
  • [ 17997-47-6 ]
Reference: [1] European Journal of Organic Chemistry, 2018, vol. 2018, # 1, p. 120 - 125
  • 95
  • [ 288-13-1 ]
  • [ 109-04-6 ]
  • [ 25700-11-2 ]
YieldReaction ConditionsOperation in experiment
87% for 8 h; Reflux (Pyr-N-PzH) Compound 3
To a 250 mL single-neck round bottomed flask were charged 15.0 g (95 mmol) of 2-bromopyridine, 25.0 g (367 mmol, 3.86 eq.) of pyrazole, and 45 mL of xylenes.
The mixture was heated at reflux for eight hours, then was cooled to room temperature.
The resulting mixture was dissolved in dichloromethane, and the organic layer washed four times with 250 mL of water (until no pyrazole was observed by GC).
Drying over magnesium sulfate, filtering and rotary evaporation gave 12.0 g (82.6 mmol, 87percent) of the product as a white solid. 1H NMR (400 MHz, CDCl3) 8.59 (m, 1H, Pyridyl 6-H), 8.39 (s, 1H, Pyrazole 5-H), 7.90 (d, 1H, Pyridyl 3-H), 7.80 (m, 1H, Pyridyl 4-H), 7.73 (s, 1H, Pyrazole 3-H), 7.15 (s, 1H, Pyridyl 5-H), 6.45 (m, 1H, Pyrazole 4-H).
75% With potassium hydroxide In dimethyl sulfoxide at 120℃; for 24 h; Dry DMSO (4 mL) was added to a mixture of 1H-pyrazole (340 mg, 5.00 mmol), 2-bromopyridine (790 mg, 5.00 mmol) and KOH (700 mg, 12.5 mmol) and heated at 120 °Cfor 24 h. The reaction mixture was quenched with saturated solution of NH4Cl and extractedwith EtOAc. The organic phase was dried over anhydrous Na2SO4, followed by evaporationunder reduced pressure to remove the solvent. Purification of the crude reaction mixture byflash column chromatography using 2.5percent acetone in petroleum ether afforded the titledcompound as low melting white solid (544 mg, 75percent).
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  • [ 18653-75-3 ]
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  • 97
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  • [ 179260-78-7 ]
  • [ 56100-19-7 ]
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  • 98
  • [ 109-04-6 ]
  • [ 4926-28-7 ]
  • [ 108-89-4 ]
  • [ 366-18-7 ]
  • [ 1134-35-6 ]
  • [ 56100-19-7 ]
YieldReaction ConditionsOperation in experiment
45 %Chromat. With nickel(II) bromide hydrate; sodium iodide In N,N-dimethyl-formamide at 20℃; Electrochemical reaction; Inert atmosphere General procedure: The controlled current preparative electrolysis were carried out with a potentiostat/galvanostat equipment. Undivided cells with 20 mL compartment were used. Zn or Fe metallic rod with 8 mm diameter was used as the sacrificial anode. Ni foam (6 cm.x.3.5 cm) was used as the cathode. It could be re-used after washing with a 6 M HCl solution following by water and acetone, and dried. The same solution was used to clean the anode. A 5 mL DMF solution containing 7percent or 20percent of NiBr2*xH2O or [Ni(bpy)]Br221 and x mmol of the corresponding mixture of 2-bromomethylpyridines or 2,6-dihalopyridines (heterocouplings in Table 1, Table 2, Table 4 and Table 5), or (2.5 mmol) of 2,6-dihalopyridines (homocoupling in Table 3) was stirred or sonicated before the electrolysis, to ensure the solubilization of reagents. A pre-electrolysis was carried out with 15 mL of the electrolytic solution (DMF, 0.1 M NaI and 0.75 mmol of 1,2-dibromoethane), passing a charge of 146 C (I=150 mA). Then, the previous prepared solution of bromopicoline or bromopyridine and the catalyst in 5 mL DMF, was added to the electrolytic cell and the constant current electrolysis (I=100 mA) applied. It is important to ensure that the cell potential must not exceed 1.8 V in order to avoid the reduction of the substrate on the cathode surface. After the total consumption of the reagent (number of coulombs described in the tables), the reaction was stopped and the solvent removed under reduced pressure. The residue was dissolved in CH2Cl2 and washed with several portions of a 6 M NH4OH solution. After drying over Na2SO4, the organic layer was evaporated under reduced pressure.
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  • 99
  • [ 109-04-6 ]
  • [ 4926-28-7 ]
  • [ 110-86-1 ]
  • [ 108-89-4 ]
  • [ 366-18-7 ]
  • [ 1134-35-6 ]
  • [ 56100-19-7 ]
YieldReaction ConditionsOperation in experiment
35 %Chromat. With nickel(II) bromide hydrate; sodium iodide In N,N-dimethyl-formamide at 20℃; Electrochemical reaction; Inert atmosphere General procedure: The controlled current preparative electrolysis were carried out with a potentiostat/galvanostat equipment. Undivided cells with 20 mL compartment were used. Zn or Fe metallic rod with 8 mm diameter was used as the sacrificial anode. Ni foam (6 cm.x.3.5 cm) was used as the cathode. It could be re-used after washing with a 6 M HCl solution following by water and acetone, and dried. The same solution was used to clean the anode. A 5 mL DMF solution containing 7percent or 20percent of NiBr2*xH2O or [Ni(bpy)]Br221 and x mmol of the corresponding mixture of 2-bromomethylpyridines or 2,6-dihalopyridines (heterocouplings in Table 1, Table 2, Table 4 and Table 5), or (2.5 mmol) of 2,6-dihalopyridines (homocoupling in Table 3) was stirred or sonicated before the electrolysis, to ensure the solubilization of reagents. A pre-electrolysis was carried out with 15 mL of the electrolytic solution (DMF, 0.1 M NaI and 0.75 mmol of 1,2-dibromoethane), passing a charge of 146 C (I=150 mA). Then, the previous prepared solution of bromopicoline or bromopyridine and the catalyst in 5 mL DMF, was added to the electrolytic cell and the constant current electrolysis (I=100 mA) applied. It is important to ensure that the cell potential must not exceed 1.8 V in order to avoid the reduction of the substrate on the cathode surface. After the total consumption of the reagent (number of coulombs described in the tables), the reaction was stopped and the solvent removed under reduced pressure. The residue was dissolved in CH2Cl2 and washed with several portions of a 6 M NH4OH solution. After drying over Na2SO4, the organic layer was evaporated under reduced pressure.
