* 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.
Step 1: To 2-chloroquinoxaline (1.0 g, 6 mmol) was added ammonia in methanol (8 mL of a 2M solution). The reaction was sealed in a vial, heated to 80° C., and stirred for 12 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in methylene chloride and filtered. Hexane was added until a precipitate formed which was filtered and found to be the desired product (5percent yield).
Reference：
[1] Angewandte Chemie - International Edition, 2015, vol. 54, # 12, p. 3773 - 3777[2] Angew. Chem., 2015, vol. 127, # 12, p. 3844 - 3848,5
[3] Organic Letters, 2013, vol. 15, # 14, p. 3734 - 3737
[4] Tetrahedron, 2010, vol. 66, # 34, p. 6958 - 6964
[5] Patent: US2003/69284, 2003, A1,
[6] Journal of the Chemical Society, 1945, p. 622,625
[7] Patent: US2537870, 1946, ,
2
[ 1196-57-2 ]
[ 1448-87-9 ]
Yield
Reaction Conditions
Operation in experiment
93%
With trichlorophosphate In toluene for 1 h; Reflux
The chlorination of the 2-hydroxy quinoxaline was carried out in neat POCl3 (2.3 eqs) at reflux for an hour and produced the 2-chloro-quinoxaline (1D-008) in very good yield. This chemistry was tested on 100 g scale and afforded typically 103-105 g (98-99percent). A quick filtration through a Pad of silica of the crude reaction mixture resulted in clean material (99percent pure by LCMS). This reaction has beenscaled up to 600 g.
Reference：
[1] Patent: US2017/143706, 2017, A1, . Location in patent: Paragraph 0050; 0106; 0107
[2] Helvetica Chimica Acta, 2001, vol. 84, # 5, p. 1112 - 1118
[3] Heterocycles, 2005, vol. 65, # 1, p. 181 - 185
[4] Heterocycles, 2006, vol. 68, # 9, p. 1973 - 1979
[5] Journal of the Chemical Society, 1945, p. 622,625
[6] Journal of the Chemical Society, 1957, p. 3236,3237
[7] Bulletin de la Societe Chimique de France, 1959, p. 1793,1796
[8] Patent: US2537870, 1946, ,
[9] Heterocycles, 1985, vol. 23, # 10, p. 2603 - 2611
[10] Chemistry Letters, 1984, p. 323 - 326
[11] Heterocycles, 2012, vol. 86, # 2, p. 1583 - 1590
3
[ 1196-57-2 ]
[ 1448-87-9 ]
Yield
Reaction Conditions
Operation in experiment
81%
at 110℃; for 12 h; Inert atmosphere
The 2.000g2-hydroxy quinoxaline in 20mL phenylphosphonic dichloride, under nitrogen conditions, 110 ° C reflux 12h. The reaction was monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature, poured into ice water slowly with constant stirring. product After precipitation, filtration, washing, drying, you can get 1.830g2- chloro quinoxaline (intermediate II-1), a yield of 81percent.
75%
for 2 h; Reflux
Place 2-hydroxyquinoxaline (2 g) and phosphorus oxychloride (20 mL) in 100 mLIn a three-neck flask, add 5 drops of DMF, and transfer the system to reflux for 2h.In a 500 mL beaker, add an appropriate amount of ice water. White solids precipitated,Yield 75percent.
75%
for 2 h; Reflux
2-hydroxyquinoxaline (2 g) and phosphorus oxychloride (20 mL) were placed in 100 mL of threeStir in the bottle, add 5 drops of DMF, reflux for 2 h, transfer the system to a 500 mL beaker, and add an appropriate amount of ice water. Precipitating whiteSolid, yield 75percent
35%
at 79 - 100℃; for 0.25 h;
General procedure: 0.13 mL of N,N-dimethylformamide was added dropwise to a slurry monohydroxy quinoxaline 1d-e (0.5g, 3.1 mmol) and thionyl chloride (0.73 g, 6.2 mmol) in 1-chlorobutane(5 mL). The resulting reaction mixture was refluxed for 15min., and then evaporated to dryness under reduced pressure to leave a solid. The residue was taken up in a minimum of CH2Cl2, filtered and washed with CH2Cl2. Concentration then give the halogenated derivatives.
Reference：
[1] Molecules, 2012, vol. 17, # 4, p. 4533 - 4544
[2] ChemMedChem, 2015, vol. 10, # 1, p. 193 - 206
[3] Patent: CN103787992, 2016, B, . Location in patent: Paragraph 0079-0082
[4] Patent: CN107602539, 2018, A, . Location in patent: Paragraph 0043
[5] Patent: CN108530435, 2018, A, . Location in patent: Paragraph 0015; 0017
[6] Tetrahedron Letters, 1999, vol. 40, # 42, p. 7477 - 7478
[7] Synthetic Communications, 2005, vol. 35, # 15, p. 1983 - 1987
[8] Synthetic Communications, 2011, vol. 41, # 23, p. 3532 - 3540
[9] Chemistry - A European Journal, 2009, vol. 15, # 19, p. 4857 - 4864
[10] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4508 - 4522
[11] Revue Roumaine de Chimie, 2017, vol. 62, # 12, p. 903 - 906
[12] Journal of Physical Organic Chemistry, 1994, vol. 7, # 10, p. 545 - 550
[13] Journal of Organic Chemistry, 2003, vol. 68, # 5, p. 2054 - 2057
[14] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 24, p. 6723 - 6728
[15] Patent: US4076806, 1978, A,
[16] Medicinal Chemistry Research, 2013, vol. 22, # 4, p. 1660 - 1673
4
[ 6935-29-1 ]
[ 1448-87-9 ]
Yield
Reaction Conditions
Operation in experiment
63%
With N,N-dimethyl-formamide; trichlorophosphate In dichloromethane at 0 - 25℃; Inert atmosphere
General procedure: The procedure is identical to general procedure I, except that reactions were conducted at 0.2 M concentration with N-oxide (1.00 equiv), POBr3 (3.00 equiv), DMF (1.50 equiv) at rt. 4.2 General procedure I for the bromination of azine N-oxides (0013) To a stirred solution of the appropriate azine N-oxides in anhydrous CH2Cl2 (0.1 M) at 0 °C is added POBr3 (1.2 equiv) followed by dropwise addition of DMF (0.5 equiv) under argon. The resulting reaction mixture was warmed to 25 °C and stirred for several hours until the reaction is complete as indicated by TLC. Saturated aqueous sodium carbonate solution is added to the reaction mixture slowly to adjust the pH to 7–8. The resulting mixture is separated and the aqueous phase is extracted with CH2Cl2 thoroughly. The organic phase is combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product, which is purified by flash column chromatography using PE/EA (100:1) as eluent.
Reference：
[1] Tetrahedron, 2016, vol. 72, # 38, p. 5762 - 5768
[2] Journal of the Chemical Society, 1953, p. 2816,2819
Reference：
[1] Journal of Physical Organic Chemistry, 1994, vol. 7, # 10, p. 545 - 550
[2] Journal of the Chemical Society, 1945, p. 622,625
[3] Bulletin de la Societe Chimique de France, 1959, p. 1793,1796
[4] Patent: US2537870, 1946, ,
[5] Journal of the Chemical Society, 1957, p. 3236,3237
[6] Journal of the Chemical Society, 1945, p. 622,625
[7] Medicinal Chemistry Research, 2013, vol. 22, # 4, p. 1660 - 1673
7
[ 1196-57-2 ]
[ 1448-87-9 ]
[ 877078-00-7 ]
Reference：
[1] Phosphorus, Sulfur and Silicon and the Related Elements, 2005, vol. 180, # 8, p. 1795 - 1807
8
[ 51-17-2 ]
[ 67-66-3 ]
[ 1448-87-9 ]
[ 91-15-6 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1980, # 12, p. 4935 - 4953
9
[ 61645-34-9 ]
[ 1448-87-9 ]
[ 1196-57-2 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1983, p. 217 - 220[2] Khimiya Geterotsiklicheskikh Soedinenii, 1983, vol. 19, # 2, p. 265 - 267
With ammonia; In methanol; hexane; dichloromethane;
Step 1: To <strong>[1448-87-9]2-chloroquinoxaline</strong> (1.0 g, 6 mmol) was added ammonia in methanol (8 mL of a 2M solution). The reaction was sealed in a vial, heated to 80 C., and stirred for 12 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in methylene chloride and filtered. Hexane was added until a precipitate formed which was filtered and found to be the desired product (5% yield).
