* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Medicinal Chemistry, 1998, vol. 41, # 13, p. 2390 - 2410
2
[ 4915-06-4 ]
[ 1899-24-7 ]
Reference：
[1] Patent: US4332952, 1982, A,
3
[ 35950-55-1 ]
[ 1899-24-7 ]
[ 563-70-2 ]
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[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 3, p. 795 - 804
4
[ 98-01-1 ]
[ 1899-24-7 ]
Reference：
[1] Tetrahedron, 1996, vol. 52, # 36, p. 11763 - 11782
[2] Zhurnal Obshchei Khimii, 1954, vol. 24, p. 575,576; engl. Ausg. S. 589, 590[3] Zhurnal Obshchei Khimii, 1957, vol. 27, p. 2012; engl. Ausg. S. 2070
[4] Collection of Czechoslovak Chemical Communications, 1996, vol. 61, # 8, p. 1233 - 1243
5
[ 35950-55-1 ]
[ 1899-24-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 3, p. 795 - 804
6
[ 585-70-6 ]
[ 1899-24-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 1998, vol. 41, # 13, p. 2390 - 2410
7
[ 1137088-24-4 ]
[ 1899-24-7 ]
Reference：
[1] Australian Journal of Chemistry, 2010, vol. 63, # 12, p. 1619 - 1626
8
[ 613-75-2 ]
[ 1899-24-7 ]
Reference：
[1] Journal of the American Chemical Society, 1930, vol. 52, p. 1170
9
[ 98-01-1 ]
[ 1899-24-7 ]
[ 2433-85-4 ]
[ 21921-76-6 ]
Reference：
[1] Asian Journal of Chemistry, 2012, vol. 24, # 2, p. 927 - 928
[2] Asian Journal of Chemistry, 2012, vol. 24, # 2, p. 927 - 928
[3] Asian Journal of Chemistry, 2012, vol. 24, # 2, p. 927 - 928
10
[ 98-01-1 ]
[ 1899-24-7 ]
[ 2433-85-4 ]
Reference：
[1] Asian Journal of Chemistry, 2012, vol. 24, # 2, p. 927 - 928
11
[ 89167-32-8 ]
[ 1899-24-7 ]
Reference：
[1] Journal of Organic Chemistry, 1941, vol. 6, p. 157,165
12
[ 854819-96-8 ]
[ 1899-24-7 ]
Reference：
[1] Journal of Organic Chemistry, 1941, vol. 6, p. 157,165
13
[ 854753-06-3 ]
[ 1899-24-7 ]
Reference：
[1] Journal of Organic Chemistry, 1941, vol. 6, p. 157,165
14
[ 98-01-1 ]
[ 1899-24-7 ]
[ 21921-76-6 ]
Reference：
[1] Asian Journal of Chemistry, 2012, vol. 24, # 2, p. 927 - 928
15
[ 613-75-2 ]
[ 7726-95-6 ]
[ 1899-24-7 ]
Reference：
[1] Journal fuer Praktische Chemie (Leipzig), 1933, vol. <2> 136, p. 232,233
[2] Journal of the American Chemical Society, 1930, vol. 52, p. 1170
16
[ 186581-53-3 ]
[ 1899-24-7 ]
[ 3199-50-6 ]
Reference：
[1] Journal of the American Chemical Society, 1931, vol. 53, p. 4192,4196
[2] Indian Journal of Chemistry - Section B Organic Chemistry Including Medicinal Chemistry, 1989, vol. 28, # 11, p. 993 - 995
17
[ 1899-24-7 ]
[ 27230-58-6 ]
[ 585-70-6 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1990, vol. 26, # 6, p. 617 - 620[2] Khimiya Geterotsiklicheskikh Soedinenii, 1990, # 6, p. 741 - 744
18
[ 1899-24-7 ]
[ 585-70-6 ]
Reference：
[1] Vestnik Moskovskogo Universiteta, 1958, vol. 13, # 5, p. 119,121[2] Chem.Abstr., 1959, p. 12267
[3] Journal of Physical Organic Chemistry, 2004, vol. 17, # 1, p. 83 - 87
19
[ 1899-24-7 ]
[ 2527-99-3 ]
Reference：
[1] Vestnik Moskovskogo Universiteta, 1958, vol. 13, # 5, p. 119,121[2] Chem.Abstr., 1959, p. 12267
Reference：
[1] Organic Letters, 2018, vol. 20, # 8, p. 2273 - 2277
[2] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 19, p. 2681 - 2683
[3] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 10, p. 2481 - 2486
24
[ 1899-24-7 ]
[ 34035-03-5 ]
Reference：
[1] Chemical Biology and Drug Design, 2017, vol. 89, # 4, p. 585 - 598
25
[ 1899-24-7 ]
[ 24067-17-2 ]
[ 7147-77-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 19, p. 2681 - 2683
[2] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 10, p. 2481 - 2486
[3] Bulletin of the Korean Chemical Society, 2015, vol. 36, # 11, p. 2621 - 2626
26
[ 1899-24-7 ]
[ 7147-77-5 ]
Reference：
[1] Chemical Biology and Drug Design, 2017, vol. 89, # 4, p. 585 - 598
27
[ 1899-24-7 ]
[ 5467-74-3 ]
[ 20005-42-9 ]
Yield
Reaction Conditions
Operation in experiment
7%
With tetrabutylammomium bromide; palladium diacetate; potassium carbonate In water at 20℃; for 5 h;
To a glass flask, 3 (113.8 mg, 0.650mmol), (4-bromophenyl)boronic acid (143.6 mg, 0.715 mmol), tetrabutylammonium bromide(209.6 mg, 0.650 mmol), Pd(OAc)2 (2.9 mg, 0.013 mmol) and K2CO3 (224.6 mg, 1.63 mmol)were added and then dissolved in deionized water (3 mL). The reaction mixture was stirred vigorously for 5 h at room temperature. After the white reaction mixture had become yellowand non-homogeneous, the mixture was diluted with water (10 mL), and the product was extracted with EtOAc. The organics were separated, filtered through a Celite pad, and dried with MgSO4. The organic solvent was removed under reduced pressure and the crude product was purified by dry-flash chromatography (SiO2: hexane/EtOAc = 9/1 to 7/3) to afford the title compound 5 (11 mg, 7 percent).
Reference：
[1] Organic Letters, 2018, vol. 20, # 8, p. 2273 - 2277
[2] Organic Letters, 1999, vol. 1, # 7, p. 965 - 967
[3] Journal of the Serbian Chemical Society, 2017, vol. 82, # 6, p. 641 - 649
[4] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 19, p. 2681 - 2683
28
[ 98-01-1 ]
[ 1899-24-7 ]
[ 2433-85-4 ]
[ 21921-76-6 ]
Reference：
[1] Asian Journal of Chemistry, 2012, vol. 24, # 2, p. 927 - 928
[2] Asian Journal of Chemistry, 2012, vol. 24, # 2, p. 927 - 928
[3] Asian Journal of Chemistry, 2012, vol. 24, # 2, p. 927 - 928
29
[ 98-01-1 ]
[ 1899-24-7 ]
[ 21921-76-6 ]
Reference：
[1] Asian Journal of Chemistry, 2012, vol. 24, # 2, p. 927 - 928
30
[ 1899-24-7 ]
[ 4915-06-4 ]
Yield
Reaction Conditions
Operation in experiment
85%
With tert.-butylhydroperoxide; ammonium acetate; iodine; sodium carbonate In ethanol at 50℃; for 4.5 h;
In a 25 mL two-necked round bottom flask equipped with a thermometer and a magnetic stirrer4mmol5-bromofuran-2-carbaldehyde (1-18), 6 mmol of NH4OAc, 4 mmol of Na2CO3, 4.4 mmol of TBHP, 0.1 mmol of I2, 5 mL of absolute ethanol Solvent, and then the reaction flask was placed in an oil bath preheated to 50 ° C and opened with a magnetic stirrer for 4.5 h. reaction The solution was stirred by adding sodium thiosulfate solution and then extracted with ether. The organic layer was separated and the solvent was evaporated under reduced pressure. The elution was carried out with a mixture of ethyl acetate / petroleum ether in a volume ratio of 1: 100 as an eluent, and the eluate containing the target compound was collected And the solvent was evaporated to give 5-bromofuran-2-carbonitrile with an isolated yield of 85percent.