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  • 100
  • [ 109-04-6 ]
  • [ 13040-77-2 ]
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  • 101
  • [ 109-04-6 ]
  • [ 652148-92-0 ]
  • [ 13040-77-2 ]
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  • 102
  • [ 109-04-6 ]
  • [ 2402-78-0 ]
  • [ 13040-77-2 ]
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  • 103
  • [ 109-04-6 ]
  • [ 139585-50-5 ]
  • [ 14162-94-8 ]
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[2] Organic Letters, 2005, vol. 7, # 4, p. 697 - 700
  • 104
  • [ 109-04-6 ]
  • [ 1121-76-2 ]
  • [ 14162-94-8 ]
Reference: [1] Organic Letters, 2011, vol. 13, # 9, p. 2310 - 2313
  • 105
  • [ 109-04-6 ]
  • [ 1970-80-5 ]
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  • 106
  • [ 109-04-6 ]
  • [ 5315-25-3 ]
  • [ 366-18-7 ]
  • [ 4411-80-7 ]
  • [ 56100-22-2 ]
YieldReaction ConditionsOperation in experiment
56 %Chromat. With nickel(II) bromide hydrate; sodium iodide In N,N-dimethyl-formamide at 20℃; Electrochemical reaction; Inert atmosphere General procedure: The controlled current preparative electrolysis were carried out with a potentiostat/galvanostat equipment. Undivided cells with 20 mL compartment were used. Zn or Fe metallic rod with 8 mm diameter was used as the sacrificial anode. Ni foam (6 cm.x.3.5 cm) was used as the cathode. It could be re-used after washing with a 6 M HCl solution following by water and acetone, and dried. The same solution was used to clean the anode. A 5 mL DMF solution containing 7percent or 20percent of NiBr2*xH2O or [Ni(bpy)]Br221 and x mmol of the corresponding mixture of 2-bromomethylpyridines or 2,6-dihalopyridines (heterocouplings in Table 1, Table 2, Table 4 and Table 5), or (2.5 mmol) of 2,6-dihalopyridines (homocoupling in Table 3) was stirred or sonicated before the electrolysis, to ensure the solubilization of reagents. A pre-electrolysis was carried out with 15 mL of the electrolytic solution (DMF, 0.1 M NaI and 0.75 mmol of 1,2-dibromoethane), passing a charge of 146 C (I=150 mA). Then, the previous prepared solution of bromopicoline or bromopyridine and the catalyst in 5 mL DMF, was added to the electrolytic cell and the constant current electrolysis (I=100 mA) applied. It is important to ensure that the cell potential must not exceed 1.8 V in order to avoid the reduction of the substrate on the cathode surface. After the total consumption of the reagent (number of coulombs described in the tables), the reaction was stopped and the solvent removed under reduced pressure. The residue was dissolved in CH2Cl2 and washed with several portions of a 6 M NH4OH solution. After drying over Na2SO4, the organic layer was evaporated under reduced pressure.
Reference: [1] Tetrahedron, 2012, vol. 68, # 10, p. 2383 - 2390
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  • [ 109-04-6 ]
  • [ 154447-04-8 ]
  • [ 56100-22-2 ]
Reference: [1] Organic Syntheses, 2002, vol. 78, p. 51 - 51
[2] Journal of Organic Chemistry, 1998, vol. 63, # 26, p. 10048 - 10051
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  • [ 109-04-6 ]
  • [ 259807-95-9 ]
  • [ 56100-22-2 ]
Reference: [1] Inorganic Chemistry, 2018, vol. 57, # 9, p. 5486 - 5498
  • 109
  • [ 109-04-6 ]
  • [ 21948-75-4 ]
  • [ 56100-22-2 ]
Reference: [1] Tetrahedron Letters, 1990, vol. 31, # 32, p. 4625 - 4628
  • 110
  • [ 109-04-6 ]
  • [ 100846-31-9 ]
  • [ 56100-22-2 ]
Reference: [1] Tetrahedron Letters, 1990, vol. 31, # 32, p. 4625 - 4628
  • 111
  • [ 109-04-6 ]
  • [ 1945-84-2 ]
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[2] Chemistry - A European Journal, 2001, vol. 7, # 23, p. 5118 - 5134
[3] Journal of Organometallic Chemistry, 2001, vol. 629, # 1-2, p. 131 - 144
[4] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 5, p. 709 - 714
[5] Synthesis, 1996, # 5, p. 589 - 590
[6] Synthesis, 1981, # 5, p. 364 - 365
[7] Synthesis, 1983, # 4, p. 312 - 314
[8] Chemistry Letters, 2011, vol. 40, # 9, p. 925 - 927
[9] Molecular Crystals and Liquid Crystals, 2012, vol. 568, # 1, p. 93 - 97,5
[10] Molecular Crystals and Liquid Crystals, 2012, vol. 568, # 1, p. 93 - 97
[11] Synlett, 2013, vol. 24, # 9, p. 1101 - 1104
[12] Patent: WO2014/124560, 2014, A1,