With hydrazine hydrate; In ethanol; at 20℃; for 48h;
In a 25 mL round bottom flask equipped with a magnetic stirrer, <strong>[1448-87-9]2-chloroquinoxaline</strong> (500 mg, 3.05 mmol) was dissolved in 10 mL of ethanol. Then an 80% hydrazine hydrate solution (0.5 mL, 8.20 mmol) was added, the reaction mixture was kept at room temperature and stirring for 48 hours. After this time, the total consumption of the raw material was evidenced by TLC and the reaction mixture evaporated under reduced pressure. The residue obtained was purified by column chromatography (eluent: chloroform / methanol 8: 2) affording 415 mg (2.57 mmol) of 1 as a shiny golden solid in 85% yield.
79%
With hydrazine hydrate; In ethanol; for 16h;Reflux;
15.0 g (91.1 mmol) of <strong>[1448-87-9]2-chloroquinoxaline</strong> are initially charged in 150 ml of ethanol. 45.6 g (911.3 mmol) of hydrazine hydrate are added, and the mixture is stirred under reflux for 16 h. The mixture is then cooled to 0 C., and the solid formed is filtered off, washed with ethanol and dried under high vacuum.Yield: 11.5 g (79% of theory)LC-MS (Method 1): Rt=1.75 min; MS (ESIpos): m/z=161 [M+H]+;1H-NMR (400 MHz, DMSO-d6): delta=8.70 (s, 1H), 8.35 (s, 1H), 7.78 (d, 1H), 7.60-7.50 (m, 2H), 7.37-7.28 (m, 1H), 4.50-4.38 (m, 2H).
78%
With hydrazine hydrate; In ethanol;Reflux;
General procedure: To 2-chloropyridine (1.1 mmol) in ethanol (5.0 mL) was added hydrazine hydrate (2 mL) dropwise at room temperature. The mixture was refluxed until completion as monitored by TLC. The reaction mixture was cooled, ethanol was removed by evaporation. Then, the residue was partitioned between ethyl acetate and water. The combined organic phase was dried over anhydrous sodium sulfate and concentrated to give the product, which was used for the following cyclization reaction without purification.
240 mg
With hydrazine hydrate; In ethanol; at 20 - 80℃; for 1h;Inert atmosphere;
Synthesis of 2-hydrazinylquinoxaline:In a 30-mL sealed tube, <strong>[1448-87-9]2-chloroquinoxaline</strong> (1.0 g) was dissolved in ethanol (8 mL) and hydrazine hydrate (8 mL) was added under nitrogen atmosphere at room temperature. The mixture was stirred and heated to reflux temperature (80 C) for 1 hr. The progress of the reaction was followed by TLC analysis using 10% MeOH:CH2Cl2 as mobile phase and visualization under UV light and/or with ninhydrin. The reaction mixture was concentrated under reduced pressure (40 C, 20 mmHg) to afford 240 mg of a white solid, which was used as such in the following step.
With trichlorophosphate; In toluene; for 1h;Reflux;
The chlorination of the 2-hydroxy quinoxaline was carried out in neat POCl3 (2.3 eqs) at reflux for an hour and produced the 2-chloro-quinoxaline (1D-008) in very good yield. This chemistry was tested on 100 g scale and afforded typically 103-105 g (98-99%). A quick filtration through a Pad of silica of the crude reaction mixture resulted in clean material (99% pure by LCMS). This reaction has beenscaled up to 600 g.
With N,N-dimethyl-formamide; trichlorophosphate; In dichloromethane; at 0 - 25℃;Inert atmosphere;
General procedure: The procedure is identical to general procedure I, except that reactions were conducted at 0.2 M concentration with N-oxide (1.00 equiv), POBr3 (3.00 equiv), DMF (1.50 equiv) at rt. 4.2 General procedure I for the bromination of azine N-oxides (0013) To a stirred solution of the appropriate azine N-oxides in anhydrous CH2Cl2 (0.1 M) at 0 C is added POBr3 (1.2 equiv) followed by dropwise addition of DMF (0.5 equiv) under argon. The resulting reaction mixture was warmed to 25 C and stirred for several hours until the reaction is complete as indicated by TLC. Saturated aqueous sodium carbonate solution is added to the reaction mixture slowly to adjust the pH to 7-8. The resulting mixture is separated and the aqueous phase is extracted with CH2Cl2 thoroughly. The organic phase is combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product, which is purified by flash column chromatography using PE/EA (100:1) as eluent.
With n-butyllithium; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; In tetrahydrofuran; at -78℃; for 0.5h;Inert atmosphere;
In a 1L three-necked flask, at -78 C under nitrogen,Add a solution of 2,2,6,6-tetramethylpiperidine (TEMPO, 20mL) in anhydrous tetrahydrofuran (200mL),To the mixed solution was added dropwise a solution of n-butyllithium (n-BuLi, 160 mmol) in tetrahydrofuran (80 mL),After reacting at 0 C for 20 minutes, the reaction solution was again placed at -78 C, and a solution of the starting material 1: <strong>[1448-87-9]2-chloroquinoxaline</strong> (16.5g, 100mmol) in tetrahydrofuran (100mL) was added dropwise, and the reaction was performed at low temperature for 30min.200 mL of concentrated hydrochloric acid and 300 mL of ethanol were added dropwise to the reaction solution, and stirred for 1 h.The reaction solution was extracted with dichloromethane and purified by column chromatography (a mixed solvent of petroleum ether PE and ethyl acetate EA).Intermediate 1: 3,3'-dichloro-2,2'-biquinoxaline (19.2 g, yield 59%) was obtained.
With benzoyl chloride In dichloromethane for 3h; Ambient temperature; different cyanides, reagents, catalyst, solvents, reaction times and temperatures;
With potassium cyanide; benzoyl chloride In chloroform; water for 0.5h; Ambient temperature; Yield given. Further byproducts given. Yields of byproduct given;
With P,P-dichlorophenylphosphine oxide; at 110℃; for 12h;Inert atmosphere;
The 2.000g2-hydroxy quinoxaline in 20mL phenylphosphonic dichloride, under nitrogen conditions, 110 C reflux 12h. The reaction was monitored by TLC. After completion of the reaction, the reaction solution was cooled to room temperature, poured into ice water slowly with constant stirring. product After precipitation, filtration, washing, drying, you can get 1.830g2- chloro quinoxaline (intermediate II-1), a yield of 81%.
75%
With N,N-dimethyl-formamide; trichlorophosphate; for 2h;Reflux;
Place 2-hydroxyquinoxaline (2 g) and phosphorus oxychloride (20 mL) in 100 mLIn a three-neck flask, add 5 drops of DMF, and transfer the system to reflux for 2h.In a 500 mL beaker, add an appropriate amount of ice water. White solids precipitated,Yield 75%.
75%
With N,N-dimethyl-formamide; trichlorophosphate; for 2h;Reflux;
2-hydroxyquinoxaline (2 g) and phosphorus oxychloride (20 mL) were placed in 100 mL of threeStir in the bottle, add 5 drops of DMF, reflux for 2 h, transfer the system to a 500 mL beaker, and add an appropriate amount of ice water. Precipitating whiteSolid, yield 75%
75%
With trichlorophosphate; In N,N-dimethyl-formamide; for 2h;Reflux;
2-Hydroxyquinoxaline (2 g) and phosphorus oxychloride (20 mL) were placed in a 100 ml three-necked flask and 5 drops of DMF were added.After refluxing for 2 hours, the system was transferred to a 500 ml beaker and precipitated by adding 200 ml of ice water.White solid,The yield was 75%.