82%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium perchlorate; acetic acid; lithium hexamethyldisilazane In acetonitrile for 15 h; Electrochemical reaction
General procedure: Preparative electrolysis experiments were performed using 263 APotentiostat/Galvanostat (Princeton Applied Research, USA). 0.1 MNaClO4–CH3CN solution (10 mL) containing aldehydes (1 mmol),TEMPO (0.1 mmol), HMDS (2.5mmol) and AcOH (2.5mmol) was electrolyzedwith stirring in an undivided cell (30 mL) equipped with twoplatinum sheets as anode (1.5 cm2) and cathode (3.0 cm2) respectivelyat a constant potential of 1.5 V vs Ag/Ag+ (0.1MAgNO3 in acetonitrile).The electrode separation was 1 cm. When the reaction was finished,10mL of saturatedNa2SO3 solution was added into the reactionmixtureand stirred for 15 min. Then the mixture was extracted with CH2Cl2(20 mL × 3). The organic layer was dried with anhydrous Na2SO4 andconcentrated in a rotary evaporator. The productswere obtained via purificationof column chromatography and their structures were confirmedby 1H NMR, 13C NMR and MS. NMR was performed on a BrukerAvance III spectrometer. GC-MS was performed on the Thermo TraceISQ instrument with TG 5MS capillary column.
Reference：
[1] Chemistry of Heterocyclic Compounds, 2002, vol. 38, # 5, p. 524 - 529
[2] Advanced Synthesis and Catalysis, 2016, vol. 358, # 7, p. 1157 - 1163
[3] RSC Advances, 2017, vol. 7, # 3, p. 1484 - 1489
[4] Electrochimica Acta, 2017, vol. 226, p. 53 - 59
[5] Patent: CN106748881, 2017, A, . Location in patent: Paragraph 0050
[6] Electrochemistry Communications, 2016, vol. 64, p. 51 - 55
[7] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1986, vol. 22, # 2, p. 140 - 145[8] Khimiya Geterotsiklicheskikh Soedinenii, 1986, vol. 22, # 2, p. 181 - 186
[9] Patent: EP1792613, 2007, A2, . Location in patent: Page/Page column 46
[10] Angewandte Chemie - International Edition, 2015, vol. 54, # 14, p. 4241 - 4245
31
[ 1899-24-7 ]
[ 67-56-1 ]
[ 4915-06-4 ]
Reference：
[1] Catalysis Science and Technology, 2016, vol. 6, # 20, p. 7429 - 7436
32
[ 1899-24-7 ]
[ 99768-12-4 ]
[ 53355-29-6 ]
Yield
Reaction Conditions
Operation in experiment
81%
With potassium fluoride; tri-tert-butyl phosphine In 1,4-dioxane; hexane at 65 - 70℃; for 4 h;
A solution of 5-bromofuraldehyde (2.43 g, 13.9 mmoles), 4-(methoxycarbonyl)phenylboronic acid (2.50 g, 13.9 mmoles), tris(dibenzylideneacetone)palladium (0) (192 mg, 0.2 mmoles) and potassium fluoride (2.42 g, 41.7 mmoles) in 1,4-dioxane (100 ml) was added with a solution of tri-toert-butylphosphine in hexane (10percent by weight, 101 mg, 0.5 mmoles). After heating at 65-70°C for 4 hours, the mixture was cooled to room temperature and treated with methylene chloride (150 ml). After stirring for 10 minutes, the mixture was filtered through Celite and the filtrate was EPO <DP n="13"/>concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with an ethyl acetate-hexane mixture (1 : 1) to give 4-(5-formyl-furan-2-yl)-benzoic acid methyl ester (2.6 g, 81percent yield).1H NMR (300 MHz, CDCl3): δ 9.70 (s, IH), 8.10 (d, 2H), 7.90 (d, 2H), 7.35 (d, IH), 6.95 (d, IH), 3.98 (s, 3H).
78%
With palladium diacetate; sodium carbonate In water; acetone at 20℃; for 0.416667 h;
To a solution of sodium carbonate (588.2 mg, 5.55 mmol) in H2O /acetone (278 mL/ 555 mL) was added 5-bromo-2-furaldehyde (1.9 g, 11 mmol), p-(methoxycarbonyl)phenyl boronic acid (2.0 g, 11 mmol) followed by palladium acetate(24.9 mg, 0.111 mmol) in acetone (278 ml). The reaction mixture was stirred at room temperature for 25 min. The reactionwas quenched by diluting with EtOAc (855 mL) and the organic layer was washed with 1 M HCl (500 mL) twice andwith brine (500 mL) once. The organic layer was dried over Na2SO4 and filtered with silica gel, which was concentratedin vacuo. The residue was purified by flash column chromatography (CH2Cl2/hexane = 9/ 1) to give compound 9 as whitesolid (2.0 g, 8.7 mmol, 78percent)
73%
With Pd(N,N-dimethyl-β-alaninate)2; sodium carbonate In ethanol; water at 120℃; for 0.166667 h; Microwave irradiation; Sealed tube
General procedure: To a solution of the appropriate bromo-substituted heterocyclic aldehydes 17a (1.0 mmol) in EtOH/H2O 5:3 (tot 12 mL) in a 35 mL CEM microwave vessel, the correspondent boronic acids 18c-d (1.2 mmol), Na2CO3 2M (2.0 mmol) and Pd(N,N-Dimethyl β-alaninate)2 (5 molpercent) were added. The vessel was capped and placed in a microwave reactor and the reaction carried out with the following method in dynamic mode: 120° C, 10 min, 50W, with high stirring. After completion the vessel was allowed to cool to room temperature and the mixture was extracted with EtOAc (3 X 10 mL). The organic phase was collected, dried over anhydrous Na2SO4, and the solvent evaporated under vacuum. The crude product (containing a small portion of the ethyl ester as a transesterification product) was then purified via silica gel column chromatography (petroleum ether/EtOAc elution gradient from a 90/10 ratio to a 80/20 ratio) to obtain the pure compounds (yield 40-60percent) (Scheme 1).
Reference：
[1] Patent: WO2006/66846, 2006, A1, . Location in patent: Page/Page column 11; 12
[2] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 9, p. 1562 - 1565
[3] European Journal of Medicinal Chemistry, 2015, vol. 101, p. 63 - 70
33
[ 1899-24-7 ]
[ 619-44-3 ]
[ 53355-29-6 ]
Yield
Reaction Conditions
Operation in experiment
78%
With potassium phosphate In N,N-dimethyl acetamide at 60℃; for 24 h; Irradiation; Green chemistry
General procedure: To a solution of 1 (0.3 mmol) and 2 (0.45mmol) in DMA (5 mL) was added 3wtpercent Pd/CeO2 (80 mg). The reaction mixture was stirred under incandescent light (0.79 Wcm-2) irradiation at 60°C for 24h. After reaction (monitored by TLC), when the reaction is complete, in test tube extraction and centrifugal separation allows for isolation of the desired product, while the catalyst can be washed with ethanol and water, dried under vacuum, and reused for the next run. After completion of the reaction (monitored by TLC), water (5 mL) was added and the mixture was extracted with EtOAc (3 × 5 mL). The combined organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (10:1 petroleum ether/EtOAc) to give the target product.