[13] Angewandte Chemie - International Edition, 2015, vol. 54, # 27, p. 7949 - 7953[14] Angew. Chem., 2015, vol. 127, # 27, p. 8060 - 8064,5
[15] Dalton Transactions, 2016, vol. 45, # 25, p. 10209 - 10221
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  • [ 109-04-6 ]
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  • [ 1945-84-2 ]
  • [ 28790-65-0 ]
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  • 114
  • [ 109-04-6 ]
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  • [ 1945-84-2 ]
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  • 115
  • [ 109-04-6 ]
  • [ 1066-26-8 ]
  • [ 1945-84-2 ]
Reference: [1] Liebigs Annales, 1996, # 12, p. 2107 - 2113
  • 116
  • [ 109-04-6 ]
  • [ 68-12-2 ]
  • [ 34160-40-2 ]
Reference: [1] Chemistry - An Asian Journal, 2016, vol. 11, # 15, p. 2103 - 2106
  • 117
  • [ 626-05-1 ]
  • [ 68-12-2 ]
  • [ 109-04-6 ]
  • [ 34160-40-2 ]
  • [ 55304-83-1 ]
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  • 118
  • [ 626-05-1 ]
  • [ 68-12-2 ]
  • [ 109-04-6 ]
  • [ 34160-40-2 ]
  • [ 55304-83-1 ]
Reference: [1] Journal of Organic Chemistry, 2001, vol. 66, # 20, p. 6775 - 6786
  • 119
  • [ 109-04-6 ]
  • [ 372-48-5 ]
  • [ 144100-07-2 ]
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  • 120
  • [ 109-04-6 ]
  • [ 144100-07-2 ]
Reference: [1] Science, 2013, vol. 342, # 6161, p. 956 - 960
  • 121
  • [ 109-04-6 ]
  • [ 591-50-4 ]
  • [ 32864-29-2 ]
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  • 122
  • [ 109-04-6 ]
  • [ 591-50-4 ]
  • [ 54151-74-5 ]
  • [ 32864-29-2 ]
Reference: [1] Organic Letters, 2001, vol. 3, # 6, p. 835 - 838
  • 123
  • [ 109-04-6 ]
  • [ 634-36-6 ]
  • [ 10385-36-1 ]
Reference: [1] Journal of the American Chemical Society, 1952, vol. 74, p. 2107
  • 124
  • [ 109-04-6 ]
  • [ 68-12-2 ]
  • [ 128071-75-0 ]
YieldReaction ConditionsOperation in experiment
56%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 1.83333 h;
Stage #2: at -78℃; for 1.33333 h;
To a cooled (–78 C) solution of diisopropylamine (20.4 g, 28.0 mL, 0.202 mol) in dry THF (400 mL), n-BuLi (0.192 mol, 58.0 mL, 3.3 M in hexane) was added at this temperature. The mixture was stirred at –78 C for 1 h, and a solution of 2-bromopyridine (25.3 g, 0.160 mol) in dry THF (150 mL) was added over 20 min. The reaction mixture was kept at –78 C for 90 min, and a cooled (–78 C) solution of DMF (35.0 g, 0.480 mol) in dry THF (25 mL) was added in one portion. The resulting mixture was stirred for additional 80 min at –78 C, then treated with NaH2PO4 (27.6 g, 0.230 mol in H2O (120 mL)), warmed to rt, and diluted with MeOt-Bu (500 mL). The organic phase was separated, washed with brine (2100 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was triturated with pentane. After decantation of the solvent, the remaining solid was recrystallized from hexanes. Yield 16.7 g, 56percent. Yellowish solid. Mp 67–69 C. 1H NMR (400 MHz, CDCl3), δ: 10.35 (s, 1H), 8.57 (dd, J = 4.7, 2.1 Hz, 1H), 8.17 (dd, J = 7.6, 2.1 Hz, 1H), 7.44 (ddd, J = 7.6, 4.7, 0.6 Hz, 1H). 13C NMR (101 MHz, CDCl3), δ: 190.4, 154.0, 144.9, 137.5, 130.1, 123.0. Anal. Calcd. for C6H4BrNO: C, 38.74; H, 2.17; N, 7.53; Br, 42.96. Found: C, 38.58; H, 2.08; N, 7.57; Br, 42.69.
54%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere; Schlenk technique
Stage #2: at -78℃; for 1 h; Inert atmosphere; Schlenk technique
According to the literature,16 a dry and argon-flushed Schlenk flask equipped with a magnetic stirring bar and a septum was charged with a solution of LDA (30.0 mmol, 0.5 M in THF) and cooled to –78 °C. 2-Bromopyridine (7.9 g, 10.0 mmol) was added dropwise to the cooled solution. The resulting mixture was stirred for 1 h at –78 °C. DMF (2.9 g, 40.0 mmol) was then added and the mixture stirred for 1h at –78 °C. The resulting solution was quenched with sat. aq NH4Cl (40 mL), extracted with EtOAc (3 × 80 mL), and the combined organic phases were dried (anhyd MgSO4). After filtration, the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography on silica gel (i-hexane/EtOAc, 8:2 + Et3N 2percent) yielding 2-bromo-3-pyridine-carboxaldehyde as a colorless oil (1.0 g, 54percent).1H NMR (400 MHz, CDCl3): δ = 10.34 (1 H, s), 8.60 (dd, J = 4.5, 2.1 Hz, 1H), 8.19 (dd, J = 7.9, 2.1 Hz, 1 H), 7.46 (dd, J = 7.9, 4.5 Hz, 1 H).