75%
With trichlorophosphate; In N,N-dimethyl-formamide; for 2h;Reflux;
2-hydroxyquinoxaline (2g)Mix with phosphorus oxychloride (20 mL) in a 100 mL three-necked flask and add 5 drops of DMF.After refluxing for 2 h, the system was transferred to a 500 mL beaker and added to an appropriate amount of ice water.A white solid precipitated in a yield of 75%.
74%
With trichlorophosphate; In N,N-dimethyl-formamide; at 90℃; for 1h;
General procedure: In the water less condition, 2-hydroxyquinoxaline was dissolved in phosphorus oxychloride and DMF, stirred and refluxed at 90 C for 1 h until the completion of the reaction. Following this, it was poured into ice water, and filtered toobtain a white solid compound 2a, with yield 74%.
35%
With thionyl chloride; N,N-dimethyl-formamide; at 79 - 100℃; for 0.25h;
General procedure: 0.13 mL of N,N-dimethylformamide was added dropwise to a slurry monohydroxy quinoxaline 1d-e (0.5g, 3.1 mmol) and thionyl chloride (0.73 g, 6.2 mmol) in 1-chlorobutane(5 mL). The resulting reaction mixture was refluxed for 15min., and then evaporated to dryness under reduced pressure to leave a solid. The residue was taken up in a minimum of CH2Cl2, filtered and washed with CH2Cl2. Concentration then give the halogenated derivatives.
With 2,3-Dimethylaniline; trichlorophosphate; In Petroleum ether;
EXAMPLE 6 STR32 A mixture of 74 g (0.5 mole) of 2-hydroxy-benzopyrazine, 12 g of dimethylaniline and 250 ml of phosphorus oxychloride was heated under reflux for 10 minutes. At about 80 C, all the material had dissolved; the reaction solution was cooled and poured onto ice, and the product was filtered off. The residue was dried on clay and was then taken up in petroleum ether, and the solution was filtered through active charcoal. The reaction solution was evaporated and 78 g (87.5% of theory) of 2-chloro-benzopyrazine of melting point 48-49 C, were obtained. STR33
Example 5; 2-(4-Methylpiperazinyl)-quinoxaline (VUF10050); <strong>[1448-87-9]2-Chloroquinoxaline</strong> (309 mg) and N-methylpiperazine (2.0 mL) were added to a microwave tube and heated at 160 C. for 5 minutes. The resulting mixture was diluted with water and extracted with EtOAc. Drying over Na2SO4 and evaporation of the solvent yielded 452 mg (98%) of product. Mp 108.6-110.9 C.; 1H NMR (CDCl3): delta (ppm) 8.56 (s, 1H), 7.85 (dd, J=1.3 Hz, J=8.2 Hz, 1H), 7.66 (dd, J=1.3 Hz, J=8.4 Hz, 1H), 7.59-7.50 (m, 1H), 7.41-7.24 (m, 1H), 3.79 (t, J=5.1 Hz, 4H), 2.54 (t, J=5.1 Hz, 4H), 2.34 (s, 3H).
Stage #1: 2-chloroquinoxaline; pyridin-4-ylacetonitrile With sodium hexamethyldisilazane In tetrahydrofuran at 20℃; for 10h;
Stage #2: With sodium peroxide; ammonium acetate In tetrahydrofuran at 20℃; for 10h;
2-hydroxy-2-quinoxalin-2-yl-propionic acid <i>tert</i>-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
Stage #1: 2-chloroquinoxaline; tert-butyl propionate With sodium hexamethyldisilazane In toluene at 20℃; for 2h;
Stage #2: With oxygen In toluene at 20℃; for 12h;
Example 1; Synthesis of 4-[1-(3,5-Bis-trifluoromethylphenyl)-2-hydroxyethyl]-2-ethyl-3,4-dihydro-2H-quinoxaline-1-carboxylic acid ethyl ester (5); The synthesis of compound (5) according to Example 1 is illustrated in FIG. 1. Step A; 2-Ethyl-quinoxaline (1); To a flame dried, nitrogen purged 500 mL flask was added <strong>[1448-87-9]2-chloroquinoxaline</strong> (2.30 g, 14.0 mmol) and Fe(acac)3 (0.25 g, 0.70 mmol). The solids were diluted with THF (100 mL) and NMP (8 mL). A solution of EtMgBr (2.23 g, 16.8 mmol) was added dropwise over 10 minutes. The red solution turned dark brown. After 20 minutes, the reaction was diluted with ether (100 mL). The flask was cooled to 0 C. in an ice bath and 1N HCl (30 mL) was added cautiously. After 10 minutes of stirring, water (100 mL) was added and the layers separated. The ether layer was washed with brine (100 mL), dried over Na2SO4, and concentrated. The crude oil was purified by column chromatography, (Biotage 40m, 10% EtOAc/hexanes) to give 2-ethylquinoxaline (1) as a light yellow oil (1.50 g, 68%).
27
Reference example 27:; 2-Amino-2-methyl-N-(2-quinoxalinyl)propylamine[0231] To 2-chloroquinoxaline (3.27 g, 20.0 mmol) were added potassium carbonate (4.15 g, 30.0 mmol) and 1,2-diamino-2-methylpropane (3.14 mL, 30.0 mmol), and the mixture was refluxed at 120 DEG C for 63 hours. The reaction mixture was filtered using Celite as a filtration aid, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Chromatorex (registered trademark) NH, Fuji Silysia, hexane/chloroform=3/1) to obtain the title compound (2.77 g, 12.8 mmol).yield: 64%<1>H NMR (DMSO-d6) delta (ppm): 8.41 (1H, s), 7.72 (1H, d, J = 7.8 Hz), 7.51-7.48 (2H, m), 7.43 (1H, t, J = 5.4 Hz), 7.30-7.24 (1H, m), 3.31 (2H, d, J = 5.4 Hz), 2.90 (2H, br s), 1.07 (6H, s)APCIMS (m/z): 217 (M + H)
A Preparation of isopropyl N-(2-quinoxalinyl)-4-aminobenzoate
Example A Preparation of isopropyl N-(2-quinoxalinyl)-4-aminobenzoate 1 mmol of 2-chloroquinoxaline and 1.5 mmol of isopropyl 4-aminobenzoate are dissolved in 5 ml of n-propanol and refluxed at a temperature of 120° C. for 4 hours. The solid which precipitates during the reaction is, after cooling, separated off by filtration and recrystallized from ethyl acetate using activated carbon, giving 91% of the compound isopropyl N-(2-quinoxalinyl)-4-aminobenzoate as a yellowish powder.
Ethyl 2-[4-(2-quinoxalyloxy)phenoxy]propionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In acetonitrile;
PREPARATION 3 Ethyl 2-[4-(2-quinoxalyloxy)phenoxy]propionate (Compound No. 10) In 50 ml of acetonitrile, 2.1 g of <strong>[65343-67-1]ethyl 2-(4-hydroxyphenoxy)propionate</strong> and 1.66 g of potassium carbonate were added and the mixture was refluxed for 1 hour and then, 1.65 g of 2-chloroquinoxaline was added and the mixture was further refluxed for 30 hours. After cooling, the precipitated inorganic salt was separated by a filtration. Acetone was distilled off from the filtrate under a reduced pressure to obtain 3.5 g of the oily residue. The residue was purified by a silica gel column chromatography (developer solvent: chloroform) to obtain 2.6 g (yield 77%) of the object compound.