Reference：
[1] Chinese Chemical Letters, 2018, vol. 29, # 6, p. 903 - 906
34
[ 1899-24-7 ]
[ 13716-12-6 ]
[ 99768-12-4 ]
[ 53355-29-6 ]
Yield
Reaction Conditions
Operation in experiment
81%
With potassium fluoride In hexane; dichloromethane
A. 4-(5-Formyl-furan-2-yl)-benzoic Acid Methyl Ester To a solution of 5-bromofuraldehyde (2.43 g, 13.9 mmol), 4-(methoxycarbonyl)phenyl boronic acid (2.50 g, 13.9 mmol), tris(dibenzylideneacetone)dipalladium(0) (192 mg, 0.21 mmol) and potassium fluoride (2.42 g, 41.7 mmol) in 1,4-doxane (100 ml) was added a solution of tri-t-butylphosphine in hexane (10 weight percent, 1.01 g, 0.5 mmol). After heating at 65-70° C. for 4 hours, the mixture was cooled to room temperature and treated with dichloromethane (150 ml). After stirring for 10 minutes, the mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluding with ethyl acetate-hexane (1:1) to provide 4-(5-formyl-furan-2-yl)-benzoic acid methyl ester (2.6 g, 81percent yield).
Reference：
[1] Patent: US2004/2526, 2004, A1,
35
[ 1899-24-7 ]
[ 53355-29-6 ]
Reference：
[1] Patent: CN106565643, 2017, A,
36
[ 1899-24-7 ]
[ 5419-55-6 ]
[ 27329-70-0 ]
Reference：
[1] Chemical Biology and Drug Design, 2017, vol. 89, # 4, p. 585 - 598
With tert.-butylhydroperoxide; ammonium acetate; iodine; sodium carbonate; In ethanol; at 50℃; for 4.5h;
In a 25 mL two-necked round bottom flask equipped with a thermometer and a magnetic stirrer4mmol5-bromofuran-2-carbaldehyde (1-18), 6 mmol of NH4OAc, 4 mmol of Na2CO3, 4.4 mmol of TBHP, 0.1 mmol of I2, 5 mL of absolute ethanol Solvent, and then the reaction flask was placed in an oil bath preheated to 50 C and opened with a magnetic stirrer for 4.5 h. reaction The solution was stirred by adding sodium thiosulfate solution and then extracted with ether. The organic layer was separated and the solvent was evaporated under reduced pressure. The elution was carried out with a mixture of ethyl acetate / petroleum ether in a volume ratio of 1: 100 as an eluent, and the eluate containing the target compound was collected And the solvent was evaporated to give 5-bromofuran-2-carbonitrile with an isolated yield of 85%.
82%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium perchlorate; acetic acid; lithium hexamethyldisilazane; In acetonitrile; for 15.0h;Electrochemical reaction;
General procedure: Preparative electrolysis experiments were performed using 263 APotentiostat/Galvanostat (Princeton Applied Research, USA). 0.1 MNaClO4-CH3CN solution (10 mL) containing aldehydes (1 mmol),TEMPO (0.1 mmol), HMDS (2.5mmol) and AcOH (2.5mmol) was electrolyzedwith stirring in an undivided cell (30 mL) equipped with twoplatinum sheets as anode (1.5 cm2) and cathode (3.0 cm2) respectivelyat a constant potential of 1.5 V vs Ag/Ag+ (0.1MAgNO3 in acetonitrile).The electrode separation was 1 cm. When the reaction was finished,10mL of saturatedNa2SO3 solution was added into the reactionmixtureand stirred for 15 min. Then the mixture was extracted with CH2Cl2(20 mL × 3). The organic layer was dried with anhydrous Na2SO4 andconcentrated in a rotary evaporator. The productswere obtained via purificationof column chromatography and their structures were confirmedby 1H NMR, 13C NMR and MS. NMR was performed on a BrukerAvance III spectrometer. GC-MS was performed on the Thermo TraceISQ instrument with TG 5MS capillary column.
With tetrabutylammomium bromide; palladium diacetate; potassium carbonate; In water; at 20℃; for 5h;
To a glass flask, 3 (113.8 mg, 0.650mmol), (4-bromophenyl)boronic acid (143.6 mg, 0.715 mmol), tetrabutylammonium bromide(209.6 mg, 0.650 mmol), Pd(OAc)2 (2.9 mg, 0.013 mmol) and K2CO3 (224.6 mg, 1.63 mmol)were added and then dissolved in deionized water (3 mL). The reaction mixture was stirred vigorously for 5 h at room temperature. After the white reaction mixture had become yellowand non-homogeneous, the mixture was diluted with water (10 mL), and the product was extracted with EtOAc. The organics were separated, filtered through a Celite pad, and dried with MgSO4. The organic solvent was removed under reduced pressure and the crude product was purified by dry-flash chromatography (SiO2: hexane/EtOAc = 9/1 to 7/3) to afford the title compound 5 (11 mg, 7 %).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; at 70.0℃;Inert atmosphere; Sealed tube;
General procedure: A bromo-aldehyde (1 mmol), boronic acid (1.1e1.3 mmol), tetrakis(triphenylphosphine)palladium (0.05 mmol), potassium carbonate(3 mmol), water (3 ml), ethanol (4 ml) and toluene (4 ml)were added to a round-bottomed flask. The reaction mixture wasflushed with argon, sealed under septa and heated at 70 C overnight.After cooling to room temperature, water (50 ml) was added,and product was extracted with ethyl acetate (3 x 50 ml). Combinedextracts were washed with brine, dried with anhydrousmagnesium sulfate and evaporated under reduced pressure. Theproduct was purified by column chromatography on silica withchloroform or a mixture of methanol and chloroform (1:9).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; at 70℃;Inert atmosphere; Sealed tube;
General procedure: A bromo-aldehyde (1 mmol), boronic acid (1.1e1.3 mmol), tetrakis(triphenylphosphine)palladium (0.05 mmol), potassium carbonate(3 mmol), water (3 ml), ethanol (4 ml) and toluene (4 ml)were added to a round-bottomed flask. The reaction mixture wasflushed with argon, sealed under septa and heated at 70 C overnight.After cooling to room temperature, water (50 ml) was added,and product was extracted with ethyl acetate (3 x 50 ml). Combinedextracts were washed with brine, dried with anhydrousmagnesium sulfate and evaporated under reduced pressure. Theproduct was purified by column chromatography on silica withchloroform or a mixture of methanol and chloroform (1:9).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 90℃;
General procedure: To a solution of substituted phenylboronic acid (3.87 mmol) in toluene/ethanol (50/50, 40 mL), 5-bromofuran-2-alsehyde (600 mg, 3.43 mmol), potassium carbonate (947.96 mg, 6.86 mmol) aq. solution (10.3 mL water), and tetrakis(triphenyphosphine)palladium(0) (35.78 mg, 0.03 mmol) were added slowly, after which the reaction mixture was stirred at 90 C. The mixture was acidified by 6 N hydrogen chloride solution, and extracted with dichloromethane. The organic layer was washed with brine, dried (MgSO4) and, filtered. The solvent was concentrated under reduced pressure to yield compound 10, 5(4-carboxaminophenyl)furan-2-aldehyde. Yield 60%; 1H NMR (300 MHz, DMSO-d6) delta: 9.65 (s, 1H), 8.11 (s, 1H), 8.02-7.94 (m, 4H), 7.69 (d, J = 3.7 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J = 3.7 Hz, 1H).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 90℃;