19%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 2 h;
Stage #2: at -78 - 20℃;
EXAMPLE 1;

2- {4-[3-(2, 4-DICHLOROPHENYL)-2-METHYLPROPIONYL]-1-PIPERAZINYL3-3- {1 S [2


(METHYLAMINO) ACETAMIDO]-3-METHYLBUTYL} PYRIDINE 1-1; Step 1A. 2-Bromo-3-formylpyridine la; Lithium diisopropylamide (131 mL, 262 mmol, 2M in THF) was added to a stirring solution of 2-bromopyridine (25 mL, 262 mmol) in THF (208 mL) at-78 °C under nitrogen. The reaction mixture was allowed to stir at-78 °C for 2 hours and then a solution of DMF (20.3 mL, 262 mmol) in THF (104 mL) was added. After the addition, the reaction mixture was allowed to warm to r. t. and was neutralized by adding a saturated solution of ammonium chloride. The crude product was extracted with ethyl acetate (3 x 200 mL), the organic layers were combined, dried over anhydrous Na2S04, filtered, and solvent removed in vacuo. The residue was purified by column chromatography on silica using 15percent ethyl acetate/hexanes as the eluent (Rf= 0.3). Compound la was recovered in 19 percent yield as a yellow oil (9.4 g, 50.5 mmol).
Reference: [1] Tetrahedron Letters, 2008, vol. 49, # 17, p. 2839 - 2843
[2] Chemical Communications, 2011, vol. 47, # 23, p. 6635 - 6637
[3] Organic Letters, 2007, vol. 9, # 5, p. 891 - 894
[4] Tetrahedron Letters, 2017, vol. 58, # 20, p. 1989 - 1991
[5] Synthesis (Germany), 2018, vol. 50, # 1, p. 155 - 169
[6] Journal of Heterocyclic Chemistry, 1993, vol. 30, # 1, p. 157 - 159
[7] Journal of Organic Chemistry, 2012, vol. 77, # 7, p. 3348 - 3364
[8] Journal of Medicinal Chemistry, 2007, vol. 50, # 25, p. 6356 - 6366
[9] Patent: WO2005/42516, 2005, A2, . Location in patent: Page/Page column 24-25
[10] Tetrahedron Letters, 1991, vol. 32, # 37, p. 4883 - 4884
[11] Tetrahedron Letters, 1993, vol. 34, # 35, p. 5653 - 5656
[12] Synthetic Communications, 1993, vol. 23, # 19, p. 2727 - 2730
[13] Synthesis, 1999, # 2, p. 306 - 311
[14] Synthesis, 2005, # 2, p. 330 - 333
[15] Tetrahedron, 2006, vol. 62, # 26, p. 6182 - 6189
[16] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 11, p. 3146 - 3151
[17] Synthesis, 2007, # 14, p. 2135 - 2144
[18] Tetrahedron, 2009, vol. 65, # 18, p. 3653 - 3658
[19] Tetrahedron Letters, 2010, vol. 51, # 31, p. 4053 - 4057
[20] Patent: EP1392687, 2017, B1, . Location in patent: Paragraph 0201-0203
  • 125
  • [ 109-04-6 ]
  • [ 109-94-4 ]
  • [ 128071-75-0 ]
YieldReaction ConditionsOperation in experiment
11%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 2 h;
Stage #2: at -78℃; for 1 h;
Stage #3: With water; ammonium chloride In tetrahydrofuran at -30℃;
Intermediate 3: lH-Pyrrolo [2,3-6] pyridine-2-carbaldehydeStep a: 2-bromonicotinaldehyde[0450] ft-BuLi (2.5 M solution, 42.0 mL, 0.105 mol) was added to a solution ofdiisopropylamine (15.5 mL, 0.11 mol) in THF (180.0 mL) at -78°C. After the mixture was stirred for 10 min, a solution of 2-bromopyridine (15.8 g, 0.10 mol) in THF (20.0 mL) was added dropwise and the mixture was stirred at -78°C for 2 h. Then HC02Et (14.8 g, 0.20 mol) was added dropwise and the reaction mixture was stirred at -78°C for another hour. The mixture was allowed to warm to -30°C and saturated NH4C1 solution was added. The resulting mixture was extracted with EtOAc and the combined organic phases were washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography (PE/EA=15: 1) to afford 2.0 g of the title compound as a light yellow solid (11percent yield).
Reference: [1] Patent: WO2012/178015, 2012, A2, . Location in patent: Page/Page column 112-113
  • 126
  • [ 109-04-6 ]
  • [ 128071-75-0 ]
Reference: [1] Patent: US2003/109539, 2003, A1,
[2] Patent: US5866589, 1999, A,
  • 127
  • [ 109-04-6 ]
  • [ 50-00-0 ]
  • [ 128071-75-0 ]
Reference: [1] Tetrahedron Letters, 1994, vol. 35, # 45, p. 8357 - 8360
  • 128
  • [ 109-04-6 ]
  • [ 132-20-7 ]
Reference: [1] Patent: CN108164455, 2018, A,
  • 129
  • [ 109-04-6 ]
  • [ 162318-34-5 ]
Reference: [1] Dalton Transactions, 2013, vol. 42, # 6, p. 2062 - 2074
[2] Dalton Transactions, 2013, vol. 42, # 18, p. 6478 - 6488
[3] Beilstein Journal of Organic Chemistry, 2015, vol. 11, p. 693 - 700