1 N,N'-Diethylcarbamimidothioic acid-(2-quinoxalinyl)ester, hydrochloride
EXAMPLE 1 N,N'-Diethylcarbamimidothioic acid-(2-quinoxalinyl)ester, hydrochloride 2-Chloroquinoxaline (3.29 g., 0.02 mole) in 50 ml. of methanol was added to 2.65 g. (0.02 mole) of N-N'-diethyl thiourea in 25 ml. of methanol. The solution was stirred at room temperature under nitrogen for 3/4 hour. The solvent was then evaporated and the residue was treated with ether which was again evaporated. The ether treatment was repeated several times. The residue was then covered with ether, treated with a little acetone and cooled. The solid which formed on standing was collected by filtration, washed, and dried. Recrystallization from methanol-ether gave 2.42 g. (40.7% yield) of product as a green solid, m.p. 91°-93° C. Analysis for: C13 H17 ClN4 S Calculated: C, 52.61; H, 5.77; N, 18.88; Cl, 11.94. Found: C, 52.24; H, 5.67; N, 18.91; Cl, 12.37.
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3h;
tert-Butyl 8-quinoxalin-2-yl-1.8-diazaspiro["4.5]decane-l-carboxylate (B-I); To a solution of 500 mg (2.08 mmol) A^ in 5 mL DMF was added 410 mg (2.5 mmol) 2-chloroquinoxoline and 575 mg (4.2 mmol) K2CO3. After heating the mixture for 3 h at 1000C, the reaction was cooled to room temperature, and dumped into a separatory funnel with EtOAc and water. The layers were separated, the aqueous was extracted with EtOAc, the combined organic extracts were washed with brine, dried over Na2SO^ and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel (EtOAc/hexanes) to provide B-I as a yellow solid. Data for B^ I: LCMS: rt = 2.34 min; m/z (M + H) = 369.1, found; 369.2 required.
Stage #1: 1-phenyl-1,1-bis(4-hydroxyphenyl)ethane With potassium carbonate In sulfolane; toluene at 20℃; for 0.75h;
Stage #2: 2-chloroquinoxaline at 80℃; for 48h; Further stages.;
trans-6-(3-fluorophenyl)-N-[4-hydroxypyrrolidin-3-yl]nicotinamide[ No CAS ]
trans-6-(3-fluorophenyl)-N-[4-hydroxy-1-quinoxalin-2-ylpyrrolidin-3-yl]nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With triethylamine; In water; butan-1-ol; at 90℃;
To a vial was added trans-6-(3-fluorophenyl)-N-[4-hydroxypyrrolidin-3-yl]nicotinamide (40 mg, 0.12 mmol <strong>[1448-87-9]2-chloroquinoxaline</strong> (29.2 mg, 0.18 mmol), n-butanol, water and triethylamine (0.3 mL of each). The reaction mixture was heated to 90 C. overnight and then cooled to room temperature and the solvent removed. The residue was taken up in DMSO and purified by RP-HPLC to give the desired product, trans-6-(3-fluorophenyl)-N-[4-hydroxy-1-quinoxalin-2-ylpyrrolidin-3-yl]nicotinamide (40 mg, 79%). HRMS (M+H) expected 430.1679, observed 430.1793
General procedure: Potassium carbonate (1.86g, 13.5mmol) was added to a solution of <strong>[6295-87-0]N-aminopyridinium iodide</strong> (1g, 4.5mmol) in acetonitrile (20mL) and the reaction mixture was vigorously stirred for 90minat room temperature to give a dark purple solution. To the reaction mixture was added a solution of the corresponding haloheterocycle (4.7mmol) in acetonitrile (5mL). The mixture was stirred and heated under reflux until all starting material had been consumed (detected by TLC). The inorganic salts were filtered off on Celite and the filtrate was evaporated in vacuo. The product was purified by chromatography on silica gel using ethanol as eluent.
Stage #1: 2-chloroquinoxaline; 2-thiopheneboronic acid MIDA ester With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate In 1,4-dioxane at 23℃; for 0.166667h; Inert atmosphere;
Stage #2: With potassium phosphate; water In 1,4-dioxane at 23 - 60℃; for 6.5h; Inert atmosphere;
Stage #1: 3,3,3',3'-tetramethyl-2,3,2',3'-tetrahydro-[1,1']spirobiindene-5,6,5',6'-tetraol With potassium carbonate In sulfolane; toluene at 20℃; for 0.75h; Inert atmosphere;
Stage #2: 2-chloroquinoxaline In sulfolane; toluene at 180℃; for 48h; Inert atmosphere;
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 80℃; for 24h;
General procedure: 2-Phenylquinoxaline (pqx) was prepared from a reaction of <strong>[1448-87-9]2-chloroquinoxaline</strong> and phenylboronic acid. <strong>[1448-87-9]2-Chloroquinoxaline</strong>(3.00 g, 18.2 mmol), phenylboronic acid (2.44 g,20.0 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.98 g, 0.85 mmol) were added to 50 mL of THF. After adding 5 mL of aqueous 4 M K2CO3, the reaction mixture was heated to 80 C for 24 h. The cooled crude mixture was poured into water, extracted with CH2Cl2 (50 mL × 3 times)and dried over anhydrous magnesium sulfate. Finally, silica column purification (n-hexane:EtOAc = 5:1) gave 3.15 g of a white solid in quantitative yield (84%).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 80℃; for 24h;
General procedure: 2-Phenylquinoxaline (pqx) was prepared from a reaction of <strong>[1448-87-9]2-chloroquinoxaline</strong> and phenylboronic acid. <strong>[1448-87-9]2-Chloroquinoxaline</strong>(3.00 g, 18.2 mmol), phenylboronic acid (2.44 g,20.0 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.98 g, 0.85 mmol) were added to 50 mL of THF. After adding 5 mL of aqueous 4 M K2CO3, the reaction mixture was heated to 80 C for 24 h. The cooled crude mixture was poured into water, extracted with CH2Cl2 (50 mL × 3 times)and dried over anhydrous magnesium sulfate. Finally, silica column purification (n-hexane:EtOAc = 5:1) gave 3.15 g of a white solid in quantitative yield (84%).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 80℃; for 24h;
General procedure: 2-Phenylquinoxaline (pqx) was prepared from a reaction of <strong>[1448-87-9]2-chloroquinoxaline</strong> and phenylboronic acid. <strong>[1448-87-9]2-Chloroquinoxaline</strong>(3.00 g, 18.2 mmol), phenylboronic acid (2.44 g,20.0 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.98 g, 0.85 mmol) were added to 50 mL of THF. After adding 5 mL of aqueous 4 M K2CO3, the reaction mixture was heated to 80 C for 24 h. The cooled crude mixture was poured into water, extracted with CH2Cl2 (50 mL × 3 times)and dried over anhydrous magnesium sulfate. Finally, silica column purification (n-hexane:EtOAc = 5:1) gave 3.15 g of a white solid in quantitative yield (84%).
With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 16h;
2.A
To a mixture of 3,8-diaza-bicyclo[4.2.0]octane-3- carboxylic acid tert-butyl ester (Intermediate 1 , 1 .07 g, 5.05 mmol) and 2- chloro-quinoxaline (1 .02 g, 6.06 mmol) in DMF (20.0 ml_) was added Cs2CO3 (3.95 g, 12.1 mmol). The reaction mixture was heated at 80 °C for 16 h then cooled to ambient temperature. The reaction mixture was partitioned between water (400 ml_) and ethyl acetate (50 ml_) twice. The organic layers were combined and washed with water. The organic layers were dried (Na2SO ), filtered and concentrated under reduced pressure to yield crude title compound (1 .84 g) which was used in the next step without purification.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 18h;Inert atmosphere;
To a stirred solution of 1 ,9-diazaspiro[5.5]undecan-2-one (TFA salt) (800 mg, 4.76 mmol) in 10 ml. DMF, <strong>[1448-87-9]2-chloroquinoxaline</strong> (937 mg, 5.71 mmol) and K2C03 (3.3 g, 23.8 mmol) were added and the reaction mixture was stirred for 18 h at 80C under a nitrogen atmosphere. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (2 x 50 ml_), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (eluent: 3% methanol in chloroform) to yield the title compound (1.0 g, 71%). [LCMS RtF = 0.37 min, [M+H]+ = 297.2]
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 18h;
To the stirred solution of 2,9-diazaspiro[5.5]undecan-1-one hydrochloride (2.2 g, 10.78 mmol) in DMF (15 mL) was added K2C03 (4.45 g, 32.24 mmol) and 2-chloro quinoxaline (1.94 g, 1 1.82 mmol). The mixture was heated at 60 C for 18 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. To the crude mixture water was added and extracted with ethyl acetate. The organic layer was dried over anhydride sodium sulfate, filtered and concentrated to obtain a yellow solid which was triturated with n-pentane to yield a yellow solid (2.5 g, 78 %). [1H-NMR (DMSO-d6, 300 MHz): delta 8.91 (s, 1H), 7.81 (d, 1 H), 7.62-7.55 (m, 2H), 7.42-7.33 (m, 2H), 4.33-4.19 (m, 2H), 3.52-3.33 (m, 2H), 3.20-3.05 (m, 2H), 2.12-1.98 (m, 2H), 1.95-1.64 (m, 4H), 1.59-1.48 (m, 2H); HPLC RtA = 3.665 min (97 %); LCMS RtA = 0.377, [M+H]+ = 297.1].