General procedure: To a solution of substituted phenylboronic acid (3.87 mmol) in toluene/ethanol (50/50, 40 mL), 5-bromofuran-2-alsehyde (600 mg, 3.43 mmol), potassium carbonate (947.96 mg, 6.86 mmol) aq. solution (10.3 mL water), and tetrakis(triphenyphosphine)palladium(0) (35.78 mg, 0.03 mmol) were added slowly, after which the reaction mixture was stirred at 90 C. The mixture was acidified by 6 N hydrogen chloride solution, and extracted with dichloromethane. The organic layer was washed with brine, dried (MgSO4) and, filtered. The solvent was concentrated under reduced pressure to yield compound 10, 5(4-carboxaminophenyl)furan-2-aldehyde. Yield 60%; 1H NMR (300 MHz, DMSO-d6) delta: 9.65 (s, 1H), 8.11 (s, 1H), 8.02-7.94 (m, 4H), 7.69 (d, J = 3.7 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J = 3.7 Hz, 1H).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 90℃;
General procedure: To a solution of substituted phenylboronic acid (3.87 mmol) in toluene/ethanol (50/50, 40 mL), 5-bromofuran-2-alsehyde (600 mg, 3.43 mmol), potassium carbonate (947.96 mg, 6.86 mmol) aq. solution (10.3 mL water), and tetrakis(triphenyphosphine)palladium(0) (35.78 mg, 0.03 mmol) were added slowly, after which the reaction mixture was stirred at 90 C. The mixture was acidified by 6 N hydrogen chloride solution, and extracted with dichloromethane. The organic layer was washed with brine, dried (MgSO4) and, filtered. The solvent was concentrated under reduced pressure to yield compound 10, 5(4-carboxaminophenyl)furan-2-aldehyde. Yield 60%; 1H NMR (300 MHz, DMSO-d6) delta: 9.65 (s, 1H), 8.11 (s, 1H), 8.02-7.94 (m, 4H), 7.69 (d, J = 3.7 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J = 3.7 Hz, 1H).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; toluene; at 120℃; for 3h;
General procedure: To a solution of 5-bromofuran-2-carboxaldehyde 4 (175.0 mg, 1.0 mmol) in a mixture of 10.0 mL of toluene and 4.0 mL ethanol was added <strong>[3900-89-8]2-chlorophenylboronic acid</strong> 3f (156.4 mg, 1.0 mmol), tetrakis(triphenylphosphine)palladium (0) (33.0 mg, 0.028 mmol) at 25°C, and 10.0 mL of satd. potassium carbonate. The solution was refluxed for 3 h. After being cooled to 25°C, the solution was diluted with dichloromethane andwashed with water. The combined organic layer was dried with sodium sulfate and the solvent was removed. The residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate (5:2) to afford 171.0 mg (83percent) of the compound 5f as a white solid.
83%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; toluene; at 120℃; for 3h;
To a solution of 5-bromofuran-2-carboxaldehyde 4 (175.0 mg, 1.0 mmol) in a mixture of 10.0 mL of toluene and 4.0 mL ethanol was added <strong>[3900-89-8]2-chlorophenylboronic acid</strong> 3f (156.4 mg, 1.0 mmol), tetrakis(triphenylphosphine)palladium (0) (33.0 mg, 0.028 mmol) at 25° C., and 10.0 mL of satd. potassium carbonate. The solution was refluxed for 3 h. After being cooled to 25° C., the solution was diluted with dichloromethane and washed with water. The combined organic layer was dried with sodium sulfate and the solvent was removed. The residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate (5:2) to afford 171.0 mg (83percent) of the compound 5f as a white solid. 1H NMR(CHCl3) delta: 9.63 (1H, s), 7.93 (1H, dd, J=7.8, 2.1 Hz), 7.39 (1H, dd, J=7.8, 1.5 Hz), 7.26 (4H, m); 13C NMR (CHCl3) delta: 177.46, 155.33, 151.52, 131.47, 130.93, 130.17, 129.07, 127.53, 127.19, 123.01, 113.21.
A [SOLUTION OF 5-BROMO-2-FURANCARBOXALDEHYDE] (0.0171 mol) in DME (65ml) was added dropwise to a solution of Pd (PPh3) 4 (0.00007 mol) in DME [(50ML)] at room temperature under N2. The mixture was stirred for 15 minutes. A solution of (3-hydroxyphenyl) boronic acid (0.0257 mol) in EtOH [(18ML)] was added. The mixture was stirred for 15 minutes. 2M [K2CO3] (75ml) was added. The mixture was stirred and refluxed for 4 hours, cooled to room temperature, concentrated and taken up by [CH2CL2.] The organic layer was washed by H20, dried over [MGS04,] filtered and evaporated. The residue (5.9g) was purified by column chromatography over silica gel (eluent : [CH2CK/CH30H] 98/2; [15-40UM).] The pure fractions were collected and the solvent was evaporated. Yielding: 3g of intermediate 1 (88%).
7-bromo-2-(5-bromofuran-2-yl)[1,2,4]triazolo[1,5-a]pyridin-5-ylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; mesitylenesulfonylhydroxylamine;
EXAMPLE 67 7-Bromo-2-(5-bromo-furan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine The title compound, MS m/e (%): 359 (M++1, 100), was prepared in accordance with the general method of example 63 from <strong>[329974-09-6]4-bromo-pyridine-2,6-diamine</strong>, O-mesitylene-sulfonylhydroxylamine, and 5-bromo-furfural. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
(S)-N-[[3-[3-fluoro-4-[4-(5-formyl-2-furyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 10h;
(S)-N-[[3-[3-Fluoro-4-[4-(5-formyl-2-thienyl-)-1- piperazinyl] [PHENYL]-2-OXO-5-OXAZOLIDINYL]] methyl] acetamide To the (S)-N-[[3-[3-Fluoro-4-(1-piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide trifluoroacetate (2.28 mmol) in [ACETONIT : RILE] (20 mL), N-ethyl-diisopropylamine (3 g, 22.8 mmol) and 5-bromo-2-thiophenecarboxaldehyde (0.64 g, 3.4 mmol) were added and heated at [80 XB0;C] for 30 hrs. The reaction mixture was cooled and evaporated in vacuo. The residue was dissolved in dichloromethane (DCM) and washed with water and sodium chloride solution. The organic layer was dried over sodium sulphate and [EVAPORATED IN VACU-O.] The residue was purified by column chromatography using DCM- 200 mL, 1% [IMEOH/DCM-200 ML,] 2% [MEOH/DCM-400ML,] 3% [MEOH/DCM-800] mL. The product eluted in 3% MeOH/DCM. The product was digested with hexane, filtered and dried in air to get 0.06 g of the title compound, m. p. [180 XB0;C (DEC), 207 XB0;C.]