[4] Chemistry - A European Journal, 2017, vol. 23, # 50, p. 12162 - 12170
  • 130
  • [ 109-04-6 ]
  • [ 287114-32-3 ]
  • [ 112275-50-0 ]
Reference: [1] Patent: WO2003/101994, 2003, A1, . Location in patent: Page 84
  • 131
  • [ 109-04-6 ]
  • [ 234111-08-1 ]
Reference: [1] Chemical Communications, 2001, # 23, p. 2450 - 2451
  • 132
  • [ 109-04-6 ]
  • [ 100523-96-4 ]
  • [ 73290-22-9 ]
  • [ 1353056-31-1 ]
  • [ 234111-08-1 ]
  • [ 265981-13-3 ]
Reference: [1] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297
  • 133
  • [ 109-04-6 ]
  • [ 100523-96-4 ]
  • [ 1353056-31-1 ]
  • [ 234111-08-1 ]
  • [ 265981-13-3 ]
Reference: [1] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297
  • 134
  • [ 109-04-6 ]
  • [ 265981-13-3 ]
YieldReaction ConditionsOperation in experiment
85%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane; toluene at -95 - -45℃; Inert atmosphere
Stage #2: With iodine In tetrahydrofuran; hexane; toluene at 20℃; Inert atmosphere
a) Under Ar atmosphere n-BuLi (12.78 mL of a 2.5 Msolution in hexanes 31.96 mmol) was added to a solution of iPr2NH (4.44 mL, 31.96 mmol) inTHF (100 mL) at -45 °C. After stirring for 0.5 h, the reaction mixture was further cooled to-95 °C (toluene/liquid N2), and 2-bromopyridine (3.02 mL, 31.65 mmol) was added. Theresulting mixture was stirred at -95 °C to -90 °C for 3 to 4 h and I2 (8.03 g, 31.65 mmol) wasadded in portions. After slowly warming to rt overnight, the mixture was quenched with 10percentaq. HOAc solution (pH 8–9) and then distilled water (50 mL) was added. The organicmaterial was extracted with diethyl ether and the resulting solution was dried over anhydrousK2CO3. The solvent was evaporated in vacuo and the crude 2-bromo-3-iodopyridine wasobtained as a brown powder. The brown powder was then dried in vacuo in a desicatortogether with KOH pellets over 3 hours. The 2-bromo-3-iodopyridine (7.66 g, 85percent) washighly pure as judged from 1H NMR and it was directly used for the next step. 1H NMR (499.93 MHz, CDCl3, 25 °C): δ = 8.05 (dd, J = 0.6, 5.2 Hz, 1H), 7.91 (dd, J = 0.6, 1.5 Hz,1H), 7.62 (dd, J = 1.5, 5.2 Hz, 1H). Data are in accordance with the literature [17].
Reference: [1] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 2682 - 2688
[2] Tetrahedron Letters, 2008, vol. 49, # 17, p. 2839 - 2843
[3] Chemical Communications, 2001, # 23, p. 2450 - 2451
[4] Synthesis, 2004, # 16, p. 2614 - 2616
[5] Angewandte Chemie - International Edition, 2008, vol. 47, # 9, p. 1662 - 1667
  • 135
  • [ 109-04-6 ]
  • [ 100523-96-4 ]
  • [ 73290-22-9 ]
  • [ 1353056-31-1 ]
  • [ 234111-08-1 ]
  • [ 265981-13-3 ]
Reference: [1] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297
  • 136
  • [ 109-04-6 ]
  • [ 100523-96-4 ]
  • [ 1353056-31-1 ]
  • [ 234111-08-1 ]
  • [ 265981-13-3 ]
Reference: [1] Chemistry - A European Journal, 2011, vol. 17, # 47, p. 13284 - 13297
  • 137
  • [ 109-04-6 ]
  • [ 927-74-2 ]
  • [ 395652-44-5 ]
YieldReaction ConditionsOperation in experiment
90% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In 1,4-dioxane at 20℃; Inert atmosphere Under nitrogen atmosphere, and at r.t., CuT (0.06 g, 0.31 mmol), dry Et3N (1.32 mL, 9.49 mmol) and bis-(triphenylphosphine)-palladium chloride (0.13 g, 0.18 mmol) were sequentially added to a solution of 2-bromopyridine (0.60 mL, 6.33 mmol) in 1,4-dioxane (10 mL). Then, but-3-yn-1-ol (0.57 mL, 7.59 mmol) was added dropwise at the same temperature.The resulting reaction mixture was left stirred overnight, then concentrated under reduced pressure, dissolved in EtOAc (80 mL) and washed with H20 (3 x 10 mL). The organic layer was dried over Na2504 and concentrated to dryness to give an oily crude (1.1 g). Purification by typical silica gel flash chromatography using a Teledyne ISCO apparatus (Cy/EtOAc from 90:10 to 30:70) afforded the pure title compound (0.84 g, 90percent), as a white solid. R= 1.25 mm. MS(ESI) m/z: 148 EM-H], 170 EM-Na], 186 EM-K]. ‘H NMR (DMSO-d6): ö 8.55—8.49 (m, 1H),7.76 (td, 1H, J= 7.8, 1.8 Hz), 7.44 (d, 1H, J= 7.8 Hz), 7.33 (ddd, 1H, J= 7.8, 4.9, 1.8 Hz), 4.92 (t, 1H, J= 5.2 Hz), 3.62-3.58 (m, 2H), 2.58 (t, 2H, J= 6.8 Hz).