With dmap; N-ethyl-N,N-diisopropylamine; In ethanol; at 160℃; for 2h;microwave sealed tube;
The mixture of 2,9-diazaspiro[5.5]undecan-1-one TFA salt ([1190586-22-1], 1.0 g, 3.5 mmol), <strong>[1448-87-9]2-chloroquinoxaline</strong> ([1448-87-9], 0.77 g, 4.6 mmol), DIPEA (3.7 ml, 21 mmol) and DMAP (22 mg, 0.18 mmol) in ethanol (10 ml) was placed in a microwave tube. The tube was sealed and the suspension was heated at 160C for 2 h under microwave conditions. The mixture was filtered and the residue washed with ethanol. The filtrate was concentrated and the precipitate filtered and washed with ethanol. The combined solid material was dissolved in ethyl acetate, washed with water and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 0.81 g (77%) of the title compound as a pale yellow solid which was not further purified. [1 H NMR (400 MHz, DMSO-af6) USD ppm 8.79 (s, 1 H), 7.78 (d, J=7.8 Hz, 1 H), 7.53 - 7.58 (m, 2 H), 7.31 - 7.39 (m, 2 H), 4.22 (dt, J=13.5, 4.4 Hz, 2 H), 3.37 - 3.49 (m, 2 H), 3.06 - 3.15 (m, 2 H), 1.91 - 2.05 (m, 2 H), 1.75 - 1.83 (m, 2 H), 1.65 - 1.75 (m, 2 H), 1.44 - 1.55 (m, 2 H); LCMS RtB = 2.80 min, [M+Hf = 297.2].
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4h;
The mixture of <strong>[1448-87-9]2-chloroquinoxaline</strong> 5.00 g (30.4 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (6.10 g, 42.6 mmol), and K2CO3 (8.40 g, 60.8 mmol) in DMF was stirred for 4 h at 100 C. The reaction mixture was diluted with water, extracted with EtOAc twice, the combined organic layer was washed with brine, dried with MgSO4, filtered, the filtrate was evaporated, and then the crude was crystallized from EtOAc-hexane to give a compound 5 as pale yellow crystals (7.2 g, 87%).
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; lithium hydroxide; In 1,4-dioxane; water; at 80℃; for 0.5h;Inert atmosphere;
General procedure: To a solution of 2-chloroheteroaryl compound 1 (0.50 mmol) in 1,4-dioxane (4.0 mL) were added pinacol boronate 3, 5, or 7 (0.60 mmol), Pd(OAc)2 (1.1 mg, 5.0 mumol), S-Phos (4.1 mg, 10.0 mumol), and 2 M LiOH solution (1.0 mL, 2.0 mmol) at room temperature, and the mixture was stirred for 30 min at 80 C under N2 atmosphere. The reaction was quenched by adding water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by silica-gel column chromatography. The solvent was removed in vacuo, and the residue was triturated with Et2O to give biaryl compounds.
3-isopropyl-4-quinoxalin-2-ylpiperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With cesium fluoride; In dimethyl sulfoxide; at 60℃; for 30h;
To a solution of <strong>[502649-32-3]tert-butyl 3-isopropylpiperazine-1-carboxylate</strong> (830 mg, 3.6 mmol) and 2-chloroquinaxaline (600 mg, 3.6 mmol) in dimethyl sulfoxide (5 mL), cesium fluoride (550 mg, 3.6mmol) was added. The reaction mixture was stirred at 60 oc for 30 hours, and then the reactionmixture was poured into water (70 mL) and extracted with diethyl ether (2x20 mL). The crudeproduct was purified by silica gel column chromatography eluting with mixture hexane:ethyl acetate10 (4:1) to afford 600 mg, 46% of the titled compound as a light-yellow solid. 1H NMR (300 MHz,15DMSO-d6) o ppm 0.84-0.90 (m, 3H), 1.16-1.25 (m, 3H), 1.50 (s, 9H), 2.20-2.30 (m, 1H), 3.00-3.12(m, 2H), 3.20-3.28 (m, 1H), 4.17-4.23 (m, 1H), 4.30-4.36 (m, 1H), 4.55-4.65 (m, 1H), 7.55-7.62 (m,1H), 7.72-7.78 (m, 1H), 7.85-7.90 (m, 1H), 8.15-7.23 (m, 1H), 8.58 (s, 1H).
With sodium tetrahydroborate; N,N,N,N,-tetramethylethylenediamine; palladium diacetate; triphenylphosphine; In tetrahydrofuran; at 25℃; for 1h;Inert atmosphere;
General procedure: Pd(OAc)2-PPh3, Pd2(dba)3-tbpf, Pd2(dba)3-DavePhos Pd2(dba)3-P(t-Bu)3 Pd2(dba)3-XantPhos and Pd(OAc)2-XPhos. Anhydrous THF (13.2 mL) was degassed by bubbling argon for few minutes, then Pd(OAc)2 (7.2 mg, 0.033 mmol, 5 mol%) and PPh3 (17.7 mg, 1.132 mmol, 20 mol%) were added and the resulting mixture stirred at room temperature for 30 min. The halogenated heterocycle (0.66 mmol), TMEDA (0.130 g, 1.12 mmol, 1.7 equiv) and finally NaBH4 (42.4 mg, 1.12 mmol, 1.7 equiv) were introduced in sequence. The mixture was stirred at room temperature or heated at 65 C under argon for the proper time. The residue was taken up in brine and extracted with ethyl acetate. The organic phase was separated, dried, the solvent was evaporated and the residue was purified by flash chromatography (mixtures of petroleum ether and ethyl acetate) to give pure hydrodehalogenated heterocycles
With triethylamine; In N,N-dimethyl-formamide; at 100℃;
General procedure: Triethylamine (4.5 g, 41.0 mmol), 2-chloroquinoline 49 (3.35 g,20.5 mmol) and azetidin-3-ol (1.5 g, 20.5 mmol) were dissolvedin DMF (50 mL) and the resulting mixture was heated to 100 Covernight. The mixture was diluted with water (100 mL) andextracted with EtOAc (2 70 mL). The combined organic extractswere combined and washed with water (50 mL) and brine(50 mL), dried over Na2SO4, and filtered. The filtrate was evaporatedin vacuo and the residue was purified by flash column chromatographyeluting with 20-70% EtOAc/petroleum ether to give3.20 g (78%) of the title compound as a white solid.