Example 17 Synthesis of N-tert-Butyl-alpha-[2-(methylsulfonyl)-furan-5-yl]nitrone A solution of 5-bromo2-furaldehyde (20 g, 0.1143 mol) and methanesulfinic acid sodium salt (25 g, 0.2427 mol) in 2-ethoxyethanol (300 mL) was refluxed for 3 h and poured into ice-water (1000 g) after cooling. The mixture was extracted with CHCl3 and the CHCl3 solution was dried over Na2SO4, filtered and rotary evaporated. The resulting residue (9.16 g) was reacted with N-tert-butylhydroxylamine (7.0 g) in CHCl3 in the presence of molecular sieves (4A, 50 g) and silica gel (10 g) at room temperature for 21 h and at refluxing temperature for 3 h. After filtration and evaporation, the residue obtained was purified by column chromatography eluted with hexanes and ethyl acetate (1:1, v:v) to give the tide compound (5.37 g, 19.2% overall yield) as a solid, m.p. 137.5 C.(Rf=0.27 on a silica gel plate using hexanes/EtOAc (1:1, v:v) as the eluant). Spectroscopic data was as follows: IR (KBr, cm-1): 3173.2 (furan CH), 2997.0 (alkyl CH), 2915.1 (alkyl CH), 1636 (C=N), 1320.9 (SO2), 1173.0 (SO2) and 1127.6 (N-O). 1H NMR (CDCl3, 270 MHz): delta=7.792 (1H, s, nitronyl CH), 7.757 (1H, d, J=3.6 Hz, furan CH), 7.204 (1H, d, J=3.6 Hz, furan CH), 3.126 (3H, s, CH3) and 1.549 (9H, s, 3 CH3). 13C NMR (CDCl3, 270 MHz): delta=151.930, 148.818, 120.386, 119.181, 114.407, 71.270, 43.235 and 27.737.
19.2%
silica gel; In 2-ethoxy-ethanol; chloroform;
Example 17 Synthesis of N-tert-Butyl-alpha-[2-(methylsulfonyl)-furan-5-yl]nitrone A solution of 5-bromo-2-furaldehyde (20 g, 0.1143 mol) and methanesulfinic acid sodium salt (25 g, 0.2427 mol) in 2-ethoxyethanol (300 mL) was refluxed for 3 h and poured into ice-water (1000 g) after cooling. The mixture was extracted with CHCl3 and the CHCl3 solution was dried over Na2 SO4, filtered and rotary evaporated. The resulting residue (9.16 g) was reacted with N-tert-butylhydroxylamine (7.0 g) in CHCl3 in the presence of molecular sieves (4A, 50 g) and silica gel (10 g) at room temperature for 21 h and at refluxing temperature for 3 h. After filtration and evaporation, the residue obtained was purified by column chromatography eluted with hexanes and ethyl acetate (1:1, v:v) to give the title compound (5.37 g, 19.2% overall yield) as a solid, m.p. 137.5 C. (Rf =0.27 on a silica gel plate using hexanes/EtOAc (1:1, v:v) as the eluant). Spectroscopic data was as follows: IR (KBr, cm-1): 3173.2 (furan CH), 2997.0 (alkyl CH), 2915.1 (alkyl CH), 1636 (C=N), 1320.9 (SO2), 1173.0 (SO2) and 1127.6 (N--O). 1 H NMR (CDCl3, 270 MHz): delta=7.792 (1H, s, nitronyl CH), 7.757 (1H, d, J=3.6 Hz, furan CH), 7.204 (1H, d, J=3.6 Hz, furan CH), 3.126 (3H, s, CH3) and 1.549 (9H, s, 3 CH3). 13 C NMR (CDCl3, 270 MHz): delta=151.930, 148.818, 120.386, 119.181, 114.407, 71.270, 43.235 and 27.737.
With potassium fluoride; tri-tert-butyl phosphine;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; hexane; at 65 - 70℃; for 4h;
A solution of 5-bromofuraldehyde (2.43 g, 13.9 mmoles), 4-(methoxycarbonyl)phenylboronic acid (2.50 g, 13.9 mmoles), tris(dibenzylideneacetone)palladium (0) (192 mg, 0.2 mmoles) and potassium fluoride (2.42 g, 41.7 mmoles) in 1,4-dioxane (100 ml) was added with a solution of tri-t°rt-butylphosphine in hexane (10% by weight, 101 mg, 0.5 mmoles). After heating at 65-70C for 4 hours, the mixture was cooled to room temperature and treated with methylene chloride (150 ml). After stirring for 10 minutes, the mixture was filtered through Celite and the filtrate was EPO <DP n="13"/>concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with an ethyl acetate-hexane mixture (1 : 1) to give 4-(5-formyl-furan-2-yl)-benzoic acid methyl ester (2.6 g, 81% yield).1H NMR (300 MHz, CDCl3): delta 9.70 (s, IH), 8.10 (d, 2H), 7.90 (d, 2H), 7.35 (d, IH), 6.95 (d, IH), 3.98 (s, 3H).
78%
With palladium diacetate; sodium carbonate; In water; acetone; at 20℃; for 0.416667h;
To a solution of sodium carbonate (588.2 mg, 5.55 mmol) in H2O /acetone (278 mL/ 555 mL) was added 5-bromo-2-furaldehyde (1.9 g, 11 mmol), p-(methoxycarbonyl)phenyl boronic acid (2.0 g, 11 mmol) followed by palladium acetate(24.9 mg, 0.111 mmol) in acetone (278 ml). The reaction mixture was stirred at room temperature for 25 min. The reactionwas quenched by diluting with EtOAc (855 mL) and the organic layer was washed with 1 M HCl (500 mL) twice andwith brine (500 mL) once. The organic layer was dried over Na2SO4 and filtered with silica gel, which was concentratedin vacuo. The residue was purified by flash column chromatography (CH2Cl2/hexane = 9/ 1) to give compound 9 as whitesolid (2.0 g, 8.7 mmol, 78%)
73%
With Pd(N,N-dimethyl-beta-alaninate)2; sodium carbonate; In ethanol; water; at 120℃; for 0.166667h;Microwave irradiation; Sealed tube;
General procedure: To a solution of the appropriate bromo-substituted heterocyclic aldehydes 17a (1.0 mmol) in EtOH/H2O 5:3 (tot 12 mL) in a 35 mL CEM microwave vessel, the correspondent boronic acids 18c-d (1.2 mmol), Na2CO3 2M (2.0 mmol) and Pd(N,N-Dimethyl beta-alaninate)2 (5 mol%) were added. The vessel was capped and placed in a microwave reactor and the reaction carried out with the following method in dynamic mode: 120 C, 10 min, 50W, with high stirring. After completion the vessel was allowed to cool to room temperature and the mixture was extracted with EtOAc (3 X 10 mL). The organic phase was collected, dried over anhydrous Na2SO4, and the solvent evaporated under vacuum. The crude product (containing a small portion of the ethyl ester as a transesterification product) was then purified via silica gel column chromatography (petroleum ether/EtOAc elution gradient from a 90/10 ratio to a 80/20 ratio) to obtain the pure compounds (yield 40-60%) (Scheme 1).