77% at 0 - 70℃; Example 199 ;3 -Methoxy- N -methyl- N -( 4-(pyridin- 2-yl)but - 3 -ynyl)benzamide; 199(A) 4-(Pyridin-2-yl)but-3-yn-1-01; To a suspension of CuI (301 mg, 1.58 mmol) in TEA (40 mL) were added 2- bromopyridine (5 g, 31.6 mmol), followed by Pd2Cl2(PPh3)2 (1.11 g, 1.58 mmol) to give a yellow orange suspension. After cooling down to 0°C under N2, 3-butyn-l-ol (2.28 g, 31.6 mmol) was added. The resulting reaction mixture turned black and it was stirred overnight at 70°C. The reaction mixture was quenched at 0°C with water, TEA was removed under low pressure, and the organic layer was extracted 3x using DCM, washed with Ammonia, water, brine, dried over MgS04, filtered and concentrated. The crude residue was purified over silicagel chromatography (prepacked 250 g silicagel column, DCM/MeOH : from 99/1 to 95/5 as eluent) to afford 3.60 g of 4- (pyridin-2-yl)but-3-yn-1-ol as a brown oil (Yield : 77percent). LCMS (RT) : 1.58min; MS (ES+) gave m/z : 148 Rf (DCM/MeOH : 95/5) =0.23
Reference: [1] Tetrahedron Letters, 2005, vol. 46, # 10, p. 1717 - 1720
[2] Journal of Organic Chemistry, 2003, vol. 68, # 3, p. 762 - 769
[3] Patent: WO2014/144836, 2014, A2, . Location in patent: Paragraph 0526; 0527
[4] European Journal of Organic Chemistry, 2011, # 2, p. 271 - 279
[5] Patent: WO2005/123703, 2005, A2, . Location in patent: Page/Page column 207
[6] Molecules, 2010, vol. 15, # 12, p. 9157 - 9173
[7] Journal of Organic Chemistry, 2003, vol. 68, # 8, p. 3327 - 3329
[8] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 8, p. 1077 - 1080
  • 138
  • [ 109-04-6 ]
  • [ 452972-08-6 ]
Reference: [1] Tetrahedron, 2002, vol. 58, # 17, p. 3323 - 3328
  • 139
  • [ 109-04-6 ]
  • [ 394223-03-1 ]
Reference: [1] Patent: WO2012/178015, 2012, A2,
  • 140
  • [ 109-04-6 ]
  • [ 144025-03-6 ]
  • [ 391604-55-0 ]
YieldReaction ConditionsOperation in experiment
97% With sodium carbonate In tetrahydrofuran; water at 70℃; for 24 h; 2-Bromopyridine (2.01 mL, 21.1 mmol), 2,4-difluorophenylboronic acid (4.00 g, 25.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.732 g, 0.633 mmol) were added to round-bottomed flask with reflux condenser and dissolved to 50 mL of THF. After 30 mL of aqueous 2N Na2CO3 was introduced, the reaction mixture was heated at 70° C. for 1 day. After cooling, the crude mixture was poured into water, extracted with CH2C12 (50 mL x 3 times), and dried over magnesium sulfate. The product was purified by silica column (n-hexane:EtOAc=4:1) to give dfppy 1 as colorless liquid (3.90 g, 97percent).
93%
Stage #1: With potassium carbonate In 1,2-dimethoxyethane for 0.5 h;
Stage #2: at 90℃; for 18 h; Heating / reflux
2-bromopyridine (1 mmol), 2,4-difluorophenylboronic acid (1.2 mmol), potassium carbonate (2.7 mmol), and dimethoxyethane (1.5 mL) were put together in a round bottom flask, to which nitrogen was injected, followed by stirring for 30 minutes. Tetrakis(triphenylphosphine)palladium (0.05 mmol) was added and a reflux condenser was connected thereto, followed by reflux at 90° C. for 18 hours. After confirming the reaction by TLC, the solvent was removed by distillation under reduced pressure at high vacuum. After extracting with ethyl acetate, the residue was purified by fresh column chromotography to give compound (C). The yield was 93percent.
93%
Stage #1: With potassium carbonate In 1,2-dimethoxyethane for 0.5 h;
Stage #2: at 90℃; for 18 h; Heating / reflux
2-bromopyridine (1 mmol), 2,4-difluorophenylboronic acid (1.2 mmol), potassium carbonate (2.7 mmol), and dimethoxyethane (1.5 mL) were put together in a round bottom flask, to which nitrogen was injected, followed by stirring for 30 minutes. Tetrakis(triphenylphosphine)palladium (0.05 mmol) was added and a reflux condenser was connected thereto, followed by reflux at 90°C for 18 hours. After confirming the reaction by TLC, the solvent was removed by distillation under reduced pressure at high vacuum. After extracting with ethyl acetate, the residue was purified by fresh column chromotography to give compound (C). The yield was 93percent.
90% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; water; toluene at 80℃; for 15 h; Inert atmosphere (1.03 g, 6.5 mmol) and tetrakis (triphenylphosphine) palladium (0.370 g, 0.32 mmol) were weighed out by adding 2-bromopyridine (1.0 g, 6.37 mmol), 2,4-difluorobenzeneboronic acid 50mL two-necked flask, the vacuum drum nitrogen cycle three times, followed by injection of toluene (9mL), saturated K2CO3(Aq) (3 mL), ethanol (3 mL), and refluxed at 80 ° C for 15 hours.Cooled to room temperature, extracted with dichloromethane and distilled water, and the organic phases were combined and dried under reduced pressure to give 1.12 g of product in 90percent yield.
87% With palladium diacetate; sodium carbonate; triphenylphosphine In ethanol; water; toluene at 105℃; for 21 h; Inert atmosphere; Reflux 2,4-difluorophenylboronic acid (2.00 g, 12.7 mmol), Pd (OAc) 2 (143 mg, 63.5 mmol), PPh3 (656 mg, 2.50 mmol), Na2 CO3 (2.65 g, 250 mmol)And 2-bromopyridine (1.74 g, 11.0 mmol) were dissolved in a mixture of toluene (30 ml), ethanol (30 ml) and water (15 ml). The mixture was heated under reflux at 105 ° C. for 21 hours under an inert atmosphere.After cooling the mixture to room temperature, the organic layer of the mixture was not observed and ethyl acetateIt was extracted with chill. The solution was dried over magnesium sulfate and evaporated. The obtained crude product was purified by SiO 2 chromatography using hexane: ethyl acetate = 9: 1 to obtain dfppy represented by the formula (xii) (1.83 g, 9.57 mmol, 87percent)
83% With potassium carbonate In tetrahydrofuran; water at 80℃; for 24 h; Heating / reflux 5.0 g of 2,4-difluorophenyl boronic acid (0.0285 mol), 3.0 g of 2-bromopyridine (0.019 mol), 150 ml of tetrahydrofuran, and a 2M potassium carbonate aqueous solution (20 ml) were added in a 250 ml double-necked, round-bottom flask under nitrogen atmosphere, and then palladium tetrakistriphenylphosphine(Pd(PPh3)4; 0.7 g, 3 molpercent) as a catalyst was added. The mixture was refluxed at 80°C for 24 hours, and the reaction was terminated. 500 ml of distilled water was put into a beaker, and the reaction mixture was poured therein, and extracted from 150 ml of dichloromethane three times. Then, 10 g of sodium sulfate was added, and stirred for 30 minutes using a rotary stirrer, and then the extracted mixture was filtered. The solvent was first removed using a rotary evaporator, and then the residue was purified by column chromatography using dichloromethane as a developing solvent to be separated by distillation under reduced pressure. The yield was 83percent. Further, an 1H-NMR of the prepared 2,4-difluoro phenyl pyridine is illustrated in the accompanying Fig. 3.