tert-butyl {2-[(5-[(5-amino-3-methyl-1,2-thiazol-4-yl)carbonyl]amino}pyridin-2-yl)amino]ethyl}methylcarbamate[ No CAS ]
tert-butyl methyl(2-[5-([3-methyl-5-(quinoxalin-2-ylamino)-1,2-thiazol-4-yl]carbonyl}amino)pyridin-2-yl]amino}ethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; N,N-dimethyl-formamide; at 110℃;Inert atmosphere; Sealed tube;
A mixture of tert-butyl. f2-[(5-f[(5-amino-3-methy[-1,2-thiazo[-4- y[)carbony[]aminolpyridin-2-y[)amino]ethy[lmethy[carbamate [Intermediate 89] (214 mg, 0.53 mmo[, 1.2 eq), <strong>[1448-87-9]2-chioroquinoxaline</strong> (CAS-RN: 1448-87-9) (72 mg, 0.44 mmo[, 1.0 eq) and cesium carbonate (329 mg, 1 mmo[, 2.3 eq) in 4.5 mL dioxane/DMF (5/1) was placed in a microwave vial that was flushed with argon.Then, palladium(II) acetate (10 mg, 0.04 mmol, 0.1 eq) and Xantphos (25 mg, 0.04 mmol, 0.1 eq) were added. Afterwards, the vial was sealed and the reaction mixture was stirred at an environmental temperature of 110 C overnight. The volatile components of the reaction mixture were removed in vacuo. The final purification of this material was achieved via preparative MPLC (Biotage Isolera: 11g NH cartridge, dichloromethane/methanol) to give 187 mg (80% yield of theory) of the title compound.UPLC-MS (Method 2): Rt = 0.88 mm; MS (EI0): m/z = 535 [M+H].1H-NMR (400 MHz, CHLOROFORM-d) delta [ppm]: 1.487 (16.00), 1.701 (0.50), 2.853 (3.91), 2.922 (3.40), 3.514 (1.29), 5.307 (2.07), 7.550 (0.61), 7.614 (0.52), 7.735 (0.47), 7.739 (0.44), 7.757 (0.60), 8.029 (0.64), 8.032 (0.57), 8.050 (1.27), 8.069 (0.62), 8.163 (0.68), 8.170 (0.66), 8.677 (1.40), 12.138 (0.51).
tert-butyl 3-[(5-amino-3-methyl-1,2-thiazol-4-yl)carbonyl]amino}benzoate[ No CAS ]
tert-butyl 3-([3-methyl-5-(quinoxalin-2-ylamino)-1,2-thiazol-4-yl]carbonyl}amino)-benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; N,N-dimethyl-formamide; at 110℃;Inert atmosphere;
A mixture of tert-butyl. 3-f[(5-amino-3-methy[- 1 ,2-thiazo[-4-y[)carbony[]aminol-benzoate [Intermediate 21] (107 mg, 0.32 mmo[, 1.2 eq), <strong>[1448-87-9]2-chioroquinoxaline</strong>(CAS-RN: 1448-87-9) (44 mg, 0.27 mmo[, 1.0 eq) and cesium carbonate (200 mg,0.62 mmo[, 2.3 eq) in 2.7 mL dioxane/DMF (5/1) was placed in a round bottomflusk that was flushed with argon. Then, palladium(II) acetate (6 mg, 0.027 mmol,0.1 eq) and Xantphos (15.5 mg, 0.027 mmol, 0.1 eq) were added. Afterwards, the reaction mixture was stirred at an environmental temperature of 110 C overnight. The volatile components of the reaction mixture were removed in vacuo. Final purification purification of this crude material was achieved via preparative HPLC(Method 1) to give 72 mg (58 % yield of theory) of the title compound.UPLC-MS (Method 1): Rt = 1.50 mm; MS (EI0): m/z = 462 [M+H].1H NMR (300 MHz, DMSO-d6) oe [ppm] = 1.55 (5, 9 H), 7.49 (t, 1 H), 7.65 (d, 2 H),7.77 (d, 1 H), 7.93 - 8.05 (m, 2 H), 8.41 (5, 1 H), 9.02 (5, 1 H), 10.49 (5 br, 1 H),11.35 (5 br, 1 H), 1xCH3 obscured by solvent signal.In a larger batch a mixture of tert-butyl 3-f[(5-amino-3-methyl-1,2-thiazol-4- yl)carbonyl]aminobenzoate [Intermediate 21] (9.3 g, 27.9 mmol, 1.2 eq), 2- chloroquinoxaline (CAS-RN: 1448-87-9) (3.8 g, 23.2 mmol, 1.0 eq) and cesiumcarbonate (17.4 g, 53.5 mmol, 2.3 eq) in 235 mL dioxane/DMF (5/1) was placed in a round bottom flusk that was flushed with argon. Then, palladium(II) acetate (522 mg, 2.3 mmo[, 0.1 eq) and Xantphos (1.3 g, 2.3 mmo[, 0.1 eq) were added. Afterwards, the reaction mixture was stirred at an environmental, temperature of 110 C overnight. The volatile components of the reaction mixture were removed in vacuo. Final purification purification of this crude material was achieved viapreparative MPLC (Biotage Isolera) dichloromethane/ethanol gradient) to give 9.4 g (88 % yield of theory) of the title compound.
With niobium pentachloride; In tetrahydrofuran; at 0 - 40℃; for 3h;Inert atmosphere;
<strong>[1448-87-9]2-Chloroquinoxaline</strong> (1) (170 mg, 1 mmol) and 15 mol%of NbCl5 were taken into a 50 mL round-bottomed flaskcontaining 10 mL of THF and then trimethyl phosphite (2a)(0.15 mL, 1.2 mmol) was added dropwise at 0 C under inert(under N2 atmosphere) conditions. Further, the temperaturewas raised slowly to 40 C and stirred for 3.0 h. The progressof the reaction was monitored by TLC using n-hexane:ethylacetate (7:3) as mobile phase. After completion of the reaction,the reaction mixture was quenched with water and extractedwith ethyl acetate. The combined organic layer waswashed with saturated brine solution (5 mL) and dried withanhydrous Na2SO4. The organic layer was concentrated underreduced pressure. The crude product was purified bycolumn chromatography using n-hexane:ethyl acetate (4:1)as an eluent to afford pure dimethyl quinoxalin-2-ylphosphonate (3a). The same procedure was followed forthe synthesis of remaining title compounds 3b-e.
With niobium pentachloride; In tetrahydrofuran; at 0 - 40℃; for 3h;Inert atmosphere;
General procedure: <strong>[1448-87-9]2-Chloroquinoxaline</strong> (1) (170 mg, 1 mmol) and 15 mol%of NbCl5 were taken into a 50 mL round-bottomed flaskcontaining 10 mL of THF and then trimethyl phosphite (2a)(0.15 mL, 1.2 mmol) was added dropwise at 0 C under inert(under N2 atmosphere) conditions. Further, the temperaturewas raised slowly to 40 C and stirred for 3.0 h. The progressof the reaction was monitored by TLC using n-hexane:ethylacetate (7:3) as mobile phase. After completion of the reaction,the reaction mixture was quenched with water and extractedwith ethyl acetate. The combined organic layer waswashed with saturated brine solution (5 mL) and dried withanhydrous Na2SO4. The organic layer was concentrated underreduced pressure. The crude product was purified bycolumn chromatography using n-hexane:ethyl acetate (4:1)as an eluent to afford pure dimethyl quinoxalin-2-ylphosphonate (3a). The same procedure was followed forthe synthesis of remaining title compounds 3b-e.
With niobium pentachloride; In tetrahydrofuran; at 0 - 40℃; for 3h;Inert atmosphere;
General procedure: <strong>[1448-87-9]2-Chloroquinoxaline</strong> (1) (170 mg, 1 mmol) and 15 mol%of NbCl5 were taken into a 50 mL round-bottomed flaskcontaining 10 mL of THF and then trimethyl phosphite (2a)(0.15 mL, 1.2 mmol) was added dropwise at 0 C under inert(under N2 atmosphere) conditions. Further, the temperaturewas raised slowly to 40 C and stirred for 3.0 h. The progressof the reaction was monitored by TLC using n-hexane:ethylacetate (7:3) as mobile phase. After completion of the reaction,the reaction mixture was quenched with water and extractedwith ethyl acetate. The combined organic layer waswashed with saturated brine solution (5 mL) and dried withanhydrous Na2SO4. The organic layer was concentrated underreduced pressure. The crude product was purified bycolumn chromatography using n-hexane:ethyl acetate (4:1)as an eluent to afford pure dimethyl quinoxalin-2-ylphosphonate (3a). The same procedure was followed forthe synthesis of remaining title compounds 3b-e.