With diisobutylaluminium hydride; In methanol; toluene;
PREPARATION 7 5-Bromo-2-furaldehyde <strong>[4915-06-4]5-Bromo-2-furylcarbonitrile</strong> (2.3 g., 13 mmoles) was dissolved in 50 ml. of ether and cooled, under nitrogen, to -10 C. Diisobutylaluminum hydride (1.9 g., 13 mmoles) as a 25% solution in toluene was added dropwise, maintaining the temperature near -10 C. The reaction was allowed to warm to room temperature and allowed to stir about 6 hours. The reaction mixture was cooled to 0 to 5 C., diluted with 1 ml. of methanol, acidified with 3 N hydrochloric acid, washed with water, and evaporated to yield 5-bromo-2-furaldehyde (1.2 g., m.p. 74-76 C.).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In methanol; water; toluene; at 80℃; for 12h;
Example 3; 5-[4-(5-Formylfuran-2-yl)-phenyl]-furan-2-carboxaldehyde (11); To a stirred solution of 5-bromofuran-2-carboxaldehyde (10 mmol), and tetrakis(triphenylphosphine) palladium (400 mg) in toluene (20 mL) under a nitrogen atmosphere was added 10 mL of a 2 M aqueous solution of Na2CO3 followed by 1,4-phenylenebisboronic acid (5 mmol) in 6 mL of methanol. The vigorously stirred mixture was warmed to 80 °C for 12 h. The solvent was evaporated, the precipitate was partitioned between methylene chloride (300 mL) and 2 M aqueous Na2CO3 (15 mL) containing 5 mL of concentrated ammonia. The organic layer was dried (Na2SO4), and then concentrated to dryness under reduced pressure to afford 11 in 93percent yield; mp 233-234 °C (EtOH). 1H NMR (DMSO-d6); delta 9.64 (s, 2H), 8.01 (s, 4H), 7.70 (d, J = 3.6 Hz, 2H), 7.43 (d, J = 3.6 Hz, 2H). MS (ESI) m/e (rel. int.): 266 (M+, 100), 238 (5), 209 (25). Anal. Calc. for C16H10O4: Cpercent 72.16; Hpercent 3.78; Found Cpercent 72.41; Hpercent 3.93.
With potassium fluoride;tris-(dibenzylideneacetone)dipalladium(0); In hexane; dichloromethane;
A. 4-(5-Formyl-furan-2-yl)-benzoic Acid Methyl Ester To a solution of 5-bromofuraldehyde (2.43 g, 13.9 mmol), 4-(methoxycarbonyl)phenyl boronic acid (2.50 g, 13.9 mmol), tris(dibenzylideneacetone)dipalladium(0) (192 mg, 0.21 mmol) and potassium fluoride (2.42 g, 41.7 mmol) in 1,4-doxane (100 ml) was added a solution of tri-t-butylphosphine in hexane (10 weight %, 1.01 g, 0.5 mmol). After heating at 65-70 C. for 4 hours, the mixture was cooled to room temperature and treated with dichloromethane (150 ml). After stirring for 10 minutes, the mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluding with ethyl acetate-hexane (1:1) to provide 4-(5-formyl-furan-2-yl)-benzoic acid methyl ester (2.6 g, 81% yield).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; toluene; at 90.0℃; for 15.0h;Inert atmosphere;
General procedure: A solution of K2C03 (2.37 gm, 3 equiv.) in water (10 mL) was added to a mixture of <strong>[913835-32-2]4-chloro-3-carboxyphenylboronic acid</strong> (1.37 gm, 1.2 equiv.) and 5-bromo-2-furaldehyde (1 gm, 1 equiv.) in toluene/ethanol (60 mL). The mixture was degassed with argon for 5 minute and then Pd(PPh3)4 (330 mg, 0.05 equiv.) was added. The reaction mixture was stirred at 90C for 15 h. The reaction mixture was cooled to room temperature, filtered through Celite and was with water (2 x 10 mL). The pH of solution was adjusted to 1-2 by addition of 6N HC1 solution. The precipitated reaction mixture was extracted with dichloromethane (3 x 100 mL); the combined organic fractions were washed with brine, dried over anhydrous Na2504, and concentrated under reduced pressure. The crude product was triturated with 20-30% EtOAc in hexanes (2 times), solid was filtered to afford 2-chloro-5-(5-formylfuran-2- yl)benzoic acid 7 (1.24 gm, 87% yield) as an off-white solid. TLC: 60% EtOAc in hexanes, Rf = 0.40 visualized with UV and KMnO4 solution.?H NMR (300 MHz, DMSO): (5 13.74 (brs, 1H, COON), 9.63 (s, 1H, CHO), 8.23 (d, 1H, J = 2.22 Hz), 8.01 (dd, 1H, J = 2.28 and 8.43 Hz), 7.70 (d, 1H, J = 8.34 Hz), 7.67 (d, 1H, J = 2.85 Hz), 7.45 (d, 1H, J = 3.75 Hz); ?3C NMR (75 MHz, DMSO): (5 178.64, 166.63, 156.44, 152.47, 132.93, 132.78, 132.13, 129.00, 128.10, 127.23, 110.56.
87%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; toluene; at 90.0℃; for 15.0h;Inert atmosphere;
A solution of K2CO3 (2.37 gm, 3 equiv.) in water (10 mL) was added to a mixture of <strong>[913835-32-2]4-chloro-3-carboxyphenylboronic acid</strong> 29 (1.37 gm, 1.2 equiv.) and 5-bromo-2-furaldehyde 28 (1 gm, 1 equiv.) in toluene :ethanol (1 : 1, v/v, 60 mL). The mixture was degassed with argon for 5 minute and then Pd(PPh3)4 (330 mg, 0.05 equiv.) was added. The reaction mixture was stirred at 90C for 15 h. The reaction mixture was cooled to room temperature, filtered through Celite and washed with water (2 x 10 mL). The pH of the solution was adjusted to 1-2 by addition of 6N HCl solution. The precipitated reaction mixture was extracted with dichloromethane (3 x 100 mL); the combined organic fractions were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure. The crude product was triturated with 20-30% EtOAc in hexanes (2 times), solid was filtered to afford 2-chloro-5-(5-formylfuran-2-yl)benzoic acid 30 (1.24 gm, 87% yield) as an off-white solid. TLC: 60% EtOAc in hexanes, Rf = 0.40; visualized with UV and KMn04 solution. lH NMR (300 MHz, DMSO): delta 13.74 (brs, 1H, COOH), 9.63 (s, 1H, CHO), 8.23 (d, 1H, / = 2.22 Hz), 8.01 (dd, 1H, / = 2.28 and 8.43 Hz), 7.70 (d, 1H, / = 8.34 Hz), 7.67 (d, 1H, / = 2.85 Hz), 7.45 (d, 1H, / = 3.75 Hz); 13C NMR (75 MHz, DMSO): delta 178.64, 166.63, 156.44, 152.47, 132.93, 132.78, 132.13, 129.00, 128.10, 127.23, 110.56. MS (ESI) mlz = 249.0 [M - H]~.
With Pd(N,N-dimethyl-beta-alaninate)2; sodium carbonate; In ethanol; water; at 120℃; for 0.166667h;Microwave irradiation; Sealed tube;
General procedure: To a solution of the appropriate bromo-substituted heterocyclic aldehydes 17a (1.0 mmol) in EtOH/H2O 5:3 (tot 12 mL) in a 35 mL CEM microwave vessel, the correspondent boronic acids 18c-d (1.2 mmol), Na2CO3 2M (2.0 mmol) and Pd(N,N-Dimethyl beta-alaninate)2 (5 mol%) were added. The vessel was capped and placed in a microwave reactor and the reaction carried out with the following method in dynamic mode: 120 C, 10 min, 50W, with high stirring. After completion the vessel was allowed to cool to room temperature and the mixture was extracted with EtOAc (3 X 10 mL). The organic phase was collected, dried over anhydrous Na2SO4, and the solvent evaporated under vacuum. The crude product (containing a small portion of the ethyl ester as a transesterification product) was then purified via silica gel column chromatography (petroleum ether/EtOAc elution gradient from a 90/10 ratio to a 80/20 ratio) to obtain the pure compounds (yield 40-60%) (Scheme 1).