83% With potassium carbonate In tetrahydrofuran; water at 80℃; for 24 h; PREPARATIVE EXAMPLE 2Iridium(2-(4'-difluorophenyl-4-yl)pyridine) (2-(2-(phenylpyridine))2 ; In order to prepare 2,4-difluoro phenyl pyridine, 5.0 g of 2,4-difluorophenyl boronic acid (0.0285 mol), 3.0 g of 2-bromopyridine (0.019 mol), 150 ml of tetrahydrofuran, and a 2M potassium carbonate aqueous solution (20 ml) were added in a 250 ml double-necked, round-bottom flask under nitrogen atmosphere, and then palladium tetrakistriphenylphosphine(Pd(PPh3)4; 0.7 g, 3 mol percent) as a catalyst was added.The mixture was refluxed at 80° C. for 24 hours, and the reaction was terminated. 500 ml of distilled water was put into a beaker, and the reaction mixture was poured therein, and extracted from 150 ml of dichloromethane three times. Then, 10 g of sodium sulfate was added, and stirred for 30 minutes using a rotary stirrer, and then the extracted mixture was filtered. The solvent was first removed using a rotary evaporator, and then the residue was purified by column chromatography using dichloromethane as a developing solvent to be separated by distillation under reduced pressure. The yield was 83percent. Further, an 1H-NMR of the prepared 2,4-difluoro phenyl pyridine is illustrated in the accompanying FIG. 3.Next, 1 g of bromo iridium complex (0.0014 mol), 0.5 g of 2,4-difluoro phenyl boronic acid (0.0021 mol), 150 ml of tetrahydrofuran, and 2M potassium carbonate aqueous solution (20 ml) were added in a 250 ml double-necked, round-bottom flask under nitrogen atmosphere, and palladium tetrakistriphenylphosphine (Pd(PPh3)4; 0.07 g, 3 mol percent) as a catalyst was added. The mixture was refluxed at 80° C. for 24 hours, and the reaction was terminated500 ml of distilled water was put into a beaker, and the reaction mixture was poured therein, and extracted from 200 ml of dichloromethane three times. Then, 10 g of sodium sulfate was added, and stirred for 30 minutes using a rotary stirrer, and then the extracted mixture was filtered. The solvent was first removed using a rotary evaporator, and then the residue was purified by column chromatography using dichloromethane as a developing solvent to be separated by rotary evaporation. Finally, iridium(2-(4'-difluorophenyl-4-yl)pyridine) (2-(2-(phenylpyridine))2 was prepared as in Formula 3, and the yield was 86percent. Further, an 1H-NMR of the prepared iridium(2-(4'-difluorophenyl-4-yl)pyridine)(2-(2-(phenylpyridine)) is illustrated in the accompanying FIG. 4.
83.5% With potassium carbonate In tetrahydrofuran at 61℃; for 4 h; Inert atmosphere Step Two: Added 200 ml of THF, 24.76 g of 2,4-Difluoro Boric acid and 22 g of 2-Bromopyridine to 1 L of four-neck flask, the solution appeared light tawny. Then added 52 g of Potassium carbonate in the solution, and yellow turbidity appeared. Then the Nitrogen gas was introduced in for 15 minutes. Added 1 g of Tetraphenyl-Phosphine-Palladium to the solution and heated, then refluxed when warmed to 61° C. As heated for 4 hours, the solution turned brown. Then the cooling and separating process, water layer was extracted with 300 ML of Ethyl Acetate, and then followed with merging and distillation steps. Finally, 25 g of white solid products can be reached by column chromatography with petroleum ether as solvent. The yield rate reached 83.5percent.1HNMR (CDCl3, 400Hz): 6.89 (m, 1H), 7.1 (m, 1H), 7.28 (m, 1H), 7.75 (m, 2H), 8.00 (m, 1H), 8.71 (d, 1H).
76.18% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran at 65℃; for 24 h; 2-bromopyridine (4.17g, 26.39mmol), 2,4- difluorophenyl boronic acid (5.00g, 31.66mmol), phosphorus tetrakistriphenylphosphine palladium (0.91g, 0.79mmol) and sodium carbonate (6.36g, 60.00mmol ) was dissolved in 100mL of tetrahydrofuran, 65 for 24 hours, cooling, water and dichloromethane, the organic layer was concentrated by column chromatography to obtain primary ligand (3.84g, yield 76.18percent). The primary ligand (2.50g, 13.08mmol) and iridium chloride (2.30g, 6.23mmol) was dissolved in 15mL ethoxyethanol, the reaction mixture was 130 ° C 12h, then was added pyridine phosphate (2.72g, 12.46mmol) and sodium carbonate (3.30g, 31.15mmol), continue 130 reaction 24h. System cooling, water and dichloromethane, the organic layer was concentrated by column chromatography to obtain a yellow solid Ir1-001 (1.06g, yield: 21.5percent).