With niobium pentachloride; In tetrahydrofuran; at 0 - 40℃; for 3h;Inert atmosphere;
General procedure: <strong>[1448-87-9]2-Chloroquinoxaline</strong> (1) (170 mg, 1 mmol) and 15 mol%of NbCl5 were taken into a 50 mL round-bottomed flaskcontaining 10 mL of THF and then trimethyl phosphite (2a)(0.15 mL, 1.2 mmol) was added dropwise at 0 C under inert(under N2 atmosphere) conditions. Further, the temperaturewas raised slowly to 40 C and stirred for 3.0 h. The progressof the reaction was monitored by TLC using n-hexane:ethylacetate (7:3) as mobile phase. After completion of the reaction,the reaction mixture was quenched with water and extractedwith ethyl acetate. The combined organic layer waswashed with saturated brine solution (5 mL) and dried withanhydrous Na2SO4. The organic layer was concentrated underreduced pressure. The crude product was purified bycolumn chromatography using n-hexane:ethyl acetate (4:1)as an eluent to afford pure dimethyl quinoxalin-2-ylphosphonate (3a). The same procedure was followed forthe synthesis of remaining title compounds 3b-e.
methyl phenyl(quinoxalin-2-yl)phosphinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With niobium pentachloride; In tetrahydrofuran; at 0 - 40℃; for 3h;Inert atmosphere;
General procedure: <strong>[1448-87-9]2-Chloroquinoxaline</strong> (1) (170 mg, 1 mmol) and 15 mol%of NbCl5 were taken into a 50 mL round-bottomed flaskcontaining 10 mL of THF and then trimethyl phosphite (2a)(0.15 mL, 1.2 mmol) was added dropwise at 0 C under inert(under N2 atmosphere) conditions. Further, the temperaturewas raised slowly to 40 C and stirred for 3.0 h. The progressof the reaction was monitored by TLC using n-hexane:ethylacetate (7:3) as mobile phase. After completion of the reaction,the reaction mixture was quenched with water and extractedwith ethyl acetate. The combined organic layer waswashed with saturated brine solution (5 mL) and dried withanhydrous Na2SO4. The organic layer was concentrated underreduced pressure. The crude product was purified bycolumn chromatography using n-hexane:ethyl acetate (4:1)as an eluent to afford pure dimethyl quinoxalin-2-ylphosphonate (3a). The same procedure was followed forthe synthesis of remaining title compounds 3b-e.
N-[2-(1-adamantyloxy)ethyl]quinoxalin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 24h;Inert atmosphere;
General procedure: A corresponding chloro-substitutedeteroarene (0.2-0.5 mmol), finely powdered K2CO3 (173 mg,1.25 mmol), DMF (1 mL), and a corresponding adamantane-containing amine (0.2-0.5 mmol) were placed into a one-neckflask equipped with a magnetic stirrer and reflux condenser and filled with dry argon, and the reaction mixture was stirred for 24 h at 140 C. When the reaction was carried out with diamines 13 and 14 (0.5 mmol), 2,6-dichloropyrazine (186 mg, 1.25 mmol) and K2CO3 (345 mg, 2.5 mmol) were used. On the reaction completion, the mixture was cooled to room temperature, dichloromethane (5 mL) was added, a precipitate was filtered off and additionally washed with dichloromethane (5 mL), the commbined organic fractions were concentrated in vacuo, the residues were analyzed by NMR spectroscopy. If necessary, the products were purified by chromatography on silica gel, using the followwing sequence of eluents: light petroleum ether-CH2Cl2 (4 : 1 ?1 : 4), CH2Cl2, CH2Cl2-MeOH (500 : 1 ? 3 : 1). The target products were obtained as faintly colored or colorless dense oils or crystalline powders. The spectral data of compound 15 arer eported in the work.20
With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 24h;Inert atmosphere;
General procedure: A corresponding chloro-substitutedeteroarene (0.2-0.5 mmol), finely powdered K2CO3 (173 mg,1.25 mmol), DMF (1 mL), and a corresponding adamantane-containing amine (0.2-0.5 mmol) were placed into a one-neckflask equipped with a magnetic stirrer and reflux condenser and filled with dry argon, and the reaction mixture was stirred for 24 h at 140 C. When the reaction was carried out with diamines 13 and 14 (0.5 mmol), 2,6-dichloropyrazine (186 mg, 1.25 mmol) and K2CO3 (345 mg, 2.5 mmol) were used. On the reaction completion, the mixture was cooled to room temperature, dichloromethane (5 mL) was added, a precipitate was filtered off and additionally washed with dichloromethane (5 mL), the commbined organic fractions were concentrated in vacuo, the residues were analyzed by NMR spectroscopy. If necessary, the products were purified by chromatography on silica gel, using the followwing sequence of eluents: light petroleum ether-CH2Cl2 (4 : 1 ?1 : 4), CH2Cl2, CH2Cl2-MeOH (500 : 1 ? 3 : 1). The target products were obtained as faintly colored or colorless dense oils or crystalline powders. The spectral data of compound 15 arer eported in the work.20
With dmap; 1,1'-bis-(diphenylphosphino)ferrocene; nickel(II) chloride hexahydrate; zinc; In acetonitrile; at 80℃; for 6h;Inert atmosphere; Sealed tube;
General procedure: Under argon protection, NiCl2·6H2O (0.05mmo 1,11.9mg), dppf (0.06mmol, 33.3mg), Zetan (0·2mmol, 13.0mg), DMAP (1.0mmol, 122.2mg), Zetan(CN)2 (0.8mmol) , 93.9mg),p-Chloroanisole (1.0 mmol, 140.6 mg) and acetonitrile (5.0 mL) were sequentially added in a 25.0 mL sealed tube, then directly put it into the oil bath at 60 C, and heating was stopped after 6h, and cooled to room temperature, the reaction solution was directly filtered through a short silica gel column, washed with dichloromethane, concentrated and purified by silica gel column chromatography( given that the product is most easily pulled out, in order to avoid loss of sample mix, unless otherwise noted, both are wet method). Eluent: petroleum ether / ethyl acetate = 20:1, the product was 117.2 mg as a white solid, yield 88%, and 1H NMR purity was greater than 98%.
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 160℃; for 0.5h;Microwave irradiation;
General procedure: A mixture of the corresponding bromo-substituted 1,4-diazine (1.0mmol), arylboronic derivative (2 or 4) (1.2mmol), Pd(PPh3)4 (58mg, 5mol %) and K3PO4 (530mg, 2.5mmol) was dissolved in 1,4-dioxane 15mL. The reaction mixture was degassed and irradiated in a microwave apparatus at 160 C (250 W) for 30min. The reaction mixture was cooled, filtered, and dissolved in a mixture of EtOAc and water (1:1, 50mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×25mL). The combined organic extracts were dried with MgSO4 and the solvents evaporated. Purification by silica gel column chromatography with EtOAc/hexane (1:4, v/v) as an eluent to afford the desired cross-coupling products.
78%
With potassium phosphate; (DPEPhos)Ni(mesityl)Br; water; In 1,4-dioxane; benzene; at 25℃; for 16h;Inert atmosphere; Sealed tube;
General procedure: Unless otherwise specified, under an inert atmosphere C1 (12.7mg, 0.016 mmol, 2 mol %), aryl halide (0.8 mmol), boronic acid(1.6 mmol), and K3PO4 (679 mg, 3.2 mmol) were added to anoven-dried 4 dram vial containing a magnetic stir bar. 1,4-Dioxane (1.3 mL) and benzene (700 muL) were added, the vial wassealed with a screwcap featuring a PTFE/silicone septum andwas removed from the glovebox. Degassed water (86 muL) wasadded via a gas-tight syringe. The reaction mixture was magneticallystirred for 16 h at room temperature. Note: On severaloccasions the base became clumpy and stuck to the bottom ofthe reaction vial; in these cases it was noted that reactions weremore successful if efficient stirring was maintained. After 16 h,the reaction mixture was taken up in EtOAc (ca. 10 mL) andextracted with distilled water (3 × 10 mL). The organic layer wasdried over anhydrous Na2SO4, filtered, and concentrated withthe aid of a rotary evaporator.