With sodium carbonate; In tetrahydrofuran; for 16h;Inert atmosphere;
Reference Example 94 5-[3,5-bis(trifluoromethyl)phenyl]furan-2-carbaldehyde; A solution of 5-bromofuran-2-carbaldehyde (2.54 g, 14.5 mmol), [3,5-bis(trifluoromethyl)phenyl]boronic acid (3.93 g, 15.2 mmol), tetrakis(triphenylphosphine)palladium (0.59 g, 0.51 mmol) and 2M sodium carbonate solution (36 mL, 72 mmol) in THF (150 mL) was stirred under an argon atmosphere for 16 hr. The reaction solution was allowed to cool to room temperature and concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate filtration, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate), and the obtained solid was disrupted in hexane to give the title compound (4.46 g, yield>99%) as a pale-yellow solid. LC/MS(ESI+)m/z: 309 (M+H)+.
99%
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; for 16h;Inert atmosphere;
A solution of 5-bromofuran-2-carbaldehyde (2.54 g, 14.5 mmol), [3,5-bis(trifluoromethyl)phenyl]boronic acid (3.93 g, 15.2 mmol), tetrakis(triphenylphosphine)palladium (0.59 g, 0.51 mmol) and 2M sodium carbonate solution (36 mL, 72 mmol) in THF (150 ml) was stirred under an argon atmosphere for 16 hr. The reaction solution was allowed to cool to room temperature and concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate filtration, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate), and the obtained solid was disrupted in hexane to give the title compound (4.46 g, yield>99%) as a pale-yellow solid. LC/MS (ESI+) m/z: 309 (M+H)+.
General procedure: A mixture of appropriate heterocyclic amine (1.0 mmol) (3) and aromatic aldehyde (1.2 mmol) (4) were stirred in tetrahydrofuran under ice-cold condition for 5 min, followed by addition of the thioglycolic acid (2.0 mmol). After 5 min, dicyclohexylcarbodiimide(1.2 mmol) was added to the reaction mixture at 0 C and the reaction mixture was stirred for an additional 3-5 h at room temperature to complete the reaction. Progresses of the reactions were monitored by TLC using acetone:chloroform (7:3) as mobile phase. The precipitated dicyclohexylurea was filtered off; the filtrate was concentrated to drynessunder reduced pressure. Deionized water was added to the residueand extracted with ethylacetate. The organic layer was successively washed with 5% aqueous sodium hydrogen carbonate and sodium chloride. Finally organic layer was dried over anhydrous sodium sulfate. The crude solid obtained on evaporation of the solvent under reduced pressure was subjected for column chromatography using silica gel 100-200 mesh using n-hexane:ethyl acetate (7:3) as the solvent system and further recrystallized in acetone to yield white/yellowish-white products[42].
(5-bromo-2-furyl)(4-chloropyrimidin-5-yl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With n-butyllithium; In tetrahydrofuran; hexane; at -78℃; for 0.166667h;
Step 1: (5-Bromo-2-furyI)(4-chIoropyrimidin-5-yl)methanol [00984] A solution of <strong>[63558-65-6]4-chloro-5-iodopyrimidine</strong> (3.60 g, 14.80 mmol) in THF (40.0 mLl) was cooled to -78 C, at which point 2.50 M of n-BuLi in hexane (7.0 mL, 17.50 mmol) was added dropwise via syringe. At the conclusion of the addition, a solution of 5-bromo-2-furaldehyde (2.0 g, 1 1.40 mmol) in THF (10.0 mL) was next added dropwise, via syringe and the reaction was stirred at -78 C for 10 min. The reaction was quenched via addition of a saturated NaHC03 solution (20 mL), and then allowed to warm to RT and extracted with EtOAc (3X). Layers were separated and the combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 0-50% EtOAc/Hex. over 25 mins) to give 2.5 g (75%) of product. NMR (400 MHz, Chloroform-d) delta 9.04 (s, 1 H), 8.95 (s, 1H), 6.28 (d, J = 3.2 Hz, 1 H), 6.19 (d, / = 3.2 Hz, 1H),6.08 (s, 1 H), 3.38 (s, 1H).
In a 100 ml eggplant-shaped flask,Compound 8 (3.73 g) and compound 9 (5. 84 g) were added,Glacial acetic acid(3.6 mL, 3.00 eq)And triethylamine(14. 7 mL 4.00 eq),And 40 mL of THF was added,Stirring, heated to 35 C reaction 1 hour, the plate, see the disappearance of raw materials, cooling to room temperature, adding sodium borohydride 3 equivalent, the reaction overnight, the plate, the disappearance of raw materials, no other by-products.The organic phase was washed with saturated brine, dried, and dried, and the residue was separated by column chromatography to give compound 10 (4. 2 g), which was followed by extraction with ethyl acetate (10 mL) Yield 72%.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; at 70℃;Inert atmosphere; Sealed tube;
General procedure: A bromo-aldehyde (1 mmol), boronic acid (1.1e1.3 mmol), tetrakis(triphenylphosphine)palladium (0.05 mmol), potassium carbonate(3 mmol), water (3 ml), ethanol (4 ml) and toluene (4 ml)were added to a round-bottomed flask. The reaction mixture wasflushed with argon, sealed under septa and heated at 70 C overnight.After cooling to room temperature, water (50 ml) was added,and product was extracted with ethyl acetate (3 x 50 ml). Combinedextracts were washed with brine, dried with anhydrousmagnesium sulfate and evaporated under reduced pressure. Theproduct was purified by column chromatography on silica withchloroform or a mixture of methanol and chloroform (1:9).
2-{(5-bromofuran-2-yl)methylene}betulonic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
General procedure: To synthesize compounds 15a-o, compound 7 (1 equiv) was dissolved in dry THF and NaH (1.2 equiv) was added to it at 0C. After 10min, respective aldehyde (1.5 equiv) was added to reaction mixture. The reaction mixture was stirred at room temperature for 1.5-2h till the completion (monitored by TLC analysis) [25]. Workup of the reaction was done by diluting the reaction mixture with ice-cold water and extracting it with ethyl acetate (3 times). The combined organic layers were dried over sodium sulphate and concentrated on rotavapour. The crude product obtained was purified by column chromatography on silica gel 60-120 mesh with EtoAc: hexane (1: 10) as the eluent to afford the desired pure products 15a-o in 90-93% yield. The spectral data of all the derivatives 15a-o are given below.
N-tert-butyloxycarbonyl-N'-methyl-N'-(5-bromofuran-2-yl-methyl)-ethylenediamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With sodium tris(acetoxy)borohydride; In dichloromethane; at 0 - 20℃; for 12h;Inert atmosphere;
To a solution of 9 (1.7g, 9.71mmol) in CH2Cl2 (20mL) was added 5-bromofuran-2-carbaldehyde (1.3g, 7.42mmol) and sodium triacetoxyborohydride (4.12g, 19.42mmol) at 0C under argon and then stirred at room temperature for 12h. The reaction solution was quenched with saturated NH4Cl (20mL) and extracted with CH2Cl2 (30 mL × 3), and the combined organic layers dried with Na2SO4. The residue was purified by column chromatography on silica gel using EtOAc/petroleum ether (1/2, V/V) as eluent to give 15 as colorless oil (2.50g, 77%); 1H NMR (400MHzCDCl3) delta 6.22 (d, 1H, J = 3.28Hz, CH), 6.16 (d, 1H, J = 3.23Hz, CH), 4.99 (br, 1H, NH), 3.54 (s, 2H, CH2), 3.21 (q, 2H, J = 5.47Hz, CH2), 2.49 (t, 2H, J = 6.29Hz, CH2), 2.24 (3H, s, CH3), 1.44 (s, 9H, (CH3)3); HRMS (ESI) m/z [M+H]+ Calcd for C13H22BrN2O3+: 333.0814. Found: 333.0810.