76.18% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran at 65℃; for 24 h; 2-bromopyridine (4.17g, 26.39mmol), 2,4- difluorophenyl boronic acid (5.00g, 31.66mmol), phosphorus tetrakistriphenylphosphine palladium (0.91g, 0.79mmol) and sodium carbonate (6.36g, 60.00mmol ) was dissolved in 100mL of tetrahydrofuran, 65 for 24 hours, cooling, water and dichloromethane, the organic layer was concentrated by column chromatography to obtain primary ligand (3.84g, yield 76.18percent).The primary ligand (2.50g, 13.08 mmol) and iridium chloride (2.30g, 6.23mmol) was dissolved in ethoxyethanol 15mL2-, the reaction mixture was 130 12h, phosphoric acid was then added pyridine (2.72g, 12.46mmol) and sodium carbonate (3.30g, 31.15mmol), continue 130 reaction 24h.System cooling, water and dichloromethane, the organic layer was concentrated by column chromatography to obtain a yellow solid BIr1-001 (1.06g, yield: 21.5percent).
76.18% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran for 24 h; Reflux The first host ligand in Example 1 was prepared as follows:2-Bromopyridine (4.17 g, 26.39 mmol),2,4-difluorobenzeneboronic acid (5.00 g, 31.66 mmol),Tetrakistriphenylphosphine palladium (0.91 g, 0.79 mmol) and sodium carbonate were added(6.36 g, 60.00 mmol) was dissolved in 100 mL of tetrahydrofuran,The reaction was refluxed for 24 hours,Cool, add water and methylene chloride,The organic layer was concentrated by column chromatography as the firstA primary ligand of an aromatic ring linked azetidin(3.84 g, yield 76.18percent).The aromatic rhizariazole (2.50 g, 13.08 mmol) as the first host ligand,And iridium trichloride (2.30 g, 6.23 mmol) were dissolved in 15 mL of ethoxyethanol,The mixture was refluxed for 12h,Iridium dimeric bridged complex was obtained.Then pyridine sulfonic acid (1.36 g, 6.23 mmol) and potassium carbonate (2.60 g, 18.70 mmol)To the above iridium dimeric bridged complex,At 120. Continue reflux 18h.Cooling system,Add water and methylene chloride,The organic phase was concentrated and subjected to column chromatography to obtain a iridium complex (1.01 g, yield: 21.5percent) as a yellow solid.
57.8% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; toluene for 24 h; Inert atmosphere; Reflux In a 100mL one-neck flask, were successively added 2-bromopyridine 5. 6g i.e. 25. 7mmol, 2, 4- difluorophenyl boronic acid 4. 5gI.e., 28. Ommol, i.e. sodium carbonate solution 20mL 2M, 20mL of toluene and 20mL of methanol and tetrakis (triphenylphosphine) palladium 0 · 80g i.e. 0. 7mmol, the reaction was heated to reflux under nitrogen for 24h. Cooling to room temperature, the reaction solution was poured into 100mL water and extracted three times each with 25mL of dichloromethane, the organic layers combined, dried over anhydrous magnesium sulfate overnight. Filtration, vacuum spin solvent, the crude product to 200-300 mesh silica gel as the stationary phase, the volume ratio of methylene chloride: petroleum ether 1: 1 mixture as an eluent to column chromatography to obtain 4.08g brown liquid a yield of 57.8percent

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  • 142
  • [ 288101-48-4 ]
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  • [ 391604-55-0 ]
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  • [ 109-04-6 ]
  • [ 221675-35-0 ]
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  • [ 198904-84-6 ]
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  • [ 73874-95-0 ]
  • [ 144465-94-1 ]
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  • [ 1054483-78-1 ]
  • [ 381233-78-9 ]
YieldReaction ConditionsOperation in experiment
70% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In water; acetonitrile at 75℃; Finally, several additional analogues designed to evaluate replacement of the pyridazine in 1 with phenyl and pyridyl moieties, were prepared using the methodology outlined in Scheme 3. Suzuki coupling of 2-bromopyridine (18) with various boronic acids afforded 19 and 20 (Ghiron et al, J. Med. Chem. 2010, 53, 4379). Treatment of 20 with P2S5 in pyridine at 120 °C provided 21 in 71percent yield. Alkylation of 21 with 2- methylbenzyl bromide in the presence of K2C03 in DMF generated 22. Scheme 3. Reagents and conditions: (a) Pd(PPh3)4, Na2C03, CH3CN/H20 (1/1), 75 °C, 4- benzylthiophenylboronic acid (54percent); (b) Pd(PPh3)4, Na2C03, CH3CN/H20 (1/1), 75 °C, 6-hydroxypyridine-3-boronic acid pinacol ester (70percent>); (c) P2S5, pyridine, 120 °C (71percent>); (d) 2-methylbenzyl bromide, K2C03, DMF (76percent).
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  • [ 163105-89-3 ]
  • [ 381233-78-9 ]
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  • 148
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  • [ 122368-54-1 ]
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  • 149
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  • [ 345310-98-7 ]
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  • 150
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  • [ 123-08-0 ]
  • [ 194017-69-1 ]
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  • 151
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  • [ 170230-27-0 ]
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  • [ 5720-07-0 ]
  • [ 168823-65-2 ]
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  • 153
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  • [ 1223063-81-7 ]
YieldReaction ConditionsOperation in experiment
27% With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; sodium carbonate In ethanol at 85℃; for 16 h; Inert atmosphere General procedure: A 10-mL Schlenk tube was charged with Pd(OAc)2 (1.7 mg, 0.0075 mmol, 3.0 mol percent), SPhos (6.2 mg, 0.015 mmol, 6.0 mol percent), Na2CO3 (53.0 mg, 0.50 mmol, 2.0 equiv), potassium 6-fluoropyridine-2-trifluoroborate (101.5 mg, 0.50 mmol, 2.0 equiv) and heteroaryl halides (0.25 mmol, 1.0 equiv), followed by the addition of ethanol (2.0 ml). The reaction was carried out at 85 °C for 16 h under the protection of nitrogen gas. Then, the reaction mixture was allowed to cool down to room temperature and the reaction solution was filtered through a thin pad of silica gel (eluting with ethyl acetate) and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to produce the desired products (ethyl acetate/hexane=1:2-1:80).
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