N‐[(3‐aminophenyl)methyl]quinoxalin‐2‐amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; at 120℃; for 6h;
2 mmol of 2-chloro-quinoxaline (purchase),2.2 mmol of 3-aminobenzylamine and 2.4 mmol of triethylamine were added to the isopropanol solution,The mixture was refluxed at 120°C for 6h.After the reaction is completed, flash silica gel column chromatography (petroleum ether:ethyl acetate=2:1),Purified N-(3-aminobenzyl)-2-amine-quinoxaline;
Stage #1: 2-chloroquinoxaline With (1,3,5-triaza-7-phosphaadamantan-1-ium-1-yl)butane-1-sulfonate; palladium diacetate In N,N-dimethyl-formamide for 0.0833333h; Schlenk technique; Inert atmosphere;
Stage #2: 6-hydroxycoumarin With potassium phosphate In N,N-dimethyl-formamide at 60℃; for 2h; Schlenk technique; Inert atmosphere;
(E)‑1‑[4‑[(quinoxalin‑2‑yl)oxy]phenyl]‑3‑(p‑tolyl)prop‑2‑en‑1‑one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With potassium carbonate; In acetonitrile; at 85℃; for 12.5h;
General procedure: Based on the reported method [26, 27], potassium carbonateas a base, acetonitrile as a solvent and intermediates 1a and 2a as the starting materials were mixed and stirred for 30 min, and refluxed at 85 C for 12 h. After the completion of the reaction, the whole reaction system was diluted with water and the resulting precipitate appeared in the continuous stirring; the mixture was separated to obtain compound 3a, with yield 72%. By following the same procedure, the title compounds 3b-3x were then obtained.
3-(furan-1-yl)-1-(4-hydroxyphenyl)-prop-2-en-1-one[ No CAS ]
(E)‑3‑(furan‑2‑yl)‑1‑[4‑(quinoxalin‑2‑yloxy)phenyl]prop‑2‑en‑1‑one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With potassium carbonate; In acetonitrile; at 85℃; for 12.5h;
General procedure: Based on the reported method [26, 27], potassium carbonateas a base, acetonitrile as a solvent and intermediates 1a and 2a as the starting materials were mixed and stirred for 30 min, and refluxed at 85 C for 12 h. After the completion of the reaction, the whole reaction system was diluted with water and the resulting precipitate appeared in the continuous stirring; the mixture was separated to obtain compound 3a, with yield 72%. By following the same procedure, the title compounds 3b-3x were then obtained.
(E)‑3‑(3‑bromophenyl)‑1‑[4‑(quinoxalin‑2‑yloxy)phenyl]prop‑2‑en‑1‑one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With potassium carbonate; In acetonitrile; at 85℃; for 12.5h;
General procedure: Based on the reported method [26, 27], potassium carbonateas a base, acetonitrile as a solvent and intermediates 1a and 2a as the starting materials were mixed and stirred for 30 min, and refluxed at 85 C for 12 h. After the completion of the reaction, the whole reaction system was diluted with water and the resulting precipitate appeared in the continuous stirring; the mixture was separated to obtain compound 3a, with yield 72%. By following the same procedure, the title compounds 3b-3x were then obtained.
(E)‑3‑(2‑bromophenyl)‑1‑[4‑(quinoxalin‑2‑yloxy)phenyl]prop‑2‑en‑1‑one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With potassium carbonate; In acetonitrile; at 85℃; for 12.5h;
General procedure: Based on the reported method [26, 27], potassium carbonateas a base, acetonitrile as a solvent and intermediates 1a and 2a as the starting materials were mixed and stirred for 30 min, and refluxed at 85 C for 12 h. After the completion of the reaction, the whole reaction system was diluted with water and the resulting precipitate appeared in the continuous stirring; the mixture was separated to obtain compound 3a, with yield 72%. By following the same procedure, the title compounds 3b-3x were then obtained.
Stage #1: 2-chloroquinoxaline With (1,3,5-triaza-7-phosphaadamantan-1-ium-1-yl)butane-1-sulfonate; palladium diacetate In N,N-dimethyl-formamide for 0.0833333h; Schlenk technique; Inert atmosphere;
Stage #2: 1-Adamantanethiol With potassium phosphate In N,N-dimethyl-formamide at 50℃; for 2h; Schlenk technique; Inert atmosphere;
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 160℃; for 0.5h;Microwave irradiation;
General procedure: A mixture of the corresponding bromo-substituted 1,4-diazine (1.0mmol), arylboronic derivative (2 or 4) (1.2mmol), Pd(PPh3)4 (58mg, 5mol %) and K3PO4 (530mg, 2.5mmol) was dissolved in 1,4-dioxane 15mL. The reaction mixture was degassed and irradiated in a microwave apparatus at 160 C (250 W) for 30min. The reaction mixture was cooled, filtered, and dissolved in a mixture of EtOAc and water (1:1, 50mL), and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×25mL). The combined organic extracts were dried with MgSO4 and the solvents evaporated. Purification by silica gel column chromatography with EtOAc/hexane (1:4, v/v) as an eluent to afford the desired cross-coupling products.
4-[2-(3-chloroquinoxalin)yl]-10-undecen-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60.4%
With sodium persulfate; sulfuric acid; silver trifluoroacetate In water; butanone at 50℃; for 24h; Inert atmosphere;
7
Add compound () into a two-necked flask equipped with magnetic stirring 10-Undecen-1-ol (766.4, 4.5mmol), 2-chloroquinoxaline (82.3mg, 0.5mmol), silver trifluoroacetate (22.1mg, 0.1mmol), sodium persulfate (178.6mg, 0.75mmol), sulfuric acid (147.1mg, 1.5mmol), The mixture was dissolved in methyl ethyl ketone/distilled water (1:1, 4mL), protected by nitrogen, and stirred at 50°C for 24 hours. TLC tracked until the raw materials disappeared and the reaction was(the volume ratio of petroleum ether and ethyl acetate was 2:1). Ester mixed solvent as a developing solvent), the reaction solution was quenched with sodium bicarbonate, washed with saturated brine, and extracted with ethyl acetate. The combined organic layer was dried with anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column with alkane/ethyl acetate to obtain 100.5 mg of the product with a yield of 60.4% and an HPLC purity of 97.0%.
With bis(1,5-cyclooctadiene)nickel (0); CyPAd-DalPhos; sodium 2,2,2-trifluoroacetate; 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 100℃; for 18h; Sealed tube; Inert atmosphere; Glovebox;
N-Arylation of Amides with Aryl Electrophiles (Figures 3 and4); General Procedure
General procedure: In a N2-filled glovebox, a screw-capped vial containing a magneticstirrer bar was charged with Ni(COD)2 (5 mol%), CyPAd-DalPhos (5 mol%), the appropriate aryl (pseudo)halide (0.45mmol, 1.0 equiv, 0.12 M), DBU (2.0 equiv), NaTFA (2.0 equiv),and the appropriate amide (1.1 equiv), followed by the additionof toluene (3.75 mL). The vial was sealed with a cap containing aPTFE septum, removed from the glovebox, and placed in a temperature-controlled aluminum heating block set to 100 °C for 18h, with magnetic stirring. The vial was then removed from theheating block and left to cool to rt. The crude reaction mixturewas filtered through a short plug of Celite and silica gel (3:1v/v), eluting with EtOAc. The volatile materials were evaporatedin vacuo, and the crude product was purified by flash-columnchromatography.
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