(E)-N-((5-bromofuran-2-yl)methylene)-2-(methylsulfonyl)ethylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94.25%
A 3-neck flask was charged with 5-bromofurfural (5.00 g, 28.56 mmol) and <strong>[104458-24-4]2-(methylsulfonyl)ethylamine hydrochloride</strong>(5.01 g, 31.38 mmol) followed by anhydrous magnesium sulfate (3.42 g, 28.50 mmol)And dry DCM 75ml kept in the low-temperature cooling tank -5 stirring for two hours, full protection of nitrogen;Triethylamine (4.75946.90 mmol) was then added dropwise to the mixture and stirring was continued at -5 for two hours.After the end of the reaction, the magnesium sulfate was removed by suction filtration under reduced pressure, and the filtrate was partitioned after washing once with a saturated aqueous sodium chloride solution.The organic phase was dried over anhydrous sodium sulfate and finally concentrated under reduced pressure to give a pale yellow solid 7.50 g (94.25% yield).
With potassium phosphate; In N,N-dimethyl acetamide; at 60℃; for 24h;Irradiation; Green chemistry;
General procedure: To a solution of 1 (0.3 mmol) and 2 (0.45mmol) in DMA (5 mL) was added 3wt% Pd/CeO2 (80 mg). The reaction mixture was stirred under incandescent light (0.79 Wcm-2) irradiation at 60C for 24h. After reaction (monitored by TLC), when the reaction is complete, in test tube extraction and centrifugal separation allows for isolation of the desired product, while the catalyst can be washed with ethanol and water, dried under vacuum, and reused for the next run. After completion of the reaction (monitored by TLC), water (5 mL) was added and the mixture was extracted with EtOAc (3 × 5 mL). The combined organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (10:1 petroleum ether/EtOAc) to give the target product.
With ammonium acetate; acetic acid; at 120℃; for 6h;
In a 200 ml three-necked flask5.1 g (29.1 mmol) of 5-bromo-2-furancarboxaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) and13.0 g (62.4 mmol) of 2 ', 4'-diethoxyacetophenone (manufactured by SIGMA-ALDRICH),38.8 g (503 mmol) of ammonium acetate,Acetic acid 30g was added and it stirred at 120 degreeC for 6 hours.Allow to cool to room temperature, add 75 ml of 60 C hot water,Extracted with toluene.The toluene phase is 75 ml of 6% aqueous sodium hydroxide solution,Washing was sequentially performed with 75 ml of 60 C. hot water.Add 50 ml of ethanol to the recovered toluene phase,The mixture was allowed to cool overnight and the precipitate was collected by filtration.After washing the precipitate with 50 ml of ethanol,It dries at 60 C and a following formula (11)Light yellow solid as cyclized body 5 represented by6.01g(Yield 37.4%) was obtained.
5-(5-chloro-2-methylphenyl)furan-2-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In ethanol; water; toluene; at 110℃;Schlenk technique; Inert atmosphere;
General procedure: 5-Bromofuran-2-carbaldehyde (175 mg, 1 mmol), boronic acid(1 mmol, 1 equiv), Pd(dppf)2Cl2.DCM (16 mg, 2% equiv), Na2CO3(318 mg, 3 mmol, 3 equiv) were added to a Shrenk flask with 6ml ofToluene, 1.5ml H2O and 1.5ml EtOH. The reaction mixture wascharged with N2 and heated at 110 C overnight. The solution wasextracted with EtOAc and the combined extracts were dried overNa2SO4. Chromatographic purification gave the titled compounds.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; at 70℃;Inert atmosphere; Sealed tube;
General procedure: A bromo-aldehyde (1 mmol), boronic acid (1.1e1.3 mmol), tetrakis(triphenylphosphine)palladium (0.05 mmol), potassium carbonate(3 mmol), water (3 ml), ethanol (4 ml) and toluene (4 ml)were added to a round-bottomed flask. The reaction mixture wasflushed with argon, sealed under septa and heated at 70 C overnight.After cooling to room temperature, water (50 ml) was added,and product was extracted with ethyl acetate (3 x 50 ml). Combinedextracts were washed with brine, dried with anhydrousmagnesium sulfate and evaporated under reduced pressure. Theproduct was purified by column chromatography on silica withchloroform or a mixture of methanol and chloroform (1:9).
5-(3-chloro-5-methoxyphenyl)furan-2-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; at 70℃;Inert atmosphere; Sealed tube;
General procedure: A bromo-aldehyde (1 mmol), boronic acid (1.1e1.3 mmol), tetrakis(triphenylphosphine)palladium (0.05 mmol), potassium carbonate(3 mmol), water (3 ml), ethanol (4 ml) and toluene (4 ml)were added to a round-bottomed flask. The reaction mixture wasflushed with argon, sealed under septa and heated at 70 C overnight.After cooling to room temperature, water (50 ml) was added,and product was extracted with ethyl acetate (3 x 50 ml). Combinedextracts were washed with brine, dried with anhydrousmagnesium sulfate and evaporated under reduced pressure. Theproduct was purified by column chromatography on silica withchloroform or a mixture of methanol and chloroform (1:9).
5-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)furan-2- carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With N-ethyl-N,N-diisopropylamine; In ethanol; at 140℃; for 0.583333h;Microwave irradiation;
To a solution of 2-oxa-5-azabicyclo[2.2.i]heptane 1 (250 mg, 1.843 mmol) in ethanol (15 mL) was added DIPEA (0.95 mL, 5.511 mmol) and 2-bromofuran (354 mg, 2.022 mmol) at room temperature. The reaction mixture was irradiated at 140 C for 35 min in microwave. After completion of the reaction (monitored by TLC and LCMS), the reaction mixture was concentrated under reduced pressure, quenched with water (50 mL) and extracted with ethyl acetate (3 times). The combined organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure; the crude compound was purified by Combiflash column chromatography eluting with 0-1% methanol in DCM to afford 170 mg (48% yield) of Int 3 as colourless oil. LCMS-Condition-i: [M+H]+ = 194.00; Rt = 1.09 min. NMR (400 MHz, CDCI3) d: 9.03 (s, lH), 7.21 (br. s, lH), 5.24 (d, J = 3.94 Hz, lH), 4.63 - 4.74 (m, 2H), 3-83 - 3-93 (m, 2H), 3.38 - 3-55 (m, 2H), 1.94 - 2.05 (m, 2H).
5-(4-bromo-2-chlorophenyl)furan-2-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; at 90℃; for 18h;Inert atmosphere;
To a solution of 5-bromofuran-2-carbaldehyde 3 (2 g, 14.29 mmol) in EtOH:DME (2:1, 30 mL) was added <strong>[1046861-20-4](4-bromo-2-chlorophenyl)boronic acid</strong> 4 (4.5 g, 14.29 mmol) and 2N Na2C03 solution (5 mL, 10.00 mmol) and degassed with argon for 20 min. To the resulting solution was added Pd(PPh3)4 (826 mg, 0.714 mmol) and degassing was continued for another 10 min at room temperature. The reaction mixture was further heated at 90 C for 18 h. After completion of the reaction (monitored by TLC and LCMS), the reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (3 times). The combined organic layer was washed with brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure and the crude compound was purified by Combiflash column chromatography eluting with 0-3% ethyl acetate in n- hexane to afford 240 mg (6% yield) of 5 as pale yellow solid. LCMS-Condition-i: [M+H]+ = 286.90; Rt = 2.28 min. NMR (400 MHz, CDCl3) d: 9-70 (s, lH), 7.90 (d, J = 8.80 Hz, lH), 7.67 (d, J = 1.96 Hz, lH), 7.52 (dd, J = 1.96, 8.31 Hz, lH), 7.31-7.36 (m, 2H).
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